Heart failure pathophysiology

Davila DF, Nunez TJ, Odreman R, de Davila CA Mechanisms of neurohormonal activation in chronic congestive heart failure pathophysiology and therapeutic implications. IntJ Cardiol. 2005 101 343-346. 

The endothelin peptides are potent vasoconstrictors that may be involved in heart failure pathophysiology through a number of mechanisms. Endothelin-1 (FT-1), the best characterized of these peptides, is synthesized by endothelial and vascular smooth muscle cells, with the release of ET-1 enhanced by NE, angiotensin II, and inflammatory cytokines. Like other peptides and hormones described earlier, ET-1 plasma concentrations are elevated in heart failure and... 

Describe the pathophysiology of heart failure as it relates to neurohormonal activation of the renin-angiotensin-aldosterone system and the sympathetic nervous system. 

From Parker RB, Patterson JH, Johnson JA. Heart failure. In DiPiro JT, Talbert RL, Yee CC, et al, (eds.) Pharmacotherapy A Pathophysiologic Approach. 6th ed. New York McGraw-Hill 2005 220, with permission. 

Urban, N. and Porth, C.M., Heart failure and circulatory shock, in Pathophysiology Concepts of Altered Health States, 5th ed., Porth, C.M., Ed., Lippin-cott-Raven Publishers, Philadelphia, 1998, chap. 20. 

The vascular endothelium produces a number of substances that are released basally into the blood vessel wall to alter vascular smooth muscle tone. One such substance is endothelin (ET-1). Endothelin exerts its effects throughout the body, causing vasoconstriction as well as positive inotropic and chronotropic effects on the heart. The resulting increases in TPR and CO contribute to an increase in MAP. Synthesis of endothelin appears to be enhanced by many stimuli, including Ag II, vasopressin, and the mechanical stress of blood flow on the endothelium. Synthesis is inhibited by vasodilator substances such as prostacyclin, nitric oxide, and atrial natriuretic peptide. There is evidence that endothelin is involved with the pathophysiology of many cardiovascular diseases, including hypertension, heart failure, and myocardial infarction. Endothelin receptor antagonists are currently available for research use only. 

The potent antidiuretic hormone AVP orchestrates the regulation of free water absorption, body fluid osmolality, cell contraction, blood volume, and blood pressure through stimulation of three G-protein-coupled receptor subtypes Vi-vascular types a and b, V2-renal, and V3-pituitary. Increased AVP secretion is the trademark of several pathophysiological disorders, including heart failure, impaired renal function, liver cirrhosis, and SIADH. As a consequence, these patients experience excess water retention or inadequate free-water excretion, which results in the dilution of sodium concentrations, frequently manifesting as clinical hyponatremia (serum sodium concentration <135mmol/L). This electrolyte imbalance increases mortality rates by 60-fold. Selective antagonism of the AVP V2 receptor promotes water... 

The most salient pathophysiological features of congestive heart failure (CHF) are diminution of ventricular contractility and profound, sympathetically mediated vasoconstriction. Agents with both peripheral vasodilating [24] and positive inotropic [25] activities ameliorate the symptoms of CHF. 

Maisel WH, Stevenson LW. Atrial fibrillation in heart failure epidemiology, pathophysiology, and rationale for therapy. [Review, 48 refs]. Am. J. Cardiol. 2003 91 20. 

Pathophysiology can influence muscarinic activity in other ways as well. Circulating autoantibodies against the second extracellular loop of cardiac M2 muscarinic receptors have been detected in some patients with idiopathic dilated cardiomyopathy and those afflicted with Chagas1 disease caused by the protozoan Trypanosoma cruzi. These antibodies exert parasympathomimetic actions on the heart that are prevented by atropine. In animals immunized with a peptide from the second extracellular loop of the M2 receptor, the antibody is an allosteric modulator of the receptor. Although their role in the pathology of heart failure is unknown, these antibodies should provide clues to the molecular basis of receptor activation because their site of action differs from the orthosteric site where acetylcholine binds (see Chapter 2). 

Since elucidation of the sequences of the genes encoding the alr a2, and subtypes of adrenoceptors, it has become clear that there are relatively common genetic polymorphisms for many of these receptor subtypes in humans. Some of these may lead to changes in critical amino acid sequences that have pharmacologic importance. Often, distinct polymorphisms occur in specific combination termed haplotypes. Some of these polymorphisms have been consistently shown to alter the susceptibility to diseases such as heart failure, to alter the propensity of a receptor to desensitize, and to alter therapeutic responses to drugs in diseases such as asthma. This remains an area of active research because studies have reported inconsistent results as to the pathophysiologic importance of some polymorphisms. 

Excessive catecholamine action is an important aspect of the pathophysiology of hyperthyroidism, especially in relation to the heart (see Chapter 38). The 13 antagonists are beneficial in this condition. The effects presumably relate to blockade of adrenoceptors and perhaps in part to the inhibition of peripheral conversion of thyroxine to triiodothyronine. The latter action may vary from one 13 antagonist to another. Propranolol has been used extensively in patients with thyroid storm (severe hyperthyroidism) it is used cautiously in patients with this condition to control supraventricular tachycardias that often precipitate heart failure. 

The net result of the action of therapeutic concentrations of a cardiac glycoside is a distinctive increase in cardiac contractility (Figure 13-5, bottom trace). In isolated myocardial preparations, the rate of development of tension and of relaxation are both increased, with little or no change in time to peak tension. This effect occurs in both normal and failing myocardium, but in the intact patient the responses are modified by cardiovascular reflexes and the pathophysiology of heart failure. 

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