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Behavioral, dietary and pharmacological modalities of cardioprotection

心脏保护的行为、饮食和药理学方式

基本信息

批准号：
9147362
负责人：
Edward Lakatta
金额：
$ 40.3万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9147362
关键词：
Acute Acute myocardial infarction Affect Age Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Aorta Apoptotic Area Attenuated Behavioral Biological Factors Blood Pressure Blood Vessels Blueberries Body Weight Brain Brain-Derived Neurotrophic Factor Caliber Caloric Restriction Cardiac Cardiac Myocytes Cardiovascular Physiology Cardiovascular system Cells Chronic Congestive Heart Failure Control Animal Coronary Coronary artery Coupling Developed Countries Development Diabetes Mellitus Diastole Diastolic heart failure Diet Dilatation - action Disease Dobutamine Elderly Evaluation Event Experimental Models Fasting Food Functional disorder Harvest Health Benefit Heart Heart Atrium Heart Rate Hour Human Hypertrophy In Situ Nick-End Labeling Incidence Inflammation Injury Ischemia Kidney Diseases Knockout Mice Left Left Ventricular Remodeling Life Ligation Long-Term Effects Longevity Malignant Neoplasms Measures Mediating Modality Modeling Morbidity - disease rate Mus Muscle Cells Myocardial Myocardial Ischemia Myocardium Outcome Physiologic pulse Play Process Property Pulse Pressure Pump Rattus Reactive Oxygen Species Regimen Reperfusion Injury Reporting Resveratrol Risk Rodent Model Role Signal Pathway Signal Transduction Stress Tests Structure Subgroup Systolic Pressure Testing Therapeutic Therapeutic Agents Time Tissues Transgenic Organisms Ventricular Wild Type Mouse Wistar Rats age related arterial stiffness attenuation coronary fibrosis density dietary antioxidant feeding fitness hemodynamics indexing interest interstitial juvenile animal male morphometry mortality novel pre-clinical pressure prevent programs protective effect red wine research clinical testing research study response success translational study

项目摘要

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 an ischemic event to increase the tolerance of the cardiac tissue to ischemic damage. I. ADF had been reported to increase the lifespan and to reduce the incidence of age-associated diseases, including cancer, diabetes and kidney disease. We had shown the cardioprotective effect of ADF in rats using the model of experimental MI induced by a permanent coronary ligation. While tissue protective properties of ADF have been proven, the effects of chronic ADF on general cardiovascular fitness remained unknown. SD rats, 4 month old, were started on ADF or ad libitum diets. Heart morphometry and function was followed for 6 months with serial Echo. At the end of the observation period, rats were subjected to a comprehensive hemodynamic evaluation via LV pressure-volume loop (PV-loop) analyses including a combined dobutamine and volume stress test, and hearts were harvested for histological assessment. The 6 month long ADF resulted in a 9% reduction (p<0.01) of cardio myocyte diameter and 3 fold increase in interstitial myocardial fibrosis. LV chamber size was not affected in ADF and EF was not reduced. Left atrial diameter increased 16% in ADF, while E/A ratio of mitral flow were reduced. PV-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. On the other hand, contrary to ADF, CR was not cardioprotective in the same experimental model. However, 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 of 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. Recent findings suggest that some of the beneficial effects of ADF on both the cardiovascular system and the brain are mediated by brain-derived neurotrophic factor (BDNF) signaling in the brain. We investigated the role of BDNF in cardio protective effects of ADF. Transgenic BDNF knockout mice showed a significant reduction of BDNF level in cardiac tissue compared to wild type controls. However, MI size at 24 hours after coronary artery ligation was similar between BDNF knockout mice and its wild type mice. It indicated a limited role of BDNF in the process of acute myocardial ischemic injury in mice. II. Antioxidant supplement. ROS play a major role in ischemia-related myocardial injury. However, 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. We had shown that adding blueberries to the diet (BD) resulted in a 24% increase (p<0.001) of ROS indexed tMPT compared with control diet (CD). 24h after coronary ligation, resulting 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). We concluded that a blueberry-enriched diet protected the myocardium from ischemic damage and demonstrated the potential to attenuate the development of post-MI CHF. To test the hypothesis that BD will attenuate the course of CHF, we introduced blueberry-enriched diet to rats 2 weeks after inducing MI by permanent ligation of a coronary artery. The outcome was a 1-year mortality and cardiac remodeling. Two weeks after coronary artery ligation, rats were divided into two groups of similar average MI size, measured by Echo, and then 12-mo dietary regimens were initiated as follows: ad libitum regular diet (control, CD, n = 27) and isocaloric food with 2% blueberry supplement (BD, n = 27) also available ad libitum. Mortality over the 12 mo 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. These results represent the first experimental evidence that a blueberry-enriched diet has positive effects on the course of CHF and thus warrants consideration for clinical evaluation. Multiple health benefits of resveratrol, a red wine extract, are well documented in pre-clinical animal studies. The recently reported property of resveratrol as SIRT1 activator made it an attractive target for the management of CHF. In this experiment we tested the effect of long-term resveratrol supplement to a diet on mortality and progression of cardiaovascular remodeling in the rat model of post-MI CHF in rats. Resveratrol enriched (5mg/kg/day) or normal ad-libitum diets were initiated two weeks after induction of MI by ligation of the left coronary artery in male Wistar rats and continued for 10 months. 10-mo mortality was similar in untreated MI rats (C, 65%) and rats treated with resveratrol (R, 61%). 77% expansion of MI over 10 months observed in C via serial Echo was also not affected by resveratrol supplement. Dilatation of LV chamber (86% for EDV, and 135% for ESV) and decline of EF (63%) observed in C via serial Echo were progressively attenuated over time in R group; however, differences between groups never reached statistical significance. Arterial blood pressure measured monthly revealed small, but statistically significant reduction of systolic and pulse pressure in R vs C. Marked decline of cardiac function associated with MI shown by invasive hemodynamic assessments at the end of the 10-mo experiment and cross-sectional in subgroups of animals throughout the experiment was mostly not affected by resveratrol supplement with the exception of PRSW (603 vs. 404 in C; p<0.05) and arterial-ventricular coupling (1.10.1 vs. 2.70.7 in C; p<0.05), both of which were similar to that in Sham. PWV, increased by 35% in C compared to Sham, normalized in R starting with 4 months of treatment (p<0.05). Results indicate that resveratrol supplement produces some beneficial effects in the rat model of post-MI CHF, suggesting its utility as an adjunct treatment to existing therapeutic regimens.

该计划的主要目标是在啮齿类动物心肌缺血模型上进行临床前实验，以测试在缺血事件发生之前饮食操作的影响，以增加心脏组织对缺血损伤的耐受性。