While the root of HF is altered myocardial function, a host of compensatory systemic responses lead to the subsequent progressive clinical syndrome (Fig. 24-2
). Altered myocardial function, ventricular remodeling, altered hemodynamics, neurohormonal
and cytokine activation, and vascular and endothelial dysfunction. Multiple alterations in organ and cellular physiology contribute to HF under various circumstances. Adaptive and maladaptive processes affect the myocardium, kidneys, peripheral vasculature, smooth and skeletal muscle, and multiple reflex control mechanisms.11
Our understanding of the mechanism behind both the development and progression has evolved dramatically over the last decade (Fig. 24-3
Changes in myocardial architecture due to injury result in myocardial contractile dysfunction. The changes in architecture come about by alterations in cardiac myocyte biology, and in myocardial and ventricular structures. Ventricular contractile dysfunction leads to altered systemic perfusion. Alterations in systemic perfusion result in neuroendocrine activation resulting in progressive alterations in myocardial architecture and contractile function. In short, myocardial injury leads to altered systemic perfusion causing neuroendorine changes that result in further ventricular dysfunction. The remainder of this section examines more closely each of the steps in this process. It is important to recognize that understanding the interplay between each of these steps is a dynamic and rapidly expanding venture.
Histologically there are four prominent features of the failing heart: (1) hypertrophy of the myocytes, (2) fibrosis, (3) myocyte disarray (or unordered appearance), and (4) apoptosis. These histological processes occur secondary to myocardial ischemia, infarction, or hemodynamic overload.12
Ventricular hypertrophy is defined by an increase in ventricular mass attributable to increase in the volume of cardiac cells. The increase in ventricular mass is due to an increase in the size of the myocytes, increased number of fibroblasts, and an increase in the extracellular matrix proteins (collagen and fibronectin).
The primary goal in preventing and ultimately managing HF is protection and preservation of the myocyte. Cardiac myocytes cease replicating and dividing early in life. Myocardial insult and injury occurs as decades progress, and the compensatory adaptation often leads to dysfunction. Preventing myocyte hypertrophy, injury, and death becomes the primary goal in altering the trajectory of the syndrome of HF. Understanding the changes that occur within the cardiac myocyte provides insight into the syndrome.
Increased pressure or volume reactivates growth factors present in the embryonic heart but dormant in the adult heart. This fetal gene expression stimulates the hypertrophy of the myocytes and the synthesis and degradation of the extracellular matrix. There is some evidence that extracellular matrix degradation may elicit side-to-side slippage or disarray of myocytes, perhaps caused by dissolution of collagen struts that normally hold cells together, whereas reparative and reactive fibrosis may represent a secondary event resulting in a stiffer ventricle. Myocyte slippage may also be caused by myocyte loss.13
Hypertrophied myocytes have alterations in contractile protein synthesis and calcium cycling. Force within the myocyte is a result of the interaction of myosin and actin. Myocyte hypertrophy alters the synthesis of myocin proteins from α-myosin heavy chain toward β-myosin heavy chain. This shift in the myosin subunit alters the kinetics by which it binds to actin resulting in contraction. Initially, this change produces an energetically favorable state, but chronically this state is unsustainable and failure occurs. Altered expression or alignment of contractile proteins within sarcomeres is important, as increasing mutations in sarcomeric proteins have been linked to inherited cardiomyopathic processes. Alteration in expression and function of the contractile proteins is signaled by mechanical wall stress, angiotensin II (AT), norepinephrine (NE), endothelin (ET), tumor necrosis factor-alpha (TNF-α), inflammatory interleukins, and intracellular calcium signaling. There are changes in the sarcomeric proteins that lead to decreased contraction velocity, reduced stroke volume, and increased ventricular volume.7
Ventricular contraction and relaxation is a dynamic process controlled by the uptake of calcium by the sarcoplasmic reticulum and the efflux of calcium within the myocyte.11
Myocyte hypertrophy impacts several intracellular proteins involved in calcium cycling. The most consistent change is a significant downregulation of expression and activity of the sarcoplasmic reticulum calcium ATP-ase (SERCA) pump. While the role of SERCA in calcium handling within the myoctye is complex and remains the topic of study, the net result is a reduction in the availability of peak systolic calcium, and an elevation and prolongation in diastolic calcium, resulting in reduced systolic contraction and delayed diastolic relaxation.
The paracrine function of the heart is markedly altered in HF. Paracrine action is the release of a locally acting endocrine substance, a system in which the target cells are close to the signaling cells. The signal transduction system in the failing myocardium is profoundly altered. The failing myocardium is induced to secrete both atrial and b-type natriuretic peptides (ANP and BNP, respectively).
Actual myocyte loss may also occur by one of two mechanisms: apoptosis or necrosis. Apoptosis is a programmed cell death that is energy-dependent, producing cell dropout. Apoptosis is a highly regulated process that causes the cell to shrink, yielding cell fragments that are surrounded by plasma membrane. This process does not invoke an inflammatory or fibrotic response. Apoptosis is stimulated by hypoxia, AT II, TNF-α, myocyte calcium overload, and mitochondrial or cell injury.14
Two forms of apoptosis appear to affect the course of postinfarction remodeling: ischemicdriven apoptosis at the site of the infarction and load-dependent or receptor-dependent apoptosis at sites remote from the ischemic areas.15
Necrosis or accidental cell death occurs when the myocyte is deprived of oxygen or energy. Energy starvation of the myocyte results from an increase in energy demand and a reduced capacity for energy production.11
The inflammatory response that is induced by overload elevates circulating levels of cytokines that in turn release reactive oxygen species and free radicals. Calcium overload increases energy expenditure and slows energy production. All these processes lead to the loss of cellular membrane integrity, causing the cell to swell and eventually burst. This loss of cellular membrane integrity releases proteolytic enzymes that cause cellular disruption. The release of cell contents initiates an inflammatory reaction that leads to scarring and fibrosis. Myocyte necrosis may be localized, as in an MI, or diffuse, as from myocarditis or idiopathic cardiomyopathy.6
The vicious cycle of the overloaded heart is depicted in Figure 24-4
▪ Figure 24-2 Sequence of events in heart failure. An increased load or myocardial abnormality leads to myocardial failure and eventually heart failure, resulting in increased sympathetic activity, increased activity of the renin-angiotensin-aldosterone system, pulmonary and peripheral congestion and edema, and decreased cardiac output reserve. Both the atrial natriuretic and b-type natriuretic plural-peptides are also released in response to increased plasma volume. (From Francis, G. S., Gassler, J. P., & Sonneblick, E. H. . Pathophysiology and diagnosis of heart failure. In J. W. Hurst [Ed.], The heart [10th ed.]. New York: McGraw-Hill.)
▪ Figure 24-3 The evolution of HF along AHA/ACC guidelines for the diagnosis and management of HF clinical stages. (From Schocken, D. D., Benjamin, E. J., Fonarow, G. C. , et al. . Prevention of heart failure. A scientific statement from the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation, CIRCULATIONAHA. 107.188965.)
▪ Figure 24-4 Energy starvation contributes to several vicious cycles that cause myocyte necrosis by increasing energy utilization and decreasing energy production. Reduced turnover of the calcium pumps of the sarcoplasmic reticulum and plasma membrane, the Na/Ca exchanger, and the sodium pump impair calcium removal from the cytosol. The resulting increase in cytosolic calcium inhibits actomyosin dissociation, which in addition to impairing relaxation increases energy utilization and so worsens the energy starvation. Aerobic energy production is also inhibited when cytosolic calcium is taken up by the mitochondria, which uncouples oxidative phosphorylation. The resulting increase in cytosolic calcium amplifies these vicious cycles and can lead to necrosis of the energy-starved cells. (From Katz, A. M., & Konstam, M. A. . Heart failure: Pathophysiology, molecular biology and clinical management. Philadelphia: Lippincott Williams & Wilkins; adapted from Katz, A. M. . Physiology of the heart [4th ed.]. Philadelphia: Lippincott Williams & Wilkins.)
Myocardial remodeling in the failing myocardium involves complex events at the molecular and cellular levels.16
When the heart is presented with an increased workload by either pressure or volume overload, or by myocardial abnormality, a number of physiologic alterations are evoked in an attempt to maintain normal cardiac pumping function. Myocardial contractility (inotropy) and relaxation (lusitropy) are impaired in patients with HF. In addition, systemic hemodynamics, which include both preload and afterload, and ventricular architecture (shape, cavity size, and wall thickness) determine ejection and filling of a failing heart (Fig. 24-5
As diastolic filling increases, ventricular dilatation occurs in response to maladaptive growth response and remodeling of the damaged or chronically overloaded heart. Renal compensatory mechanisms cause sympathetic stimulation, thus increasing the end-diastolic volume or preload. The Frank-Starling response is immediately activated as a consequence of increased diastolic volume. According to the Frank-Starling law, length-dependent changes in contractile performance during diastole increases the force of contraction during systole. The increased preload augmenting contractility is the major mechanism by which the ventricles
maintain an equal output as their stroke volumes vary.7
It may be useful to consider normal and impaired myocardial function within the framework of the Frank-Starling mechanism, as illustrated by analysis of LV function curves (Fig. 24-6
). Cardiac output or cardiac index (CI) is used as a measure of ventricular work; LV end-diastolic pressure or pulmonary artery wedge pressure (PAWP) is used as a reflection of preload. The normal relation between ventricular end-diastolic volume and ventricular work is shown in Figure 24-6
by curve 1. Optimal contractility occurs at a diastolic volume of 12 to 18 mm Hg. If the heart is physiologically stressed, as occurs in acute MI, the initial drop in cardiac output stimulates the sympathetic nervous system. An increase in sympathetic tone elevates heart rate and contractility, illustrated in Figure 24-6
by curve 2. As the cardiac workload increases and myocardial dysfunction persists, HF progresses. HF progression is reflected by further elevation of end-diastolic volume (preload) and ventricular dilatation. This increased preload, in turn, may further contribute to depressed ventricular contractility and the development of congestive symptoms (Fig. 24-6
, curve 3).17
▪ Figure 24-5 Patterns of ventricular hypertrophy and remodeling in various forms of cardiomyopathy. (From Katz, A. M., & Konstam, M. A. . Heart failure: Pathophysiology, molecular biology and clinical management. Philadelphia: Lippincott Williams & Wilkins; adapted from Konstam, M. A. . Systolic and diastolic dysfunction in heart failure? Time for a new paradigm. Journal of Cardiac Failure, 9, 1-3.)
▪ Figure 24-6 Left ventricular function curves. Curve 1: Normal function curve, with a normal cardiac output at optimal filling pressures. Curve 2: Cardiac hyperfunction, with an increased cardiac output at optimal filling pressures. Curve 3: Compensated heart failure, with normal cardiac outputs at higher filling pressures. Curve 4: Decompensated heart failure, with a decrease in cardiac output and elevated filling pressures. Curve 5: Cardiogenic shock, with extremely depressed cardiac output and marked increase in filling pressures. (Adapted from Michaelson, C. R. . Congestive heart failure [p. 61]. St. Louis: CV Mosby.)
The normal left ventricle is able to adjust to large changes in aortic impedance (afterload) with small changes in output, in part by calling on the Frank-Starling response and, perhaps, by augmenting the contractile force as an intrinsic property of the normal myocardium. In contrast, the damaged left ventricle loses this compensatory ability and becomes sensitive to even small changes in impedance.18
Because increased activity of the sympathetic nervous system or the renin-angiotensin-aldosterone system (RAAS) results in vasoconstriction of the small arteries and arterioles, increased impedance of LV filling is imposed, decreasing the stroke volume and cardiac output. Because HF is characterized by heightened activity of these neurohormonal vasoconstrictor systems, a positive-feedback loop can be generated in which impaired pump performance increases impedance to LV ejection, further impairing pump performance.
Changes in the composition of the myocardium occur in response to injury or overload and result in structural remodeling, divided into both cellular and noncellular changes. Several of the cellular changes have be discussed in the prior section and include changes within the cardiomyocytes (hypertrophy, apoptosis, and necrosis) but several alterations in other cell types, such as fibroblasts, vascular smooth muscle cells, monocytes and macrophages, also contribute to ventricular remodeling. Noncellular components of the myocardium likewise contribute to remodeling. There is an increase in interstitial deposition of collagen fibers and an increase in perivascular deposition of collagen, leading to thickening of the walls of the small intramyocardial arteries and arterioles.
Throughout the body there is a fine balance of synthesis and degradation. Fibroblasts within the myocardium produce collagen. Excesses in ventricular collagen are thought to be caused by both an increase in collagen synthesis by the myofibroblasts and an associated reduction in collagenase activity.19
The balance of synthesis and degradation of myocardial fibrosis is complex. But it is intriguing that many of the substances known to be elevated in patients with HF are highly profibrotic and include angiotensin II, ET, NE, aldosterone, and interleukin-6. In contrast many substances that facilitate degradation seem to be lacking in patients with HF, including bradykinin, prostaglandins, and TNF-α.11
Thus, myocardial fibrosis, which accounts for a large part of the structural changes seen in patients with HF, may be the consequence of the loss of regulation that exists between synthesis and degradation.
Neurotransmitters such as NE, secreted at sympathetic nerve junctions within the myocardium, attempt to help the myocardium meet the increasing demands of the body. β-Receptors located within the myocardium serve as the portal to activation. Stimulation of β1-receptors leads to increased heart rate, contractility, and speed of relaxation. Myocardial injury leads to neurohormonal activation that prompts a dramatic reduction of both the number and function of β-receptors within the myocardium, resulting in impaired signal transduction and disturbances in myocellular calcium metabolism.
The metabolism of the failing myocardium likewise is altered adversely. In fact, the hyperadrenergic state of HF initiates a metabolic vicious cycle. The principal energy source in a normal myocardium is free fatty acids, but in hypertrophic states, switches to glucose utilization. Myocardial energy generation and utilization may have a profound effect on cellular energy levels. Altered myocardial carbohydrate metabolism and related insulin resistance are currently variables of interest in abnormal myocardial energetics.
Ventricular volume overload and increased diastolic wall stress lead to replication of sarcomeres, elongation of myocytes, and ventricular dilatation or eccentric hypertrophy. Maladaptive growth and changing myocyte phenotype leads to myocyte thickening (seen in diastolic dysfunction and concentric hypertrophy) and myocyte elongation (seen in systolic dysfunction and eccentric hypertrophy).20
These large, genetically abnormal cells cannot contract as efficiently as normal cells (Fig. 24-7
Concentric and eccentric hypertrophy impair ventricular filling. Decreased cavity size, as seen in concentric hypertrophy, decreases compliance and thus impedes venous return. Eccentric hypertrophy, which increases end-diastolic volume and pressure,
is also accompanied by a decrease in compliance.12
Mechanisms responsible for diastolic dysfunction include hypertrophy, as described, which causes an increase in passive chamber stiffness (decreased compliance) and decreased active relaxation. Decreased levels of activity of SERCA (sarco/endoplasmic reticulum calcium ATPase) to remove calcium from the cytosol and increased levels of phospholamban (a SERCA inhibitory protein) lead to a net effect of impaired relaxation. This same net effect is seen in myocardial ischemia, abnormal ventricular loading (e.g., in hypertrophic or dilated cardiomyopathy), asynchrony, abnormal flux of calcium ions, and hypothyroidism. Of interest, SERCA decreases with age, coincident with impaired diastolic dysfunction.6
Wall stiffness and associated decreased compliance is increased with age and is caused, in part, by diffuse fibrosis. Decreased compliance is also noted in patients with focal scar or aneurysm after MI. Infiltrative cardiomyopathies (e.g., amyloidosis) can also increase wall stiffness. Pericardial constriction or tamponade causes mechanical increased resistance to filling of part or all of the heart.20
Interactions with LV hypertrophy (LVH), ischemia, and diastolic dysfunction create a vicious cycle in which LVH predisposes to ischemia, the ischemia causes impairment of relaxation in the heart with LVH, and the severity of subendocardial ischemia worsens. Several mechanisms appear to lower subendocardial perfusion pressure. Coronary vascular remodeling occurs with increased medial thickness and perivascular fibrosis. The increased LV mass and inadequate vascular growth results in a loss of coronary vasodilator reserve so that there is a limited ability to increase myocardial perfusion in response to an increased oxygen demand. In addition, increased diastolic pressure exerts a compressive force against the subendocardium and restricts subendocardial perfusion.20
▪ Figure 24-7 Phenotype change of the heart at the cellular and organ levels. Normal muscle can grow in a physiologic way, as seen in the athlete’s heart. Concentric hypertrophy can result from pressure overload; eccentric hypertrophy due to volume overload, or dilated cardiomyopathy. (Adapted from Drexler, H., & Hasenfuss, G. . Physiology of the normal and failing heart. In M. Crawford, & J. P. Di-Marco [Eds.], Cardiology. London: Mosby.)
Altered Systemic Perfusion Results in Neuroendocrine Activation
The major elements of the neuroendocrine response may be described as activation of the sympathic nervous system, RAAS, and inflammatory systems. While each of these homeostatic mechanisms represents a beneficial short-term response to impaired cardiac function, they also are associated with detrimental maladaptive long-term consequences (Table 24-3
The systemic response to a decrease in cardiac output accelerates heart rate, vasoconstricts arteries and veins, increases the ejection fraction and, by promoting salt and water retention by the kidneys, increases blood volume. Salt and water retention, vasoconstriction, and cardiac stimulation are mediated by signaling molecules that play a regulatory and counter-regulatory role in HF (Table 24-4
). The various mediators evoke similar and often overlapping responses. When a regulatory signal turns on a process, counter-regulatory signals are released to turn off the process.7
Activation of the Sympathetic Nervous System.
The most important stimulus for vasoconstriction in HF is sympathetic activation that releases catecholamines. Plasma levels of NE become elevated. NE binds to α1
-adrenergic receptors increasing vascular tone to raise SVR (afterload) and mean systemic filling pressure, thereby augmenting venous return or preload (Fig. 24-8
In HF, stimulation of the sympathetic nervous system represents the most immediately responsive mechanism of compensation. Stimulation of the β-adrenergic receptors in the heart causes an elevation in heart rate and contractility to raise stroke volume and cardiac output. Sympathetic over-activity in HF may exert adverse effects on the structure and function of the myocardium
by the process of remodeling. Myocardial remodeling involves hypertrophy and apoptosis of myocytes, regression to a cellular phenotype, and changes in the nature of the extracellular matrix.11
Table 24-3 ▪ NEUROHORMONAL RESPONSE: SHORT- AND LONG-TERM RESPONSES
Salt and water retension
↑ Preload, maintain cardiac output
Edema, anasarca, pulmonary congestion
↑ Afterload, maintain blood pressure
↓ Cardiac output, ↑ energy expenditure, cardiac necrosis
Cardiac β-adrenergic drive
↑ Contractility, ↑Relaxation
↑ Cytosolic calcium (arrhythmias, sudden death
↑ Heart rate
↑ Cardiac energy demand (cardiac necrosis)
Cachexia (skeletal catabolism)
Skeletal muscle myopathy
Cell thickening (normalize wall stress, maintain cardiac output)
Cell elongation (dilation, remodeling, increased wall stress)
↑ Sarcomere number
↑ Cardiac energy demand (cardiac myocyte necrosis)
Adapted from Katz, A. M., & Konstam, M. A. (2008). Heart failure: Pathophysiology, molecular biology and clinical management. Philadelphia: Lippincott Williams & Wilkins.
Attenuating the myocardial response to NE is an important counter-regulatory change in patients with HF. Chronic sympathetic stimulation inhibits β-receptor synthesis and reduces the ability of the β-receptor to respond to the stimulus of NE. β-Receptor downregulation reduces the amount of receptors available to bind to NE. Mechanisms responsible for β1-receptor downregulation help protect the failing heart from the adverse effects of sustained sympathetic stimulation.
Table 24-4 ▪ REGULATORY AND COUNTER REGULATORY SIGNALING MOLECULES
I. Signaling Molecules Whose Major Role is Regulatory
Catecholamines (peripheral effect)
Renin-angiotensin-aldosterone system (angiotensin II)
Arginine vasopressin or ADH
Retention of fluid by kidneys
Stimulation of cell growth and proliferation
Increased contractility, relaxation, heart rate
II. Signaling Molecules Whose Major Role is Counter Regulatory
Catecholamines (peripheral effect)
Atrial natriuretic peptide
Reduced fluid retention by the kidneys
Decreased cardiac contractility, relaxation, heart rate
Inhibition of cell growth and proliferation
Adapted from Katz, A. M., & Konstam, M. A. (2008). Heart failure: Pathophysiology, molecular biology and clinical management. Philadelphia: Lippincott Williams & Wilkins.
Activation of the RAAS.
The RAAS plays an important role in HF; AT has a vast range of biologic activities (Fig. 24-9
). In addition to stimulating aldosterone, AT is a potent vasoconstrictor.11
There are four recognized AT receptor sites, but the AT1 receptors, which predominate in adult hearts, exert their regulatory effects in myocytes: vasoconstriction, increased myocardial contractility,
cell growth (hypertrophy), and apoptosis (programmed cell death). The AT2 receptor, a “fetal phenotype,” promotes counter-regulatory effects, including vasodilatation and decrease in growth and proliferation of cells. The AT1 receptor is downregulated in patients with HF.24
▪ Figure 24-8 Increased sympathetic activity may contribute to the pathophysiology of HF by multiple mechanisms. (B-AR, postsynaptic β-adrenergic receptor; RAS, renin-angiotensin system. (Adapted from Floras, J. S. . Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. Journal of American College of Cardiology, 22[4, Suppl. A], 72A-84A.)
▪ Figure 24-9 The renin-angiotensin-aldosterone system is activated in patients with heart failure. Multiple stimuli may contribute to renal release of renin into the systemic circulation, including increased sympathetic efferent activity, decreased tubular sodium delivery, reduced renal perfusion, and diuretic therapy. Natriuretic peptides (ANP, BNP), and vasopressin (ADH) (striped arrows) may inhibit release of renin. Angiotensin I is converted to angiotensin II, which is a potent vasoconstrictor; it promotes sodium reabsorption by increasing aldosterone secretion, and by a direct effect on the tubules, stimulates water intake by acting on the thirst center. (Adapted from Paganelli, W. C., Craeger, M. A., & Dzau, V. J. . Cardiac regulation of renal function. In T. O. Cheung [Ed.], International textbook of cardiology. New York: Bergamman Press.)
ADH is a pituitary hormone that plays a central role in regulation of plasma osmolality and free water clearance. It is released into the circulation in response to hyperosmolarity and AT. It causes vasoconstriction via vasopressin 1 receptors (Fig. 24-10
ET is also a potent vasoconstrictor, which is stimulated by ADH, catecholamines, AT, and growth factors. Two ET receptor sites, ET-A and ET-B, have been identified. The ET-A elicits, in addition to peripheral vasoconstriction, an increase in inotropy, fluid retention, and growth or hypertrophy. The ET-B receptor is less well understood, although it can mediate vasoconstriction and also a vasodilator effect through increased levels of nitric oxide (NO) and prostaglandins. Plasma ET correlates directly with PA pressures and PA resistance and may play a role in pulmonary hypertension seen in patients with HF.11
Counter-regulatory mediators that cause vasodilatation include the natriuretic peptides, NO, bradykinin, dopamine, and some of the prostaglandins, all of which act directly to relax arteriolar smooth muscle. NO, a free-radical gas initially known as endothelial-derived relaxing factor, is synthesized by the vascular endothelium. Inability of the endothelium to respond to vasodilator stimulus of NO may contribute to the exercise intolerance in patients with HF. Bradykinin and related peptides are vasodilators. Bradykinin is a substrate for angiotensin-converting enzyme (ACE) that is also responsible for the production of AT. In addition, bradykinin also inhibits maladaptive growth.6
Adrenomedullin is a peptide with vasodilating and natriuretic properties. It also has positive inotropic effects. The clinical importance of these effects on HF is not fully established.25
Dopamine, which is a precursor to NE, is a catecholamine that has central and peripheral effects. At low concentrations, dopamine relaxes smooth muscle; this vasodilatation lowers peripheral resistance and dilates renal blood vessels. Prostaglandin synthesis is stimulated by NE, AT, and ADH. The vasodilators are prostacyclin (PGI2) and prostaglandin E2. Because they are short-lived, they act locally to exert their effects, either released from one cell to work on another (paracrine effect) or binding to the same cell that released the prostaglandin (autocrine effect). In patients with HF, these counter-regulatory effects are often overwhelmed by the vasoconstrictor response.11
Renal compensation is triggered initially by a decrease in kidney perfusion, which decreases glomerular filtration rate (GFR) and activates the RAAS, resulting in an increased SVR and increased sodium and water absorption.22
Under normal physiologic conditions these pathways act in concert to maintain volume status, vascular tone, and optimize cardiac output. However, chronic activation of these systems leads to worsening of the syndrome.26
Mediators of the selective vasoconstrictor response include NE, ADH, AT, and ET.27
Aldosterone, a steroid hormone, increases tubular sodium reabsorption along with AT and NE. ADH acts on the collecting ducts to promote water reabsorption. In early HF, catecholamine, ADH, and ET play the major role in stimulating aldosterone secretion.23
In patients with advanced HF, the most important stimulus for aldosterone release is AT, whose levels are increased with diuretic therapy.22
Natriuretic peptides are counter-regulatory mediators produced in the body. This family of peptides includes ANP, BNP, and clearance natriuretic peptide (CNP). The heart itself produces ANP and BNP. ANP is stored mainly in the right atria, and an increase in atrial distending pressure, however produced, leads to the release of ANP. BNP, identified initially in the brain, is synthesized in the ventricles and is released in response to increased ventricular pressure.27
CNP is produced in blood vessels and in the brain. CNP appears to act primarily as a clearance receptor that regulates levels of the peptides and reduces vascular resistance
but has no natriuretic property. Both ANP and BNP promote vasodilatation and sodium excretion.28
They may also attenuate sympathetic tone, RAAS activity (see Fig. 24-9
), ADH, and the growth or hypertrophy of the ventricle.6
All three peptides are elevated in HF29 (see Fig. 24-10
▪ Figure 24-10 Arginine vasopressin (ADH) is a peptide released from the posterior pituitary gland. Angiotensin II and osmoreceptors stimulate vasopressin release; the natriuretic peptides (ANP, BNP) inhibit vasopressin secretion. Vasopressin causes vasoconstriction, renal reabsorption of water, and renal secretion of renin. (Cusco, J. A. & Creager, M. A. . Neurohumoral, renal, and vascular adjustments in heart failure. In W. S. Colucci & E. Braunwald (Eds.), Atlas of heart failure. Cardiac function and dysfunction [2nd ed.]. Philadelphia: Blackwell Science.)
The syndrome of HF is more accurately a syndrome of concomitant cardiac and renal dysfunction, each accelerating the progression of the other. Renal dysfunction in patients with HF is common and is an independent risk factor for morbidity and mortality.30
Studies have demonstrated that for every 0.5 mg/dL increase in serum creatinine there is an associated 7% risk of death.26
Interestingly, renal dysfunction is equally prevalent in patients with HF with either preserved or reduced ejection fractions.32
What is not known is whether worsening renal function itself leads to increased morbidity and mortality or if it is a marker of more severe cardiac and renal diseases.
Local and systemic inflammation plays an important role in HF, particularly in regard to disease progression.33
Cytokines are signaling peptides whose actions include cell growth and cell death through direct toxic effects on the heart and peripheral circulation. The proinflammatory or “stress-activated” cytokines include TNF-α and some interleukins (e.g., IL-1α, IL-6, IL-8, IL-12). The cardiac myocytes themselves are capable of synthesizing these proinflammatory cytokines in response to various forms of cardiac injury.34
The local inflammatory response can appear within minutes of an abnormal stress. Local inflammation of the cytokines and other mediators includes deleterious effects of LV remodeling, which include myocyte hypertrophy, alteration in fetal gene expression, contractile defects, and progressive myocyte loss through apoptosis. In addition, there may be promotion of LV remodeling through alterations of the extracellular matrix. A number of studies have shown that the local proinflammatory molecules are activated as early as New York Heart Association (NYHA) class I, which is before some of the classic neurohormonal responses, that tend to be activated in the latter stages (NYHA II thru IV). There are important signaling interactions between the RAAS and the sympathetic nervous system, along with the proinflammatory cytokines.35
Activation of the systemic inflammatory response is found in advanced HF. Cardiac cachexia and skeletal muscle myopathy, which contributes to the fatigue and muscle weakness seen in HF, is a part of the systemic inflammatory response; the elevation of the proinflammatory cytokines correlates with the severity of the syndrome. The knowledge of the role of inflammation remains incomplete. As with the hemodynamic defence reaction, the inflammatory response may be initially beneficial, but when sustained becomes deleterious.
Left-sided HF, associated with elevated pulmonary venous pressure and decreased cardiac output, appears clinically as breathlessness, weakness, fatigue, dizziness, confusion, pulmonary congestion, hypotension, and death.
Weakness or fatigue is precipitated by decreased perfusion to the muscles. Abnormalities of skeletal muscle histology and biochemistry also play a role, along with deficient endothelial function. Patients describe a feeling of heaviness in their arms and legs, and there is a reduction in exercise capacity. Cardiac cachexia is a severe complication of HF and is considered a terminal manifestation. Circulating cytokines are known to be important in tissue catabolism.
Decreased cerebral perfusion caused by low cardiac output leads to changes in mental status, such as restlessness, insomnia, nightmares, or memory loss. Anxiety, agitation, paranoia, and feelings of impending doom may develop as the syndrome progresses.
During the course of HF, pulmonary congestion progresses through three stages: stage 1, early pulmonary congestion; stage 2, interstitial edema; and stage 3, alveolar edema.27
During the early phase, little measurable increase in interstitial lung fluid is noted. There are few clinical manifestations during this phase.
Interstitial edema usually occurs when the PAWP exceeds 18 mm Hg, leading to a net filtration of fluid into the interstitial space. Clinical manifestations of interstitial edema are varied. Engorged pulmonary vessels, elevated PA pressure, and reduced lung compliance cause increased exertional dyspnea.22
If LV function is severely impaired, orthopnea or a nonproductive cough may be present. Paroxysmal nocturnal dyspnea may also occur because of postural redistribution of blood flow that increases venous return and pulmonary vascular pressure when the patient is in a recumbent position. Congestion of the bronchial mucosa that increases airway resistance and the work of breathing may also contribute to paroxysmal nocturnal dyspnea.
Pulmonary crackles are first noted over the lung bases, and as the PAWP increases, they progress toward the apices.
Stage 3 occurs when the PAWP rises to 25 to 28 mm Hg, causing rapid movement of fluid out of the intravascular and interstitial spaces into the alveoli. As the edema progresses, the alveoli no longer remain open because of the large fluid accumulation. At this point, the alveolar-capillary membrane is disrupted, fluid invades the large airways, and the patient describes or exhibits frothy, pinktinged sputum. Acute pulmonary edema is a catastrophic indicator of HF. These pulmonary congestion stages are broad categories. The correlation between a patient’s PCWP and clinical symptoms is highly variable and most likely dependent upon the duration of illness and individual compensatory mechanisms.
Right-sided HF, associated with increased systemic venous pressure, gives rise to the clinical signs of jugular venous distension, hepatomegaly, dependent peripheral edema, and ascites.22
Dependent ascending peripheral edema is a manifestation in which edema begins in the lower legs and ascends to the thighs, genitalia, and abdominal wall. Patients may notice their shoes fitting tightly or marks left on the feet from their shoes or socks. Weight gain is what most patients recognize; consistent self-weighing in the morning helps to detect subtle changes in fluid status. An adult may retain 10 to 15 lb (4 to 7 L) of fluid before edema occurs.
Congestive hepatomegaly characterized by a large, tender, pulsating liver, and ascites also occurs. Liver engorgement is caused by venous engorgement, whereas ascites results from transudation of fluid from the capillaries into the abdominal cavity. Gastrointestinal symptoms such as nausea and anorexia may be a direct consequence of the increased intra-abdominal pressure.
Another finding related to fluid retention is diuresis at rest. When at rest, the body’s metabolic requirements are decreased, and cardiac function improves. This decreases systemic venous pressure, allowing edema fluid to be mobilized and excreted. Recumbency also increases renal blood flow and GFR, also increasing diuresis. Table 24-6
lists the various subjective and objective indicators for LV and right ventricular (RV) failure.