40. Masoudi FA, Rathore SS, Wang Y, et al. National patterns of use and effectiveness of angiotensin- converting enzyme inhibitors in older patients with heart failure and left ventricular systolic dysfunction. Circulation. 2004;110:724–731. 41. Smith NL, Chan JD, Rea TD, et al. Time trends in the use of b-blockers and other pharmacotherapies in older adults with congestive heart failure. Am Heart J. 2004;148:710–717. 42. Masoudi FA, Gross CP, Wang Y, et al. Adoption of spironolactone therapy for older patients with heart failure and left ventricular systolic dysfunc- tion in the United States, 1998–2001. Circulation. 2005;112:39–47. CHAPTER 2 THE EPIDEMIC OF HEART FAILURE––––––19 This page intentionally left blank Chapter 3 What Causes Heart Failure? ALEXANDER R. LYON, MA, BM, BCH, MRCP/PHILIP A. POOLE-WILSON, MD, FRCP, FMEDSCI Introduction 21 Definition 21 Different Syndromes Referred to as Heart Failure and FUndamental Causes 22 Coronary Heart Disease—Acute Occlusion 24 Coronary Heart Disease—Left Ventricular Remodeling 25 Other Conditions Causing Reduced Coronary Blood Flow 28 Hypertension 28 Valve Disease 29 Primary Disease of Cardiac Muscle—the Cardiomyopathies 30 Hypertrophic Cardiomyopathy 35 Restrictive Cardiomyopathy 36 ᭤ INTRODUCTION Heart failure is a clinical entity diagnosed by doc- tors. The key features of the syndrome are an abnormality of the heart and the presence of symptoms, typically, tiredness and shortness of breath, which is worse on exercise. Heart failure is common, becoming more common, can be eas- ily diagnosed, is detectable, and effective treat- ments are available. Death in heart failure occurs most commonly as a result of a cardiac event such as an arrhythmia (sudden death), ischemia of the heart muscle (e.g., myocardial infarction, heart attack), or decompensated heart failure. Thus the natural history of heart failure begins and ends with the heart (Fig. 3-1). But almost all of the clin- ical characteristics of patients with heart failure result from persistent stimulation of interacting compensatory mechanisms not just in the heart but in the peripheral circulation and body organs. The clinical manifestations and pathophysiology of heart failure should be considered as a multi- system disease. ᭤ DEFINITION The most widely quoted definition of heart fail- ure is that heart failure is “A pathophysiological state in which an abnormality of cardiac function is responsible for the failure of the heart to pump blood at a rate commensurate with the requirements of the metabolising tissues.” 1 Other early definitions have emphasized one or other 21 Copyright © 2007 by The McGraw-Hill Companies, Inc. Click here for terms of use. physiological or biochemical abnormalities. More recently, definitions have emphasized the clinical nature of heart failure, for example, “A clinical syndrome caused by an abnormality of the heart and recognized by a characteristic pat- tern of haemodynamic, renal, neural, and hor- monal responses.” 2,3 The European Society of Cardiology emphasized the need for three cri- teria: typical symptoms and signs, an abnor- mality of the heart, and preferably a response to treatment. 4 More recently the American College of Cardiology and the American Heart Association stated “Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.” A similar definition has been used in major guidelines. 5 These recent definitions encompass the obvi- ous central premise that a primary disease or dysfunction of the heart is present. Cardiac failure is a syndrome, not a specific disease. Management should be targeted to treat the cause as well as the spectrum of pathophysiology that comprises the syndrome. Thus, it is logical to classify the causes of cardiac failure based upon disease pathology. ᭤ DIFFERENT SYNDROMES REFERRED TO AS HEART FAILURE TO AND FUNDAMENTAL CAUSES A simple but clinically useful way to consider heart failure is to first make the distinction between acute heart failure, shock, and chronic heart fail- ure (Table 3-1). Acute heart failure is synony- mous with pulmonary edema and is a medical emergency. The extreme symptom of breathless- ness is closely related to the elevated left ventric- ular pressure. Shock is a condition characterized by a low systolic blood pressure (systolic pres- sure <90 mm Hg), oliguria or anuria, and evidence 22––––––HEART FAILURE: A PRACTICAL APPROACH TO TREATMENT Time Mild Moderate Severe Quality of life Loss of myocardium Fall of BP—baroreceptors ergoreflexes & chemoreflexes activated Maintains hormone activation Bacterial invasion Immune & inflammatory response Onset of cachexia Hastens demise Onset of heart failure Death Sudden death Coronary events Progression Figure 3-1 Progression of heart failure. ᭤ Table 3-1 Syndromes of heart failure Entity Synonym or variant Acute heart Pulmonary edema failure Circulatory Cardiogenic shock (poor collapse peripheral perfusion, oliguria, hypotension) Chronic heart Untreated, overt, congestive, failure undulating, treated, compensated of a constricted circulation such as cold periphery, sweating, and mental confusion. Chronic heart fail- ure is a condition where persistent damage to the heart leads to a progressive state with persistent symptoms. Many adjectives are added to the term to emphasize one or other feature (Table 3-1). The fundamental causes of heart failure are easily stated and reflect the anatomical and phys- iological features of the heart (Table 3-2). The most common is myocardial disease. Myocardial dam- age has traditionally been classified as due to one or other manifestation of coronary heart disease or as a cardiomyopathy (Table 3-3). Hypertension is commonly associated with heart failure and particularly with the progression of heart failure. But hypertension is rarely the immediate or only cause of heart failure. Patients with hypertension often have coronary heart disease because hypertension is an important risk factor causing damage to the endothelium and promoting the development of atherosclerosis. Such classifica- tions focus on clinical characteristics. A different approach is to consider the basic mechanisms of heart failure but that has no clinical application at present (Table 3-4). Many words are added to the term heart fail- ure (Table 3-5). These are often jargon. Forward and backward failure reflects old ideas on the pathophysiology of heart failure and should no longer be used. Right and left heart failure usually refer to pulmonary edema and breathlessness (left heart failure) or evidence of fluid overload such as raised venous pressure, enlarged liver, and peripheral edema (right heart failure). This jargon CHAPTER 3 WHAT CAUSES HEART FAILURE?–––––23 ᭤ Table 3-2 General categories for causes of heart failure 1. Myocardial disease 2. Valve disease 3. Pericardial disease 4. Congenital heart disease 5. Arrhythmias ᭤ Table 3-3 Myocardial causes of heart failure Coronary artery disease In all its many manifestations Cardiomyopathy Dilated (DCM) - specific or idiopathic (IDCM) Hypertrophic (HCM or HOCM or ASH) Restrictive ARVC Hypertension Drugs b-blockers Calcium antagonists Antiarrhythmics Other or unknown DCM—dilated cardiomyopathy; IDCM—idiopathic dilated cardiomyopathy; HCM—hypertropic cardiomyopathy; HOCM—hypertropic obstructive cardiomyopathy; ASH— asymmetric septal hypertrophy; ARVC—arrhythmic right ventricular cardiomyopathy ᭤ Table 3-4 Fundamental abnormalities in failing myocardium 1. Loss of muscle 2. Incoordinate contraction and abnormal timing of contraction 3. Extracellular Fibrosis, altered extracellular architecture, shape and size of ventricle, slippage of cells, fiber orientation 4. Cellular Change of cell structure Loss of intracellular matrix, hypertrophy, hyperplasia Change of cell function—systolic and/or diastolic Loss/aging of intrinsic repair mechanisms Molecular Calcium release and/or uptake Response of contractile proteins to calcium ᭤ Table 3-5 Other terms used to describe heart failure 1. Forward and backward heart failure 2. Right and left ventricular failure 3. Systolic and diastolic heart failure 4. High- and low-output heart failure is largely nonsense, since the commonest cause of right heart failure is left heart failure; fluid reten- tion in chronic heart failure is a consequence of retention of salt and water as a result of under- perfusion of the kidney. In recent years, a distinction has been made between systolic and diastolic heart failure. Diastolic heart failure is often referred to as heart failure with preserved ventricular func- tion. This distinction is the source of much dis- cussion and controversy. In simple terms, diastolic function exists when the heart remains of a normal size and systolic heart failure exists when the heart is enlarged. The old adage was that “a big heart is a bad heart.” Diastolic heart failure is common in the elderly and in the pres- ence of myocardial ischemia and hypertension. One further distinction is of clinical impor- tance. There exists a group of conditions where the cardiac output is greatly elevated in the pres- ence of symptoms and signs identical to those found in heart failure (Table 3-6). This is often referred to as high-output heart failure but such a phrase is misleading as the fundamental cause is not the heart but other features of the circula- tion or body systems. A better terminology is to refer to these conditions as circulatory failure. Diseases of any of the constitutive compo- nent tissues of the heart and associated great vessels can result in cardiac failure. The etiology can be approached from a reductionist perspec- tive, starting at the whole organ and tissue level, and progressing to the cellular, subcellular, and molecular causes (proteomic and genomic), or vice versa from the expansionist perspective, starting at the molecular level, and “expanding up to the tissue and organ level.” The prevalence of the different causes varies depending upon gender, age, and geographical region. In the Caucasian population of Western Europe, the United States, and Australasia, ischemic heart disease predominates, whereas in the Afro-Caribbean population, hypertension is the commonest cause. Chagas’ disease caused by the parasite Trypanosoma cruzi is responsi- ble for 20% of cardiac failure in South America/Brazil, 6 but is only seen in returning travelers and immigrants from this region in European hospitals. Coronary Heart Disease—Acute Occlusion Coronary heart disease, consequent to atheroscle- rosis, is the commonest cause of heart failure in Western populations, accounting for up to 70% of cases. 7,8 The heart is critically dependent on a sup- ply of oxygen from the coronary circulation; the adenosine triphosphate (ATP) in heart muscle will support about five beats. An acute coronary occlusion causes diastolic contractile dysfunc- tion within 6 seconds and systolic dysfunction within 20 seconds. Intracellular acidosis develops with the switch from aerobic to anaerobic metab- olism, and the intracellular accumulation of phos- phate from the breakdown of creatine phosphate and ATP. Hydrogen and phosphate ions interfere directly with the contractile proteins to promote the formation of weak myofilament cross bridges. The ATP depletion reduces sarcoplasmic reticu- lum calcium ATPase and sodium-potassium ATPase activity. The ATP-inhibited K + channel opens, and triggers an efflux of potassium out of the cell (within seconds), which is subsequently amplified by reduced sodium-potassium ATPase activity. This disrupts the ionic fluxes across the sarcolemma and reduces the calcium removal from the cytoplasm during diastole, depleting the sarocoplasmic reticulum calcium stores and result- ing in smaller systolic calcium transients. Lactate accumulation causes mitochondrial damage and 24––––––HEART FAILURE: A PRACTICAL APPROACH TO TREATMENT ᭤ Table 3-6 Causes of circulatory failure (high-output cardiac failure) Anemia Thyrotoxicosis Beriberi Arteriovenous fistula Cirrhosis of the liver Paget’s disease Pregnancy Renal cell carcinoma disrupts action potential generation. The result is cardiac tissue with abnormal electrical activity, excitation-contraction coupling, and reduced contractile tension. Total occlusion of the artery leads to hemorrhagic necrosis of the myocardium supplied by the artery, leading to irreversible myocardial infarction. If the occluded coronary is reopened after an initial delay of 30 minutes or more, but before complete necrosis has devel- oped, then the return of oxygen results in the rapid production of free radicals within 2–4 min- utes of reperfusion (reperfusion injury). 9 These free radicals damage nucleic acids, cell mem- branes, and intracellular proteins, initiating the intracellular cascade via the p38 kinase and c-Jun N-terminal kinase pathways, activation of the cas- pase cascades, resulting in apoptosis and further myocardial damage (Fig. 3-2). The wave front of infarction starts at the endo- cardial border and progresses to the epicardium in areas of severe ischemia. The infarcted wall becomes acutely dyskinetic (paradoxical outward movement during systole), and ventricular dilata- tion begins. This occurs within the constraints of the pericardium, which reaches its limits of com- pliance in the acute phase and exerts a constric- tive effect on the acutely infarcted ventricle. The increase in left ventricular diastolic pressure after acute coronary occlusion in the dog angioplasty model can be inhibited by prior removal of the pericardium. 10 Coronary Heart Disease—Left Ventricular Remodeling Should the patient survive the acute episode of myocardial infarction, a process of left ventricu- lar remodeling is initiated, with further architec- tural and structural changes to the ventricle (Tables 3-7 and 3-8). The word was first used in 1982 so as to distinguish between extension of an infarct, expansion of an infarct, and changes in distant myocardium. 11,12 Remodeling occurs in both the infarcted and remaining nonin- farcted regions, further contributing to ventricu- lar dysfunction. The extent of ventricular dysfunction depends on the size and location of the infarct, the presence of previous infarcts elsewhere in the heart, the remaining coronary supply with or without collaterals, and the involvement of other cardiac structures, which influence ventricular function such as the con- ducting tissue, heart valves, and pericardium. The region of necrosis involves damaged myocytes and disruption of the extracellular matrix. Loss of type I collagen fibers and intermy- ocyte collagen struts occurs due to activation of matrix metalloproteinases (1, 2, and 9 predomi- nate in the heart), and is replaced by a deposi- tion of collagen III and IV from fibroblasts, stimulated by aldosterone and angiotensin II. 13,14 There is an overall increase in the myocardial collagen content from 5% up to 25%, but it is laid down in an irregular fashion, which dis- rupts the fine myocardial architecture. This allows myocyte slippage in the longitudinal direction, leading with the loss of cells and vas- culature to infarct thinning and expansion. 15,16 CHAPTER 3 WHAT CAUSES HEART FAILURE?–––––25 ᭤ Table 3-7 Modish terms and concepts in coronary heart disease 1. Stunning 2. Hibernation 3. Mummified myocardium 4. Stuttering ischemia 5. Preconditioning 6. Remodeling 7. Chronic ischemia 8. Ischemic cardiomyopathy Seconds Minutes Minutes 0 10 20 30 40 50 60 5 30 60 Chest pain ECG changes Stunned myocardium Cell necrosis Total cell necrosis 100 0 50 Normal (%) Diastolic dysfunction Systolic dysfunction Loss of K + Acidosis Figure 3-2 Timing of events after onset of myocardial ischemia. This is more extensive in areas with complete absence of blood supply. The presence of collat- erals, or late revascularization of the culprit ves- sel, reduces infarct expansion. It is more evident in anterior infarcts, and leads to an increase in left ventricular circumference up to 25% during the first week. This expansion alters the geome- try of the left ventricle, with the normal ellipsoid shape progressively replaced by a more spheri- cal shape. Sphericity indices have been used to quantify this change, based upon the ratio of the observed biplane ventricular volume divided by the volume of a theoretical ventricle with the same biplane circumference but perfectly spher- ical geometry. The normal human left ventricle has a sphericity index of 0.66 at end diastole and 0.55 at end systole. After anterior myocardial infarction, the sphericity index increases, with the subsequent reduction in efficiency of blood ejection from the chamber, higher filling pres- sures, and reduced exercise capacity. 17 The infarction of one region of the left ven- tricular wall requires the remaining myocardium to compensate mechanically in order to maintain adequate cardiac output. Eccentric hypertrophy with sarcomeric replication in series occurs, 18 resulting in further increases in ventricular dimen- sions and compliance. The increased wall stress may stimulate the remaining noninfarcted myocardium to hypertrophy in a concentric man- ner, most commonly seen at the border zone of the infarct. This process starts 1–2 months after the initial infarction, and may progress for years unless a terminal cardiac event intervenes. Transient ischemia can produce temporary reduction in contractile function, which is termed myocardial stunning (Tables 3-7 and 3-8). A defin- ition of stunned myocardium (stunning) is mechanical dysfunction that persists after reperfu- sion despite the absence of irreversible damage and despite the restoration of normal or near-nor- mal coronary flow. 19 The delayed recovery, from a few hours up to several days, occurs despite restoration of normal coronary flow in the absence of irreversible damage. At a cellular level, there is a transient increase in oxygen consump- tion, despite continuous impairment of mechani- cal function. This inefficient utilization of oxygen may represent reduced myofilament calcium sen- sitivity despite increases in cytosolic calcium lev- els, possibly due to changes in myosin ATPase activity. This is compounded by smaller degrees of free radical production, including nitric oxide- derived free radicals, which also contribute to the dysfunction of myocardial stunning. Stunning can occur in a variety of clinical settings. Early reper- fusion after myocardial infarction, whether spon- taneous or secondary to therapeutic thrombolysis 26––––––HEART FAILURE: A PRACTICAL APPROACH TO TREATMENT ᭤ Table 3-8 Ventricular dysfunction, stunning, hibernation, and clinical syndromes Acute ventricular Immediate contractile failure (<2 minutes) Angioplasty (PCI) dysfunction Stunning (approximately >2 minutes Stable or unstable angina <15 minutes) but before any structural Prinzmetal’s angina change with near-normal coronary flow Early thrombolysis and dysfunction reversible Cardiac surgery Chronic ventricular Early hibernation (hours but <3 months) Unstable angina dysfunction or repetitive stunning Post-infarction Silent ischemia Chronic hibernation (>3 months) Stable angina Dysfunction with reduced coronary blood Heart failure due to flow but reversible coronary heart disease Aortic stenosis PCI—percutaneous coronary intervention or primary angioplasty, may salvage ischemic but noninfarcted myocardium within the territory of the culprit vessel. This is of significant importance clinically, as imaging may reveal large areas of akinetic or dyskinetic myocardium in the early post-infarct recovery period, but after allowing the stunned myocardium to recover, the long-term dysfunction may not be so severe, with the asso- ciated prognostic implications. 20 During unstable angina, and after exercise in patients with stable but critical epicardial stenoses, regional wall motion abnormalities have been demonstrated, which recover with relief of angina and/or rest. 21 The recovery time is related to the duration of angina on the treadmill or at rest, and may take over 24 hours in severe cases. Myocardial stun- ning is common after cardiac surgery requiring cardioplegia and cardiopulmonary bypass, due to the global myocardial ischemia generated with cessation of coronary flow. 22 This setting demon- strated that whilst inotropic agents can increase contractile function of stunned myocardium, the increase in oxygen consumption induced by the inotropic stimulation is out of proportion to the mechanical improvement. Sudden increases in myocardial oxygen consumption, such as the catecholamine surges seen in acute subarachnoid hemorrhage and pheochromocytoma patients, 23,24 create a supply-demand mismatch and can cause myocardial stunning. Hibernating myocardium is another descrip- tion of myocardial dysfunction, which has become widespread. 25 The word was first used by Diamond in 1978 when he commented, “Reports of sometimes dramatic improvement in segmental left ventricular function following coro- nary bypass surgery, although not universal, leaves the clear implication that ischemic nonin- farcted myocardium can exist in a state of function hibernation.” 26 But the term was popularized by Rahimtoola in 1985 who described it thus “A state of persistently impaired myocardial and left ven- tricular dysfunction at rest due to reduced coronary blood flow that can be partially or completely restored to normal if the myocardial oxygen supply/demand relationship is favorably altered, either by improving blood flow and/or reducing demand.” 27 Hibernation refers to viable myocardium, which is exposed to chronic ischemia, with hypocontractility, which is reversible on restoration of normal blood flow. As implicated by this definition, hibernation can only be diag- nosed with absolute accuracy in retrospect after revascularization has been performed. In contrast to the pathology of acute occlusion described ear- lier, mild-moderate ischemia results in transient reduction of creatine phosphate and increase in lactate production, but by 60–85 minutes these return to near normal, and infarction does not occur, despite persistent hypoperfusion. The sub- sequent changes may represent an evolutionary “protective” mechanism, as fetal cardiac gene expression patterns are activated, and the chroni- cally ischemic myocytes undergo structural cellu- lar changes with sarcomere loss, increased abundance of glycogen granules, rough endo- plasmic reticulum and mitochondria, and an increase in collagen strands. 28 These changes occur over a timescale of days to weeks, and with initially isolated functional hibernation, progressing later to structural and functional hibernation, which may be associated with wall thinning. 29 The classical changes in left ventricular func- tion caused by coronary artery disease and described above occur within the region supplied by the stenotic or occluded artery. Therefore, regional wall motion abnormalities can be explained by coronary disease. However, global left ventricular dysfunction without regional vari- ation can also be caused by coronary disease. This is usually advanced three vessel disease, and may be the result of infarction, hibernation, and/or stunning. This often occurs in patients without symptoms of angina, who present with symptoms of cardiac failure. In a study of patients with global left ventricular impairment (without a history of ischemic heart disease [symptoms or documented previous history]), 52% of patients <72 years of age had coronary artery disease as defined by at least one epicardial stenosis of ≥50%. 30 Furthermore milder stenoses, which are not flow-limiting, may cause downstream myocar- dial dysfunction through a variety of mechanisms CHAPTER 3 WHAT CAUSES HEART FAILURE?–––––27 including cholesterol and thrombus embolism, previous occlusion and recanalization, and as regions initiating focal spasm. Other Conditions Causing Reduced Coronary Blood Flow Whilst atherosclerosis is the commonest form of coronary disease, many other conditions can cause heart failure by reducing coronary blood supply. These include congenital coronary anom- alies, especially the interarterial anomalous left coronary artery, coronary artery fistulae, the left main stem arising from the pulmonary trunk, and the stenosed “slit-like” left main orifice. Coronary vasculitides, for example, periarteritis nodosa, Kawasaki disease, systemic lupus ery- thematosus (SLE), aortic dissection involving the coronary ostia or aortic valve may all cause myocardial dysfunction. Hypertension Hypertension is also a common cause of heart failure, accounting for 14% cases in one U.K. population-based study. 8 In the Framingham study, a 20 mm Hg increase in systolic blood pressure was associated with a 56% increased risk for developing heart failure. 31 Advances in primary care have led to a decrease in the inci- dence with improved detection and treatment. The majority of hypertensive patients have no specific identifiable cause, so called “essential hypertension,” which places an insidious after- load strain on the heart through a variety of mechanisms including sodium and water reten- tion, arteriolar vasoconstriction, reduced vascular compliance, faster reflection of the pulse wave from stiffer small peripheral arteries, and activa- tion of a range of neurohormonal systems. The left ventricle demonstrates subtle abnormalities in hypertensive patients even before hypertrophy develops. These start with supranormal contrac- tion with increased fractional shortening and wall stress. The left ventricle hypertrophies in a concentric manner to compensate, although animal studies using gene knockout techniques have revealed that left ventricular hypertrophy (LVH) is not necessary for maintenance of ade- quate cardiac output in the setting of increased afterload. 32 The transcriptional changes bringing about cardiac hypertrophy occur over different timescales (Table 3-9). Therefore, pathological hypertrophy should be viewed as the first stage of hypertensive cardiac failure, although cardiac output is maintained. Many of the molecular cascades, which induce hypertrophy, also cause myocyte apopto- sis and lead to myocyte dysfunction. Angiotensin II, endothelin, the gp130 signaling family, cal- cineurin-mediated gene expression, stretch- induced free radical production, and the three subfamilies of the mitogen-activated protein kinase family (ERK, JNK, and p38 kinase) are all activated during development of ventricular hypertrophy, and play roles in the transformation from the hypertrophied but stable myocardium to the irreversibly damaged and dysfunctional myocardium of the failing heart. 33,34 Gap junction remodeling also occurs between hypertrophied cardiac myocytes, leading to increased dispersion of electrical activity. 35,36 LVH causes reduced diastolic compliance, longer isovolumic relaxation time, leading to increased dependence on the atrial systole for 28––––––HEART FAILURE: A PRACTICAL APPROACH TO TREATMENT ᭤ Table 3-9 Cardiac hypertrophy— transcriptional changes 30 minutes Immediate early genes c-fos, c-jun, Erg-1, c-myc, Hsp70 6–12 hours b-MHC, skeletal a-actin a-tropomyosin, ANP Na/K ATPase 12–24 hours MLC-2, cardiac a-actin >24 hours Increased RNA, increased protein Increased sarcomerogenesis Increased cell size b-MHC—b-myosin heavy chain; ANP—atrial natriuretic peptide; ATPase—adenosine tri phosphatase; RNA— ribonucleic acid [...]... cause of incident heart failure in the population Eur Heart J 20 01 ;22 :22 8 23 6 31 Haider AW, Larson MG, Franklin SS, et al Systolic blood pressure, diastolic blood pressure, and pulse pressure as predictors of risk for congestive heart failure in the Framingham Heart Study Ann Intern Med January 7, 20 03; 138(1):10–6 32 Esposito G, et al Genetic alterations that inhibit in vivo pressure-overload hypertrophy... Circulation 20 02; 105:85– 92 33 Sugden PH Signalling pathways in cardiac myocyte hypertrophy Ann Med 20 01;33:611– 622 34 Spragg DD, Leclercq C, Loghmani M, et al Regional alterations in protein expression in the dyssynchronous failing heart Circulation 20 03; 108: 929 –9 32 35 Teunissen BE, Jongsma HJ, Bierhuizen MF Regulation of myocardial connexins during hypertrophic remodelling Eur Heart J November 20 04 ;25 (22 ):1979–89... occurrence of oxidative stress Eur Heart J 20 02; 23: 1877–1885 20 Katz AM Is the failing heart energy depleted? Cardiol Clin 1998;16:633–44, viii 21 Tang WH, Francis GS Novel pharmacological treatments for heart failure Expert Opin Investig Drugs 20 03; 12: 1791–1801 22 Kawaguchi M, Hay I, Fetics B, Kass DA Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection... the Heart Rhythm Society Circulation September 20 , 20 05;1 12( 12) :e154–e235 Mendez GF, Cowie MR The epidemiological features of heart failure in developing countries: a review of the literature Int J Cardiol 20 01;80 (2 3) :21 3–9 McDonagh TA, Morrison CE, Lawrence A, et al Symptomatic and asymptomatic left-ventricular systolic dysfunction in an urban population Lancet September 20 , 1997;350(9081): 829 –33... 20 02; 121 (5):1638–50 Zhang X, Li SY, Brown RA, et al Ethanol and acetaldehyde in alcoholic cardiomyopathy: from bad to ugly en route to oxidative stress Alcohol April 20 04; 32( 3):175–86 Naidoo DP Beriberi heart disease in Durban: a retrospective study S Afr Med J August 15, 1987; 72( 4) :24 1–4 Keen WW Quebec beer-drinker’s cardiomyopathy JAMA December 25 , 1967 ;20 2(13):1145 CHAPTER 3 WHAT CAUSES HEART FAILURE? –––––41... with chronic heart failure Br Heart J 1989;61 :23 28 4 Task FM, Swedberg K, Writing Committee, et al Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 20 05): the Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology Eur Heart J 20 05;1 ;26 (11):1115–1140 5 Hunt SA, Abraham WT, Chin MH, et al ACC/AHA 20 05 Guideline... Extracellular degradative pathways in myocardial remodeling and progression to heart failure J Card Fail 20 02; 8:S3 32 S338 17 Burlew BS, Weber KT Cardiac fibrosis as a cause of diastolic dysfunction Herz 20 02; 27: 92 98 18 Abraham WT, Fisher WG, Smith AL, et al Cardiac resynchronization in chronic heart failure N Engl J Med 20 02; 346:1845–53 19 Ceconi C, La Canna G, Alfieri O, et al Revascularization of... April 5, 20 01;410(6 829 ):701–5 This page intentionally left blank Chapter 4 Pathophysiology of Heart Failure GARY S FRANCIS, MD W H./WILSON TANG, MD Introduction 43 Adaptive Responses of the Myocardium in Heart Failure 44 Index Event—How Does Heart Failure Start? 44 Maladaptive Responses of the Myocardium in Heart Failure .45 How Adaptations in Heart Failure. .. necrosis factor-a (TNF-a )- split collagen cross-link with cell slippage and LV dilation Angiotensin II-induced apoptosis further promotes remodeling (From Opie LH Cellular basis for therapeutic choices in heart failure Circulation 20 04;110 :25 59 25 61 With permission from Lippincott Williams & Wilkins.) the myocytes properly There has been a longstanding assumption that MMPs are active in heart failure and... differential induction of peptide growth factor mRNAs Circulation 1995; 92: 2385 23 90 52 –––– HEART FAILURE: A PRACTICAL APPROACH TO TREATMENT 14 Kajstura J, Leri A, Castaldo C, et al Myocyte growth in the failing heart Surg Clin North Am 20 04;84:161–177 15 Weber KT Fibrosis in hypertensive heart disease: focus on cardiac fibroblasts J Hypertens 20 04 ;22 :47–50 16 Spinale FG, Gunasinghe H, Sprunger PD, et al Extracellular . Table 3-5 Other terms used to describe heart failure 1. Forward and backward heart failure 2. Right and left ventricular failure 3. Systolic and diastolic heart failure 4. High- and low-output heart. b-MHC, skeletal a-actin a-tropomyosin, ANP Na/K ATPase 12 24 hours MLC -2 , cardiac a-actin > ;24 hours Increased RNA, increased protein Increased sarcomerogenesis Increased cell size b-MHC—b-myosin. Circulation. September 20 , 20 05;1 12( 12) :e154–e235. 6. Mendez GF, Cowie MR. The epidemiological features of heart failure in developing countries: a review of the literature. Int J Cardiol. 20 01;80 (2 3) :21 3–9. 7.