Preventing and Reversing Interstitial Fibrosis in HFpEF

预防和逆转 HFpEF 的间质纤维化

• 批准号: 10232045
• 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/10232045
• 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; 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; military veteran; 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.

心力衰竭伴保留射血分数(HFpEF)是一个日益普遍的问题，尤其是 在日益老龄化的退伍军人中。它占所有心力衰竭患者的一半以上。在那里的时候 在了解心脏疾病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，在理解机制或 HFpEF的治疗。从临床的角度来看，肥胖等共病的流行， 这些患者中的糖尿病、COPD和高血压导致了炎症假说，即HFpEF 也与冠状动脉微血管功能障碍有关。尽管如此，炎症的因果重要性 而在HFpEF表型的发展过程中冠状动脉血流调节受损仍不清楚。预付款 由于缺乏合适的疾病动物模型，对HFpEF机制的了解一直受到限制。 目前，唯一可用的模型包括无控制的慢性高血压伴严重的左心室。 肥厚(LVH)。虽然这些都让我们了解了高血压心脏病和舒张压 在过去的50年里，它们可能与大多数HFpEF患者没有直接关系。第一, 大多数HFpEF患者已控制或仅有轻微的收缩压升高，且常无左室肥厚。 第二，与HFpEF患者不同，高血压心脏病进展为收缩功能障碍 (HFrEF)。因此，许多HFpEF患者的典型左心室顺应性降低是如何发生的 在没有持续性高血压的情况下发展仍然是一个谜。在前一年内完成的工作 资助期导致了HFpEF心脏表型的大型动物模型的发展 产生重复短暂的低压压力过载。这模拟了典型的不稳定性收缩期高血压 伴随年龄增长的全身动脉顺应性降低的患者，其中HFpEF特别普遍。 最初，短暂的压力超负荷的特征是牵张引起的“顿抑”，伴有局部的心肌细胞凋亡。 而肌钙蛋白I的释放发生在没有心肌缺血的情况下。在2周内，LV减少 顺应性、心肌细胞丢失和心肌细胞肥大发生，间质显著增加 纤维化症。这伴随着向心性向内左室重构，但像大多数HFpEF患者一样， 静息状态下无严重左室肥厚或高血压失控。的中心假说 这一建议是牵张诱导的心肌细胞损伤与反复不稳定的收缩期高血压和 预负荷升高导致慢性肌钙蛋白I释放和引发的心肌炎性反应 通过促炎症的巨噬细胞。这会导致心肌细胞丢失和间质纤维化的发展。 这种进展可以通过减轻纤维化和巨噬细胞反应的干预措施来预防 慢性心肌细胞损伤。我们将使用猪HFpEF模型将三种有希望的抗纤维化药物 有机制研究支持但未翻译的心肌纤维化啮齿动物模型的干预措施 一种疾病的大型动物模型。目标1将检验以下假设：HFpEF的发展 表型可以通过限制重复后促炎症巨噬细胞的募集来预防 压力超负荷致心肌细胞损伤与胶束负载CCR2抑制剂。目标2将测试 假设N-乙酰-丝氨酰-天冬氨酸(Ac-SDKP)是一种纤维化多肽抑制剂，可以逆转 通过抑制巨噬细胞建立间质纤维化并改善左心室顺应性 对心肌细胞损伤的反应。目标3将验证冠状动脉内心肌球源性细胞可以 通过逆转纤维化促进巨噬细胞极化向修复性表型转变并改善左心室顺应性 以及促进心肌细胞的增殖。我们的长期目标是用心改善对退伍军人的照顾 通过更好地理解导致HFpEF的机制并确定新的 可以预防或逆转间质纤维化的靶向治疗，以增加LV依从性。