The Second Human and Veterinary Crosstalk Symposium on Aldosterone
Dr Tim Watson reports on how cutting edge science, served with consummate French culture and hospitality, furthered understanding of the role of aldosterone in heart failure.
Glorious autumn sun illuminated the UNESCO World Heritage Site of Bordeaux, France over the first weekend of October 2011 and provided a magnificent setting for the Second Human and Veterinary Symposium on Aldosterone. Hosted by Ceva Animal Health, two years on from the first symposium, the meeting brought together over 100 scientists and clinicians. Experts from both human and veterinary fields discussed the role that aldosterone plays in heart failure and the clinical benefits that come from blocking its action.
The first presentation was given by Professor Allan Struthers, who runs the Heart Failure service atNinewellsHospitalinDundee. Professor Struthers described how Angiotensin Converting Enzyme (ACE) Inhibitors are routinely used in human medicine and work by blocking the production of angiotensin II. This is a key component of the potentially harmful Renin-Angiotensin-Aldosterone System (RAAS) and ultimately triggers the synthesis of aldosterone (Fig 1).
It has, however, been recognised that aldosterone is not fully suppressed by ACE inhibitors and ‘aldosterone breakthrough’ – a phenomenon in which aldosterone levels return to normal - occurs in a significant proportion of patients receiving long-term ACE inhibitor therapy. There are several reasons for this, including the stimulation of aldosterone by raised potassium concentrations and the production of aldosterone through pathways that do not involve ACE (Fig 1).
Professor Struthers explained that this was significant as, in human patients, aldosterone has been linked with a variety of harmful cardiovascular outcomes, including hypertension, left ventricular hypertrophy, cardiac fibrosis, poor exercise tolerance and sometimes fatal arrhythmias. This has led to the exploration as to whether adding an aldosterone antagonist, such as spironolactone, to therapy with an ACE inhibitor could provide additional clinical benefits.
Human trial work looking at the use of aldosterone antagonists was discussed in detail by Professor Faiez Zannad, from theUniversityofHenri Poincaréin France, and Professor Bertram Pitt, from theUniversityofMichigan. Three large-scale studies (RALES,EPHESUSand EMPHASIS-HF) have been carried out; all have demonstrated that aldosterone blockade (with either spironolactone or eplerenone) reduces the risk of mortality in heart failure patients with left ventricular systolic dysfunction. This is seen in those with mild as well as severe symptoms. Professor Pitt went on to say that he is currently engaged in a trial (called the TOPCAT study) looking at efficacy of aldosterone antagonists in heart failure patients with normal systolic function.
The question of how this relates to veterinary patients was explored by Professor Clarke Atkins, from the Collegeof Veterinary Medicineat North CarolinaStateUniversity, who explained that aldosterone was a “toxin” which reduced vascular and ventricular compliance and may lead to or worsen heart failure. On the subject of aldosterone breakthrough, Professor Atkins explained that furosemide is known to stimulate the RAAS. In a study looking at 22 Cavalier King Charles Spaniels with congestive heart failure (CHF) caused by mitral valve disease, aldosterone breakthrough was shown to occur in patients receiving 21 weeks of enalapril and furosemide.1 In addition, in a short term study looking at healthy dogs, aldosterone was shown to increase three-fold after receiving 7 days of furosemide, despite these dogs also receiving an ACE inhibitor.2
Clinical benefits of aldosterone antagonists in dogs were proven in a study involving 212 dogs with CHF caused by mitral valve disease.3 This showed that the addition of spironolactone to first-line therapy, which also included an ACE inhibitor and diuretic support, reduced the risk of cardiovascular mortality by 69%. In an extension of this work, Dr Michele Borgarelli, Associate Professor atKansasStateUniversity, is coordinating a study (called DELAY) to assess whether using spironolactone in addition to an ACE inhibitor in asymptomatic patients can delay the onset of heart failure. The results are expected in 2015.
The final session of the day focused on intriguing links between cardiac and renal disease. Professor Rebecca Stepien, from theUniversityofWisconsin, discussed the simultaneous occurrence of cardiac and renal dysfunction in dogs with mitral valve disease. It was her opinion that canine patients may develop clinical signs of CHF while having evidence of pre-existing renal dysfunction or, more commonly, renal dysfunction may develop as cardiac disease progresses. This may also be influenced by the addition of medical therapy such as furosemide, which is known to activate the RAAS and thereby contribute to the development of renal dysfunction.
In the final presentation, Dr Frédéric Jaisser, Research Director at INSERM inParis, explored in more detail the role of aldosterone in chronic kidney diseases and the potential benefit of aldosterone antagonists. He explained that, as well as harmful effects on the heart, aldosterone can also promote proteinuria and decrease glomerular filtration rate. Aldosterone receptors are found in various renal sites and appear to be involved in the pathology of diabetic and hypertensive nephropathy, nephrosclerosis and nephrotoxicity.
Several human studies have demonstrated positive clinical outcomes when aldosterone antagonists are used in the treatment of diabetic and other protein-losing nephropathies, and end-stage renal disease. Further work is, however, needed to assess whether spironolactone, for example, might deliver similar benefits in veterinary patients.
Overall, the Symposium provided a fascinating and stimulating look at the cutting edge of veterinary and human medical science. The debate that followed these presentations, and which ensued late into the evening, left delegates in no doubt that aldosterone continues to be a ‘hot topic’ for human physicians and veterinary clinicians alike. As on-going research reveals more and more about the role of aldosterone and aldosterone antagonists, the onerous task for Ceva is to find an equally spectacular location for a third symposium in 2013.
To obtain the full proceedings from the Symposium and to listen to any of the lectures online, visit http://cardiosymposium2011.ceva.com/.