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.

射血分数保留性心力衰竭（HFpEF）是一个日益普遍的问题， 在一个老龄化的退伍军人群体中。它占所有心力衰竭患者的一半以上。虽然 在了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，在理解机制或 HFpEF的治疗从临床的角度来看，肥胖等共病的患病率， 这些患者的糖尿病、COPD和高血压导致了炎症假说， 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 以及HFpEF表型发展中冠状动脉血流调节受损仍不清楚。进展 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不受控制的慢性高血压伴严重左心室肥厚， 肥厚（LVH）。虽然这些已经告知了我们对高血压性心脏病和舒张期心脏病的理解， 尽管在过去50年中，HFpEF的功能障碍发生率很高，但它们可能与大多数HFpEF患者没有直接相关性。第一、 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，且常无LVH。 其次，与HFpEF患者相反，高血压心脏病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的发展如何导致 在没有持续高血压的情况下发展仍然是一个谜。前一个月完成的工作 资助期导致了HFpEF心脏表型的大型动物模型的开发 由反复短暂的左心室压力超负荷引起。这模拟了典型的不稳定收缩期高血压， 伴随HFpEF特别普遍的衰老的全身动脉顺应性降低的患者。 最初，短暂的压力超负荷的特点是牵张诱导的“顿抑”，伴有局部心肌细胞凋亡 和肌钙蛋白I的释放发生在没有心肌缺血的情况下。2周内，LV降低 顺应性、肌细胞损失和肌细胞肥大的发展伴随着间质性的显著增加。 纤维化与大多数HFpEF患者一样， 静息时无严重左心室肥大或不受控制的高血压。的中心假设 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有关， 前负荷升高导致慢性肌钙蛋白I释放和心肌炎症反应， 通过促炎巨噬细胞。这导致肌细胞损失和间质纤维化的发展。 这种进展可以通过减弱纤维化和巨噬细胞对纤维化的反应的干预来预防。 慢性肌细胞损伤我们将使用猪HFpEF模型来翻译三种有前途的抗纤维化药物， 在啮齿动物心脏纤维化模型中进行的机制研究支持干预措施，但未转化为 一个大型动物疾病模型。目的1将检验HFpEF的发展 表型可以通过限制促炎性巨噬细胞的募集来预防， 压力超负荷诱导的心肌细胞损伤与胶束负载CCR 2抑制剂。目标2将测试 纤维化肽抑制剂N-乙酰-丝氨酰-天冬氨酰-脯氨酸（Ac-SDKP）可逆转 建立间质纤维化，并通过减少巨噬细胞来改善左心室顺应性 对肌细胞损伤的反应。目的3将检验冠状动脉内心脏球衍生细胞可以 促进巨噬细胞极化为修复表型，并通过逆转纤维化改善LV顺应性 以及促进肌细胞增殖。我们的长期目标是用心改善退伍军人的护理 通过更好地理解导致HFpEF的机制和识别新的 靶向治疗可以预防或逆转间质性纤维化，以增加LV顺应性。