COMPENSATORY MECHANISMS
Several natural compensatory mechanisms are called into action in patients with heart failure that buffer the fall in cardiac output and help preserve sufficient blood pressure to perfuse vital organs. These compensations include (1) the Frank–Starling mechanism, (2) neurohormonal alterations, and (3) the development of ventricular hypertrophy and remodeling (Fig. 9.8).
Frank–Starling Mechanism
As shown in Figure 9.3, heart failure caused by impaired left ventricular contractile function causes a downward shift of the ventricular performance curve. Consequently, at a given preload, stroke volume is decreased compared with normal. The reduced stroke volume results in incomplete chamber emptying, so that the volume of blood that accumulates in the ventricle during diastole is higher than normal (see Fig. 9.3, point b). This increased stretch on the myofibers, acting via the Frank–Starling mechanism, induces a greater stroke volume on subsequent contraction, which helps to empty the enlarged left ventricle and preserve forward cardiac output (see Fig 9.8).
This beneficial compensatory mechanism has its limits, however. In the case of severe heart failure with marked depression of contractility, the curve may be nearly flat at higher diastolic volumes, reducing the augmentation of cardiac output achieved by the increased chamber filling. Concurrently in such a circumstance, marked elevation of the end-diastolic volume and pressure (which is transmitted retrograde to the left atrium, pulmonary veins, and capillaries) may result in pulmonary congestion and edema (see Fig. 9.3, point c).
Neurohormonal Alterations
Several important neurohormonal compensatory mechanisms are activated in heart failure in response to the decreased cardiac output (Fig. 9.9). Three of the most important involve (1) the adrenergic nervous system, (2) the renin–angiotensin–aldosterone system, and (3) increased production of antidiuretic hormone (ADH). In part, these mechanisms serve to increase systemic vascular resistance, which helps to maintain arterial perfusion to vital organs, even in the setting of a reduced cardiac output. That is, because blood pressure (BP) is equal to the product of cardiac output (CO) and total peripheral resistance (TPR),
a rise in TPR induced by these compensatory mechanisms can nearly balance the fall in CO and, in the early stages of heart failure, maintain fairly normal BP. In addition, neurohormonal activation results in salt and water retention, which in turn increases intravascular volume and left ventricular preload, maximizing stroke volume via the Frank–Starling mechanism.
a rise in TPR induced by these compensatory mechanisms can nearly balance the fall in CO and, in the early stages of heart failure, maintain fairly normal BP. In addition, neurohormonal activation results in salt and water retention, which in turn increases intravascular volume and left ventricular preload, maximizing stroke volume via the Frank–Starling mechanism.
Although the acute effects of neurohormonal stimulation are compensatory and beneficial, chronic activation of these mechanisms often ultimately proves deleterious to the failing heart and contributes to a progressive downhill course, as described later.
Adrenergic Nervous System
The fall in cardiac output in heart failure is sensed by baroreceptors in the carotid sinus and aortic arch. These receptors decrease their rate of firing in proportion to the fall in BP, and the signal is transmitted by the 9th and 10th cranial nerves to the cardiovascular control center in the medulla. As a result, sympathetic outflow to the heart and peripheral circulation is increased, and parasympathetic tone is diminished. There are three immediate consequences (see Fig. 9.9): (1) an increase in heart rate, (2) augmentation of ventricular contractility, and (3) vasoconstriction caused by stimulation of α-receptors on the systemic veins and arteries.
The increased heart rate and ventricular contractility directly augment cardiac output (see Fig. 9.2). Vasoconstriction of the venous and arterial circulations is also initially beneficial. Venous constriction augments blood return to the heart, which increases preload and raises stroke volume through the Frank–Starling mechanism, as long as the ventricle is operating on the ascending portion of its ventricular performance curve. Arteriolar constriction increases the peripheral vascular resistance and therefore helps to maintain blood pressure (BP = CO × TPR). The regional distribution of α-receptors is such that during sympathetic stimulation, blood flow is redistributed to vital organs (e.g., heart and brain) at the expense of the skin, splanchnic viscera, and kidneys.
Renin–Angiotensin–Aldosterone System
This system is also activated early in patients with heart failure (see Fig. 9.9), mediated by increased renin release. The main stimuli for renin secretion from the juxtaglomerular cells of the kidney in heart failure patients include (1) decreased renal artery perfusion pressure secondary to low cardiac output, (2) decreased salt delivery to the macula densa of the kidney owing to alterations in intrarenal hemodynamics, and (3) direct stimulation of juxtaglomerular β2-receptors by the activated adrenergic nervous system.
Renin is an enzyme that cleaves circulating angiotensinogen to form angiotensin I, which is then rapidly cleaved by endothelial cell-bound angiotensin-converting enzyme (ACE) to form angiotensin II (AII), a potent vasoconstrictor (see Chapter 13). Increased AII constricts arterioles and raises total peripheral resistance, thereby serving to maintain systemic blood pressure. In addition, AII acts to increase intravascular volume by two mechanisms: (1) at the hypothalamus, it stimulates thirst and therefore water intake; and (2) at the adrenal cortex, it acts to increase aldosterone secretion. The latter hormone promotes sodium reabsorption from the distal convoluted tubule of the kidney into the circulation (see Chapter 17), serving to augment intravascular volume. The rise in intravascular volume increases left ventricular preload and thereby augments cardiac output via the Frank–Starling mechanism in patients on the ascending portion of the ventricular performance curve (see Fig. 9.3).
Antidiuretic Hormone
Secretion of this hormone (also termedvasopressin) by the posterior pituitary is increased in many patients with heart failure, presumably mediated through arterial baroreceptors, and by increased levels of AII. ADH contributes to increased intravascular volume because it promotes water retention in the distal nephron. The increased intravascular volume serves to augment left ventricular preload and cardiac output. ADH also appears to contribute to systemic vasoconstriction.
Although each of these neurohormonal alterations in heart failure is initiallybeneficial, continued activation ultimately proves harmful. For example, the increased circulating volume and augmented venous return to the heart may worsenengorgement of the lung vasculature, exacerbating congestive pulmonary symptoms. Furthermore, the elevated arteriolar resistance increases the afterload against which the failing left ventricle contracts and may therefore impair stroke volume and reduce cardiac output (see Fig. 9.9). In addition, the increased heart rate augments metabolic demand and can therefore further reduce the performance of the failing heart. Continuous sympathetic activation results in downregulation of cardiac β-adrenergic receptors and upregulation of inhibitory G proteins, contributing to a decrease in the myocardium’s sensitivity to circulating catecholamines and a reduced inotropic response.
Chronically elevated levels of AII and aldosterone have additional detrimental effects. They provoke the production of cytokines (small proteins that mediate cell–cell communication and immune responses), activate macrophages, and stimulate fibroblasts, resulting in fibrosis and adverse remodeling of the failing heart.
Because the undesired consequences of chronic neurohormonal activation eventually outweigh their benefits, much of today’s pharmacologic therapy of heart failure is designed to moderate these “compensatory” mechanisms, as examined later in the chapter.
Natriuretic Peptides
In contrast to the ultimately adverse consequences of the neurohormonal alterations described in the previous section, the natriuretic peptides are natural “beneficial” hormones secreted in heart failure in response to increased intracardiac pressures. The best studied of these are atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). ANP is stored in atrial cells and is released in response to atrial distention. BNP is not detected in normal hearts but is produced when ventricular myocardium is subjected to hemodynamic stress (e.g., in heart failure or during myocardial infarction). Recent studies have shown a close relationship between serum BNP levels and the clinical severity of heart failure.
Actions of the natriuretic peptides are mediated by specific natriuretic receptors and are largely opposite to those of the other hormone systems activated in heart failure. They result in excretion of sodium and water, vasodilatation, inhibition of renin secretion, and antagonism of the effects of AII on aldosterone and vasopressin levels. Although these effects are beneficial to patients with heart failure, they are usually not sufficient to fully counteract the vasoconstriction and volume-retaining effects of the other activated hormonal systems.
Other Peptides
Among other peptides that are generated in heart failure is endothelin-1, a potent vasoconstrictor, derived from endothelial cells lining the vasculature (see Chapter 6). In patients with heart failure, the plasma concentration of endothelin-1 correlates with disease severity and adverse outcomes. Drugs designed to inhibit endothelin receptors (and therefore blunt adverse vasoconstriction) improve LV function in heart failure patients, but long-term clinical benefits have not been demonstrated.
Ventricular Hypertrophy and Remodeling
Ventricular hypertrophy and remodeling are important compensatory processes that develop over time in response to hemodynamic burdens. Wall stress (as defined earlier) is often increased in developing heart failure because of either LV dilatation (increased chamber radius) or the need to generate high systolic pressures to overcome excessive afterload (e.g., in aortic stenosis or hypertension). A sustained increase in wall stress (along with neurohormonal and cytokine alterations) stimulates the development of myocardial hypertrophy and deposition of extracellular matrix. This increased mass of muscle fibers serves as a compensatory mechanism that helps to maintain contractile force andcounteracts the elevated ventricular wall stress (recall that wall thickness is in the denominator of the Laplace wall stress formula). However, because of the increased stiffness of the hypertrophied wall, these benefits come at the expense of higher-than-normal diastolic ventricular pressures, which are transmitted to the left atrium and pulmonary vasculature (see Fig. 9.8).
The pattern of compensatory hypertrophy and remodeling that develops depends on whether the ventricle is subjected to chronic volume or pressure overload. Chronic chamber dilatation owing to volume overload (e.g., chronic mitral or aortic regurgitation) results in the synthesis of new sarcomeres in series with the old, causing the myocytes to elongate. The radius of the ventricular chamber therefore enlarges, doing so in proportion to the increase in wall thickness, and is termedeccentric hypertrophy. Chronic pressureoverload (e.g., caused by hypertension or aortic stenosis) results in the synthesis of new sarcomeres in parallel with the old (i.e., the myocytes thicken), termed concentric hypertrophy. In this situation, the wall thickness increases without proportional chamber dilatation, and wall stress may therefore be reduced substantially.
Such hypertrophy and remodeling help to reduce wall stress and maintain contractile force, but ultimately, ventricular function may decline, allowing the chamber to dilate out of proportion to wall thickness. When this occurs, the excessive hemodynamic burden on the contractile units produces a downward spiral of deterioration with progressive heart failure symptomatology.
