Myocardial and Vascular Stiffness in Diabetics with Heart Failure and a Norman EF

描述(由申请人提供)： 大卫·阿吉拉尔博士是一位坚定致力于临床研究事业的非侵入性心脏病专家。他在哈佛医学院布里格姆妇女医院完成了内科住院医师和心脏病学研究，目前是贝勒医学院(BCM)的医学助理教授。这项指导职业发展奖(K01)将通过几种机制发展阿吉拉尔博士的职业生涯，包括每周一次的指导会议、临床科学家培训计划以及德克萨斯大学公共卫生学院和BCM的教学课程。作为该奖项的一部分，阿吉拉尔博士将阐述患有心力衰竭(HF)且射血分数(EF)正常的糖尿病患者的主动脉和左心室(LV)舒张期僵硬的重要性，并将测试使用胰高血糖素样肽-1(GLP-1)受体激活剂(Exenatide)的治疗策略对主动脉和LV舒张期僵硬度的影响。糖尿病常见于EF正常的心衰患者，并与发病率和死亡率增加有关。糖尿病患者产生这些不良结局的机制尚不清楚，是改善预后的障碍。我们假设，在心衰且EF正常的患者中，糖尿病患者的LV舒张期硬度将比非糖尿病患者更大，并且这种增加的LV舒张期硬度将与主动脉硬度的增加相关。我们还假设，这种增加的LV舒张期硬度将与增加心肌胶原蛋白积聚的血清生物标志物相关。晚期糖基化终末产物(AGEs)在这一过程中的重要性将通过检验这一假设来检验，即主动脉僵硬和左室舒张僵硬的增加与血清AGEs水平的增加直接相关。最后，我们假设，在EF正常的心衰患者中，使用埃塞那肽治疗12周的2型糖尿病将与改善主动脉和左室舒张僵硬以及改善异常心肌胶原沉积的血清生物标志物有关。鉴于糖尿病患病率的增加，以及糖尿病和EF正常的心衰所造成的疾病负担，这项工作具有重大的公共卫生意义。阿吉拉尔博士将研究导致心衰和EF正常的糖尿病患者不良结果的机制，并将测试一种针对糖尿病的治疗策略，希望改善这一高风险组患者的结果。

DESCRIPTION (provided by applicant): Dr. David Aguilar is a non-invasive cardiologist strongly committed to a career in clinical research. He completed his internal medicine residency and cardiology fellowship at the Brigham and Women's Hospital, Harvard Medical School and is currently an Assistant Professor of Medicine at Baylor College of Medicine (BCM). This Mentored Career Development Award (K01) will develop Dr. Aguilar's career through several mechanisms, including weekly mentoring meetings, the Clinical Scientist Training Program, and didactic coursework at the University of Texas School of Public Health and BCM. As part of the award, Dr. Aguilar will address the importance of aortic and left ventricular (LV) diastolic stiffness in diabetic patients with heart failure (HF) and normal ejection fraction (EF) and will test the effects of a treatment strategy with a glucagon-like peptide-1 (GLP-1) receptor activator (exenatide) on aortic and LV diastolic stiffness. Diabetes is commonly seen in patients with HF and normal EF and is associated with increased morbidity and mortality. The mechanisms contributing to these adverse outcomes in diabetic patients are poorly understood and represent a barrier to improving outcomes. We hypothesize that, in patients with HF and normal EF, LV diastolic stiffness will be greater in diabetic patients than in non-diabetic patients and that this increased LV diastolic stiffness will correlate with increased aortic stiffness. We also hypothesize that this increased LV diastolic stiffness will correlate with serum biomarkers of increased myocardial collagen accumulation. The importance of advanced glycation end products (AGEs) in this process will be examined by also testing the hypothesis that increased aortic stiffness and LV diastolic stiffness are directly correlated with increased serum levels of AGEs. Finally, we hypothesize that treatment of type 2 diabetes with exenatide for 12 weeks in individuals with HF and normal EF will be associated with improvement in aortic and LV diastolic stiffness and in serum biomarkers of abnormal myocardial collagen accumulation. Given the increasing prevalence of diabetes and the burden of disease attributed to both diabetes and HF with normal EF, this work has significant public health implications. Dr. Aguilar will study mechanisms contributing to the adverse outcomes in diabetic individuals with HF and normal EF and will test a diabetes-specific treatment strategy in hopes of improving outcomes in this high-risk group of patients.