I. The broad objective of this program is to perform preclinical experimentation on animal models of myocardial ischemia and subsequent chronic heart failure (CHF) to elucidate the mechanisms of its development and to evaluate the potential of different therapeutic modalities to limit the extent of myocardial damage and to prevent or attenuate the development of CHF. Beta-2 adrenergic receptors in treatment of CHF. The role of beta-adrenergic receptors (AR) subtype signaling in development of CHF is clearly important. It is widely accepted now that beta-1 AR activation is associated with development of CHF. Recent data indicate that stimulation of beta-1 AR is proapoptotic, thus, the use of beta-1 AR antagonists became a recommended therapy for HF. The possible role of beta-2 AR agonists remains debatable;however the consensus is that, as with beta-1 AR, activation of beta-2 AR during CHF is harmful. Recent research in LCS using single myocytes indicated that beta-2 AR agonist, fenoterol, possesses a unique cardioprotective property, and, in fact is antiapoptotic. Capitalizing on this finding we studied the effects of chronic treatment with beta-2 AR agonist, fenoterol, and beta-1 AR blocker, metaprolol, in rats starting 2 weeks after ligation of a coronary artery. Our results indicated that both beta-2 AR agonist and beta-1 AR blocker reduced the apoptosis in myocardium, but beta-2 AR agonist was superior to beta-2 AR blocker in attenuation of left ventricular remodeling and functional decline. Moreover, beta-2 agonist treatment arrested the infarct expansion, resulting in actual decrease of the relative infarct size. These two therapies affected different aspects of cardiac function: metaprolol improved systolic cardiac performance by increasing left ventricular elastance, while fenoterol achieved the same result by reducing the arterial elastance (after-load). Metaprolol did not improve diastolic function, while fenoterol normalized it. Combined treatment with beta-1 blocker and beta-2 agonist resulted in morphometric and functional improvements similar to a treatment with beta-2 agonist alone. In additional experiments we showed that a treatment with a combination of beta -1 blocker, metaprolol and beta-2 agonist, fenoterol is clearly superior to a single therapy with beta1-blocker in reduction of cardio myocyte apoptosis, attenuation of LV remodeling, and it actually improves the LV function. In a yearlong experiment we demonstrated a significant survival benefit of combined therapy with beta-2 agonist and beta-1 blocker compared with any single therapy alone. Moreover, a therapeutic benefit of beta-2 agonist lasted only 2 months after coronary ligation, while the effect of combined therapy lasted six months. In the present study we compared the effects of the beta 1 AR blocker-beta 2 AR agonist combination with a combination of beta 1AR blocker and angiotensin converting enzyme inhibitor (ACEi), i.e., the current therapy of choice for CHF. Two weeks after coronary artery ligation rats were divided into groups of similar average myocardial infarct (MI) size measured by echocardiography, and the following 12-mo treatments were initiated: fenoterol (250 g/kg/day), a beta 2 AR agonist, and metoprolol (100 mg/kg/day), a beta 1AR blocker;metaprolol and enalapril (20 mg/kg/day), an ACEi;and a combination of all three compounds. These treatment groups were compared to a non-treated (nT) and sham groups. The 12-mo mortality was significantly reduced in all treatment groups (44% in beta1-beta2+, 56% in beta 1-beta 2+ACEi, 59% in beta 1-ACEi vs 81% in nT). Bi-monthly Echo revealed significant attenuation of the left ventricular (LV) chamber remodeling, LV functional deterioration, and MI expansion in all three treatment groups, but effects were significantly more pronounced when treatment included a beta 2AR agonist. We concluded that the combination of 1AR blocker and 2AR agonist is equipotent with a combination of beta 1AR blocker and ACEi in the treatment of CHF with the respect to mortality and exceeds the latter with respect to cardiac remodeling and MI expansion. Thus, this novel therapeutic regimen for CHF merits clinical trial consideration. II. We have reported that blueberry-enriched diet (BD) attenuates necro-apoptosis and inflammation in peri-infarct area in experiments on rats and thus reduces surgically induced myocardial infarction. Since it is now generally accepted that a major factor leading to progression of CHF is cumulative cell loss in myocardium, we tested the hypothesis that BD would attenuate the course of CHF, including mortality and cardiac remodeling during the first year after induction of myocardial infarction in rats. Two weeks after coronary artery ligation, rats were divided into two groups of similar average MI size, measured by echocardiography, and the following 12-mo dietary regimens were initiated - ad libitum regular diet (control, CD, n=27) and isocaloric food with 2% blueberry supplement (BD, n=27) also available ad libitum. These dietary groups were compared to each other and to the sham group (SH). The 12-mo mortality was reduced by 22% in BD compared with CD (p<0.01). In the course of developing CHF, BD had no effect on the body weight, heart rate or blood pressure. Bi-monthly Echo revealed significant attenuation of the LV chamber remodeling, LV posterior wall thinning, and MI expansion in BD compared with CD. In fact, BD arrested the MI expansion. This is the first experimental evidence that a blueberry-enriched diet has positive effects on the course of CHF and thus warrants consideration for clinical testing.
