Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
PATHOPHYSIOLOGY OF CARDIOVASCULAR SYSTEM DISORDERS Mehtap KACAR KOÇAK M.D. PhD Pathophysiologist 1 Learning Objectives • • • • • • • • • Describe to Cell adhesion molecules Describe to injury of ischemia-reperfusion Describe to atherosclerosis Describe to hypertension Ischemic heart diseases Myocardial infarction Heart failure Cor pulmonale (right heart failure) Rheumatic Heart Disease 2 INTEGRATING CELLS INTO TISSUES • Junctions: • Cell to cell • Gap junction • Tight junction • Anchoring junction • Cell to matrix • Focal adhesions • Hemidesmosomes 3 • The appearance of multicellular organisms allows specialization of cells and formation of organs. • A special matrix, the extracellular matrix, ECM, fills out the space between cells • ECM also binds cells together, acts as reservoir for growth factors and hormones, and creates an environment in which molecules and cells can migrate. • By means of cell adhesion molecules, CAMs, cells are capable of recognizing each other • Plasma membrane receptors take care of cell-ECM interactions 4 Junctions 5 Figure 3-14: Types of cell junctions Key Junction Proteins: Connexin, cadherins, occludin & integrins 6 7 CELL-CELL ADHESION MOLECULES (NONJUNCTIONAL MECHANİSM) • Cadherins • Ig superfamily CAMs • Selectins • Integrins 8 CADHERINS • A family of Ca2+-dependent CAMs • Ca2+ causes dimerization of Cadherins • The binding is homophilic 9 IMMUNOGLOBULİN (Ig) FAMİLY MEMBERS: • • • • • Include: * ICAM-1(Intracellular adhesion molecule 1), * ICAM-2 (Intracellular adhesion molecule 2), * VCAM-1 (Vascular cell adhesion molecule-1) * PECAM-1(Platelet Endothelial Cell adhesion molecule 1) • Structure: type 1 transmembrane glycoproteins • containing Ig homology domains 10 Expression patterns of Ig adhesion molecules: • IL-1 and TNF upregulate ICAM-1 and VCAM-1 expression on endothelium. • ICAM-2 is expressed constitutively on the endothelial surface. • PECAM-1 is expressed constitutively on endothelial cells at intercellular junctions and on leukocytes. 11 Ligands of Ig adhesion molecules: ICAM-1, ICAM-2 and VCAM-1 bind leukocyte integrins. 12 Selectins: • • • • • • • • Three highly homologous members: endothelial (E), platelet (P) and leukocyte (L) Structure: type 1 transmembrane glycoproteins E- and P-selectins are expressed by endothelial cells. L-selectin is expressed by leukocytes. P- and L-selectins are expressed constitutively. Cytokines (IL-1 and TNF) upregulate the transcription of E- and P-selectins. P-selectin is stored in cytoplasmic granules and a variety of stimuli can induce rapid translocation to the cell surface (within seconds). 13 Expression patterns of endothelial cell adhesion molecules: Inducible expression Stored in cytoplasm Constitutively expressed E-selectin P-selectin ICAM-2 VCAM-1 PECAM-1 ICAM-1 14 (Leukocyte) integrins: • Integrins are heterodimeric transmembrane proteins composed of alpha and beta chains. • Integrins provide a link between the cell cytoskeleton and the extracellular matrix. • Integrins are clustered in focal adhesion complexes. 15 Adhesion molecules relevant to inflammation: • Adhesion molecules are proteins with structural domains that mediate the adhesion of leukocytes to endothelial cells. • Adhesion molecules are proteins that contain structural domains. • Each adhesion molecule can bind one or several ligands or counter-receptors. 16 Leukocyte integrin ligands: • Leukocyte integrins bind members of the Ig gene superfamily as well as other proteins. • Integrin Counter-receptors • L2 ICAM-1, ICAM-2 • (LFA-1, CD11a/CD18) • M2 ICAM-1, fibrinogen, iC3b • (Mac-1, CD11b/CD18) • 41 VCAM-1, fibronectin CS-1 • (VLA-4, CD49d/CD29) 17 Endothelial Cell Activation Inflammatory cytokines (e.g., IL-1 or TNF) activate endothelial cells to express adhesion molecules. Unactivated Activated nonadhesive for leukocytes hyperadhesive for leukocytes 18 Integrin activation during inflammation NORMAL INFLAMMATION 19 Leukocyte adhesion cascade A sequence of activation and adhesion events leading to the extravasation of leukocytes at the site of inflammation. • • • • Capture and Rolling (Fast-slow)-Selectins Firm Adhesion-Integrins Transmigration Block in any one of them greatly reduces leukocyte accummulation in the damaged tissue. 20 21 22 Leukocyte Adhesion Cascade. Capture and Rolling • Cytokines released by injury activate venular endothelial cells and induce them to express P-selectin (stored in Weibel-Palade bodies) on their surface which interacts with a glycoprotein on leukocytes. • As a result the leukocytes roll along the endothelium forming bonds at the leading edge and breaking them at the trailing one. • L-selectin expressed by leukocytes also participates in the rolling process. It may be necessary for the initial attachment to the endothelium. In absence of P-selectin rolling is less efficiently mediated by L-selectin. • E-selectin expressed by activated endothelial cells is required to slow down rolling of leukocytes and initiates stronger adhesion. 23 General mechanism of cell injury • The three common forms of cell injury are; • 1- hypoxic injury (and following reperfusion injury) • 2- reactive oxygen species (ROS) and free radical-induced injury • 3- chemical injury (CCl4) 24 25 ISCHEMIA - REPERFUSION INJURY • Hypoxia, or lack of sufficient oxygen, is the single most common cause of cellular injury. • Hypoxia can result from: • a decreased amount of oxygen in the air , • loss of Hb or Hb function, • decreased production of red blood cells, • diseases of the respiratory and cardiovascular system, • poisoning of the oxidative enzymes (cytochromes) within the cells. • The most common cause of hypoxia is ischemia (reduced blood supply). 26 • Ischemic injury is often caused by gradual narrowing of arteries (arteriosclerosis), and complete blockage by blood clots (thrombosis). • Cellular responses to hypoxic injury have been extensively studied in heart muscle. • Within 1 minute after blood supply to the myocardium is interrupted, the heart becomes pale. • Within 3 to 5 minutes, the ischemic portion of the myocardium ceases to contract. 27 • The abrupt lack of contraction is caused by a rapid decrease in mitochondrial phosphorylation, which results in insufficient ATP production. • Lack of ATP leads to an increase in anaerobic metabolism, which generates ATP from glycogen when there is insufficient oxygen. 28 29 Irreversible damage characterized by two events: • 1- lack of ATP generation because of mitochondrial dysfunction, • 2- major disturbances and damage in membrane function. • Acid hydrolases from leaking lysosomes are activated in the reduced pH of the injured cell and they digest cytoplasmic and nuclear components. • Leakage of intracellular enzymes into the peripheral circulation provides a diagnostic tool for detecting tissue-specific cellular injury and death using blood samples (troponin-MI, liver transaminases-hepatic injury) 30 Reperfusion injury • Restoration of oxygen, however, can cause additional injury called reperfusion injury. • Xanthine dehydrogenase, an enzyme which normally utilizes oxidized nicotinamide adenine dinucleotid (NAD+) as an electron acceptor, is converted during reperfusion with oxygen to xanthine oxidase. 31 • During ischemic period, excessive ATP consumption leads to the accumulation of the purine catabolites hypoxanthine and xanthine ; • Which upon subsequent reperfusion and influx of oxygen are metabolized by xanthine oxidase to make massive amounts of superoxide and hydrogen peroxide. • In addition the highly reactive free radical nitric oxide is generated. 32 • These radicals can all cause membrane damage and mitochondrial calcium overload. • Neutrophils are especially affected with reperfusion injury, and neutrophil adhesion to the endothelium enhances the process. 33 34 Free radicals and reactive oxygen species-induced injury • An important mechanism of membrane damage is injury induced by free radicals, especially ROS called oxidative stress. • Oxidative stress occurs when excess ROS overwhelms endogenous antioxidant systems. • Free radicals may be initiated within cells by : • 1- the absorption of extreme enerjy sources (UV, x-ray) • 2- endogenous (during normal metabolic process) • 3- enzymatic metabolismof exogenous chemicals or drug. 35 36 • Free radicals and ROS, three are particularly important in regard to cell injury: • 1- lipid peroxidation • 2- alterations of proteins causing fragmentation of polypeptide chains, • 3- alterations DNA, including breakage of single strands.. 37 38 39 CARDIOVASCULAR DISORDERS: Vascular Disease • Outlines: • Pathophysiology of Atherosclerosis • Pathophysiology of Hypertension 40 Arteriosclerosis • Arteriosclerosis is a chronic disease of arterial system characterized by abnormal thickening and hardening of the vessel walls. • In arteriosclerosis the tunica intima undergoes a series of changes that decrease the artery’s ability to change lumen size. • Smooth muscle cells and collagen fibers migrate into the tunica intima, causing it to stiffen and thicken. 41 Arteriosclerosis: Pathophysiology • General term for all types of arterial changes • Best for degeneration in small arteries and arterioles • Loss of elasticity, walls thick and hard, lumen narrows 42 Atherosclerosis • Atherosclerosis is a form of arteriosclerosis in which the thickening and hardening of the vessel is caused by the accumulation of lipid-laden macrophages within the arterial wall, which leads to the formation of a lesion called plaque. • It is leading contributor to coronary artery and cerebrovascular disease. 43 Atherosclerosis: Pathophysiology • Presence of atheromas • Plaques • Consist of lipids, cells, fibrin, cell debris • Lipids usually transported with lipoproteins 44 Consequences of Atherosclerosis 45 Lipoproteins and Transport 46 Atherosclerosis--Diagnosis • Analysis of serum lipids: • Total cholesterol, triglycerides, LDL, HDL • LDL • High cholesterol content • Transports cholesterol liver cells • Dangerous component • HDL • “good” • Low cholesterol content • Transports cholesterol cells liver 47 Atherosclerosis—Risk Factors • • • • • • • • • Age Gender (Male) Genetic factors Obesity, diet high in cholesterol, animal fats Cigarette smoking Sedentary life style Diabetes mellitus Poorly controlled hypertension Smoking •LDL↑ •HDL↓ •hyperhomocystinemia •CRP ↑ •Serum fibrinogen ↑ •Oxidative stress •Peridontal disease 48 Pathophysiology of atherosclerosis • Atherosclerosis is an inflammatory disease. • Atherosclerosis begins with injury to the endothelial cells that line artery walls. (Risk factors!!!) (remember leukocyte adhesion) • Pathologically the lesions progress from: endothelial injury and dysfunction to fatty streak to • fibrotic plaque to • complicated lesions. 49 • Once injury has occured, endothelial dysfunction and inflammation lead to the following events: • 1. injured ECs become inflamed and cannot make normal amounts of antithrombotic and vasodilating cytokines. • 2. numerous inflammatory cytokines are released, including TNF-α, IF-γ, IL-1, toxic oxygen radicals, and heat shock proteins. 50 • 3. growth factors are also released, including AngII, FGF, PDGF, which stimulate smooth muscle cell proliferation in the affected vessels. • 4. macrophages adhere to injured endothelium by way of adhesion molecules such as VCAM-1. • 5. these macrophages then release enzymes and toxic oxygen radicals that create oxidative stress, oxidize LDL, and further injure the vessel wall. 51 • The oxidation of LDL is an important step in atherogenesis. (smoking, diabetes, hypertension…) • Inflammation with oxidative stress and activation of macrophages is the primary mechanism. • The oxidized LDL penetrates into the intima of the arterial wall and is engulfed by macrophages. Macrophages filled with oxidized LDL are called foam cells. • Once these lipid-laden foam cells accumulate in significant amounts, they form a lesion called a fatty streak. • At this point SMCs proliferate, produce collagen, and migrate over the fatty streak forming a fibrous plaque. • Plaques that have ruptured are called complicated plaques. 52 53 54 55 56 Clinical manifestations of atherosclerosis • Coronary artery disease (CAD) (major cause of myocardial ischemia) • Stroke • Hypertension 57 HYPERTENSION • Hypertension is defined as a sustained elevation of systemic arterial blood pressure. • Hypertension is caused by increases in cardiac output, total peripheral resistance, or both. 58 59 Classification of hypertension • Primary hypertension (essential or idiopathic hypertension): most cases of combined systolic and diastolic hypertension have no known cause and are diagnosed as primary hypertension. This type affects 90% to 95% of hypertensive individuals. • Secondary hypertension: It is caused by altered hemodynamics associated with a primary disease, such as renal disease. (5%to 8% of cases) 60 Classification of hypertension • Isolated systolic hypertension: It is elevated SBP accompained by normal DBP. This type is a manifestation of increased cardiac output or rigidity of the aorta or both. • Malignant hypertension (rapidly progressive hypertension in which diastolic pressure is usually above 140 mmHg) can cause encephalopathy, cerebral edema. 61 Factors associated with primer hypertension • • • • • • • • • • Family history of hypertension, Advancing age, Gender (male), Black race, High dietary sodium intake, Glucose intolerance (diabetes mellitus), Smoking, Obesity, Heavy alcohol consumption, Low dietary intake of potassium, calcium, magnesium. 62 Pathophysiology of primary hypertension • Primary hypertension is the result of a complicated interaction between genetics and environment and their effects on vascular and renal function. • Multiple pathophysiologic mechanism mediate these effects including the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAA), adductin, and natriuretic peptides. • Inflammation, endothelial dysfunction and insulin resistance also contribute to both increased peripheral resistance and increased blood volume. 63 64 • In the healty indivudial, the Symphatetic NS contributes to the maintenance of adequate blood pressure and tissue perfusion • by promoting cardiac contractility and heart rate (maintenance of adequate cardiac output) and, • by inducing arteriolar vasoconstruction (maintenance of adequate peripheral resistance). 65 • In indivudials with hypertension, overactivity of the SNS can result from increased productionof catecholamines (E, NE) or from increased receptor activity involving these neurotransmitters. • Increased SNS activity causes heart rate and systemic vasoconstruction, thus raising the blood pressure. 66 • Dysfunction of the RAA system in the hypertensive indivudual can lead to persistent increases in peripheral resistance and renal salt retention. • Angiotensin II also causes structural changes in blood vessels (remodeling) that contribute to permanent increases in peripheral resistance and make vessels more vulnerable to endothelial dysfunction and platelet aggregation. • Angiotensin II is also responsible for the hypertrophy of the myocardium associated with hypertension. • Aldosterone not only contributes to sodium retention by the kidney but also has further deleterious effects on the cardiovascular system. 67 68 • Natriuretic hormones modulate renal sodium excretion and include; • Atrial natriuretic peptide (ANP), • Brain natriuretic peptide (BNP), • C-type natriuretic peptide (CNP), • Urodilanton. • The function of these hormones can be effected by excessive sodium intake; inadequate dietary intake of K, Mg, Ca and obesity. • Therefore; salt retention leads to water retention and increased blood volume, which contributes to an increasein blood pressure. 69 • Inflammation plays a role in the pathogenesis of hypertension. • Endothelial injury and tissue ischemia result in the release of vasoactive inflammatory cytokines. • Endothelial dysfunction in primary hypertension is characterized by • a decreased production of vasodilators, such as nitric oxide, and • increased production of vasoconstructors, such as endothelin. • Insulin resistance is associated with endothelial dysfunction in primary hypertension even without overt diabetes. 70 • Diabetes and insuline resistance also cause changes in SNS and RAA activity, cause renal glomerular dysfunction and contributeto the target organ effects. • Primary hypertension is the result of an interaction between many of the abovedescribes processes. • The majority of these factors influence renal sodium excretion and shift the pressure-natriuresis relationship. 71 72 Secondary hypertension • Secondary hypertension is caused by a systemic disease process that raises peripheral vascular resistance or cardiac output. • If the cause is identified and removed before permanent structural changes occur, blood pressure returns to normal. 73 74 Isolated systolic hypertension • Elevations of systolic pressure are caused by increases in cardiac output or total peripheral vascular resistance or both. • For example; aortic valve insufficiency, arterioventricular fistula, thyrotoxic crisis, paget disease of the bone and beriberi. 75 Complicated hypertension • Chronic hypertension damages the walls of systemic blood vessels. • Within the walls of arteries and arterioles, smooth muscle cells undergo hypertrophy and hyperplasia with associated fibrosis of the tunica intima and media in a process called “vascular remodeling” . 76 77 • Endothelial dysfunction, angiotensin II, catecholamines, insulin resistance, and inflammation all contribute this process. • Once significant fibrosis has occured, reduced blood flow and dysfunction of the organs perfused by these affected vessels is inevitable. • Target organs for hypertension include the kidney, brain, heart, extremities and eyes. 78 79 Clinical manifestations of hypertension • The early stages of hypertension have no clinical manifestations other than elevated blood pressure. • Most important no signs and symptoms cause the individual to seek health care; thus hypertension is called a lanthanic (silent) disease. • Initial signs vague, nonspecific • Fatigue, malaise, morning headache 80 Coronary Artery Disease, Myocardial Ischemia • Coronary artery disease (CAD) is a condition in which the blood supply to the heart muscle is partially or completely blocked. 81 •CAD is almost always due to the build-up of cholesterol and other fatty materials (called atheromas or atherosclerotic plaques) in the wall of a coronary artery. •Occasionally CAD results from a spasm of an artery, and rarely, the cause is a birth defect, or an infection leading to inflammation of the arteries (arteritis), or physical damage (from an injury or radiation therapy). 82 • CAD is the most common cause of myocardial ischemia. The major complications of coronary artery disease are chest pain due to myocardial ischemia (angina) and heart attack (myocardial infarction). • CAD is the most common type of cardiovascular disease, occurring in about 5 to 9% of people aged 20 and older. The death rate increases with age and overall is higher for men than for women. After age 55, the death rate for men declines, and the rate for women continues to climb. After age 70 to 75, the death rate for women exceeds that for men who are the same age. 83 Risk factors of CAD • A- Nonmodifiable (major) risk factors: • 1- Advanced age • 2- Male gender or woman after menopause, • 3- Family history (Genetics) 84 Risk factors of CAD • • • • • • • • B- Modifiable risk factors: 1- Dyslipidemia, 2- Hypertension 3- Cigarette smoking, 4- Diabetes and insulin resistance, 5- Obesity, 6- Sedentary life-style, 7- Atherogenic diet. 85 Risk factors of CAD • C- Novel risk factors: • 1- Markers of inflammation and thrombosis, • 2- Hyperhomocysteinemia, • 3- Infection. 86 Dyslipidemia and CAD • The strong link between CAD and elevated plasma Lipoprotein concentrations (lipids, phospholipids, cholesterol, and triglycerides) is well documented. • Dyslipidemia refers to abnormal concentrations of serum lipoproteins. These abnormalities are the result of a combination of genetic and dietary factors. 87 Criteria for dyslipidemia Optimal Near optimal Total cholesterol LDL Triglycerides HDL Desirable Low < 200 <100 100-129 <150 <40 Borderline High Very High 200-239 ≥240 130-159 160189 ≥190 150-199 200499 ≥500 ≥60 Data from expert panel on detection, eveluation, and treatment of high blood cholesterol in adults, 88 JAMA 285:2486-2497, 2001) • Primary or familial dyslipoproteinemias result from genetic defects that cause abnormalities in lipid-metabolizing enzymes and abnormal cellular lipid receptors. • Secondary causes of dyslipidemia include several common systemic disorders such as diabetes, hypothyroidism, pancreatitis and renal nephrosis. 89 90 • An increased levels of LDL is a strong indicator of coronary risk. • (remember to atherosclerosis!!!) • Low levels of HDL also are strong indicator of coronary risk, and high levels of HDL may be more protective for the development of atherosclerosis than low levels of LDL. • HDL responsible for “reverse cholesterol transport”, which returns excess cholesterol from into the tissues to the liver for metabolism. • HDL also participate in endotheial repair and decreases thrombosis. 91 • Exercise, weight loss, fish oil consumption can result in modest increases in HDL. • Niacin, fibrates, and statins are drugs that can cause modest increases in HDL. • Other lipoproteins associated with increased cardiovascular risk include elevated serum VLDL (triglycerides) and lipoprotein (a). 92 Hypertension and CAD • Hypertension is responsible for a twofold to threefold increased risk of atherosclerotic cardiovascular disease. • A reduction in systolic blood pressure of only 12-13 mmHg can reduce the risk of CAD by as much as 21%. • It contributes to endothelial injury a key step in atherogenesis and causes myocardial hypertrophy, which increases myocardial demand for coronary flow. 93 Smoking and CAD • Studies indicate that 20% of the annual mortality from CAD is traceable to cigarette smoking. • Nicotine stimulates the release of catecholamines (E, NE), which increase heart rate and peripheral vascular constriction. As a result, blood pressure increases, as do cardiac workload and oxygen demand. Elevated catecholamines also stimulated release of free fatty acids. • Cigarette smoking is associated with an increase in LDL, a decrease in HDL, an induction of a prothrombotic state, as well as increases in inflammatory markers of CAD such as CRP and fibrinogen. • After smoking is disconytinued, the risk associated with CAD may decrease as much as 50% in 1 year. 94 Diabetes mellitus and CAD • DM is an extremely important risk factor for CAD. • DM is associated with a two fold increase in the risk for CAD death and up to a sixfold risk for stroke. • Diabetes and insulin resistance have multiple effects on the cardiovascular system throıgh the production of toxic ROS taht alter vascular cell function. • These effects can include endothelial damage, thickening of the vessel wall, increased inflammation and leukocyte adhesion, increased thrombosis, glycation of vascular proteins, and decreased production of endothelial-derived 95 vasodilators such as nitric oxide. Obesity and CAD • Obesity is caused by genetics, diet and inadequate physical exercise. • Abdominal obesity has the strongest link with increased CAD risk and is related to insulin resistance, decreased HDL, increased blood pressure. • A sedentary life-style not only increases the risk of obesity but also has an independent effect on increasing CAD risk. 96 Markers of inflammation and thrombosis and CAD • CRP is an indirect measure of atherosclerotic plaque; related inflammation and is an important indicator of CAD risk. • Elevated levels of CRP are associated with CAD. • Other markers of inflammation associated with CAD include the erytrocyte sedimentation rate, von Willebrand factor concentration, IL-6, IL-18, fibrinogen. 97 Hyperhomocysteinemia and CAD • Hyperhomocysteinemia occurs because of a genetic lack of the enzyme that break down homocysteine (an amino acid) or because of nutritional deficiency of folate, cobalamin (vit B12), or pyridoxine (vit B6). • Mechanism by which it contributes to coronary disease include associated increases in LDL, decreases in endogenous vasodilators, and an increased tendency for thrombosis. 98 Infection and CAD • Emerging is evidence that infection may play role in atherogenesis and CAD risk. • Studies have found that several microorganisms, especially Chlamydia pneumonae, and Helicobacter pylori are often present in atherosclerotic lesions. • Serum antibodies to microorganisms have been linked to an increased risk for CAD as has the presence of periodontal disease. 99 Myocardial ischemia • The coronary arteries normally supply blood flow sufficient to meet demands of the myocardium as it labors under varying workloads. • Oxygen extraction from these vessels occurs with maximal efficiency. • If efficient exchange meet myocardial oxygen needs, healthy coronary arteries are able to dilate to increase the flow of oxygenated blood to the myocardium. 100 • Myocardial ischemia develops if the supply of coronary blood cannot meet the demand of the myocardium for oxygens and nutrients. • Imbalances between coronary blood supply and myocardial demand can result from a number of conditions. • The most common cause of decreased coronary blood flow and resultant myocardial ischemia is the formation of atherosclerotic plaques in the coronary circulation. 101 • As the plaque increases in size, it may partially occlude vessel lamina, thus limiting coronary flow and causing ischemia especially during exercise. • Some plaques are “unsatble”, meaning they are prone to ulceration or rupture. • When this occurs, underlying tissues of the vessel wall are exposed resulting in platelet adhesion and thrombus formation. • This can suddenly cut off blood supply to the heart muscle resulting in acute myocardial ischemia and, if the vessel obstruction cannot be reversed rapidly, ischemia progress to infarction. 102 • Myocardial ischemia also can result from other causes of decreased blood and oxygen delivery to the myocardium, such as coronary spasm, hypotension, arrhythmias, and decreased oxygen-carrying capacity of the blood (anemia, hypoxemia). 103 • Myocardial cells become ischemic within 10 seconds of coronary oclusion. • After several minutes the heart cells lose the ability to contract, and cardiac output decreases. • Ischemia also causes conduction abnormalities that lead to chnages in the electrocardiogram and may initiate dysrhythmias. • Anaerobic processes take over, and lactic acid accumulates. 104 • Cardiac cells remain viable for approximately 20 min under ischemic conditions. • If blood flow is restored, aerobic metabolism resumes, contractility is restored and cellular repair begins. • If perfusion is not restored within 40-60 min, an irreversible stage of injury characterized by diffuse mitochondrial swelling, damage to cell membrane and marked depletion of glycogen begins. 105 Clinical manifestations of myocardial ischemia • Stable angina, • Prinzmetal angina, • Silent ischemia and mental stress 106 Stable angina • Chronic coronary obstruction result in recurrent predictable chest pain called stable angina. • Angina pectoris is chest pain caused by myocardial ischemia. • The discomfort is usually transient lasting approximately 3 to 5 minutes. • Angina pectoris is typically experienced as substernal chest discomfort, ranging from a sensation of heaviness or pressure to moderately severe pain. 107 • The pain is presumably caused by the buildup of lactic acid or abnormal stretching of the ischemic myocardium that irritates myocardial nerve fibers. • Pallor, diaphoresis, and dyspnea may be associated with the pain. • Stable angina is caused by gradual luminal narrowing and hardening of the arterial walls, so affected vessels cannot dilate in response to increased myocardial demand associated with physical exertion ar emotional stress. • The pain is usually relieved by rest and nitrates. 108 Prinzmetal angina • Prinzmetal angina is chest pain attributable to transient ischemia of the myocardium that occurs unpredictably and almost exclusively at rest. • Pain is caused by vasospasm of one or more major coronary arteries with or without associated atherosclerosis. • The pain often occurs at night during rapid eye movement sleep and may have a cyclic pattern of occurence. 109 Silent ischemia • Myocardial ischemia often does not cause detectable symptoms such as angina. Ischemia can be totally asymptomatic and referred to as silent ischemia. • Another area that receiving renewed interest is the lack of angina even though an artery is occluded, in some individuals during mental stress. • The increases in blood pressure induced by mental stress and increases in myocardial oxygen demand may play role in the pathophysiology of myocardial ischemia induced by mental stress. • Chronic stress has been linked to a hypercoagulable state that may contribute to acute ischemic events. 110 111 112 Clinical manifestations and evaluation • Physical examination may disclose extra, rapid heart sounds (S3). • The presence of xanthelasmas (small fat deposits) around the eyelids or arcus senilis of the eyes ( a yellow lipid ring around the cornea) suggest dyslipidemia and possible atherosclerosis. • ECG, • Coronary angiography, • SPECT (single-photon emission computed tomography) 113 114 Acute Coronary Syndromes: • Unstable angina, • Myocardial infarction 115 116 Unstable angina • Unstable angina is a form of acute coronary syndrome that result in reversible myocardial ischemia. • A fairly small fissuring or superficial erosions of the plaque leads to transient episodes of thrombotic vessels occlusion and vasoconstruction at the site of plaque damage. • This thrombus is labile, and occludes the vessel for no more than 10 to 20 min, with return of perfusion before significant myocardial necrosis occurs. 117 118 Clinical manifestations of unstable angina • Unstable angina presents as new onset angina, angina that is occuring at rest, or angina that increasing in severity or frequency. • Physical examination may reveal evidence of ischemic myocardial dysfunction such as tachycardia, S3 gallop, or pulmonary congestion. 119 120 Myocardial infarction (MI) • When coronary blood flow is interrupted for an extended period of time, myocyte necrosis occurs. This results in myocardial infarction. • Pathologically there are two major types of MI; • * subendocardial infarction, • * transmural infarction. 121 • Coronary artery completely obstructed • Prolonged ischemia and cell death of myocardium • Most common cause is atherosclerosis with thrombus • 3 ways it may develop: • Thrombus obstructs artery • Vasospasm due to partial occlusion • Embolus blocks small branch of coronary artery • Majority involve Left ventricle • Size and location of infarction determine severity of damage 122 • Function of myocardium contraction and conduction quickly lost • Oxygen supplies depleted • 1st 20 minutes critical • Time Line • 1st 20 min critical • 48 hrs inflammation begins to subside • 7th day necrosis area replaced by fibrous tissue • 6-8 weeks scar forms 123 Pathophysiologic changes in MI • 1- cellular ınjury, • 2- cellular death, • 3- structural and functional changes, • 4- repair 124 Cellular injury • Cardiac cells can withstand ischemic conditions for about 20 minutes before cellular death take place. • After only 30 to 60 second of hypoxia, ECG changes are visible. • After 8 to 10 seconds of decreased blood flow, the affected myocardium becomes cyanotic and cooler. • Myocardial oxygen reserves are used very quickly (about 8 s) after complete cessation of coronary flow. • Glycogen stores decrease and anaerobic metabolism begins. 125 • Glycolysis can supply only 65% to 70% of the total myocardial energy requirement and produces much less ATP than aerobic process. • Hidrogen ions and lactic acid accumulate. • Oxygen deprivation also is accompained by electrolyte disturbances, spesifically loss of potassium, calcium and magnesium from cells. • Myocardial cells deprived of necessary oxygen and nutrients lose contractility, thereby diminishing the pumping ability of the heart. 126 • Normally, the myocardium takes up varying quantities of catecholamines. • Significant arterial occlusioncauses the myocardial cells to release catecholamines, predisposing the individual to serious imbalances of sympathetic and parasympathetic function, irregular heartbeats (dysrhythmia) and heart failure. • Catecholamines mediate the release of glycogen, glucose and stored fat fom body cells. • Therefore plasma concentrations of free fatty acids and glycerol rise within 1 hour after onset of acute MI. • Excessive levels of free fatty acids can have a harmful detergent effects on cell membranes. • NE elevates blood sugar levels through stimulation of liver and skeletal muscle cells. (hyperglycemia is noted 72 hours after an acute MI) 127 • Angiotensin II is released during myocardial ischemia and contributes to the pathogenesis of MI in several ways. • It result in the systemic effects of peripheral vasoconstruction and fluid retention. • These hemostatic responses are counterproductive in that they increase myocardial work and thus exacerbate the effects of the loss of myocyte contractility. • AngII is also released locally, where it is a growth factor for VSMC, myocytes and cardiac fibroblasts; promote catecholamines release; and causes coronary artery spasm. 128 Cellular death • After about 20 min of myocardial ischemia, irreversible hypoxic injury causes cellular death and tissue necrosis. • Necrosis of myocardial tissue result in the release of certain enzymes through the damaged cell membranes into the interstitial spaces. • The lymphatics pick up the enzymes and transport them into the bloodstream, where they can be detected by serologic tests. 129 Structural and functioanl changes 130 • The severity of functional impairment depends on the size of the lesion and the site of infarction. • Functional changes can include: • 1- decreased cardiac contractility with abnormal wall motion, • 2- altered left ventricular compliance, • 3-decreased stroke volume, • 4- decreased ejection fraction, • 5- increased left ventricular end-systolic pressure, • 6- SA node malfunction. • Life-threatening dysrhythmias and heart failure often follow MI 131 Repair • MI causes a severe inflammatory response that ends with wound repair. • Repair consists of degradation of damaged cells, proliferation of fibroblasts, and synthesis of scar tissue. • Within 24 hours leukocytes infiltrate the necrotic area and proteolytic enzymes from scavenger neutrophils degrade necrotic tissue. • By the second week insulin secretion increases to mobilize glucose from the repair process. • After 6 weeks the necrotic area is completely replaced by scar tissue, which is strong but unable to contract and relax like healty myocardial tissue. 132 MI: signs and symptoms • Pain • Sudden, substernal area • Radiates to left arm and neck • Less severe in females • Pallor, sweating, nausea, dizziness (vasovagal reflexs and catecholamines release) • Anxiety and fear • Hypotension, rapid and weak pulse (low Cardiac Output) • Low grade fever 133 MI—Diagnostic Tests • ECG • Serum enzyme and isoenzyme test • High serum levels of myosin and troponin • Abnormal electrolytes • Leukocytosis • Arterial blood gases • Pulmonary artery pressure measure • Determines ventricular function 134 MI—Complications • Arrhythmias • 25% pts sudden death after MI • Due to ventricular arrhythmias and fibrillation • Heart block • Premature ventricular contraction (PVCs) • Cardiogenic shock • CHF 135 Heart Failure • Heart failure is a disorder in which the heart pumps blood inadequately, leading to reduced blood flow, back-up (congestion) of blood in the veins and lungs, and other changes that may further weaken the heart. 136 CHF—Etiology • Increased demands on heart cause failure • Depends on ventricle most adversely affected • Ex: Hypertension increases diastolic bp • Requires L ventricle to contract more forcibly to open aortic valve • Ex: Pulmonary disease • Damages lung caps, increases pulm resistance • Increase work load to R vent 137 CHF—Etiology • Causes of failure on affected side: • Infarction that impairs pumping ability or efficiency of conduction system • Valve defects • Congenital heart defects • Coronary artery disease 138 classification • 1- congestive heart failure (left heart failure), • 2- right heart failure, • 3- high-output failure 139 congestive heart failure (left heart failure), • Congestive heart failure, is categorized as a systolic heart failure or diastolic heart failure. 140 141 Left Heart Failure Systolic Dysfunction: Disorders that cause systolic dysfunction may impair the entire heart or one area of the heart. As a result, the heart does not contract normally. Coronary artery disease is a common cause of systolic dysfunction. It can impair large areas of heart muscle because it can reduce blood flow to large areas of heart muscle. Diastolic Dysfunction: Inadequately treated high blood pressure is the most common cause of diastolic dysfunction. High blood pressure stresses the heart because the heart must pump blood more forcefully than normal to force blood into the arteries against the higher pressure. Eventually, the heart's walls thicken (hypertrophy), then stiffen. The stiff heart does not fill quickly or adequately, so that with each contraction, the heart pumps less blood than it normally does. 142 • In systolic dysfunction, the heart contracts less forcefully and cannot pump out as much of the blood that is returned to it as it normally does. As a result, more blood remains in the lower chambers of the heart (ventricles). Blood then accumulates in the veins. • Cardiac output depends on heart rate and stroke volume. • Stroke volume is influenced by three major factor; contractility, preload, afterload. 143 • In diastolic dysfunction, the heart is stiff and does not relax normally after contracting. Even though it may be able to pump a normal amount of blood out of the ventricles, the stiff heart does not allow as much blood to enter its chambers from the veins. As in systolic dysfunction, the blood returning to the heart then accumulates in the veins. Often, both forms of heart failure occur together. 144 145 146 147 148 Mechanisms and Examples that Cause Left Sided Heart Failure Impaired Contractility Increased Afterload (Pressure Overload) 1. Myocardial infarction 1. Aortic Stenosis 2. Transient myocardial ischaemia 2. Uncontrolled hypertension 3. Chronic volume overload a. Mitral regurgitation b aortic regurgitation Systolic Dysfunction 4. Dilated cardiomyopathy Left-sided Heart Failure Impaired Ventricular Relaxation Diastolic Dysfunction Increased Afterload (Pressure Overload) 1. Left ventricular hypertophy 1. Mitral Stenosis 2. Hypertrophic cardiomyopathy 2. Pericardial constriction or 3. Restrictive cardiomyopathy tamponade 4, Transient myocardial ischaemia 149 150 Right ventricular failure • RVF can result from left HF when the increase in left ventricular filling pressure that is reflected back into the pulmonary circulation is severe enough. • As pressure in the pulmonary circulation rises, the resistance to right ventricular emptying increases. • The right ventricle is poorly prepared to compensate for this increased workload and will dilate and fail. 151 152 • COR PULMONALE: • When RHF happens, pressure will rise in the systemic venous circulation, resulting in peripheral edema and hepatosplenomegaly. • When RHF occurs in the absence of LHF, it is caused most commonly by diffuse hypoxic pulmonary disases (COPD, ARDS, cystic fibrosis), and this type of right ventricular dysfunction is called “COR PULMONALE”. 153 154 High-output heart failure • High-output failure is the inability of the heart to adequately supply the body with blood-borne nutrients, despite adequate blood volume and normal or elevated myocardial contractility. • In high-output failure the heart increases its output but the body’s metabolic needs are still not meet. • Common causes of high-output failure are anemia, septicemia, hyperthyroidism and beriberi. 155 156 CHF—Signs and Symptoms • Forward effects • Similar with failure on either side • Decrease blood supply to tissue and general hypoxia • Fatigue, weakness, dyspnea (breathlessness), cold intolerance, dizziness • Compensation mechanism • Indicated by tachycardia, pallor, daytime oliguira 157 CHF—Signs and Symptoms • Systemic backup effects of R-sided failure • Edema in feet, legs • Hepatomegaly, splenomegaly • Ascites • Acute R-sided failure • Increased pressure on SVC • Flushed face, distended neck veins, headaches, vision problems 158 CHF—Diagnostic Tests • Radiographs • Catheterization • Arterial blood gases 159 Diagnostic Tests for Cardiovascular Function • ECG • Monitors arrhythmias, MI, infection, pericarditis • Studies conduction activation and systemic abnormalities • Ausculation • Studies heart sounds using stethoscope • Exercise stress test • Assess general cardiovascular function • Checks for exercise-induced problems • Chest X-ray Film • Shows shape, size of heart • Evidence of pulmonary congestion associated with heart failure • Nuclear imaging 160 Diagnostic Tests • Cardiac Catheterization • Visualize inside of heart, measure pressure, assess valve and heart function • Determine blood flow to and from heart 161 Diagnostic Tests • Angiography • Visualization of blood flow in coronary artery • Obstruction assessed and treated • Basic catheterization • Balloon angioplasty 162 Diagnostic Tests • Doppler Studies • Assessment of blood flow in peripheral vessels • Microphone records sounds of blood flow • Can detect obstruction • Blood tests • Assess triglyceride and cholesterol levels • Electrolytes • Hb, hematocrit, cbcs • Arterial Blood Gas Determination • Essential for pts with shock, MI • Check current oxygen levels, acid-base balance 163 General Treatment Measures for Cardiac Disorders • Dietary modification • Regular exercise program • Quit smoking • Drug therapy 164 ACUTE RHEUMATIC FEVER • Autoimmune consequence of infection with Group A streptococcal infection • Results in a generalised inflammatory response affecting brains, joints, skin, subcutaneous tissues and the heart. 165 • RF is a delayed autoimmune response to Group A streptococcal pharyngitis. The clinical manifestation of the response and its severity in an individual is determined by host genetic susceptibility, the virulence of the infecting pathogen and a conducive environment. • RF is thought to occur only after GAS infection of the upper respiratory tract although this thinking has been challenged by those working in tropical areas where skin infections are rife. 166 ACUTE RHEUMATIC FEVER • The clinical presentation can be vague and difficult to diagnose. • Currently the modified DuckettJones criteria form the basis of the diagnosis of the condition. 167 • It is thought that 0.3-30% of untreated group A beta haemolytic streptococcal infection progress to develop acute rheumatic fever. 168 Carapetis. Lancet 2005;366:155 169 170 RHEUMATIC HEART DISEASE • Rheumatic Heart Disease is the permanent heart valve damage resulting from one or more attacks of ARF. • It is thought that 40-60% of patients with ARF will go on to developing RHD. 171 RHEUMATIC HEART DISEASE • The commonest valves affecting are the mitral and aortic, in that order. However all four valves can be affected. 172 RHEUMATIC HEART DISEASE • Sadly, RHD can go undetected with the result that patients present with debilitating heart failure. • At this stage surgery is the only possible treatment option. 173 RHEUMATIC HEART DISEASE • Patients living in poor countries have limited or no access to expensive heart surgery. • Prosthetic valves themselves are costly and associated with a not insignificant morbidity and mortality. 174 RHEUMATIC FEVER IS PREVENTABLE Costa Rica Cuba 175 The main content of the activities focused around early detection and treatment of sore throats and streptococcal pharyngitis. The project also included primary and secondary prevention of RF/RHD, training of personnel, health education, dissemination of information, community involvement and epidemiological surveillance. 176 There was a progressive decline in the occurrence and severity of acute RF and RHD, with a marked decrease in the prevalence of RHD in school children. A marked and progressive decline was also seen in the incidence and severity of ARF. There was an even more marked reduction in recurrent attacks of RF as well as in the number and severity of patients requiring hospitalization and surgical care. 177 What are the clinical features of strep sore throat? 178 179 180 Hallmarks of STREP sore throat • • • • • • Tender lymph nodes Close contact with infected person Scarlet fever rash Excoriated nares( crusted lesions) in infants Tonsillar exudates in older children Abdominal pain • GOLD STANDARD: POSITIVE THROAT CULTURE 181 Hallmarks of VIRAL sore throat • • • • • • • Coryza: runny nose or mouth ulcers Other family with COLD symptoms Evidence of another viral infection Itchy watery eyes Hoarseness and cough: non-specific Fever: not specific Red Throat: not specific 182 What are the treatment regimens of streptococcal sore throat? 183 Primary Prevention of Rheumatic Fever by treating sore throat Antibiotic Administration Dose Benzathine benzyl penicillin Single IM injection 1.2 MU > 30kg 600 000 U < 30 kg Phenoxymethyl penicillin (Pen VK) PO for 10 days 250-500mg qds for 10 days 125mg qds X 10 if <30 kg Erythromycin ethylsuccinate PO for 10 days Use same dose as above. Oral penicillin is less efficacious than Penicillin IMI Anaphylaxis is extremely unusual 184