The Pathophysiology of Heart Failure

Chapter 37

The Pathophysiology of Heart Failure Anthony J. Muslin Novartis Institutes for Biomedical Research, Inc., Cambridge, MA

INTRODUCTION AND DEFINITIONS In heart failure (HF) structural or functional damage to the heart leads to a progressive clinical syndrome associated with symptoms such as shortness of breath and fatigue. A recent definition states that HF “can result from any structural or functional cardiac disorder that impairs the ability of the heart to function as a pump to support a physiological circulation. The syndrome of heart failure is characterized by symptoms such as breathlessness and fatigue, and signs such as fluid retention” (1). Within the general category of HF there are subtypes of the syndrome that are commonly mentioned in the scientific literature and in medical practice (2). In systolic heart failure the dominant feature of the syndrome is a large, dilated heart with reduced contractile function. In diastolic heart failure the symptoms of dyspnea, fatigue, and reduced exercise capacity are associated with normal or near-normal cardiac contractile function but with impaired cardiac relaxation and filling. Often there is left ventricular hypertrophy in this form of HF. In right-sided heart failure markedly reduced right ventricular systolic function is associated with jugular venous distension, hepatojugular reflex, ascites, hepatosplenomegaly, and peripheral edema. Right-sided heart failure is most commonly caused by left-sided heart failure, but can also arise in response to severe lung disease with pulmonary hypertension, idiopathic pulmonary hypertension, right ventricular infarction, and congenital heart disease (2). In left-sided heart failure pulmonary congestion is the dominant feature with absent or minimal jugular venous distension, peripheral edema, ascites, or hepatosplenomegaly. In acute decompensated heart failure a rapid change in heart failure signs and symptoms necessitates urgent medical therapy, often in the setting of an intensive care unit (3). Heart failure is a progressive condition that begins after an initial deleterious event, often called an “index event”, damages the myocardium or disrupts the functional ability of the myocardium to generate contractile force (4). The initial deleterious event may have a rapid onset, as occurs in myocardial infarction, or may have a

Muscle. DOI: http://dx.doi.org/10.1016/B978-0-12-381510-1.00037-5 © 2012 Elsevier Inc. All rights reserved.

slow onset, as occurs in chronic pressure overload with systemic hypertension or aortic stenosis. The common feature of all of the initial deleterious events is that they always produce a decrement in the ability of the heart to pump blood. After the initial event that damages the myocardium, many patients remain asymptomatic and only develop symptoms after cardiac dysfunction has been present for a prolonged period of time. One explanation for the prolonged asymptomatic period in many patients is that multiple compensatory mechanisms are activated in response to cardiac injury or reduced cardiac output (4). These compensatory mechanisms maintain the patient in the physiological range of cardiac output so that their functional capacity is maintained or only minimally reduced. Unfortunately, many of these compensatory mechanisms promote pathological cardiac remodeling that eventually worsens the underlying injury to the myocardium and leads to the onset of symptoms. In some cases, the initial deleterious event is so damaging that symptoms begin immediately. For example, in patients who suffer from a large myocardial infarction as a consequence of occlusion of proximal portion of the left anterior descending coronary artery, cardiac function may be dramatically reduced in the minutes or hours after injury (5). In such patients, symptoms such as systemic hypotension, poor end-organ perfusion, and altered mental status may rapidly develop and prove to be fatal. Interestingly, in most cases of HF, symptoms of systemic hypotension and poor end-organ perfusion only develop in end-stage patients. Indeed, many of the symptoms of HF are not a consequence of poor tissue perfusion, but rather are a consequence of the compensatory mechanisms, such as fluid retention by the kidneys, that will be discussed below.

SYMPTOMS OF HEART FAILURE Patients with HF present with a wide variety of symptoms and few are specific for the condition (6). The symptoms

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of HF may develop chronically or acutely. In chronic HF the main symptoms are shortness of breath with exertion or when lying down; fatigue and weakness; swelling in the legs, ankles, and feet; reduced exercise capacity; persistent cough or wheezing; weight gain; swelling of the abdomen; reduced appetite; rapid or irregular heart rate; and decreased ability to concentrate (6). In acute decompensated HF, the main symptoms are similar to those of chronic HF except that they develop suddenly and are much more severe. In addition, in acute decompensated HF, there is severe shortness of breath with pink-tinged sputum. The shortness of breath that occurs in HF is often due to the extravasation of fluid from the pulmonary capillaries into the alveoli. This extravasation of fluid is a consequence of the delicacy of the pulmonary capillary circulation and the elevated left atrial and pulmonary venous pressure that occurs in HF (7). Clinicians often measure the pulmonary capillary wedge pressure by use of a balloon-tipped pulmonary artery catheter as a surrogate for the left atrial pressure. Elevated left atrial pressure occurs in HF because of fluid retention and increased ventricular stiffness that is a consequence of myocardial fibrosis and defective cardiomyocyte diastolic relaxation. The fatigue and weakness that occurs in HF may be a direct consequence of poor end-organ perfusion or may be due to pulmonary congestion. The abdominal and leg swelling is a consequence of both fluid retention and increased central venous pressure that can occur when the right ventricle is functionally impaired. The reduced appetite may be a consequence of the fluid retention in the abdomen or of reduced perfusion of the intestines. The rapid or irregular heart rate is a consequence of elevated adrenergic tone that is often present in HF.

SIGNS AND RADIOGRAPHIC FEATURES OF HEART FAILURE When a patient with HF is examined by a health professional, several signs are frequently observed. These include tachycardia, hypotension, and tachypnea (6). Lung examination frequently reveals crackles, heard most commonly at the lung bases and when more severe, throughout the lung fields. The presence of diffuse pulmonary crackles suggests the development of pulmonary edema. In severe cases of pulmonary edema, cyanosis indicative of hypoxemia may be observed. Examination of the heart can reveal a displaced and sustained apical impulse, indicative of cardiac enlargement and delayed cardiac emptying. Auscultation of the heart can reveal a ventricular gallop sound called an S3, which can be a marker of increased intra-cardiac pressure (6). The presence of a pan-systolic murmur may be

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indicative of mitral or tricuspid regurgitation, which can both develop as a functional consequence of cardiac enlargement. Examination of the neck may reveal increased jugular venous pressure (6). Examination of the abdomen may reveal a hepatojugular reflex, or the presence of hepatomegaly, splenomegaly, or ascites. These signs are often indicative of increased central venous pressure. Examination of the legs may reveal peripheral pitting edema. Imaging studies of patients with HF are often critical for making an accurate diagnosis. The electrocardiogram can help to determine whether sinus tachycardia or a more ominous arrhythmia is present, whether there is evidence of acute or prior myocardial infarction, or if there is left or right ventricular hypertrophy. The chest X-ray can demonstrate enlargement of the cardiac silhouette indicative of ventricular or atrial dilation and can also show pulmonary vascular redistribution, pleural effusions, or pulmonary edema (6). Transthoracic echocardiography is a vital diagnostic tool that can accurately determine cardiac chamber sizes, ventricular wall thickness, cardiac valve function, diastolic ventricular function, and systolic ventricular function. In many patients with HF, ventricular and atrial dilation is observed and is associated with reduced diastolic and systolic ventricular function. Furthermore, functional mitral or tricuspid regurgitation is often observed in patients with advanced HF. Magnetic resonance imaging instead of transthoracic echocardiography can also be used to evaluate cardiac structure and function.

THE INITIAL DELETERIOUS EVENT In all cases of systolic HF, an initial deleterious event damages the myocardium in either an acute or chronic fashion. This event is the trigger that leads to all of the compensatory mechanisms that initially alleviate but ultimately promote the progression of the syndrome of systolic HF (Figure 37.1). Although there are many initial deleterious events that may ultimately result in the development of HF, some of the more common and notable triggers are listed below.

Myocardial Infarction One of the most common, if not the most common, initial deleterious events in HF is myocardial infarction. Myocardial infarction typically occurs as a consequence of the development of an acute occlusive thrombosis in a coronary artery at the site of an atherosclerotic lesion. Often, the atherosclerotic lesion has ruptured prior to the event, leading to the exposure of pro-thrombotic molecules, such as tissue factor, with resultant platelet

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Initial myocardial injury • Myocardial infarction • Systemic hypertension, other causes of pressure overload • Aortic valve regurgitation, other causes of volume overload • Viral myocarditis, other causes of myocarditis • Chagas disease • Alcoholic cardiomyopathy • Cocaine cardiomyopathy • Peripartum cardiomyopathy • Drug cardiotoxicity • Genetic causes of cardiomyopathy

Pathological left ventricular remodeling

Neurohormonal response • Activation of sympathetic nervous system • Activation of renin-angiotensin system • Activation of arginine vasopressin system • Increased release of endothelin-1 • Atrial and brain natriuretic peptide release • Increased release of neuropeptide Y • Increased urotensin II • Reduced release of apelin • Increased release of adrenomedullin

• Cardiomyocyte hypertrophy • Cardiomyocyte apoptosis • Cardiac fibroblast proliferation and fibrosis • Altered excitation–contraction coupling • Desensitization to β-adrenergic stimulation • Altered contractile protein expression • Left ventricular dilation • Functional mitral valvular regurgitation

Deleterious outcomes Progressive pump failure, symptoms including dyspnea and edema, sudden death

FIGURE 37.1 A simplified scheme describing the pathophysiology of heart failure. In heart failure, an initial myocardial injury leads to a neurohormonal response, which while often initially compensatory, may contribute to pathological left ventricular remodeling, ultimately resulting in deleterious outcomes due to progressive pump failure.

adhesion and thrombus formation (8,9). Myocardial infarction can rarely occur in the absence of atherosclerotic vascular disease for example, as a consequence of embolism from a left ventricular thrombus. In response to occlusive thrombosis of a coronary artery, the myocardium that is supplied by that artery rapidly becomes ischemic. In the absence of oxygen and nutrients, cardiomyocytes supplied by the occluded artery may become necrotic or apoptotic. Depending on the amount of myocardium supplied by the occluded coronary artery, the initial myocardial infarction may be of variable size. Cardiomyocytes that do not die after the initial myocardial infarction, but that are in the infarct borderzone, may be subjected to increased biomechanical stress after the initial event, and may be predisposed to die in the weeks and months after the initial event (10). Furthermore, cardiomyocytes that are in the uninvolved myocardium are subjected to volume stress that often results in hypertrophic growth. Pathologic cardiac remodeling after myocardial infarction, which consists of cardiomyocyte hypertrophy in the uninvolved myocardium, apoptosis of cardiomyocytes in the infarct borderzone, and scar formation and thinning in the infarct zone, contributes to the development of HF (10).

Systemic Hypertension and Other Causes of Pressure Overload Systemic hypertension is an extremely common condition defined as an increase in blood pressure (typically $140/ 90 mm Hg) (11). Systemic hypertension is usually asymptomatic in patients until end-organ damage occurs. Endorgan damage attributable to systemic hypertension includes cerebrovascular accidents, chronic kidney disease, and HF (12). The myocardial response to systemic hypertension is complex and is discussed in detail in other chapters of this volume. In brief, systemic hypertension leads to the growth of individual cardiomyocytes, the increased deposition of extracellular matrix protein in the myocardium, and the proliferation of cardiac fibroblasts. Taken together, these myocardial responses to systemic hypertension result in the growth of the left ventricle. This process is called cardiac hypertrophy. Cardiac hypertrophy also occurs in response to pressure overload caused by other conditions, such as aortic vascular stenosis and coarctation of the aorta (13). Cardiac hypertrophy that occurs in response to systemic hypertension can result in both diastolic and

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systolic HF. In the case of diastolic HF, the ability of the heart to contract is preserved, but the ability of the heart to dilate and fill is reduced (14). If the ability of the left ventricle to fill is significantly reduced, forward flow of blood is compromised and HF results. In some patients with systemic hypertension and cardiac hypertrophy, cardiac dilation gradually ensues in association with reduced contractile function (13). Although the factors that contribute to the progression of cardiac hypertrophy to cardiac dilation with systolic dysfunction are not well described, this progression clearly occurs in some patients. Chronic low-grade death of cardiomyocytes due to apoptosis is one potential mechanism for the progression from cardiac hypertrophy to dilation (15).

Aortic Valve Regurgitation, Mitral Valve Regurgitation, and Other Causes of Volume Overload Volume overload often occurs in response to mitral or aortic regurgitation, wherein a significant portion of blood ejected by the left ventricle in systole is not delivered to the systemic circulation, but instead is either returned to the left ventricle or delivered to the left atrium (16). Therefore, in order to pump sufficient blood to supply peripheral tissues and organs, increased blood must be pumped by the left ventricle. In the case of aortic regurgitation, volume overload is combined with pressure overload because of the systemic hypertension that develops (17). A similar situation occurs with large arteriovenous fistulae (18). Pressure overload commonly promotes the development of a prolonged period of cardiac hypertrophy with maintained contractile function, followed by the eventual development of cardiac dilation and systolic dysfunction. In contrast, volume overload often does not promote a prolonged period of cardiac hypertrophy with maintained contractile function, but instead leads to more rapid cardiac dilation, at least when examined in animal models (19).

Viral Myocarditis A variety of viral illnesses can affect the myocardium, causing myocarditis and the development of heart failure. In myocarditis, histopathologic examination of cardiac samples reveals an inflammatory cellular infiltrate with or without cardiomyocyte necrosis (20). Viral myocarditis is the most common cause of myocarditis in North America and Western Europe. Adenovirus and enterovirus were previously the most frequently identified viruses, but recently parvovirus B-19 and human herpesvirus-6 have

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been identified most often in endomyocardial biopsy samples (20). Hepatitis C viral infection has also been linked to myocarditis. Less commonly, cytomegalovirus, herpes simplex virus, and Epstein Barr virus have been found in cardiac biopsy samples from patients with myocarditis. Human immunodeficiency virus has also been associated with myocarditis (20). A variety of non-viral infectious agents can also cause myocarditis. The list of potential pathogens that are associated with myocarditis is long and includes bacteria such as Corynebacterium diphtheriae (diphtheria), Mycobacterium (tuberculosis), Streptococcus group A (rheumatic fever), and Streptococcus pneumoniae (20). Spirochetes such as Borrelia burgdorferi, the causative agent for Lyme disease, and Rickettsia such as Coxiella burnetii, the causative agent of Q fever, can promote the development of myocarditis. Fungal, protozoal (see Chagas disease below), and helminthic pathogens can also cause myocarditis. In addition, there are a variety of non-infectious causes of myocarditis that can result in the development of HF including: autoimmune diseases, such as systemic lupus erythematosus, giant cell myocarditis, dermatomyositis, and scleroderma; and systemic diseases such as sarcoidosis, celiac disease, and hypereosinophilic syndrome (20). The prognosis of patients with acute myocarditis with lymphocytic infiltration and mild symptoms with preserved left ventricular ejection fraction is excellent. Most patients with mild symptoms improve spontaneously with no residual cardiac dysfunction On the other hand, patients with acute myocarditis who present with HF symptoms and a depressed left ventricular ejection fraction (,45%) have a 4-year mortality of 56% (21).

Chagas Disease Chagas disease is a tropical parasitic disease that occurs as a result of infection with the flagellate protozoan Trypanosoma cruzi. The protozoan is transmitted to humans by blood-sucking bugs of the family Reduviidae. It may also be transmitted by blood transfusions or organ donations. The disease occurs primarily in Mexico, Central and South America where approximately 8 10 million people are infected (22). Chagas disease is associated with the development of a cardiomyopathy that is progressive and often fatal. Chagas disease has three phases: acute, latent, and chronic. The heart is the most commonly affected organ. In the acute phase of Chagas disease, cardiac involvement may be mild to severe, and is fatal in 3 5% of patients. In the latent phase, which is typically very prolonged (10 30 years), cardiac involvement is usually minimal or absent. However, approximately 30% of patients eventually develop late-phase disease and the heart is involved

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The Pathophysiology of Heart Failure

in over 94% of patients with late-phase disease. HF is the cause of death in 58% of these patients (22). The histopathologic findings of late-phase Chagasic cardiomyopathy are dramatic and complex. One hallmark is that there areas of myocardial micronecrosis and inflammation with lymphocytic infiltration and interstitial fibrosis (22). Many hearts show a thinning and bulging of the apical portion of the left ventricle. Adipose replacement of the right ventricular wall is also detected in patients with Chagasic cardiomyopathy. A direct toxic effect of parasitic infection in the myocardium likely plays a role in the necrosis of cardiomyocytes. Furthermore, inflammatory cytokines and other autoimmune mechanisms have been proposed to play an important role in the pathogenesis of this disease.

Alcoholic Cardiomyopathy Heavy sustained alcohol use is associated with the development of a cardiomyopathy, although a causal link has not been established (23). Heavy alcohol use is reported in nearly 40% of patients with idiopathic dilated cardiomyopathy (23). The incidence of alcoholic cardiomyopathy is estimated to be about 1 2% of heavy alcohol users. However, given widespread heavy alcohol use in the United States and other industrialized nations, alcoholic cardiomyopathy may account for 21% to 36% of nonischemic dilated cardiomyopathy (24). The amount and duration of alcohol consumption required to induce alcoholic cardiomyopathy is unknown, but most patients with asymptomatic depressed left ventricular contractile function have consumed at least 90 grams of alcohol a day for at least 5 years (23). There may be a prolonged asymptomatic phase of left ventricular dysfunction in alcoholic cardiomyopathy. The pathophysiology of alcoholic cardiomyopathy is not well understood. One hypothesis is that oxidative metabolism of alcohol in the liver and heart results in the production of acetaldehyde, a toxic metabolite that impairs cardiac excitation contraction coupling, inhibits ryanodine receptor-mediated calcium release from the sarcoplasmic reticulum, and inhibits cardiomyocyte protein synthesis (25,26). Alcohol ingestion has also been reported to result in activation of the rennin angiotensin system, and increased angiotensin II activity in the heart may contribute to the pathogenesis of alcoholic cardiomyopathy. In one study, dogs were administered alcohol or alcohol plus the angiotensin receptor-blocker irbesartan, and those animals administered the ARB had markedly preserved cardiac function compared to those that did not receive the ARB (27). Finally, nutritional deficiency is common in patients who are heavy consumers of alcohol, and this can include deficiencies in thiamine, selenium, and zinc (23).

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At the time of presentation, alcoholic cardiomyopathy is usually characterized echocardiographically by depressed left ventricular contractile function, dilated left ventricular chamber size, and increased left ventricular mass (23). The prognosis of alcoholic cardiomyopathy may be better than for idiopathic dilated cardiomyopathy.

Cocaine Cardiomyopathy Cocaine is a widely used drug of abuse that is associated with the development of a cardiomyopathy (23). The exact incidence of cocaine cardiomyopathy, the amount and duration of cocaine use required to develop cardiomyopathy, and the mechanistic etiology of the syndrome are not well understood (23). Cocaine use stimulates thromboxane production and platelet hypercoagulability leading to intracoronary thrombus formation. Cocaine prevents the re-uptake of norepinephrine and dopamine at presynaptic adrenergic nerve terminals, leading to adrenergic excess. This profound sympathomimetic activity may account for many of the deleterious effects of cocaine use on the myocardium. Pathologic studies of patients with cocaine cardiomyopathy have revealed contraction band necrosis of the myocardium, similar to what is observed in patients with pheochromocytoma (28). This suggests that adrenergic excess may play a key role in the pathogenesis of cocaine cardiomyopathy. Cocaine may also be directly toxic to myocardium, causing myocardial inflammation, oxidative stress, and cardiac fibrosis (29).

Peripartum Cardiomyopathy Peripartum cardiomyopathy is a distinct syndrome in which HF develops in the last month of pregnancy or within 5 months after delivery. The incidence of this syndrome varies with geographical location and occurs in approximately 1:15,000 pregnancies in the United States (30). Peripartum cardiomyopathy is diagnosed when there is no other identifiable cause of HF and no heart disease was present before the last month of pregnancy (31,32). Furthermore, the diagnosis of peripartum cardiomyopathy is made when the ejection fraction is depressed and there is left ventricular dilation (LV end-diastolic dimension .2.7 cm/m2). Peripartum cardiomyopathy is a distinct entity, but the pathophysiology of this condition is not well understood. It is possible that viral myocarditis, abnormal immune response to pregnancy leading to cardiac inflammation, increased myocyte apoptosis, a maladaptive response to the hemodynamic stresses of pregnancy, excessive prolactin production, malnutrition, increased adrenergic tone, or

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myocardial ischemia contribute to the development of this condition (33). The prognosis of peripartum cardiomyopathy varies depending on the mean initial left ventricular ejection fraction at the time of diagnosis. In a cohort of 55 patients in whom the initial ejection fraction was less than 20%, 62% of patients improved, 24% of patients remained the same, 10% required cardiac transplantation, and 4% worsened (34).

Drug Cardiotoxicity A variety of prescribed drugs have been associated with the development of cardiomyopathy and heart failure. In particular, several drugs used in cancer chemotherapy have been shown to cause cardiac injury and cardiomyopathy (35,36). Anthracyclines are potent anti-neoplastic agents that have well-described cardiotoxic effects. Indeed, the cardiotoxic effects of anthracycline administration result in slowly progressive deterioration of cardiac function and an increased risk of developing HF. Heart damage may occur with cumulative doses of anthracycline agents as low as 200 mg/m2 (37). Trastuzumab, a humanized monoclonal antibody that targets the HER2 growth factor receptor, is another chemotherapeutic agent that has significant cardiotoxic effects that may lead to the development of HF (38,39).

Genetic Causes of Cardiomyopathy A variety of monogenic mutations have been linked to the development of dilated cardiomyopathy and HF (40). Although many of these mutations are rare, the sum total of all patients with causal mutations for dilated cardiomyopathy is not insignificant. Autosomal dominant forms of dilated cardiomyopathy are more common than autosomal recessive or X-linked inheritances (40). Many of the monogenic mutations are in genes encoding sarcomeric or cytoskeletal proteins, including titin, desmin, δ-sarcoglycan, troponin T, α-myosin heavy chain, and lamin A/C (40).

NEUROHORMONAL RESPONSES TO THE INITIAL DELETERIOUS EVENT Activation of the Sympathetic Nervous System In response to decreased cardiac output after an initial deleterious event in the myocardium, the sympathetic nervous system is activated (41,42) (Figure 37.1). Activity of the sympathetic nervous system is manifested by release of norepinephrine at the termini of sympathetic axons in heart and other tissues. Sympathetic nervous system activity also promotes the release of epinephrine from adrenal

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cortex. Activation of the sympathetic nervous system is usually accompanied by a decrease in parasympathetic tone. Decreased parasympathetic tone is manifested by reduced release of acetylcholine by parasympathetic axons in heart and other tissues (41). Together, these compensatory responses promote increased heart rate and cardiac contractility. There are a variety of mechanoreceptors and metaboreceptors throughout the body that control sympathetic and parasympathetic responses in the heart. Sympathetic nervous system activity is typically inhibited by “highpressure” baroreceptors in the carotid sinus and the aortic arch (4). Furthermore, sympathetic tone is also inhibited by “low pressure” mechanoreceptors in the pulmonary circulation. Sympathetic nervous system activity is activated by non-baroreflex peripheral chemoreceptors and muscle meta-baroreceptors. The baroreceptors in the carotid sinus and the aortic arch also regulate parasympathetic tone in the opposite manner by which they regulate sympathetic tone (4). In HF patients, the circulating concentrations of norepinephrine are significantly elevated and may be 2 3 times those of healthy patients as a consequence of increased sympathetic nervous system activity (43). Norepinephrine and epinephrine act on β-adrenergic receptors in cardiomyocytes, and activation of β1 receptors results in increased heart rate and cardiac contractility (44). NE and epinephrine also act on α1-adrenergic receptors in heart resulting in a modest increase in cardiac contractility, and also on α1-adrenergic receptors in peripheral arteries, resulting in increased vasoconstriction (4). The combined activation of α and β adrenergic receptors in the heart and peripheral vasculature result in increased cardiac output but also increased myocardial oxygen demand and increased incidence of cardiac arrhythmias.

Activation of the Renin Angiotensin System Angiotensin II is a potent vasoconstrictor that is generated in increased amounts in HF (45). Sympathetic stimulation of the kidney and renal hypoperfusion lead to increased renin release from the juxtaglomerular apparatus (46). Renin is a secreted protease that cleaves four amino acids from angiotensinogen to produce angiotensin I. Angiotensinogen is secreted into the blood stream by the liver. Angiotensinconverting enzyme (ACE) is another secreted protease that cleaves two amino acids from angiotensin I to generate angiotensin II. Angiotensin-converting enzyme is expressed in many tissues, including the myocardium. Other secreted proteases, including kallikrein and cathepsin G, may also cleave angiotensinogen to generate angiotensin I. Angiotensin II, like norepinephrine and epinephrine, acts by binding to cell surface G-protein-coupled receptors. Angiotensin II receptor type 1 (AT1) predominates

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in vascular smooth muscle cells, where stimulation results in vasoconstriction. In the myocardium, AT1 receptors predominate in nerve cells, while AT2 receptors predominate in cardiac fibroblasts. Angiotensin II action in the adrenal cortex leads to the release of the hormone aldosterone (47). Angiotensin II action may be adaptive in response to acute reductions in cardiac contractile function, but clearly has deleterious consequences after chronic action. Angiotensin II promotes peripheral vasoconstriction that increases myocardial oxygen demand. Furthermore, angiotensin II promotes the proliferation of cardiac fibroblasts and the deposition of extracellular matrix resulting in cardiac fibrosis (48). Furthermore, angiotensin II-stimulated aldosterone release results in sodium reabsorption in the distal tubules of the kidney, and also promotes cardiac fibrosis (49). Aldosterone also promotes myocardial inflammation that has deleterious consequences.

Activation of the Arginine Vasopressin System In many patients with HF, circulating levels of the pituitary hormone arginine vasopressin (AVP) are elevated and this elevation may correlate with the severity of the cardiac dysfunction (50). AVP is typically released in response to increased osmolality of the plasma; for example, in response to hypernatremia. AVP promotes increased water retention by the proximal collecting ducts of the kidney to help reduce plasma osmolality. In patients with HF, plasma levels of AVP are elevated out of proportion to the plasma osmolality, and this typically results in significant hyponatremia. There are multiple AVP receptors, and the V2 receptor is expressed in the epithelium of the proximal collecting duct and the thick ascending limb in the kidney (51). All of the AVP receptors are G-protein-coupled receptors. The V1a receptors are widely expressed and are most highly expressed in vascular smooth muscle cells. Activation of V1a receptors results in vasoconstriction and platelet aggregation. AVP also binds to V1b receptors that are primarily expressed in the central nervous system.

Increased Release of Endothelin The endothelin family of vasoactive peptides is released at increased levels in HF. Endothelin-1 is the predominant isoform found in plasma. Preproendothelin is primarily released by endothelial cells but is made in other tissues, including the myocardium. Multiple secreted proteases are involved in the processing of preproendothelin to endothelin-1. In vitro, endothelin release from endothelial cells can be promoted by stimulation with norepinephrine, angiotensin II, thrombin, transforming growth factor-beta and other secreted factors (4). ET-1 plasma levels are

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significantly elevated in HF although the mechanisms of this elevation are not well understood (52). Endothelin-1 binds to G-protein-coupled receptors on the surface of vascular smooth muscle cells, cardiomyocytes, and other cell types. ETA receptors promote vasoconstriction, cardiomyocyte hypertrophy, cardiac fibrosis, and increased cardiomyocyte contractile function (53).

Increased Release of Brain Natriuretic Peptide and Atrial Natriuretic Peptide The atrial natriuretic peptide family consists of five peptides that are secreted into the extracellular space where they bind to cell surface receptors that promote intracellular guanylate cyclase activity (54,55). Atrial natriuretic peptide (ANP) is a 28 amino acid molecule that is primarily produced in the cardiac atria. Brain natriuretic peptide (BNP) is a 32 amino acid molecule that is primarily produced in the cardiac ventricles. ANP and BNP production is induced by increased cardiac wall tension and is also regulated by the action of angiotensin II and endothelin-1 (56). Both peptides are released as prohormones that are cleaved by extracellular proteases. ANP has a short plasma half-life of 3 minutes, while BNP has a half-life of 20 minutes. Natriuretic peptides are degraded by neutral endopeptidase 24.11 (NEP), which is widely expressed. BNP and ANP preferentially bind to the natriuretic peptide A receptor (NPR-A) (55). Activation of NPR-A results in natriuresis, vasorelaxation, inhibition of renin and aldosterone, inhibition of fibrosis, and increased lusitropy. Many of the physiological actions of natriuretic peptides are beneficial to patients with heart failure. Indeed, infusion of recombinant BNP in patients with acute decompensated heart failure results in hemodynamic benefits, although survival has not been shown to be improved (55).

Increased Release of Neuropeptide Y Neuropeptide Y (NPY) is a peptide that is released from sympathetic nerve terminals with norepinephrine (57). NPY binds to Y1 receptors in blood vessels to cause vasoconstriction. Circulating levels of NPY are elevated in patients with HF (58).

Increased Myocardial Expression of Urotensin II Urotensin II is an 11 amino acid secreted cyclic peptide that is widely expressed in the cardiovascular system and that binds to a G-protein-coupled receptor called GPR14 or the urotensin receptor (UR) (59). Urotensin II expression in the myocardium is increased in HF (60).

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Urotensin II is a potent vasoconstrictor peptide that also induces cardiac fibrosis and hypertrophy (59).

Reduced Release of Apelin Apelin is a secreted peptide that binds to the G-protein protein-coupled receptor APJ in myocardium and in blood vessels (4). Apelin action promotes nitric oxide-mediated endothelium-dependent vasorelaxation. Apelin also is a potent cardiac inotrope that does not cause cardiomyocyte hypertrophy. Apelin also inhibits AVP to cause diuresis. In patients with HF, plasma apelin concentrations are reduced, but are increased following cardiac resynchronization therapy (61).

Increased Release of Adrenomedullin Adrenomedullin is a 52 amino acid secreted peptide agonist that was first discovered in pheochromocytomas but that is also expressed in myocardium. Adrenomedullin expression in myocardium and serum levels of adrenomedullin are elevated in patients with HF (62). Adrenomedullin has vasodilatory and natriuretic activities (63).

PATHOLOGICAL LEFT VENTRICULAR REMODELING In response to an initial deleterious event in the myocardium, a variety of neurohormonal response are triggered that are likely compensatory in the short term, but may be ultimately maladaptive. These compensatory neurohormonal responses cause a progressive deterioration in myocardial structure and function that culminates in symptomatic HF (Figure 37.1).

Cardiomyocyte Hypertrophy Heart failure arising after a variety of initial deleterious events is associated with the growth of individual cardiomyocytes. In the case of pressure overload-induced HF, cardiomyocyte hypertrophy occurs as an early event in disease progression. In response to myocardial infarction, cardiomyocyte hypertrophy often occurs in the remote, uninvolved myocardium. Cardiomyocyte hypertrophy is a common response to many forms of pressure or volume overload, and to the action of extracellular ligands such as angiotensin II and endothelin-1. Cardiomyocyte hypertrophy is beneficial in that it reduces wall stress and provides for a larger number of sarcomeric contractile elements (2). Cardiomyocyte hyperplasia may occur to a limited extent in response to cardiomyocyte injury or death, but the capacity for hyperplasia is quite limited in adult myocardium (2,4).

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Cardiomyocyte hypertrophy has several deleterious effects, including altered intracellular calcium handling and reduced velocity of relaxation (2,4). Furthermore, cardiomyocyte hypertrophy may predispose cell to undergo cell death by apoptosis. Altered cardiomyocyte sarcomeric organization, intracellular hypoxia or ATP deficiency, inefficient calcium fluxes, and other mechanisms have been suggested to explain the link between hypertrophy and contractile dysfunction (4).

Cardiomyocyte Death HF is a progressive condition and the death of individual cardiomyocytes may play an important role in this process given the limited capacity of adult myocardium to regenerate. Cardiomyocytes may die by several mechanisms, including necrosis, apoptosis, and autophagy (2,4). The relative importance of these forms of cardiomyocyte death is under intense scientific investigation and is discussed in more detail elsewhere in this volume. The role and manner of cardiomyocyte death in the progression of HF likely varies depending on the initial deleterious injury to the myocardium. In the case of myocardial infarction, cardiomyocyte apoptosis and necrosis occurs in the infarct borderzone in the days and weeks after the infarct contributing to pathological cardiac remodeling. In the case of pressure overload due to hypertension or aortic stenosis, cardiomyocyte apoptosis occurs at a chronic low level throughout the myocardium. With viral myocarditis, cardiomyocyte necrosis occurs as a consequence of viral infection or due to the action of infiltrating leukocytes (4). Although adult myocardium likely retains some ability to regenerate via intrinsic stem cell differentiation or because of adult cardiomyocyte mitosis, this ability is limited and likely cannot compensate for increased rates of cardiomyocyte death. However, the importance of cardiomyocyte death in the progression of HF remains unknown relative to other factors that contribute to cardiac dysfunction.

Cardiac Fibroblast Proliferation and Cardiac Fibrosis Increased cardiac fibrosis is a common histopathologic feature in HF (2). For example, in patients with HF secondary to hypertension, there is increased collagen type I deposition in the myocardium compared to hypertensive patients without HF (64). Cardiac fibroblast and myocardial extracellular matrix density is in a steady state in normal myocardium (2). Indeed, extracellular matrix deposition by fibroblasts and degradation by extracellular proteases occur continuously so that the myocardial interstitium is dynamically regulated.

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In cardiac hypertrophy and in the myocardial response to cardiomyocyte death, cardiac fibroblast proliferation and increased extracellular matrix deposition occur (2). In response to myocardial infarction, cardiac fibroblast proliferation and extracellular matrix deposition play a critical role in preventing cardiac rupture (65). However, increased cardiac fibroblast proliferation and matrix deposition have a variety of deleterious consequences, including changing the shape of the ventricle and reducing compliance. These effects may significantly impair diastolic function. In addition, foci of fibrotic tissue may contribute to the development of ventricular arrhythmias.

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isoproterenol-stimulated cAMP accumulation, and decreased isoproterenol-stimulated inotropy (69,70). Increased myocardial norepinephrine levels may contribute to the downregulation and uncoupling of β1-adrenergic receptors in the myocardium. In addition, there is increased concentration of G-protein-coupled receptor kinase 2 (GRK2, βARK1) (71). GRK2-mediated phosphorylation of the intracellular portion of β-adrenergic receptors promotes β-arrestin binding resulting in uncoupling from G-proteins and internalization in clathrin-coated vesicles. In most cases, internalized receptors are dephosphorylated and recycled to the plasma membrane, but in some situations, receptors are degraded upon internalization (72).

Altered Excitation Contraction Coupling Altered Contractile Protein Expression and Function

In excitation contraction coupling, the depolarization of the cardiomyocyte plasma membrane is linked to the rapid release of calcium ions from the sarcoplasmic reticulum into the cytosol to help trigger sarcomeric actomyosin crossbridge formation and the generation of contractile force (66). During excitation, the cardiomyocyte plasma membrane potential rises above 240 mV due to voltage-gated sodium channel (SCN5A) opening, and this triggers the opening of the L-type calcium channel (Cav1.2). Calcium ions entering the cell via Cav1.2 bind to and activate the ryanodine receptor (RyR2), resulting in massive calcium release from the sarcoplasmic reticulum into the cytosol. As the cytosolic calcium concentration rises above 1 μM, calcium ions binds to troponin C, causing a change in the conformation of troponin C/tropomyosin complexes that allows myosin to bind to actin resulting myofilament shortening (66). Calcium ions are then pumped back into the sarcoplasmic reticulum by the sarcoplasmic/endoplasmic reticulum ATPase (SERCA2a). Some calcium ions are pumped out of the cell by the Na1/Ca21 exchanger (NCX). In HF, there is evidence that many features of excitation contraction coupling are dysregulated in cardiomyocytes. Diastolic calcium concentrations are known to be elevated in cardiomyocytes obtained from patients with end-stage HF (67). In addition, serine phosphorylation of the ryanodine receptor (RyR2) is increased in myocardium obtained from patients with HF (66). This increase in RyR2 phosphorylation, perhaps due to the action of protein kinase A, may promote diastolic calcium leak, lessening the contractile impact of systolic calcium release. Alternatively, Ca21/calmodulin kinase IIδ that is known to be expressed at increased levels in myocardial HF samples may promote the hyperphosphorylation of RyR2 in HF, leading to diastolic calcium leak (68).

The mechanical structures in cardiomyocytes that generate force are the sarcomeres: complex structures containing a variety of proteins that are precisely organized and regulated. In HF, embryonic forms of sarcomeric genes may be expressed (2,4). In rodents the predominant myosin heavy chain expressed in adult ventricular myocardium is the “fast” α-myosin heavy chain (MHC) isoform which has high ATPase activity. In response to pressure overload or experimental myocardial infarction, there is myosin heavy chain switching to the “slow” fetal β-MHC isoform which has lower ATPase activity. In humans, normal adult myocardium expresses mainly the β-MHC isoform, although about 33% of MHC is the “fast” α-MHC isoform. In humans with HF, there is dramatic reduction of α-MHC expression to 2% of the total (73). Also, in patients with HF who had improvement in left ventricular function in response to beta-blockers had increased α-MHC expression. Alterations in the expression of myofilament regulatory proteins also may play a role in the pathogenesis of HF. Troponin T isoform switching has been reported in patients with end-stage HF. In normal heart, cTnT3 is the predominant isoform; however, in end-stage HF the fetal cTnT1 and the cTnT4 isoforms are expressed at increased levels and this may contribute to reduced maximal active tension (74). In addition to altered expression of MHC isoforms, in heart samples obtained from HF patients there is evidence of proteolytic degradation of myofilaments. The volume of myofibril per cardiomyocyte is decreased in end-stage HF (75).

Desensitization to β-Adrenergic Stimulation

Left Ventricular Dilation

In patients with HF, ventricular tissue specimens demonstrate reduced β1-adrenergic receptor density, reduced

Dilation of the left ventricle is a common feature in HF, especially in the case of systolic HF (2). In diastolic HF

or right-sided HF, left ventricular cavity size may be normal (2,4). The anatomic and molecular mechanisms of left ventricular dilation, which may occur rapidly over hours or even minutes, are not well understood. Relative cardiomyocyte “slippage” may explain some of the dilation. Remodeling of the extracellular matrix may also play an important role in more chronic left ventricular chamber dilation.

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Cardiac Muscle

Stroke volume

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Normal LV function y’ x’ Reduced LV function

y x

Functional Mitral Valve Regurgitation As the left ventricular dilates and its shape changes to become more spherical, the function of the mitral valve apparatus is affected, and in some cases this results in functional mitral regurgitation (76). Mitral regurgitation is commonly observed in patients with end-stage HF. Mitral regurgitation causes a volume overload situation that can exacerbate the progression of HF.

HEMODYNAMIC ALTERATIONS IN HEART FAILURE In response to the initial deleterious event that damages the myocardium, a variety of compensatory mechanisms occur that help to normalize cardiac output and functional capacity. These mechanisms include the release of a variety of hormones and peptides that promote fluid retention, vasoconstriction, and tachycardia. In response to increased intravascular volume, the left ventricular filling pressure increases.

Increased Preload According to the Frank Starling mechanism, the left ventricle is able to increase its force of contraction and therefore stroke volume in response to increases in venous return and hence preload (2,4) (Figure 37.2). Perturbations in afterload or inotropy move the Frank Starling curve up or down. In HF, the Frank Starling curve is moved down (flattened) so that more venous return and filling pressure is required to increase contractility and stroke volume. This change in the Frank Starling curve helps to explain why increasing fluid retention occurs as cardiac dysfunction worsens in HF. More and more preload is required to increase stroke volume as inotropy decreases. Eventually, in end-stage HF, stroke volume becomes much more afterload-dependent, so that reductions in afterload have a more pronounced effect on cardiac output than they do in normal hearts (4). As venous return and preload rise, myocyte stretching occurs that increases sarcomere length. Increased sarcomere length results in increased force generation, called length-dependent activation. As preload increases, this results in more active tension by muscle fibers and also

Volume challenge: X

Y

Preload

FIGURE 37.2 A depiction of the Frank Starling mechanism of compensation in heart failure. According to the Frank Starling mechanism, the left ventricle raises its force of contraction and therefore stroke volume in response to increased preload (2,4). Changes in afterload or inotropy move the curve up or down. In heart failure, the Frank Starling curve is moved down and flattened due to reduced inotropy, so that more venous return and hence preload is required to increase stroke volume.

results in a higher velocity of fiber shortening. As sarcomere length increases, the calcium sensitivity of troponin C rises, and this increases the amount of tension developed by the muscle fiber (77). Fluid retention in HF helps to normalize stroke volume and cardiac output via the Frank Starling mechanism, but the increase in preload results in increased left atrial, pulmonary venous, and pulmonary capillary wedge pressures that causes pulmonary congestion and edema (2,4) (Figure 37.2). As pulmonary congestion becomes more chronic, pulmonary arterial hypertension can ensue and cause right ventricular injury and failure. As the right ventricle fails, symptoms of peripheral edema, ascites, and abdominal organomegaly occur. Therefore, the fluid retention that is compensatory in the early phases of left ventricular HF, and that help to normalize stroke volume and cardiac output, causes a variety of maladaptive changes that result in unpleasant symptoms in the patient. Increasing intravascular volume and preload also contribute to ventricular dilation. The precise mechanisms by which the ventricle dilates are not well understood, although relative slippage of adjacent cardiomyocytes or changes in extracellular matrix may explain some of the dilation that can occur acutely or chronically. Ventricular dilation helps to increase stroke volume.

Increased Afterload A common observation in HF is increased vasoconstriction and cardiac afterload (78). Elevated norepinephrine,

Chapter | 37

The Pathophysiology of Heart Failure

epinephrine, angiotensin II, endothelin-1, aldosterone, and vasopressin levels in HF also contribute to increased vasoconstriction and afterload. While increased afterload decreases stroke volume and cardiac output by the Frank Starling mechanism, it can help to maintain perfusion to vital organs such as the brain and the kidney by shunting blood away from less vital organs and tissues. The increase in afterload that occurs as a result of neurohormonal activation has a deleterious effect on the myocardium, contributing to the development of additional cardiomyocyte hypertrophy and death. Therefore, increased afterload as a result of neurohormonal activation is postulated to play a major role in the progression of HF.

Increased Heart Rate Increasing heart rate is also commonly observed in patients with HF (79). Increasing the heart rate and increasing the stroke volume are the two ways to increase cardiac output (CO 5 HR X SV). The increase in heart rate in HF is largely due to sympathetic activation and parasympathetic inhibition. Elevated levels of norepinephrine and epinephrine in the heart increase the heart rate through their effects on pacemaker cells in the SA node. In animal models, sustained tachycardia induced by electronic pacemakers can independently cause the development of HF, and it has been proposed that sinus tachycardia in humans with HF may contribute to the progression of the disease (79). Norepinephrine and epinephrine also have inotropic effects on the myocardium, shifting the Frank Starling curve upward. However, chronic hyperactivation of β1adrenergic signaling pathways has a variety of deleterious effects: including the promotion of cardiomyocyte apoptosis, the induction of cardiac fibrosis, the downregulation of β1-adrenergic receptor plasma membrane localization, the uncoupling of β1-adrenergic receptors from adenylate cyclase, and the upregulation of GRK2 (80 82).

CURRENT THERAPY OF HEART FAILURE AND RELATIONSHIP TO PATHOPHYSIOLOGY Current therapy for symptomatic heart failure is mainly designed to reduce the neurohormonal compensatory response of the body to the initial cardiac injury (83). Therapy is not designed to reverse the initial deleterious injury. However, in the future, the use of cell-based therapy may be employed to reverse the initial myocardial injury. The cornerstone of current therapy is the use of agents that block the action of angiotensin II, catecholamines, and

533

aldosterone. In particular, ACE inhibitors or angiotensin receptor blockers (ARBs) are used with beta-adrenergic receptor blockers and aldosterone antagonists. The use of agents that antagonize the effects of AVP and endothelin-1 are currently being evaluated for their efficacy in HF. Nonspecific vasodilators, such as hydralazine and nitrates, are also frequently used. Furthermore, diuretics, such as furosemide, are also commonly employed for the treatment of fluid retention in HF. Although several agents have been developed that increased cardiac contractility, none of these agents has been shown to prolong life in HF. These agents include the β1-agonist dobutamine and the phosphodiesterase inhibitor milrinone. In patients where angiotensin II, catecholamine, and aldosterone antagonism do not ameliorate symptoms, more aggressive therapeutic options are often considered, including the use of mechanical ventricular assist devices, total artificial hearts, or heart transplantation (83).

REFERENCES 1. National Collaborating Center for Chronic Conditions. Chronic heart failure. National clinical guidelines for diagnosis and management in primary and secondary care. London: National Institute for Clinical Excellence (NICE);2003. pp. 1 163. 2. Francis GS, Sonnenblick EH, Tang WHW, Poole-Wilson P. Pathophysiology of heart failure. In: Fuster V, O’Rourke RA, Walsh RA, Poole-Wilson P, editors. Hurst’s the heart. 12th ed New York: McGraw Hill Medical;2008. pp. 691 712. 3. Gheorgiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: current state and framework for future research. Circulation 2005;112:3958 68. 4. Mann DL. Pathophysiology of heart failure. In: Libby P, Bonow RO, Mann DL, Ziples DP, editors. Braunwald’s Heart disease: a textbook of cardiovascular medicine. 8th ed. Philadelphia, PA: Saunders Elsevier;2008. pp. 541 60. 5. Rackley CE, Russell RO Jr. Left ventricular function in acute and chronic coronary artery disease. Annu Rev Med 1975;26:105 20. 6. Dar O, Cowie MR. The epidemiology and diagnosis of heart failure. In: Fuster V, O’Rourke RA, Walsh RA, Poole-Wilson P, editors. Hurst’s The heart. 12th ed. New York: McGraw Hill Medical;2008. pp. 713 23. 7. Picano E, Gargani L, Gheorghiade M. Why, when, and how to assess pulmonary congestion in heart failure: pathophysiological, clinical, and methodological implications. Heart Fail Rev 2010;15:63 72. 8. Davies MJ, Thomas AC. Plaque fissuring the cause of acute myocardial infarction, sudden ischaemic death, and crescendo angina. Br Heart J 1985;53:363 73. 9. Falk E. Plaque rupture with severe pre-existing stenosis precipitating coronary thrombosis. Characteristics of coronary atherosclerotic plaques underlying fatal occlusive thrombi. Br Heart J 1983;50:127 34. 10. Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation 2000;101:2981 8.

534

11. Carretero OA, Oparil S. Essential hypertension. Part I: Definition and etiology. Circulation 2000;101:329 35. 12. He J, Whelton PK. Elevated systolic blood pressure as a risk factor for cardiovascular and renal disease. J Hypertens Suppl 1999;17: S7 13. 13. Tarazi RC, Levy MN. Cardiac responses to increased afterload. State-of-the-art review. Hypertension 1982;4(3 Pt 2):8 18. 14. Volpe M, McKelvie R, Drexler H. Hypertension as an underlying factor in heart failure with preserved ejection fraction. J Clin Hypertens 2010;12:277 83. 15. Gonzalez A, Lopez B, Ravassa S, Querejeta R, Larman M, Diez J, et al. Stimulation of cardiac apoptosis in essential hypertension: potential role of angiotensin II. Hypertension 2002;39:75 80. 16. Carabello BA. The management of functional mitral regurgitation. Curr Cardiol Rep 2007;9:112 7. 17. Bekeredjian R, Grayburn PA. Valvular heart disease: aortic regurgitation. Circulation 2005;112:125 34. 18. Alyono D, Ring WS, Anderson MR, Anderson RW. Left ventricular adaptation to volume overload from large aortocaval fistula. Surgery 1984;96:360 7. 19. Dudas Gyo¨rki Z, Kolla´r A, Manczur F, Ke´kesi V, Vo¨ro¨s K. Echocardiographic characterisation of cardiac dilatation induced by volume overload in a canine experimental model. Acta Vet Hung 2007;55:41 50. 20. Blauwet LA, Cooper LT. Myocarditis. Prog Cardiovasc Dis 2010;52:274 88. 21. Mason JW, O’Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med 1995;333:269 75. 22. Rossi MA, Tanowitz HB, Malvestio LM, Celes MR, Campos EC, Blefari V, et al. Coronary microvascular disease in chronic Chagas cardiomyopathy including an overview on history, pathology, and other proposed pathogenic mechanisms. PLoS Negl Trop Dis 2010;4(8) pii: e674. 23. Awtry EH, Philippides GJ. Alcoholic and cocaine-associated cardiomyopathies. Progr Cardiovasc Dis 2010;52:289 99. 24. Piano MR. Alcoholic cardiomyopathy: incidence, clinical characteristics, and pathophysiology. Chest 2002;121:1638 50. 25. Ren J, Davidoff AJ, Brown RA, et al. Acetaldehyde depresses shortening and intracellular Ca21 transients in adult rat ventricular myocytes. Cell Mol Biol 1997;43:825 34. 26. Schreiber SS, Oratz M, Rothschild MA. Alcoholic cardiomyopathy: the effect of ethanol and acetaldehyde on cardiac protein synthesis. Recent Adv Stud Cardiac Struct Metab 1975;7:431 42. 27. Cheng CP, Cheng HJ, Cunningham C, et al. Angiotensin II type 1 receptor blockade prevents alcoholic cardiomyopathy. Circulation 2006;114:226 36. 28. Tazelaar H, Karch S, Stephens B. Cocaine and the heart. Hum Pathol 1987;18:195 9. 29. Virmani R, Robinowitz M, Smialek J, et al. Cardiovascular effects of cocaine: an autopsy study of 40 patients. Am Heart J 1989;117:1928 9. 30. Kuklina VE, Callaghan WM. Cardiomyopathy and other myocardial disorders among hospitalizations for pregnancy in the United States 2004 2006. Obstet Gynecol 2010;115:93 100. 31. Demakis JG, Rahimtoola SH. Peripartum cardiomyopathy. Circulation 1971;44:964 8.

PART | II

Cardiac Muscle

32. Hibbard J, Lindheimer M, Lang R. A modified definition for peripartum cardiomyopathy and prognosis based on echocardiography. Obstet Gynecol 1999;94:311 6. 33. Cruz MO, Briller J, Hibbard JU. Update on peripartum cardiomyopathy. Clin Obstet Gynecol 2010;:37. 34. Amos AM, Jaber WA, Russell SD. Improved outcomes in peripartum cardiomyopathy with contemporary [therapy]. Am Heart J 2006;152:509 13. 35. Gianni L, Herman EH, Lipshultz SE, Minotti G, Sarvazyan N, Sawyer DB. Anthracycline cardiotoxicity: from bench to bedside. J Clin Oncol 2008;26:3777 84. 36. Cheng H, Force T. Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics. Circ Res 2010;106:21 34. 37. Elliott P. Pathogenesis of cardiotoxicity induced by anthracyclines. Semin Oncol 2006;33(3 Suppl. 8):S2 7. 38. Chen T., Xu T., Li Y., Liang C., Chen J., Lu Y., et al. Risk of cardiac dysfunction with trastuzumab in breast cancer patients: a meta-analysis. Cancer Treat Rev 37:312 20. 39. Pinder MC, Duan Z, Goodwin JS, Hortobagyi GN, Giordano SH. Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 2007;25:3808 15. 40. Keller DI, Carrier L, Schwartz K. Genetics of familial cardiomyopathies and arrhythmias. Swiss Med Wkly 2002;132:401 7. 41. Cohn JN, Levine TB, Francis GS, Goldsmith S. Neurohumoral control mechanisms in congestive heart failure. Am Heart J 1981;10(3 Pt 2):509 14. 42. Dzau VJ, Hollenberg NK, Williams GH. Neurohumoral mechanisms in heart failure: role in pathogenesis, therapy, and drug tolerance. Fed Proc 1983;42:3162 9. 43. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984;311:819 23. 44. Rang HP, Dale MM, Ritter JM, Flower RJ. Noradrenergic transmission. In: Rang and dale’s pharmacology, 6th ed. Edinburgh: Elsevier Churchill Livingstone;2007. pp. 169 170. 45. van de Wal RM, Plokker HW, Lok DJ, Boomsma F, van der Horst FA, van Veldhuisen DJ, et al. Determinants of increased angiotensin II levels in severe chronic heart failure patients despite ACE inhibition. Int J Cardiol 2006;106:367 72. 46. Kurtz A. Renin release: sites, mechanisms, and control. Annu Rev Physiol 2011;73:377 9. 47. Karlberg BE. Adrenergic regulation of renin release and effects on angiotensin and aldosterone. Acta Med Scand Suppl 1983;672:33 40. 48. Lijnen PJ, van Pelt JF, Fagard RH. Stimulation of reactive oxygen species and collagen synthesis by angiotensin II in cardiac fibroblasts. Cardiovasc Ther. ePub ahead of print July 8, 2010, doi: 10.1111/j.1755-5922.2010.00205.x. 49. Carey RM. Aldosterone and cardiovascular disease. Curr Opin Endocrinol Diabetes Obes 2010;17:194 8. 50. Nakamura T, Funayama H, Yoshimura A, Tsuruya Y, Saito M, Kawakami M, et al. Possible vascular role of increased plasma arginine vasopressin in congestive heart failure. Int J Cardiol 2006;106:191 5. 51. Veeraveedu PT, Palaniyandi SS, Yamaguchi K, Komai Y, Thandavarayan RA, Sukumaran V, et al. Arginine vasopressin

Chapter | 37

52.

53. 54.

55. 56. 57. 58.

59.

60.

61.

62.

63.

64.

65.

66. 67.

The Pathophysiology of Heart Failure

receptor antagonists (vaptans): pharmacological tools and potential therapeutic agents. Drug Discov Today 2010;15:826 41. Stewart DJ, Cernacek P, Costello KB, Rouleau JL. Elevated endothelin-1 in heart failure and loss of normal response to postural change. Circulation 1992;85:510 7. Iglarz M, Clozel M. At the heart of tissue: endothelin system and end-organ damage. Clin Sci 2010;119:453 63. Potter LR, Yoder AR, Flora DR, Antos LK, Dickey DM. Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications. Handb Exp Pharmacol 2009;191:341 66. Lee CY, Burnett Jr JC. Natriuretic peptides and therapeutic applications. Heart Fail Rev 2007;12:131 42. Rademaker MT, Richards AM. Cardiac natriuretic peptides for cardiac health. Clin Sci 2005;108:23 36. McDermott BJ, Bell DNPY. and cardiac diseases. Curr Top Med Chem 2007;7:1692 703. Hulting J, Sollevi A, Ullman B, Franco-Cereceda A, Lundberg JM. Plasma neuropeptide Y on admission to a coronary care unit: raised levels in patients with left heart failure. Cardiovasc Res 1990;24:102 8. Ross B, McKendy K, Giaid A. Role of urotensin II in health and disease. Am J Physiol Regul Integr Comp Physiol 2010;298: R1156 72. Douglas SA, Tayara L, Ohlstein EH, Halawa N, Giaid A. Congestive heart failure and expression of myocardial urotensin II. Lancet 2002;359:1990 7. Mullens W, Bartunek J, Wilson Tang WH, Delrue L, Herbots L, Willems R, et al. Early and late effects of cardiac resynchronization therapy on force-frequency relation and contractility regulating gene expression in heart failure patients. Heart Rhythm 2008;5:52 9. Jougasaki M, Wei CM, McKinley LJ, Burnett Jr JC. Elevation of circulating and ventricular adrenomedullin in human congestive heart failure. Circulation 1995;92:286 9. Rademaker MT, Charles CJ, Lewis LK, Yandle TG, Cooper GJ, Coy DH, et al. Beneficial hemodynamic and renal effects of adrenomedullin in an ovine model of heart failure. Circulation 1997;96:1983 90. Querejeta R, Lo´pez B, Gonza´lez A, Sa´nchez E, Larman M, Martı´nez Ubago JL, et al. Increased collagen type I synthesis in patients with heart failure of hypertensive origin: relation to myocardial fibrosis. Circulation 2004;110:1263 8. Jugdutt BI. Remodeling of the myocardium and potential targets in the collagen degradation and synthesis pathways. Curr Drug Targets Cardiovasc Haematol Disord 2003;3:1 30. Kushnir A, Marks AR. The ryanodine receptor in cardiac physiology and disease. Adv Pharm 2010;59:1 30. Zaugg CE, Buser PT. When calcium turns arrhythmogenic: intracellular calcium handling during the development of hypertrophy and heart failure. Croatian Med J 2001;42:24 32.

535

68. Hoch B, Meyer R, Hetzer R, et al. Identification and expression of delta-isoforms of the multifunctional Ca21/calmodulin-dependent protein kinase in failing and nonfailing human myocardium. Circ Res 1999;84:713 21. 69. Bristow MR, Ginsburg R, Umans V, et al. Beta 1- and beta 2adrenergic-receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective beta 1-receptor down-regulation in heart failure. Circ Res 1986;59:297 309. 70. Bristow MR, Hershberger RE, Port JD, Minobe W, Rasmussen R. Beta 1- and beta 2-adrenergic receptor-mediated adenylate cyclase stimulation in nonfailing and failing human ventricular myocardium. Mol Pharmacol 1989;35:295 303. 71. Ping P, Anzai T, Gao M, Hammond HK. Adenylyl cyclase and Gprotein receptor kinase expression during development of heart failure. Am J Physiol 1997;273(2 Pt 2):H707 17. 72. Petrofski JA, Koch WJ. The beta-adrenergic receptor kinase in heart failure. J Mol Cell Cardiol 2003;35:1167 74. 73. Nakao K, Minobe W, Roden R, Bristow MR, Leinwand LA. Myosin heavy chain gene expression in human heart failure. J Clin Invest 1997;100:2362 70. 74. Nassar R, Malouf NN, Mao L, Rockman HA, Oakeley AE, Frye JR, et al. cTnT1, a cardiac troponin T isoform, decreases myofilament tension and affects the left ventricular pressure waveform. Am J Physiol Heart Circ Physiol 2005;288:H1147 56. 75. VanBuren P, Okada Y. Thin filament remodeling in failing myocardium. Heart Fail Rev 2005;10:199 209. 76. Kono T, Sabbah HN, Rosman H, Alam M, Jafri S, Goldstein S. Left ventricular shape is the primary determinant of functional mitral regurgitation in heart failure. J Am Coll Cardiol 1992;20:1594 8. 77. Tavi P, Han C, Weckstro¨m M. Mechanisms of stretch-induced changes in [Ca21]i in rat atrial myocytes: role of increased troponin C affinity and stretch-activated ion channels. Circ Res 1998;83:1165 77. 78. Palazzuoli A, Nuti R. Heart failure: pathophysiology and clinical picture. Contrib Nephrol 2010;164:1 10. 79. Heusch G. Heart rate and heart failure. Circ J 2011;75:229 36. 80. Communal C, Colucci WS. The control of cardiomyocyte apoptosis via the beta-adrenergic signaling pathways. Arch Mal Coeur Vaiss 2005;98:236 41. 81. Brouri F, Findji L, Mediani O, Mougenot N, Hanoun N, Le Naour G, et al. Toxic cardiac effects of catecholamines: role of beta-adrenoceptor downregulation. Eur J Pharmacol 2002;456:69 75. 82. Osadchii OE. Cardiac hypertrophy induced by sustained beta-adrenoreceptor activation: pathophysiological aspects. Heart Fail Rev 2007;12:66 86. 83. Misra A, Mann DL. Treatment of heart failure beyond practice guidelines. Role of cardiac remodeling. Circ J. 2008;72(Suppl. A): A1 7.