Reduced contractile reserve: a therapeutic target in heart failure with normal EF

描述(由申请人提供)：射血分数保留的心力衰竭(HFpEF)是一种由于非特异性症状和临床表现而难以诊断的疾病。这种疾病发生在老年人身上，他们经常有其他疾病和衰老的迹象，这使得心力衰竭的诊断变得更加困难。最近，有人认为HFpEF主要是一种舒张性疾病，实际上是多因素作用的，收缩功能异常和血管僵硬增加在疾病病理中起作用。目前还没有任何治疗方法可以降低这种疾病的高死亡率。然而，很少有研究评估这一人群在生理应激期增加的情况，尽管临床上一贯表现为运动耐量受损，休息时几乎没有症状。这项研究探讨了HFpEF的多因素生理学，详细研究了收缩储备和血管僵硬异常对该疾病的特异性，并探讨了这些异常的可修复性。所使用的技术是非侵入性的，包括心脏功能的超声心动图评估，以及使用眼压计测量动脉硬度。这项研究的第一个目的是通过观察小剂量多巴酚丁胺2-肾上腺素能刺激前后HFpEF与其他临床上有重要区别的组的射血分数的变化，探讨一种潜在的HFpEF诊断试验的特异性。在第二个目标中，该研究将调查钙通道阻滞剂氨氯地平恢复正常心肌收缩反应的能力。在第三个目标中，将探讨动脉僵硬在HFpEF药物反应中的作用。预计通过这项研究获得的对这种多因素疾病复杂生理学的更好理解将导致更合理的大型临床试验的设计，研究有望用于HFpEF的药物，这些药物不仅影响舒张期功能，而且还影响收缩储备和动脉特性。 公共卫生相关性：心力衰竭伴保留射血分数(HFpEF)占美国心力衰竭病例的50%以上，主要影响老年人口。没有任何治疗方法能影响HFpEF的死亡率，一次住院五年的死亡率超过50%。该项目探索HFpEF患者潜在的心血管生理学，目的是确定新的治疗目标，以改进这一毁灭性疾病的治疗。

DESCRIPTION (provided by applicant): Heart failure with preserved ejection fraction (HFpEF) is a difficult disease to diagnose due to nonspecific symptoms and clinical findings. The disease occurs in the elderly, who often have other illnesses and signs of aging that make diagnosis of heart failure more difficult. Recently, it has been suggested that HFpEF, which has primarily been thought to be a diastolic disease, is in fact multifactorial, with elements of abnormal systolic function and increased vascular stiffness playing a role in disease pathology. No treatment has been shown to reduce the high mortality of the disease. However, few studies have evaluated this population of patients during periods of increased physiologic stress, despite the consistent clinical presentation of impaired exercise tolerance with few symptoms at rest. This study explores the multifactorial physiology of HFpEF, with a detailed investigation of the specificity of abnormalities in contractile reserve and vascular stiffness for this disease, and exploration of the modifiability of these abnormalities. The techniques used are non-invasive, involving echoardiographic evaluation of cardiac function, and measurement of arterial stiffness using tonometry. The first aim of the study is to explore the specificity of a potential diagnostic test for HFpEF by investigating the change in ejection fraction before and after 2-adrenergic stimulation with low-dose dobutamine in HFpEF compared to other groups important to distinguish clinically, specifically patients with shortness of breath due to pulmonary disease, and those with hypertension and left ventricular hypertrophy without clinical heart failure. In the second aim, the study will investigate the ability of the calcium channel blocker, amlodipine, to restore normal contractile responses of the myocardium. In the third aim, the role of arterial stiffness in drug responses in HFpEF will be explored. It is anticipated that improved understanding of the complex physiology of this multifactorial disease gained through this study will lead to more rational design of large clinical trials studying promising agents for HFpEF that impact not only diastolic function, but contractile reserve and arterial properties as well. PUBLIC HEALTH RELEVANCE: Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of heart failure cases in the United States, affecting a primarily elderly population. No treatment has been shown to affect mortality in HFpEF, which is more than 50% at five years a hospitalization. This project explores the underlying cardiovascular physiology of patients with HFpEF with the goal of identifying new therapeutic targets that would allow improved treatment of this devastating disease.