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The effects of canrenone on left ventricle diastolic function, left atrial compliance and on atrial natriuretic hormones in some subjects with “challenge hypertension”
International medical literature reports that many hypertensive patients (25-40%: the percentage varies according to the different aspects of clinical settings) do not reach blood pressure targets (1) despite the availability of numerous classes of antihypertensive drugs. This is known as resistant hypertension or, because of the therapeutic challenge, “challenge hypertension” (CH). It is also frequent in patients already treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The CH, moreover, is a negative prognostic factor particularly because of a resulting left ventricular diastolic dysfunction that causes heart failure. An important rule seems to come from a basal increase of aldosterone level or aldosterone escape. This seems to occur because this hormone is controlled not only by angiotension II, but also by many substances such as potassium, adipokines, endotelina and some others.
In fact aldosterone seems to play a key role in cardiovascular disease. The receptors of this hormone are not only in the kidneys but also in the brain, heart and vessels and some animal models of aldosterone excess have demonstrated very severe cardiac damage, perivascular inflammation, microinfarctions and renal and heart fibrosis. (2-3-4-5). These data confirm in humans the deleterious role of aldosterone in particular due to some vicious cycles contributing to the development of myocardial hypertrophy, cardiovascular fibrosis and arterial stiffness.
The solution to this problem seems to come from aldosterone antagonists (spironolactone, canrenone, eplerone). Some clinical studies have shown that canrenone (an inexpensive aldosterone antagonist with very low side effects) induces an improvement of diastolic function without a significant effect on LV hypertrophy, probably inhibiting the aldosterone profibrotic action and obtaining a net reduction of myocardial collagen content (6).
Proposal to evaluate the response of left ventricular function of 30 patients with challenge hypertension to 50 or 100 mg of canrenone
Evaluation will be performed by repeated control of echocardiographic parameters, left atrial function and NT-proBNP. We also will use Tissue Doppler Imaging to identify and follow early left ventricular dysfunction. Careful monitoring of serum creatinine and electrolyte levels will be carried out.
At the end of the study we will be able to identify the best dose of aldosterone we can recommend to control hypertension and left ventricular diastolic dysfunction. In possible successive evaluations other end points such as mortality, morbility, quality of life and hospitalization will be evaluated.
Finally given the increasing knowledge of resistant hypertension and left ventricular diastolic dysfunction a prospective randomized controlled trial of canrenone would perhaps be timely.
Authors: Ferlisi A., Guida G. F., Di Vincenzo D.*, M. Traina
ASP Palermo Guadagna and Cimino Hospitals*, DISMOT Department Palermo University
1. Calhoun DA et al. – Resistant hypertension: diagnosis, evaluation, and treatment: A scientific statement from the American Heart Association professionale education committee of the council for high blood pressure research. Circulation 2008;117:e510-e526
2. Ortense RM, Williams GH – Aldosterone action in DeGrrot LJ, Jamenson JL eds Endocrinology, 4th edition WG Saunders, Philadelphia PA 2001:1783-9
3. Wang W – Chronic administration of aldosterone depresses barocereptor reflex function in the dog. Hypertension 1994;24:571-5
4. Schmidt BMV et al. – Short term cardiovascular effects of aldosteronein healthy male volunteers – J Endocrinol Metab 1999; 84:3528-33
5. Schachter M. Aldosterone antagonism: new ideas, new drugs Br J Cardiol 2002; 9-533-7
6. A. M. Grandi e coll. Aldosterone Antagonist Improves Diastolic Function in Essential Hypertension -Hypertension 2002;40;647-652