Aldosterone-induced vasculopathy: a new reversible cause of cardiac death.

Abstract

JRAAS 2001;2:211-14 The traditional view is that angiotensin II (Ang II) is the principal culprit in the renin-angiotensinaldosterone system (RAAS). However, it is now appreciated that aldosterone is a second culprit and that the harmful effects of aldosterone are additional to those of Ang II. The relative importance of Ang II and aldosterone can be illustrated by the fact that during chronic angiotensin-converting enzyme inhibitor (ACE-I) therapy, there is more escape of aldosterone than there is of Ang II. Indeed, we recently showed that both aldosterone and plasma Ang II are elevated in many CHF patients who are being treated with chronic ACE-I therapy, but in our patients, 38% had an elevated aldosterone while only 15% had an elevated plasma Ang II level. The important clinical point is that there is plenty of residual aldosterone around for this to be a potential problem,even in the presence of an ACE-I. Indeed, one could now say that in ACE-I-treated CHF patients, aldosterone escape increases mortality while Ang II escape does not. This is based on the fact that the RALES study with aldosterone blockade was positive, while the effect of valsartan in ValHeFT was neutral, as far as mortality was concerned. Initially, the idea that aldosterone ‘escaped’ in the presence of an ACE-I came as a surprise, but it should not really be surprising, since aldosterone is under the control not only of Ang II, but also of potassium. Therefore, although ACE-I-induced reductions in Ang II should suppress aldosterone, this is counterbalanced by the stimulation of aldosterone by ACE-I-induced K increases. What, therefore, are the harmful effects of aldosterone in CHF? Interestingly, it is now recognised that aldosterone exerts major effects on all the principal mechanisms which produce cardiac death. It is therefore worth first discussing the more general idea of what these principal mechanisms are, irrespective of aldosterone. Coronary artery disease is obviously a key factor leading to cardiac death. As well as coronary disease, another main factor which independently promotes cardiac death is left ventricular dysfunction, which is usually accompanied by left ventricular fibrosis. Indeed, the feature of LV dysfunction which is particularly arrhythmogenic is the accompanying LV fibrosis. Patchy LV fibrosis means that the electrical currents have to take detours around the fibrotic areas, which promotes arrhythmias. The third main factor influencing cardiac death are those which are extrinsic to the heart, but which are pro-arrhythmic in themselves. Of these, the most important factor is autonomic (sympathovagal) imbalance. Here, it is the balance between the sympathetic and the parasympathetic nervous system which counts. The sympathetic nervous system (SNS) is pro-arrhythmic while the parasympathetic is antiarrhythmic. This is exemplified by animal studies which show that vagal stimulation not only improves survival, but also reduces arrhythmias in animals undergoing coronary artery ligation, which inevitably activates the SNS. In patients, cardiac autonomic balance is best measured by heart rate variability and baroreflex testing. Innumerable studies have shown that abnormalities in both heart rate variability and baroreflex testing are independently and significantly linked with cardiac death. It is clear that, at any given LVEF, a poor heart rate variability and/or poor baroreceptor function are strongly linked with impending cardiac death. As mentioned above, aldosterone has adverse effects on all aspects of this: coronary endothelial dysfunction,LV fibrosis and autonomic imbalance. However, the adverse effect of aldosterone on all three of these factors may well stem from its ability to produce its own vasculopathy.