CARDIAC MUSCLE CONTRACTION AND HEART FAILURE

In addition to its role in the action potential, Ca⁺⁺ is intimately involved in the contractile process. The contraction of cardiac muscle is initiated by extracellular Ca⁺⁺ entering the cell with the slow inward current. The immediate source of contractile Ca⁺⁺ in the heart comes largely from intracellular stores, however. Ca⁺⁺ entering the cell during an action potential must first traverse the plasma membrane through voltage-sensitive Ca⁺⁺ channels. This influx of Ca⁺⁺ during the slow inward current triggers the release of much larger amounts of intracellular Ca⁺⁺ from the sarcoplasmic reticulum (SR). The sudden increase in cytoplasmic Ca⁺⁺ stimulates contraction.

Tropomyosin and troponin, which are associated with actin, regulate the interaction between actin and myosin. The binding of Ca⁺⁺ to troponin C initiates a series of conformational changes in troponin and tropomyosin that alter the interaction of tropomyosin and troponin I with actin, favoring the coupling of actin with myosin. Adenosine triphosphate (ATP) is hydrolyzed by myosin-bound adenosine triphosphatase (ATPase) when the actomyosin complex is formed, and chemical energy is converted into mechanical work. The contraction cycle is completed by the active reuptake of Ca⁺⁺ by the SR (and mitochondria) and extrusion from the cell by Na⁺-Ca⁺⁺ exchange.

Drugs such as the β-adrenergic receptor agonists increase cardiac contractility by increasing intracellular cyclic 3′,5′-adenosine monophosphate (cAMP), which enhances Ca⁺⁺ influx and accelerates uptake of Ca⁺⁺ by the SR, ultimately making more Ca⁺⁺ available for contraction.¹² The latter effect results from the phosphorylation of phospholamban, a protein associated with the Ca⁺⁺ pump of the SR. The effect of Ca⁺⁺ on troponin may also be enhanced by cAMP.

In heart failure, the heart is unable to maintain the requisite cardiac output. The mechanics underlying this failure are incompletely understood. The ability of the SR to participate in the trafficking of Ca⁺⁺ seems to be hindered.²¹ The Na⁺-Ca⁺⁺ exchange sites seem to be increased in heart failure, leading to a decrease in intracellular Ca⁺⁺. There are likely to be multiple biochemical defects in heart failure, however.

According to Starling’s law of the heart, cardiac output, or, more precisely, the ventricular stroke volume, increases as ventricular filling pressure increases. Stated simply, the heart pumps whatever is supplied to it by way of venous return, maintaining a near-optimal heart size. As ventricular end-diastolic pressure increases, ventricular stroke work and stroke volume increase. Normal heart function is within well-defined limits and is described by a single curve (Figure 25-1).

FIGURE 25-1 Operation of the Frank-Starling mechanism in the preload compensation for heart failure. The three curves represent ventricular function curves in the normal state, in congestive heart failure (CHF), and in heart failure after treatment with digoxin. Points N through D indicate, in sequence, normal cardiac status (N), depression of contractility with decompensated heart failure (A), Frank-Starling compensation (B), increase in contractility with digoxin (C), and reduction in use of Frank-Starling preload compensation that digoxin allows (D). Points N, D, and B indicate the same cardiac output on the vertical axis, but each point is at a different end-diastolic pressure on the horizontal axis. The excessive end-diastolic pressures causing congestive symptoms and the lowered levels of cardiac performance resulting in low-output symptoms are shown by the hatched areas.

(From Mason DT: Regulation of cardiac performance in clinical heart disease: interactions between contractile state mechanical abnormalities and ventricular compensatory mechanisms, Am J Cardiol 32:437-448, 1973.)

When cardiac contractility is reduced in heart failure, three mechanisms are available by which the heart can compensate for the defect: (1) an increase in ventricular end-diastolic pressure, which enhances cardiac output (Frank-Starling preload mechanism); (2) an increase in number of contractile units (hypertrophy); and (3) use of chronotropic and inotropic reserves of the heart through reflex mechanisms (sympathetic activity). If these mechanisms are sufficient to produce normal cardiac output, the heart failure is said to be compensated. In this condition, a new ventricular function curve is generated (see Figure 25-1). For any given ventricular end-diastolic pressure, however, ventricular stroke work, stroke volume, and cardiac output are lower in the failing heart than in the normal heart. Consequently, the heart enlarges to maintain cardiac output, and heart rate increases to help compensate for poor cardiac function.

If the ventricular end-diastolic pressure becomes too elevated (i.e., the heart is working to the far right along the Frank-Starling curve), venous pressures upstream also increase excessively, leading to symptoms of “backward” heart failure. Signs and symptoms include pulmonary congestion and dyspnea (left-sided failure) and systemic venous distention and edema (right-sided failure). If compensatory mechanisms are unable to maintain cardiac output sufficient for the needs of the peripheral tissues, “forward” heart failure ensues. Adverse effects from impaired tissue perfusion include weakness, lassitude, and acute renal failure. In chronic heart failure, aspects of backward and forward failure interact to produce clinical manifestations. Salt and water retention caused by forward failure contributes to the venous hypertension and edema associated with backward failure. Conversely, impaired gas exchange in the congested lungs augments muscle weakness and fatigue associated with reduced cardiac output and delivery of oxygen to skeletal muscle.

Heart failure occurs whenever the workload placed on the heart exceeds the ability of the heart to perform. Heart failure often arises from myocardial infarction or hypertension. Myocardial infarction can lead to heart failure as a result of a reduction in the heart’s ability to perform work (pump failure).

An increase in total peripheral vascular resistance, as seen in hypertension or as a reflex reaction in congestive heart failure, can contribute to heart failure because of increased outflow resistance on cardiac contraction. The first reaction of the heart to an increase in outflow resistance is often enlargement, resulting in temporary higher efficiency in cardiac function. This initial reaction is followed, however, by progressive signs of cardiac failure characterized by decreased stroke volume and stroke work, as indicated earlier. Reducing preload and afterload by reducing peripheral resistance is an important strategy in treating heart failure.

Figure 25-2 shows some important adaptive mechanisms that result from heart failure. These changes, including an increase in sympathetic discharge, can compensate for the heart failure. If these and other responses are insufficient, however, the heart failure becomes uncompensated. Adaptive mechanisms also include an increase in production of angiotensin II, leading to remodeling of the heart over time.¹⁰ Remodeling results in cardiac hypertrophy, and several cellular changes, which, although they tend to compensate for heart failure, may hasten the course of the disease. This cardiac remodeling in heart failure has a parallel in hypertension, in which vascular smooth muscle slowly undergoes hypertrophy and hyperplasia.

FIGURE 25-2 Adaptive mechanisms in heart failure. A decrease in cardiac output leads to a cascade of events that result in a compensatory increase in cardiac output (box). In addition, activation of the renin-angiotensin system leads to changes that put further burden on the failing heart and promote detrimental and long-term remodeling of the cardiovascular system.

As a result of the complexity of changes in heart failure, there are numerous processes that can be targeted by drugs: neurohumoral events, vascular dynamics, fluid volume, the sympathetic nervous system, and contractility of the heart.¹⁰ The pharmacologic features of angiotensin-converting enzyme (ACE) inhibitors and other vasodilators, diuretics, β blockers, and catecholamines are discussed elsewhere in this book. They are also discussed in this chapter in relation to the treatment of heart failure. The cardiac glycosides are not extensively discussed elsewhere in the book and so are discussed more fully in this chapter than other drugs used for heart failure.

DRUGS USED IN THE TREATMENT OF CHRONIC HEART FAILURE

Table 25-1 lists the drugs used to treat heart failure and their mechanisms of action. The drugs are often used in combination. Heart failure can be classified as diastolic or systolic failure. In diastolic failure, the heart has inadequate distention and inadequate filling capabilities. Contraction as measured by the ejection function may be normal. This type of heart failure is often seen in patients with hypertension. Systolic heart failure is a deficiency in contractility with a low ejection fraction.

TABLE 25-1 Treatment of Heart Failure

ACE, Angiotensin-converting enzyme.

* Carvedilol is a β blocker that also blocks α₁ adrenoceptors.

† Usually only for a few days.

The primary drugs used to treat chronic heart failure are ACE inhibitors, angiotensin II receptor blockers, thiazide and loop diuretics, β-adrenergic receptor blockers, aldosterone antagonists, digoxin, and directly acting vasodilators. For short-term acute treatment, certain catecholamines, nesiritide, other vasodilators, and the phosphodiesterase III inhibitors have special application. Figure 25-3 shows the drugs used in each type of heart failure.^4,7

FIGURE 25-3 Heart failure and choice of drug. The choice of digoxin depends on the presence of systolic failure, especially if it occurs with atrial fibrillation. Dobutamine, dopamine, nesiritide, nitroglycerin, nitroprusside, inamrinone, and milrinone are reserved for short-term therapy in refractory cases. ACE, Angiotensin-converting enzyme.

Aldosterone Antagonists

The action of spironolactone as a diuretic is caused by its antagonism of aldosterone at the convoluted tubule of the kidney. Antagonism of aldosterone leads to several other effects that are beneficial in patients with heart failure. These are shown in Figure 25-4. K⁺-sparing actions help in preventing hypokalemia. Reducing Mg⁺⁺ loss seems to reduce ventricular arrhythmias in patients with heart failure. Because aldosterone can inhibit norepinephrine uptake (uptake 2), spironolactone prevents the enhanced sympathetic activation from aldosterone.¹⁸ Spironolactone also blocks the inhibition of the baroreceptor reflex seen with aldosterone. A consequence of inhibiting the baroreceptor reflex is the lack of parasympathetic nerve response.¹³ The latter response is important in counteracting the adverse effects of sympathetic stimulation, such as arrhythmias and cardiac ischemia. Myocardial fibrosis is also inhibited by spironolactone.

FIGURE 25-4 Effects of spironolactone in treating congestive heart failure. The beneficial effects of spironolactone are the result of inhibiting the several effects of aldosterone at its receptors.

Spironolactone has many salutary effects in heart failure. These beneficial effects also occur when it is used with other drugs such as ACE inhibitors. Because the reduction of aldosterone release by ACE inhibitors is only partial, an added benefit is gained from the use of an aldosterone antagonist.

Eplerenone is another aldosterone receptor antagonist for the treatment of heart failure. Compared with spironolactone, it has a lower affinity for the androgen receptor and is reported to have a lower incidence of related side effects including gynecomastia.

DIGOXIN

Digoxin is a cardiac glycoside that is often called digitalis, referring to the plant from which it is derived. Digoxin is currently indicated for the treatment of congestive heart failure and the management of atrial flutter and fibrillation.

The first detailed scientific study of digitalis on record was made by Sir William Withering¹⁹ of Shropshire, England, in 1785. In his treatise, “An Account of the Foxglove, and Some of Its Medical Uses; With Practical Remarks on Dropsy, and Other Diseases,” Withering detailed clinical uses for the leaf of the Digitalis purpurea (purple foxglove) plant and described its effects on the heart. His recognition of the potential usefulness of digitalis plant derivatives was occasioned by their extensive use in local folk medicines. Withering ascribed the beneficial effects of digitalis in treating dropsy to a direct diuretic effect, although he was aware of beneficial effects on the heart as well. He also detailed many toxic effects of the plant.

The history of the use of digitalis since Withering’s time has been characterized by a realization of its potential therapeutic benefits on the one hand and its low margin of safety on the other. Advances in digitalis research and clinical use up to the present have contributed greatly to our knowledge of this drug class.

Chemistry and Classification

The term digitalis is often used interchangeably with the term cardiac glycoside. Both terms refer to many compounds, naturally occurring or semisynthetic, that have similar cardiotonic effects. Only one such compound, digoxin, is commonly used clinically in the United States today. Another agent, digitoxin, is available in Canada and elsewhere. The structure of digoxin is shown in Figure 25-5. The molecule is composed of a steroid ring structure. Other distinguishing molecular characteristics include an α,β-unsaturated lactone ring, and a carbohydrate moiety in glycosidic linkage at C₃. The presence of a sugar in glycosidic linkage accounts for the name glycoside. A steroid plus lactone lacking the sugar group is generically called a genin or aglycone. The genin of digoxin is digoxigenin.

FIGURE 25-5 Structural formula and composition of digoxin.