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Fresh ideas to take back to practice

by
01 February 2010, at 12:00am

Dr TIM WATSON reports on proceedings at a recent symposium on heart failure

THE historic vineyards of Bordeaux and the elegant Château Giscours were the stunning backdrops to a recent gathering of Europe’s foremost veterinary cardiologists. 

The occasion was a symposium, hosted by Ceva Animal Health, bringing together specialists in human and animal science to discuss the role of aldosterone in heart failure and the therapeutic benefit of blocking its activity.

Cardiologists’ interest in aldosterone has largely been stimulated by the fact that the aldosterone antagonists, spironolactone and eplerenone, substantially reduce cardiovascular mortality in humans. These benefits are not related to any diuretic or blood pressure effect of aldosterone blockade, but appear to be a consequence of blocking the mineralocorticoid receptors (MR) that mediate the remodelling activity of aldosterone.

Scientific understanding of the role of aldosterone and its receptors in the heart was the subject of the symposium’s first two presentations, which were given by Dr Nicolette Farman and Dr Frédérick Jaisser from the French National Institute of Health and Medical research (INSERM) in Paris.

Their research group has been pivotal in showing that MR are expressed in cardiomyocytes and in endothelial and smooth muscles cells of coronary blood vessels, the aorta and resistance arteries. Although the exact function of aldosterone and MR in these tissues is poorly understood, it is clear that over-activation of MR contributes to the progression of heart disease and failure.

Aldosterone is known to have a profibrotic effect and chronic activation of MR has been associated with cardiac fibrosis, endothelial dysfunction and vascular wall remodelling. These effects are, however, seen regardless of plasma aldosterone concentrations and are independent of blood pressure, suggesting that it is increased expression and/or activation of MR, rather than hyperaldosteronism, that is responsible for cardiovascular pathology. 

The pathogenic role of these receptors in cardiac tissues is highlighted by the observation that blocking MR with low doses of spironolactone prevents cardiac and vascular remodelling in humans and a variety of animal models of heart failure. This includes dogs, with a recent study showing that spironolactone reduces atrial fibrosis and prevents conduction defects in dogs with congestive heart failure induced by rapid ventricular pacing.1

Conundrum re-examined

The science linking experimental MR studies with clinical benefits was further explored by Dr Johann Bauersachs from the University Hospital in Würzburg, Germany.

He began by re-examining the conundrum that, while aldosterone induces cardiac fibrosis and plasma levels predict the risk of mortality in humans suffering acute myocardial infarction or congestive heart failure, benefits from MR antagonists are seen in patients with normal aldosterone concentrations.

Dr Bauersachs’ own research has shown that cardiac MR expression is increased in heart failure patients, thereby indicating that it is over- expression of the receptor, rather than increased production of aldosterone, that is deleterious.

Other contributing factors might include activation of MR by glucocorticoids, oxidative stress, and changes in gene expression – so-called “foetal switching” – in the failing heart.

The relevance of experimental models to canine clinical disease was debated during this and the subsequent presentation from Professor Robert Hamlin of Ohio State University. While models cannot truly replicate either myxomatous mitral valve disease (MMVD) or dilated cardiomyopathy, both speakers argued that the pathology of end stage heart failure is similar regardless of the cause and that canine models, including those in which heart failure is induced by rapid pacing, chordectomy or micro-embolism, do have value.

MR antagonists

Developments in the use of MR antagonists in humans were reviewed by Professor Bertram Pitt from the University of Michigan School of Medicine, who led clinical studies demonstrating that spironolactone reduces three-year mortality by over 30% in patients with chronic severe heart failure.

He stressed that clinical benefits are greater the sooner that therapy is started and are in addition to other cardiac therapies, including angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, β blockers, loop diuretics and digoxin.

On-going studies are examining the efficacy of spironolactone in patients with mild heart failure and Professor Pitt expressed the firm belief that, in the future, MR antagonists will play a key role in preventing many forms of heart failure.

The spotlight then switched to veterinary experiences with spironolactone and Dr Claudio Bussadori from Milan, Italy, who is dually qualified as a veterinarian and medical doctor, described a large clinical trial of spironolactone in dogs with moderate to severe mitral valve regurgitation caused by MMVD.

A total of 221 dogs entered into a double-blinded, placebo-controlled study that took place in 32 veterinary practices across France, Germany, Belgium and Italy. The dogs received either spironolactone at a dose of 2mg/kg/day or placebo, and were monitored for 15 months. All dogs were concurrently receiving an ACE inhibitor and approximately 50% were on frusemide.

The primary end points were cardiac-related death or euthanasia, or severe worsening of disease.

Analysis of clinical trials such as this spironolactone study is complicated and can be difficult to understand, but was expertly explained by Professor John Bland from the Department of Health Statistics at the University of York.

His analysis revealed that the estimated survival rates for dogs treated with placebo or spironolactone at 15 months were 66% and 84%, respectively (P<0.05). The hazard ratio, which is an indication of the efficacy of treatment, was 0.45 (P<0.05).

This meant that there was a 55% reduction in the risk of death or worsening of cardiac disease in dogs treated with spironolactone.

When only cardiac death or euthanasia were considered, the survival rate for spironolactone-treated dogs was 92%, compared with 73% for the placebo group (P<0.01), and there was a 69% reduction in risk of mortality (P<0.05).

Substantially greater

Putting these results in context, Professor Bland indicated that the magnitude of benefit was such that, had it been a human clinical trial, the study would have been stopped on ethical grounds so that all patients could receive spironolactone.

The 69% reduction in 15-month mortality is substantially greater than that seen in the equivalent human study, which amounted to 31% over three years.2

In closing proceedings, Mark Prikazsky, the president and CEO of Ceva Santé Animale, remarked that the symposium was inspired by the philosophy of “one medicine” and the advances that might be accrued by exchanging expertise between human and veterinary fields.

Judging from the buzz over dinner later that night, it certainly achieved that goal and left all those who attended with new thoughts and ideas to take back to both the laboratory and clinic.

  1. Yang, S-s., et al. (2008) Effects of spironolactone on electrical and structural remodeling of atrium in congestive heart failure dogs. Chinese Medicine Journal 121: 38-42.
  2. Pitt, B., et al. (1999) The effects of spironolactone on morbidity and mortality in patients with severe heart failure. New England Journal of Medicine 341: 709-717.