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.

用保留的射血分数（HFPEF）的心力衰竭是一个越来越普遍的问题，尤其是如此 在老化的退伍军人人口中。它占心力衰竭患者的一半以上。那里 在理解心脏患者的机制和治疗方面取得了很大进步 减少射血分数时的失败，了解机制或 HFPEF的处理。从临床的角度来看，合并症（例如肥胖症）的流行率 这些患者的糖尿病，COPD和高血压导致HFPEF为炎症假说 也与冠状动脉微血管功能障碍有关。然而，炎症的因果重要性 HFPEF表型发育中冠状动脉流量调节受损尚不清楚。进步 在理解HFPEF的机制中，由于缺乏合适的疾病模型而受到限制。 目前，唯一可用的模型涉及不受控制的慢性高血压，严重的左心室 肥大（LVH）。尽管这些信息使我们对高血压心脏病和舒张期的理解 在过去50年中，功能障碍可能与大多数HFPEF患者无直接相关。第一的， 大多数HFPEF患者患有控制或仅轻度收缩压高血压，而LVH通常不存在。 第二，与HFPEF患者相反，高血压心脏病发展为收缩功能障碍 （HFREF）。这是许多HFPEF患者典型的左心室依从性降低的发展 在没有持续高血压的情况下发展仍然是一个谜。上一次完成的工作 资金期导致了HFPEF心脏表型的大型动物模型的发展 由重复的简短LV压力超负荷产生。这模拟了不稳定的收缩期高血压 HFPEF特别普遍的全身性伪影衰老降低的患者。 最初，短暂的压力超负荷的特征是伸展引起的“惊人”，局灶性心肌细胞凋亡 在没有心肌缺血的情况下，发生的肌钙蛋白I释放。在2周内，LV减少 合规性，心肌丧失和心肌细胞细胞肥大发展，间质显着增加 纤维化。与大多数HFPEF患者一样，这伴随着同心内向LV重塑 静止时没有严重的左心室肥大或不受控制的高血压。中心假设 该提议是拉伸引起的肌细胞损伤与重复不稳定的收缩压和 预紧升高导致慢性肌钙蛋白I释放和开始的心肌炎症反应 通过促炎巨噬细胞。这导致肌细胞丧失和间质纤维化的发展。 可以通过减弱纤维化和巨噬细胞反应的干预措施来预防这种进展 慢性心肌损伤。我们将使用猪HFPEF模型翻译三个有希望的抗纤维化 在心脏纤维化的啮齿动物模型中，机械研究支持但未翻译的干预措施 到大型疾病模型。 AIM 1将检验HFPEF发展的假设 可以通过限制重复后促炎性巨噬细胞的募集来预防表型 压力超负荷引起的肌细胞损伤，胶束上装有CCR2抑制剂。 AIM 2将测试 假设N-乙酰基 - 甲状腺甲基 - 丙烯酸 - 丙烯酸酯（AC-SDKP）是一种纤维化的肽抑制剂，可以逆转 通过减弱巨噬细胞来建立的间质纤维化并改善左心室依从性 对心肌损伤的反应。 AIM 3将检验以下假设，即冠状动脉圈衍生的细胞可以 通过逆转纤维化来促进巨噬细胞极化为修复表型并提高LV的依从性 还促进心肌细胞增殖。我们的长期目标是改善内心的退伍军人的照顾 通过更好地理解导致HFPEF的机制并确定新颖的机制来失败 可以预防或逆转间质纤维化以提高LV依从性的目标治疗方法。