Pathophysiology of Heart Failure with a Normal Ejection Fraction in the Elderly

描述（由申请人提供）：心力衰竭经常发生在射血分数正常（HFNEF）的患者中，受影响的受试者主要是老年人和伴有几种合并症的女性。尽管这些患者存在多种潜在的临床病理和共病条件，但通常采用一个共同的病理生理学解释来解释其临床症状，同心性肥大导致腔室尺寸小，舒张容量降低（在特定充盈压力下体积减小）。在这些患者中，高静息左心室充盈压是维持正常心输出量所必需的。我们的初步数据显示，尽管HFNEF通常被认为是单一血流动力学机制的结果，但亚群存在明显不同的潜在病理生理。具体来说，我们记录了HFNEF的一个重要亚组心室容量增加和血浆容量扩大，与容量过载状态一致。在射血分数正常的情况下，随着舒张末期血容量的增加，中风量必须增加，表明高输出状态。高输出状态涉及外周（即心外）机制，包括贫血等。贫血可能是老年HFNEF患者运动不耐受、心室重构异常以及整体健康状况和生活质量受损的一个重要的、可改变的因素。我们的试点数据表明，老年HFNEF住院患者的贫血患病率很高（bbb50 %），其中大多数（76%）通过血容量分析有真正的贫血，这与青光膜滤过率有关，表明红细胞生成素产生不足可能是其贫血的机制。此外，我们的研究表明，与没有贫血的老年HFNEF患者相比，贫血的HFNEF患者的生活质量更差，症状更严重，血流动力学和心血管结构改变也更严重。最后，初步数据表明，给贫血的HFNEF受试者服用促红细胞生成素可以改善亚极限和最大极限运动能力。我们的长期目标是阐明HFNEF综合征的病理生理机制并开发有效的治疗方法，因此我们建议评估HFNEF治疗老年贫血的影响。本研究的具体目的是提供一个全面的、基于机制的评估，以纠正老年受试者的HFNEF对心室结构和功能、功能能力和整体健康状况的影响。我们建议对120名老年HFNEF患者进行一项随机、前瞻性、双结合研究，以验证皮下促红细胞生成素与显著的反向心室重构、运动能力增加和健康状况改善相关的假设。主要测量将包括6分钟步行，最大耗氧量和通过过期气体分析的通气无氧阈值；血容量分析，标准化问卷测量肾功能和健康状况，三维超声心动图测量左室容积、质量和功能。本研究将探讨贫血在老年HFNEF患者病理生理中的作用，并确定针对贫血是否能影响心室重构和功能、运动能力和健康状况。贫血是导致HFNEF患者容量超负荷状态的众多心脏外因素之一。

DESCRIPTION (provided by applicant): Heart failure frequently occurs in patients with a normal ejection fraction (HFNEF) and affected subjects are predominately elderly, women with several co-morbid conditions. Despite the diversity of underlying clinical pathologies and co-morbid conditions present in these patients, a common pathophysiologic explanation is generally applied to explain their clinical symptoms, concentric hypertrophy leading to a small chamber size with decreased diastolic capacitance (decreased volume at a specific filling pressure). In such patients, the high resting left ventricular filling pressure is required for such hearts to maintain normal cardiac output. Our preliminary data revealed that although HFNEF is commonly thought of as being the result of a single hemodynamic mechanism, subgroups exist with distinctly different underlying pathophysiologies. Specifically, we documented that a significant subgroup with HFNEF have increases in ventricular volumes and expanded plasma volumes, consistent with a volume overload state. In the setting of a normal ejection fraction with end diastolic volume increased, stroke volume must increase, indicating a high output state. High output states involve peripheral (i.e.extra-cardiac) mechanisms, including anemia among others. Anemia may be an important, modifiable contributor to exercise intolerance in elderly HFNEF patients, abnormal ventricular remodeling and impaired overall health status and quality of life. Our pilot data suggests that the prevalence of anemia is high (> 50%) in elderly patients hospitalized with HFNEF, most of these subjects (76%) have a true anemia by blood volume analysis, which is associated with the glornerular filtration rate, suggesting that inadequate production of erythropoeitin may be a mechanism for their anemia. We have additionally, shown that anemic HFNEF subjects have poorer quality of life, more severe symptoms along with hemodynamic and structural cardiovascular changes compared with elderly subjects with HFNEF without anemia. Finally, preliminary data suggests that erythropoeitin adminstration to anemic HFNEF subjects results in improvements in submaximal and maximal exercise capacity. Concordant with our long-term goal to elucidate the pathophysiologic mechanisms that underlie the the syndrome of HFNEF and to develop effective therapies, we propose to evaluate the impact of treating anemia in elderly subjects with HFNEF. The specific aims of the current study are to provide a comprehensive and mechanistically based assessment of how correcting anemia in elderly subjects with HFNEF can impact on ventriuclar structure and funciton, functional capacity and overall health status. We propose to perform a randomized, prospective, double bind study in 120 elderly subjects with HFNEF to test the hypothesis that the administration of subcutaneous erythropoietin will be associated with significant reverse ventricular remodeling, increased exercise capacity and improved health status. Principle measurements will include six minute walk, maximal oxygen consumption and ventilatory anaerobic threshold by expired gas analysis; blood volume analysis, mesaures of renal function, health status by standardized questionnaires, and LV volumes, mass and function by three dimensional echocardiography. This study will examine the role of anemia in the pathophysiology of elderly patients with HFNEF and determine whether targeting anemia, one of many extra-cardiac factors that could contribute to the volume overload state that is characteristic of HFNEF, can ventricular remodeling and function, exercise capacity and health status. .