Physiology of the Failing Heart

The treatment of both acute and chronic heart failure is based on our current understanding of the multitude of changes that occur in this condition. The major underlying cause of heart failure is an impairment of myocardial contractile function. The associated decrease in stroke volume and cardiac output initiates a multifaceted sequence of neurohormonal and vascular events that affect preload, afterload, and heart rate. For many years heart failure was attributed to left ventricular dysfunction, which was corrected by use of positive inotropic agents, such as digoxin. It is now clear that heart failure represents a highly complex series of events that include neuroendocrine activation. This has resulted in reevaluation of the approaches to management. Whereas the hemodynamic model may still apply to patients with acute failure, the new model focuses on prevention of progression in the outpatient setting by preventing or delaying the development of left ventricular remodeling.

Left Ventricular Remodeling

Remodeling of the heart occurs through complex structural changes in one or more cardiac chambers, especially the ventricles. These result in an increase in end-diastolic and end-systolic volume along with changes in cardiac shape and left ventricular mass (Frank-Starling curves are shown in Figure 23-1). Impaired contractility was previously thought to be responsible for heart failure, although a specific biochemical abnormality could not be identified. This idea has given way to the concept that heart failure involves endogenous neurohormones and cytokines in response to an initial “index event,” usually an acute injury to the heart or genetic mutation. Coronary artery disease and hypertension account for most cases, with myocardial infarction being a major contributor. Any insult, whether acute myocardial infarction, essential hypertension, aortic stenosis, or volume overload caused by aortic insufficiency, idiopathic cardiomyopathy, or inflammatory disease, leads to activation of specific mediators involved in the remodeling process.

FIGURE 23–1 Frank-Starling ventricular function curve. Force of contraction, expressed as left ventricular dP/dt (rate of pressure development during early systolic phase) is a function of (1) left ventricular volume before the onset of contraction or (2) sarcomere length. The length of the sarcomere, the unit between two Z lines of a myofibril, in the normal heart is 1.7 to 1.8 μm at the endocardial and epicardial layers and 2.0 μm in the middle layer. The reduced force of contraction in a failing heart is partly compensated for by an increase in the end-diastolic volume, which increases the length of the sarcomere, thereby increasing the force of contraction or the stroke volume (A, arrow). Positive inotropic interventions in the normal heart are canceled by shortening of the muscle (B, arrow). Digitalis glycosides shift the ventricular function curve and reduce the end-diastolic volume required for the muscle to develop the necessary force of contraction (C, arrow).

Neurohormonal systems defend against changes in intravascular volume and act to maintain regional blood flow and regulate systemic blood pressure. Initially, they compensate for the decline in ventricular function and mask the underlying deficiency. Chronic activation of multiple compensatory mechanisms perpetuates progression to irreversible myocyte injury and worsening of cardiac function. Initiating factors include: stretch of the ventricular myocardium, increased cytokine and growth factor production, nitric oxide (NO) production, tumor necrosis factor, natriuretic peptides, free radical-mediated oxidative stress, ischemia, activation of myocardial metalloproteinases, proapoptotic factors, and chronic inflammation. Heart failure is usually accompanied by an increase in sympathetic nervous system (SNS) activation along with chronic up regulation of the renin-angiotensin-aldosterone system (RAAS) and effects of aldosterone on heart, vessels, and kidneys. CHF should be viewed as a complex, interrelated sequence of events involving hemodynamic, nonhemodynamic, genetic, energetic, and neurohormonal events.

Sympathetic Nervous System

In the failing heart, the loss of contractile function leads to a decline in cardiac output and a decrease in arterial blood pressure. The baroreceptors sense the hemodynamic changes and initiate countermeasures to maintain support of the circulatory system. Activation of the SNS serves as a compensatory mechanism in response to a decline in left ventricular stroke volume. This helps maintain adequate cardiac output by increasing myocardial contractility and heart rate (β₁ adrenergic receptors) and by increasing vasomotor tone (α₁ adrenergic receptors) to maintain systemic blood pressure (see Chapters 11 and Chapters 19). Over the long term, this hyperadrenergic state leads to irreversible myocyte damage, cell death, and fibrosis. In addition, the augmentation in peripheral vasomotor tone increases left ventricular afterload, placing an added stress upon the left ventricle and an increase in myocardial O₂ demand, factors involved in ventricular remodeling. The frequency and severity of cardiac arrhythmias are enhanced in the failing heart, in part as a result of the increased adrenergic tone.

Systolic Heart Failure

The most frequent cause for chronic systolic dysfunction is ischemic cardiomyopathy, characterized by a reduction in the ventricular ejection fraction and enlargement of the left ventricle, due to a failure of the left ventricle to empty as a result of impaired myocardial contractility or pressure overload. This results from destruction of myocytes, impaired myocyte function, or fibrosis. Chronic pressure overload, caused by untreated long-standing hypertension or aortic stenosis, decreases the left ventricular ejection fraction by increasing resistance to forward flow. Initially, the increase in the left ventricular end-diastolic pressure (volume) results in a compensatory enhancement in stroke volume due to the pressure-induced lengthening of the sarcomeres that invokes the Frank-Starling mechanism (see Fig. 23-1), thereby partially compensating for the failing ventricle. The marked diastolic derangement in filling and the decreased ventricular distensibility do not permit adequate stretch of the myocytes because it occurs under conditions that require an increase in cardiac output. Therefore, in the presence of systolic heart failure, the Frank-Starling mechanism fails to adequately increase stroke volume in response to exercise.

The compensatory increase in sympathetic tone plus the activation of the RAAS system maintains arterial blood pressure. However, homeostatic mechanisms also increase total peripheral resistance (left ventricular afterload). Circulating blood volume is also increased, further contributing to maintenance of arterial pressure. Over the long term, this places an additional burden on the failing heart. Moreover, because increases in peripheral resistance decrease tissue perfusion for a given blood pressure, and tissue perfusion is more important than blood pressure, these mechanisms may not be advantageous in the long term.

Energy efficiency is reduced in chronic heart failure because a greater wall tension is required to develop the necessary intraventricular pressure, and peripheral resistance is increased. Energetic efficiency decreases further when relaxation is inhibited in the hypertrophied heart and when the heart rate is increased by activation of the SNS, resulting in a reduced stroke volume.

Chronic pressure overload, as in uncontrolled hypertension, contributes to hypertrophy. Stretching of the sarcolemma, the ensuing influx of Na⁺, and increased angiotensin II concentrations in plasma are possible causes. The number of myocardial cells does not increase in adults, but each cell enlarges. Remodeling may occur in association with such hypertrophy. Remodeling involves a shift of isoforms of functional proteins, such as myosin, creatine kinase, and Na⁺,K⁺-adenosine triphosphatase (ATPase). These are adaptive events but may ultimately contribute to ventricular remodeling. Furthermore the hypertrophied heart loses compliance (i.e., the ability to relax).

Diastolic Heart Failure

Diastolic dysfunction may result from impaired early diastolic relaxation, increased stiffness of the ventricular wall, or both. Hypertension, valvular disease, or congenital abnormalities lead to development of diastolic dysfunction, with hypertrophied or poorly compliant ventricular walls impeding filling of the left ventricle. Diastolic relaxation is an energy-dependent process, which is impaired by myocardial ischemia and a temporary loss of energy production. In this case ventricular filling can be achieved only at a greater than normal filling pressure because of reduced left ventricular wall compliance. Abnormalities may be attributable in part to an increase in interstitial connective tissue. Hypertrophic myocytes exhibit abnormal Ca⁺⁺ cycles characterized by prolonged Ca⁺⁺ transients and impaired relaxation. Current evidence implicates the local activity of angiotensin II and elevated circulating levels of aldosterone, both of which are implicated in the development of myocardial fibrosis. They lead to deposition of excessive amounts of collagen and a decrease in ventricular compliance, increased chamber stiffness, or a decrease in distensibility. Patients with diastolic dysfunction may have a normal cardiac output, suggesting that pharmacological management will differ from patients with systolic heart failure.

Angiotensin-Converting Enzyme Inhibitors

Baroreceptor-mediated activation of the SNS leads to an increase in renin release and formation of angiotensin II (see Chapter 19), which causes intense vasoconstriction and stimulates aldosterone production (Fig. 23-2). This is decreased by the angiotensin-converting enzyme (ACE) inhibitors, which inhibit formation of angiotensin II from angiotensin I, as discussed in Chapter 20.

FIGURE 23–2 Renal release of renin leading to the formation of angiotensin II and subsequent activation of AT₁ receptor-mediated events.

Angiotensin II acts through AT₁ and AT₂ receptors, although most of its actions occur through AT₁ receptor activation. Although the AT₂ receptor is distributed widely in fetal tissues, its distribution is limited in adults. Angiotensin II mediates cell growth, vasoconstriction, Na⁺ and fluid retention, and sympathetic activation (Table 23-1). The central role of the RAAS in the development and progression of cardiovascular disease and, in particular, CHF is well established. In addition to regulation of blood pressure and maintenance of fluid and electrolyte balance, short-term activation of the RAAS in heart failure improves cardiac output through fluid and Na⁺ retention (increased preload), whereas long-term activation results in vasoconstriction, increased afterload, and decreased cardiac output. These mechanisms, together with SNS activation, induce a vicious cycle of increased preload, afterload, and cardiac workload, leading to increased myocardial O₂ consumption, loss of myocytes through apoptosis, and progressive worsening heart failure.

TABLE 23–1 Effects of Angiotensin II

β Adrenergic Receptor Blocking Drugs

There is overwhelming evidence to support the use of β receptor blockers in CHF; however, the mechanisms involved remain unclear. Part of the beneficial effects of these agents may derive from slowing of heart rate, which would improve coronary blood flow and decrease myocardial O₂ consumption. This would lessen the frequency of ischemic events and potential for development of a lethal arrhythmia. Activation of the SNS can provoke arrhythmias by increasing cardiac automaticity, increasing triggered activity leading to ventricular arrhythmias, which may account for the ability of β receptor blockers to reduce the incidence of sudden cardiac death in patients with ischemic heart disease and heart failure.

The β receptor blockers inhibit the adverse effects of the SNS in patients with heart failure. Whereas cardiac adrenergic drive initially serves as a compensatory mechanism to support the failing heart, long-term activation leads to a down regulation of β₁ receptors and an uncoupling from adenylyl cyclase (see Chapter 1), thereby reducing myocardial contractility. The β receptor blockers may be beneficial through resensitization of the down regulated receptor, improving myocardial contractility.

Angiotensin Receptor Blockers

Another approach is to block AT₁ receptors with the use of angiotensin receptor blockers (ARBs). The currently available drugs selectively block AT₁ receptors and replicate many of the actions of ACE inhibitors; they do not block AT₂ receptors. Activation of AT₂ receptors may cause vasodilation, preventing hypertrophy of vascular smooth muscle and cardiomyocytes, production of bradykinin, and release of NO. There is also overexpression of AT₂ receptors in the failing heart. There may also be non-ACE-dependent formation of angiotensin II by enzymes, such as chymase, cathepsin G, trypsin, and tissue plasminogen activator. An ARB might block the deleterious actions mediated by AT₁ receptors while preserving the desirable effects of AT₂ receptor activation. Although the hemodynamic and clinical effects may appear similar, ACE inhibitors and ARBs should not be regarded as being identical.

Aldosterone Antagonists

The elevated circulating angiotensin II levels in the patient with CHF lead to greatly increased production of aldosterone (see Chapter 39), an important mediator in the progressive development of CHF. Aldosterone binds to mineralocorticoid receptors in renal epithelial cells and promotes Na⁺ retention, Mg⁺⁺ and K⁺ loss, sympathetic activation, parasympathetic inhibition, myocardial and vascular fibrosis, baroreceptor dysfunction, impaired arterial compliance, and vascular damage. Aldosterone antagonists include spironolactone and eplerenone, which may reduce norepinephrine (NE) release from cardiac sympathetic nerves and increase plasma K⁺. The elevated concentrations of aldosterone in CHF led to the concept that inhibition of aldosterone receptors could be beneficial, and competitive aldosterone antagonists are now part of the therapeutic armamentarium.

Cardiac Glycosides

The cardiac glycosides increase the force of myocardial contraction, alter electrophysiological properties in specialized regions, and have extracardiac actions associated with toxicity. Cardiac glycosides influence the heart through a direct inhibition of membrane Na⁺,K⁺-ATPase and an indirect increase in vagal tone (Table 23-2). Their cardiotoxic effects are an overextension of the same mechanisms responsible for their positive inotropic actions.

TABLE 23–2 Effects of Cardiac Glycosides on Electrophysiological Properties of the Heart

Cardiac glycosides increase contractile force; however, unlike catecholamines, they do not increase the rate of relaxation. By decreasing the activity of the Na⁺,K⁺-ATPase, they cause a progressive gain in intracellular Na⁺ with each cardiac cycle. This increase promotes Ca⁺⁺ influx by Na⁺/Ca⁺⁺ exchange (Fig. 23-3). The net result is an increased intracellular Ca⁺⁺, enhancing the Ca⁺⁺ transient resulting from an augmented Ca⁺⁺ loading of the sarcoplasmic reticulum. In the presence of a digitalis glycoside, a new steady state is achieved where an increased amount of Ca⁺⁺ is released after depolarization, increasing force development (stroke volume; see Fig. 23-1).

FIGURE 23–3 Membrane ion flux of Na⁺ and Ca⁺⁺ in heart. Glycoside-induced inhibition of Na⁺,K⁺-ATPase secondarily promotes Na⁺/Ca⁺⁺ exchange.

Electrophysiological effects of cardiac glycosides vary among different regions of the heart. They decrease automaticity within the sinoatrial (SA) and atrioventricular (AV) nodes as a result of an increase in parasympathetic tone along with a concomitant decrease in sympathetic tone. The increase in parasympathetic tone on the AV node leads to a decrease in conduction velocity and an increase in effective refractory period. Thus digitalis glycosides indirectly decrease heart rate and impair impulse transmission across the AV node.

The major direct effects are in the atrial muscle, AV node, and ventricles (see Table 23-2). In atria, they prolong the effective refractory period and decrease conduction velocity, effects opposite to those elicited by their indirect actions. However, the direct effects in the AV node summate with the indirect actions to further impair conduction velocity and increase the refractory period.

There are also significant extracardiac effects of digitalis glycosides. Most cells express membrane Na⁺,K⁺-ATPases, but those in excitable tissues have a higher affinity for cardiac glycosides. Whether or not a cell is affected depends on factors such as the Na⁺