Different Therapeutic Approaches forTreatment of Chronic Heart Failure

慢性心力衰竭的不同治疗方法

• 批准号: 7964059
• 负责人: Mark Talan
• 金额: $ 42.02万
• 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/7964059
• 关键词: Adrenergic Antagonists; Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Affect; Agonist; Angiotensin-Converting Enzyme Inhibitors; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apoptosis; Apoptotic; Area; Attenuated; Blood Pressure; Blueberries; Body Weight; Cardiac; Cells; Chronic; Clinical Trials; Combined Modality Therapy; Consensus; Coronary; Coronary artery; Data; Deterioration; Developed Countries; Development; Diet; Dilated Cardiomyopathy; Echocardiography; Elderly; Enalapril; Experimental Models; Fenoterol; Food; Heart Rate; Heart failure; Infarction; Inflammation; Left; Left Ventricular Function; Left Ventricular Remodeling; Ligation; Measures; Metoprolol; Modality; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardium; Performance; Property; Rattus; Receptor Activation; Receptors, Adrenergic, beta-1; Relative (related person); Reporting; Research; Rodent; Role; Severities; Signal Transduction; Testing; Therapeutic; Treatment Protocols; Ventricular; attenuation; beta-2 Adrenergic Receptors; beta-adrenergic receptor; functional decline; functional improvement; improved; mortality; myocardial infarct sizing; novel therapeutic intervention; novel therapeutics; pre-clinical; prevent; programs; research clinical testing; research study; success; translational study

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.

I. 该项目的总体目标是对心肌缺血和随后的慢性心力衰竭 (CHF) 动物模型进行临床前实验，以阐明其发展机制，并评估不同治疗方式限制心肌损伤程度和预防或减轻 CHF 发展的潜力。 Beta-2 肾上腺素受体治疗 CHF​​。 β-肾上腺素能受体 (AR) 亚型信号传导在 CHF 发展中的作用显然很重要。现在人们普遍认为 beta-1 AR 激活与 CHF 的发生有关。最近的数据表明，刺激 beta-1 AR 可以促进细胞凋亡，因此，使用 beta-1 AR 拮抗剂成为心力衰竭的推荐治疗方法。 beta-2 AR 激动剂的可能作用仍存在争议。然而，共识是，与 beta-1 AR 一样，CHF 期间 beta-2 AR 的激活是有害的。最近使用单肌细胞进行的 LCS 研究表明，β2 AR 激动剂非诺特罗具有独特的心脏保护特性，而且实际上具有抗细胞凋亡作用。利用这一发现，我们在冠状动脉结扎后 2 周开始，研究了用 β-2 AR 激动剂非诺特罗和 β1 AR 阻滞剂美普洛尔对大鼠进行长期治疗的效果。我们的结果表明，β-2 AR激动剂和β-1 AR阻滞剂均减少心肌细胞凋亡，但β-2 AR激动剂在减轻左心室重构和功能下降方面优于β-2 AR阻滞剂。此外，β2激动剂治疗阻止了梗塞扩张，导致相对梗塞面积实际减小。这两种疗法影响心脏功能的不同方面：美托洛尔通过增加左心室弹性来改善心脏收缩性能，而非诺特罗通过降低动脉弹性（后负荷）来达到相同的结果。美他洛尔不能改善舒张功能，而非诺特罗则使其正常化。 β1 阻滞剂和 β2 激动剂联合治疗可导致形态和功能改善，与单独使用 β2 激动剂治疗类似。在其他实验中，我们表明，β-1受体阻滞剂、美心洛尔和β-2激动剂非诺特罗的联合治疗在减少心肌细胞凋亡、减弱左心室重构方面明显优于单用β1-受体阻滞剂治疗，并且实际上改善了左心室功能。 在一项为期一年的实验中，我们证明了与单独使用任何单一疗法相比，β-2 激动剂和 β-1 阻滞剂联合疗法具有显着的生存获益。此外，β2激动剂的治疗效果在冠状动脉结扎后仅持续2个月，而联合治疗的效果可持续6个月。 在本研究中，我们比较了 β 1 AR 阻滞剂-β 2 AR 激动剂组合与 β 1 AR 阻滞剂和血管紧张素转换酶抑制剂 (ACEi) 组合（即当前 CHF 的治疗选择）的效果。冠状动脉结扎两周后，大鼠被分成通过超声心动图测量的平均心肌梗塞（MI）大小相似的组，并开始以下12个月的治疗：非诺特罗（250μg/kg/天），一种β2AR激动剂，和美托洛尔（100mg/kg/天），一种β1AR阻滞剂；美他洛尔和依那普利（20 毫克/公斤/天），一种 ACEi；以及所有三种化合物的组合。将这些治疗组与未治疗组（nT）和假手术组进行比较。所有治疗组的 12 个月死亡率均显着降低（β1-β2+ 组为 44%，β1-β2+ACEi 组为 56%，β1-ACEi 组为 59%，nT 组为 81%）。每两个月一次的 Echo 显示所有三个治疗组的左心室 (LV) 室重塑、左心室功能恶化和 MI 扩张均显着减弱，但当治疗包含 β2AR 激动剂时，效果明显更为明显。我们得出的结论是，在治疗CHF时，1AR阻滞剂和2AR激动剂的组合与β1AR阻滞剂和ACEi的组合在死亡率方面等效，而在心脏重塑和MI扩张方面超过后者。因此，这种新的 CHF 治疗方案值得临床试验考虑。 二.我们报道，在大鼠实验中，富含蓝莓的饮食（BD）可减轻梗塞周围区域的坏死性细胞凋亡和炎症，从而减少手术引起的心肌梗塞。由于现在普遍认为导致 CHF 进展的主要因素是心肌中累积的细胞损失，因此我们测试了 BD 会减轻 CHF 病程的假设，包括大鼠心肌梗死诱导后第一年的死亡率和心脏重塑。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，并开始以下 12 个月的饮食方案 - 随意饮食常规饮食（对照，CD，n = 27）和含 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 的 12 个月死亡率降低了 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。这是第一个实验证据表明富含蓝莓的饮食对 CHF 的病程具有积极影响，因此值得考虑进行临床测试。