Porth's Essentials of Pathophysiology, 4e

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Circulatory Function

U N I T 5

Natriuretic Peptides The heart muscle produces and secretes a family of related peptide hormones, called the natriuretic peptides (NPs), which have potent diuretic, natriuretic, vascular smooth muscle, and other neurohumoral actions that affect cardiovascular function. Two of the four known NPs most commonly associated with heart failure are atrial natriuretic peptide and B-type natriuretic pep- tide. 10,14 As the name indicates, atrial natriuretic peptide (ANP) is released from atrial cells in response to atrial stretch, pressure, or fluid overload. B-type natriuretic peptide (BNP), so named because it was originally found in extracts of the porcine brain, is primarily secreted by the ventricles as a response to increased ventricular pres- sure or fluid overload. Although the NPs are not secreted from the same chambers in the heart, they have very sim- ilar functions. In response to increased chamber stretch and pressure, they promote rapid and transient natriure- sis and diuresis through an increase in the glomerular filtration rate and an inhibition of tubular sodium and water reabsorption. The NPs also facilitate complex interactions with the neurohormonal system, inhibiting the sympathetic nervous system, the renin-angiotensin- aldosterone system, and the antidiuretic hormone (ADH), also known as vasopressin. Circulating levels of both ANP and BNP are elevated in persons with heart failure. The concentrations are well correlated with the extent of ventricular dysfunction, increasing up to 30-fold in persons with advanced heart disease. 14 Assays of BNP are used clinically in the diagnosis of heart fail- ure and to predict the severity of the condition. Endothelins The endothelins, released from the endothelial cells throughout the circulation, are potent vasoconstrictors. Like angiotensin II, endothelin can also be synthesized and released by a variety of cell types, such as cardiac myocytes. There are three endothelin (ET) peptides (ET-1, ET-2, and ET-3). 10,15 In addition to vasoconstrictor actions, the endothelins induce vascular smooth muscle cell pro- liferation and cardiac myocyte hypertrophy and fibrosis; increase the release of ANP, aldosterone, and catechol- amines; and exert antinatriuretic effects on the kidneys. They also have been shown to have a negative inotropic action in patients with heart failure. 15 Plasma ET-1 levels also correlate directly with pulmonary vascular resistance, and it is thought that ET-1 may play a role in mediating pulmonary hypertension in persons with heart failure. 10 Myocardial Hypertrophy and Remodeling The development of myocardial hypertrophy constitutes one of the principal mechanisms by which the heart com- pensates for an increase in workload. 10,16 Although ven- tricular hypertrophy improves the work performance of the heart, it is also an important risk factor for subsequent cardiac morbidity and mortality. Inappropriate hypertro- phy and remodeling can result in changes in structure (i.e., muscle mass, chamber dilation) and cardiac function (i.e., impaired systolic or diastolic function) that often lead to further pump dysfunction and hemodynamic overload.

heart failure. 5,6,8 Both cardiac sympathetic tone and catecholamine (epinephrine and norepinephrine) lev- els are elevated during the late stages of most forms of heart failure. By direct stimulation of heart rate and cardiac contractility, regulation of vascular tone, and enhancement of renal sodium and water retention, the sympathetic nervous system initially helps to maintain perfusion of the various body organs. Although the sympathetic nervous system response is meant to maintain blood pressure and cardiac out- put, it quickly becomes maladaptive and contributes to the deterioration of heart function. An increase in sympathetic activity can lead to tachycardia, vaso- constriction, and cardiac arrhythmias. Acutely, tachy- cardia significantly increases the workload of the heart, thus increasing myocardial oxygen demand and leading to cardiac ischemia, myocyte damage, and decreased contractility (inotropy). An increase in sys- temic vascular resistance causes an increase in cardiac afterload and ventricular wall stress. By promoting arrhythmias, the catecholamines released with sympa- thetic nervous system stimulation also may contrib- ute to the high rate of sudden death seen with heart failure. Other sympathetic mediated effects include decreased renal perfusion and additional augmenta- tion of the renin-angiotensin-aldosterone system, as well as decreased blood flow to skin, muscle, and abdominal organs. 12 Renin-Angiotensin-Aldosterone Mechanism One of the most important effects of lowered cardiac output in heart failure is a reduction in renal blood flow and glomerular filtration rate, which leads to sodium and water retention by way of aldosterone production. With decreased renal blood flow, there is a progressive increase in renin secretion by the kidneys with parallel increases in circulating levels of angiotensin II. 10–13 The increased concentration of angiotensin II contributes directly to generalized and excessive vasoconstriction, as well as facilitating norepinephrine release and inhibit- ing reuptake of norepinephrine by the sympathetic ner- vous system. 8 Angiotensin II also provides a powerful stimulus for aldosterone production by the adrenal cor- tex (see Chapter 18). Aldosterone increases tubular reabsorption of sodium, with an accompanying increase in water reten- tion. Because aldosterone is metabolized in the liver, its levels are further increased when heart failure causes liver congestion. Angiotensin II also increases the level of antidiuretic hormone (ADH), which serves as a vasoconstrictor and inhibitor of water excretion (see Chapter 8). In addition to their individual effects on sodium and water balance, angiotensin II and aldoste- rone are also involved in regulating the inflammatory and reparative processes that follow tissue injury. 10 However, the sustained expression of aldosterone may stimulate fibroblast and collagen deposition, resulting in ventricular hypertrophy as well as fibrosis within the vasculature and myocardium, and thereby contributing to reduced vascular compliance and increased ventricu- lar stiffness. 10