Behavioral, dietary and pharmacological modalities of cardioprotection

心脏保护的行为、饮食和药理学方式

• 批准号: 8931608
• 负责人: Edward Lakatta
• 金额: $ 16.45万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 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/8931608
• 关键词: 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; Caliber; Caloric Restriction; Cardiac; Cardiac Myocytes; Cardiovascular Physiology; Cardiovascular system; Cells; Chronic; Control Animal; Coronary; Coronary artery; Coupling; Developed Countries; Development; Diabetes Mellitus; Diastole; Diastolic blood pressure; Diastolic heart failure; Diet; Dilatation - action; Disease; Dobutamine; EFRAC; Echocardiography; Elderly; Evaluation; Event; Experimental Models; Fasting; Fibrosis; Food; Functional disorder; Harvest; Health Benefit; Heart; Heart Atrium; Heart Rate; Heart failure; Human; Hypertrophy; In Situ Nick-End Labeling; Incidence; Inflammation; Injury; Ischemia; Kidney Diseases; Left; Left Ventricular Remodeling; Life; Ligation; Long-Term Effects; Longevity; Malignant Neoplasms; Measures; Modality; Modeling; Morbidity - disease rate; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Outcome; Physiologic pulse; Play; Property; Pulse Pressure; Pump; Rattus; Reactive Oxygen Species; Regimen; Reperfusion Injury; Reporting; Resveratrol; Risk; Rodent Model; Role; Signal Pathway; Stress Tests; Structure; Subgroup; Systolic Pressure; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Ventricular; Wistar Rats; Working stroke; age related; arterial stiffness; attenuation; density; dietary antioxidant; feeding; fitness; hemodynamics; indexing; interest; interstitial; juvenile animal; male; morphometry; mortality; myocardial infarct sizing; novel; pre-clinical; pressure; prevent; programs; red wine; research clinical testing; research study; response; success; translational study

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. 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. We had shown the cardioprotective effect of ADF in rats using the model of experimental myocardial infarction 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. 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. On the other hand, contrary to ADF, calorie restriction (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. II. Antioxidant supplement. Reactive oxygen species (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). Twenty-four hrs after coronary ligation, 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). We concluded that a blueberry-enriched diet protected the myocardium from ischemic damage and demonstrated the potential to attenuate the development of post-MI chronic heart failure. To test the hypothesis that BD will attenuate the course of chronic heart failure (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 echocardiography, 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. These dietary groups were compared to each other and to a sham group (SH). 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 chronic heart failure (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-myocardial infarct (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 descending 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 echocardiography (Echo) was also not affected by resveratrol supplement. Dilatation of LV chamber (86% for end-diastolic pressure, and 135% for end-systolic pressure) and decline of ejection fraction (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 preload recruitable stroke work (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. Pulse wave velocity, 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心肌缺血的啮齿动物模型上进行临床前实验，以测试缺血事件之前饮食控制的效果，以提高心脏组织对缺血损伤的耐受性。 I. 替代日禁食（ADF），即每隔一天才提供随意食物的喂养方案，据报道可以延长寿命并减少与年龄相关的疾病，包括癌症、糖尿病和肾病的发病率。我们使用永久性冠状动脉结扎诱发的实验性心肌梗塞模型，展示了 ADF 对大鼠的心脏保护作用。虽然 ADF 的组织保护特性已得到证实，但慢性 ADF 对一般心血管健康的影响仍然未知。 4 个月大时，雄性 SD 大鼠开始服用 ADF 或继续随意饮食。通过连续超声心动图对心脏形态测量和功能进行为期 6 个月的随访。观察期结束时，通过压力-容量环分析（包括联合多巴酚丁胺-容量压力测试）对大鼠进行全面的血流动力学评估，并收获心脏进行组织学评估。为期六个月的 ADF 导致心肌细胞直径减少 9% (p<0.01)，间质性心肌纤维化增加 3 倍。 ADF 中左心室大小未受影响，射血分数未降低。 ADF 中的左心房直径增加了 16%，而多普勒测量的二尖瓣血流中的 E/A 比值降低了。 ADF 中的压力-容量环分析显示舒张期心脏僵硬，组织学分析表明心肌纤维化与对照心脏相比增加了 3 倍。联合多巴酚丁胺和容量负荷显示 ADF 中左心室舒张顺应性显着降低，而收缩泵功能没有增加，表明心脏储备减少。因此，大鼠的慢性 ADF 会导致舒张功能障碍的发生，并导致心脏储备减少。因此，ADF是一种新颖且独特的行为诱发舒张性心力衰竭的实验模型。 ADF 对大鼠的有害作用需要进一步研究 ADF 对人类心血管功能的影响。 另一方面，与 ADF 相反，热量限制 (CR) 在同一实验模型中没有心脏保护作用。然而，与随意喂养的年龄对照动物相比，24 个月大的大鼠一生中保持 30% 热量减少，与年龄相关的心肌肥厚程度较低，收缩功能较高。虽然随意喂养的 24 个月大的大鼠不能通过心率增加来应对多巴酚丁胺攻击，但 24 个月大的 CR 动物表现出年轻动物典型的适当心率反应。此外，与随意喂养的年龄匹配的对照组相比，24个月大的CR大鼠的心肌纤维化和与年龄相关的心肌细胞密度损失较少。此外，与 AL 动物相比，CR 大鼠的主动脉脉搏波速度较低，表明动脉僵硬度较低。然而，CR 并不能阻止与年龄相关的心肌细胞损失。因此，与 ADF 相反，CR 可以促进心脏健康并延缓与年龄相关的心血管结构和功能的变化。 二.抗氧化剂补充剂。活性氧（ROS）在缺血相关的心肌损伤中发挥着重要作用。然而，尝试使用合成抗氧化剂来阻止 ROS 的有害影响却产生了好坏参半或负面的结果，这引发了人们对天然产物中抗氧化剂的兴趣。我们已经证明，与对照饮食 (CD) 相比，在饮食 (BD) 中添加蓝莓可使 ROS 指数 tMPT 增加 24% (p<0.001)。 冠状动脉结扎后 24 小时，BD 大鼠的心肌梗塞 (MI) 比 CD 大鼠减少 24% (p<0.05)。与 CD 大鼠相比，在 BD 风险心肌区域中观察到 TUNEL(+) 心肌细胞显着减少（2% vs 9%），炎症细胞减少 40%（p<0.05）。我们得出的结论是，富含蓝莓的饮食可以保护心肌免受缺血性损伤，并证明有可能减轻心肌梗死后慢性心力衰竭的发展。 为了验证 BD 会减轻慢性心力衰竭 (CHF) 病程的假设，我们在通过永久结扎冠状动脉诱导 MI 两周后向大鼠引入富含蓝莓的饮食。结果是一年死亡率和心脏重塑。冠状动脉结扎两周后，将大鼠分为两组，通过超声心动图测量平均心肌梗死大小相似，然后开始如下12个月的饮食方案：随意饮食常规饮食（对照，CD，n = 27）和添加2%蓝莓补充剂的等热量食物（BD，n = 27）也可随意饮食。将这些饮食组相互比较并与假手术组（SH）进行比较。与 CD 相比，BD 12 个月内的死亡率降低了 22%（p<0.01）。在CHF发生过程中，BD对体重、心率或血压没有影响。双月回波显示，与 CD 相比，BD 的左室室重塑、左室后壁变薄和 MI 扩张显着减弱。事实上，BD 阻止了 MI 的扩张。这些结果代表了第一个实验证据，表明富含蓝莓的饮食对 CHF 病程具有积极影响，因此值得考虑进行临床评估。 临床前动物研究充分记录了白藜芦醇（一种红酒提取物）的多种健康益处。最近报道的白藜芦醇作为 SIRT1 激活剂的特性使其成为治疗慢性心力衰竭 (CHF) 的有吸引力的目标。在本实验中，我们测试了长期饮食中补充白藜芦醇对大鼠心肌梗死后 (MI) CHF 大鼠模型的死亡率和心血管重塑进展的影响。通过结扎雄性 Wistar 大鼠的左冠状动脉降支诱导 MI 两周后，开始富含白藜芦醇（5mg/kg/天）或正常的随意饮食，并持续 10 个月。未经治疗的 MI 大鼠（C，65%）和用白藜芦醇治疗的大鼠（R，61%）的 10 个月死亡率相似。通过连续超声心动图 (Echo) 在 C 中观察到 10 个月内 MI 扩大 77% 也不受白藜芦醇补充剂的影响。在 R 组中，通过连续回波在 C 中观察到的左心室扩张（舒张末压为 86%，收缩末压为 135%）和射血分数下降（63%）随着时间的推移逐渐减弱；然而，组间差异从未达到统计学显着性。每月测量的动脉血压显示，R 相对于 C 的收缩压和脉压有小幅但具有统计显着性的降低。10 个月实验结束时的侵入性血流动力学评估和整个实验期间动物亚组的横断面评估表明，与 MI 相关的心功能显着下降，除了预负荷可招募的中风工作外，大多不受白藜芦醇补充剂的影响（603 比 404）。 C; p<0.05）和动脉-心室耦合（C 中为 1.10.1 vs. 2.70.7；p<0.05），两者均与 Sham 中相似。 与 Sham 相比，C 组脉搏波速度增加了 35%，从治疗 4 个月开始，R 组脉搏波速度正常化（p<0.05）。结果表明，白藜芦醇补充剂对 MI 后 CHF 大鼠模型产生一些有益作用，表明其可作为现有治疗方案的辅助治疗。