Aldosterone Cardiac failure

As with other K+-sparing diuretics, spironolactone often is coadministered with thiazide or loop diuretics in the treatment of edema and hypertension. Such combinations result in increased mobilization of edema fluid while causing lesser perturbations of K+ homeostasis. Spironolactone is particularly useful in the treatment of primary hyperaldosteronism (adrenal adenomas or bilateral adrenal hyperplasia) and of refractory edema associated with secondary aldosteronism (cardiac failure, hepatic cirrhosis, nephrotic syndrome, and severe ascites). Spironolactone is considered the diuretic of choice in patients with hepatic cirrhosis. Added to standard therapy, spironolactone substantially reduces morbidity and mortality and ventricular arrhythmias in patients with heart failure. 

ACE inhibitors are approved for the treatment of hypertension and cardiac failure [5]. For cardiac failure, many studies have demonstrated increased survival rates independently of the initial degree of failure. They effectively decrease work load of the heart as well as cardiac hypertrophy and relieve the patients symptoms. In contrast to previous assumptions, ACE inhibitors do not inhibit aldosterone production on a long-term scale sufficiently. Correspondingly, additional inhibition of aldosterone effects significantly reduces cardiac failure and increases survival even further in patients already receiving diuretics and ACE inhibitors. This can be achieved by coadministration of spironolactone, which inhibits binding of aldosterone to its receptor. 

In excess, carbenoxolone produces effects similar to those of aldosterone excess (sodium retention and hypokalaemia leading to hypertension, edema, and cardiac failure). 

A test dose should be given to patients who are in cardiac failure (or who are already taking a diuretic for another reason, e.g. hypertension). Maintenance of blood pressure in such individuals may depend greatly on an activated renin-angiotensin-aldosterone system and a standard dose of an ACE inhibitor can cause a catastrophic fall in blood pressure. Except for captopril, most ACE inhibitors (including enalapril) are prodrugs, which are inactive for several hours after dosing. This has favoured the use of captopril... 

Spironolactone. Plasma aldosterone is elevated in heart failure. Spironolactone acts as a diuretic by competitively blocking the aldosterone-receptor, but in addition it has a powerful effect on outcome in cardiac failure (see below). 

Spironolactone (Aldactone) is structurally similar to aldosterone and competitively inhibits its action in the distal tubule (exchange of potassium for sodium) excessive secretion of aldosterone contributes to fluid retention in hepatic cirrhosis, nephrotic syndrome and congestive cardiac failure (see specific use in chapter 24), in which conditions as well as in primary h)q)ersecretion (Conn s syndrome) spironolactone is most useful. Spironolactone is also useful in the treatment of resistant hypertension, where increased aldosterone sensitivity is increasingly recognised as a contributory factor. 

Spironolactone (see p. 534) is a competitive aldosterone antagonist which also blocks the mineralocorticoid effect of other steroids it is used in the treatment of primary hyperaldosteronism and as a diuretic, principally when severe oedema is due to secondary hyperaldosteronism, e.g. cirrhosis, congestive cardiac failure. 

MacFadyen RJ, Lee AF, Morton JJ et al (1999) How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure Heart 82 57-61... 

Zannad F, Dousset B, Alla F. Treatment of congestive heart failure Interfering the aldosterone-cardiac extracellular matrix relationship. Hypertension 2001 38 1227-1232. 

ACE inhibitors and angiotensin 11 receptor inhibitors limit the action of angiotensin II and suppress aldosterone production. These effects have benefits in the treatment of cardiac failure and hypertension because the resulting vasodilation and water loss lowers blood pressure. 

Aldosterone secretion is increased in patients with cirrhosis and cardiac failure, diseases associated with an increase in body fluid volume. To interpret the paradoxical observations made in experimental animals and in patients, investigators have proposed that aldosterone secretion is controlled by selective variations within the total fluid volume, rather than from changes in the total body fluid volume. 

Aldosterone secretion is increased in cardiac failure. Feces of cardiac patients are abnormally low in sodium and high in potassium. This finding is associated with plasma levels of aldosterone that are 25-50 times normal (4-5 mg). That the increased aldosterone levels contribute to the edema is suggested by the fact that... 

Primary sodium excess. This occurs in primary aldosteronism (Conn s syndrome) when there is an inappropriate secretion of aldosterone. Hypokalaemia, possibly accompanied by hypernatraemia, are features of this condition. Secondary aldosteronism, when aldosterone is secreted in conditions where there is stimulation of the renin-angiotensin system by reduced renal blood flow (e.g. hypoproteinaemic states or cardiac failure), can also be considered as a cause of abnormal sodium metabolism. Hypernatraemia, however, is not a feature of this condition and the plasma sodium level may even be low. 

Angiotensin-II AT, Human cDNA Artherosderosis, cardiac hypertrophy, congestive heart failure, hypertension, myocardial infarction, renal disease, cancer, diabetes, obesity, glaucoma, cystic fibrosis, Alzheimer s disease, Parkinson s disease Smooth muscle contraction, cell proliferation and migration, aldosterone and ADH release, central and peripheral sympathetic stimulation, extracellular matrix formation, tubular sodium retention, neuroprotection... 

Endothelin eta Human cDNA Acute pancreatitis, artherosderosis, cancer, hypertension, congestive heart failure, diabetes, obesity, inflammation, myocardial ischemia, prostatic hypertrophy, pulmonary fibrosis, stroke, ulcer, pain Vasoconstriction, bronchoconstriction, positive cardiac inotropy, proliferative responses, aldosterone secretion, neuroprotection... 

In heart failure, cardiac output rises again because ventricular afterload diminishes due to a fall in peripheral resistance. Venous congestion abates as a result of (1) increased cardiac output and (2) reduction in venous return (decreased aldosterone secretion, decreased tonus of venous capacitance vessels). 

Secondary hypotension is a sign of an underlying disease that should be treated first. If stroke volume is too low, as in heart failure, a cardiac glycoside can be given to increase myocardial contractility and stroke volume. When stroke volume is decreased due to insufficient blood volume, plasma substitutes will be helpful in treating blood loss, whereas aldosterone deficiency requires administration of a mineralocor-ticoid (e.g., fludrocortisone). The latter is the drug of choice for orthostatic hypotension due to autonomic failure. A parasympatholytic (or electrical pacemaker) can restore cardiac rate in bradycardia. 

Inhibition of ACE inhibits the synthesis of angiotensin II. This results in vasodilatation and a lesser tendency for sodium and water reabsorption due to the reduction in aldosterone. Angiotensin II is a mediator of trophic processes responsible for cardiac and vascular hypertrophy seen in heart failure or hypertension. This can be reversed by ACE inhibition. 

Potassium-sparing diuretics are useful both to avoid excessive potassium depletion and to enhance the natriuretic effects of other diuretics. Aldosterone receptor antagonists in particular also have a favorable effect on cardiac function in people with heart failure. 

Neurohumoral (extrinsic) compensation involves two major mechanisms (previously presented in Figure 6-7)—the sympathetic nervous system and the renin-angiotensin-aldosterone hormonal response—plus several others. Some of the pathologic as well as beneficial features of these compensatory responses are illustrated in Figure 13-2. The baroreceptor reflex appears to be reset, with a lower sensitivity to arterial pressure, in patients with heart failure. As a result, baroreceptor sensory input to the vasomotor center is reduced even at normal pressures sympathetic outflow is increased, and parasympathetic outflow is decreased. Increased sympathetic outflow causes tachycardia, increased cardiac contractility, and increased vascular tone. Vascular tone is further increased by angiotensin II and endothelin, a potent vasoconstrictor released by vascular endothelial cells. The result is a vicious cycle that is characteristic of heart failure (Figure 13-3). Vasoconstriction increases afterload, which further reduces ejection fraction and cardiac output. Neurohumoral antagonists and vasodilators... 

Diuretics are the mainstay of heart failure management and are discussed in detail in Chapter 15. They have no direct effect on cardiac contractility their major mechanism of action in heart failure is to reduce venous pressure and ventricular preload. This results in reduction of salt and water retention and edema and its symptoms. The reduction of cardiac size, which leads to improved pump efficiency, is of major importance in systolic failure. Spironolactone and eplerenone, the aldosterone antagonist diuretics (see Chapter 15), have the additional benefit of decreasing morbidity and mortality in patients with severe heart failure who are also receiving ACE inhibitors and other standard therapy. One possible mechanism for this benefit lies in accumulating evidence that aldosterone may also cause myocardial and vascular fibrosis and baroreceptor dysfunction in addition to its renal effects. 

Cardiac glycosides bring about diuresis by increasing both cardiac output and renal blood flow the latter in turn reverses the renal compensatory mechanism activated in congestive heart failure. Consequently, the production of aldosterone is reduced, sodium retention is reversed, and the excretion of edematous fluid is enhanced (Figure 35.5). 

Another example of a GeMM transgenic model displaying clinical like conditions including cardiac hypertrophy, fibrosis, and heart failure is the a-myosin heavy chain promoter 11 p-hydroxysteroid dehydrogenase type 2 transgenic mouse (18). Eplerenone (INSPRA , Pfizer Inc.), a selective aldosterone blocker, was tested in this model and proved to ameliorate the phenotype. This model revealed the deleterious consequences of inappropriate mineralocorticoid receptor activation in the heart and supported the notion that aldosterone blockade may provide additional therapeutic benefit in the treatment of heart failure. 

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