15 Fév Beta-blockers boost Aldosterone antagonists’ effects in a severe rat heart failure model
Heart failure is a common, costly, and potentially fatal condition. It is a clinical syndrome characterized by the functional inability of the ventricle to meet the metabolic demands of the body.It affects about 40 million people globally every year. Overall around 2% of adults have heart failure and rates are predicted to increase. In the year after diagnosis the risk of death is about 35% after which it decreases to below 10% each year.
Treatment focuses on improving the symptoms and preventing the progression of the disease. Treatments include lifestyle and pharmacological modalities, and occasionally various forms of device therapy and rarely cardiac transplantation. Beta-blockers are a class of drugs used to control symptoms of heart failure by slowing the heart rate, which allows the left ventricle to fill more completely. Beta-blockers may be used together with other medicines that are usually used to treat heart failure, such as angiotensin-converting enzyme (ACE) inhibitors or diuretics.
Researchers from Lariboisiere University Hospital, Paris looked into Aldosterone antagonists (AAs) as complements to beta-blocker (BB). Aldosterone has been shown to cause coronary inflammation, cardiac hypertrophy, myocardial fibrosis, ventricular arrhythmias, and ischemic and necrotic lesions. There are currently two aldosterone antagonists commercially available in the United States, spironolactone and eplerenone. Spironolactone is a nonselective aldosterone antagonist, and eplerenone is selective to the aldosterone receptor. According to previous studies AA have beneficial effects on ventricular histological and electrical remodeling and improve noradrenaline uptake. Adding an AA to a beta-blocker (BB) further improves cardiac mortality in heart failure patients. The researchers tried to see if BB added to AA modifies beneficial effects of spironolactone.
The researchers produced surgically severe myocardial infarction (MI). Three months after surgery, left ventricular (LV) function was assessed by echocardiography. The rats were given different therapeutic combinations involving spironolactone, atenolol or both for 4 weeks. Holter transducers were implanted to record 24-hour ventricular electrical parameters. Invasive left ventricular end diastolic pressure (LVEDP) was also recorded. LV samples were used for histological analysis and catecholamine assay.
Rats with MI had significantly increased LVEDP, LV, collagen content, ventricular premature complexes. As expected, at nonhypotensive doses, spironolactone and atenolol similarly improved LVEDP. Compared with MI, although spironolactone significantly decreased ventricular premature complexes, LV collagen and noradrenaline contents, and improved meanRR and SDRR, whereas atenolol had effects only on meanRR and SDRR. Addition of atenolol to spironolactone further improved spironolactone effects on all these parameters.
Therefore, AA improved, independently of the cardiac function, histological and electrical remodelling after MI. A BB added to an AA did not blunt these beneficial effects, but further improved them
J Cardiovasc Pharmacol. 2012 Sep;60(3):315-21. doi:10.1097/FJC.0b013e318260e688.
Syncrosome, a scientific preclinical CRO based in France, also uses a rat with Chronic coronary ligature to model Heart failure for efficacy testing. They monitor, Doppler echocardiography, Coronary artery ligation, reperfusion, blood pressure, heart rate, planimetry, histology and morphological and functional biomarkers. By combining all these parameters, they can most reliably test for appropriate reaction.
Key words: preclinical CRO, preclinical study, animal model, animal research, myocardial, heart failure, infarction, echocardiography, heart, rat model, good model, ventricle, myocardial infarction, Congestive heart failure, Aldosterone, Beta blockers