10 Avr New combination in a rat preclinical Congestive heart failure model shows promising results
Congestive heart failure (CHF), occurs when the heart is unable to pump sufficiently to maintain blood flow to meet the body’s needs. Signs and symptoms commonly include shortness of breath, excessive tiredness, and leg swelling. Since the 1980, ACE inhibitors (ACEi) are used in patients to treat chronic heart failure (CHF) by blocking the renin-angiotensin system. Convincing experimental data in rodent models in the beginning of the decade helped establish the beneficial clinical of these molecules.
Following experimental evidence in rats, 1-adrenergic receptor (AR) blockers were first used in the 90s after clinical trials showed a 35% reduction in mortality and significant reversal of cardiac remodelling in patients with CHF. A combination of 1-AR blockers with ACEi (or angiotensin receptor blockers) was subsequently recommended by the American Heart Association, and is now considered a standard therapy for CHF. However, CHF still remains a major cause of morbidity and mortality, particularly in the elderly. The search for new pharmaceutical approaches to fight CHF is thus still on.
Experimental evidence in the rat model points to the antiapoptotic, and thus cardioprotective, properties of 2-AR agonists. Studies have clearly demonstrated the therapeutic effectiveness of combined 1-AR blockers and 2-AR agonist therapy in animal models of CHF. However, clinical studies for this combination haven’t yet gone through due to largely hypothetical objections. This first is that 2-AR stimulation accelerates the heart rate and, therefore, could be proarrhythmic. Moreover, chronic-AR stimulation leads to down-regulation and desensitization of 2-AR and, therefore, cannot be effective.
Fundamentally the problem also lies in the fact that this regimen hasn’t been compared with the standard CHF treatment, an ACE inhibitor combined with a 1-AR blocker. Therefore, Researchers from the NIH in the US tried to compare the effectiveness of 12 month treatment regimen of the combination of a 1-AR blocker and 2-AR agonist with the standard combination of 1-AR blocker and ACE inhibitor in a well characterized rat experimental model of post-MI dilated cardiomyopathy.
Two weeks after coronary artery ligation, the rats were divided into groups of similar average MI size (measured by echocardiography) and given different treatments for 12 months: fenoterol, a 2-AR agonist + metoprolol, a 1-AR blocker; metoprolol + enalapril, an ACEi ; and a combination of all three drugs. The 12-month mortality was significantly reduced in all treatment groups. There was a significant decrease of the left ventricular (LV) chamber remodeling visible by echocardiography. An attenuation of the LV functional deterioration was also observed, as well as a limitation to MI expansion in all three treatment groups.
However, the researchers noticed that these improvements were significantly more pronounced when treatment included a 2-AR agonist. Moreover, a combination of 1-AR blocker and 2-AR agonist seemed to show equivalent results with the respect to mortality than the standard therapeutic combination used to treat CHF that includes a 1-AR blocker and ACEi. However, it even showed better effects with respect to cardiac remodelling and MI expansion. These results in rats are very encouraging and, urge the consideration of this combination for clinical investigations.
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 331, No.1 157107/3512754 JPET 331:178–185, 2009
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