INTRODUCTION
Heart failure is defined differently by various authors (see Chap. 1), but for the clinician, it is fundamentally a complex clinical syndrome, and not a stand-alone diagnosis. Like anemia or renal failure, it has many causes and etiologies. Although the pathophysiology is to some extent dependent on the etiology, there are many common features regardless of the underlying cause and there are always some underlying structural abnormalities. The clinical symptoms include shortness of breath and fatigue, either at rest or during exertion. In advanced cases, there is usually evidence of salt and water retention.

This chapter will deal with pathophysiologic mechanisms that contribute to the development and progression of signs and symptoms of heart failure. In general, heart failure implies structural disease of the heart with functional consequences to the circulation. It causes signs and symptoms in patients, and can theoretically occur from any form of heart disease. Hypertension, coronary artery disease, valvular heart disease, and cardiomyopathy are leading causes of heart failure in the Western world (see Chap. 3). Heart failure should be distinguished from circulatory failure, which occurs when a component of the circulation impedes circulatory homeostasis, such as excessive circulating volume from acute renal failure. In such cases, the heart itself may be structurally and functionally normal, so that the term “circulatory failure” may be preferred by some. Heart failure may also occur in patients with acute infective endocarditis when the heart is suddenly overloaded with acute aortic regurgitation, at least in the early stages. Myocardial performance may be normal in such settings, but the heart is structurally and functionally abnormal because of sudden valvular insufficiency. These multiple variations and various terminologies have added some confusion as to what really constitutes heart failure. For purposes of this chapter, heart failure is a clinical syndrome (i.e., there are signs and symptoms) with some underlying structural heart disease.

ADAPTIVE RESPONSES OF THE MYOCARDIUM IN HEART FAILURE
The heart has many short-term adaptations to offset a perceived reduction in myocardial performance or excessive hemodynamic load. The use of the Frank-Starling mechanism allows increased preload or enhanced end-diastolic volume to sustain cardiac performance, both under normal conditions and during heart failure. The sympathetic nervous system is activated, thus increasing the force of contraction of the heart and the heart rate. The sympathetic nervous system, among other mechanisms, also facilitates the activation of the renin-angiotensin-aldosterone system (RAAS), which operates to restore circulating volume (if it is reduced) and protect blood pressure (if it is falling), thereby maintaining perfusion of vital organs mainly via physiologic effects of angiotensin II. The heart under chronic “siege” can also increase its own mass, with or without chamber dilatation, to augment the number of contractile filaments.1 The increase in myocardial mass and remodeling of the heart occurs over a prolonged period of time (usually months to years), while activation of the Frank-Starling mechanism, the sympathetic nervous system, and the RAAS occur nearly instantaneously. Together, these mechanisms converge to allow the heart to physiologically adapt to impaired function and perverse loading conditions.2 Circulatory homeostasis and cardiac output can be maintained despite a reduced ejection fraction. These adaptive myocardial responses allow blood pressure to be protected and allow the development of clinical overt heart failure to be forestalled.

Release of counter-regulator peptides from the heart such as natriuretic peptides may also aid the failing heart by promoting peripheral vasodilation, natriuresis and diuresis, and by offsetting activation of the sympathetic nervous system and the RAAS.3 These adaptive responses are evolutionary remnants that have provided a survival advantage long before heart failure was ever a threat. They continue to provide short-term and some long-term adaptation in patients with heart failure.

Index Event—How Does Heart Failure Start?
Heart failure has a beginning, and this is often referred to as the “index event.” This event may be clinically obvious, such as the sudden loss of large amounts of contractile tissue, as might occur in the setting of an acute myocardial infarction (AMI). Or, the index event might be insidious, such as the development of poorly treated hypertension, the gradual development of aortic stenosis, aortic insufficiency, or mitral insufficiency. In some cases, the index event might go undiagnosed, such as the onset of lymphocytic infiltrative myocarditis or amyloid heart disease. Or, the index event might be clinically silent, such as the expression of mutant gene or genes that eventually lead(s) to hypertrophic or dilated cardiomyopathy. Recognizing, defining, and understanding the index event is very important in grasping how the heart failure will likely evolve, the pace at which it will worsen, the prognosis, and the appropriate treatment. To say the patient has “heart failure” is not enough. The etiology, mechanism of onset, and progression should be considered in all cases. Physicians should make an attempt to know where the patient is in the natural history of the syndrome, and how the process is unfolding over time. That being said, in the “real world,” many patients with heart failure do not have an obvious underlying cause identified, despite extensive evaluation (Chap. 7).

MALADAPTIVE RESPONSES OF THE MYOCARDIUM IN HEART FAILURE
Eventually, if the mass of poorly or noncontracting myocardial tissue is sufficiently large, or if the loading conditions are very adverse, the heart will fail. The cardiac output will progressively fall, the arterial-mixed venous oxygen difference may widen, and the kidneys begin to retain salt and water. Concomitant with these changes, the patient may become progressively more symptomatic with shortness of breath, fatigue, and “congestion.” These changes may wax and wane, can take days or years to express themselves, and can sometimes be remarkably attenuated with proper treatment. The pace at which the natural history of heart failure unfolds is highly variable and depends on many extrinsic factors (diet, response to medications, compliance of drug therapy, etc.) as well as intrinsic factors (gene expression, age, severity of index event, etc.) that often lie beyond the control of the physician. This is why it has been so difficult to predict prognosis in individual patients. Nevertheless, it is always worth considering the underlying mechanisms of how each individual patient arrived at the point that the physician first sees them. In a sense, heart failure represents adaptations that have “gone awry,” or fail to curb the relentless progression of the syndrome.

HOW ADAPTATIONS IN HEART FAILURE GO WRONG
Most of the adaptations that occur in patients with heart failure evolved for short-term benefit, such as to allow “fight or fright” (the sympathetic nervous system), to ward off hemodynamic compromise from blood loss (sympathetic nervous system and RAAS), or severe dehydration (RAAS). As rudimentary life-forms gradually moved from the salty oceans to land, those who evolved mechanisms to conserve salt and water (such as the RAAS) ensured themselves a distinct survival advantage in a relatively salt and water-poor environment. The evolution of the sympathetic nervous system also ensured survival in the face of imminent danger in a very hostile environment by protecting blood pressure, promoting hemostasis, and increasing heart rate, awareness and the ability to escape the hostile environment. These are very old evolutionary steps, perhaps some 600 million years old that were never powerful enough to ward off the ultramodern scourge of coronary heart disease, myocardial infarction, hypertension, valvular heart disease, and heart failure. Thus, although they may still be adaptive in the early stages of heart failure, they ultimately become very counterproductive, contributing importantly to the pathophysiology of the heart failure as myocardial dysfunction progressively worsens. This transition from adaptive to maladaptive activation of the sympathetic nervous system and RAAS, and from early structural changes in the heart and vasculature to progressive organ dysfunction, best characterizes the pathophysiology of heart failure. Ultimately, there is the release of a host of potentially detrimental neurohormones and cytokines, more perverse loading conditions, a change in the size and shape of the heart, ineffective attempts at maintaining circulatory homeostasis, and multiorgan failure.

The Frank-Starling Mechanism
Simply stated, the Frank-Starling mechanism refers to the fact that the energy of contraction is a function of the muscle fiber length. The end-diastolic volume regulates the work of the heart. The sarcomere length in normal dog hearts at the midwall of the left ventricle averages 2.1 µm at end diastole, and 1.8 µm at end systole. Although Starling believed that a descending pressure-volume limb occurred in the canine heart, this is in reality not likely. Mitral valve incompetence occurs at very high left ventricular (LV) distending pressures, resulting in mitral regurgitation and a decrease in cardiac output. In skeletal muscle, there is a descending limb, as there is a diminishing overlap of thick and thin filaments with increasing muscle length. Such is not the case with the heart, where there is a narrow optimal length of sarcomeres at 2.2 µm. Stretching beyond that point may diminish LV performance.

Patients with heart failure have a blunted Starling relationship at rest and during exercise, so that for any degree of stretching of the myocardium due to elevated end-diastolic volume, there is less incremental change in the contractile state of the myocardium.4 In heart failure, ventricular function curves cannot be elevated to normal ranges by the adrenergic overdrive, probably in part because the failing heart is relatively deplete of tissue norepinephrine as well as b1receptor density. Even during exercise, the ventricular function curve’s upward movement is blunted. Patients with progressive heart failure continue to use their day-to-day Starling forces to drive forward flow, but their ability to respond to increased end-diastolic volume is clearly diminished. They manifest less “cardiac reserve” when called upon to increase myocardial contractility.

Distribution of Cardiac Output and the Role of the Peripheral Vasculature
There is usually increased vascular tone in patients with more advanced heart failure. This crude attempt to maintain perfusion pressure in the face of a falling blood pressure also occurs in the setting of hypovolemia, which is a much older biological phenomenon than heart failure. Volume depletion has had many millions of years to allow for favorable mutations to counteract the problem. Those species that were able to adjust to a paucity of salt and water in the environment evolved systems that conserve salt and volume, thus enhancing perfusion to vital organs in order to survive. The sympathetic nervous system and the RAAS serve this purpose. Of some interest, they also appear to be activated in patients with very early LV dysfunction even prior to the development of symptoms.5

Blood flow is also redistributed in patients with heart failure, with more relative flow being directed towards vital organs such as the brain, heart, and splanchnic beds despite an overall reduction in cardiac output. Skeletal muscle flow is also increased at rest in heart failure, while renal blood flow is reduced. Reflex control mechanisms are altered in a complex manner to help facilitate redistribution of flow. Baroreceptor reflexes are impaired, so there is less bradycardia during a rise in arterial pressure. There may also be some structural changes in the vessel walls, thus reducing vascular compliance. The sodium content of the vascular wall may be increased, contributing to arterial stiffening and increased thickness of the vascular wall.

The response to hyperemia is blunted in heart failure, and exercise-induced vasodilation is also clearly attenuated. This is at least in part due to peripheral vascular endothelial dysfunction common to the heart failure condition. Some of the vasodilator response can be restored by administering L-arginine, a precursor to endotheliumderived nitric oxide (NO). There may be impaired expression of NO synthase in the peripheral vasculature of patients with heart failure, whereas inducible NO synthase may be increased in the myocardium, leading to diminished myocardial responsiveness to catecholamines. Therefore, NO’s role in the heart failure syndrome is very complex, and may be quite discordant in the peripheral vasculature and heart muscle.6 The level of myocardial NO in the failing heart has been a point of controversy. Increased expression of inducible NO synthase has been observed in failing myocardium.7 NO may mediate the effects of inflammatory cytokines (e.g., tumor necrosis factor-a [TNF-a]) on b-adrenergic receptor function, making the heart less responsive to catecholamines. It may also act to facilitate apoptosis. Its role in the syndrome of heart failure is not yet very clear, but it likely has some role that remains poorly defined.

Taken together, these changes in cardiac output distribution, altered reflexes, and impaired conductance of flow are probably adaptive in offsetting a low cardiac output. Redistribution of blood flow to more vital organs likely offers an additional survival advantage. However, over time such “adaptive” responses may worsen renal function, impair exercise tolerance, and favor tissue and circulatory congestion. While we know that the RAAS is activated in response to dehydration, diuretics, a low-sodium diet, and a hyponatremic perfusate to the macula densa of the kidney, we still do not clearly understand what activates the sympathetic nervous system in patients with heart failure. However, activation of the sympathetic nervous system has long been associated with a poor prognosis, and likely plays a predominant role in the long-term pathophysiology of heart failure along with prolonged activation of the RAAS.8,9 Many of the changes observed in the size, shape, and geometry of the heart itself in the syndrome of the heart failure are likely related to excessive sympathetic stimulation and heightened RAAS activity, which act as growth factors to promote myocyte hypertrophy.10

Ventricular Remodeling
When the heart is under perverse loading conditions, whether it is volume or pressure overload, it responds with myocyte hypertrophy. Pure volume overload tends to elongate the cardiac cell due to new sarcomeres being laid down in series, so-called eccentric hypertrophy. Pure pressure overload leads to an increase in cell size due to the generation of new sarcomeres being laid down in a parallel fashion, so-called concentric hypertrophy.11 The length of the sarcomeres does not change, but because of more sarcomeres per cell, the size of the cell increases. The typical mammalian myocyte may be 130–160 µm long, but lengths up to 400 µm can be observed in specimens taken fresh from diseased hearts in patients undergoing heart transplantation for severe chronic heart failure.12 Although there is the possibility that some cardiac myocytes may undergo cellular division, this is unusual. For the most part, the cardiac myocyte responds to altered loading conditions by changing its size and shape. This in turn leads to a change in the size and shape of the heart, so-called myocardial “remodeling.” The regulation of how the altered pressure or volume signal is transduced in such a way as to specify eccentric or concentric hypertrophy is still poorly understood, but different gene patterns are involved for each phenotype.13 In heart failure, there is often a hybrid of both eccentric and concentric hypertrophy, with length usually being disproportionately affected. It is the convergence of abnormal loading conditions and neurohormone release that contributes to myocyte hypertrophy, thus leading to increase LV mass (essentially an adaptive response). However, as the LV chamber relentlessly dilates, systolic wall stress may increase, thus impairing LV systolic function, and hastening the transition from left ventricular hypertrophy (LVH) to heart failure.

In chronic coronary disease, a relative volume overload may develop, stimulating the remaining viable cardiac myocytes to elongate, producing an eccentric type of hypertrophy. However, acute ischemia and myocardial infarction themselves stimulate myocyte hypertrophy directly, and often a hybrid of concentric and eccentric hypertrophy is observed in patients with ischemic cardiomyopathy. The elongation of the cardiac myocyte is associated with chamber dilation, though clearly other mechanisms come into play in the cardiac dilative process, including possibly cell dropout (apoptosis and necrosis) and “slippage” of myocytes away from proper alignment.14

LV mass is increased nearly equally in both pressure- and volume-overloaded hearts. Wall thickness is greater in pressure-overloaded hearts, but is also sufficiently thickened in volume-overloaded hearts to counterbalance the increased radius, so that the ratio of wall thickness and chamber radius can be kept normal. This is important, for if wall thickness fails to keep pace with increased radius, wall systolic stress will increase and myocardial performance will diminish. It appears as though myocardial hypertrophy develops in a manner that maintains systolic stress within normal limits. The wall thickening, at least early in heart failure, can be looked upon as a way to maintain myocardial performance by maintaining systolic wall stress. When the LV chamber size continues to dilate, wall thickness may be insufficient and clinical decompensation can occur. The changes in the geometry of the heart are critical to the eventual transition from increased LV mass to overt heart failure. The structural changes define the chronic progression of the heart failure syndrome (Fig. 4-1). The large, dilated heart is far less economical, and more likely to have serious (sometimes fatal) dysrhythmias than hearts with no structural changes, and severe dyssynchrony (electrical and mechanical) is more common.

Cardiomyopathy is the byproduct of long-standing adverse loading conditions, unrelenting neurohormonal stimulation, increased production of matrix metalloproteinases (MMPs), and enhanced cell dropout due to apoptosis and necrosis of cardiac myocytes. Of course, the myocytes themselves may demonstrate intrinsically reduced contractile strength, but this has been difficult to study. Cells isolated from their in situ milieu to undergo in vitro studies may not be truly representative of in vivo myocytes. Nevertheless, alterations in calcium excitation-contraction coupling, b-adrenergic receptor coupling to downstream proteins, myosin adenosine triphosphatase (ATPase) activity, and other regulatory proteins have been repeatedly demonstrated to be abnormal in heart failure. However, the quantitative contribution that each of these changes make to altered organ function has been elusive, and probably varies depending on the conditions under which the studies are done.

Alterations in Interstitial Matrix
In addition to an increase in myocyte size, there is increased collagen deposition within the heart as heart failure progresses. Both reactive and replacement collagen deposition are noted.15 The ratio of fibroblasts to cardiac myocytes is roughly 4:1 in human hearts. Heart failure tends to “activate” fibroblasts to produce more collagen. Increased deposition of collagen tends to make the chamber stiff, thus altering the pressure/volume relation in diastole. LV filing may be impaired. For any given left ventricular end-diastolic volume (LVEDV), there may be a greater incremental change in corresponding pressure, thus raising pulmonary capillary wedge pressure under certain conditions. This becomes an even greater problem for patients with severe hypertrophy and small LV chambers, as often observed in heart failure with preserved LV systolic function. The increased synthesis of collagen is probably related to activation of fibroblasts by angiotensin II, aldosterone, and altered stress/strain forces on the heart (Fig. 4-2).

The heart’s interstitial matrix is rich in types I and III fibrillar collagen. Type III collagen provides a weave of struts that probably helps align the myocytes properly. There has been a long-standing assumption that MMPs are active in heart failure and may sever these struts, thus allowing the myocytes to be “pulled apart,” so-called myocyte slippage.16 If this is so, it is likely that this mechanism could contribute to chamber dilation. Likewise, the activity of tissue inhibitors of metalloproteinases (TIMPs), a family of proteins that normally inhibit MMPs, may be decreased in the myocardium of patients with heart failure, thus facilitating the action of MMPs to degrade collagen struts and produce myocyte slippage.

Despite the reduction or dissolution of collagen struts normally present to align myocytes, the quantity of myocardial interstitial collagen may increase in heart failure and thus contribute to diastolic dysfunction.17 Muscle and chamber stiffness is overall increased, which has important consequences for LV filling pressure and its relation to LVEDV.

Myocyte Loss
Both reduction in LV performance and LV remodeling may be related to cell dropout or myocyte loss. Myocardial necrosis occurs, either localized as in AMI, or diffuse as seen in dilated cardiomyopathy or toxic cardiomyopathy. In contrast to necrosis, apoptosis is a genetically programmed type of cell death unassociated with inflammation or release of troponin, eventuating in phagocytosis of the remnants of the cardiac myocytes. Both types of cell death occur in heart failure, but the quantitative contribution they make to the remodeling process or cardiac dysfunction cannot be easily measured. The amount of apoptosis seems to be highly variable in various studies, but certainly could contribute to myocardial dysfunction in some cases.

TRANSITION FROM INCREASED CELL MASS TO HEART FAILURE
As the heart gradually adapts to the perturbed circulatory homeostasis of early heart failure, the LV mass increases and there may be insufficient capillary density to properly energize some cardiac myocytes. Myocardial contractility, as measured by Vmax, is diminished, and there is a decline in isometric force development and shortening velocity. Eventually, the amount of wall thickness needed to normalize systolic wall stress may be insufficient and myocardial performance further declines. Abnormalities of important cellular proteins that regulate Ca2+ exchange, excitation-contraction coupling, and force-frequency relation can be measured. However, it is not always clear if these are primary or secondary abnormalities. Nevertheless, altered excitation-contraction may be phenotypically expressed as a dyssynchronously contracting ventricle with associated electrocardiographic bundle branch block. Such patients may be greatly benefited by cardiac resynchronization therapy (i.e., biventricular pacing).18 Abnormal proteins exist and likely contribute to reduced myocardial performance and dyssynchrony. b-Receptor density is reduced, presumably in part due to excessive local concentration of norepinephrine, and there appears to be an unhinging of the membrane bound b-receptors from the Gs proteins, and a tighter coupling to the Gi proteins, thus attenuating the response to excessive norepinephrine on the heart. This is presumably an evolutionary conserved protective effect, thus preventing lethal overstimulation of the heart by catecholamines. The net result, however, is a likely reduction in myocardial reserve, as might be needed during exercise.

The transition from adaptive increases in myocardial mass to maladaptive changes leading to overt heart failure is complex and as yet not fully understood. Nevertheless, the observations of the excessive sympathetic drive and unrelenting activity of the RAAS has led investigators toward the development of b-adrenergic blocking drugs and drugs that block the RAAS, therapies proven to be the cornerstones of treatment.

Altered Myocardial Energetic in Heart Failure
Coronary blood flow at rest is often normal in patients with heart failure, but has been found to be reduced in some patients with dilated cardiomyopathy and in some with ischemic cardiomyopathy. Capillary density may be reduced as LV mass increases. Patients with LVH typically demonstrate reduced coronary reserve, a feature consistent with diminished hyperemic response common to many vascular beds in the setting of heart failure. Coronary blood flow may also diminish to match reduced contractile state, a condition referred to as “hibernating myocardium.” Importantly, hibernating but viable myocardium may improve with revascularization.19

There has been controversy as to whether myocardial oxidative phosphorylation is abnormal in heart failure. Myocardial failure in the setting of abnormal loading conditions may be associated with an inability of the mitochondria to keep pace with the needs of the contractile apparatus, the so-called “energy-starved” heart proposed by Katz and colleagues.20 Reductions in creatine phosphorylation and creatine kinase activity have been proposed, and may account for the abnormal PCr/ATP (Phosphocreatine/Adenosine triphosphate) ratio noted on nuclear magnetic resonance spectroscopy in some failing human hearts. A reduction in high-energy phosphates in the failing heart may ultimately reduce the hydrolysis of ATP, thereby reducing the amount of available energy for contraction.

Other Peptides and Inflammatory Cytokines
There is a host of neurohormones, peptides, and cytokines that are found to be increased in the syndrome of heart failure. Some may simply be markers of disease or epiphenomena, and others such as arginine vasopressin (AVP), brain natriuretic peptide (BNP), endothelin (ET), and TNF-a may play some pathophysiologic role. A number of novel strategies have been designed to block these counterproductive neurohormones (AVP, ET, and TNF-a inhibitors) or augment the counter-regulatory ones (BNP).21 To date, such strategies have been largely unsuccessful in improving survival, but such therapeutic agents often provide short-term improvement in hemodynamics and in renal function. Only b-adrenergic blockers and RAAS blockers have consistently improved long-term survival.

Diastolic and Systolic Heart Failure

Patients with systolic heart failure tend to have impaired emptying of the end-diastolic volume and impaired diastolic filling of the ventricle, whereas patients with diastolic heart failure have preserved systolic emptying of the ventricle, but often pronounced impairment of LV filling. The LV chamber tends to dilate in systolic heart failure to accommodate a low ejection fraction, whereas patients with preserved systolic function and heart failure tend to have normal or even small LV chamber size. Diastolic heart failure is characterized by LVH and a stiff chamber with impaired relaxation. Controversy remains regarding the definition of so-called “diastolic heart failure” and what the core lesion might be.22 Clinicians should be aware, however, that the two conditions (i.e., systolic and diastolic heart failure) often coexist and are indistinguishable at the bedside. They generally respond to the same therapies, suggesting that they share some common pathophysiologic features.

SUMMARY
Heart failure is a complex clinical syndrome characterized by underlying structural heart disease and/or cardiac dysfunction. The patients complain of dyspnea and fatigue, either at rest or with exertion. Virtually any form of heart disease can eventually lead to heart failure, so the etiologic basis is vast. Unifying features include activation of the sympathetic nervous system, heightened activity of the RAAS, and LV remodeling. Neurohormonal activation is a rapidly responding process that restores circulatory homeostasis in the short term, but over time contributes importantly to the pathogenesis of heart failure. LV remodeling is also adaptive in the early stages of heart failure, but ultimately is an inefficient mechanism for maintaining homeostasis. Multiple mechanisms also contribute to the pathogenesis of heart failure, providing many potential therapeutic options.

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