Heart failure renin-angiotensin-aldosterone system

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

Development and progression of heart failure involves activation of neurohormonal pathways, including the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS). 

Once vasodilatation was considered to be a good strategy, as it improves HF symptoms. However later studies showed that the disease itself was not influenced. The accent of HF treatment has moved to progression prevention with rigorous suppression of the renin angiotensin aldosterone system. Therapy with /3-blockers was also proven to be effective for the reduction of mortality. These treatments should be started early and the evaluation of their effectiveness in individual patients is difficult. As brain natriuretic peptide (BNP) is produced by the heart and more BNP is released in heart failure, the measurement of BNP in the blood has become popular as surrogate marker for the severity of heart failure and for the response of treatment for heart failure. 

Unger T, Li J. The role of the renin-angiotensin-aldosterone system in heart failure. J Renin Angiotensin Aldosterone Syst. 2004 5(suppl 1) ... 

The results of SPICE (The Study of Patients Intolerant of Converting Enzyme Inhibitors) and of the previously published RESOLVD led to the design of the current CHARM trial, which is investigating the effect of candesartan in 6600 patients with heart failure in three different ways versus an ACE inhibitor in patients with preserved left ventricular function versus placebo in patients intolerant of ACE inhibitors and in addition to ACE inhibitors in all other patients. While waiting for the results of this trial it is advisable to continue to use ACE inhibitors as the initial therapy for heart failure. In patients with documented intolerance of ACE inhibitors (which may represent 10-20% of patients with heart failure) angiotensin receptor antagonists may be useful as a substitute to block the renin-angiotensin-aldosterone system. 

Reed S, Greene P, Ryan T, Cerimele B, Schwertschlag U, Weinberger M, Voelker J. The renin angiotensin aldosterone system and frusemide response in congestive heart failure. Br J Clin Pharmacol 1995 39(l) 51-7. 

Insulin edema is a rare complication, more often seen in the earlier years of insulin therapy (SEDA-11, 364). It is mostly seen when dysregulated patients with progressive weight loss are treated with relatively high amounts of insulin. Reduced sodium excretion (88), sodium reabsorption, and water retention by a possible direct action of insulin on the kidney may be involved (89). The role of aldosterone or of inhibition of the renin-angiotensin-aldosterone system in insulin edema is unclear. Insulin edema is a specific adverse effect, but it can aggravate pulmonary edema, congestive heart failure, and hypertension. Treatment consists of reduction of the insulin dose, after which the edema resolves within 3 days. 

Numerous neuroendocrine biomarkers correlate with severity of cardiac dysfunction. Heart failure is associated with increase in peripheral vascular resistance due to increases in sympathetic tone, norepinephrine, renin, angiotensin II, arginine vasopressin, and endothelin-1. The increased venous pressure causes atrial distension that stimulates production and release of atrial and brain natriuretic peptides (ANP, BNP) from the atria and ventricles, respectively. ANP inhibits the renin-angiotensin-aldosterone system. In humans and mammals, BNP has been found to be an early biomarker of left ventricular hypertrophy developing with doxorubicin cardiotoxicity, congestive heart failure, or occult dilated cardiomyopathy (Erkus et al. 2006 Walker 2006 Oyama, Sisson, and Solter 2007). 

Captopril, l-[(2S)-3-mercapto-2-methyl-propionyl]-L-proline, the first orally active inhibitor of the angiotensin-converting enzyme (ACE) on the market. The positive effects of captopril and other ACE inhibitors like enalapril in hypertension and heart failure result primarily from suppression of the renin-angiotensin-aldosterone system. Captopril causes a fall in blood pressure in hypertensive patients [M. A. Ondetti et al.. Science 1977,196,441 ... 

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... 

Adams KF, Jr. Pathophysiologic role of the renin-angiotensin-aldosterone and sympathetic nervous systems in heart failure. Am J Health Syst Pharm. 2004 61(suppl 2) S4-S13. 

Beta-adrenoceptor blockers. The realisation that the coiuse of chronic heart failure can be adversely affected by activation of the renin-angiotensin-aldosterone and sympathetic nervous systems led to exploration of possible benefit from P-adrenoceptors in a condition where, paradoxically, such drugs can have an adverse effect. Clinical trials have, indeed, shown that bisoprolol, carvedilol or metoprolol lower mortality and decrease hospitalisation when added to diuretics, digoxin and an ACE inhibitor (see below). 

Abbreviations NSAID = nonsteroidal anti-inflammatory drugs, PG = prostaglandin, RBF = renal blood flow, GFR = glomerular filtration rate,HTN = hypertension, DM = diabetes mellitus, = potassium, RAA = renin-angiotensin- aldosterone, CHF = congestive heart failure, AGE = angiotensin-converting enzyme, SLF = systemic lupus erythematosis. 

Secondary hyperaldosteronism results from stimulation of the zona glomerulosa by an extra-adrenal factor, usually the renin-angiotensin system. Excessive potassium intake can create a physiologic increase in aldosterone, as can oral contraceptive use, pregnancy (10 times normal by the third trimester), and menses. Congestive heart failure, cirrhosis, renal artery stenosis, and Bartter s syndrome also can lead to elevated aldosterone concentrations. 

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