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女性，患有多种共病。尽管这些患者存在基础临床病理和共病状况的多样性，但通常采用常见的病理生理学解释来解释其临床症状，即向心性肥大导致小腔尺寸和舒张期电容降低（特定充盈压下的容量降低）。在这样的患者中，高静息左心室充盈压是这样的心脏维持正常心输出量所必需的。我们的初步数据显示，虽然HFNEF通常被认为是一个单一的血流动力学机制的结果，亚组存在明显不同的基础病理生理学。具体而言，我们记录了HFNEF的显著亚组具有心室容积和扩张血浆容积的增加，与容量超负荷状态一致。在舒张末期容积增加的正常射血分数的设置中，每搏输出量必须增加，指示高输出量状态。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、心室重构异常和整体健康状况和生活质量受损的重要、可改变的因素。我们的初步数据表明，在HFNEF住院的老年患者中，贫血的患病率很高（> 50%），这些受试者中的大多数（76%）通过血容量分析具有真正的贫血，这与肾小球滤过率相关，这表明红细胞生成素的产生不足可能是其贫血的机制。此外，我们还发现，与无贫血的HFNEF老年受试者相比，贫血HFNEF受试者的生活质量较差，症状沿着加重，并伴有血流动力学和心血管结构的改变。最后，初步数据表明，对贫血HFNEF受试者施用促红细胞生成素导致次最大和最大运动能力的改善。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，我们建议评估治疗HFNEF老年受试者贫血的影响。本研究的具体目的是提供一个全面的和机制为基础的评估，如何纠正HFNEF老年受试者的贫血可以影响心室结构和功能，功能能力和整体健康状况。我们建议在120例HFNEF老年受试者中进行一项随机、前瞻性、双重结合研究，以检验皮下注射促红细胞生成素与显著逆转心室重构、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、最大耗氧量和通过呼气分析确定的无氧阈值;血容量分析、肾功能测量、通过标准化问卷确定的健康状况以及通过三维超声心动图确定的LV体积、质量和功能。本研究将检查贫血在HFNEF老年患者的病理生理学中的作用，并确定是否靶向贫血（可能导致HFNEF特征性容量超负荷状态的许多心外因素之一）可以影响心室重塑和功能、运动能力和健康状况。.

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. .