Preventing and Reversing Interstitial Fibrosis in HFpEF

预防和逆转 HFpEF 的间质纤维化

• 批准号: 10015539
• 负责人: John M Canty
• 金额: --
• 依托单位: VA WESTERN NEW YORK HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10015539
• 关键词: Address; Aging; Allogenic; Animal Disease Models; Animal Model; Apoptosis; Attenuated; Cardiac; Cardiovascular Diseases; Caring; Cause of Death; Cell Therapy; Cells; Cessation of life; Chronic; Chronic Obstructive Airway Disease; Clinical; Congestive Heart Failure; Coronary; Development; Devices; Diabetes Mellitus; Diuretics; EFRAC; Family suidae; Fibrosis; Functional disorder; Funding; Heart failure; Hospitalization; Human; Hypertension; Hypertrophy; Impairment; Incidence; Inflammation; Inflammatory; Inflammatory Response; Injury; Intervention; Left; Left Ventricular Hypertrophy; Left Ventricular Remodeling; Left ventricular structure; Micelles; Microvascular Dysfunction; Modeling; Muscle Cells; Myocardial; Myocardial Ischemia; Obesity; Patients; Peptides; Pharmaceutical Preparations; Phenotype; Population; Pre-Clinical Model; Prevalence; Proline; Regulation; Research; Rest; Risk Factors; Rodent Model; Stretching; Symptoms; Testing; Translating; Troponin I; Vent; Ventricular; Veterans; Work; comorbidity; coronary fibrosis; disability; hypertensive heart disease; improved; inhibitor/antagonist; interstitial; macrophage; novel; preservation; pressure; prevent; recruit; response; systolic hypertension

Heart failure with a preserved ejection fraction (HFpEF) is an increasingly prevalent problem and particularly so amongst an aging Veterans population. It accounts for over half of all patients with heart failure. While there have been considerable advances in understanding the mechanisms and treatment of patients with heart failure when ejection fraction is reduced, there have been few advances in understanding the mechanisms or treatment of HFpEF. From a clinical standpoint, the prevalence of comorbid conditions such as obesity, diabetes, COPD and hypertension in these patients has led to the inflammatory hypothesis where HFpEF is also associated with coronary microvascular dysfunction. Nevertheless, the causal importance of inflammation and impaired coronary flow regulation in the development of the HFpEF phenotype remain unclear. Advances in understanding mechanisms of HFpEF have been limited by the lack of suitable animal models of disease. At present, the only available models involve uncontrolled chronic hypertension with severe left ventricular hypertrophy (LVH). While these have informed our understanding of hypertensive heart disease and diastolic dysfunction over the last 50 years, they may not be directly relevant to the majority of HFpEF patients. First, most patients with HFpEF have controlled or only mild systolic hypertension and LVH is frequently absent. Second, in contrast to patients with HFpEF, hypertensive heart disease progresses to systolic dysfunction (HFrEF). Thus, how the development of reduced left ventricular compliance typical of many HFpEF patients develops in the absence of sustained hypertension remains an enigma. Completed work during the previous funding period has resulted in the development of a large animal model of the HFpEF cardiac phenotype produced by repetitive brief LV pressure overload. This simulates the labile systolic hypertension typical of patients with reduced systemic arterial compliance accompanying aging where HFpEF is particularly prevalent. Initially, brief pressure overload is characterized by stretch-induced “stunning” with focal myocyte apoptosis and troponin I release occurring in the absence of myocardial ischemia. Within 2-weeks, reduced LV compliance, myocyte loss and myocyte cellular hypertrophy develop with a prominent increase in interstitial fibrosis. This is accompanied by concentric inward LV remodeling yet, like most patients with HFpEF, the absence of severe left ventricular hypertrophy or uncontrolled hypertension at rest. The central hypothesis of this proposal is that stretch-induced myocyte injury associated with repetitive labile systolic hypertension and preload elevation leads to chronic troponin I release and a myocardial inflammatory response that is initiated by proinflammatory macrophages. This leads to myocyte loss and to the development of interstitial fibrosis. This progression can be prevented by interventions that attenuate fibrosis and the macrophage response to chronic myocyte injury. We will use the swine HFpEF model to translate three promising antifibrotic interventions that are supported by mechanistic studies in rodent models of cardiac fibrosis but not translated to a large animal model of disease. Aim 1 will test the hypothesis that the development of the HFpEF phenotype can be prevented by limiting the recruitment of proinflammatory macrophages following repetitive pressure overload-induced myocyte injury with micelles loaded with a CCR2 inhibitor. Aim 2 will test the hypothesis that N-Acetyl-Seryl-Aspartyl-Proline (Ac-SDKP), a peptide inhibitor of fibrosis, can reverse established interstitial fibrosis and improve left ventricular compliance by attenuating the macrophage response to myocyte injury. Aim 3 will test the hypothesis that intracoronary cardiosphere derived cells can promote macrophage polarization to a reparative phenotype and improve LV compliance by reversing fibrosis as well promoting myocyte proliferation. Our long-term objective is to improve the care of Veterans with heart failure by developing a better understanding of the mechanisms leading to HFpEF and identifying novel targeted treatments that can prevent or reverse interstitial fibrosis to increase LV compliance.

射血分数保留的心力衰竭（HFpEF）是一个日益普遍的问题，尤其如此 在老龄化退伍军人中，它占所有心力​​衰竭患者的一半以上。 在理解心脏病患者的机制和治疗方面取得了相当大的进展 当射血分数降低时出现故障，在理解其机制或 从临床角度来看，肥胖等合并症的患病率 这些患者的糖尿病、慢性阻塞性肺病和高血压导致了炎症假说，其中 HFpEF 是 然而，炎症的因果重要性也与冠状动脉微血管功能障碍有关。 HFpEF 表型发展中冠状动脉血流调节受损的进展仍不清楚。 由于缺乏合适的疾病动物模型，对 HFpEF 机制的理解受到限制。 目前，唯一可用的模型涉及未控制的慢性高血压伴严重左心室 这些都让我们了解了高血压性心脏病和舒张期高血压。 过去 50 年的功能障碍，它们可能与大多数 HFpEF 患者没有直接关系。 大多数 HFpEF 患者的收缩期高血压得到控制或仅有轻度收缩期高血压，并且经常不存在 LVH。 其次，与 HFpEF 患者相比，高血压心脏病会进展为收缩功能障碍 (HFrEF) 因此，许多 HFpEF 患者典型的左心室顺应性降低是如何发生的。 在没有持续高血压的情况下发展仍然是一个谜。 资助期间开发了 HFpEF 心脏表型的大型动物模型 由反复短暂的左心室压力超负荷产生，这模拟了典型的不稳定收缩期高血压。 伴随衰老而全身动脉顺应性降低的患者，其中 HFpEF 尤其普遍。 最初，短暂的压力超负荷的特点是拉伸引起的“震慑”和局灶性心肌细胞凋亡 在没有心肌缺血的情况下，肌钙蛋白 I 的释放在 2 周内降低了 LV。 顺应性、肌细胞丢失和肌细胞肥大随着间质的显着增加而发展 与大多数 HFpEF 患者一样，这伴随着向心向内的左室重构。 休息时没有严重的左心室肥厚或不受控制的高血压。 该建议认为，拉伸引起的肌细胞损伤与反复不稳定的收缩期高血压和 前负荷升高导致慢性肌钙蛋白 I 释放并引发心肌炎症反应 这会导致肌细胞丢失并导致间质纤维化。 这种进展可以通过减弱纤维化和巨噬细胞对纤维化反应的干预措施来预防。 我们将使用猪 HFpEF 模型来转化三种有前景的抗纤维化药物。 心脏纤维化啮齿动物模型的机制研究支持但尚未转化的干预措施 目标 1 将检验 HFpEF 发展的假设。 可以通过限制重复性刺激后促炎巨噬细胞的募集来预防表型 目标 2 将测试负载 CCR2 抑制剂的胶束引起的压力过载引起的心肌细胞损伤。 假设 N-乙酰-丝氨酰-天冬氨酰-脯氨酸 (Ac-SDKP) 是一种纤维化肽抑制剂，可以逆转 通过减弱巨噬细胞建立间质纤维化并改善左心室顺应性 目标 3 将检验冠状动脉内心肌细胞可以对心肌细胞损伤做出反应的假设。 促进巨噬细胞极化至修复表型，并通过逆转纤维化提高左室顺应性 我们的长期目标是改善退伍军人的心脏护理。 通过更好地理解导致 HFpEF 的机制并识别新的失败 可以预防或逆转间质纤维化以增加左心室顺应性的靶向治疗。