The broad objective of this program is to perform preclinical experimentation on rodent models of myocardial ischemia to test the effect of dietary manipulations prior to ischemic event to increase the tolerance of the cardiac tissue to ischemic damage. I. Alternative Day Fasting (ADF), i.e., the feeding regimen when ad lib food is available only every other day, had been reported to increase the lifespan and to reduce the incidence of age-associated diseases, including cancer, diabetes and kidney disease. Neuroprotective effects of ADF against ischemic injury of the brain have also been reported. We investigated the cardioprotective effect of ADF in rats using the model of experimental myocardial infarction induced by a permanent coronary ligation. After three months of ADF or regular, daily, feeding ad libitum (AL), 5-mo old rats were subjected to coronary ligation or sham operation. A subset of rats was sacrificed 24 hours later to measure the size of myocardial infarction (MI) and the extent of apoptosis. The remainder of the animals were continued for 10 weeks on the same food regimen, during which time the progression of left ventricular (LV) remodeling was assessed by serial echocardiography. After ten weeks LV function was measured by pressure-volume loops analyses, and hearts were evaluated histologically. We showed that 24 hrs following coronary ligation the ischemic area of myocardium, i.e., the area at risk (AAR), was similar in both groups, but in ADF rats MI size, expressed as a percent of AAR, was more than 2-fold smaller, apoptosis in the AAR was reduced by more than 4-fold, and the inflammatory response was significantly reduced. At 10 wks, late LV remodeling and MI expansion occurred in AL rats but not in ADF rats, and LV pump function and arterio-ventricular coupling were superior in ADF vs AL rats. The myocyte hypertrophy in areas remote from the MI was also absent in ADF rats. The results indicate that Intermittent Food Deprivation protects the heart from ischemic injury in part, at least, via an enhanced anti-apoptotic mechanism. In another experiment, we demonstrated that ADF improves glycemic control and results in the increase of the levels of circulating adiponectin. Because recent studies have shown that adiponectin can protect the heart against ischemic injury, adiponectin may mediate, at least in part, the cardioprotective effect of ADF. While tissue protective properties of ADF have been proven, the effects of chronic ADF on general cardiovascular fitness remained unknown. At 4-mo of age, male SD rats were started on ADF or continued on ad libitum diets. Heart morphometry and function was followed for 6 months with serial echocardiography. At the end of the observation period, rats were subjected to a comprehensive hemodynamic evaluation via pressure-volume loop analyses including a combined dobutamine - volume stress test, and hearts were harvested for histological assessment. The six-month long ADF resulted in a 9% reduction (p<0.01) of cardiomyocyte diameter and 3 fold increase in interstitial myocardial fibrosis. Left ventricular chamber size was not affected in ADF and ejection fraction was not reduced. Left atrial diameter increased 16% in ADF, while E/A ratio in Doppler-measured mitral flow was reduced. Pressure-volume loop analyses in ADF revealed a stiff heart during diastole, and histological analyses demonstrated a 3-fold increase of myocardial fibrosis vs control hearts. Combined dobutamine and volume loading showed a significant reduction in LV diastolic compliance and a lack of increase in systolic pump function in ADF, indicating a diminished cardiac reserve. Thus chronic ADF in rats results in development of diastolic dysfunction with diminished cardiac reserve. Therefore, ADF is a novel and unique experimental model of behaviorally induced diastolic heart failure. The deleterious effect of ADF in rats warrants additional studies of ADF effect on cardiovascular function in humans. Contradiction of results of ADF experiments (ADF is cardioprotective but results in reduction of diastolic compliance and cardiac reserve) prompted the initiation of similar studies with direct reduction of caloric intake (CR). Similar to the experimental design described above, rats were maintained either on regular ad libitum diet, or on the diet consisting of 30% calorie reduction. After 3 mos of respective diet the MI was induced by a permanent ligation of the left descending coronary artery. MI measured histologically 24 hrs following intervention did not reveal any significant differences in MI size or apaptosis/inflammation in the area at risk. Follow-up serial echocardiographic assessment in a subgroup of rats did not reveal any differences between groups with respect to LV remodeling, function or MI expansion. Thus, contrary to ADF, CR is not cardioprotective. On the other hand, 24-mo old rats maintained throughout their life on 30% caloric reduction showed a lower degree of age-related myocardial hypertrophy and higher systolic function than their ad libitum fed age control animals. While ad libitum fed 24-mo old rats could not respond to dobutamine challenge by the heart rate increase, the 24-mo old CR animals demonstrated the proper heart rate response typical for younger animals. Moreover, 24-mo old CR rats had less myocardial fibrosis and less age-related loss of density of cardiomyocytes than ad libitum fed age-matched control. Additionally, the CR rats had lower pulse wave velocity measured in aorta than AL animals, indicating lower arterial stiffness. However, CR did not prevent the age-related loss of cardiomyocytes. Thus, contrary to ADF, CR promoted cardiac fitness and delayed age-related changes in the cardio-vascular structure and function. II. Blueberry supplement. Reactive oxygen species (ROS) play a major role in ischemia-related myocardial injury. However, the attempts to use synthetic antioxidants to block the detrimental effects of ROS have produced mixed or negative results, precipitating the interest in antioxidants found in natural products. Blueberries have the highest antioxidant capacity among fruits and vegetables, and had been shown to reduce neurological deficits observed in aged animal models. The objective of this study was to assess the cardioprotective properties of a blueberry enriched diet (BD). Following 3-mo exposure to BD or a regular control diet (CD), the threshold for mitochondrial permeability transition (tMPT) was measured in isolated cardiomyocytes obtained from young male Fischer-344 rats. Compared to CD, BD resulted in a 24% increase (p<0.001) of ROS indexed tMPT. The remaining animals were subjected to a permanent ligation of descending coronary artery. Twenty-four hrs later, resulting myocardial infarction (MI) in rats on BD was 24% less than in CD rats (p<0.05). Significantly fewer TUNEL(+) cardiomyocytes (2% vs 9%) and 40% fewer inflammation cells were observed in the myocardial area at risk of BD compared to CD rats (p<0.05). In other groups of rats immediately after coronary ligation, the original diet was either continued or switched to the opposite one, and their cardiac remodeling and MI expansion were followed by serial echocardiography for 10 weeks. Results of echo measurements indicated that rates of post MI cardiac remodeling and MI expansion were proportional to original myocardial damage governed by the previous diet. However, BD or its withdrawal after MI induction attenuated or accelerated this effect. We concluded that blueberry-enriched diet protected the myocardium from ischemic damage and demonstrated the potential to attenuate the development of post MI chronic heart failure.
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