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HF can be caused by a number of different cardiovascular disease processes (see Table 68–1), and the interplay between the causative injury and development and progression of HF is complex. However, several important concepts have emerged with the latest developments in genetics and molecular biology. In addition, these index cardiac or extracardiac injuries can stimulate responses that can be roughly grouped into categories of neurohormonal activation for cellular and molecular responses and remodeling for hemodynamic responses with much overlap and redundancy (Fig. 68–3). Although initially adaptive, continued neurohormonal activation and adverse remodeling can, in turn, result in further cardiac and extracardiac injury (eg, vascular, pulmonary, renal) in a vicious cycle. Relatively little is known regarding what exactly precipitates the transition from a chronic, compensated state to acute decompensated state in many cases. Interestingly, some patients can spontaneously resolve their HF through mechanisms that are not well understood and remain a focus of active exploration.
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Mechanism of Cardiovascular Injury and Progression
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Altered Cellular Proteins
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Alterations are found in the failing heart in numerous contractile proteins, especially in heredity-based dilated cardiomyopathies. In the latter situation, these alterations can interact with additional injuries or abnormal loading conditions to result in HF. Such alterations found in the contractile proteins (myosin and actin), regulatory proteins (troponins and tropomyosin), and cytoskeletal proteins (myosin-binding protein C and titin) are likely to contribute to diminished myocardial performance. In the failing human heart, many changes in gene expression at the messenger ribonucleic acid (mRNA) or protein level have been found in hearts explanted at the time of cardiac transplantation. However, interpretation of end-stage HF findings may be complicated by many factors (eg, receiving multiple inotropic drugs) that can obscure the initial pathogenesis.
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The fact that more than half of the volume of cardiac myocytes is comprised of contractile proteins speaks volumes about the importance of contractile proteins in cardiac function. Briefly, a myocardial cell contains bundles of myofibril, which is made of functional units of sarcomere. A sarcomere contains myosin (thick) and actin (thin) filaments (Fig. 68–4).18 Hydrolysis of adenosine triphosphate (ATP) causes myosin and actin to slide past each other, shortening myofibrils and ultimately producing myocyte contraction; this is the foundation of the power of myocardium. Myosin contains both heavy and light chains. Two myosin heavy-chain (MHC) isoforms are present in mammalian heart, α- and β-MHC. The α-MHC is cardiac specific and is more enzymatically active. The less active β-MHC is present in the heart and in slow-twitch skeletal muscle. The distribution of α- and β-MHC is developmentally and hormonally regulated. Mechanical stress, such as pressure overload, induces an α- to β-MHC transition in the ventricles of experimental animals, thus imparting a slower but more economical type of work for the overloaded heart.
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There is a general agreement that myofibril function is decreased in the failing human heart, but its causative role remains controversial. Downregulation of α-MHC and upregulation of β-MHC using mRNA measurements from right ventricular endomyocardial biopsies from non-HF and HF patients has been demonstrated, and their sequential changes can be observed with recovery of cardiac performance.19,20 This alteration, if translated into protein expression, would decrease myosin adenosine triphosphatase (ATPase) enzyme velocity and slow the speed of contraction. Although such adaptive changes may provide a survival advantage in the face of increased load, slower contraction and relaxation could also contribute to abnormal myocardial relaxation (also known as lusitropy). In addition, isoform changes involving both the heavy and the light chains, as have been suggested, can play a role in HF. However, in contrast to smaller mammalian species such as mouse, rat, and rabbit, in which many of mechanistic experiments have been performed, the human ventricle contains a large amount of slow β-MHC to begin with (at least 90%). An isoform shift to increase the large amount of β-MHC already present in the cell may not translate to a significant difference in its function. In addition to myosin heavy- and light-chain isoform switches, other well-understood pathologic events also contribute to altered cardiac function in various forms of HF. Point mutations of virtually all of the sarcomere proteins cause hypertrophic cardiomyopathy. Similarly, mutations in the cytoskeletal proteins that provide the molecular scaffolding for the sarcomere have been found in both dilated and hypertrophic cardiomyopathies. Echocardiographic studies have demonstrated that 20% of first-degree relatives of patients with idiopathic dilated cardiomyopathy have enlarged LV cavities. In addition, some of the circulating autoantibodies specific to the heart and its contractile proteins have been linked to development of HF21; a high incidence of circulating anti-heart antibodies is observed among first-degree relatives with dilated cardiomyopathy and can precede development of cardiomyopathy.22,23
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Cell Membrane Ion Channels and Intracellular Calcium Kinetic Proteins
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Plasma membrane ion channels initiate excitation-contraction by generating and propagating the action potentials that depolarize the myocardium (Fig. 68–5).24 These ion channels contain several subunits that surround the ion-selective pore. The intracellular calcium (Ca2+) release channels are found in the sarcoplasmic reticulum (SR) and are quite different from those of the plasma membrane. The SR Ca2+ release channels are referred to as ryanodine receptors (RyRs) and interact with the ligand inositol triphosphate (IP3). The Ca2+ pump ATPases are found in both the plasma membrane and SR. Both calcium pumps are activated by cytosolic Ca2+. The sodium (Na+)-Ca2+ exchanger transports Ca2+ out of the cytosol into the extracellular space, using the osmotic energy of the Na+ gradient across the plasma membrane to generate active transport. The Na+-potassium (K+)-ATPase pump uses energy derived from ATP hydrolysis to exchange Na+ that enters the cell for K+ lost from the cytosol during repolarization. Also, Ca2+- binding storage proteins (eg, calsequestrin) maintain a Ca2+ store that can be readily used during excitation-contraction coupling. The heart's voltage-gated ion channels (especially inward Na+ channels) are altered in the failing heart, as are outwardly rectifying K+ channels.25,26 A common feature of both animal and human models of HF is prolongation of the action potential. Both decreased Na+ influx and K+ efflux are contributory and are mediated by reduced activity of the myocardial membrane (also known as sarcolemma) Na+ and K+ channels, respectively. This aberrant channel behavior contributes to the arrhythmias, which are the second most common cause of death of patients with HF.
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Excitation-Contraction Coupling Proteins
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Excitation-contraction coupling links plasma membrane depolarization to the release of Ca2+ into the cytosol, where it binds to troponin C, permitting the force-generating interaction between myosin and actin and ultimately contraction (see Fig. 68–5). Relaxation is also an energy-dependent process, but is not simply a reversal of the steps in excitation-contraction coupling. During relaxation, Ca2+ is actively transported out of the cytosol by entirely different molecular pumps. The basic mechanism of cardiac excitation-contraction coupling involves Ca2+ entry from the extracellular fluid by means of the voltage-dependent L-type Ca2+ channel to produce a trigger in increasing [Ca2+]i and opening of the intracellular SR Ca2+ release channel or RyR. Key defects in SR Ca2+ uptake and release are present in HF, including dysregulation of RyR, RyR2/Ca2+ release channel macromolecular complexes, and the SR Ca2+ transport proteins, especially the sarcoplasmic-endoplasmic reticulum Ca2+ ATPase (SERCA) and phospholamban, a reversible inhibitor of cardiac SR Ca2+-ATPase activity.27 Other Ca2+-cycling proteins, such as Na+-Ca2+ exchanger proteins, can also be altered in HF.28 Hyperphosphorylation of phosphokinase A, oxidation, or nitrosylation of RyR2 can lead to SR Ca2+ depletion, increased risk of arrhythmias, and impaired contractility. HF is characterized by reduced myosin-actin myofibril activation and decreased Ca2+ available for activation as well as heightened cytosolic Ca2+ levels in diastole. Some studies have shown increased myosin-actin myofibril Ca2+ sensitivity and altered Ca2+ kinetics.29 These abnormalities of Ca2+ metabolism can affect HF manifestation to varying degrees. Several potential therapeutic strategies to improve utilization of Ca2+ are being tested in humans, including those targeting SERCA2a and RyR2, and many more are being tested in animal models.30,31
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Metabolic Adaptations and Maladaptations
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The healthy heart works incredibly hard in maintaining forward blood flow every day; it pumps more than 7000 L/d and extracts energy from more than 6000 g of ATP daily.32 Not surprisingly, many abnormalities and inefficiencies in myocardial energy metabolism have been shown to occur in HF; these include altered energy substrate with an increased dependence on glucose, decreased oxidative phosphorylation, and high-energy phosphate and mitochondrial dysfunction.33 This is a potentially valuable area of therapeutic exploration because decreased myocardial metabolism and resulting dysfunction can result in adverse compensatory remodeling in the rest of the heart. Improving myocardial metabolism, in particular, of stunned or hibernating myocardium (as happens with chronic oxygen deprivation from coronary artery disease) may break this cycle of adverse remodeling.
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The primary substrate of energy in the normal myocardium is fatty acid, with a small contribution by glucose, lactate, amino acids, and ketones.34 Although the myocardial uptake of fatty acids and glucose appears to be preserved in HF, there is a shift from primarily fatty acid metabolism to glucose metabolism through changes in enzymatic regulation. Interestingly, this increased dependence on glucose metabolism is similar to the fetal heart's use of glucose as the primary energy substrate in the relatively hypoxic environment.35 This is likely an initially adaptive mechanism as energy extraction from glucose is much more efficient than from fatty acids; in addition, abnormalities of glucose transport in this setting have been shown to be harmful to the myocardium.36 However, insulin resistance is common in HF and may limit the benefits of a shift in metabolism to glucose.
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Energy Production and Storage
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Oxidative phosphorylation is the mitochondrial process by which ATP is produced in myocardial cells. In HF, there is a reduction in oxidative phosphorylation capacity, as evidenced by reduced high-energy phosphate levels, such as phosphocreatine and ATP, and an altered phosphocreatine-to-ATP ratio.37 This reduction in dilated cardiomyopathy has been closely associated with future mortality.38
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Mitochondrial ATP production is linked to myocardial need by highly efficient shuttling of high-energy phosphates via creatine kinase, adenosine monophosphate (AMP)–activated protein kinase and adenylate kinase, and glycolysis. Dysregulation of any of these enzymatic pathways is associated with myocardial dysfunction; for example, creatine kinase activities are reduced in HF, which results in a decrease in shuttling of high-energy phosphate.
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Mitochondrial Dysfunction
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Mitochondria are the driving power source of the cell; the majority of ATPs are produced by the mitochondria. There is evidence that suggests that abnormalities in mitochondria may contribute to the development and progression of HF, but many of the areas are incompletely evaluated.39 Genetic mutations affecting key mitochondrial structures, such as mitochondrial ATP synthase and acylglycerol kinase, have been shown to result in myocardial dysfunction.40,41 Some of the proven HF medications, such as angiotensin-converting enzyme (ACE) inhibitors, are associated with an improvement in mitochondrial function, as evidenced by an increase in high-energy phosphate such as ATP and creatine phosphate, the mitochondrial oxygen consumption rate,42 and viable but metabolically stunned myocytes.33 Dysfunction of the mitochondria includes abnormalities in the production of new mitochondria, enhanced generation of reactive oxidative species in the mitochondria, and dysregulation of mitochondrial iron handling.
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Neurohormonal Activation
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The neurohormonal system is one of the first activated responses to myocardial injury or to alternations in cardiac loading. Decreased cardiac output (any combination of decreased blood pressure, pulse pressure, and perfusion) is sensed by various mechanoreceptors throughout the body including the left ventricle, carotid sinus, aortic arch, and afferent renal arterioles. When there is diminished activation of these receptors, as in HF, the neurohormonal system is activated in an attempt to maintain cardiac output and vital organ perfusion.
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The sympathetic nervous system is activated early, followed by the renin-angiotensin-aldosterone system (RAAS). Nonosmotic release of AVP (also known as vasopressin or antidiuretic hormone)43 and underfilling of renal arterial bed result in Na+ and water retention. Heightened peripheral vasoconstriction, increased myocardial contractility and heart rate, and increased blood volume restore cardiac output and arterial pressure in the short term.
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However, sustained and unopposed neurohormonal activation has many important adverse consequences at the cellular level, including facilitation of myocyte hypertrophy, collagen synthesis, and fibrosis, as well as promoting apoptosis and return to fetal isoforms of contractile proteins.44,45,46,47,48 Cardiac myocyte necrosis also occurs in response to pathophysiologic levels of endogenous and low-dose exogenous angiotensin II infusion.49 Activation of the sympathetic nervous system contributes to tachycardia and arrhythmias and can be directly toxic to the myocardium.50,51 With increased sympathetic tone in HF, increased phosphorylation of the ryanodine component of the L-type Ca2+ channel can lead to abnormalities of Ca2+ activation.
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Although neurohormonal activation is typically in balance with vasodilatory and natriuretic effects of counter-regulatory pathways, such as natriuretic peptides, nitric oxide, prostaglandins, and bradykinin, cardiosensory activity is impaired as HF progresses, and fails to keep unopposed neurohormonal activation in check.52
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For unclear reasons, cardiac afferent activity to the central nervous system is reduced, leading to unhindered, efferent excitatory responses from the brain to the periphery. Reflex vasoconstrictor responses to unloading the heart are paradoxically blunted.53 HF parasympathetic (vagal) tone is decreased, and heart rate variability is markedly reduced. Furthermore, decreased heart rate variability can provide independent prognostic value in the identification of patients at risk for cardiac death.54 Beat-to-beat QT interval variability on surface electrocardiograms (given relatively stable heart rate) is thought to be closely related to the subtle variations in ventricular repolarization duration as well as sympathetic nervous system activation, most likely through SR Ca2+ release.55 Increased QT interval variability has been associated with the presence of coronary artery disease, LV hypertrophy, and LV systolic dysfunction, as well as increased risk of death, sudden cardiac death, and ventricular tachycardia or fibrillation shocks in patients with implantable cardiac defibrillators. However, these data are largely based on retrospective analysis, and prospective studies are needed in a well-defined population before routine use can be recommended.
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A large number of these neurohormones and their inert counterparts circulate in increased concentrations in HF or with altered activity levels and have been evaluated as potential biomarkers (Table 68–2). Because some of these biomarkers are quite intimately linked with key pathophysiologic processes in the development and progression of HF, they constitute a fertile field for potential diagnostic, prognostic, and therapeutic targets.
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As a matter of fact, neurohormonal mechanisms are the targets of several important and successful therapeutic interventions in HF and hypertension, and have a key role in determining prognosis.56,57 ACE inhibitors, β-adrenergic blockers, and aldosterone antagonists now have a prominent role in the treatment of HF, and new, more innovative neurohormonal-blocking agents (eg, neprilysin inhibitors) are being rapidly developed, adding strong support to the neurohormonal hypothesis.58,59,60
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Autonomic Nervous System Imbalance
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Normally, the balance between the sympathetic and parasympathetic system is tightly regulated and maintained. In HF, one of the earliest activated pathways is the sympathetic nervous system, and the withdrawal of parasympathetic tone results in a predominantly sympathetic milieu.61 Vascular constriction, tachycardia, increased myocardial contractility, diaphoresis, and oliguria are manifestations of increased sympathetic drive, but often at the expense of increased myocardial oxygen demand.
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In addition, HF is characterized by abnormal reflex control mechanisms. Peripheral vascular resistance (systemic vascular resistance) is increased; this is likely caused by a combination of locally active heightened vasoconstrictors (norepinephrine [NE], angiotensin II, endothelin, vasopressin, neuropeptide Y) and by structural changes in blood vessels from fluid retention and reduced endothelial-dependent vasodilatation. These later changes are closely associated with limitations of exercise in HF.62 There is also defective cardiac parasympathetic control and altered baroreceptor function and reduced cardiac sympathetic activity in response to a variety of stimuli.53,63,64,65,66 β-Blockers, shown to improve clinical outcomes in HF, reduce β1-receptor–related catecholamine activity and oppose sympathetic activation.67 In animal models, renal sympathetic denervation, which aims to reduce renal sympathetic activation, was shown to improve survival and LV function as well as decrease myocardial fibrosis.68
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Sympathetic nervous system activation and subsequent increase in plasma NE levels are noted in patients with HF.69 Plasma NE levels correlate with functional class and extent of hemodynamic dysfunction.70,71,72 Although early studies of plasma NE level showed promise as a useful research and prognostic marker for patients with HF, contemporary analyses failed to show incremental benefit of NE use for prognosis beyond other established biomarkers and clinical models such as the Seattle Heart Failure Model.73 Moxonidine, an imidazoline agonist that decreases NE levels in HF patients, failed to improve HF clinical outcomes and, in fact, was associated with increased risk of death and HF hospitalizations.74,75 Interestingly, myocardial stores of NE were found to be depleted in advanced HF patients, and severe New York Heart Association (NYHA) class IV HF patients may be quite dependent on catecholamine support (ie, continuous dobutamine infusion) to maintain suitable organ perfusion. However, there is no question that high circulating levels of NE are toxic to the myocardium and are partly responsible for progressive adverse LV remodeling.76 NE is thus a double-edged sword in HF.
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Myocardial Receptor Dysfunction
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The failing heart commonly demonstrates a decreased responsiveness to inotropic stimuli. A reduction in myocardial β-adrenergic receptors and the subsequent second messenger cyclic adenosine monophosphate (cAMP) plays an important role.77 β-Adrenergic stimulation contributes importantly to the cardiac response to exercise, and β-adrenergic desensitization and uncoupling can be at least partially responsible for the reduced chronotropic and inotropic response to peak exercise commonly found in patients with HF. The β-adrenergic receptor abnormalities in HF appear to be caused by desensitization and uncoupling of the β1-receptor produced by local rather than systemic alterations in catecholamines. In severe HF, the NE stores in sympathetic nerve endings are depleted. In a sense, the failing myocardium becomes functionally denervated. cAMP responses are reduced by approximately 30% to 35%, leading to further contractile dysfunction. Despite downregulation of the β1-receptor, a relatively high proportion of β2-receptors remains to mediate chronotropic and inotropic responses.78 However, there is some uncoupling of the β2-receptor from its G protein and a modest upregulation of the Gαi subunit, further contributing to a depressed response to chronotropic and inotropic stimuli.79 There is also a marked decrease in cardiac β-adrenergic responsiveness with aging, which has clinical implications because HF is heavily concentrated in the elderly population.80
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The desensitization and uncoupling of β-adrenergic receptors that occurs early with mild-to-moderate ventricular dysfunction is related to the degree of HF and is associated with a reduced response to β-adrenergic stimulation with drugs such as dobutamine. Long-term stimulation of β-adrenergic receptors can enhance myocardial β-adrenergic receptor kinase activity, leading to further desensitization and uncoupling of the β-adrenergic receptor.81
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Of great therapeutic interest, β-adrenergic blockade with metoprolol and bisoprolol, relatively cardioselective β1-blockers, upregulates the β1-receptor, but carvedilol, a nonselective β1- and β2-blocker with additional α1-blocking activity, does not increase β1-receptor density.82,83 These drugs improve LV function substantially in approximately two-thirds of patients. The ventricular improvement seen with chronic β-blocker use may not be caused by upregulation of β-adrenergic receptors alone, and the beneficial effects of β-adrenergic receptor blockade in HF remains incompletely explained. Moreover, high plasma NE levels do not predict benefit from carvedilol,84 suggesting that there is not a simple relationship between activation of the sympathetic nervous system and response to β-adrenergic blocking drugs in patients with HF.
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The Renin-Angiotensin-Aldosterone System
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The RAAS plays a pivotal role in the pathogenesis of HF (see Fig. 68–4),59 and consistent benefit has been derived from ACE inhibitor, angiotensin II receptor blocker (ARB), and aldosterone antagonist therapy in HF patients.58,85 Mechanisms responsible for the release of renin from the renal cortex have been exhaustively studied and include increased sympathetic drive in the kidneys, β-adrenergic receptor activation, and actual or perceived hypovolemia with hyponatremia or hypochloremia at the level of renal macular densa or arteriole.86,87,88 Renin proteolytic enzyme has little biologic activity, but it interacts with angiotensinogen to split off two amino acids to form angiotensin I. This is then cleaved by ACE (distributed widely in the vascular system, especially the lungs) to produce angiotensin II, a peptide with a vast range of biologic activities. Angiotensin II in turn stimulates release of aldosterone from the adrenal cortex, which also has an array of biologic effects, including K+ and water retention, renal salt excretion through increased urinary K+ loss by affecting the Na+-K+ exchange, and enhanced collagen turnover and organ remodeling.
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There are at least four recognized angiotensin II receptors, but much of the activity is promoted by the AT1 receptor. AT1 receptor actions include arterial vasoconstriction, hypertrophy, apoptosis in myocytes, polydipsia, NE release, sensitization of blood vessels to NE, AVP release, and aldosterone release. The AT2 receptor appears to have somewhat counter-regulatory effects, including antigrowth and antiremodeling, antiapoptosis, vasodilatation, and activation of the kinin–nitric oxide–cyclic 3′,5′-guanosine monophosphate system.89 Because AT1 receptor–blocking drugs (ARBs) increase angiotensin II levels, they can indirectly activate unoccupied AT2 receptor activity. Angiotensin II levels tend to escape the pharmacologic effects of chronic ACE inhibition, irrespective of dosage, and can stimulate AT2 receptor activity.90 Although all of these components of the RAAS can be measured peripherally, local tissue activities may have a greater impact on the RAAS and reflect true biological activity of these components. Both ACE inhibitors and ARBs reduce cardiovascular events, and the role of the RAAS in the pathogenesis of heart and vascular disease, including progressive HF, is quite significant and remains an active area of investigation for therapeutic options.
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HF is frequently characterized by water retention in excess of Na+ retention, leading to hyponatremia. The hyponatremia is caused in part by the nonosmotic release of AVP from the neurosecretory cells located in the hypothalamus; AVP acts on the kidneys to reduce free water clearance and to promote vasoconstriction. Release of AVP in HF probably occurs by means of activation of carotid baroreceptors.91 Plasma AVP levels are often, but not always, increased in patients with LV dysfunction and HF.92,93 AVP acts on the V2 receptors in the collecting duct of the kidney via adenylate cyclase to translocate aquaporin-2 water channels from cytoplasmic vesicles to the apical surface of the collecting duct. AVP also increases aquaporin-2 synthesis. Activation of V1 receptors in vascular tissue contributes to heightened vascular resistance and myocardial dysfunction in HF.94 Hyponatremia is a powerful predictor of poor outcome in HF, and elevated AVP levels in HF patients are associated with severe HF. Reliable measurement of circulating AVP is challenging because of a short half-life, but the C-terminal portion of the precursor of pro-vasopressin, copeptin, has been shown to be a strong predictor of cardiovascular outcomes in HF.95 Despite its association with HF prognosis, therapeutic effects from modulation of AVP may be challenging. For example, tolvaptan, an oral AVP antagonist that improves hyponatremia, failed to improve HF mortality.96,97
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A family of natriuretic peptides, including atrial natriuretic peptide (ANP), BNP, and C-type natriuretic peptide (CNP), is encoded by separate genes, each with a tissue-specific distribution, regulation, and biologic activity.98 ANP and BNP are often increased in patients with HF, and this has been leveraged to assist in the diagnosis of acute HF.99 ANP is a 28-amino-acid peptide that is normally synthesized and stored in the atria and to some extent in the ventricles. It is released into the circulation during atrial distension. BNP is synthesized mainly by the ventricles and is released in LV dysfunction or early HF after cleavage (presumably by a protease, corin or furin) from the propeptide to BNP and NT-proBNP (Fig. 68–6).100 For the most part, these peptides act via guanylate cyclase receptors to promote vasodilatation (ANP, BNP, CNP) and natriuresis (ANP, BNP). The natriuretic peptides, ANP and BNP in particular, are considered counter-regulatory because they tend to reduce right atrial pressure, systemic vascular resistance, aldosterone secretion, sympathetic nerve stimulation, RAAS activity, and hypertrophy of cells and can enhance Na+ excretion when infused.52
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BNP is removed from circulation by a number of mechanisms, including passive clearance by high-flow organs, such as kidneys; membrane-bound, receptor-mediated clearance; and enzymatic processes including neutral endopeptidases, meprin-A, and dipeptidylpeptidase-4.101,102
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Interestingly, data suggest that patients with HF may in fact have low circulating levels of biologically active BNP despite elevated detected levels of BNP and NT-proBNP; this is because commercially available BNP and NT-proBNP assays detect a mixture of the intended target BNP or NT-proBNP, pro-BNP, and degraded BNP fragments in the overall measured level.103 Regardless, both BNP and NT-proBNP have proven diagnostic and prognostic value in HF as biomarkers (ACC/AHA HF guideline recommendation Class I), and their potential role in guiding HF therapy is being evaluated.99,104,105,106
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Recently, drugs designed to inhibit degradation of natriuretic peptides (neutral endopeptidase or neprilysin inhibitor), among other effects, have been combined with ARBs (sacubitril/valsartan) and have shown mortality and morbidity benefit in HF.58
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Endothelins are a family of vasoconstrictor peptides produced by vascular endothelial cells and may play a role in HF and pulmonary hypertension. Although blood levels are increased in patients with HF,107 endothelin-1 (ET-1) is more of a paracrine than an endocrine hormone.108 Myocardial tissue ET-1 levels may be increased in HF more as a result of decreased clearance rates than as a result of increased synthesis. Endothelial cells synthesize ET-1 rapidly and convert so-called big ET-1 into ET-1 by an endothelin-converting enzyme. Both elevated ET-1 and big ET-1 have been shown to be associated with adverse clinical outcomes in chronic HF patients,109 but the incremental role of adding ET to established markers of prognosis remains unclear. The synthesis of ET-1 is enhanced by angiotensin II, NE, growth factors, insulin, hypoxia, oxidized low-density lipoproteins, shear stress, and thrombin.110 Its synthesis is antagonized by ANP and prostaglandins.
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Endothelin acts on at least two types of G protein–coupled receptors, A and B. The ET-A receptor increases smooth muscle vasoconstriction, cell proliferation, and hypertrophy and mainly resides on vascular smooth muscle cells. The ET-B receptor, which is mainly endothelial, promotes vasodilatation that is probably mediated by a variety of mechanisms, including increased production of nitric oxide (NO) and prostaglandins and activation of K+ channels. ET-1 can also act on the heart to cause hypertrophy, on the adrenal gland to release aldosterone, and on the kidney to promote Na+ and water retention. However, blocking the effects of ET-1 has not been shown to improve symptoms or prognosis in HF in contrast to its beneficial effects in patients with pulmonary arterial hypertension.111,112
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Inflammatory Responses and Remodeling
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Cellular Responses and Cytokines
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It is now widely recognized that there is a strong association between inflammation and cardiovascular diseases. Many of the biomarkers of inflammation, such as erythrocyte sedimentation rate, C-reactive protein, tumor necrosis factor-α (TNF-α), Fas, and interleukin (IL) 1, 6, and 18, are recruited after myocardial injury, such as myocardial infarction, and are thought to be involved in the initiation of the repair process and remodeling as well as cardiac cachexia in certain subgroups of patients with injury.113,114,115,116,117 These same biomarkers are also elevated in HF and associated with poor HF prognosis independent of traditional risk factors and baseline characteristics.118 There is increasing evidence that a systemic inflammatory state caused by comorbidities may be intricately involved, especially in HFpEF, but more information is needed before a causative statement can be made.119 Practical application of these biomarkers is challenging because of the nonspecific nature of inflammation and difficulty in adjusting for potential covariables that may affect them.
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Elevated circulating levels of TNF-α can mediate cell growth, negative inotropy, and apoptosis. In cachectic HF patients, TNF-α has been associated with a marked activation of the RAAS.115 Disappointingly, inhibitors of circulating TNF-α have not been shown to alter the outcome of HF in humans despite the beneficial effects in animal studies.120 Another potential target of interest is the inflammasome. The inflammasome is a macromolecular structure that plays a central role in the inflammatory response to injury by first sensing the injury and then amplifying the inflammatory response by activating powerful cytokines. This activation of the inflammasome in the heart in the setting of injury may promote adverse ventricular remodeling and HF.121 In a mouse acute myocardial infarction model, infusion with Nod-like receptor P3 (NLRP3) inhibitor resulted in > 40% reduction in infarct size and > 70% reduction in troponin I levels (Fig. 68–7), but no clinical trials have been done to date.122
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Nitric Oxide, Endothelial Dysfunction, and Oxidative Stress
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Reactive oxygen species (ROS) are produced as a byproduct of normal aerobic metabolism and are involved in a variety of key cellular signaling and immune responses, such as myocardial excitation-contraction coupling and myocardial growth. Typically, free ROS are scavenged and neutralized by antioxidants, but when this balance between ROS and antioxidants is thrown off, these species can promote progressive cellular injury or oxidative stress.123 Prolonged exposure of ROS can lead to activation of specific pathways of oxidant stress with available substrates, such as NO, leading to enzyme activation and deactivation, DNA breakage, and lipid peroxidation, which are ultimately responsible for the subsequent myocyte apoptosis and pathologic remodeling seen in HF. Growing evidence has supported the role of heightened oxidative stress in the pathophysiology of HF.124
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Biomarkers of oxidative stress such as myeloperoxidase, albeit nonspecific, are often elevated in patients with chronic HF.125,126 Markers of oxidative stress were positively correlated to HF severity irrespective of its underlying cause.124 However, the precise mechanisms contributing to oxidative stress in HF are multifactorial. Catecholamines and angiotensin II promote pro-oxidant activities within the myocardium, including enhanced superoxide (O2–) formation and generation of NO-derived oxidants, as a necessary consequence of increased myocardial oxygen consumption. Several studies have also observed an association between insulin resistance and HF in the absence of overt diabetes.127,128 Animal and human studies indicate that endothelium-dependent vasodilatation is abnormal in a number of disease states, including atherosclerosis, hypertension, HF, hyperhomocysteinemia, insulin resistance, and hypercholesterolemia. Endothelial dysfunction has been demonstrated in patients with HF.129 As already discussed briefly, such endothelial dysfunction in HF (ie, failure to vasodilate in response to a specific endothelial-dependent vasodilator or exertion) can be caused by a reduced release of NO during stimulation. The basal release of NO can be preserved or even enhanced in HF and can be compensatory by antagonizing neuroendocrine vasoconstrictor forces.130 However, impairment of endothelium-dependent peripheral vasodilatation can be a factor contributing to exercise intolerance in patients with chronic HF, perhaps by limiting nutritive skeletal muscle flow during exercise.131 This dysfunction of the endothelium can be related to deconditioning in later stages of HF and, with training, it can be largely reversible. The roles of NO and NO synthase (NOS) in the failing heart are much more complex, and new data are emerging.132,133 NO has been considered to be present as a freely diffusible molecule, which inhibits the positive inotropic response to β-adrenergic stimulation in the failing heart.134 Smaller physiologic amounts of NO produced by constitutive NOS (cNOS or NOS3) are necessary for normal function and have an antioxidant effect that can protect cells. The inducible isoform of NOS (iNOS or NOS2) is overexpressed in human HF and, therefore, can contribute to worsening HF because high levels of NO in the heart can induce proapoptotic and cytotoxic effects.135 NO can act in subcellular signaling compartments or modules. Furthermore, covalent modification of cysteine thiol moieties of proteins (S-nitrosylation) can be an important second messenger signaling process, working in parallel with ROS and nitrogen species.136 Therefore, disruption of this cyclic guanosine monophosphate signaling process can lead to nitroso-redox imbalance by either increased formation of ROS or decreased production of reactive nitrogen species.137
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As HF progresses, there are important changes in the peripheral circulation, particularly downregulation of the NO system. Under normal conditions, NO permits peripheral arteriole dilatation and increased peripheral blood flow in response to exercise. As this system downregulates, peripheral dilatation does not occur with exercise; the lack of appropriate blood flow limits exercise and decreased functional capacity. With exercise training, this system can be restored and clinical status improved.
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Extracellular Matrix Changes
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The extracellular matrix in the heart provides the scaffolding within which contractile cardiomyocytes are housed; it contains a basement membrane, collagen network, proteoglycans, and glycosaminoglycans. Of the different types of collagens, type I and III collagens are the predominant forms found in fibrils deposited in scar tissue after myocardial injury, more specifically demonstrated in myocardial infarction models. These collagens are initially synthesized by cardiac fibroblasts as procollagen precursors before both the N-terminal and the C-terminal are cleaved by proteinases, and then the resulting tropocollagen is assembled into mature fibrils. Markers of collagen turnover, such as serum N-terminal type III collagen peptide (PIIINP), have been associated with increased death and hospitalization rates, and procollagen type I and PIIINP levels appeared to decrease following aldosterone antagonist therapy in chronic HF patients.138 In the 967 Framingham subjects without HF, PIIINP levels were not independently associated with LV mass, fractional shortening, end-diastolic dimensions, or left atrial size.139 The role of PIIINP in the pathophysiology of HFpEF has not been evaluated to date.
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The extracellular matrix is a rather dynamic system that is constantly turned over. In the setting of cardiac or extracardiac injury, regulation of extracellular matrix likely plays an important role in ventricular remodeling and fibrosis. For example, bone morphogenetic protein 1, a C-proteinase, plays a crucial role in the processing of extracellular matrix proteins and collagen deposition and regulation of excessive collagen deposition in fibrosis after tissue injury.140 Recent studies have found that gene expression of tissue inhibitor of metalloproteinases 1 (TIMP-1) and matrix metallopeptidase 9 (MMP-9) was significantly increased in the border zone of myocardial infarct models as well as ischemic HF models in rats, and that treatment with antifibrotic therapy can prevent the upregulation of MMP-9, ultimately leading to suppression of collagen deposition.141,142 Interestingly, concentrations of TIMP-1 appeared to correlate with diastolic LV dysfunction,143 In a multimarker analysis of HF patients, a panel that included TIMP-1 as well as NT-proBNP, hs-TnT, growth differentiation factor 15, and insulin-like growth factor-binding protein 4 had the best performance in predicting all-cause mortality at 3-year follow-up.144
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Soluble ST2 (sST2) initially gained attention as a marker of inflammation, cell proliferation, and autoimmune diseases involving T-helper type 2 lymphocyte responses. Since then, the close relationship between the failing heart and sST2 has come to light. In response to the biomechanical stretch of cardiomyocytes and cardiac fibroblasts, the ST2 gene is strongly upregulated, and circulating sST2 levels increase. sST2 interacts with circulating IL-33, a protein with antifibrosis and antiremodeling effects when it binds to the membrane-bound ligand receptor (ST2L), and appears to mediate the heart's ability to adapt to biomechanical stress. In experimental models, interruption of ST2L expression or infusion of high concentrations of sST2 leads to unchecked ventricular hypertrophy, fibrosis, remodeling, and higher risk for death.145 Elevated concentrations of sST2 have been closely associated with the phenotype of cardiac decompensation and remodeling and very strongly linked to adverse clinical outcomes in HF. sST2 testing for risk prediction in both acute and chronic HF recently received a Class IIb recommendation in the recent ACC/AHA HF guidelines.3 Studies have shown that sST2 adds independent and additive information to clinical assessment and natriuretic peptides.146
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A member of the lectin family closely involved in immune modulation, galectin-3 is found in a variety of cells and tissues, including the heart. Galectin-3 is involved in the initiation of the inflammatory cascade following cardiac insult and contributes to ventricular remodeling by the way of tissue repair, myofibroblast proliferation, and fibrogenesis. The galectin-3 gene is induced in animal HF models, and when galectin-3 is instilled in the pericardium, there is a considerable increase in collagen deposition.147 Murine gene knockout models showed that lack of galectin-3 offered partial protection from LV pressure and volume overload with a slower progression to ventricular dysfunction and HF. Circulating values of galectin-3 are elevated in acute and chronic HF, and data suggest that they may identify a high-risk HF phenotype resistant to conventional HF management.148,149,150 Galectin-3 testing also received a Class IIb recommendation in the ACC/AHA HF guidelines for risk prediction in HF,85 but in a head-to-head analysis, galectin-3 testing failed to show independent and additive value to sST2 in a multivariable model; when sST2 was added to a baseline model that included age, sex, LVEF, estimated glomerular filtration rate, NYHA class, diabetes mellitus, ischemic etiology HF, hemoglobin, Na+, β-blocker treatment, ACE inhibitors or ARB, and NT-proBNP for all-cause mortality at 5 years, there was a significant improvement in the C-statistic from 0.757 to 0.770 (P = .004), whereas addition of galectin-3 did not significantly change the C-statistic in a discrimination analysis (C-statistic 0.760, P = .14).151
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Myocyte Regeneration and Apoptosis
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A normal human heart weighs approximately 300 g and contains approximately 2 × 1010 myocytes. Until recently, the accepted understanding was that myocyte cell division in the human heart ceased a few weeks after birth.152 Thereafter, enlargement of the heart was a result of cell hypertrophy or the laying down of collagen in the extracellular space. That view was based on the observations that cancer in the heart is extremely rare, DNA turnover is almost undetectable except in pathologic states, and pathologists disputed whether mitotic figures of myocytes had ever been seen. Approximately 20% of myocytes in the human heart have two nuclei, so that cell separation, rather than mitosis, could bring about a small increase in the total cell number. The precise mechanism for the suppression of cell division in the human heart is unknown. What is established is that damage to human heart muscle results in fibrosis and any repair process, if it were to exist, is insufficient to overcome the rate of loss of cells. In some species, such as the salamander and zebra fish, damage to myocardium is repaired by the generation of new myocardial cells, and the process is under genetic control. If the major problem in the worsening of HF is the continuing loss of myocytes, then a new approach is to either inhibit the loss of cells through the processes of apoptosis or necrosis or to promote the growth of new cells.
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Apoptosis is increased in pressure overload LV remodeling and post–myocardial infarction animal models as well as in humans (over 200-fold increase in explanted hearts).153,154 Rodent models appeared to show some promise in apoptosis as a potential target for therapy.155 However, the extent to which apoptosis contributes to progressive LV dysfunction in HF patients is unclear because the absolute apoptosis rates are quite low at 0.08% to 0.25%, compared with 0.001% to 0.002% in controls.156
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Growth Differentiation Factor-15
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A member of the transforming growth factor-β family, growth differentiation factor-15 (GDF-15) is involved in regulating response to injury in a broad array of tissues, including the heart. In the setting of ischemia or pressure overload, the gene for GDF-15 is strongly induced, and the resulting protein appears to modulate myocardial strain, remodeling, and apoptosis.157 Circulating GDF-15 levels are increased in HF patients and correlate with prognosis, but their ability to add independent information over existing biomarkers and clinical variables was minimal.158
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Stem Cell and Gene Therapy
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For the past few decades, much effort has been spent in an effort to increase the number of myocytes in human myocardium either by introducing other cells (eg, cells derived from bone marrow, induced pluripotent stem cells), which are intended to transform into cardiac myocytes, or by the stimulation of resident primitive cells within cardiac muscle. Most of the randomized controlled stem cell trials to date have been limited by their small size. Recent meta-analyses evaluating stem cell trials in post–myocardial infarction and HF patients showed a small improvement in ejection fraction in post–myocardial infarction patients, but overall failed to show significant improvement in mortality or morbidity (reinfarction, hospitalization, restenosis, and target vessel revascularization) with stem cell therapy.159,160,161 However, results are limited by the heterogeneity of individual trials, including stem cell types, cell modification, and dose, frequency, and method of delivery. Several studies published after these meta-analyses appear to show promise. A recent promising study demonstrated individual and synergistic benefit of bone marrow–derived mesenchymal stem cells and c-kit–positive cardiac stem cells in a swine ischemia/reperfusion injury model. Both cardiosphere-derived cells via intracoronary injection and mesenchymal stem cells via transendocardial stem cell injection also showed regenerative effects in patients with ischemic cardiomyopathy.162,163
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Experts continue to encourage further exploration in stem cell therapy because the potential benefit from targeting specific mechanisms contributing to progressive LV dysfunction is large. In addition, the primary benefit of stem cell therapy may not be from the adult stem cell differentiating and regenerating into the target tissue, but rather from their paracrine activities, such as secretion of numerous cytokines and growth factors, including those that modulate inflammation, adverse LV remodeling, collagen deposition, angiogenesis, apoptosis, mitochondrial dysfunction, and microvascular dysfunction.164,165,166,167,168,169,170,171
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In the largest gene transfer study to date in the HF population, intracoronary injection of adeno-associated virus 1 (AAV1)/SERCA2a failed to improve clinical outcomes in patients with HFrEF despite promising previous studies. However, the gene therapy was not associated with serious safety issues and may assist in future gene therapy trial designs.172
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Cardiac remodeling is defined as cardiac structural changes that happen in response to cardiovascular injury, neurohormonal activation, or abnormal hemodynamic loading conditions. Although initially adaptive, when sustained, remodeling can contribute to the development and progression of HF.
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Physiologic Adaptations and Maladaptations
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Oxygen deprivation, which is most often caused by coronary artery disease, results in impaired relaxation and weakened contraction, as can be seen in transient angina pectoris. This is readily reversible. With prolonged ischemia, decreased contraction (hypokinesis or akinesis) can persist for hours beyond return of blood flow (stunning). If coronary blood flow is chronically reduced, the myocardium can fail to contract normally even if there is no myocardial necrosis (hibernation). With a more serious loss of flow, infarction can occur; the time to infarction can be quite variable as a result of factors such as collateral coronary artery blood flow and myocardial oxygen requirement (also called myocardial demand). All of these stages can produce significant myocardial dysfunction for which the unaffected myocardium will sustain this load. The result is myocardial hypertrophy (increase in myocardial cell size with or without an increase in myocardial mass) of the nonaffected portion of the ventricle; if this is inadequate, an increase in ventricular volume and pressure occurs using the Frank-Starling mechanism to sustain stroke volume (Fig. 68–8).
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In HF, myocardial demand may be increased for a variety of reasons, including increased myocardial wall tension caused by myocardial hypertrophy and inefficient contractile energy metabolism. This increase can result in extraction of a greater amount of oxygen from each unit of coronary blood flow and widened coronary arteriovenous oxygen differential. Although significant reduction in coronary perfusion as the primary etiology of HF (in the absence of obstructive coronary artery disease) has not been documented, coronary microvascular flow is often impaired in acute dilated cardiomyopathy.173
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Even when myocardial perfusion is normal at rest, exercise can bring out significant impairment in HF patients including widened coronary arteriovenous oxygen difference caused by exercise-induced LV dilatation, impaired coronary vascular bed dilation during reactive hyperemia in the setting of LV hypertrophy and elevated filling pressures (which can normally increase up to five times), and tachycardia-induced reduction in diastolic filling time for coronary arteries.174
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Force-Frequency Response in Heart Failure
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Normally, an increase in the frequency of stimulation and heart rate is accompanied by an increased rate of force development, a decreased duration of contraction, and an enhanced rate of relaxation (Bowditch effect). This tends to preserve or increase contractile force while preserving diastolic filling time. In the setting of HF, an increase in stimulation and heart rate is accompanied by a decrease in the rate of myocardial performance; some impairment of systolic function can be related to impaired LV filling as well as negative inotropic effect as a result of alterations in intracellular Ca2+ handling. Further reduction in contractile force and inability to decrease duration of contraction can worsen myocardial performance during exercise.175,176
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Hemodynamic Perturbations: The Hemodynamic Hypothesis
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In the early stages of HF, the ventricular end-diastolic pressure (EDP) and cardiac output can be normal at rest. However, with exercise or stress (and the accompanying increase in cardiac output and afterload caused by increased blood pressure and heart rate), there is an increase in EDP. The ability to increase cardiac output in response to the increase in oxygen consumption is also reduced. As HF progresses, the resting EDP increases and end-diastolic and end-systolic volumes increase. This results in reduced elastic recoil of the ventricle during diastolic relaxation and is reflected in loss of rapid early diastolic ventricular filling (as revealed by a reduced E wave of the echocardiogram). This helps to further increase the mean diastolic pressure. The elevated ventricular diastolic pressure increases pulmonary venous and capillary pressures and decreases pulmonary compliance. These changes, in combination with increased volume status, can result in pulmonary edema and clinical symptoms of dyspnea.
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HF can develop from pressure or volume overload. In pressure overload, myocytes hypertrophy to overcome the increased demands of the excess load. Hypertrophied cells contract and relax more slowly and can be subject to metabolic limitations. In addition, hypertrophied myocardial cells can have a shortened life span. This is of considerable prognostic importance because cardiac myocytes appear to have a reduced capacity to proliferate. When age-related myocyte loss is added to the picture, particularly in association with a decrease in myocyte contractile activity, diastolic dysfunction can occur. As the process continues, ventricular dilatation can occur with systolic dysfunction as well. Loss of myocytes—whether segmental, as in acute myocardial infarction, or diffuse, as in dilated cardiomyopathy—sets up a vicious cycle that leads to reactive hypertrophy in the remaining myocytes. As compensatory hypertrophy becomes more marked in some disease states, the contractility unit of the myocardium often declines because of molecular changes in the heart's contractile proteins and activation system. This is especially likely to occur in response to pressure overload, as in systemic arterial hypertension or aortic stenosis, but also ensues when myocytes are lost from any mechanism.
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The Frank-Starling Law and Heart Failure Hemodynamics
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The volume of blood that the heart moves forward can be described as cardiac output (usually described as liters per minute), which depends on both the stroke volume (SV; the base unit of the volume of blood moving forward per heartbeat and usually described as liters per beat or milliliters per beat) and heart rate (beats per minute). Although many factors contribute to SV for a given heart, in general, SV depends on three major factors: preload, contractility, and afterload. Preload describes the end-diastolic ventricular volume (EDV) and is determined by the volume of the blood circulating as well as the ability of the ventricle to relax and fill. Contractility describes the force generated by shortening of the sarcomere or the ability to pump blood forward. Afterload is the opposing force to flow, such as peripheral arterial pressure, that the moving blood encounters once it is pumped out of the heart. LV hemodynamics are described next, but several of the concepts can be applied to the right ventricle with some important differences; for example, the right ventricle is not meant to withstand a high-pressure system, and its ability to compensate for acute changes in pressure is much more limited.
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The Frank-Starling law describes the increase in SV when EDV is increased and is critical for the response to LV systolic dysfunction (see Fig. 68–8). Inadequate emptying of the left ventricle leads to increased EDV (also referred to as increased preload), sarcomere lengthening as a result of LV stretch from increased EDV, and an increase in SV during the next contraction. For any given amount of Ca2+ released into the myocyte, there is increased cross-bridge formation and enhanced sensitivity of the myofilament to Ca2+ as the sarcomeres lengthen.
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In systolic LV dysfunction, the extent of shortening for a given diastolic fiber length and afterload is reduced. The left ventricle can initially maintain a normal or near-normal SV with an increased EDV and thus maintain end-diastolic fiber length. Eventually, the filling pressure increases inordinately, limiting this compensatory mechanism. The dilated left ventricle requires more tension in the LV walls to generate the same pressure, as per the Laplace relationship, which describes that the pressure inside the ventricle is inversely related to the radius of the ventricle and directly related to the tension in the LV wall. Furthermore, the dilated left ventricle can lose elasticity, like an overstretched elastic band, and EDV can increase somewhat without an increase in LV EDP, reflecting a shift in the passive pressure-volume curve to the right. An obligatory reduction in ejection fraction occurs when SV is maintained in the face of a large EDV (ejection fraction = SV/EDV). Eventually, further increases in EDP produce little change in EDV, thus flattening the SV-EDP curve. There is no true descending limb to the Frank-Starling curve because increasing preload indefinitely will ultimately lead to mitral regurgitation, displacing the increased pressure. As the heart dilates, the increase in wall stress according to the Laplace relationship will also increase afterload, which can account for any observed reduction in SV as the heart dilates further (ie, the perception of a descending limb). It is important to keep in mind that LV performance depends not only on systolic pump function, but also on active relaxation, diastolic elastic recoil, passive diastolic properties, and vascular loading conditions. It is likely that at high LV EDP, valvular incompetence (mitral regurgitation) is a major cause of a decrease in cardiac output. Thus, in end-stage HF in the intact circulation, the Frank-Starling curve flattens.
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Loading Conditions and the Concept of the Laplace Relationship
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A characteristic feature of the dilated, failing heart is that it gradually becomes less sensitive to preload (EDV and fiber length) and more sensitive to afterload stress. At very high LV filling pressures (> 30 mm Hg), when the sarcomeres are fully stretched and the preload reserve is exhausted, the SV becomes exquisitely sensitive to alterations in the afterload. The impedance to ejection includes blood viscosity, vascular resistance, vascular distensibility, and myocardial wall tension. Much of the afterload is made up of ventricular myocardial wall tension. In the ventricle, the tension on the walls increases as ventricular chamber volume increases, even if intraventricular pressure remains constant. As the ventricle empties, tension is reduced, even as pressure increases. Calculations of myocardial wall tension are defined by the Laplace equation and are expressed in terms of tension, T, per unit of cross-sectional area (dynes per centimeter [dyn/cm]).
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Within a cylinder, the law of Laplace states that wall tension is equal to the pressure within a thick-walled cylinder times the radius of curvature of the wall:
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where T is wall tension (dyn/cm), P is pressure (dyn/cm2), R is the radius (cm), and h is wall thickness. Wall tension is proportional to the radius. Because the heart has thick ventricular walls, wall tension is distributed over a large number of muscle fibers, thereby reducing tension on each.
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Because the geometry of the ventricles is more complex than that of a cylinder, ventricular wall tension cannot be measured with precision. Wall stress, the force distributed across an area, is actually more correct, but is seldom measured.
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Two fundamental principles stem from the relationship between the geometry of the ventricular cavity and the tension on its muscular walls: (1) dilatation of the ventricles leads directly to an increase in tension on each muscle fiber, and (2) an increase in wall thickness reduces the tension on any individual muscle fiber. Therefore, ventricular hypertrophy reduces afterload by distributing tension among more muscle fibers.
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The wall tension is highest in the inner surface of the heart. The endocardial surfaces must do more work and, therefore, are more vulnerable to reductions in coronary blood flow. Dilatation of the heart decreases cardiac efficiency as measured by myocardial oxygen consumption, unless hypertrophy is sufficient to normalize wall stress. In HF, wall tension (or stress) is high, and thus, afterload is increased. The energetic consequences of the law of Laplace can have some role in progressive deterioration of energy-starved cardiac myocytes in the failing heart.
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Another major disadvantage of the dilated ventricle is the inability to decrease the average radius during contraction. In the normal heart, wall tension falls during ventricular ejection as the volume decreases, even though pressure is rising. In HF, given the dilated heart with reduced ejection, the average tension in the myocardial fibers actually can continue to increase from the beginning of the ejection until peak systolic pressure is reached, adding additional afterload during ejection. The rate of myocardial fiber shortening is reduced, further contributing to diminished myocardial performance. It is difficult to overstate the importance of the law of Laplace when considering the syndrome of HF. This contrast is apparent in mitral insufficiency. With preserved contractility and a relatively small EDV, mitral insufficiency leads to rapid unloading of volume and reduced tension. When ventricular dilatation occurs with decreased ventricular contractility, ejection is reduced, and tension remains high during systole, leading to an unsteady state that cannot be maintained for long.
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Overstretched myocardial cells can induce programmed cell death (apoptosis), thereby contributing to further disease progression.177,178 The plasticity of progressive dilatation is now more apparent, with remarkable reversal of dilatation observed in response to ACE inhibitors and β-blockers, cessation of alcohol use in patients with alcoholic cardiomyopathy, and spontaneous improvement in patients with inflammatory myocarditis.
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Myocyte Response to Altered Loading Conditions
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In response to increased load, whether created by increased pressure or loss of myocytes, hypertrophy occurs and tends to normalize the load per cell. With an increased volume load, myocytes elongate and, to a small extent, may undergo division.179 Hyperplasia and apoptosis of myocytes occur with abnormal loading, but involve less than 1% of the cardiac myocytes. Reprogramming of the cardiac myocytes occurs, resulting in a more fetal-like state. More BNP is synthesized. Metabolism begins to favor glucose over free fatty acids. The myocytes enlarge, presumably rendering a short-term structural and functional advantage.180 The reprogramming requires altered signals, both mechanical and chemical, to reach the nucleus of the cardiac myocyte to set into motion new gene transcription.46 Contractile proteins are altered and improve energetic efficiency. Ultimately, there is a transition from hypertrophy to HF,181 which has been recognized for a long time, but is still not well understood. In a sense, myocyte hypertrophy leads to the structural changes of LV remodeling, thus creating a large, dilated, and poorly functioning heart. The processes of cellular remodeling and subsequent architectural changes in cell and chamber size and shape are highly complex and include many components other than myocardial cell hypertrophy.46 Myocardial fibrosis and cell dropout occur, and perhaps myocyte slippage can occur, increasing dilatation. As cardiac output falls, multiple neurohormones, including renin and NE, are released in an attempt to preserve blood pressure and organ perfusion,182 and atavistic counter-regulatory natriuretic peptides (such as BNP) are released in an attempt to offset vasoconstriction, hypertrophy, and volume conservation.52 Multiple molecular mechanisms,46,183 some of which primarily affect the cardiac interstitium and others the cardiac myocytes, are involved in the process.
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Maladaptive remodeling of cardiac myocyte size and shape begins long before clinical HF begins.184,185 Alterations in myocyte proteins and mitochondria size, as well as changes in myocardial interstitium and collagen content and architecture, are seen in response to a variety of injuries, including pressure overload, volume overload, and myocardial ischemia.185,186 Additional phenotypic changes in HF include apoptosis.153,187 It is important to recognize that much of the neuroendocrine activation that occurs in a primordial attempt to conserve organ perfusion appears to facilitate this myriad of pathologic changes in the heart at the cellular level, thereby possibly contributing to the success of neuroendocrine blockers as therapy for HF. Lastly, there is no single phenotypic change, protein expression, or signal transduction pathway that is dominant. Rather, there is extraordinary redundancy in these mechanisms. This observation has important implications for therapy. For example, blocking one neuroendocrine system can lead to enhanced overactivity of other neuroendocrine systems.