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CARDIOLOGY 1 Contents I. Atrial fibrillation.....................................................................................................................................3 Dr. Csaba Herczku, Dr. Laszlo Czopf, Dr. Miklos Rabai, Dr. Barbara Sandor II. The diagnosis and management of heart failure..................................................................................29 Dr. Tamas Habon, Dr. Robert Halmosi, Dr. Roland Gal, Dr.Barbara Sandor III. Ischemic heart disease, stable coronary artery disease (SCAD), angina pectoris................................51 Prof. Dr. Kalman Toth, Dr. Laszlo Czopf, Dr. Peter Kenyeres, Dr.Katalin Biro Supported by the grant of TAMOP 4.1.1. C 2015 2 I. Atrial fibrillation Dr. Csaba Herczku1, Dr. Laszlo Czopf2, Dr. Miklos Rabai2, Dr. Barbara Sandor2 1 Gottsegen Gyorgy Hungarian Institute of Cardiology, Budapest, Hungary 2 st 1 Department of Medicine, Medical School, University of Pecs, Pecs, Hungary 1. Definition Atrial fibrillation (AF) is defined as a cardiac arrhythmia with the following characteristics: (1) The surface ECG shows absolutely irregular RR intervals (AF is therefore sometimes known as arrhythmia absoluta), i.e. RR intervals that do not follow a repetitive pattern. (2) Instead of distinct P waves on the surface ECG, f waves can be seen. Some apparently regular atrial electrical activity may be seen in some ECG leads, most often in lead V1. (3) The atrial cycle length (when visible), i.e. the interval between two atrial activations, is usually variable and <200 ms (>300 bpm). 2. Types of atrial fibrillation Clinically, it is reasonable to distinguish five types of AF based on the presentation and duration of the arrhythmia: first diagnosed, paroxysmal, persistent, long-standing persistent and permanent AF. (1) Every patient who presents with AF for the first time is considered a patient with first diagnosed AF, irrespective of the duration of the arrhythmia or the presence and severity of AF-related symptoms. (2) Paroxysmal AF is self-terminating, usually within 48 h. Although AF paroxysms may continue for up to 7 days, the 48 h time point is clinically important. After this first 48 h the likelihood of spontaneous conversion is low and anticoagulation must be considered. (3) Persistent AF is present when an AF episode either lasts longer than 7 days or requires termination by cardioversion, either with drugs or by direct current cardioversion (DCC). (4) Long-standing persistent AF has lasted for ≥1 year when it is decided to adopt a rhythm control strategy. (5) Permanent AF is said to exist when the presence of the arrhythmia is accepted by the patient (and physician). Hence, rhythm control interventions are not pursued in patients with permanent AF. If rhythm control strategy is adopted, the arrhythmia will be redesignated as long-standing persistent AF. This classification is useful for clinical management of AF patients, especially when AF-related symptoms are also considered. Therapeutic decisions require careful consideration of additional individual factors and co-morbidities. Silent AF (asymptomatic) may manifest as an AF-related complication (ischaemic stroke or tachycardiomyopathy) or may be diagnosed by an opportunistic ECG. Silent AF may present as any of the temporal forms of AF. In lone AF neither structural heart disease nor thrombotic risk factors can be found. It is conventional to divide AF into cases which are described as “valvular” or “non-valvular”. The term valvular AF is used to imply that AF is related to rheumatic valvular disease (predominantly mitral stenosis) or prosthetic heart valves. 3. Epidemiology Atrial fibrillation is the most common sustained cardiac arrhythmia, occurring in 1-2% of the general population; over 6 million Europeans suffer from this arrhythmia. AF may long remain undiagnosed (silent AF), and many patients with AF will never present to hospital. Hence, the true prevalence of AF is probably closer to 2% of the population. The prevalence of AF increases with age, from 0.5% at 40-50 years, to 5-15% at 80 years, and its prevalence is expected to at least double in the next 50 years as the population ages. Men are more often affected than women. 3 Much earlier detection of the arrhythmia might allow the timely introduction of therapies to protect the patient, not only from the consequences of the arrhythmia, but also from the progression of AF from an easily treated condition to an utterly refractory problem. 4. Mechanisms of atrial fibrillation 4.1. Atrial factors Any kind of structural heart disease may trigger a slow but progressive process of structural remodelling in both the ventricles and the atria. In the atria, proliferation and differentiation of fibroblasts into myofibroblasts and enhanced connective tissue deposition and fibrosis are the hallmarks of this process. Structural remodelling results in electrical dissociation between muscle bundles and local conduction heterogeneities facilitating the initiation and perpetuation of AF. This electroanatomical substrate permits multiple small re-entrant circuits that can stabilize the arrhythmia. 4.2. Electrophysiological mechanisms The initiation and perpetuation of a tachyarrhythmia requires both triggers for its onset and a substrate for its maintenance. These mechanisms are likely to co-exist at various times. Focal mechanisms potentially contribute to the initiation and perpetuation of AF. Cellular mechanisms of focal activity might involve both triggered activity and re-entry. Because of shorter refractory periods as well as abrupt changes in myocyte fibre orientation, the pulmonary veins (PVs) have a stronger potential to initiate and perpetuate atrial tachyarrhythmias. According to the multiple wavelet hypothesis, AF is perpetuated by continuous conduction of several independent wavelets propagating through the atrial musculature in a seemingly chaotic manner. Fibrillation wavefronts continuously undergo wavefront-waveback interactions, resulting in wavebreak and the generation of new wavefronts, while block, collision, and fusion of wavefronts tend to reduce their number. As long as the number of wavefronts does not decline below a critical level, the multiple wavelets will sustain the arrhythmia. 4.3. Genetic predisposition AF has a familial component, especially AF of early onset. During the past years, numerous inheritable cardiac syndromes associated with AF have been identified. Both short and long QT syndromes and Brugada syndrome are associated with supraventricular arrhythmias, often including AF. It also frequently occurs in a variety of inherited conditions, including hypertrophic cardiomyopathy, a familial form of ventricular pre-excitation, and abnormal LV hypertrophy associated with mutations in the PRKAG gene. Other familial forms of AF are associated with mutations in the gene coding for atrial natriuretic peptide, loss-of-function mutations in the cardiac sodium channel gene SCN5A, or gain of function in a cardiac potassium channel. 5. Atrial flutter Atrial flutter is similar to AF caused by a re-entrant rhythm in either the right or left atrium. It is typically initiated by a premature electrical impulse arising in the atria and propagated due to differences in refractory periods of atrial tissue resulting in a localized self-perpetuating loop. In atrial flutter the atrial cycle length is longer than in AF (e.g. ≥200 ms). While on ECG leads F waves can be identified, the pulse is regular or regularly irregular. In type I (typical or common) atrial flutter the reentrant loop circles in the right atrium, passing through the cavo-tricuspid isthmus (e.g. a body of fibrous tissue in the lower atrium between the inferior vena cava, and the tricuspid valve). Type I atrial flutter is divided into two subtypes: counterclockwise atrial flutter and clockwise atrial flutter depending on the direction of the current passing through the loop. Counterclockwise atrial flutter is more commonly seen. The flutter waves in this rhythm are inverted in ECG leads II, III, and aVF, while in the clockwise atrial flutter F waves are upright in leads II, III, and aVF. Type II flutter follows a re-entry pathway different from that in type I flutter, and is typically faster and has a rare appearance. Left atrial flutter is common after incomplete left atrial ablation procedures. 4 Atrial flutter is associated with similar clinical manifestations and consequences to AF. Although, there are some specific considerations particular to treatment of atrial flutter, in general, it should be managed in the same way as atrial fibrillation. 6. Clinical consequences 6.1. Atrial fibrillation-related cardiovascular consequences AF is associated with increased rates of hospitalizations, haemodynamic changes - left ventricular (LV) dysfunction, degraded quality of life, reduced exercise capacity, stroke and other thrombo-embolic events and death. Hospitalizations due to AF account for one-third of all admissions for cardiac arrhythmias. Haemodynamic changes affected by different factors in patients with AF involve loss of coordinated atrial contraction, high ventricular rates, irregularity of the ventricular response, and decrease in myocardial blood flow, as well as long-term alterations such as atrial and ventricular cardiomyopathy. Acute loss of coordinated atrial mechanical function after the onset of AF reduces cardiac output by 515%. This effect is more pronounced in patients with reduced ventricular compliance since atrial contraction contributes significantly to ventricular filling. High ventricular rates limit ventricular filling due to the short diastolic interval. Rate-related interventricular or intraventricular conduction delay may lead to dyssynchrony of the left ventricle and reduce cardiac output further. Moreover, these changes are often associated with angina and symptomatic heart failure. Persistent elevation of ventricular rates above 120-130 bpm may produce ventricular tachycardiomyopathy. Reduction of the heart rate may restore normal ventricular function and prevent further dilatation and damage to the atria. In addition, irregularity of the ventricular rate can reduce cardiac output. Fluctuations of the RR intervals cause a large variability in the strengths of subsequent heart beats, often resulting in pulse deficit. In patients with pre-excitation syndromes, fast and potentially life-threatening ventricular rates may occur (FBI arrhythmia). Quality of life and exercise capacity are impaired in patients with AF. Patients with AF have a significantly poorer quality of life compared with healthy controls, the general population, or patients with coronary heart disease in sinus rhythm. Thrombo-embolic events are associated with flow abnormalities in AF which are evidenced by stasis within the left atrium, with reduced left atrial appendage (LAA) flow velocities, and visualized as spontaneous echo-contrast on transoesophageal echocardiography (TEE). The LAA is the dominant source of embolism (90%) in non-valvular AF. Abnormalities of blood constituents are well described in AF and include haemostatic and platelet activation, as well as inflammation and growth factor abnormalities. Ischaemic strokes in association with AF are often fatal, and those patients who survive are left more disabled by their stroke and more likely to suffer a recurrence than patients with other causes of stroke. AF confers a 5-fold risk of stroke, and one in five of all strokes is attributed to this arrhythmia. Undiagnosed, silent AF is a likely cause of some cryptogenic strokes. Paroxysmal AF carries the same stroke risk as permanent or persistent AF. Cognitive dysfunction, including vascular dementia, may be related to AF. Small observational studies suggest that asymptomatic embolic events may contribute to cognitive dysfunction in AF patients in the absence of an overt stroke. Death rates are doubled by AF, independently of other known predictors of mortality. Only antithrombotic therapy has been shown to reduce AF-related deaths. 6.2. Cardiovascular and other conditions associated with atrial fibrillation AF is associated with a variety of cardiovascular conditions. Conditions associated with AF are also markers for global cardiovascular risk and/or cardiac damage rather than simply causative factors. Ageing increases the risk of developing AF, possibly through age-dependent loss and isolation of atrial myocardium and associated conduction disturbances. Hypertension is a risk factor for incident (first diagnosed) AF and for AF-related complications such as stroke and systemic thrombo-embolism. 5 Symptomatic heart failure (New York Heart Association (NYHA) classes II-IV) is found in 30% of AF patients and AF is found in up to 30-40% of heart failure patients, depending on the underlying cause and severity of heart failure. Heart failure can be both a consequence of AF (e.g. tachycardiomyopathy or decompensation in acute onset AF) and a cause of the arrhythmia due to increased atrial pressure and volume overload, secondary valvular dysfunction, or chronic neurohumoral stimulation. Tachycardiomyopathy should be suspected when LV dysfunction is found in patients with a fast ventricular rate but no signs of structural heart disease. It is confirmed by normalization or improvement of LV function when good AF rate control or reversion to sinus rhythm is achieved. Valvular heart diseases are found in 30% of AF patients. AF caused by left atrial (LA) distension can be an early manifestation of mitral stenosis and/or regurgitation. AF occurs in later stages of aortic valve disease. While rheumatic valvular disease associated with AF was a frequent finding in the past, it is now relatively rare in Europe. Cardiomyopathies carry an increased risk for AF, especially in young patients. Relatively rare cardiomyopathies are found in 10% of AF patients. Atrial septal defect is associated with AF in 10-15% of patients. This association has important clinical implications for the antithrombotic management of patients with previous stroke or transient ischaemic attack (TIA) and an atrial septal defect. Other congenital heart defects at risk of AF include patients with single ventricle, after Mustard operation for transposition of the great arteries, or after Fontan surgery. Coronary artery disease is present in ≥20% of the AF population. Whether uncomplicated coronary artery disease per se (atrial ischaemia) predisposes to AF and how AF interacts with coronary perfusion are uncertain. Overt thyroid dysfunction can be the sole cause of AF and may predispose to AF-related complications. In recent surveys, hyperthyroidism or hypothyroidism was found to be relatively uncommon in AF populations, but subclinical thyroid dysfunction may contribute to AF. Obesity is found in 25% of AF patients, and the mean body mass index was 27.5 kg/m 2 in a large, German AF registry (equivalent to moderately obese). Diabetes mellitus requiring medical treatment is found in 20% of AF patients, and may contribute to atrial damage. Chronic obstructive pulmonary disease (COPD) is found in 10-15% of AF patients, and is possibly more a marker for cardiovascular risk in general than a specific predisposing factor for AF. Sleep apnoea, especially in association with hypertension, diabetes mellitus, and structural heart disease, may be a pathophysiological factor for AF because of apnoea-induced increases in atrial pressure and size, or autonomic changes. Chronic renal disease is present in 10-15% of AF patients. Renal failure may increase the risk of AFrelated cardiovascular complications. 7. Diagnosis The risk of AF-related complications is not different between short AF episodes and sustained forms of the arrhythmia. It is therefore important to detect paroxysmal AF in order to prevent AF-related complications (e.g. stroke). An irregular pulse should always raise the suspicion of AF, but an ECG recording is necessary to diagnose AF. Clinical symptoms such as palpitations or dyspnea should trigger ECG monitoring to demonstrate AF. More intense and prolonged monitoring is justified in highly symptomatic patients (with recurrent syncope, and with a potential indication for anticoagulation especially after cryptogenic stroke). In patients with rhythm or rate control treatment, the frequency of 12-lead ECG recording depends on the type of antiarrhythmic drug treatment, the potential side effects, complications, and risks of proarrhythmia. When arrhythmia or therapy-related symptoms are suspected, monitoring using Holter recordings, transtelephonic recordings, patient- and automatically activated devices, or external loop recorders should be considered. Implantable devices capable of intracardiac atrial electrogram recording such as dual-chamber pacemakers and defibrillators can detect AF appropriately. 6 Any arrhythmia that has the ECG characteristics of AF and lasts sufficiently long for a 12-lead ECG to be recorded, or at least 30 s on a rhythm strip, should be considered as AF. The heart rate in AF can be calculated from a standard 12-lead ECG by multiplying the number of RR intervals on the 10 s strip (recorded at 25 mm/s) by six. 8. Management 8.1. Diagnostic evaluation A thorough medical history should be obtained from the patient with AF. The acute management of AF patients should concentrate on relief of symptoms and assessment of AF-associated risk. Clinical evaluation should include determination of AF-related symptoms (EHRA score), estimation of stroke risk (CHA2DS2VASc score), estimation of bleeding risk (HAS-BLED score) and search for conditions that predispose to AF (see section 6.2.) and for complications of the arrhythmia (see section 6.1.). Management of AF patients is aimed at reducing symptoms and at preventing severe complications of AF. The EHRA score provides a simple clinical tool for assessing symptoms during AF (Table 1). EHRA I no symptoms EHRA II mild symptoms; normal daily activity not affected EHRA III severe symptoms; normal daily activity affected EHRA IV disabling symptoms; normal daily activity discontinued Table 1. The EHRA score system The EHRA score only considers symptoms that are attributable to AF and reverse or reduce upon restoration of sinus rhythm or with effective rate control. Prevention of AF-related complications relies on antithrombotic therapy, control of ventricular rate, and adequate therapy of concomitant cardiac diseases. These therapies may already alleviate symptoms, but symptom relief may require additional rhythm control therapy by cardioversion, antiarrhythmic drug therapy, electrical cardioversion or ablation therapy. Patients with AF and signs of acute heart failure require urgent rate control and often cardioversion. An urgent echocardiogram should be performed in haemodynamically compromised patients to assess LV and valvular function and right ventricular pressure. Patients with stroke or TIA require immediate stroke diagnosis, usually via emergency computed tomography (CT) and adequate cerebral revascularization. The time of onset of the arrhythmia episode should be established to define the type of AF (see section 2.). Most patients with AF <48 h in duration can be cardioverted on low molecular weight heparin (LMWH) without risk for stroke. If AF duration is >48 h or there is doubt about its duration, TEE may be used to rule out intracardiac thrombus prior to cardioversion. The transthoracic echocardiogram can provide useful information to guide clinical decision making, but cannot exclude thrombus in the LAA. Patients with AF should be assessed for risk of stroke and risk of bleeding. Most patients with acute AF will require anticoagulation unless they are at low risk of thrombo-embolic complications (no stroke risk factors) and no cardioversion is necessary (e.g. AF terminates within 24-48 h). After the initial management of symptoms and complications, underlying causes of AF should be sought. The 12-lead ECG should be inspected for signs of structural heart disease. An echocardiogram is useful to detect ventricular, valvular, and atrial disease as well as rare congenital heart disease. Thyroid function tests, a full blood count, a serum creatinine measurement and analysis for proteinuria, measurement of blood pressure, and a test for diabetes mellitus are useful. A serum test for hepatic function may be considered in selected patients. A stress test is reasonable in patients with signs or risk factors of coronary artery disease. Patients with persistent signs of LV dysfunction and/or signs of myocardial ischaemia are candidates for coronarography. 8.2. Antithrombotic management 8.2.1. Risk of thrombo-embolism As it was mentioned before AF is associated with increased thrombotic tendency due to stasis in the left atrium with decreased left atrium appendage flow which is the dominant source of embolism in nonvalvular AF. During AF management risk stratification for stroke and thrombo-embolism is required. 7 Major risk factors are prior stroke or TIA, or thrombo-embolism, and older age (≥75 years). The presence of some types of valvular heart disease (mitral stenosis or prosthetic heart valves) would also categorize such valvular AF patients as high risk. Clinically relevant non-major risk factors are heart failure (moderate to severe systolic LV dysfunction, defined as left ventricular ejection fraction ≤40%), hypertension, or diabetes. Other non-major risk factors include female sex, age 65-74 years, and vascular disease (specifically, myocardial infarction, complex aortic plaque and peripheral artery disease). Risk factors are cumulative and the simultaneous presence of two or more non-major risk factors would justify a stroke risk that is high enough to require anticoagulation. This risk factor-based approach in non-valvular AF can also be expressed as an acronym: CHA2DS2-VASc score (Table 2). Letter Risk factors Score CHA2DS2-VASc score Stroke rate (%/year) C congestive heart failure/LV dysfunction 1 0 0% H hypertension 1 1 1.3% A2 age >75 2 2 2.2% D diabetes mellitus 1 3 3.2% S2 stroke/TIA/thrombo-embolism 2 4 4% V vascular disease 1 5 6.7% A age 65-74 1 6-7 9.6-9.8% Sc sex category (i.e. female sex) 1 8 6.7% Maximum score 9 9 15.2% Table 2. The CHA2DS2-VASc score system 8.2.2. Risk of bleeding An assessment of bleeding risk should be part of the patient evaluation before anticoagulation. Rates of intracranial haemorrhage are considerably lower than in the past, typically between 0.1 and 0.6%. This may reflect lower anticoagulation intensity, careful dose regulation, or better control of hypertension. Various bleeding risk scores have been validated for bleeding risk in anticoagulated patients, but all have different modalities in evaluating bleeding risks and categorization into low-, moderate-, and high-risk groups, usually for major bleeding risk. Using the results of a cohort of 3,978 European subjects with AF from the EuroHeart Survey, a new simple bleeding risk score (HAS-BLED score) has been derived (Table 3). The HAS-BLED score has a good predictive value, correlates well with the intracranial haemorrhage events and highlights risk factors that can be actively managed to reduce the bleeding risk. Letter Clinical characteristics Score H hypertension 1 A abnormal renal and liver function (1 point each) 1 or 2 S stroke 1 B bleeding 1 L labile INRs 1 E elderly (e.g. age >65 years) 1 D drugs or alcohol (1 point each) 1 or 2 Maximum score 9 Table 3. The HAS-BLED score system Hypertension is defined as systolic blood pressure >160 mmHg. Abnormal kidney function is defined as the presence of chronic dialysis, renal transplantation or serum creatinine ≥200 mmol/L. Abnormal liver function is defined as chronic hepatic disease (e.g. cirrhosis) or biochemical evidence of significant hepatic derangement (e.g. bilirubin >2 x upper limit of normal, in association with aspartate aminotransferase/alanine aminotransferase/alkaline phosphatase >3 x upper limit normal, etc.). Bleeding refers to previous bleeding history and/or predisposition to bleeding, e.g. bleeding diathesis, anaemia, etc. Labile INRs (international normalized ratio) refers to unstable/high INRs or poor time in therapeutic range (e.g. <60%). Drugs/alcohol use refers to concomitant use of drugs, such as antiplatelet agents, nonsteroidal anti-inflammatory drugs, or alcohol abuse, etc. 8 8.2.3. Antithrombotic therapy The CHA2DS2-VASc and HAS-BLED scores are useful score systems to aid practical decision-making for thromboprophylaxis in non-valvular AF. Decision-making needs to balance the risk of stroke against the risk of major bleeding, especially intracranial bleeding, which is the most feared complication of anticoagulation therapy and confers a high risk of death and disability. Thus, a formal bleeding risk assessment is recommended for all patients with AF, and in patients with a HAS-BLED score ≥3, caution and regular review are appropriate, as well as efforts to correct the potentially reversible risk factors for bleeding. The HAS-BLED score per se should not be used to exclude patients from antithrombotic therapy but allows clinicians to make an informed assessment of bleeding risk and makes them think of the correctable risk factors for bleeding. In the absence of thrombotic risk factors (CHA2DS2-VASc score <1) (e.g. patients aged <65 with lone AF) antithrombotic therapy is not recommended. Thus, female patients with gender alone as a single risk factor (still a CHA2DS2-VASc score of 1) would not need anticoagulation if they clearly fulfill the criteria of age <65 and lone AF. 8.2.3.1. Vitamin K antagonist therapy In atrial fibrillation with at least 1 risk factor for stroke and thrombo-embolism (CHA2DS2-VASc score ≥1) oral anticoagulation (OAC) therapy, such as vitamin K antagonist (VKA) (warfarin, acenocumarol) treatment adjusted to intensity range of INR 2.0-3.0 is suggested. VKA blocks the formation of vitamin Kdependent coagulation factors (factors II, VII, IX, and X), and the onset of the therapy should overlap with LMWH administration (increased thrombotic risk due to VKA-induced inhibition of antithrombotic factors, such as protein C and S) which should be continued until INR reaches the therapeutic range. In a meta-analysis, the relative risk reduction with VKA was highly significant and amounted to 64%, corresponding to an absolute annual risk reduction in 2.7% of all strokes. This reduction was similar for both primary and secondary prevention and for both disabling and non-disabling strokes. Of note, many strokes occurring in the VKA treated patients occurred when patients were not taking therapy or were subtherapeutically anticoagulated. One of the many problems with anticoagulation with VKA is the high interindividual and intraindividual variation in INRs. VKAs also have significant drug, food, and alcohol interactions. On average, patients may stay within the intended INR range of 2.0-3.0 for 60-65% of the time in controlled clinical trials, but many studies suggest that this figure may be <50%. Indeed, having patients below the therapeutic range for <60% of the time may completely offset the benefit of VKA. Although rate of intracranial bleeding increases with INR values >3.5-4.0, there is no increment in bleeding risk with INR values between 2.0 and 3.0 compared with lower INR levels. The fear of falls may be overstated, as a patient may need to fall 3̴ 00 times per year for the risk of intracranial haemorrhage to outweigh the benefit of OAC in stroke prevention. In the presence of high INR values without any bleeding VKA therapy should be suspended until INR reaches the therapeutic range. When bleeding is associated with high INR levels administration of parenteral antidote (vitamin K) and transfusions (fresh frozen plasma and red blood cells) would be essential. In a life-threatening situation immediate hemodynamic stabilization as well as appropriate interventions (neurosurgical, gastroenterological, surgical, urological, pulmonological or otolaryngological) are required. 8.2.3.2. Novel oral anticoagulants Several novel oral anticoagulant (NOAC) drugs have been developed for stroke prevention: the oral direct thrombin inhibitors (dabigatran) and the oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban). In contrast to VKAs, these drugs block the activity of one single step in coagulation. The RE-LY trial compared two doses of dabigatran (110 mg b.i.d. or 150 mg b.i.d.) to warfarin aiming for an INR of 2.0-3.0. For the primary efficacy endpoint of stroke and systemic embolism, high dose of dabigatran was superior to warfarin, with no significant difference in the primary safety endpoint of major bleeding. Lower dose of dabigatran was non-inferior to warfarin, with 20% fewer major bleedings. In the ROCKET-AF trial high-risk patients with AF were randomized to either treatment with rivaroxaban 20 mg o.d. (15 mg daily for those with estimated creatinine clearance: 30-49 mL/min) or warfarin. Rivaroxaban was non-inferior to warfarin for the primary endpoint of stroke and systemic 9 embolism. There was no reduction in rates of mortality or ischaemic stroke, but a significant reduction in haemorrhagic stroke and intracranial haemorrhage could be observed. The primary safety endpoint was the composite of major- and clinically relevant non-major bleeding, there was no significant difference between rivaroxaban and warfarin but, with rivaroxaban, there was a significant reduction in fatal bleeding, as well as an increase in gastrointestinal bleeds requiring transfusion. The ARISTOTLE trial compared apixaban (5 mg b.i.d. with a dose adjustment to 2.5 mg b.i.d. in patients ≥80 years, weight ≤60 kg or with a serum creatinine ≥133 mmol/L) to a dose-adjusted warfarin therapy aiming for an INR of 2.0-3.0. There was a significant reduction in the primary efficacy outcome of stroke or systemic embolism by 21% with apixaban compared with warfarin, with a 31% reduction in major bleeding and a significant 11% reduction in all-cause mortality. Rates of haemorrhagic stroke and intracranial haemorrhage were significantly lower in patients treated with apixaban than with warfarin. Gastrointestinal bleeding was similar between the treatment arms. The ENGAGE AF-TIMI 48 trial has shown that both edoxaban daily dosages (60 mg and 30 mg) were non-inferior to warfarin for preventing stroke or systemic embolism in AF patients with moderate to high risk for stroke, meanwhile edoxaban therapy was associated with significantly less major bleeding than VKA treatment. At a CHA2DS2-VASc score of 1, apixaban and both doses of dabigatran had a positive net clinical benefit, while in patients with CHA2DS2-VASc score ≥2, all NOACs were superior to warfarin, with a positive net clinical benefit, irrespective of bleeding risk. When switching from a VKA to a NOAC, the INR should be allowed to fall to about 2.0 before starting the NOAC, all of which have rapid onset of anticoagulation effect. All NOACs can be given in fixed doses without routine laboratory monitoring and have fewer drugdrug and food-drug interactions than VKAs. 8.2.3.3. Antiplatelet therapy The ACTIVE A trial found that major vascular events were reduced in patients receiving aspirin plus clopidogrel, compared with aspirin monotherapy, primarily due to a 28% relative reduction in the rate of stroke with combination therapy. The BAFTA study showed that VKA (target INR 2-3) was superior to aspirin 75 mg daily in reducing the fatal or disabling stroke (ischaemic or haemorrhagic), intracranial haemorrhage, or clinically significant arterial embolism by 52%, with no difference in the risk of major haemorrhage between warfarin and aspirin. In the ACTIVE W trial, anticoagulation therapy with warfarin was superior to the combination of clopidogrel plus aspirin with no difference in bleeding events between treatment arms. Major bleeding was similar to that seen with VKA therapy only. Thus, in case on stroke risk factors (CHA2DS2-VASc score ≥1) antiplatelet therapy with aspirin plus clopidogrel, or - less effectively - aspirin only, should only be considered in AF patients who refuse any OAC, or cannot tolerate anticoagulants for reasons unrelated to bleeding. In case of no risk factors (CHA2DS2VASc score <1) no antithrombotic therapy is preferred rather than antiplatelet therapy. 8.2.3.4. Antithrombotic and antiplatelet therapy - special situations Many anticoagulated AF patients have stable coronary or carotid artery disease and/or peripheral artery disease, and common practice is to treat such patients with VKA plus one antiplatelet drug, usually aspirin. Adding aspirin to VKA does not reduce the risk of stroke or vascular events (including myocardial infarction), but substantially increases bleeding events. Thus, in patients with stable vascular disease (e.g. with no acute ischaemic events or PCI/stent procedure in the preceding year), VKA monotherapy should be used, and concomitant antiplatelet therapy should not be prescribed, since VKA therapy for secondary prevention in patients with coronary artery disease is at least as effective as aspirin. In AF patients undergoing elective percutaneous coronary intervention (PCI), drug-eluting stents should be limited to clinical and/or anatomical situations, such as long lesions, small vessels, diabetes, etc., where a significant benefit is expected compared with bare-metal stents, and triple therapy (OAC, aspirin, and ADP receptor blocker) should be used for 4 weeks followed by long-term therapy (up to 12 months) with OAC plus ADP receptor blocker daily (or aspirin in case of intolerance). In case of drug-eluting stent implantation, triple therapy should be administered for 3-6 months following OAC and ADP receptor 10 blocker therapy. When anticoagulated AF patients are at moderate to high risk of thrombo-embolism, an uninterrupted anticoagulation strategy can be preferred during PCI, and radial access should be used as the first choice even during therapeutic anticoagulation (INR 2-3). In patients with acute coronary syndrome (ACS) and/or percutaneous coronary intervention, dual antiplatelet therapy with aspirin plus an ADP receptor blocker thienopyridine (clopidogrel or prasugrel or ticagrelor) is recommended. In AF patients hospitalized with ACS and treated by PCI, bare-metal stent implantation is recommended instead of drug-eluting stents plus instead of dual antiplatelet therapy, triple therapy should be given. In this special case VKA non-treatment was associated with an increase in mortality and major adverse cardiac events, with no significant difference in bleeding rates between VKAtreated and non-treated patients. The prevalence of major bleeding with triple therapy is 2.6-4.6% at 30 days, which increases to 7.4-10.3% at 12 months. Thus, short term triple therapy (3-6 months) seems to have an acceptable risk-benefit ratio, which could be extended in selected patients at low bleeding risk (HAS-BLED score <3). Following this initial treatment, longer therapy (up to 12 months) with OAC plus ADP receptor blocker (or aspirin in case of intolerance) has to be given. At high bleeding risk (HAS-BLED score ≥3) 1 month long triple therapy is suggested followed by combination of OAC and ADP receptor blocker up to 12 months. After 1 year treatment lifelong OAC only is recommended. Gastric protection with a proton pump inhibitor should be considered (in almost all cases). 8.2.3.5. Cardioversion Increased risk of thrombo-embolism following cardioversion is well recognized. Therefore, anticoagulation is considered mandatory before elective (electrical and pharmacological) cardioversion for AF of >48 h or AF of unknown duration. Antithrombotic treatment should be given for at least 3 weeks before cardioversion and should be continued for a minimum of 4 weeks after cardioversion because of risk of thrombo-embolism due to post-cardioversion left atrial dysfunction (so-called atrial stunning). In patients with risk factors for stroke or AF recurrence, antithrombotic treatment should be continued lifelong irrespective of apparent maintenance of sinus rhythm following cardioversion. The mandatory 3-week period of thromboprophylaxis prior to cardioversion can be shortened if transoesophageal echocardiogram (TEE) measurement reveals no LA or LAA thrombus. TEE may not only show thrombus within the LAA, but may also identify spontaneous echo-contrast (sign of slow circulation) or complex aortic plaque. If no LA thrombus is detected LMWH should be started prior to cardioversion and continued thereafter until the OAC therapy. If TEE detects a thrombus in the left atrium or LAA, VKA (INR 2.0-3.0) treatment is required for at least 3 weeks and TEE should be repeated. If thrombus resolution is evident, cardioversion can be performed, and post-cardioversion OAC is continued lifelong. If thrombus is still evident, the planned rhythm control strategy may be changed to a rate control strategy. In patients with a definite AF onset <48 h, cardioversion can be performed expediently under the cover of LMWH. In patients with risk factors for stroke, OAC therapy should be started after cardioversion and continued lifelong. No OAC is required in patients without thrombo-embolic risk factors. In patients with AF <48 h with haemodynamic instability (angina, myocardial infarction, shock, or pulmonary oedema), immediate DC cardioversion should be performed with LMWH administration before and OAC therapy after the cardioversion. 8.2.3.6. Acute stroke An acute stroke is a common first presentation of a patient with AF. There are limited trial data to guide their management, and there is concern that patients within the first 2 weeks after cardioembolic stroke are at greatest risk of recurrent stroke because of further thrombo-embolism. However, anticoagulation in the acute phase may result in intracranial haemorrhage or haemorrhagic transformation of the infarct. In patients with AF presenting with an acute stroke or TIA, uncontrolled hypertension should be appropriately managed before antithrombotic treatment is started, and cerebral imaging, CT or magnetic resonance imaging (MRI), should be performed to exclude haemorrhage. In the absence of haemorrhage, anticoagulation should begin after 2 weeks, but, in the presence of haemorrhage, anticoagulation should not be given. In patients with AF and acute TIA, anticoagulation treatment should begin as soon as possible in the absence of cerebral infarction or haemorrhage. 11 8.2.3.7. Valvular AF In patients with AF related to valvular disease (e.g. mitral stenosis and prosthetic valves) only VKA therapy is approved, since the RE-ALIGN trial with dabigatran has shown increased risk in thrombo-embolic and bleeding events in the NOAC arm compared to warfarin therapy. 8.2.3.8. Atrial flutter The risk of stroke in atrial flutter is similar to that seen in atrial fibrillation. Thus, thromboprophylaxis in patients with atrial flutter should follow the same guidelines as in atrial fibrillation patients. 8.2.3.9. Non-pharmacological methods to prevent stroke The left atrial appendage is thought to be the main site of atrial thrombogenesis. Thus, AF patients with contraindications to chronic anticoagulation therapy might be considered as candidates for LAA orifice occlusion which may reduce atrial thrombus formation and development of stroke. Participants in the PROTECT AF trial received either percutaneous closure of the LAA (using a WATCHMAN device) plus subsequent discontinuation of warfarin or VKA treatment (INR range 2-3) without any intervention. In case of the primary efficacy endpoint (stroke, systemic embolism and cardiovascular death) WATCHMAN device was considered non-inferior to that of VKA treatment. 8.3. Rate and rhythm management The acute management of patients with AF is driven by acute protection against thrombo-embolic events and acute improvement of cardiac function. The severity of AF-related symptoms should drive the decision for acute restoration of sinus rhythm (in severely compromised patients) or acute management of the ventricular rate (in most other patients). 8.3.1. Rate control 8.3.1.1. Acute rate control An inappropriate ventricular rate and irregularity of the rhythm can cause symptoms (i.e. palpitations, dyspnea, fatigue, and dizziness) and severe haemodynamic distress in AF patients. Patients with a rapid ventricular response usually need acute control of their ventricular rate leading to reduced symptoms and improved haemodynamics, by allowing enough time for ventricular filling and prevention of tachycardiomyopathy. In stable patients, this can be achieved by oral administration of beta-blockers or non-dihydropyridine calcium channel antagonists. In severely compromised patients, i.v. verapamil or metoprolol can be useful to slow atrioventricular node conduction rapidly. In the acute setting, the target ventricular rate should usually be 80-100 bpm. In selected patients, amiodarone may be used, especially in those with severely depressed LV function. AF with slow ventricular rates may respond to atropine (0.5-2 mg i.v.), but many patients with symptomatic bradyarrhythmia may require either urgent cardioversion or placement of a temporary pacemaker lead in the right ventricle. 8.3.1.2. Long-term rate control Acute initiation of rate control therapy should usually be followed by a long-term rate control strategy. The optimal level of heart rate control with respect to morbidity, mortality, quality of life, and symptoms remains unknown. Previous guidelines recommended strict rate control aiming at a resting heart rate between 60-80 bpm and 90-115 bpm during moderate exercise. On the other hand, strict rate control therapy sometimes required implantation of a pacemaker for symptomatic bradycardia, while higher resting heart rates were not associated with an adverse prognosis. The recently published RACE II trial did not identify a benefit of strict rate control over lenient rate control therapy. The trial suggests that an initially lenient rate control approach should be used, aiming at a resting heart rate of <110 bpm. The dose of rate control drugs can be increased and drugs can be combined until this target has been achieved. If patients remain symptomatic, especially if complaints relate to excessive rate or irregularity, a stricter rate control target (resting heart rate <80 bpm and a target heart rate of <110 bpm during moderate exercise) should be pursued. The ventricular rate should be reduced until the patient becomes asymptomatic or 12 symptoms become tolerable. In case of strict rate control a 24 h Holter monitor should be performed to assess pauses and bradycardia. In patients who remain symptomatic on strict rate control therapy, rhythm control therapy may be considered. 8.3.1.3. Pharmacological rate control The main determinants of the ventricular rate during AF are the conduction characteristics and refractoriness of the atrioventricular node and the sympathetic and parasympathetic tone. Drugs commonly used are beta-blockers, digitalis and non-dihydropyridine calcium channel antagonists. Furthermore, amiodarone may be suitable for some patients with otherwise refractory rate control. Combinations of drugs may be necessary. Beta-blockers (i.e. metoprolol, bisoprolol, atenolol, carvedilol) may be especially useful in the presence of high adrenergic tone or symptomatic myocardial ischaemia occurring in association with AF. Digoxin and digitoxin are effective in controlling heart rate at rest, but not during exercise. In combination with a beta-blocker either may be effective in patients with or without heart failure. Digoxin treatment normally affects ECG morphology causing ST depression and T wave inversion. On the other hand digoxin may cause adverse effects including life-threatening situations (i.e. nausea, vomiting, diarrhea, blurred vision, dizziness, confusion, agitation, delirium, psychosis, ECG changes: PQ interval prolongation, bradycardia, AV block, bigeminia, ventricular tachycardia and fibrillation) due to its narrow therapeutic index. Regular daily dose is 125 µg, while the therapeutic range in serum is 0.5-1.0 ng/ml. In case of abnormal renal function digitoxin should be used instead of digoxin. Amiodarone is an effective rate control drug. Intravenous amiodarone is effective and well tolerated in haemodynamically ill patients. It may also be instituted for chronic treatment when conventional measures are ineffective. Amiodarone, usually initiated for rhythm control, may continue to be used inadvertently for rate control when patients have lapsed into permanent AF. Unless safer agents are unsuitable, amiodarone should be discontinued in this setting. Dronedarone (e.g. deiodined amiodarone) is effective as a rate-controlling drug for chronic treatment, significantly decreasing the heart rate at rest and during exercise. The effects of dronedarone are additive to those of other rate control agents. Non-dihydropyridine calcium channel antagonists (verapamil and diltiazem) are effective for acute and chronic rate control of AF. The drugs should be avoided in patients with systolic heart failure because of their negative inotropic effect. 8.3.2. Pharmacological rhythm control and electrical cardioversion 8.3.2.1. Pharmacological cardioversion The main motivation to initiate rhythm control therapy is relief of AF-related symptoms. Conversely, asymptomatic patients (or those who become asymptomatic with adequate rate control therapy) should not generally receive antiarrhythmic drugs. Many episodes of AF terminate spontaneously within the first hours or days. If medically indicated (e.g. in severely compromised patients), in patients who remain symptomatic despite adequate rate control, or in patients in whom rhythm control therapy is pursued and the chance for a successful cardioversion is fairly high, pharmacological cardioversion of AF may be initiated by a bolus administration of an antiarrhythmic drug. Most patients who undergo pharmacological cardioversion require continuous medical supervision and ECG monitoring during the drug infusion and for a period afterwards (usually about half the drug elimination half-life) to detect proarrhythmic events such as ventricular proarrhythmia, sinus node arrest, or atrioventricular block. Flecainide (Na+ channel blocker, class Ic) given i.v. to patients with AF of short duration (especially <24 h) has an established effect (67-92% at 6 h) on restoring sinus rhythm. The usual dose is 2 mg/kg over 10 min. The majority of patients convert within the first hour after i.v. administration. It is rarely effective for termination of atrial flutter or persistent AF. Propafenone (Na+ channel blocker, class Ic) is an effective antiarrhythmic drug in converting recentonset AF to sinus rhythm. Within a few hours, the expected conversion rate was between 41 and 91% after i.v. use (2 mg/kg over 10-20 min). The time to conversion varies from 30 min to 2 h. Propafenone has only a limited efficacy for conversion of persistent AF and for atrial flutter. 13 Flecainide and propafenone should be avoided in patients with underlying heart disease involving abnormal LV function and ischaemia. In addition, owing to its weak beta-blocking properties, propafenone should be avoided in severe obstructive lung disease. These drugs with their high proarrhythmic effect may prolong QRS duration causing polymorphic ventricular tachycardia. Furthermore they may inadvertently increase the ventricular rate due to conversion to atrial flutter and 1:1 conduction to the ventricles. Thus, they should be combined with beta-blocker therapy which enhances the AV node conduction delay. Cardioversion with amiodarone (K+ and other channel blocker, class III) occurs several hours later than with flecainide or propafenone. The conversion rate at 24 h is 80-90% after amiodarone treatment. Treatment should be started with a loading dose (5 mg/kg i.v. over 1 h) followed by a continuous perfusion for 24 h. It may cause phlebitis, hypotension and decreased ventricular rate as side effects. In patients with recent-onset AF, ibutilide (K+ and other channel blocker, class III) in one or two infusions of (1 mg over 10 min each, with a wait of 10 min between doses), has a conversion rate ̴50% within 90 min. The most important side effect of ibutilide is most often non-sustained polymorphic ventricular tachycardia, while the QTc interval is expected to increase by ̴60 ms. Ibutilide is more effective for conversion of atrial flutter than AF. In summary, in suitable patients with recent-onset AF (generally <48 h duration), a trial of pharmacological cardioversion to sinus rhythm can be recommended with i.v. flecainide or propafenone (when there is little or no underlying structural heart disease) or amiodarone (when there is structural disease). The anticipated conversion rate is ≥50% within ̴15-120 min. 8.3.2.2. Pill-in-the-pocket approach Oral administration of flecainide or propafenon (conversion between 2 and 6 h) may be effective in case of recent-onset AF. According to a trial, oral propafenone (450-600 mg) or flecainide (200-300 mg) can be administered by the patient safely and effectively out of hospital. This approach may be used in selected, highly symptomatic patients with infrequent (e.g. between once per month and once per year) recurrences of AF and they could be instructed to take flecainide or propafenone when symptoms of AF occur. In order to implement the pill-in-the-pocket technique, patients should be screened for indications and contraindications, and the efficacy and safety of oral treatment should be tested in hospital. 8.3.2.3. Electrical cardioversion - direct current cardioversion (DCC) The conversion rate with DCC is higher than with antiarrhythmic drugs. It requires the presence of a trained physician initiating appropriate conscious sedation or anaesthesia and the use of biphasic external defibrillators because of their lower energy requirements and greater efficacy compared to those of monophasic defibrillators. The defibrillator has to be in synchronized mode. Currently, two conventional positions are commonly used for electrode placement. Several studies have shown that anteroposterior electrode placement is more effective than anterolateral placement. DCC is usually defined as termination of AF, documented as the presence of two or more consecutive P waves after shock delivery. If initial shocks are unsuccessful for terminating the arrhythmia, the electrodes should be repositioned and cardioversion repeated (maximum 2-3 times). In pacemaker-dependent patients the electrode paddle should be at least 8 cm from the pacemaker battery and an increase in pacing threshold should be anticipated. These patients should be monitored carefully. After cardioversion, the device should be interrogated and evaluated to ensure normal function. Outpatient/ambulatory DCC can be undertaken in patients who are haemodynamically stable and do not have severe underlying heart disease. At least 3 h of ECG and haemodynamic monitoring are needed after the procedure, before the patient is allowed to leave the hospital. The risks and complications of cardioversion are associated primarily with thrombo-embolic events, post-cardioversion arrhythmias, and the risks of general anaesthesia. The procedure is associated with 12% risk of thrombo-embolism, which can be reduced by adequate anticoagulation in the weeks prior to cardioversion or by exclusion of left atrium thrombi before the procedure (e.g. TEE examination). Skin burns are a common complication. In patients with sinus node dysfunction, especially in elderly patients with structural heart disease, prolonged sinus arrest without an adequate escape rhythm may occur. A pacing catheter or external pacing 14 pads may be needed if asystole or bradycardia occurs after the electric shock. Dangerous arrhythmias, such as ventricular tachycardia and fibrillation may arise in the presence of hypokalaemia, digitalis intoxication, or improper synchronization. The patient may become hypoxic or hypoventilated from sedation, but hypotension and pulmonary oedema are rare. Although atrial flutter is relatively resistant to chemical cardioversion, and often deteriorates into atrial fibrillation prior to spontaneous return to sinus rhythm, it is considerably more sensitive to DCC than AF, and usually requires a lower energy shock. 8.3.2.4. Long-term rhythm control Antiarrhythmic treatment is mostly motivated and initiated by attempts to reduce AF-related symptoms. In case of recurrent AF, long-term rhythm control is recommended on the basis of choosing safer, although possibly less efficacious medication before resorting to more effective but less safe therapy. Clinically successful antiarrhythmic drug therapy may reduce rather than eliminate recurrence of AF which is associated with frequent drug-induced proarrhythmia or extra-cardiac side effects. Beta-blockers are only modestly effective in preventing recurrent AF except in the context of thyrotoxicosis and exercise-induced AF. The perceived antiarrhythmic effect may also be explained by improved rate control that may render recurrent AF silent. Thus, beta-blockers (class II in Vaughan Williams classification) are not considered effective antiarrhythmic drugs in AF. In a recent meta-analysis of 44 randomized controlled trials comparing antiarrhythmic drugs against control (placebo or no treatment), sodium channel blockers with fast (disopyramide, quinidine) or slow (flecainide, propafenone) binding kinetics, and agents causing either pure potassium channel blockade (dofetilide), potassium channel blockade plus beta-blockade (sotalol), or mixed ion channel blockade plus antisympathetic effects (amiodarone) significantly reduced the rate of recurrent AF. Overall, the likelihood of maintaining sinus rhythm is doubled by the use of antiarrhythmic drugs. Amiodarone was superior to class I agents and sotalol. The number of patients needed to be treated was 3 with amiodarone, 4 with flecainide, 5 with dofetilide and propafenone, and 8 with sotalol. In the meta-analysis, the number of patients needed to be treated for 1 year was 2-9. Withdrawal due to side effects was frequent (1 in 9-27 patients), and all drugs except amiodarone increased the incidence of proarrhythmia. Most of the trials enrolled relatively healthy patients without severe concomitant cardiac disease. Although mortality was low in all studies (0-4.4%), rapidly dissociating sodium channel blockers (disopyramide phosphate, quinidine sulfate) were associated with increased mortality (e.g. QT-prolonging effect associated with risk for drug-induced torsades de pointes). Flecainide approximately doubles the likelihood of maintaining sinus rhythm. Flecainide was initially evaluated for paroxysmal AF, but is also used to maintain sinus rhythm after DCC. It can be safely administered to patients without significant structural heart disease, but should not be used in patients with coronary artery disease or in those with reduced LVEF (e.g. prolonging QRS duration causing potential risk of proarrhythmia). Concomitant AV node blockade is recommended because of the potential of flecainide to convert AF to atrial flutter, which then may be conducted rapidly to the ventricles. Propafenone also prevents recurrent AF. In addition, propafenone has a weak beta-blocker effect. It can be safely administered in patients without significant structural heart disease. Precautions similar to those for flecainide should also be observed with propafenone as well. Amiodarone is a good therapeutic option in patients with frequent, symptomatic AF recurrences despite therapy with other antiarrhythmic drugs. Unlike most other agents, amiodarone can be safely administered to patients with structural heart disease, including patients with heart failure. The risk of drug-induced torsade de pointes is lower with amiodarone than with other potassium channel blockers, possibly due to its multiple ion channel inhibition. However, drug-induced proarrhythmia is seen with amiodarone, and the QT interval should be monitored closely. Amiodarone can cause several non-cardiac side effects such as abnormalities in the thyroid gland function (e.g. hypo and hyperthyroidism), interstitial lung disease (e.g. pulmonary fibrosis), elevation in the liver enzyme levels (jaundice, hepatomegaly and hepatitis are rare), symptomless corneal micro-deposits and light-sensitive blue-grey discoloration of the skin (patients should avoid exposure to the sun and use of suncream). Sotalol less effectively prevents recurrent AF than amiodarone, although in the SAFE-T study, the efficacy of sotalol to maintain sinus rhythm was not inferior to amiodarone in the subgroup of ischaemic 15 heart disease patients. Drug-induced proarrhythmia with sotalol is due to excessive prolongation of the QT interval and/or bradycardia. Careful monitoring for QT prolongation and abnormal TU waves is mandatory. In patients reaching a QT interval 500 ms, sotalol therapy should be stopped. Dronedarone is a multichannel blocker that inhibits the sodium, potassium, and calcium channels, and has non-competitive antiadrenergic activity. Similarly to sotalol, propafenone, and flecainide, its efficacy to maintain sinus rhythm is lower than that of amiodarone. In the DIONYSOS study in patients with persistent AF, dronedarone was less effective but also less toxic than amiodarone (e.g. fewer thyroid, neurological, skin, and ocular events). The safety profile of dronedarone is advantageous in patients without structural heart disease and in stable patients with heart disease. Specifically, dronedarone appears to have a low potential for proarrhythmia. 8.3.2.5. Choice of antiarrhythmic drugs AF occurring in patients with little or no underlying cardiovascular disease can be treated with almost any antiarrhythmic drug that is licensed for AF therapy. In these patients, beta-blockers represent a logical first attempt to prevent recurrent AF when the arrhythmia is clearly related to mental or physical stress. Since beta-blockers are not very effective in many other patients with lone AF, flecainide, propafenone, sotalol or dronedarone are usually prescribed. Cardiovascular diseases have conventionally been divided into a variety of pathophysiological substrates: hypertrophy, ischaemia, and congestive heart failure. For each of these it has been recommended that specific drugs be avoided. In patients with LV hypertrophy, sotalol is thought to be associated with an increased incidence of proarrhythmia. Flecainide and propafenone may be used, but there is some concern about proarrhythmic risk, especially in patients with marked hypertrophy (LV wall thickness >14 mm), and associated with coronary artery disease. Dronedarone was demonstrated to be safe and well tolerated in patients with hypertension and possible LV hypertrophy, although definitive data do not exist. Amiodarone should be considered when symptomatic AF recurrences continue to impact on the quality of life of these patients. In coronary artery disease, the CAST trial proved that flecainide and propafenone are contraindicated since they increased the mortality after myocardial infarction. Studies on post-myocardial infarction patients suggest that sotalol may be used relatively safely in coronary artery disease. In view of the better safety and potential outcome benefit, dronedarone may be preferable as the first antiarrhythmic option, in patients with symptomatic AF and underlying cardiovascular disease. If dronedarone fails to control symptoms, amiodarone therapy might then be necessary, which is considered as the drug of last resort in this population due to its extra-cardiac side effect profile. In patients with heart failure dronedarone and amiodarone are the only agents available in Europe that can be safely administered to patients with stable NYHA class I-II heart failure. Dronedarone is contraindicated in patients with NYHA class III-IV or recently (within the previous 4 weeks) decompensated heart failure. In such patients, amiodarone should be used. It is challenging to make recommendations concerning the choice between amiodarone and dronedarone for patients with structural heart disease. Dronedarone was tested in the ATHENA trial which has shown numerical, but not significant reduction in cardiovascular mortality and in overall deaths in the dronedarone treated AF patients. Amiodarone has not been evaluated in a large-scale randomized controlled trial similar to ATHENA, but several meta-analyses have failed to identify a beneficial effect on cardiovascular outcomes (e.g. amiodarone dose not decrease cardioivascular mortality). In its favour, amiodarone has been used for many years without the emergence of any consistent and obvious cardiac toxicity. On the other hand, general toxicity relating to amiodarone is considerable when used at higher doses, but less when given at ≤200 mg per day. 8.3.3. Rhythm control with left atrial catheter ablation In general, catheter ablation should be reserved for patients with AF which remains symptomatic despite optimal medical therapy, including rate and rhythm control. Whether to undertake an ablation procedure in a symptomatic patient the following should be taken into account: (1) The stage of atrial disease (i.e. AF type, LA size, AF history) (2) The presence and severity of underlying cardiovascular disease 16 (3) Potential treatment alternatives (antiarrhythmic drugs, rate control) (4) Patient preference Operator experience is an important consideration when considering ablation as a treatment option since the possible complications in relation with a radiofrequency ablation are potentially life threatening or disabling. The overall death rate related to the procedure is 0.7%. The EURObservational Research Programme demonstrated that acute severe complication rates were 0.6% for stroke, 1.3% for tamponade, 1.3% for peripheral vascular complications, and around 2% for pericarditis. The incidence of silent cerebral infarctions varies significantly among different ablation technologies, ranging from 4% to 35%. Catheter ablation is usually undertaken in patients with symptomatic paroxysmal AF that is resistant to at least one antiarrhythmic drug, however depending on the patients choice, it can be a first-line therapy in patients with no or minimal structural heart disease and paroxysmal AF. Studies and meta-analyses of studies performed mostly in patients with paroxysmal AF, comparing antiarrhythmic drugs and catheter ablation and have shown a clearly better rhythm outcome after catheter ablation. The MANTRA-PAF and RAAFT II trials compared catheter ablation of AF to antiarrhythmic drug therapy as a first-line rhythm control intervention and demonstrated that significantly more patients in the ablation group were free from any AF and symptomatic AF. The one year AF free survival after catheter ablation varied between 56-89%, while with antiarrhythmic drugs it was found to be between 7.3 and 43%. For patients with either persistent AF or long-standing persistent AF, and no or minimal organic heart disease, extensive and frequently repeated ablation procedures may be necessary. Ablation therapy should be maintained for those who are refractory to antiarrhythmic drug treatment but ablation can be an alternative to amiodarone treatment in younger patients. For symptomatic paroxysmal and persistent AF in patients with relevant organic heart disease antiarrhythmic drug treatment (e.g. amiodarone) is recommended before catheter ablation. Ablation strategy in these patients may result significant improvement in ejection fraction and functional endpoints. The benefit of AF-ablation has not been demonstrated in asymptomatic patients. 8.3.3.1. Ablation considerations and concepts in AF Before ablation 12-leads ECG and Holter recording should be performed to demonstrate the arrhythmia. Transthoracic echocardiogram can identify structural heart disease. CT or MRI imaging can help to design the ablation strategy by revealing anatomical alterations and can be used for merge procedures where the image is integrated into the electroanatomical map during ablation. It is now possible to visualize atrial fibrosis before ablation by MRI, which helps in detecting the localization of possible conductive gaps before a repeated procedure. LA thrombus (usually within the LAA) should be excluded (by TEE or CT/MRI). The concept behind the treatment of AF with catheter ablation includes partly the elimination of the triggers mainly from the pulmonary veins (PVs) which may induce and sustain AF and to modify the arrhythmia substrate that is the left atrium itself. 8.3.3.2. Trigger elimination by PV ablation Triggered AF episodes initiated by focal firing from within the PVs led to the strategy of electrically isolating these triggers from atrial substrate. This was achieved by circumferential mapping catheter that was positioned within the PV ostia to guide ablation and target the connecting fibers by segmental ablation until the elimination of PV potentials. This ablation method carries a risk for ostial stenosis and occlusion hence the ablation is performed close to the PV ostia. 8.3.3.3. Linear PV isolation and circumferential PV ablation, complex fractionated electrograms To reduce the risk of PV stenosis ablation sites were moved further towards the atrial side forming a long lesion around one or both ipsilaterel PVs. This ablation technique not simply electrically isolates the pulmonary veins but also the antral left atrial tissue which may serve as a substrate for maintenance of AF. The PVs and the antrum are critical for maintenance of AF. Left atrial macroreentrant or focal tachycardias are more common after this type of ablation due to incomplete lines or circles which makes a challenge both for pharmacological and invasive treatment. 17 Ablation strategies that target the PVs and/or the PV antrum are the cornerstone for the most AF ablation procedures. Patients with persistent or long-standing persistent AF or with left atrial macroreentrant tachycardias may need additional linear ablation on the posterior left atrium between the pulmonary veins or from the left inferior pulmonary vein to the mitral isthmus. Thus, a compartmentalization of the left atrium can be achieved. The ablation of complex fractionated electrograms (CFAEs) as a complementary technique can be useful in patients with persistent AF. 8.3.3.4. Technical possibilities, ablation tools The elimination of the pulmonary vein potentials by segmental ablation required only a circumferential and an ablation catheter. The recently applied technique with widespread ablation round the pulmonary veins in the antrum requires the application of electroanatomical mapping systems which provide detailed information about the left atrial anatomy and pulmonary veins. The integration of CT or MRI images into the system is also possible. To overcome the limitations of the sequential point-by-point ablations several single-shot devices have been developed using cryoenergy and balloon technology or expandable circumferential catheters and radiofrequency. The learning curve for the operator is shorter with these devices but their potential collateral damage is still under investigation. Left atrial ablation is also possible as a part of cardiac surgery or as a standalone operation. The cutand-sew technique is also known as the maze-procedure. Freedom from AF is 75-95% up to 15 years after the procedure. Alternative energy sources, like radiofrequency, cryoablation, high-intensity focused ultrasound can replicate the maze lines. The FAST trial compared the outcome of catheter ablation and surgical ablation and the rhythm outcome was better after surgical ablation. 8.3.3.5. Anticoagulation therapy peri-ablation Catheter ablation of AF may be performed with fewer complications when OAC therapy is continued. VKA should be kept at low therapeutic levels (such as an INR of 2 to 2.5) throughout ablation, but experience with NOAC is limited. Intravenous heparin administration with activated clotting time control during the procedure is mandatory even with uninterrupted OAC therapy. This regimen helps to reduce peri-procedural thrombo-embolic events (strokes). Continuation of long-term OAC therapy post-ablation is recommended in all patients with a CHA2DS2-VASc score ≥2, irrespective of apparent procedural success. For those patients with lower risk score anticoagulation should be continued for a minimum of 3 months after the ablation. 8.3.3.6. Monitoring for atrial fibrillation recurrences Symptom-based follow-up may be sufficient as symptom relief is the main aim of AF ablation. More standardized ECG monitoring, 12-leads ECG, Holter recordings, transtelephonic recordings, loop recorders, or implantable devices capable of intracardiac atrial electrogram recording (if they were implanted by standard device implantation indications) may be necessary to compare different procedures and ablation methods. Expert consensus recommends an initial follow-up visit at 3 months, with 6 monthly intervals thereafter for at least 2 years. Besides reconnection of previously isolated PVs iatrogenic atrial re-entrant tachycardia due to incomplete lines of ablation is the major cause of post-ablation arrhythmia which may require another ablation procedure. The most important predictor for a late recurrence appears to be early recurrence of AF after the ablation procedure. The technology behind AF ablation and the follow up tools of these patients evolve rapidly mainly focusing on reducing the risk of peri-procedural complications and on reducing the learning curve of this complex procedure. The relatively lower success rate that can be achieved in comparison with other invasive electrophysiological procedures are due to the nature of the disease. Further investigation to understand the mechanism and pathophysiology of AF is also mandatory. Very important messages of the recent guidelines are that AF ablation has only indication in symptomatic patients and the postprocedural anticoagulation management is based on the stroke risk stratification rather than on the apparent success of the procedure. 18 8.3.3.7. Atrial flutter - catheter ablation in the right atrium Because of the reentrant nature of atrial flutter, it is often possible to ablate the circuit that causes atrial flutter. In case of type I atrial flutter a linear lesion to produce bidirectional block at the cavo-tricuspid isthmus (e.g. the inferior right atrial isthmus connecting the tricuspid annulus to the inferior caval vein) can block the conduction and terminate the arrhythmia. The recurrence rate of atrial flutter after isthmus ablation is lower than 5%. In patients with AF ablation who also have documented atrial flutter an additional isthmus ablation is recommended. It is not uncommon to experience atrial flutter after the initiation of antiarrhythmic medication (sodium channel blockers) for atrial fibrillation. In this case a hybrid therapy (antiarrhythmic medication + isthmus ablation) can be successful. 8.3.4. Rate versus rhythm control The initial therapy after onset of AF should always include adequate antithrombotic treatment and control of the ventricular rate. The decision to add rhythm control therapy to the management of AF requires individual decision and should therefore be discussed at the beginning of AF management. Before choosing rate control alone as a long-term strategy, the clinician should consider how much permanent AF is likely to affect the individual patient in the future and how successful rhythm control is expected to be. Symptoms related to AF are an important determinant in making the choice between rate and rhythm control (e.g. EHRA score) in addition to factors that may influence the success of rhythm control (i.e. long history of AF, older age, more severe associated cardiovascular diseases, other associated medical conditions, and enlarged LA size). Several randomized trials (AFFIRM, RACE, AF-CHF, PIAF, STAF) compared outcomes of rhythm vs. rate control strategies in patients with AF. The AFFIRM, RACE and AF-CHF found no difference in all-cause mortality between patients on rhythm and rate control therapy. The AFFIRM database analysis has suggested that harmful effects of antiarrhythmic drugs (a mortality increase of 49%) may have offset the benefits of sinus rhythm (associated with a 53% reduction in mortality), while an analysis of the RACE database suggested that underlying heart disease impacts prognosis more than AF itself. In the AFFIRM, RACE, or AF-CHF trials, development of heart failure was not different between rate control and rhythm control therapy. The RACE trial with highly selected patients with heart failure undergoing extensive catheter ablation for AF suggests that LV function may deteriorate less or even improve in patients undergoing rhythm control management. The AFFIRM, RACE, STAF and PIAF trials found no differences in quality of life with rhythm control compared with rate control. The quality of life is significantly impaired in patients with AF compared with healthy controls and post-hoc analyses suggest that maintenance of sinus rhythm may improve quality of life and associated with improved survival. There is a clear lack of connection between the negative outcome of AF patients compared with those in sinus rhythm (see section 6.1.) and the outcome of all rate vs. rhythm trials. The outcome of the ATHENA (e.g. a trial with AF patients on dronedarone treatment found numerical reduction in cardiovascular mortality and in overall deaths) trial is the first signal that safely maintained sinus rhythm may prevent relevant outcomes in AF, but this trial alone cannot reconcile the lack of connection. It may be concluded that rate control is a reasonable strategy in elderly patients, in whom the level of symptoms related to AF is acceptable (EHRA score is 1). Rhythm control therapy is reasonable for ameliorating symptoms, but should not result in cessation of antithrombotic therapy, rate control therapy, or therapy of underlying heart disease. There is a clear need for a controlled trial to assess the effects of catheter ablation and safe antiarrhythmic drugs as novel means for sinus rhythm maintenance on severe cardiovascular outcomes compared with rate control. 9. Acknowledgement This summary about atrial fibrillation represents the current opinion of the European Society of Cardiology and based on its management guidelines of 2010 and on the focused update of 2012. 19 10. Quiz 1. In atrial fibrillation f waves and absolutely regular RR intervals can be seen on surface ECG: A: true B: false 2. Valvular atrial fibrillation is associated with (2 right answers): A: aortic stenosis B: aortic regurgitation C: mitral stenosis D: prosthetic heart valves E: heart failure 3. Prevalence of atrial fibrillation in Europe (1 right answer): A: 0.1-0.5% B: 0.5-1.0% C: 1.0-2.0% D: 2.0-3.0% E: 4.0-5.0% 4. Features of persistent atrial fibrillation (2 right answers): A: lasts longer than 7 days B: self-terminating C: presence of the arrhythmia is accepted, no rhythm control is employed D: cardioversion e.g. by amiodarone (not spontaneously) E: lasted for ≥1 year when rhythm control therapy is decided 5. Features of atrial flutter (3 right answers): A: ventricular rate is ≥200/min B: F waves are positive in clockwise atrial flutter C: reentrant loop circles can be detected mostly in the right atrium D: regular or regularly irregular pulse E: atrial cycle length is <200 ms 6. Possible clinical consequences of atrial fibrillation (3 right answers): A: cognitive dysfunction B: embolism of the left lower limb C: pulmonary embolism D: heart failure E: ishaemic heart disease 7. The most common location of the thrombus in atrial fibrillation (1 right answer): A: right atrium appendage B: left atrium appendage C: apical region of the left ventricle D: atrial surface of the mitral valve E: ventricular surface of the aortic valve 20 8. Features of paroxysmal atrial fibrillation (2 right answers): A: associated with right sided heart failure B: cardioversion could be achieved after bisoprolol C: does not last longer than 7 days D: cardioverted by propafenone E: does not require anticoagulation 9. Diagnostic tools of atrial fibrillation (3 right answers): A: Holter monitoring B: transtelephonic ECG C: loop recorders D: stress echocardiography E: OGTT 10. Conditions frequently associated with atrial fibrillation (3 right answers): A: chronic prostatitis B: ischaemic heart disease C: overt thyroid dysfunction D: aging E: claudication intermittens 11. Risk factors of stroke in atrial fibrillation (2 right answers): A: male sex B: diabetes mellitus C: frequent alcohol consumption D: heart failure E: anticoagulation therapy 12. CHA2DS2-VASc and HAS-BLED score of a female, 67 year old atrial fibrillation patient with obesity, hypertension, stones in the gallbladder, fibromas in the left breast, COPD, left sided nephrectomy, elevated creatinin level and prior right sided stroke (1 right answer): A: CHA2DS2-VASc score: 3, HAS-BLED score: 2 B: CHA2DS2-VASc score: 1, HAS-BLED score: 6 C: CHA2DS2-VASc score: 5, HAS-BLED score: 2 D: CHA2DS2-VASc score: 3, HAS-BLED score: 1 E: CHA2DS2-VASc score: 5, HAS-BLED score: 4 13. Risk factors of bleeding in atrial fibrillation (3 right answers): A: abnormal liver function B: prior GI bleeding C: age >60 years D: labile INR E: peripheral artery disease 21 14. Possible medications for rate control therapy in atrial fibrillation (3 right answers): A: ivabradine B: metoprolol C: digitoxin D: amlodipine E: amiodarone 15. Target frequency in lenient rate control of atrial fibrillation (1 right answer): A: ventricular frequency <110 bpm B: atrial frequency <110 bpm C: ventricular frequency <80 bpm D: atrial frequency <80 bpm E: ventricular frequency <60 bpm 16. Features of rate control therapy in atrial fibrillation (3 right answers): A: bisoprolol can decrease palpitation B: strict rate control is more frequently associated with loss of consciousness C: digoxin blocks sinus node activity D: amiodarone is contraindicated for rate control E: dronedarone can significantly decrease the heart rate at rest and during exercise 17. Features of digoxin therapy (4 right answers): A: effective for rate control at rest but not during exercise B: adverse effects of digoxin are nausea, vomiting, blurred vision, confusion, etc C: signs of normal digoxin effect on ECG are ST depression and T inversion D: in case of abnormal renal function digitoxin should be used instead of digoxin E: therapeutic range in serum is 0.5-2.0 ng/ml 18. Anticoagulation therapy is indicated in (2 right answers): A: atrial flutter B: coronary heart disease C: prosthetic heart valve implantation D: carotis stenosis E: pulmonary hypertension 19. Besides atrial fibrillation rivaroxaban can be used in (3 right answers): A: pulmonary embolism B: prosthetic heart valve implantation C: deep vein thrombosis D: peripheral artery disease E: after hip replacement surgery 22 20. Features of vitamin K antagonist therapy in atrial fibrillation (2 right answers): A: target INR should be between 3.0-4.0 B: alcohol consumption increases the effect of acenocumarol C: transfusion of fresh frozen plasma reverses the effect of vitamin K antagonist therapy D: dabigatran can cause cardioversion E: warfarin has higher antithrombotic effect than apixaban 21. Features of dabigatran therapy in atrial fibrillation (2 right answers): A: efficient therapy requires INR between 2.0-3.0 B: causing strict rate control C: direct thrombin inhibition D: intravenous administration E: no food interaction 22. Stroke preventive medications in atrial fibrillation (3 right answers): A: clopidogrel B: apixaban C: amiodarone D: enoxaparin E: verapamil 23. Possibilities of rhythm control therapy for atrial fibrillation patients with ischaemic heart disease (3 right answers): A: propafenone B: carvedilol C: dronedarone D: sotalol E: direct current cardioversion 24. Possible side effects of amiodarone (3 right answers): A: pulmonary fibrosis B: kidney failure C: corneal micro-deposits D: elevated liver enzymes E: cataract 25. Features of antiarrhythmic medications in atrial fibrillation (1 right answer): A: flecainide can be indicated in atrial fibrillation patients with severe left ventricular hypertrophy B: amiodarone decreases mortality C: sotalol can prolong QT interval D: propafenone is a potassium channel blocker E: diltiazem can be given to atrial fibrillation patients with heart failure 23 26. Features of electrical cardioversion (3 right answers): A: atrial flutter is more sensitive to electrical cardioversion than atrial fibrillation B: the conversion rate with direct current cardioversion is lower than with antiarrhythmic drugs C: the defibrillator has to be in synchronized mode D: electrical cardioversion may cause prolonged sinus arrest E: there is no risk for thrombo-embolic events during direct current cardioversion 27. The approximate one year arrhythmia free survival after atrial fibrillation ablation (1 right answer): A: ≤14% B: 15-33% C: 34-55% D: 56-89% E: ≥90% 28. Anatomical structures which provide mainly the trigger and the substrate of atrial fibrillation (2 right answers): A: caval veins B: pulmonary veins C: right and left atrial appendage D: peri-mitral atrial tissue E: antral left atrial tissue 29. It is not recommended to perform ablation therapy in asymptomatic paroxysmal atrial fibrillation: A: true B: false 30. False allegation regarding atrial fibrillation ablation (1 right answer): A: after atrial fibrillation ablation expert consensus recommends an initial follow-up visit at 3 months, with 6 monthly intervals thereafter for at least 2 years B: continuation of long-term anticoagulation therapy is recommended in all patients with a CHA2DS2VASc score ≥2 irrespective of apparent procedural success C: symptom-based follow-up may be sufficient as symptom relief is the main aim of ablation D: the most important predictor for a late recurrence appears to be the early recurrence of atrial fibrillation after the ablation procedure E: a permanent pacemaker implantation with atrial lead can be recommended for the follow-up after AF ablation to be able to evaluate the success rate precisely 24 11. Right answers 1. B 2. C,D 3. C 4. A,D 5. B,C,D 6. A,B,D 7. B 8. B,C 9. A,B,C 10. B,C,D 11. B,D 12. E 13. A,B,D 14. B,C,E 15. A 16. A,B,E 17. A,B,C,D 18. A,C 19. A,C,E 20. B,C 21. C,E 22. A,B,D 23. C,D,E 24. 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The diagnosis and management of heart failure Dr. Tamas Habon, Dr. Robert Halmosi, Dr. Roland Gal, Dr. Barbara Sandor 1 Department of Medicine, Medical School, University of Pecs, Pecs, Hungary st 1. Introduction 1.1. Definition and terminology Heart failure (HF) can be defined as an abnormality of cardiac structure or function leading to failure of the heart to deliver oxygen at a rate commensurate with the requirements of the metabolizing tissues, despite normal filling pressures (or only at the expense of increased filling pressures). Heart failure is defined, clinically, as a syndrome in which patients have typical symptoms (e.g. breathlessness, ankle swelling, and fatigue) and signs (e.g. elevated jugular venous pressure, pulmonary crackles, and displaced apex beat) resulting from an abnormality of cardiac structure or function at rest. The main terminology used to describe heart failure is historical and is based on the measurement of left ventricle ejection fraction (EF). EF is the stroke volume (which is the end-diastolic volume minus the end-systolic volume) divided by the end-diastolic volume. The EF is considered important in heart failure, not only because of its prognostic importance (the lower is the EF the poorer is the survival) but also because most clinical trials selected patients based upon EF. 1.1.1. Terminology related to the ejection fraction (EF) Heart failure is divided into two different types: heart failure due to reduced ejection fraction (HFrEF) also known as heart failure due to left ventricular systolic dysfunction or systolic heart failure (EF <40%) and heart failure with preserved ejection fraction (HFpEF) also known as diastolic heart failure (Table 1). Patients with an EF in the range of 40-50% therefore represent a ‘grey area’ and most probably have primarily mild systolic dysfunction. The diagnosis of HFrEF requires three conditions to be satisfied (1) symptoms typical of HF (2) signs typical of HF (3) reduced LVEF The diagnosis of HFpEF requires four conditions to be satisfied (1) symptoms typical of HF (2) signs typical of HF (3) normal or only mildly reduced LVEF and LV not dilated (4) structural heart disease (LV hypertrophy/LA enlargement) and/or diastolic dysfunction Table 1. Diagnosis of heart failure 1.1.2. Terminology related to the time-course of HF A patient who has never exhibited the typical signs or symptoms of cardiac insuffiency is described as having asymptomatic systolic dysfunction (or whatever the underlying cardiac abnormality is). Patients who have had heart failure for some time are often said to have ‘chronic heart failure’. A treated patient with symptoms and signs, which have remained generally unchanged for at least a month, is said to be ‘stable’. If chronic stable HF deteriorates, the patient may be described as ‘decompensated’ and this may happen suddenly, i.e. ‘acutely’, usually leading to hospital admission, an event of considerable prognostic importance. 1.1.3. Terminology related to the symptomatic severity of HF The quantification of heart failure symptoms is useful for assessing the adequacy of therapy and determining prognosis. The New York Heart Association (NYHA) functional classification is most often used for this purpose (Table 2). 29 The NYHA classification provides a shorthand means of detecting changes in the patient’s symptomatic status that occur over time or in response to treatment, and it facilitates communication between various providers about the patient’s clinical status. The Killip classification may be used to describe the severity of the patient’s condition in the acute setting of myocardial infarction (Table 3). It is important to note, however, that symptom severity correlates poorly with ventricular function, and that although there is a clear relationship between severity of symptoms and survival, patients even with mild symptoms may still have a relatively high absolute risk of hospitalization and death. Class Symptoms no limitation of physical activity Class I (mild) ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath) slight limitation of physical activity Class II (mild) comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea marked limitation of physical activity Class III (moderate) comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea unable to carry out any physical activity without discomfort Class IV (severe) symptoms of cardiac insufficiency at rest if any physical activity is undertaken, discomfort is increased Table 2. The New York Heart Association Functional Classification (NYHA) of Heart Failure Killip classification Cardiac decompensation Cardiac arrest (%) Hospital mortality (%) Class I no heart failure 5 6 Class II heart failure 15 17 Class III pulmonary oedema 46 38 Class IV cardiogenic shock 77 81 Table 3. The Killip classification of heart failure in acute setting of myocardial infarction 2. Epidemiology Heart failure prevalence is continously rising throughout the world. The worldwide prevalence and incidence rates of heart failure (HF) are approaching epidemic proportions, as evidenced by the relentless increase in the number of HF hospitalizations, the growing number of HF-attributable deaths, and the spiraling costs associated with the care of HF patients. Approximately 1-2% of the adult population in developed countries has HF, with the prevalence rising to more than 10% among persons 70 years of age or older. Worldwide, HF affects almost 23 million people and in the United States, heart failure affects 5.8 million people, and each year 550 000 new cases are diagnosed. The prevalence of symptomatic HF in the general European population is similar to that in the United States, and ranges from 0.4% to 2%. The relative incidence of HF is lower in women than in men. In the Hillingdon study the incidence of heart failure increased from 0.2/1000 person years in those aged 45-55 years to 12.4/1000 person years in those aged >85 years. In the Rotterdam study the incidence increased from 2.5/1000 person years (age 55-64 years) to 44/1000 person years (age >85 years). The lifetime risk of developing HF is approximately one in five for a 40-year-old person. The overall prevalence of HF is thought to be increasing, in part because our current therapies of cardiac disorders are allowing patients to survive longer. Approximately 50% of HF patients have a normal or preserved EF (EF >40-50%). HFpEF has a different epidemiological and etiological profile from HFrEF. HFpEF is a systemic disorder with complex, multifactorial pathophysiology and clinical heterogeneity. Patients are older and more often female and obese than those with HFrEF. They are less likely to have coronary heart disease and more likely to have hypertension and atrial fibrillation (AF). HFpEF has a better prognosis than HFrEF. 30 3. Etiology Usually myocardial diseases cause systolic ventricular dysfunction. However, abnormalities of the ventricular diastolic function or of the valves, the pericardium, endocardium, heart rhythm, and conduction can also cause HF (and more than one abnormality can be present). Based on population-attributable risks, hypertension has the greatest impact on the development of HF, accounting for 39% of HF events in men and 59% in women. Despite its much lower prevalence in the population (3-10%), myocardial infarction also has a high attributable risk in men (34%) and women (13%). Valvular heart disease only accounted for 7% to 8% of HF. In industrialized countries, coronary artery disease (CAD) has become the predominant cause in men and women, and is responsible for 60% to 75% of HF cases. Both CAD and hypertension interact to augment the risk of HF. There are many other causes of systolic HF (Table 4), which include previous viral infection (recognized or unrecognized), alcohol abuse, chemotherapy (e.g. doxorubicin or trastuzumab) or metabolic disorders, etc. In 20% to 30% of the HF cases with a depressed EF, the exact causative basis is not known. These patients are referred to as having non-ischemic, dilated, or idiopathic cardiomyopathy if the cause is unknown (although the cause is thought to be unknown, some of these cases may have a genetic basis). Rheumatic heart disease remains a major cause of HF in Africa and Asia, especially in the young. Myocardial disease: coronary artery disease, cardiomyopathy’s (1) familial cardiomyopathy’s: - hypertrophic, dilated, arrhythmogenic right ventricular, restrictive, left ventricular non-compaction (2) acquired cardiomyopathy’s: - myocarditis (inflammatory cardiomyopathy): • infective: bacterial, spirochaetal, fungal, protozoal, parasitic, rickettsial, viral • immune-mediated: vaccines, drugs, lymphocytic/giant cell myocarditis, sarcoidosis, autoimmune, eosinophilic (Churg-Strauss) • toxic: drugs (e.g. hemotherapy, cocaine), alcohol, heavy metals (copper, iron, lead) - endocrine/nutritional: phaeochromocytoma, hypophosphataemia, hypocalcaemia, thyreotoxicosis, vitamin deficiency (e.g. thiamine), selenium deficiency, beri-beri - pregnancy - infiltration (amyloidosis, malignancy) Valvular heart disease: mitral, aortic, tricuspid, pulmonary Pericardial disease: constrictive pericarditis, pericardial effusion Endocardial disease: endomyocardial diseases with hypereosinophilia (hypereosinophilic-syndromes), endomyocardial disease without hypereosinophilia (e.g. endomyocardial fibrosis), endocardial fibroelastosis Congenital heart disease Arrhythmia: tachyarrhythmia, atrial, ventricular, bradyarrhythymia, sinus node dysfunction Conduction disorders: atrioventricular block, LBBB High output states: anaemia, sepsis, thyrotoxicosis, Paget’s disease Pressure overload (hypertension) Volume overload: renal failure, Iatrogenic (e.g. post-operative fluid infusion) Pulmonary heart disease: cor pulmonale, pulmonary vascular disorders Table 4. Causes of heart failure 4. Pathophysiology of heart failure Heart failure is caused by any condition which reduces the efficiency of the myocardium, or heart muscle, through damage or overloading (volume or pressure) (Figure 1). HF begins after an index event (e.g. ischaemic event or high blood pressure) produces an initial decline in pumping capacity of the heart. Following this initial decline in pumping capacity of the heart, a variety of compensatory mechanisms are activated, including the adrenergic nervous system, the renin-angiotensin system, and the cytokine systems. In the short term, these systems are able to restore cardiovascular function to a normal homeostatic range with the result that the patient remains asymptomatic. However, 31 with time, the sustained activation of these systems can lead to secondary end-organ damage within the ventricle, with worsening LV remodeling and subsequent cardiac decompensation. As a result of worsening LV remodeling and cardiac decompensation, in patients undergo the transition from asymptomatic to symptomatic HF. One of the most important adaptations is activation of the sympathetic (adrenergic) nervous system, which occurs early in the course of HF. It may contribute to the pathophysiologic process of congestive heart failure by multiple mechanisms involving cardiac, renal, and vascular function. In the heart, increased sympathetic nervous system outflow may lead to desensitization of beta-adrenergic receptors, myocyte hypertrophy, necrosis, apoptosis, and fibrosis. In the kidneys, increased sympathetic activation induces arterial and venous vasoconstriction, activation of the renin-angiotensin system, increase in salt and water retention, and attenuated response to natriuretic factors. In the peripheral vessels, neurogenic vasoconstriction and vascular hypertrophy are induced by increased sympathetic nervous system activity. In contrast to the sympathetic nervous system, the components of the RAAS are activated comparatively later in HF. Renal hypoperfusion and increased sympathetic stimulation of the kidney leading to increased renin release from the juxtaglomerular apparatus. Angiotensin II is a vasoconstrictor and promotes Na+ resorption by increasing aldosterone secretion and by a direct effect on the tubules. Interruption of these two compensatory mechanisms is the basis of the effective treatment of HF. Circulating levels of different hormones including brain natriuretic peptide (BNP) and cytokines are also elevated in HF, with a positive correlation with the severity of HF. Figure 1. The pathophysiology of heart failure 5. Prognosis and stages of heart failure 5.1. Prognosis Although several reports have suggested that the mortality for HF patients is improving, the overall mortality rate remains higher than for many cancers (e.g. bladder, breast, uterus, and prostate). Before 1990, the modern era of treatment, 60-70% of patients died within 5 years of diagnosis, and the hospitalisation (and rehospitalisation) rate was very high in many countries. Effective treatment has improved both of these outcomes, with a relative reduction in hospitalization rate in recent years of 3050% and a smaller but significant decrease in mortality. The 1 year median survival in NYHA IV functional stage is less than 50%. European studies have confirmed a similarly poor long-term prognosis. The aggregate data suggest that women with HF have a better overall prognosis than men. Patients with HFpEF have a better prognosis than those with HFrEF. Differences in survival between these two forms of HF are variably reported but generally minimal (Figure 2). 32 Figure 2. Progression of heart failure 5.2. Stages of heart failure A new approach developed to the classification of HF, one that emphasized both the development and progression of the disease. HF should be viewed as a continuum that comprises four interrelated stages (Figure 3). Figure 3. Stages of heart failure 33 Stage A includes patients who are at high risk for developing HF, but without structural heart disease or symptoms of HF (e.g., patients with diabetes or hypertension). Stage B includes patients who have structural heart disease but without symptoms of HF (e.g., patients with a previous myocardial infarction and asymptomatic LV dysfunction). Stages A and B patients are best defined as those with risk factors that clearly predispose toward the development of HF. Stage C then denotes patients with current or past symptoms of HF associated with underlying structural heart disease (most patients with HF). Stage D includes patients with refractory HF requiring special interventions (e.g., patients with refractory HF who are awaiting cardiac transplantation, surgical procedures, or for end-of-life care, such as hospice). 6. Diagnosis 6.1. Physical examination A complete medical history and carefully focused physical examination serve as the core of the diagnostic process. The diagnosis of HF can be difficult, especially in the early stages. Quantification (NYHA functional classification) of heart failure symptoms and signs is useful for assessing the adequacy of therapy, stability over time and determining prognosis. 6.1.1. Symptoms Although symptoms (Table 5) bring patients to medical attention, many of the symptoms of HF are non-specific and do not, therefore, help discriminate between HF and other problems. Symptoms that are more specific (i.e. orthopnea and paroxysmal nocturnal dyspnea) are less common, especially in patients with milder symptoms, and are insensitive. Dyspnea, shortness of breath, and fatigue are common complaints of heart failure patients. Patients with worsening heart failure frequently experience exertional dyspnea, and this symptom often triggers a visit to the clinic or emergency department. Patients may sleep with their heads elevated to relieve symptoms of pulmonary congestion. Classically, the patient experiences nocturnal awakenings usually occurring at a fixed time after retiring (often in the range of 1 to 2 hours) precipitated by the subjective feeling of air hunger, smothering, or drowning. A history of weight gain, increasing abdominal girth, and the onset of oedema in dependent organs (extremities or scrotum) is helpful when it is present but also is nonspecific. Symptoms can also change rapidly; for example, a stable patient with mild symptoms can become suddenly breathless at rest with the onset of an arrhythmia, and an acutely unwell patient with pulmonary oedema and NYHA class IV symptoms may improve rapidly with the administration of a diuretic. 6.1.2. Signs By observing or palpating the apical impulse and percussing the left cardiac borders, the examiner can determine heart size. A characteristic holosystolic murmur of mitral insufficiency or aortic stenosis is heard in many heart failure patients. Tricuspid insufficiency, which is also common, can be differentiated from mitral insufficiency by the location of the murmur at the left sternal border. The presence of a third heart sound suggests increased ventricular filling volume or diminished relaxation; a fourth heart sound usually indicates ventricular stiffening. An increase in the intensity of either gallop sound during inspiration indicates that it is derived from the right ventricle. A key objective of the examination is to detect and to quantify pulmonary or systemic congestion. Oedema, a common finding in volume-overloaded heart failure patients, may be the result of venous insufficiency. A more definitive test for assessment of a patient’s volume status is by the measurement of JVP (jugular vein pressure). Not only does an elevated JVP detect systemic congestion, but there is good sensitivity (70%) and specificity (79%) between high JVP and elevated left-sided filling pressure. Pulmonary congestion is detected on physical examination from signs indicating the presence of fluid in the pleural space or lung parenchyma. Dullness to percussion and diminished breath sounds at one or both lung bases suggest the presence of a pleural effusion. Leakage of fluid from pulmonary capillaries into the lung parenchyma can be manifested as rales, rhonchi or wheezes. Pulmonary rales due to heart failure are usually fine in nature and extend from the base upward. The occurrence of so-called cardiac asthma is due to the presence of fluid in the bronchial wall as well as secondary bronchospasm. 34 Detection of reduced cardiac output (CO) and systemic hypoperfusion (fatigue, somnolence or loss of mental acuity, low body temperature, tachycardia and cool, mottled extremities, etc.) is a key component of the examination. Whereas patients with poor systemic perfusion due to low CO usually have low systolic and narrow pulse pressures, this relationship is not exact. Many patients with systolic blood pressure in the range of 80 mmHg (or even lower) may have adequate perfusion. Others with reduced CO maintain blood pressure in the normal range at the expense of tissue perfusion by greatly increasing systemic vascular resistance. Typical symptoms More specific signs breathlessness elevated jugular venous pressure orthopnea hepatojugular reflux paroxysmal nocturnal dyspnea third heart sound (gallop rhythm) reduced exercise tolerance laterally displaced apical impulse fatigue, increased time to recover after exercise cardiac murmur ankle swelling Less typical symptoms Less specific signs nocturnal cough peripheral oedema (ankle, sacral, scrotal) wheezing pulmonary crepitations weight gain (>2 kg/week) dullness at lung bases (pleural effusion) weight loss (in advanced heart failure) reduced air entry, tachypnea bloated feeling irregular pulse loss of appetite tachycardia confusion (especially in the elderly) hepatomegaly depression ascites palpitations tissue wasting (cachexia) Table 5. Symptoms and signs typical of heart failure 6.2. General diagnostic tests 6.2.1. Electrocardiography Electrocardiogram (ECG) is one of the most useful tests in patients with suspected HF. The ECG shows the heart rhythm and electrical conduction, i.e. whether there is sinoatrial disease, atrioventricular (AV) block, or abnormal intraventricular conduction. These findings are also important for decisions about treatment (e.g. rate control and anticoagulation for AF, pacing for bradycardia, or CRT if the patient has left brundle branch block). The ECG may also show evidence of LV hypertrophy or Q waves (indicating loss of viable myocardium), giving a possible clue to the aetiology of HF. A completely normal ECG makes systolic HF unlikely. 6.2.2. Chest X-ray Chest radiography remains a useful component of the assessment, particularly when the clinical presentation is ambiguous. A “butterfly” pattern of alveolar opacities that fan out bilaterally from engorged hilar pulmonary arteries to the periphery of the lungs is the classic pattern of congestion seen in decompensated heart failure. The most prominent chest radiographic findings in heart failure are cardiomegaly, Kerley B lines, peribronchial cuffing, pleural effusion. 6.2.3. Natriuretic peptides Where the availability of echocardiography is limited, an alternative approach to diagnosis is to measure the blood concentration of a natriuretic peptide, a family of hormones secreted in increased amounts when the heart is diseased or the load on any chamber is increased (e.g. by AF, pulmonary embolism, and some non-cardiovascular conditions, including renal failure). Measurement of natriuretic peptide (BNP, NT-proBNP, or MR-proANP) should be considered to exclude alternative causes of dyspnea (if the level is below the exclusion cut-point, HF is very unlikely) and obtain prognostic information. 35 6.2.4. Routine laboratory tests In addition to standard biochemical (Na+, K+, creatinine/estimated glomerular filtration rate (eGFR), inflamantory parameters) and haematological tests (haemoglobin, haematocrit, ferritin, leucocytes, and platelets), it is useful to measure thyroid-stimulating hormone (TSH) as thyroid disease can mimic or aggravate HF. As well as a pre-treatment check, biochemical monitoring is important after the initiation of the treatment, while the dose is being up-titrated and during longer term follow-up. 6.3. Cardiac imaging Imaging plays a central role in the diagnosis of HF and in guiding treatment. Of the several imaging modalities available, echocardiography is the method of choice in patients with suspected HF. It may be complemented by other modalities, chosen according to their ability to answer specific clinical questions and taking account of contraindications to, and risks of, specific tests. 6.3.1. Echocardiography The echocardiogram is the most useful tests in patients with suspected HF. Transthoracic echocardiography can be performed without risk to the patient, does not involve radiation exposure, and can be performed at the bedside if necessary. Echocardiography may be limited in some patients because available imaging planes and image quality depend on acoustic windows, which may be suboptimal as a result of obesity, emphysema, or other causes. It is particularly well suited for evaluating the structure and function of both the myocardium and heart valves and providing information about intracardiac pressures and flows. Information about the pericardium, endocardium and the morphology and relative sizes of the cardiac chambers may suggest specific diagnoses. Echocardiography may also aid in deciding what treatments will help the patient, such as medication, insertion of an implantable cardioverter-defibrillator or cardiac resynchronization therapy. We can determine with echocardiography the stroke volume (SV, the amount of blood in the heart that exits the ventricles with each beat), the end-diastolic volume (EDV, the total amount of blood at the end of diastole), and the SV in proportion to the EDV, a value known as the ejection fraction (EF). Echocardiography can also help determine if acute myocardial ischemia is the precipitating cause, and may manifest as regional wallmotion abnormalities on echo. Diastolic function is easily assessed by echocardiography with Doppler and Tissue Doppler measurements. Echocardiographic measurements are also used to estimate right-sided heart pressures noninvasively, which may be useful in assessing and managing heart failure patients. TOE is, however, valuable in patients with complex valvular disease (especially mitral disease and prosthetic valves), suspected endocarditis, and in selected patients with congenital heart disease. TOE is also used to check for thrombus in the left atrial appendage of patients with AF. Exercise or pharmacological (dobutamin) stress echocardiography may be used to identify the presence and extent of inducible ischaemia and to determine whether non-contracting myocardium is viable. 6.3.2. Cardiac MRI CMR is a non-invasive technique that provides most of the anatomical and functional information available from echocardiography, including evaluation of ischemia and viability, as well as additional assessments. MRI is regarded as the gold standard with respect to accuracy and reproducibility of volumes, mass, and wall motion. It is particularly valuable in identifying inflammatory and infiltrative conditions, and in predicting prognosis in patients with these. MRI is also useful in the work-up of patients with suspected cardiomyopathy, arrhythmias, suspected cardiac tumours (or cardiac involvement by tumor), or pericardial diseases, and is the imaging method of choice in patients with complex congenital heart disease. Major limitations: (1) implanted pacemakers or defibrillators (except for newer, MRI compatible devices) (2) claustrophobia (3) GFR <30 mL/min/m2 (gadolinium-based contrast agent can cause nephrogenic systemic fibrosis) (4) highly irregular rhythms 36 6.3.3. Coronary angiography Coronary angiography should be considered in patients with angina pectoris or a history of cardiac arrest if the patient is otherwise suitable for coronary revascularization. Coronary angiography should be strongly considered for patients with systolic left ventricular dysfunction and a strong suspicion of hibernating myocardium based on the findings of noninvasive evaluation. In patients with normal systolic function but otherwise unexplained episodes of acute pulmonary edema, coronary angiography may be necessary to rule out ischemically related systolic and/or diastolic left ventricular dysfunction. 6.3.4. Other special imagings Single-photon emission computed tomography (SPECT) and positron emission tomography (PET) alone or with computed tomography (PET-CT) may be useful in assessing ischaemia and viability if CAD is suspected, and provides prognostic as well as diagnostic information. The main use of coronary CT in patients with HF is a non-invasive means to visualize the coronary anatomy in patients with low or intermediate cardiovascular risk. 6.4. Other investigations Measurement of intracardiac pressures and cardiac output by right-heart catheterization is less commonly performed now than in the past either as part of the diagnostic workup or for guiding therapy because biomarkers and noninvasive imaging techniques provide much of the information. In patients with suspected constrictive or restrictive cardiomyopathy, cardiac catheterization used in combination with other noninvasive imaging techniques may help to establish the correct diagnosis. In patients with suspected myocarditis and infiltrative diseases (e.g. amyloidosis, endomyocardial biopsy may be needed to confirm the diagnosis. Exercise testing allows objective evaluation of exercise capacity and exertional symptoms, such as dyspnea and fatigue. The 6-min walking test and a variety of treadmill and bicycle protocols are available. When more precise information is needed (e.g. before cardiac transplantation), cardiopulmonary exercise testing (spiroergometry) is also often used because it provides better quantification of exercise capacity and can determine whether the cause of exercise limitation is cardiac. The role of genetic testing in ‘idiopathic’ dilated and hypertrophic cardiomyopathy is described in detail elsewhere. Currently this is recommended in patients with ‘idiopathic’ dilated and hypertrophic cardiomyopathy and AV block or a family history of premature unexpected sudden death. 7. Therapy 7.1. Treatment of heart failure with reduced ejection fraction (systolic heart failure - HFrEF) Medical care for heart failure (HF) includes a number of nonpharmacologic, pharmacologic, and invasive strategies to limit and reverse the manifestations of heart failure. The goals of treatment in patients with established HF are to relieve symptoms and signs (e.g. oedema), prevent hospital admission, and improve survival. It is important to recognize that LV dysfunction may develop transiently in various different clinical settings, which may not lead invariably to the development of the clinical syndrome of HF. 7.1.1. Prevention of heart failure Depending on the severity of illness, nonpharmacologic therapies include dietary Na+ and fluid restriction; physical activity as appropriate; and attention to weight gain. Identification and correction of the condition(s) responsible for the cardiac structural and/or functional abnormalities are critical, insofar as some conditions that provoke LV structural and functional abnormalities are potentially treatable and/or reversible. Clinicians should aim to screen for and treat aggressively comorbidities such as hypertension, diabetes and coronary heart disease, which are thought to underlie the structural heart disease. HF patients should be advised to stop smoking and to limit daily alcohol consumption. 37 Certain drugs are known to make HF worse and should also be avoided. For example, nonsteroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase 2 (COX-2) inhibitors, are not recommended in patients with chronic HF. Although heavy physical labor is not recommended in HF, routine modest exercise has been shown to be beneficial in patients with NYHA Classes I to III. Caloric supplementation is recommended for patients with advanced HF and unintentional weight loss or muscle wasting (cardiac cachexia). Dietary restriction of Na+ (3 g daily) is also recommended for all patients with the clinical syndrome of HF and preserved or depressed EF. 7.1.2. Pharmacological treatment 7.1.2.1. Treatments recommended in potentially all patients with systolic heart failure - first line therapy Angiotensin-converting enzym inhibitors (ACEIs), angiotensin receptor blockers (ARBs), betaadrenergic receptor blockers (beta-blockers) and mineralocortico-steroid receptor inhibitors (MRA) have emerged as cornerstones of modern first line HF therapy for systolic heart failure patients (EF ≤40%) to reduce the risk of HF hospitalization and the risk of premature death and to improve survival (Figure 4, Table 6). Figure 4. Treatments for patients with chronic symptomatic systolic heart failure (NYHA class II-IV) 38 Initial dose (mg) Target dose (mg) ACEIs captopril 6.25 (3x) 50 (3x) enalapril 2.5 (2x) 10-20 (2x) lisinopril 2.5-5 (1x) 20-35 (1x) ramipril 2.5 (1x) 5 (2x) Beta-blockers bisoprolol 1.25 (1x) 10 (1x) carvedilol 3.125 (1x) 25-50 (2x) metoprolol (CR/XL) 12.5/25 (1x) 200 (1x) nebivolol 1.25 (1x) 10 (1x) ARBs candesartan 4-8 (1x) 32 (1x) valsartan 40 (2x) 160 (2x) losartan 50 (1x) 150 (1x) MRAs eplerenone 25 (1x) 50 (1x) spironolactone 25 (1x) 25-50 (1x) Table 6. Titration of first line therapy 7.1.2.1.1. Renin-angiotensin-aldosterone system inhibitors (RAAS inhibitors) There is overwhelming evidence that angiotensin-converting enzym inhibitors (ACEIs) should be used in symptomatic and asymptomatic patients with a reduced EF (<40%). ACEIs interfere with the RAAS by inhibiting the enzyme that is responsible for the conversion of angiotensin I to angiotensin II. However, because ACEIs also inhibit kininase II, they may lead to the upregulation of bradykinin, which may further enhance the effects of angiotensin suppression. ACEIs stabilize LV remodeling, improve symptoms, prevent hospitalization, and prolong life. ACE inhibitors are also beneficial in asymptomatic LV systolic dysfunction (NYHA class I). It should be start as early as possible in the course of disease and should be initiated in low doses, followed by increments in dose if lower doses have been well tolerated. Titration (Table 6) is generally achieved by doubling the dosage every 3 to 5 days. The dose of ACE inhibitor should be increased until the doses used are similar to those that have been shown to be effective in clinical trials. For stable patients, it is acceptable to add therapy with beta-blocking agents before full target doses of ACEIs are reached. Blood pressure, renal function, and K+ level should be evaluated within 1 to 2 weeks after initiation of ACEIs. The efficacy of ACEIs has been consistently demonstrated in clinical trials with patients with asymptomatic and symptomatic LV dysfunction. These trials recruited a broad variety of patients and the consistency of data from some studies has shown that asymptomatic patients with LV dysfunction will have less development of symptomatic HF and fewer hospitalizations when treated with an ACEI. ACEIs have also consistently shown benefit for patients with symptomatic LV dysfunction. The CONSENSUS and the SOLVD trial showed that ACE inhibitor therapy reduces mortality (relative risk reduction: 27% in CONSENSUS and 16% in SOLVD-Treatment). ACE inhibitors occasionally cause worsening of renal function, hyperkalaemia, symptomatic hypotension, cough, and, rarely, angioedema. ACE inhibitor treatment should only be used in patients with normal - to moderately compromised renal function (creatinine ≤221 mmol/L or eGFR ≥30 mL/min/1.73 m2) and a normal serum K+ level (<5.0 mmol/l). Angiotensin receptor blockers (ARBs) are well tolerated in patients who are intolerant of ACEIs because of the development of cough, skin rash, and angioedema and should therefore be used in same indications (in symptomatic and asymptomatic patients with an EF less than 40%), who are ACE-intolerant for reasons other than hyperkalemia or renal insufficiency. Clinical trials have demonstrated that ARBs are as effective as ACEIs in reversing the process of LV remodeling, improving symptoms, preventing hospitalization, and reducing HF morbidity and mortality. 39 Spironolactone and eplerenone are synthetic mineralocorticoid receptor antagonists (MRAs) that act on the distal nephron to inhibit Na+-K+ excretion at the site of aldosterone action. Although spironolactone and eplerenone are both weak diuretics, clinical trials have shown that both of these agents have profound effects on cardiovascular morbidity and mortality. An MRA is recommended for all patients with persisting symptoms (NYHA class II-IV) and an EF ≤35%, in spite of ACEI plus beta-blocker treatment to reduce the risk of HF hospitalization and the risk of premature death. They can cause hyperkalaemia and worsening renal function. Spironolactone has antiandrogenic and progesterone-like effects, which may cause gynecomastia (1-10%) or impotence in men and menstrual irregularities in women. Eplerenone has greater selectivity for the mineralocorticoid receptor than for steroid receptors, and has less sex hormone side effects. One direct renin inhibitor (aliskiren) is currently being evaluated in some morbidity-mortality trials. It is not presently recommended as an alternative to an ACE inhibitor or ARB. 7.1.2.1.2. Beta-adrenergic receptor blockers (beta-blockers) Beta-blocker therapy represents a major advance in the treatment of HF. Beta-blockers interfere with the harmful effects of the sympathetic nervous system by competitively antagonizing one or more adrenergic receptors. Beta-blockers cause time-dependent improvements in ventricular structure (LV remodelling) and function (ejection fraction). Other beneficial actions include reductions in heart rate and blood pressure, prolonging left ventricular diastolic filling time, inhibition of the renin-angiotensin system, reduction of arrhythmias, and anti-ischemic effects (improving the myocardial oxygen support). Beta-blockers indicated in symptomatic heart failure patients (EF ≤40%), since many trials have shown that beta-blockers reduce mortality (relative risk reduction: ̴34%), HF hospitalization ( 2̴ 8-36%) and improves quality of life within 1 year of starting treatment. Three beta-blockers have been shown to be effective in reducing the risk of death in patients with chronic HF. Bisoprolol and sustained-release metoprolol succinate are cardio selective beta-blockers acting primarily on beta-1 receptors, and carvedilol is a non-selective beta-blocker with additional alpha-receptor blocking and antioxidant properties. It should be started as early as possible in the course of disease. The dose should be increased until the doses used are similar to those that have been reported to be effective in clinical trials. The dose titration of beta-blockers should proceed no sooner than at 2-week intervals, because the initiation and/or suddenly increased dosing of these agents may lead to worsening heart failure (fluid retention). Side effects of the therapy with beta-blockers are bradyarrhythmias, prolonged intraventricular conduction (AV-block), bronchoconstriction (rare side effect), hypotension and worsening renal function. Treatment can be accompanied by feelings of general fatigue or weakness. 7.1.2.1.3. Other treatments recommended in selected patients with systolic heart failure Ivabradine is a drug that inhibits the If channels in the sinus node. It’s only known pharmacological effect is to slow the heart rate in patients with sinus rhythm (it does not slow the ventricular rate in AF). Ivabradine should be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF ≤35%, a heart rate remaining ≥70 b.p.m., and persisting symptoms (NYHA class II-IV) despite treatment with an evidence-based dose of beta-blocker (or maximum tolerated dose), ACE inhibitor (or ARB), and an MRA (or ARB). If beta-blockers are contraindicated, ivabradine may be considered. The primary mechanism of cardiac glycosides (digoxin and digitoxin) involves inhibition of the Na+/K+ ATPase, mainly in the myocardium. This inhibition causes an increase in intracellular Na+ levels, resulting in a reversal of the action of the Na+/Ca2+ exchanger leading to increased contractility. The inhibition of the sodium pump may also improve baroreceptor sensitivity in HF and may explain some of the neurohormonal effects of digoxin. Digoxin has important parasympathetic effects, leading to an increase in vagal tone that counterbalances the increased activation of the adrenergic system in advanced HF (negative chronotrop). In patients with symptomatic HF and AF, digoxin may be used to slow the ventricular rate, although other treatments are preferred. It reduces the risk of HF hospitalization in patients with an EF ≤45% despite treatment of beta-blockers or who are unable to tolerate beta-blockers. The use of digoxin should be restricted to heart failure with AF already on beta-blocker, and there are low levels of evidence to use in sinus rhythm. The principal cardiac adverse effects of digoxin are the atrial and ventricular arrhythmias, particularly in the context of hypokalaemia, heart block and ectopic and reentrant cardiac rhythms. 40 7.1.2.2. Other pharmacological treatment Combination of hydralazine and isosorbide dinitrate (H-ISDN) may be considered as an alternative to an ACE inhibitor or ARB, if neither is tolerated, to reduce the risk of HF hospitalization and risk of premature death in patients with an EF ≤45% and symptomatic heart failure (NYHA class II-IV). Omega-3 polyunsaturated fatty acids (n-3 PUFAs) have favorable effects on inflammation, platelet aggregation, blood pressure, heart rate, and LV function. The GISSI-HF study has shown that long-term administration of omega-3 fatty acids results in a significant reduction in both all-cause mortality. Novel, promising therapeutical option is the usage of angiotensin receptor blocker-neprylisin inhibitor (ARNI). 7.1.2.3. Management of fluid status - diuretics Many clinical manifestations of heart failure result from excessive salt and water retention that leads to an inappropriate volume expansion of the vascular and extravascular space causing symptoms of the disease. Although both digitalis and low doses of ACEIs enhance urinary Na+ excretion, only few volumeoverloaded HF patients can maintain proper Na+ and fluid balance without the use of diuretic drugs. The effects of diuretics on mortality and morbidity have not been studied in patients with HF, unlike ACE inhibitors, beta-blockers, and MRAs (and other treatments). However, diuretics relieve dyspnea and oedema and are recommended for this reason in patients with signs and symptoms of congestion, irrespective of EF (Figure 2). Classification of diuretics in heart failure: (1) loop diuretics (e.g. furosemide, torasemide) (2) tiazides (e.g. hidrochlorotiazide) and tiazide-like diuretics (e.g. indapamide) (3) K+-sparing diuretics (e.g. MRAs, amiloride, triamterene) The loop diuretics have emerged as the preferred diuretic (moderate to severe symptoms or renal insufficiency) agents for use in most patients with HF. The aim of using diuretics is to achieve and maintain euvolaemia (the patient’s ‘dry weight’) using the lowest achievable therapy dose. Diuretics should be initiated in low doses and then titrated upward to relieve signs and symptoms of fluid overload. A typical starting dose of furosemide for patients with systolic HF and normal renal function is 20-40 mg, although doses of 80 to 160 mg are often necessary to achieve adequate diuresis. Because of the steep doseresponse curve and effective threshold for loop diuretics, it is critical to find an adequate dose of loop diuretic that leads to a clear-cut diuretic response. Once patients have achieved an adequate diuresis, it is important to document their dry weight and make certain that patients weigh themselves daily to maintain their dry weight. Loop diuretics produce a more intense and shorter diuresis than thiazides, which cause a more gentle and prolonged diuresis. Thiazides may be less effective in patients with reduced kidney function. Loop diuretics are usually preferred to thiazides in HFrEF although they act synergistically and the combination may be used (usually on a temporary basis) to treat resistant oedema. Intravenous administration of diuretics may be necessary to relieve congestion acutely. In symptomatic patients, diuretics should always be used in combination with ACEIs (or ARB), beta-blockers and MRA if it is possible. The major complications of diuretic use include electrolyte (hypokalaemia) and metabolic disturbances, volume depletion, and worsening of renal function (azotemia). The interval for reassessment should be individualized based on the severity of illness and underlying renal function, past history of electrolyte imbalances, and/or need for more aggressive diuresis. 7.1.2.4. Treatments that may cause harm in symptomatic systolic heart failure (NYHA class II-IV) Most calcium channel blockers (with the exception of amlodipine, felodipine, lercanidipine) should not be used as they have a negative inotropic effect and can cause worsening HF. NSAIDs and COX-2 inhibitors should be avoided if possible as they may cause Na+ and water retention, worsening renal function and worsening HF. Finally, the addition of an ARB (or renin inhibitor) to the combination of an ACE inhibitor and a mineralocorticoid receptor antagonist is not recommended because of the risk of renal dysfunction and hyperkalaemia. 41 7.2. Treatment of heart failure with preserved ejection fraction (diastolic heart failure - HFpEF) Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome characterized by heart failure (HF) signs and symptoms and a normal or near-normal left ventricular ejection fraction (LVEF). More specific diagnostic criteria have evolved over time and include signs/symptoms of HF, objective evidence of diastolic dysfunction, disturbed left ventricular (LV) filling, structural heart disease, and elevated brain natriuretic peptides. However, multiple cardiac abnormalities are often present apart from diastolic LV dysfunction, including subtle alterations of systolic function, impaired atrial function, chronotropic incompetence, or haemodynamic alterations, such as elevated pre-load volumes. Extracardiac abnormalities and comorbidities, such as hypertension, atrial fibrillation, diabetes, renal or pulmonary disease, anaemia, obesity and deconditioning may contribute to the HFpEF syndrome (Figure 5). Lowgrade inflammation with endothelial dysfunction, increased reactive oxygen species production, impaired nitric oxide (NO) bioavailability, and the resulting adverse effects on cardiac structure and function are considered a mechanistic link between frequently encountered comorbidities and the evolution and progression of HFpEF. Figure 5. Heterogenity of the heart failure with preserved ejection fraction (HFpEF) In contrast to the treatment of HF with reduced EF, information to guide the pharmacologic therapy for patients with HFpEF is lacking. Present treatment strategies for HFpEF are largely based on assumptions of its pathophysiologic mechanisms and on extrapolations from proven strategies used in HF with a reduced EF. The pharmacological therapy of diastolic heart failure is based mainly on empiric data, and aims to the normalization of blood pressure, reduction of left ventricular dimensions and increased heart rate, maintenance of normal atrial contraction and treatment of symptoms caused by congestion. Beneficial effects of ACEIs and ARBs may be utilized in patients with diastolic dysfunction, especially in those with hypertension. Beta-blockers appear to be useful in lowering heart rate and thereby prolonging left ventricular diastolic filling time. Diuretics are used to control Na+ and water retention and relieve reathlessness and oedema as in HFrEF. Adequate treatment of hypertension and myocardial ischaemia is also considered to be important, as is control of the ventricular rate in patients with AF. The drugs that should be avoided in HFrEF should also be avoided in HFpEF, with the exception of calcium channel blockers. 7.3. Non-pharmacological (device, surgery) therapy of heart failure 7.3.1. Implantable cardioverter defibrillator (ICD) Approximately half of the deaths in patients with HF, especially in those with milder symptoms, occur suddenly and unexpectedly, and many, if not most, of these are related to ventricular arrhythmias. Prevention of sudden death is an important goal in HF. 42 While the optimal pharmacological therapy mentioned earlier reduce the risk of sudden death, they do not abort it and the specific antiarrhythmic drugs do not decrease the mortality (and may even increase it). In primary prevention an ICD is recommended in a patient with symptomatic HF (NYHA class II-III) and an EF ≤35% despite ≥3 months of treatment with optimal medical therapy, who is expected to survive for more than 1 year with good functional status, to reduce mortality (the risk of sudden death). ICDs reduce mortality in survivors of cardiac arrest (secondary prevention) and in patients with sustained symptomatic (haemodinamic instability) ventricular arrhythmias. Consequently, an ICD is recommended in such patients, irrespective of EF, with good functional status, a life expectancy of more than 1 year. 7.3.2. Cardiac resynchronization therapy (CRT) Several conduction abnormalities are commonly seen in association with chroni heart failure. Among these are abnormalities of ventricular conduction, such as bundle branch blocks, that alter the timing and pattern of ventricular contraction so as to place the already failing heart at a further mechanical disadvantage. These ventricular conduction delays produce suboptimal ventricular filling, a reduction in left ventricular contractility, prolonged duration of mitral regurgitation, and paradoxical septal wall motion. Taken together, these mechanical manifestations of altered ventricular conduction have been termed ventricular dysynchrony. Ventricular dysynchrony may now be addressed with pacing therapy through the implantation of pacing leads to both the right and left ventricles. This form of pacing therapy has come to be known as cardiac resynchronization therapy (CRT). It reduces the risk of HF hospitalization and the risk of premature death (reduce motality). CRT-P (biventricular pacemaker) or CRT-D (CRT+ICD) is recommended in patients with NYHA II-IV: (1) in sinus rhythm or in atrial fibrillation (2) left brundle branch block (LBBB) QRS morphology on ECG (with a QRS duration of ≥120 ms, optimal in QRS duration ≥150 ms), or irrespective of QRS morphology (with a QRS duration of ≥150 ms) (3) patients with uncontrolled heart rate (in atrial fibrillation) who are candidates for AV junction ablation for rate control. (4) low EF (≤35%) (5) who are expected to survive with good functional status for more than 1 year 7.3.3. Surgical Therapy The surgical therapy of heart failure includes coronary revascularization, aneurysmectomy, valve surgery (repair or replacement), ventricular assist device implantation (LVAD, RVAD, BIVAD) and heart transplantation. 7.4. Treatment of acute heart failure Although not ‘evidence based’ in the same way as treatments for chronic HF, the key drugs are oxygen (oxigen saturation <90%), diuretics and vasodilators. Opiates and inotropes are used more selectively, and mechanical support of the circulation is required only rarely. Non-invasive ventilation (NIV) is used commonly in many centres, but invasive ventilation is required in only a minority of patients. Most patients with dyspnea caused by pulmonary oedema obtain rapid symptomatic relief from administration of an i.v. diuretic, as a result of both an immediate venodilator action and subsequent removal of fluid. Opiates such as morphine may be useful in some patients with acute pulmonary oedema as they reduce anxiety, relieve distress associated with dyspnea, reducing preload and may also reduce sympathetic drive. Vasodilators such as nitroglycerine reduce preload and afterload and increase stroke volume, and are probably most useful in patients with hypertension. Use of an inotrope such as dobutamine, levosimendan should usually be reserved for patients with such severe reduction in cardiac output that vital organ perfusion is compromised. Systolic blood pressure, heart rhythm and rate, saturation of peripheral oxygen (SpO2) using a pulse oxymeter, and urine output should be monitored on a regular and frequent basis until the patient is stabilized. 43 8. Quiz 1. The true statement in relation to the prevalence of heart failure: A: the prevalence of heart failure among adults is between 1-2% and shows a downward trend B: the prevalence of heart failure among adults is between 4-5% and shows an upward trend C: the prevalence of heart failure among adults is between 1-2% and shows an upward trend D: the prevalence of heart failure among adults is between 4-5% and shows a downward trend 2. Characteristics of patients in functional class IV. according to the NYHA classification: A: ordinary physical activity cause fatigue, palpitation, or dyspnea B: the patient's condition can only be stabilized via intravenous inotropic therapy C: unable to do any physical activity without discomfort, symptoms of cardiac insufficiency at rest D: ACE inhibitor and beta-blockers can not be applied in this case 3. Characteristics of skeletal muscle in a heart failure patient: A: stuctural changes in the sceletal muscle with increase of type IIb fibers B: biochemical alteration C: ergoreflex alteration D: all of the above 4. The false sentence: A: BNP is mainly released from the right ventricle at elevated filling pressure B: ARBs are act on ATII AT1 receptors C: in heart failure beta-receptor down regulation is observed D: excessive diuretic treatment enhance the activation of the sympathetic nervous system 5. Brain natriuretic peptide (BNP) is secreted primarily from the brain during heart failure, therefore it is considered important in the diagnosis of heart failure. A: true-true B: false-false C: true-false D: false-true 6. The true sentence: A: RAAS system activation is crucial in the pathogenesis of heart failure B: during heart failure the number of beta-receptors rises (upregulation) C: sympathetic nervous system activation only occurs in end-stage disease D: all 3 statements above are true 7. In the treatment of heart failure the following statement is true: A: digitals therapy improve survival, and patients become less symptomatic B: ACE inhibitors reduce the risk of HF hospitalization but increase the risk of premature death C: beta-blocker reduce the risk of HF hospitalization and the risk of premature death D: mineralocorticoid antagonist only indicated in severe, refractory cases 8. In the treatment of heart failure the following statement is true: A: digitalis is indicated in all systolic heart failure patients B: ACE inhibitor is always indicated if no contraindication present C: beta-blockers not indicated in high dose, because it has a negative inotropic effect D: Ca-antagonist is always indicated 44 9. The true statement in case of diastolic heart failure (HFpEF): A: diastolic heart failure (HFpEF) is common, it occurs in 10-20% of heart failure cases B: usually these patients are elderly, diabetic, obes, hypertensive and women C: evidences are available when choosing its treatment D: all 3 statements above are true 10. Thallium reinjection scintigraphy is mainly used in the diagnosis of heart failure: A: the separate of viable (hibernating) myocardium from necrosis B: detection of previous myocardial infarction C: imaging of Coronary Artery Calcium D: determination of left ventricular systolic function 11. Meaning of class „I. A” recommendation: A: intervention is not useful/effective and may be harmful B: intervention is useful and effective, data derived from multiple randomized clinical trials C: chinidin or other class I. A type antiarrythmic medication therapy is indicated D: intervention is useful based on expert, consensus opinion 12. In the diagnosis/prognostics of heart failure the following biomarkers can be applied: A: natrium, CN, creatinin B: troponin, CK C: galectin-3, BNP, NT-ProBNP D: blood sugar, LDL-cholesterol, CRP 13. It is important for a person with heart failure to: A: make sure they get the flu shot every year B: receive the pneumovax vaccination to prevent pneumonia C: see their heart failure doctor regularly D: all of the above 14. The recommended total daily amount of Na+ that persons with heart failure should eat is: A: about 3,000 milligrams B: more than 2,500 milligrams C: less than 2,000 milligrams D: 500 milligrams 15. The best medicine to take in case of headache or pain in person with heart failure: A: aspirin B: acetaminophen C: NSAID D: morphin 16. How often should a person with heart failure exercise? A: every week B: every day C: exercise is contraindicated in heart failure D: 2-3 times per week 45 17. Persons with heart failure should call their doctor if they have which of the following symptoms: A: weight gain of 2-3 kg in 1-2 days B: increased swelling of the ankles and/or stomach C: more shortness of breath D: all of the above 18. The best time of day for persons with heart failure to weigh themselves is: A: at bedtime B: upon awakening in the morning C: at or around lunchtime D: when they remember to do it 19. How often should a person with heart failure weigh themselves? A: every day B: every week C: every month D: once in a while 20. If a person with heart failure gains 2-3 pounds in a few days, this usually means he/she: A: is eating too many calories and gaining weight B: has extra water in the body C: needs to drink more fluid D: needs to be getting more exercise to burn calories 21. Calcium channel blocker which is contraindicated in HFrEF: A: amlodipine B: verapamil C: levosimendan D: bisoprolol 22. Resynchronization therapy (CRT) is clearly indicated (class I A): A: for all patients with heart failure below EF 35% B: in case of (RBBB) C: in all cases of Left bundle branch block (LBBB) D: in patients in sinus rhythm with QRS duration of ≥120 ms, LBBB QRS morphology and an EF ≤35% 23. In the case of heart failure it is essential to determine when examining myocardial ischemia: A: the localization of ischemia B: the extent of ischemia C: the presence of necrotic or hibernating myocardium D: all of the above 24. First-line drugs in the treatment of chronic systolic heart failure: A: diuretics + beta-blockers + ACE inhibitors B: digtalis + beta-blockers + mineralocorticoid receptor blockers C: beta-blockers + ACE inhibitors + mineralocorticoid receptor blockers D: digitalis + diuretics + ACE inhibitors 46 25. In the outpatient heart failure service, according to the ESC Long-Term Registry data, what percentage of patients achieving target dose of ACE inhibitors/beta-blockers? A: above 50% B: below 30% C: above 30% D: below 20% 26. A contraindicated drug combination in heart failure: A: beta-blocker + ACE inhibitor + mineralocorticoid receptor antagonist (MRA) B: angiotensin receptor blocker + ACE inhibitor + MRA C: beta-blocker + ACE inhibitor + ivabradine D: digoxin + beta-blocker + ACE inhibitor 27. The recommended beta-blockers when heart failure is associated with COPD: A: it is not recommended B: it has no restrictions C: beta-1 selective blockers are preferable D: non-selective, with combined action is recommended (ie. carvedilol) 28. From the following which statement is not true? Diuretic resistance… A: … is common and occurs in one in three heart failure patients especially from moderate to severe heart failure B: … may be worsened by NSAIDs, which - through the inhibition of prostaglandin synthesis - reduce renal perfusion and this way inhibit the effect of diuretics C: … means that on the "usual" dose diuretic therapy the hyperhydration of the extracellular space is not reduced D: … is very rare, only occurs when heart failure is combined with severe kidney disease 29. The strength of heart muscle contractions can be increased by: A: reducing the concentration of intracellular Ca2+ of heart muscle cells B: the activation of beta-adrenergic signaling system of heart muscle cells C: increasing plasma K+ concentrations D: increasing the concentration of intracellular inorganic phosphate of heart muscle cells 30. 64 years old woman has chronic systolic heart failure. Her ejection fraction is 30%, in NYHA II. She received enalapril 20 mg b.i.d., bisoprolol 10 mg o.d., eplerenone 50 mg o.d. and furosemide 40 mg at stable dose more than 3 months. Her ECG shows sinus rhythm, typical LBBB, QRS 150 msec and her heart rate is 78 min-1. She has not fluid retention. Her NTproBNP level is 2000 pg/ml. What is the next step? A: to increase the dose of furosemide B: ICD implantation C: CRT-D implantation D: introduction of ivabradine 31. Not part of the patient’s self-care management: A: avoiding excessive fluid intake B: introducing and titrating neurohormonal antagonists C: performing exercise training regularly D: understanding indications, dosing and effects of drugs 47 9. Right answers 1. C 2. C 3. D 4. A 5. D 6. A 7. C 8. B 9. B 10. A 11. B 12. C 13. D 14. C 15. B 16. B 17. D 18. B 19. A 20. B 21. B 22. D 23. D 24. C 25. B 26. B 27. C 28. C 29. B 30. D 31. B 48 10. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] McMurray JVJJ, Adamopoulos S, Anker SD, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33: 1787-1847. Chronic heart failure: national clinical guideline for diagnosis and management in primary and secondary care: partial update. Nat Clin Guideline Centre 2010; 19-24. Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth edition. Elservier Saunders, Philapelphia 2012; 520. ISBN: 978-0-8089-2436-4. Khot UN, Jia G, Moliterno DJ, et al. Prognostic importance of physical examination for heart failure in non-ST-elevation acute coronary syndromes: the enduring value of Killip classification. JAMA 2003; 290: 2174-2181. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 2007; 93: 1137-1146. Upadhya B, Taffet GE, Cheng CP, et al. Heart failure with preserved ejection fraction in the elderly: scope of the problem. J Mol Cell Cardiol 2015; 83: 73-87. Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth edition. Elservier Saunders, Philapelphia 2012; 557. ISBN: 978-0-8089-2436-4. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm 2011; 8: 1308-1339. Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth edition. Elservier Saunders, Philapelphia 2012; 544. ISBN: 978-0-8089-2436-4. Nohria A, Cusco JA, Creager MA. Neurohormonal, renal and vascular adjustments in heart failure. Atlas of Heart Failure. Fourth edition. Current Medicine, Philadelphia, 2005; 106. Stewart S, Ekman I, Ekman T, et al. Population impact of heart failure and the most common forms of cancer: a study of 1 162 309 hospital cases in Sweden (1988 to 2004). Circ Cardiovasc Qual Outcomes 2010; 3: 573-580. Leier CV, Chatterjee K. The physical examination in heart failure. Part I-II. Congest Heart Fail 2007; 13: 41-47 and 99104. Ewald B, Ewald D, Thakkinstian A, et al. Meta-analysis of B type natriuretic peptide and N-terminal pro B natriuretic peptide in the diagnosis of clinical heart failure and population screening for left ventricular systolic dysfunction. Intern Med J 2008; 38: 101-113. Sicari R, Nihoyannopoulos P, Evangelista A, et al. Stress echocardiography expert consensus statement: European Association of Echocardiography (EAE) (a registered branch of the ESC). Eur J Echocardiogr 2008; 9: 415-437. Raman SV, Simonetti OP. The CMR examination in heart failure. Heart Fail Clin 2009; 5: 283-300. Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth edition. Elservier Saunders, Philapelphia 2012; 550-551. ISBN: 978-0-8089-2436-4. McMurray J, Cohen-Solal A, Dietz R, et al. Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice. Eur J Heart Fail 2005; 7: 710-721. Granger CB, McMurray JJ, Yusuf S, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: The CHARM-Alternative trial. Lancet 2003; 362: 772-776. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341: 709-717. Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth edition. Elservier Saunders, Philapelphia 2012; 574-577. ISBN: 978-0-8089-2436-4. Swedberg K, Komajda M, Bohm M, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 2010; 376: 875-885. The Digitalis Investigation Group. The effect of digoxin on mortality and morbidity in patients with heart failure. N Engl J Med 1997; 336: 525-533. Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth edition. Elservier Saunders, Philapelphia, 2012; 565-567. ISBN: 978-0-8089-2436-4. Goldstein RE, Boccuzzi SJ, Cruess D, et al. Diltiazem increases late-onset congestive heart failure in postinfarction patients with early reduction in ejection fraction. The Adverse Experience Committee; and the Multicenter Diltiazem Postinfarction Research Group. Circ 1991; 83: 52-60. Mamdani M, Juurlink DN, Lee DS, et al. Cyclo-oxygenase-2 inhibitors versus non-selective nonsteroidal antiinflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet 2004; 363: 1751-1756. Czuriga I, Borbely A, Czuriga D, et al. Heart failure with preserved ejection fraction (diastolic heart failure). Orv Hetil 2012; 153: 2030-2040. Zipes DP, Camm AJ, Borggrefe M, et al. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death - executive summary: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice 49 Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Eur Heart J 2006; 27: 2099-2140. [28] Braunwald E, Bonow R, Mann DL, et al. Braunwald’s heart disease: a textbook of cardiovascular medicine. Ninth edition. Elservier Saunders, Philapelphia 2012; 592. ISBN: 978-0-8089-2436-4. [29] Brignole M, Auricchio A, Baron-Esquivias G, et al. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. The Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013; 34: 2281-2329. 50 III. Ischemic heart disease, stable coronary artery disease (SCAD), angina pectoris Prof. Dr. Kalman Toth, Dr. Laszlo Czopf, Dr. Peter Kenyeres, Dr.Katalin Biro 1 Department of Medicine, Medical School, University of Pecs, Pecs, Hungary st 1. Introduction and epidemiology In developed countries with a decline of infectious diseases, violent and accident death with an increase in life expectancy and age, chronic diseases and their complications came into view as a death cause. More than half of deaths are caused by cardiovascular diseases, and 75 percent of these cases are related to ischemic heart disease. The ischemic heart disease is the leading cause of death in developed countries and - based on epidemiological forecast - it is going to be a leading cause of death in developing countries as well. In 2001 17 million people died due to cardiovascular disease, and this number can reach 25 million by 2020. Ischemic heart disease is a most important factor in morbidity statistics, the disease and its complaints will require vast amounts of money, posing a huge burden on the society. The occurrence of stable angina increases gradually with age in both genders: in the agegroup of 45-64 it is 4-7%, in the agegroup of 65-84 it can reach 10-14%. In middle aged patients, complaints more frequently occur in women (primarily due to the higher risk of functional angina), while in the elderly the occurrence is more frequent in men and the main cause is significant coronary artery disease. The all-cause mortality of the disease is 1.2-2.4% annually. The incidence of the disease, morbidity and mortality can vary considerable from region to region due to genetics, lifestyle and public health conditions. Cardiovascular risk is lower in the Western-European region, in the Mediterranean and Scandinavian regions, while the risk is higher in Central and Eastern Europe (including Hungary). The prevalence of stable angina in Europe is around 20 thousand to 40 thousand in a million people. 2. Risk factors In most cases ischemic heart disease is caused by coronary stenosis due to atherosclerosis. In the development and progression of the disease, in the formation of complications the following factors were identified (the most important major risk factors are in bold type): (1) non-modifiable risk factors: • age • male gender • genetics, positive family history • already developed atherosclerosis, previous events (heart attack, stroke, peripheral artery disease) (2) modifiable factors partially influenced by: • smoking • hypertension • diabetes mellitus • dyslipidemia (primarily high total-, LDL- and low HDL-cholesterol level, secondarily high level of triglyceride) • obesity and metabolic syndrome • physical inactivity • stress, depression (3) beside the above mentioned risk factors the role of some other factors includes: • impaired hemorheological parameters (fibrinogen, hematocrit, plasma viscosity and whole blood viscosity, leukocyte count) • hyperuricemia 51 • hyperhomocysteinemia • infections, chronic inflammation (increased C reactive protein) • microalbuminuria, decreased glomerular filtration rate (GFR) (chronic kidney diseases) • oxidative stress, air pollution • high heart rate The SCORE chart (Figure 1) provides an estimated risk of fatal cardiovascular events within ten years based on gender, age, smoking habit, blood pressure and blood cholesterol level. The chart was worked out for different European risk regions; Hungary belongs to high risk countries. Patients have high risk when: (1) they had a cardiovascular event (2) they suffer from diabetes mellitus (type II, or type I with micro/macroalbuminuria) (3) metabolic syndrome is proven (4) the risk based on the SCORE chart is ≥5% Figure 1. Risk chart (SCORE) Ten-year risk of fatal cardiovascular disease in populations at high cardiovascular disease risk 3. Definition and pathophysiology of angina pectoris Ischemic heart disease is a generic term, involving diseases and clinical conditions, when myocardial oxygen supply is lower than oxygen demand. As a consequence, aerobic myocardial metabolism shifts to energetically unfavorable anaerobic metabolism. 3.1. Consequences of ischemia Lack of energy impairs different normal myocardial functions; these appear parallel but at different levels of energy deficiency. The sequel appearance of symptoms listed below is called ischemic cascade: (1) Levels of lactic acid produced by anaerobic metabolism and K+ stuck extracellularly due to dysfunction of the Na/K pump are elevated in the blood coming from the ischemic region. It can be detected by blood sampling from the coronary sinus, but invasiveness makes it unused in practice. (2) Break-up of actin-myosin binds, muscle relaxation needs energy. Impairment of the procedure causes diastolic dysfunction, the earliest detectable symptom. (3) Following diastolic function, systolic function becomes impaired as well. Hypo-akinesia of the affected region and the reduction of ejection fraction can be detected. 52 (4) Disturbance of active ion transport changes the normal electrolyte gradients, repolarization, impulse generation and conduction get impaired. ST-T abnormalities, QRS morphology changes, arrhythmias, blocks may appear on the ECG. (5) Ischemia usually means the lack of oxygen, the deficiency of blood flow and wash out as well. Cumulating metabolites irritate sensatory nerve endings and provoke ischemic pain, angina pectoris. (6) When the most severe form of the metabolic disorder occurs, myocardial necrosis takes place. Extensive transmural necrosis may even result in wall rupture. After healing a scar remains, without the ability for contraction or electrical activity, with passive paradox movement caused by intraventricular pressure, possibly with aneurysm formation, and an electric window leading to pathological Q wave. Repeated or chronic ischemic episodes trigger adaptation mechanisms that help cells to better tolerate a subsequent ischemia (preconditioning). Persistent weak blood supply promotes the growth of collateral vessels; the affected region will gain blood from other large vessels as well. On the other hand, degeneration and remodeling processes may lead to the impairment of electrical and mechanical functions. Degeneration of the impulse generating and conducting system may lead to ectopic beats (SVES, VES), sinus bradycardia, sick sinus syndrome, AV blocks, bundle branch and fascicular blocks, and other ventricular conduction abnormalities. Scars and muscle fibers with different conduction velocity can be the base of reentry tachycardias (atrial fibrillation, ventricular tachycardia, ventricular fibrillation). Mechanical dysfunction causes hypokinesia and akinesia, pump function decreases and ventricles dilate leading to secondary valvular insufficiency. Papillary muscle dysfunction may also contribute to that. Severe, acute ischemia resolved in time may cause myocardial stunning. The myocardium avoids necrosis, but its mechanical function gets severely impaired. This state is spontaneously reversible, contractile function is usually restored within days or weeks. In chronic ischemia the mechanical and often also the electrical function of the myocardium become impaired; it becomes hibernated, but remains viable, able to live. Restoration from ischemia (revascularization) may improve its function. 3.2. Cause of ischemia Ischemia is caused by reduced oxygen supply and increased oxygen demand, or most often the combination of these. 3.2.1. Reduced oxygen supply 3.2.1.1. Reduced blood flow in the coronary arteries (1) increased coronary vascular resistance (either in epicardial large vessels or small vessels): • atherosclerotic stenosis of vessels • vasospasm • thrombus formation (temporary or permanent) • embolism • significant augmentation of circulating blood viscosity (e.g. polyglobulia, paraproteinaemias) (2) Significantly reduced cardiac output • arrhythmias - severe/critical bradycardia - mechanically ineffective tachycardia (ventricular tachycardia, ventricular fibrillation) • vitiums - flow limiting mitral stenosis, aortic valve stenosis - significant valve insufficiency causing low effective cardiac output, left-right shunts (3) Deteriorated circulation during diastole - nutritive circulation of left ventricular happens mostly in diastole, in systole wall stretch constricts intramural vessels • low diastolic pressure - bradycardia - hypovolemia - hypotension - aortic valve insufficiency • in case of reduced diastolic time: e.g. tachycardia, significant extrasystolia 53 3.2.1.2. Reduced oxygen content of blood (1) arterial hypoxia: pulmonary edema, pulmonary diseases (2) reduced oxygen-carrying capacity: anemia (3) damaged oxygen delivery: CO-poisoning, alkalosis, methemoglobinemia 3.2.2. Increased oxygen demand: (1) Conditions requiring increased cardiac output (physiological increase in heart rate and blood pressure) • physical activities • fever • hyperthyroidism • anemia • pregnancy • other sympathomimetic effects (e.g. emotional stress, drugs) (2) Increased heart rate ratio of systolic time (working period) increases, diastolic time (resting) decreases: any kind of tachycardia (3) Increased wall tension • hypertension • aortic valve stenosis • myocardial/ventricular dilation (based on the Laplace law) (4) Increased myocardial mass • adaptive hypertrophy (e.g. hypertension) • hypertrophy (HCM) Among the factors limiting oxygen supply the most common is the narrowing of the coronary arteries. The oxygen extraction of myocardium unlike in skeletal muscle is nearly normal in baseline. Increased oxygen supply can be reached by increasing the dilatation of arteries resulting in improved coronary flow. In healthy subjects coronary reserve capacity can be fivefold higher than in cardiovascular patients. Under atherosclerotic narrowing the reserve capacity is decreasing and ischemia can occur as a result of even smaller load or effect of any other insult. The subendocardial myocardium lies the farthest away from epicardial vessels, the blood gets here last with the lowest perfusion pressure, and circulation is squeezed by the contraction of the myocardium for the longest time here. In ischemia the first injured area is typically the subendocardial myocardium. The atherosclerotic plaque can rupture; the core lying below the endothelium is thrombogenic. Extensive platelet aggregation and thrombus formation can occur resulting in total occlusion of the artery and - in the lack of adequate collateral circulation - it can cause severe ischemia of the distal part of myocardium (e.g. acute coronary syndrome). It depends on a local thrombotic-antithrombotic balance whether the thrombus is permanent or dissolves in time. Even if the thrombus dissolves, further progression of plaque formation is likely. The atherosclerotic narrowing is a fixed resistance, which cannot be compensated by vasodilatation of the distal part of the blood vessel. When in the surrounding areas vasodilatation occurs (e.g. an increase in the blood flow by own demand), the blood flow goes toward the smaller resistance, the flow through the narrowed vessel can be deteriorated (steal effect). In most cases the combination of the above facts can lead to ischemia. A few examples: (1) An atherosclerotic stenosis is completely closed by thrombus formation due to plaque rupture, leading to necrosis (STEMI). (2) An atherosclerotic stenosis may lead to angina during physical activity (stable angina pectoris). (3) In case of atherosclerotic stenosis, an additional atrial fibrillation with high ventricular may lead to heart failure within days. (4) In case of severe atherosclerotic coronary artery stenosis, additional atrial fibrillation with high ventricular rate may lead to pulmonary edema and increase in necroenzyme levels. 54 4. Anatomy of coronary arteries The lesion of each coronary artery leads to perfusion disturbances in special areas (Table 1), causing special signs and deviations in ECG and mechanical alterations. Likewise, these kind of alterations could help to find a culprit lesion (responsible for symptoms). Coronary artery system Supplied areas Left main – LM Left anterior descendent - LAD anterior part of the right ventricle • septal branches anterior part of the septum • diagonal branches (D) anterior part of the left ventricle Circumflex artery - Cx left and right atrium • obtuse marginal (OM) lateral part of the left ventricle Right coronary artery - RCA right atrium • acut marginal (AM) sinus node • posterior descending artery (PDA) lateral and posterior part of the right ventricle posterior part of the septum AV node posterior and inferior wall of the left ventricle Table 1. Coronary arteries and their supplied areas In most cases the strong PDA branch comes from RCA (right dominance, 70%). Rarely this branch originates from Cx (left dominance, 10%), or can originate both from RCA and Cx as well (co-dominance, 20%). Usually LM divides into two branches: LAD and Cx (bifurcation), but sometimes another third, intermediate (IM) branch originates as well (trifurcation), supplying the anterolateral part of the left ventricle. In chronic coronary artery narrowing strong collateral network may develop between branches (homocollateral - between branches of the same large vessel, heterocollateral - between branches of different large vessels): (1) RCA-conus artery ─ LAD (2) LAD-septal arteries ─ RCA-PDA (through the septum) (3) LAD ─ RCA-PDA (at the apex) (4) RCA-PDA ─ Cx (at the crux) 5. Clinical manifestation of ischemic heart disease A distinction should be made between unstable and stable coronary heart disease. The course and the severity of these two diseases are different, thus diagnostic procedures and therapy should be different. 5.1. Acute coronary syndromes (ACS) The unstable coronary artery disease or acute coronary syndrome means the acute impairment of coronary flow, the appearance of acute ischemia. Acute circulatory obstruction is usually caused by thrombus or vasospasm over atherosclerotic narrowing. It threats or leads to myocardial necrosis, or can result in acute heart failure, life-threatening arrhythmia, sudden cardiac death. To make a diagnosis and start the appropriate treatment is an emergency task. Acute ischemic coronary syndrome is a work diagnosis based on threatening symptoms, which is classified by necroenzymes and deviation of ECG. 5.1.1 Unstable angina In unstable angina atherosclerotic plaque rupture leads to release of vasoactive and trombogenic agents causing vasospasm and thrombotic occlusion of the vessel. The occlusion dissolves in time, necrosis does not develop, but this may be a threatening sign for an oncoming myocardial infarct in the near future. Unstable angina is suspected: (1) first angina attack of the patient (2) angina in resting position or at minimal exertion (3) angina presenting at always smaller exertion (crescendo angina) 55 (4) in acute/subacute phase of myocardial infarction after initial complaints resolve, angina may appear (so-called postinfarction angina) On the ECG during angina acute ischemic variations can be observed, mostly changes or movement of ST-T phase, (ST depression (rarely elevation) coronary T wave or T wave pseudonormalization). Slight increase in troponin level may appear in lab tests, but increase in CK(MB), GOT or LDH level cannot be detected. 5.1.2. Myocardial infarction - heart attack Myocardial infarction is associated with acute ischemia leading to myocardial necrosis. The laboratory test shows typical enzyme kinetics, first increasing later on decreasing enzyme level. Among the markers examined increase of troponin can be observed first, but in a really early phase it may still be negative as well, therefore in ACS checking troponin within 3 hours is essential. The complaints include resting chest pain, longer than 20-30 minutes, persisting after nitrate therapy, possibly associated with symptoms of acute heart failure (dyspnea, pulmonary edema) and vegetative symptoms: sweating, nausea, vomiting (in inferior myocardial infarction), tachycardia (sympathetic excitement), bradycardia (effect of vagal verve), fear of death. Based on the ECG morphology two different types of myocardial infarctions can be differed: (1) ST segment elevation acute myocardial infarction (STEMI) (2) non-ST elevation ACS (NSTEMI, NSTE-ACS) STEMI is usually caused by total occlusion of a large epicardial artery that - in the absence of early recanalization - leads to the necrosis in the whole wall thickness (transmural). More than 0.1 mV-t ST elevation can be observed in connected ECG leads. New appearance of left bundle branch block is considered as STEMI as well. Diagnosis of STEMI can be established by the clinical symptoms and ECG alone. Do not hesitate to start a therapy, waiting for the troponin level is a mistake. In case of NSTEMI, no ST elevation can be seen on ECG; usually ST depression and T wave alteration may occur, but the ECG readings can be normal as well. On the other hand, the diagnosis requires elevation of necroenzymes. In NSTEMI some blood flow still remains in the affected area, the whole area does not die; primarily the subendocardial region suffers injury. NSTEMI can be caused by: (1) obstruction of a smaller coronary artery (2) partial obstruction of a large epicardial vessels (3) total obstruction of a large epicardial vessels if the affected area is supplied by adequate collateral blood vessels (4) the heart with advanced vessel stenosis is affected by another severe, spontaneously not resolving insult (e.g. clinically significant hemorrhage, anaemia, hyperviscosity, hypoxaemia, shock or extreme tachyarrhythmia) 5.2. Stable coronary artery disease: In stable coronary artery disease temporary, spontaneously reversible angina episodes without necrosis may occur, or slow deterioration in heart work may be observed. The incidences of severe complications are less frequent, so detailed diagnosis and therapy does not justify emergency. The prognosis is relatively good; the yearly mortality is 0.9-1.4%. When symptoms suggesting instability arises, patients should be treated similarly to that in acute coronary syndrome. The incidence of heart attack is 0.5-2.6% annually. The leading symptom is angina pectoris, which means discomfort, squeezing pain or pressure in the chest. In most cases it appears in the retrosternal region and radiates to the left arm, sometimes to the jawbone, to the neck or teeth as well. In severe cases dyspnea, weakness, nausea, restlessness may occur. Commonly it can be provoked by physical exertion, emotional stress, breathing of cold air, heavy meal, or waking up in the morning, but it can be triggered or aggravated by any pathophysiological factor mentioned in the previous section. The threshold of angina varies; it can be different in the same person. Pain is rarely longer than 10-15 minutes and attenuated or relieved by using nitrates or rest. In case of typical angina, the three main attributes of the pain (quality of pain, provocation, relief) is similar to the above mentioned characteristics. This kind of angina is called stable angina pectoris 56 (Heberden angina), based on chronic atherosclerotic narrowing of coronary arteries, where blood flow gets insufficient during workload. Typically the same occurrence, duration, characteristics, localization of complaints and cessation of pain can be anticipated. In case of atypical angina, only two of the three main characteristics can be observed. In microvascular angina pain usually occurs after exertion, but does not show tight correlation with the level of load, may appear later, often develops following exercise. It is often stronger and lasts longer than stable angina, and may remain over 30 minutes. It has a poor response to nitrate. It is caused by increased vascular tone and spasm of the small vessels, there is no significant alteration on large vessels. In vasospastic angina the quality of the pain is typical, but it is usually not provoked by physical exertion, it can appear in resting position as well. It starts with mild pain, pain increases, and stagnates for up to 15 minutes, then decreases. Usually it responses well to nitrate. Ischemia is caused by dynamic narrowing due to vasospasm. Atherosclerotic narrowing is not significant, but vasospasm usually appears near an atherosclerotic plaque, however, sometimes normal vessels can be affected. A special form is Prinzmetal (variant) angina, where a large epicardial artery is affected by spasm, and temporary transmural ischemia and ST elevation may develop. Complaints usually arise at night, or in resting position, physical exertion rarely provokes it, and it often appears at the same time. The duration of complaints can be longer than in stable angina pectoris, and a response to nitrate can vary in patients. It is often accompanied by migraine or Raynaud phenomenon. If none or just one of the mentioned features of chest pain occurs, non-anginal chest pain is considered. It often arises from extracardial cause. A wide spectrum of cardiac, pulmonary, mediastinal, skeletal, and gastrointestinal disorders can cause chest pain. Pain may not be the leading symptom of the ischemic attack in neuropathic, diabetic, elderly patients; it can be moderate or even missing. Rather other symptom of ischemia e.g. dyspnea, weakness can be the main complaint. In patients who are prone to such silent ischemia the above symptoms can be considered angina equivalent. In stable coronary artery disease sometimes the leading symptom is not angina, but consequences of ischemic cardiomyopathy: (1) chronic heart failure may develop after myocardial infarction due to left ventricular dysfunction, postinfarction aneurysm formation or as result of hibernating myocardium; infarction of papillary muscle may also result in mitral insufficiency (2) acute heart failure and pulmonary edema may arise as a result of extensive myocardial ischemia global ischemia, or ischemia of the residual, intact myocardium with decreased left ventricular function - or acute mitral regurgitation due to acute papillary muscle ischemia (3) the result of acute ischemia can be longer due to stunning, and due to „low output failure” it can cause fatigue (4) temporary or permanent arrhythmias may occur during angina (5) the threatening complication, sudden cardiac death may occure due to malignant ventricular arrhythmias (e.g. ventricular tachycardia, ventricular fibrillation), acute bradyarrhytmia (sinus arrest, high grade AV block) or acute heart failure In addition, the following cases are considered stable coronary heart disease as well: (1) patients after myocardial infarction (2) patients became asymptomatic by revascularization or medical therapy (3) asymptomatic patients, in whom proper investigation proved the presence of resting or provokable ischemia or significant coronary stenosis 6. Diagnostic procedures in ischemic heart disease 6.1. Medical history Ask the patient about known coronary disease: did he suffered a heart attack earlier, did he have proper investigation for this reason, maybe percutaneous intervention, CABG. Is the information reliable? There are many patients affixed with the diagnosis of myocardial infarction, without proper diagnostic procedures and adequate therapy. Risk factors of the patients should be highlighted. 57 6.2. Complaints Explore characteristics and frequency of chest pain, provoking and attenuating factors. Is it typical, atypical or non-anginal chest pain? Is there any possibility for instability? Is there any dyspnea, fatigue, any complaints referring to heart failure or angina-equivalent symptoms? Is arrhythmia present (irregular, fast heart beat, pulse measured as fast, slow or irregular)? In non-anginal chest pain specific questions for differential diagnosis need to be asked. Classification of angina severity based on the Canadian Cardiovascular Society (CCS) score: (1) CCS I - ordinary activity does not cause angina, just a rapid or high exertion at work (2) CCS II - slight limitation of ordinary activity; hurry, climbing stairs, climbing more than one floor, exertion after meal can provoke angina (3) CCS III - marked limitation of ordinary physical activity; walking at regular or slow speed, walking along a flat field causes complaints (4) CCS IV - any kind of physical activity causes chest discomfort; angina appear on minimal exertion or even in resting position 6.3. Physical examination There are no typical alterations for SCAD. In acute heart failure pulmonary congestion and gallop rhythm can be observed and during angina with papillary ischemia temporary mitral regurgitation can be diagnosed. We have to watch risk factors and symptoms provoking angina (obesity, high blood pressure, arrhythmias, signs of heart failure, missing peripheral pulses, heart murmur, ankle-brachial index, signs of anemia, nodes in the thyroid gland, fever). 6.4. Lab tests, biochemical tests Biochemical test are usually not suitable for direct diagnosis of ischemic heart disease. Necroenzymes such as troponin T and I, creatinine kinase, GOT, LDH - are used to prove myocardial infarction, to diagnose acute/subacute stadium, to follow up the course, and to recognize a reinfection. They should be checked an acute cases and suspected instability of SCAD. Other lab parameters give information about risk factors, effects and side effects of the therapy, and help to detect any ischemia-provoking factor. Electrolytes (K+, Na+, Mg2+); electrolyte-alterations can be a background in many arrhythmias. In hypokalemia and hypomagnesaemia tachycardia and ectopic impulse generation can appear, in hyperkalemia bradycardia and conduction abnormalities may occur. Many cardiac drugs can influence its level (furosemide and thiazide diuretics decreases the K+ level, while spironolactone and K+ supplementation increase it), for this reason it has to be checked regularly. Renal function (CN, creatinine, GFR); renal failure is a cardiac risk factor. Heart failure can cause deterioration of the renal function. Numerous drugs can aggravate the renal function (spironolactone, ACE inhibitors, ARB, overdosing of diuretics), some drugs are contraindicated is renal failure (spironolactone) or dosage reduction is necessary (LMWH, NOAC). Liver function (GOT, GPT, LDH); these parameters are not specific necroenzymes as well. Higher levels of these enzymes can refer to liver congestion. Many drugs can cause liver injury (statin, amiodarone). Blood count; acute infection, anemia, polyglobulia (hyperviscosity) can trigger ischemia. Carbohydrate metabolism (blood sugar, HbA1c, oral glucose tolerance test); these parameters are used in the diagnosis of diabetes or hypoglycemia and for the evaluation of therapy. Lipids (total-, HDL-, LDL-cholesterol, triglyceride); these parameters are used in the diagnosis of dyslipidemia and for the evaluation of the cholesterol lowering therapy. Thyroid gland function (TSH, T3, T4); hyperthyroidism can cause arrhythmia and hyperkinetic circulation. Hypothyroidism may lead to accelerated atherosclerosis. BNP/NT-proBNP; marker of heart failure, it provides help in differential diagnostics. 6.5. Instrumental examinations The anatomical imaging diagnostic procedures conclude to the degree of narrowing, an expected severity of the disease by visualizing large coronary arteries. With their help the critical narrowing of blood vessels, which can be a target of revascularization procedures, can be detected. 58 Functional examinations can provide information about blood flow, tissue perfusion and electric and mechanical dysfunction of myocardium. In most cases oxygen supply can fulfil resting oxygen demand, ischemia may only occur during exertion. Functional examinations can be carried out during exertion for provoking and detecting ischemia under controlled conditions. During physical examination oxygen demand is increased by physical activity. There are different protocols used for treadmill or bicycle (rarely arm ergometer), which can quantify the patient’s capacity. Physiological alterations during daily life routine can be better demonstrated, the patient’s capacity, and physiological responses to the exertion (blood pressure, pulse) can be assessed. In some patients physical exertion could not be induced due to their limited mobility, difficulty in cooperation or low capacity, or a required work load cannot be achieved. Sometimes intensive physical activity is not possible because of the examination method or circumstances. In these cases pharmacological stress tests can be performed: (1) dobutamine is a positive chronotropic and inotropic drug, increasing the work and oxygen demand of the myocardium (2) dypiridamole and adenosine has a vasodilating potential, they can provoke ischemia by earlier mentioned steal effect Ischemia provoked by stress - although with a low chance (around 0.5-25/10000 examination) - may involve life-threatening arrhythmia and fatal complications as well; therefore it should be carried out under proper surveillance, in emergency preparedness (defibrillation, reanimation). 6.5.1. ECG examinations Myocardial repolarization and depolarization disturbances, injury of the impulse generation and conducting system due to ischemia can be detected with ECG. The following alterations can refer to ischemia, but their appearance is not mandatory, and similar alterations may occur for other reasons. The differentiation at adequate lead can refer to the site of ischemia on 12-leading ECG. Alterations on ECG: (1) ST elevation: transmural ischemia, aneurysm (2) ST depression: subendocardial ischemia (3) coronary T (symmetric, negative T wave): ischemia, previous myocardial infarction, Wellen’s syndrome (deep negative T wave in V2-V3, severe, sign of significant LAD stenosis threatening with obstruction) (4) T wave pseudonormalization: resting coronary T wave turns around (becomes positive) (5) flat T wave (6) hyperacute T wave (wide based, asymmetric, high, peaky T): first sign of STEMI, Prinzmetal angina (7) pathological Q wave: previous or ongoing transmural infarction (8) R reduction, inadequate R wave increment: non-transmural infarction (9) left bundle branch block • in case of new onset of left branch block the infarction is considered STEMI • in left branch block Q wave, ST segment and T wave cannot be assessed, but • the direction of ST segment and T wave is normally opposite of QRS (typically in V1: negative main wave, ST elevation and positive T wave, in V6: positive main wave, ST depression, negative T); if this relationship between QRS and T wave is upset or ST segment and T wave change significantly, ischemia may be present (10) QRS morphology, variation of axis (11) frequent ventricular premature beats, nsVT, ventricular tachycardia, ventricular fibrillation (12) atrial fibrillation (13) sick sinus syndrome, AV blocks 6.5.1.1. Resting ECG All patients with suspected coronary atherosclerosis should have a resting 12-lead ECG recorded. Compare the ECG with an earlier one if available. Resting ECG will establish a baseline for comparison with ECG during complaint or during exercise stress testing and for follow-up of the patient. 59 6.5.1.2. ECG exercise testing Exercise ECG is a most frequently used stress test. During the most commonly used Bruce protocol the patient is walking or running on the treadmill, whose speed and slope increases every 3 minutes. This exercise is limited by the patient’s symptom, not stopped at a predefined level, but in optimal cases continued up to the capability (or compliance) of the patient. The exercise should be interrupted if continuing is dangerous, e. g. patient cannot keep up with a treadmill due to musculoskeletal diseases, claudication or dizziness; severe angina or threatening ECG alterations appear, hemodynamic instability or extreme increase in blood pressure is detected. The maximal load level, blood pressure and heart rate response, arrhythmias and repolarization alterations are assessed. At least 0.1 mV (1 mm) horizontal or downsloping ST depression at 60/80 ms after J point in connected leads is considered significant. The evaluation is assisted by signal averaging software, filtering out movement and respiratory artefacts, but a real time ECG assessment is essential. Mostly in small vessel disease, ECG alterations present during the resting period after exercise. ST depression during exercise ECG (unlike in resting ECG) refers only to the appearance of ischemia and not to its localization. This method is unsuitable for the detection of ischemia in abnormal resting repolarization (LBBB, ventricular pacemaker, WPW syndrome). Its limited value may give a false-positive result in left ventricular hypertrophy, ventricular strain, intraventricular conduction disorder, electrolyte alterations and atrial fibrillation or in digitalis effect. If the patient does not reach 85% of the expected maximal heart rate (in sinus rhythm it is 220 minus the age of the patient), ischemia cannot be ruled out in case of negative result. Antianginal drugs may prevent provoking ischemia, thus if the aim of the examination is prove to SCAD, the examination should be performed without antianginal medications; beta-blockers, calcium channel blockers, nitrates, trimetazidine and digitalis should be suspended. If the aim of the examination is the assessment of the therapeutic efficacy in SCAD patient and follow-up, medication should not be stopped. 6.5.1.3. Holter ECG 24-hour ECG monitoring may detect arrhythmias and ischemic periods during daily routine. It has an importance primarily in the load-unrelated vasospastic and silent ischemia. 6.5.1.4. Transtelephonic ECG Patients can make an ECG during chest pain with this simple ECG instrument, and send it to a call center. Presence or lack of arrhythmia and repolarization alteration at the time of complaints can be identified by this instrument. 6.5.2. Echocardiography Resting two-dimensional echocardiography is recommended for all patients suspected to have coronary artery disease. Segmental wall motion disorder (hypokinesia, akinesia, paradox movement), and reduced ejection fraction may refer to ongoing ischemia or past infarction. The examination may identify other disorders (hypertrophy, valvular disorders) that may contribute to the provoking and worsening of ischemia or may be non-ischemic causes of chest pain and dyspnea. Stress echocardiography can be performed using exercise or pharmacological stress. Exercise stress is preferred due to the aforementioned advantages; however, imaging during movement is technically more difficult. The latter is no issue in pharmacological stress. Pharmacological (preferably dobutamine) stress is recommended in significant resting wall motion disorders. Imaging quality may be improved by the application of echo-contrast agents (microbubble solution). Possible findings in stress echo: (1) new wall motion disorder (decrease in systolic wall thickening) during stress test refers to ischemia (2) contrast agents help not only to better visualize wall motions, but to assess tissue perfusion as well (3) diastolic dysfunction is an early sign of ischemia, new methods like tissue Doppler imaging and strain rate analysis helps its better assessment (4) dobutamine stress testing can be used to assess viability of akinetic regions. Wall segments producing motion by low-dose dobutamine indicate viable myocardium 60 6.5.3. Myocardial perfusion scintigraphy Patients receive an intravenous bolus of isotope that distributes in the myocardium according to the perfusion rate. Distribution is visualized by SPECT; low activity areas represent impaired perfusion. During stress testing, the isotope is injected just before the peak of exercise or pharmacological stress, and this image is compared to a resting one. Permanent perfusion defect that is present on both stress and resting image indicates dead or hibernated myocardium. Transient perfusion defect indicates blood supply sufficient at rest but insufficient during stress. The examination is usually performed using 99mTc-MIBI isotope that supplanted the previously used thallium-201. Longer half-life of thallium results in lower useful activity during imaging, image quality, if worse, radiation burden of the patient and his environment is higher. Another disadvantage is the redistribution of the isotope, as cells in poorly perfused regions start to accumulate it as a K+ analog, making timing of injection and imaging critical. This property, on the other hand, makes it suitable to detect hibernated but living myocardium, preserving thallium for viability examinations. Myocardial perfusion scintigraphy can be performed using positron emitting isotopes and PET imaging as well. Its image quality and diagnostic value is superior to SPECT, but high cost and poor availability makes it rarely used. 6.5.4. Cardiac MR (CMR) The method can visualize walls and cavities and more objectively assess wall motions and left ventricular function. It may be used when transthoracic echocardiography is unable to answer the clinical question (usually because of a restricted acoustic window). Gadolinium contrast agent can identify areas having died due to acute or previous myocardial infarction that cumulate the contrast agent with a delay compared to unaffected tissue (delayed/late enhancement). This is the only method to quantify the extent and transmurality of an infarction and connected to the inspection of wall motion, most accurate assessment of viability. Dobutamine stress CMR to detect newly onset wall motion disorders is an alternative of stress echocardiography in the case of restricted acoustic window. The new perfusion CMR providing information about tissue perfusion is an alternative of SPECT. Coronary MR angiography is theoretically also possible, but because of its worse resolution and long imaging time it is not used. CMR is an evolving, developing method providing multimodal information about ischemia with a single examination, unfortunately the need for expensive instrumental background makes it not widely available. 6.5.5. Chest X-ray Chest X-ray cannot identify ischemic heart disease, but it is useful to detect other causes of chest pain and dyspnea (pulmonary or skeletal origin) during the differential diagnosis. It is recommended in any patient with such complaints. 6.5.6. Coronary CT Modern multidetector row, at least 64-slice CT systems are suitable for non-invasive anatomical imaging of coronary vessels with adequate speed and resolution. Besides, chest CT provides help in the differential diagnosis of chest pain and dyspnea. “Triple rule-out CT” assesses coronary disease, pulmonary embolism and aortic dissection in the background of acute chest pain during a single examination. The amount of Ca2+ in the coronary vessels can be assessed without contrast agents (Agatston score) (based on pixels above 130 Hounsfield unit), that indicates the extent of atherosclerosis but gives no information about the presence of significant stenoses. Coronary CT angiography using contrast agent displays coronary vessel walls and lumen. Magnitude of stenoses can be quantified, significant stenoses can be identified. Imaging is based on data of several heart beats using ECG-gating. The patient should be able to hold his breath and not move during the imaging. Synchronization of images needs low-rate, rhythmical heartbeats; atrial fibrillation, significant extrasystolia, tachycardia greatly worsens image quality (short acting beta-blocker may be used if necessary). Severe obesity is a confounding factor as well. Quantification of stenoses may be inaccurate in significant calcification (Agatston score above 400), stents and graft stenosis after CABG. 61 6.5.7 Hybrid techniques: SPECT/CT, PET/CT, PET/CMR Combination of methods allows the acquisition of both anatomical and functional information during one examination, and the assessment of their relationship (if perfusion is sufficient despite significant stenosis; if there is functional disorder despite non-significant lesion). Additional information from one method may help to correct the artefacts of the other method as well (based on the chest shape displayed by CT, it is possible to correct radiation absorption due to obesity or breasts that would otherwise appear as perfusion defect on SPECT). 6.5.8. Coronary angiography Coronary angiography is an invasive, anatomical imaging method; it is rarely used for diagnosis only. Its purpose is to detect the need and possibility of revascularization, which can be done during the same session. The examination is performed in local anesthesia by the cannulation of the radial (nowadays it is preferred due to the less bleeding complications) or the femoral artery, through which a catheter is led to the coronary arteries, selectively dying them with contrast agent and visualizing them with fluoroscopy. Anatomically significant stenoses can be identified: over 50% of the area in the case of the left main, and over 70% for other branches. Anatomically not significant, but long or multiple stenoses may considerably hinder blood flow, and can be hemodinamically significant. This can be assessed by FFR (fractional flow reserve) measurement comparing pressures proximal and distal to the stenosis. A stenosis with FFR below 0.8 is considered hemodinamically significant. The measurement is gaining recognition; recently only stenosis above 90% is considered obviously significant, for stenoses between 50-90%, measurement of FFR is recommended. 6.6. Strategy of diagnostics in coronary artery disease Examinations aim not only the diagnosis of coronary artery disease, but the assessment of severity, risk stratification of the patient, follow-up of the patient and measurement of therapeutic effectiveness as well. If at any time instability is suspected, diagnostics (complaints, ECG, troponin level) and therapy for acute coronary syndrome should be followed. 6.6.1. Diagnosis The following examinations should be performed in case of suspected coronary artery disease: (1) taking case history, complaints and physical examination (2) blood chemistry to clarify risk factors (3) 12-lead resting ECG for diagnostic purpose and later comparison (4) resting echocardiography (5) chest X-ray for differential diagnosis if chest complaints are present Knowing sex, age and characteristics of complaints, pre-test probability (PTP) of coronary artery disease can be calculated according to population data (Table 2). Presence of risk factors and positive test results increase this probability. Typical angina Atypical angina Non-anginal chest pain Age Male Female Male Female Male Female 30-39 59 28 29 10 18 5 40-49 69 37 38 14 25 8 50-59 77 47 49 20 34 12 60-69 84 58 59 28 44 17 70-79 89 68 69 37 54 24 >80 93 76 78 47 65 32 Table 2. Pre-test probability (PTP) of patients for coronary artery disease according to sex, age and characteristics of chest pain (%) Patients with ejection fraction below 50% and complaints of typical angina are considered high-risk, and invasive diagnostics is indicated without any further non-invasive testing. Further tests may help to prove or reject the diagnosis. Any examinations, however, can provide false positive or negative results that adversely affect the decision making. 62 If pre-test probability is already high, above 85% (typical angina of old male), further non-invasive diagnostic testing is useless: positive result does not add much to decision making, while negative result is more probable to be false than indicating the lack of coronary artery disease (based on Bayes’ theorem). Such patients should be considered to have coronary artery disease and be referred for coronary angiography. Non-invasive testing may still be applied for risk stratification and planning of therapy. In low, below 15% pre-test probability (young female with atypical or non-anginal chest pain), coronary artery disease is unlikely, further testing is unnecessary. Other causes of chest pain should be considered. In the presence of repeated, angina-like complaints, functional coronary artery disease (vasospasm, small vessel disease) may be suspected. If pre-test probability is between 15-85%, further testing should be performed; the choice of method depends on the local practice, human and instrumental resources and patient features. Keep the mentioned limitations of tests in mind. Exercise stress testing for disabled patients, ECG based tests in the presence of left bundle branch block, stress echocardiography for patients with restricted acoustic window, coronary CT in atrial fibrillation, CMR or scintigraphy in claustrophobia are poor choices. Exercise ECG is usually easily available and performable. It is the preferred method for patients with PTP of 15-65% if they are able to do the exercise. It has a good specificity but weaker sensitivity, thus in patients with PTP of 65-85% the number of false negative results increase. In this case the test is recommended for diagnosis only if other methods are not available or applicable. Stress echocardiography, stress myocardial perfusion scintigraphy, rarely stress CMR are possible alternatives if exercise ECG is not possible or not recommended. Coronary CT angiography has an excellent negative predictive value. It may be a first choice to rule out coronary artery disease in patients with low to moderate risk (15-50% PTP). On the other hand, since Agatston score above 400 or considerable focal calcification may result in inaccurate assessment of stenoses, the method is not recommended in higher PTP; coronary angiography should be chosen for anatomical imaging. A positive test result proves coronary artery disease. If the result is uncertain, equivocal or uninterpretable, a second non-invasive test (stress testing or coronary CT angiography) or if necessary (e.g. the patient is unsuitable for other tests) direct coronary angiography should be performed. 6.6.2. Risk stratification The tests mentioned help not only to make the diagnosis, but to assess the risk of the patient as well, which is needed for therapy planning. During exercise ECG, poor workload capacity, onset of angina or ST depression indicate higher risk. These are summed up in the Duke treadmill score: Duke treadmill score = T – 5 x STmax – 4 x angina index T: duration of exercise in minutes STmax: maximal ST deviation in mm Angina index: 0: no angina 1: angina that did not force termination of exercise 2: exercise limiting angina ≥+5: low risk -10 – +4: moderate risk ≤-11: high risk Stress imaging refers to high risk, if the area of ischemia exceeds 10% of the myocardium (10% for scintigraphy, 3 segments with induced wall motion disorder for stress echocardiography or stress CMR). Risk is low, if no ischemia is detected. High risk is considered with anatomical imaging in significant left main or proximal LAD stenosis or proximal three vessel disease. Other significant stenoses indicate moderate risk. Annual mortality is below 1% in low risk, 1-3% in moderate and above 3% in high risk cases. Beyond the aforementioned estimation, consider the presence of other risk factors and symptoms, like hypertension, diabetes, smoking, dyslipidemia, chronic kidney disease, peripheral arterial disease, stroke, previous myocardial infarction, symptoms of heart failure and especially intensity, frequency and refractoriness of angina. Accordingly, more aggressive diagnostic strategy may be chosen (e.g. coronary angiography is indicated primarily for a patient with typical angina and ejection fraction below 50%). 63 7. Treatment of SCAD In the past decades medical and instrumental therapy has made huge progress, thereby cardiovascular death and frequency of myocardial infarction could be reduced significantly, symptoms, quality of life and life expectancy have been improved. On the other hand it is important to remember that coronary sclerosis is a progressive disease, progression primarily may be slowed down by the elimination of risk factors. The treatment of modifiable risk factors is really important both in primary and secundary prevention. 7.1. Lifestyle changes The effective treatment of the disease require a long-term change in patient attitude in relation to smoking, nutrition, exercise, medication habits and also the adequate compliance with a patient. Education related to the disease, complications, therapy, life style, medical information, stress management and information about psychosocial risk factors is considered, which can be achieved by involving healthcare professionals (nurses, psychologists, dietetics). Cardiac rehabilitation involves control of risk factors, optimization of medication, moreover patient’s exercise capacity is assessed under well-controlled conditions and its improvement is aimed based on a training plan. Cardiac rehabilitation is offered not only for patients after myocardial infarction or recent coronary intervention, but should be considered in all patients suffering from chronic angina. Smoking is maybe the most aggressive, but the most easily eliminateable risk factor, complete and final smoking cessation is essential. All smoking patients should be advised to quit and offered cessation assistance, even advice on pharmacological help (bupropion, vareniclin) to stop smoking. Nicotine replacement therapy can be useful and safe. Passive smoking should be avoided as well. Healthy diet helps to reduce body weight, to optimize the lipid profile and carbohydrate balance and to reduce blood pressure. Energy intake should be limited to the amount of energy needed. Saturated fatty acids should make up no more than 10% of energy intake, use poly-unsaturated fatty acids. A good source is to consume fish at least twice a week. Trans unsaturated fatty acids should be consumed as little as possible, below 1%. Salt consumption per day should not exceed 5 g. 30-45 g of fiber consumption per day is recommended from wholegrain products, fruits and vegetables. Consume 200-200 g vegetables and fruits 2-3 times per day. To follow a Mediterranean diet, using extra virgin olive oil and consumption of oily seeds is beneficial. Moderate alcohol consumption, primarily wine intake is beneficial, but should be not more than 20 g/day (2 glasses) in males, and 10 g/day (1 glass) in females. Regular physical activity helps to lose weight, improves dyslipidemia, assists glucose uptake independently to insulin, reduces blood pressure and increases capacity. Moderate intensity aerobic exercise training at least 3 times a week and for 30 min per session is recommended. Patients with sedentary lifestyle should start light-intensity exercise programs. In patients having suffered from myocardial infarction, underwent PCI or CABG, or suffering from stable angina or chronic heart failure, safe workload level can be assessed using controlled level loading like exercise ECG. Sexual activity refers to 6 MET physical exertion, but increase in blood pressure and pulse can be higher. Sexual activity may provoke angina, use of nitroglycerin before sexual activity can decrease or prevent it in SCAD patients. It may be necessary to assess safe physical workload capacity in heart failure, angina pectoris. In vascular disease erectile dysfunction often occurs, in these cases PDE5-inhibitor potency increasing drugs (sildenafil, tadalafil, vardenafil) are usually applicable. Their application is not advised in hypotensive patients, in NYHA III-IV stadium, after recent cardiovascular event and in refractory angina. Their application is absolutely contraindicated when using nitrate, because a synergist effect can cause severe hypotension. Patients taking PDE5-inhibitor in angina cannot receive nitrate until the drug is completely eliminated (24-48 hours). Achieving the optimal body weight positively influences the blood pressure, dyslipidemia and glucose metabolism. Weight reduction in overweight and obese people is recommended. The goal usually is to reach and keep 20-25 kg/m2 BMI range, waist circumference in ladies below 80 cm, in males below 94 cm. Lipid control is another important issue. In high risk patients to LDL-cholesterol level should be kept below 1.8 mmol/l target value or if or possible, it should be reduced by 50% at least. Significant hypertriglyceridemia has to be treated. If it cannot be achieved by statin monotherapy alone, other complementary therapy (ezetimibe, fibrate, nicotine-acid, PCSK-9 inhibitor) can be used. For patients before PCI high doses of statin is recommended. 64 Blood pressure control: Usually the aim is below 140 mmHg systolic value and below 90 mmHg diastolic value, in diabetic population below 140/85 mmHg value is recommended. Primarily, as detailed later, drugs that prevent death and relieve angina symptoms are recommended (ACE inhibitor/ARB, betablocker, Ca channel blocker). Control of diabetes mellitus and carbohydrate balance: The optimal glycemic control is essential. The aim is to keep HbA1C under 7% (6.5-6.9%). ACE inhibitor and beta-blocker should be given for renal protection if tolerated. Psychosocial factors: In cases of clinically significant symptoms of depression, symptoms or anxiety and hostile behavior a psychologist or psychiatrist can be involved, and appropriate psychotherapy or medication should be considered. Influenza vaccination is recommended annually for patients with SCAD, especially in elderly. Hormone replacement therapy: based on epidemiological data we assumed the protective effect of estrogen, but large randomized multicenter trials showed that in ladies over 60 years the hormone replacement therapy did not improve, but deteriorated mortality. Preventive hormone replacement therapy is contraindicated. 7.2. Pharmacological therapy Pharmacological therapy of stable coronary artery disease has dual goal: on one hand to improve prognosis by preventing myocardial infarction and cardiac death, on the other hand to improve the quality of life by reducing the frequency and severity of complaints. 7.2.1. Antianginal medications Antianginal, antiischemic medicines reduce the myocardial oxygen demand or improve its perfusion. Nitrates are the longest used effective medication. As a NO donor, they dilate coronary vessels, relieve vasospasm and improve perfusion. They reduce preload and afterload and reduce the myocardial oxygen demand. Short-acting sublingual nitrates are used for rapid ease of effort or vasospastic angina and for the prevention of anticipated angina (e.g. before sexual activity). Most commonly nitroglycerine (0.3-0.6 mg/dose every 5 minutes, max. 1.2 mg) and isosorbid-dinitrate (5 mg) are applied. Long-acting nitrates are aimed to prevent angina attacks. Prolonged, continuous application leads to tolerance, thus a daily at least 10-12 hour-long intermission is recommended. Isosorbid-mononitrate, isosorbid-dinitrate, and transdermal nitroglycerin belong to this group. The most common side effects are hypotension and headache. Application with PDE5 inhibitor potency boosters is prohibited. Administration of short-acting nitrates should be careful in the case of severe aortic stenosis or hypertrophic obstructive cardiomyopathy limiting cardiac output since they may lead to a drop in cerebral blood flow and collapse due to whole body steal effect. Beta-blockers’ negative ino- and chronotropic effect decrease myocardial oxygen demand, and the longer diastolic filling time improves oxygen supply as well. They not only reduce angina, but improve mortality owing to their antiarrhythmic effect as well. For post-infarction and heart failure patients without contraindication their use is compulsory, they should be used in first line, but they can be recommended for any patients with stable coronary artery disease. Most frequently used representatives are metoprolol, bisoprolol, nebivolol and carvedilol. Lower doses should be administered first, then it should be up-titrated to the tolerated level. Target heart rate in stable coronary artery disease is around 60/min. Side effects: beta-blockers may increase vascular tone and worsen the symptoms in vasospastic angina and severe limb ischemia, in such cases nebivolol that has direct vasodilator effect may also be applied. Bronchospasm in COPD and asthma may be increased, which can be avoided using more selective agents (e.g. nebivolol). Beta-blockers may lead to bradycardia or AV block, co-administration with other heart ratelowering drugs should be done carefully. Cold limbs, fatigue, depression and erectile dysfunction may rarely occur. Calcium channel blockers (CCB) dilate coronary arteries, open collaterals and improve the blood flow in ischemic areas. They reduce the blood pressure, the afterload, and thus the myocardial oxygen demand. Ankle edema is a common side effect that can be reduced with ACE inhibitors. 65 Dihydropyridine type calcium channel blockers (nifedipine, amlodipine, lercanidipine, felodipine, lacidipine) affect the vascular smooth muscle, and have little effect on the myocardium. Non-dihydropyridine type calcium channel blockers (verapamil, diltiazem) affect the vascular smooth muscle and the myocardial calcium channels as well; they have both antihypertensive and antiarrhythmic effect. They may cause bradycardia and AV block, co-administration with beta-blockers is contraindicated. They should not be used in the presence of reduced ejection fraction because of their negative inotropic effect. Ivabradine, a selective If-channel inhibitor, reduces the activation rate of the sinus node, lowers the heart rate thus prolongs diastole. It has no other significant effect or side effect, does not influence blood pressure or contractility. It is indicated if the resting heart rate is above 70/min despite of beta-blocker treatment (or in case of beta-blocker contraindication), and only in sinus rhythm. Trimetazidine affects metabolism. Oxidation of fatty acids is inhibited, metabolism is shifted toward glucose oxidation that provides the same energy using less oxygen, being more favourable during ischemia. Ranolazine is a selective inhibitor of the late sodium channel, leading to the reduction in intracellular Ca level, muscle contraction and wall tension. It prolongs QT, thus it should be carefully used in the presence of long QT or with other QT prolonging agents. Nicorandil stimulates ATP sensitive potassium channel and dilates the coronary arteries. Plaque stabilizing effect is supposed as well. Molsidomine is a direct NO donor, vasodilator. Nitrate-like tolerance is less common. 7.2.2. Medication for event prevention Life expectancy can be improved by preventing acute thrombotic events and preserving left ventricular function. Antiplatelet agents prevent vessel occluding thrombus formation on ruptured plaques. They are used for the prevention of myocardial infarction, atherothrombotic TIA and stroke and peripheral arterial occlusions as well. Increased bleeding risk should be expected as a side effect (gastrointestinal, intracranial and skin hemorrhages). Effectiveness of antiplatelet agents can be tested in vitro, in many patients inadequate platelet aggregation inhibition may be found (non-responders). Such methods may help drug selection in special cases, routine application, however, it does not improve the prevention of thrombotic events, and thus is not recommended. Acetylsalycilic acid, aspirin irreversibly inhibits cyclooxygenase (COX)-1, prevents the synthesis of thromboxane A2 and platelet activation. Much lower doses are enough for the cardioprotective effect than for pain relief (75-150 mg daily), higher doses usually only increase side effects. Thienopyridines: (1) clopidogrel hinders the amplification of platelet aggregation by irreversible inhibition of ADP P2Y12 receptor. Long-term administration of clopidogrel is slightly more effective compared to aspirin, but cost effectiveness and safety reasons make it only a second line choice in this indication, in cases of aspirin intolerance or non-response. (2) prasugrel, a new generation thienopyridine, has more reliable pharmacokinetics than its precursor. (3) ticagrelor is a novel reversible ADP receptor inhibitor. Both proved to be more effective in treatment and secondary prevention of STEMI compared to clopidogrel; at the cost of increased bleeding complications. They are indicated in selected cases of STEMI. Beta-blockers are not only antianginal agents, but reduce mortality as well. See detailed description in the previous section. Statins (fluvastatin, simvastatin, atorvastatin, rosuvastatin) have pleiotropic effects: they reduce cholesterol level, slow the progression and stabilize atherosclerotic plaques, have antioxidant and antiinflammatoric effect. Their administration is recommended even in normal cholesterol level. Side effects involve myopathy, rarely rhabdomyolysis and liver failure (especially in hypothyroidism, alcoholism, and taking of antimycotics), thus periodic check of liver function of CK is recommended. Inhibition of the renin-angiotensin-aldosterone system with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB); these medications have several beneficial effects in addition to blood pressure and afterload reduction (they inhibit myocardial and vascular remodeling, have 66 antiproliferative/antiatherogenic effect, stabilize coronary plaques, improve endothelial function, increase fibrinolysis). They are recommended in the first line in coronary artery disease, especially in cases of hypertension, diabetes, renal failure or heart failure with reduced ejection fraction. ACE inhibitors (e.g. perindopril, ramipril, enalapril, fosinopril, quinapril) are preferred; in cases of intolerance (pl. dry cough) ARBs can be a substitute (e.g. losartan, valsartan, telmisartan, irbesartan). Combination with CCBs further improves prognosis, combination of ACE inhibitors with ARBs on the other hand has no further benefits but increase the risk of renal failure and thus is usually contraindicated. The use of mineralocorticoid receptor antagonists (spironolactone, eplerenone) is recommended in post-infarction patients with reduced ejection fraction beside ACE inhibitor and beta-blocker treatment, in the presence of symptoms of heart failure or diabetes. 7.2.3. Strategy of medical treatment in stable coronary artery disease First of all, lifestyle modification and control of risk factors should be done. 7.2.3.1. Prevention of cardiovascular events (1) antiplatelet agents: aspirin, or clopidogrel in aspirin intolerance (2) statin: reduce LDL-cholesterol level below 1.8 mmol/l, or at least by 50% if target level cannot be reached (3) ACE inhibitors: in patients with hypertension, diabetes, renal failure, previous myocardial infarction, ejection fraction below 40% or heart failure (majority of coronary artery disease patients) 7.2.3.2. Reducing angina symptoms: (1) short-acting nitrates to use on demand (2) first line: • beta-blocker or heart rate-lowering CCB (if one is ineffective, it may be switched to the other) • beta-blocker and dihydropyridine type CCB together (3) second line: • ivabradine • long-acting nitrates • trimetazidine • (nicorandil, ranolazine: not marketed in Hungary) 7.2.3.3. Special cases: (1) for 1 year after acute coronary syndrome, and for 3-12 months following PCI and stent implantation dual antiplatelet therapy is necessary beside the standard therapy: aspirin and clopidogrel should be used together (in selected cases prasugrel or ticagrelor may be used instead of clopidogrel) (2) microvascular angina: • control of risk factors • short-acting nitrates to use on demand (usually only partially effective) • first line beta-blockers, supplemented by CCBs and long-acting nitrates if necessary • first line CCBs, if threshold of angina is variant • ACE inhibitors/ARBs • alpha-blockers are sometimes effective • statins • xanthine derivates (aminophylline) may reduce angina pain by adenosine receptor blockade (3) vasospastic angina: • Holter ECG (and transtelephonic ECG) may help diagnosis • control of risk factors (especially smoking cessation and avoiding vasospastic drugs) • aspirin • short-acting nitrates to use on demand • first line CCBs • long-acting nitrates • beta-blockers should be avoided (may increase spasm), if necessary, nebivolol is preferred 67 (4) in therapy refractory cases: • high dose CCB and nitrate • antiadrenergic agents (guanethidine, clonidine) • stent implantation at the location of the spasm • pharmacological or surgical sympathectomy 7.3. Myocardial revascularization Revascularization aims to improve myocardial blood supply by elimination, dilation or bypassing stenoses and obstructions. They are invasive, potentially dangerous interventions, which if used properly, are able to improve patients’ life quality and life expectancy. In stable coronary artery disease, invasive treatments do not always have benefit over optimal medical therapy. Furthermore, complications may bring the patient in worse condition than before. Revascularisation should only be chosen in well-founded cases and only after the start of optimal medical therapy. The first step to invasive treatment is invasive diagnostics, coronary angiography which identifies the significant vessel stenoses. In many cases, it is possible to solve such stenoses during the same session via the same arterial access. Coronary angiography is recommended in the following cases: (1) ejection fraction below 50% and typical angina complaints (2) high pretest probability and severe symptoms (3) high risk patient according to non-invasive testing (annual cardiovascular mortality >3%) (4) for medium risk patients (1-3% annual cardiovascular mortality) coronary angiography or optimal medical therapy alone may be chosen according to individual assessment, for low risk patients (annual cardiovascular mortality below 1%) medical therapy should be preferred (5) if complaints indicate angina that is not improved by the introduction and intensification of medical therapy (refractory angina) coronary angiography may be performed Only viable myocardium has reason to be revascularized. In doubtful cases (state after STEMI, akinetic segments) viability testing should be performed. The larger the ischemic area, the more benefit can be expected from revascularization. In cases of small endangered myocardium, the risk of complications exceeds the potential benefit, optimal medical therapy should be continued instead of revascularization. Based on the result of coronary angiography revascularization is recommended in the following cases: (1) significant stenosis of the LM (2) significant stenosis of the proximal LAD (3) area of ischemia is over 10% of the left ventricle (4) significant stenosis of 2 or 3 vessels with reduced left ventricular function (EF <40%) (5) significant stenosis of any vessel in cases of limiting angina refractory to medical therapy Stenosis is considered significant, if the area is reduced by over 90% or by 50-90% if FFR <0.8 (previous definition considered 50% stenosis of the LM or 70% stenosis of other vessels). Non-significant stenoses should not be revascularized, as it yields no benefit, while it has the same risk for complications. Patients who are not candidate for invasive procedures: (1) do not treat invasively patients, whose life expectancy (e.g. patient with end stage tumor) or quality of life (old, bedridden patient with poor cognitive functions) can not be improved (2) consent or rejection to the invasive procedure after getting informed should be the patient’s decision, just as what level of invasiveness (PCI or CABG) is accepted, the decision can be changed later to either direction (e.g. a patient refusing an elective intervention may accept it in case of an acute infarction) (3) patients, who are not candidate for revascularization, coronary angiography should be avoided, even in the presence of acute coronary syndrome Complications of invasive coronary angiography: (1) bleeding form the arterial access (especially using antiplatelet drugs), hematoma, dissection and pseudoaneurysm formation are possible; compression bandage is applied for several hours after the intervention to prevent these (2) aortic dissection (3) contrast-induced nephropathy, acute renal failure, and metformin associated lactic acidosis (4) allergy to contrast agent 68 7.3.1. Percutaneous coronary intervention (PCI), percutaneous transluminal coronary angioplasty (PTCA) During POBA (plain old balloon angioplasty) a deflated balloon is positioned into the stenosis using a guide wire and fluoroscopy, and then it is inflated with high pressure (4-20 atmospheres), pressing the plaque into the vessel wall and dilating the lumen. Complications: (1) coronary vessel rupture (2) vessel dissection and subsequent occlusion is possible (3) the vessel is occluded during inflation, which may cause angina and troponin elevation, in severe cases myocardial infarction, acute heart failure, life threatening arrhythmias may take place (4) plaque rupture creates thrombogenic surface and may lead to postprocedural infarction; dual antiplatelet therapy is important after the intervention (5) the dilated section may narrow back due to the elastic elements of the vessel After balloon predilation or in one step with the dilation (direct stenting) a mesh tube, stent, can be placed. The basic version is a bare metal stent (BMS). The stent supports the vessel wall and prevents elastic recoil. It can stabilize intimal flap in cases of dissection. Complications: (1) stent thrombosis: the stent is a thrombogenic surface; complete occlusion, infarction may occur. (2) in-stent restenosis: stent may irritate the vessel wall maintaining chronic inflammation, thus the endothelium slowly grows into the stent reducing the risk of thrombosis but narrowing the lumen. (3) stent malposition: when placing a stent in a kinking section, calcified plaque or bifurcation, or using not ideal sized balloon or stent, the stent may not fully lean against the vessel wall. The gap increases the risk of thrombosis. Side vessel may be occluded. Young patient may “grow out” the stent. Drug eluting stent (DES) emits cytostatic agents into the vessel wall hindering the endothelial growth. It reduces the risk of restenosis, but the thrombogenic surface remains open longer as well, with a longer chance for stent thrombosis. Application of drug eluting balloon (DEB) leaves no stent behind, but the vessel wall is impregnated with cytostatic agent during the balloon dilation, which prevents reendothelization during the critical period of time. There is no risk of stent thrombosis and stent malposition. Second generation biodegradable, resorbable stents work like DES at the time of implantation, giving adequate support to the vessel wall. Later struts break up making physiological vasoconstriction and dilation possible, then during the years it is completely absorbed eliminating the risk of stent thrombosis and malposition, and in case of restenosis a stent does not hinder a subsequent intervention either. In cases of chronic total occlusion (CTO), regular dilation is not possible as guide wire cannot be led through the occlusion. Using special techniques - special guide wire, rotablator, laser - the occlusion can be pierced and dilated, but success rate is worse than with regular stenoses. After PCI, thrombogenic surface of the damaged endothelium and the implanted stents requires dual antiplatelet therapy: (1) for 12 months after acute coronary syndrome with or without PCI (2) for at least 1 month after elective PCI and BMS implantation (3) for at least 6 month after elective PCI and DES implantation (4) possibly longer if high thrombotic and low bleeding risk is present (5) in high bleeding risk or before urgent but not acute operation for 3 months after DES implantation After that clopidogrel may be withdrawn but aspirin should be continued lifelong. Premature discontinuation of dual antiplatelet therapy greatly increases the risk of stent thrombosis (highest in the first weeks after intervention, and attenuated later on). Stent thrombosis causes myocardial infarction (usually STEMI) with high mortality, and brings the patient in worse condition than before the intervention. 7.3.2. Coronary artery bypass grafting During coronary artery bypass grafting (CABG) or aorto-coronary bypass grafting (ACBG) well perfused grafts are attached distal to the stenoses. Venous graft, usually v. saphena magna (VSG or SVG) attached to the ascending aorta may be used. The other solution is arterial grafts, left or right internal mammary artery (LIMA, RIMA) with their natural origin, or radial artery graft attached to the aorta. Grafts may get stenosed or occluded after some time, the patency of arterial grafts are better - “more important vessels” should receive the arterial grafts. PCI of stenosed grafts is possible. 69 CABG is considered high risk operation with many possible serious complications. It involves the opening of the chest and it means a great stress for the patient. Classical method involves establishing a cardiopulmonary bypass (extracorporal circulation) after which the heart is stopped, and restarted after the operation (on-pump surgery). The newer technique, off-pump surgery is performed on beating heart, with the stabilization of the operated part, without using the heart-lung machine. With adequate skill, it has fewer complications than on-pump surgery. 7.3.3. Choosing the method of revascularization PCI is an easier, quicker, cheaper method of revascularization that means much smaller stress and risk for the patient with fewer complications. It advanced to the foreground and with the development of the technique more and more lesions can be treated transcatheterly. Some situations, however, still cannot be solved this way, have very high risk for PCI, or have a worse outcome with PCI than with CABG; in these cases the latter is still preferred, if the patient is otherwise suitable for the operation. When choosing between PCI and CABG we should assess local practice, instruments and expertise, the patient’s eligibility for operation, the clinical setup (acute/urgent/elective) as well, and sometimes consultation is required between the non-invasive cardiologist, interventional cardiologist, heart surgeon and other partner disciplines (e.g. anesthetist) (heart team). PCI is contraindicated, if balloon inflation or possible periprocedural complication may cause life threatening global ischemia (e.g. LM PCI accompanied by significant RCA stenosis). LM and proximal LAD lesions mean higher risk. Risk for patients with severely reduced ejection fraction is greater as well. CABG is preferred in complex anatomical situations, which is technically difficult to solve with PCI, require many stents and has many possibilities for complication. SYNTAX score sums up the situation, weighing the location of stenoses (LM and proximal LAD is more important than a secondary branch of Cx) and other complicating factors (area of stenosis, presence of CTO, stenosis at bifurcation, long stenosis, kinking stenosis, calcified stenosis). In non-complicated cases (low SYNTAX score) LM or three vessel diseases might be treated with PCI. In cases of multivessel disease in diabetic patients CABG might be more beneficial. If a patient is candidate but unsuitable for CABG, PCI and if possible, at least partial (palliative) revascularization should be considered. 70 8. Quiz Choose at least one correct answer for each question. It is also possible that there is more than one right answer for one question. 1. Which of the following is a changeable risk factor of coronary artery disease? A: age B: genetics C: hypertension D: smoking 2. Which appears the earliest in case of ischemia? A: ST segment depression B: myocardial necrosis C: diastolic dysfunction D: systolic dysfunction 3. Which limits oxygen supply? A: fever B: coronary stenosis C: anemia D: critical bradycardia 4. Which myocardial area is most exposed to the risk of ischemia? A: subendocardial region B: epicardial region C: the whole wall D: apex of the heart 5. Which mechanism plays an important role in stable coronary artery disease? A: plaque B: thrombus C: vasospasm D: embolization 6. Which is NOT true for stable coronary artery disease? A: it is usually caused by the atherosclerotic stenosis of coronary vessels B: thrombus formation on a ruptured plaque plays an important role C: angina is a common symptom D: risk of severe complication is high, thus emergency treatment is required 7. Chronic ischemia may lead to: A: AV block B: reduction of pump function C: hypertrophy of myocardium D: dilation of left ventricle 8. Which coronary branch supplies the anterior wall of the left ventricle? A: RCA B: LAD C: Cx D: PDA 71 9. Which belongs to stable coronary artery disease? A: effort angina B: crescendo angina C: acute myocardial infarction D: microvascular angina 10. The patient regularly experiences squeezing chest pain after going up one floor that ceases after resting. Which condition is suspected? A: vasospastic angina B: typical angina pectoris C: crescendo angina D: microvascular angina 11. Characteristics of stable angina pectoris: A: always appears for the same physical exercise B: weather changes, front may provoke it C: emotional stress may aggravate it D: may be provoked by hypertensive crisis 12. Characteristic of Prinzmetal angina: A: calcium channel blockers relieve the acute attack B: it is often accompanied by migraine or Raynaud phenomenon C: it is caused by vasospasm D: ST elevation is not present during the attack 13. Characteristic of unstable angina: A: first occurance of angina pectoris should be considered unstable, and also when angina occurs at rest or at minimal exertion B: during chest pain ST depression can be detected on ECG but sometimes ST elevation may also occur C: often symmetrical negative T wave develops, or pseudonormalization of T wave can be observed in postischemic condition D: the value of CK-MB, Troponin-T and I is always increased, but it is not as high as in the case of myocardial infarction 14. According to the classification of the Canadian Cardiovascular Society (CCS), which class does angina that occurs at low intensity workload and considerably limits everyday activity belong to? A: CCS I B: CCS II C: CCS III D: CCS IV 15. In case of suspected coronary artery disease, which tests should be performed by all means? A: exercise ECG B: 12-lead resting ECG C: echocardiography D: taking case history, complaints and physical examination 16. Which of the following is an anatomical imaging method? A: exercise ECG B: coronary angiography C: coronary CT angiography D: echocardiography 72 17. Which statement is incorrect? A: in case of normal resting ECG, ischemia can be excluded B: transthoracic echocardiography can reveal left ventricular function, segmental wall motion disorders and diastolic dysfunction as well C: exercise ECG is of diagnostic value in case of horizontal or downsloping ST depression ≥0.1 mV at 60 or 80 ms after J-point in one or more than one leads D: diagnostic value of ST segment alteration in recovery is poor 18. Which test is recommended next for a patient with atrial fibrillation and left bundle branch block who walks hard because of knee arthrosis? A: coronary CT angiography B: exercise ECG C: stress myocardial perfusion scintigraphy D: coronary angiography 19. At which pre-test probability is stress ECG recommended? A: <15% B: 15-65% C: 65-85% D: >85% 20. How can resting echocardiography help the diagnostics of coronary artery disease? A: ejection fraction helps to assess the risk of patient B: by visualizing the stenosis of coronary vessels C: detecting the segments with wall motion disorder may help to identify the culprit lesion D: to assess the viability of akinetic wall segments 21. Which medication is recommended to be temporarily stopped before exercise ECG if the test is aimed to establish the diagnosis of coronary artery disease? A: beta blocker B: trimetazidine C: ACE inhibitor D: Ca2+ channel blocker 22. Which method is suitable to assess myocardial viability? A: stress myocardial perfusion SPECT using 99mTc-MIBI isotope B: gadolinium contrast cardiac MR C: dobutamine stress echocardiography D: coronary angiography 23. What is the next recommended examination for a patient with typical angina and reduced ejection fraction? A: exercise ECG B: coronary angiography C: stress myocardial perfusion scintigraphy D: coronary CT angiography 24. For which patient is coronary angiography recommended? A: young female with stabbing chest pain at rest lasting for seconds B: middle aged male with hypertension, diabetes, without left ventricle wall motion disorder on resting echocardiography but with extensive transient perfusion defect of the anterior wall on scintigraphy C: cachectic patient with metastasizing colon tumor and NSTEMI D: 65-year-old patient with typical angina and ejection fraction of 40% 73 25. The correct answer: A: complete physical inactivity is recommended for patients with previous myocardial infarction, PCI or CABG B: decrease in the daily salt consumption (<5 gr) is advised for patients with coronary artery disease C: the BMI goal is 20-25 kg/m2, where total mortality is the lowest D: hormone replacement therapy (oestrogen) is recommended in women over 60 years for primary or secondary prevention of coronary artery disease 26. The goal for serum LDL cholesterol in high risk cardiovascular patients: A: less than 3.5 mmol/l B: less than 2.5 mmol/l C: less than 1.8 mmol/l D: 3 mmol/l is acceptable in case of low dose statin therapy 27. Recommended blood pressure in coronary artery disease: A: systolic value 140 mmHg, diastolic value 90 mmHg B: systolic value 150 mmHg, diastolic value 90 mmHg C: in diabetic population below 140/85 mmHg D: in diabetic population below 135/80 mmHg 28. Which drugs have both antianginal effect and improve survival? A: statins B: beta blockers C: nitrates D: Ca channel blockers 29. Which drugs are recommended in first line treatment of stable angina? A: aspirin B: trimetazidine C: statins D: short acting nitrates used on demand 30. Which statement is correct? A: target heart rate in stable coronary artery disease is around 55-60 beats per minute B: target heart rate in stable coronary artery disease is around 65-75 beats per minute C: ivabradine can be used in stable coronary artery disease, if patient has sinus rhythm and target heart rate cannot be reached with beta blocker D: ivabradine can be used in stable coronary artery disease, if patient has atrial fibrillation and target heart rate cannot be reached with beta blocker 31. Which medication is recommended for angina of mainly vasospastic origin? A: metoprolol (beta blocker) B: amlodipine (Ca channel blocker) C: rosuvastatin (statin) D: nitroglycerin spray (short acting nitrate) 32. Which statement is correct? A: single antiplatelet therapy is sufficient after BMS stent implantation B: lifelong dual antiplatelet therapy is required after DES stent implantation C: dual antiplatelet therapy is necessary for 12 months after acute coronary syndrome, even if no stent was implanted D: no antiplatelet therapy is needed 2 years after stent implantation 74 33. Which statement is correct? A: routine measurement of platelet aggregation is essential to assess the effectiveness of antiplatelet therapy B: dual altiplatelet therapy (aspirin+clopidogrel) is required after stent implantation C: riclopidine is not recommended in cease of neutropenia or thrombocytopenia D: aspirin reversibly inhibits thromboxane A2 synthesis 34. Which revascularization method may lead to stent thrombosis? A: POBA B: BMS C: DES D: CABG 35. In which case is CABG the preferred method of revascularization? 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