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Diastolic Dysfunction and Anaesthetic Implications Dr S Kumar MD PhD Sr Consultanat & Head, Cardiac Anesthesiology, Meenakshi Mission Hospital and Research Centre, Madurai. Epidemiological and clinical studies have confirmed the trend of increasing incidence of chronic HF internationally [1]. HF remains largely a disease of the elderly and in patients older than 65 years it is the most common diagnosis at hospital discharge and the most frequent cause of readmission [2]. Diastolic dysfunction refers to abnormalities in left ventricular distensibility, filling or relaxation regardless of signs and symptoms of HF or left ventricular ejection fraction . Diastolic dysfunction in the absence of symptoms is common in elderly hypertensive patients. Heart failure with a preserved ejection fraction (HFpreEF), or diastolic HF, refers to the clinical syndrome of HF coupled with evidence of diastolic dysfunction and is estimated to occur in approximately 50% of patients with chronic HF [3]. In patients older than 70 years, the adjusted mortality rate for HFpreEF is equivalent to those patients with reduced systolic function [3]. It is projected that in the developed world the proportion of the population >65 years old and the number of surgical procedures in this group of patients will increase dramatically with at least one in two persons undergoing an operation in the remainder of their lifetime . It is therefore imperative that anaesthetists and intensivists appreciate the impact of diastolic dysfunction and HFpreEF on the aging heart. DEFINITION In 1998 Paulus et al. developed the European Criteria for HFpreEF [4]. This group suggested that there must be objective evidence of HF with a normal or mildly impaired systolic function (left ventricular ejection fraction (LVEF) > 45%) and abnormal left ventricular (LV) relaxation. All three criteria are required for the diagnosis of HFpreEF. Plasma levels of B-natriuretic peptide (BNP) are elevated in patients with HF, independent of the aetiology of HF [5]. The updated consensus statement from the European Society of Cardiology is summarized in Table 1. This report considers an LV wall index >122 g/m2 or an LV wall mass index >149 g/m2, in the presence of symptoms, adequate evidence for the diagnosis of diastolic HF when other modalities such as Tissue Doppler Imaging (TDI) are inconclusive in the context of elevated BNP levels [6]. Table 1. The European Society of Cardiology Criteria for Diastolic Heart Failure[6] The European consensus criteria for diastolic HF 1. Signs and symptoms of CHF Effort dyspnoea, orthopnea, pulmonary rales/oedema. Cardiopulmonary exercise testing (VO2max < 25 ml/kg/min) 2. Normal or mildly reduced ejection fraction and normal chamber size LVEF > 50% and Normal LV end diastolic volume(<97 mL/m2) 3. Abnormal LV relaxation, filling or diastolic distensibility or stiffness Echocardiographic: Tissue Doppler (E/Ea > 15) LA volume P34 ml/m2 if E/Ea between 9 and 14 Cardiac catheterisation: LVEDP > 16 mmHg Biomarkers NT-proBNP > 220 pg/ml or BNP > 200 pg/ Ml All three criteria are required for the diagnosis of diastolic heart failure PATHOPHYSIOLOGY The four phases of diastolic function are depicted in Fig. 1. The structural, functional and molecular mechanisms involved in diastolic dysfunction can conceptually be divided in those that occur at the cardiomyocyte level and those that are extrinsic to the myocyte. Figure 1. The four phases of diastole. The first point of intersection marks the end of the isovolumic relaxation (IR) phase and mitral valve opening. In the rapid filling phase the left atrial (LA) pressure is higher than the left ventricular (LV) pressure. The second pont of intersection LV pressure exceeds LA pressure resulting in decelerating flow. During the slow filling phase there is almost no pressure difference between the two chambers. Atrial contraction raises the LA pressure above the LV pressure. The period between the first two intersection points corresponds to the E wave seen on transmitral flow. CARDIOMYOCYTE At the myocyte level, changes in calcium homeostasis result in an increased diastolic cytosolic calcium. This may be as a result of (1) abnormalities in the sarcoplasmic reticulum calcium (SR Ca2+) reuptake due to decreases in SR Ca2+ ATPase (2) abnormalities in the ionic channels responsible for calcium transport, and (3) changes in the state of phosphorylation of proteins such as phospholamban, calmodulin and calsequestrin that modify SR Ca2+ ATPase function . Increased cytosolic calcium causes abnormalities in both active relaxation and passive stiffness. Altered troponin I function, a shift towards higher intracellular Na+, Changes in the cardiomyocyte cytoskeleton proteins and abnormalities in myocardial phosphate metabolism can produce diastolic dysfunction [7]. EXTRACELLULAR MATRIX The myocardial extracellular matrix is a dynamic tissue that responds to environmental cues and tissue injury. Changes in fibrillar collagen may be responsible for the development of diastolic dysfunction and diastolic HF [7]. Increased matrix metalloproteinases (MMP) activity results in a 2-tiered response. Initially the myocytes respond to increased collagen destruction by myocardial hypertrophy and increased collagen production. Over a period of time, there is a decreased rate of pressure decrement during diastole [7]. Elevations of collagen turnover occur in patients with asymptomatic diastolic dysfunction as well as diastolic HF [7]. In addition, the magnitude of collagen turnover correlates directly with the severity of diastolic dysfunction[7]. AGE RELATED CHANGES IN DIASTOLIC FUNCTION During aging, changes related to increased myocardial and ventricular stiffening and diminished β-adrenergic receptor responsiveness are highly significant. At the myocyte level, age-related reductions in SERCA2 levels and activity result in abnormal diastolic sequestration of calcium [8]. An increase in activity of phospholamban also impairs diastolic function. Aging is associated with a β-adrenergic associated signal dampening [9]. This may be due to receptor down regulation or due to reduced receptor coupling to adenyl cyclase via Gs proteins. Age related degeneration of the conducting system makes elderly patients prone to arrhythmia and further compromises diastolic function . Aging is associated with systolic-ventricular and arterial stiffening , which may influence diastolic function in several ways. Arterial stiffening increases myocardial oxygen consumption for a given stroke volume and ventricular systolic stiffening exacerbates this effect. The increased arterial stiffness results in ventricular hypertrophy to preserve systolic function at the expense [10]. ASSESSMENT OF DIASTOLIC FUNCTION ECHOCARDIOGRAPHY In the perioperative and critical care context, Transthoracic echocardiography (TTE) is often technically challenging. This may be due to difficulties with patient positioning, or a reduction of the acoustic window by high levels of positive end expiratory pressure, the presence of injuries, drains or dressings on the precordial area. Transesophageal echocardiography (TEE) has been recommended to overcome these limitations . The reference ranges are derived from awake patients undergoing TTE in the lateral decubitus position. This is in contrast to the supine anaethetised patient receiving mechanical ventilation under dynamic haemodynamic conditions influenced by anaesthetic drugs. A summary of the criteria commonly used to define diastolic dysfunction is presented in Table 2.Refinements in echocardiography technology include Tissue Doppler Imaging (TDI), colour TDI, strain and strain rate and have become an important part of clinical practice. TDI has two important limitations. Firstly, the measured velocities are dependent on the angle of insonation. Secondly TDI is of limited utility in analyzing regional wall motion abnormalities as TDI cannot differentiate actively contracting myocardium from infarcted myocardium that is tethering. PROGNOSIS Several variables have been identified as independent clinical predictors of mortality in patients with HF. These include age, New York Heart Association Class IV symptoms, CAD, Diabetes, peripheral vascular disease and the presence of valvular heart disease. Whether patients survive longer after a diagnosis of systolic HF than a diagnosis of systolic HF is still debated [7]. Hospital readmission rates and length of hospital stay for patients with HFpreEF are similar to SHF and the former have a higher likelihood of functional limitations or labile symptoms on follow-up [7]. Table 2. Criteria used to define diastolic dysfunction (modified from Nageuh et al. [11] and Gabriel et al. [12] Criteria Normal adult E/A ratio Deceleration time (ms) IVRT (ms) 1–2 150–240 Impaired relaxation (stage 1) Pseudonormal (stage 2) <1 1–1.5 (reverses with Valsalva maneuver) >240 150–200 Reversible restrictive (stage 3) Irreversible restrictive (stage 4) >1.5 1.5–2 (no change with Valsalva maneuver) <150 <150 <70 70–90 >90 <90 <70 PV S/D ratio >1 >1 <1 <1 PV Arev-MV A wave (ms) <0 <0 or >30 >30 >30 >30 Arev velocity (cm2) <35 <35 >35 >35 >35 Vp >55 E’ velocity >8 LA volume index <34 ml/m2 >45 <1 <45 <45 <45 <8 <8 <8 <8 <34 ml/m2 >34 ml/m2 >34 ml/m2 >34 ml/m2 When outcome from HF is adjusted for the contribution of co-morbidity, there is a uniformly poor prognosis regardless of the ejection fraction. Information regarding the prognosis in asymptomatic diastolic dysfunction is sparse. A community based study of 2042 patients 45 years and older found that patients with diastolic dysfunction without a history of cardiac failure have a significant risk of death [13]. ANAESTHETIC IMPLICATIONS PRE-OPERATIVE ASSESSMENT There is no specific risk model for predicting perioperative risk in patients with HfpreEF. When planning surgical procedures in patients with stable HF, it is important to identify those patients that are unlikely to survive long enough to accrue benefit from the procedure. Data from studies describing the clinical profile of cardiac transplant patients have highlighted the difficulties in predicting survival in patients with advanced HF. There is limited data on perioperative risk stratification for isolated diastolic dysfunction. Patients requiring vascular surgery have been shown to frequently have asymptomatic isolated diastolic dysfunction that is associated with a significantly higher rate of major adverse cardiovascular events (MACE) [7]. Isolated diastolic dysfunction has been shown to increase the risk for postoperative atrial fibrillation in cardiac surgical patients [14]. These observations make a compelling case for the routine assessment of perioperative diastolic function. EXERCISE CAPACITY AND DIASTOLIC DYSFUNCTION Exercise capacity is a useful pre-operative screening test. Exercise intolerance is often the earliest clinical presentation of diastolic dysfunction and is a major determinant of quality of life. During exercise, patients with diastolic dysfunction are unable to augment their cardiac output by increasing their end diastolic volume. Left ventricular end diastolic pressure and pulmonary venous pressure rises, reducing the pulmonary compliance and increasing the work of breathing. IMPLICATIONS IN THE PERIOPERATIVE PERIOD It is highly likely that elderly patients with vascular disease or hypertension would have some degree of diastolic dysfunction [7]. Induction of anaesthesia results in significant alterations in ventricular filling in patients with diastolic dysfunction. In patients requiring cardiac surgery, diastolic dysfunction has been shown to be a better predictor of haemodynamic instability than systolic dysfunction [15]. Moderate and severe diastolic dysfunction is also independently associated with difficulties with separation from cardiopulmonary bypass [15]. Pre-operative diastolic dysfunction is associated with a range of adverse outcomes including higher mortality, worse mitral regurgitation and longer hospital stay in patients requiring surgical ventricular restoration, mitral valve annuloplasty or elective vascular surgery. The presence of pre-operative diastolic dysfunction is a strong independent predictor for developing post-operative atrial fibrillation after cardiac surgery. There are two mechanism by which acute myocardial ischaemia induces diastolic dysfunction [7] .The first mechanism is by arterial hypoxaemia and occurs within 2 min, The second mechanism is by perfusion ischaemia and occurs at about 20–30 min. Diastolic dysfunction is commonly associated with LVH. The choice of anaesthetic technique has been shown to influence diastolic properties in patients with preexisting diastolic dysfunctiona balanced anaesthetic technique with positive pressure ventilation, no difference between sevoflurane and propofol on diastolic function was observed [16]. The mechanism by which propofol affects diastolic function is similar to volatile anaesthesia. DIASTOLIC DYSFUNCTION AND SEPSIS The occurrence of myocardial dysfunction in patients with sepsis carries a significant burden of mortality (70%) compared with those patients that do not have myocardial dysfunction. Munt et al., have demonstrated similar abnormalities in diastolic performance in a group of 24 critically ill patients [17]. This report also identified abnormalities of LV filling as being independently predictive of mortality. Baitugaeva et al. examined diastolic performance in 59 patients between the ages of 18– 24 years with sepsis, severe sepsis and septic shock and noted a significant relationship between diastolic dysfunction and pro-inflammatory cytokines [18]. PEDIATRIC PATIENTS WITH CARDIAC DISEASE A study of cardiac growth in healthy children using TDI showed a correlation between diastolic function and age [7]. ASD closure in adult patients is characterised by an increase in left ventricular dimensions, elevations in N-terminal proBNP, delayed improvement in exercise tolerance and even HF [19]. This makes a convincing case for early closure of ASD. Recent studies using TDI and strain rate and strain, after complete repair of TOF, have found significant systolic and diastolic dysfunction of the right ventricle. These patients have a significant risk of late right ventricular failure, and pulmonary insufficiency [20]. These reports provide further evidence that complete repair of TOF should be performed during infancy as delayed repair exposes the myocardium to chronic hypoxaemia and hypertrophy. TREATMENT The treatment of diastolic heart failure is less well defined than the treatment of systolic heart failure. NONPHARMACOLOGIC INTERVENTIONS Lifestyle modifications are recommended to reduce the risk of all forms of cardiovascular disease. Measures include weight loss, smoking cessation, dietary changes, and exercise. Identification and treatment of comorbid conditions, such as high blood pressure, diabetes, and hypercholesterolemia, are important in reducing the risk of subsequent heart failure.[25] PHARMACOLOGIC THERAPY Pharmacologic treatment of diastolic heart failure is directed at normalizing blood pressure, promoting regression of left ventricular hypertrophy, preventing tachycardia, treating symptoms of congestion, and maintaining atrial contraction.[25] The basis for drug therapy remains empiric, and the recommendations discussed in this section come from the ACC/AHA guidelines and the ICSI evidence-based practice guideline.[25] Treatment with diuretics and vasodilators often is necessary to reduce pulmonary congestion. However, caution is required to avoid excessive diuresis, which can decrease preload and stroke volume. Patients with diastolic dysfunction are highly sensitive to volume changes and preload. The potential benefits of beta blockers stem from their ability to decrease heart rate, increase diastolic filling time, decrease oxygen consumption, lower blood pressure, and cause regression of left ventricular hypertrophy. The multiple benefits of angiotensin-converting enzyme (ACE) inhibitors in the treatment of cardiovascular disease make them highly promising therapeutic agents. ACE inhibitors cause regression of left ventricular hypertrophy, decrease blood pressure, and prevent or modify cardiac remodeling; these actions provide strong theoretical support for the use of these agents in patients with diastolic dysfunction. In theory, the use of calcium channel blockers may be beneficial, because these agents decrease blood pressure, decrease oxygen demand, and dilate coronary arteries. However, data are lacking on patient-oriented outcomes such as morbidity and mortality. Calcium channel blockers should be used with caution in patients with coexisting systolic and diastolic dysfunction. The longacting dihydropyridine class of calcium channel blockers is safe for use in patients with systolic heart failure, but nondihydropyridine agents should be avoided. CONCLUSION Diastolic dysfunction and HF remain underappreciated in the peri-operative and critical care environment. Epidemiological data predict that diastolic HF will become the more frequently encountered type of HF encountered in clinical practice. Advances in echocardiography technology have been instrumental in our understanding of ventricular function. Currently, therapeutic options specific to this group of patients is limited and mortality has remained unchanged. In contrast to patients with reduced EF, the prognosis for those with HTPreEF has failed to improve in the last three decades. The potential public health burden should make diastolic dysfunction and diastolic HF a priority. 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