Allopurinol Improves Diastolic Function in African Americans with Resistant Hypertension

心力衰竭(HF)是退伍军人管理局内发病率、死亡率和医疗费用不断上升的主要原因。这个 不成比例增加的心衰类型是射血分数保留的心衰(HFpEF)，通常 由高血压和左心室(LV)压力超负荷引起。据估计，10%至20%的高血压患者 患者患有顽固性高血压(RHTN)，定义为血压受控或血压失控 包括利尿剂的≥3药物的使用。我们先前报告了显著的左心室肥厚和 RHTN患者中收缩功能正常的舒张期功能障碍。年黑人成年人中的高血压 美国是世界上患病率最高的国家之一，这与左心室结构的不利变化有关 和功能。高血压是50%患有心力衰竭的黑人成年人的潜在因素，也是最大的风险因素 8黑人成年人的心力衰竭发病率增加了50%，这在很大程度上是由于 与黑人成年人相比，黑人成年人高血压的患病率和严重性更高，心力衰竭的发生时间更早8年 和白人在一起。尽管黑人成人的心力衰竭死亡率最高，但他们的比例一直偏低。 在临床试验中。黑人成年人中更大的心力衰竭负担需要进一步的工作来发现有效的 针对这一高危人群的预防和治疗策略。黑人中更大的高频负担 成人呼吁进一步的工作，以发现有效的预防和治疗策略，以应对这种高风险 人口。该项目的长期目标是制定一项有效的战略来改善非洲人的健康 使用HFpEF的美国退伍军人。我们最近报道了血浆黄嘌呤氧化酶(XO)活性升高 与患有RHTN的黑人成年人相比，他们的线粒体DNA损伤相关分子产物(DAMP)水平 患有RHTN的白人成年人。这支持了普遍的共识，即黑人成年人的氧化应激更高。 XO氧化次黄嘌呤和黄嘌呤，生成过氧化氢和超氧化物作为副产品。这些 产品破坏线粒体，导致生物能量功能障碍和氧化剂的进一步放大 线粒体DNA抑制物的产生和产生。线粒体DNA抑制剂是天然免疫的有效激活剂。 反应通过几个途径，包括激活TLR(Toll样受体)，促进前- 炎性细胞因子释放。我们已经显示了舒张压(r=0.876，p&lt；.001)，LV舒张末 质量指数(r=0.503，p=0.012)、缩短率(r=-0.546，p=0.006)、壁厚(r=0.428，p=0.001)、 中壁半径与壁厚比(r=0.354，p=0.008)和舒张期早期充盈率(r=-0.422，p=0.04)。 与6个月时黑人患者的XO活动有关，但与白人RHTN患者无关。鉴于更高级别的 XO活性和线粒体DNA抑制黑人，我们假设抑制XO可以改善左室舒张功能 在患有RHTN的非裔美国黑人中发挥作用。我们将在以下目标中解决这一假设。 目的1.左室舒张功能受损是高血压性充血性心力衰竭症状的主要原因。因此，我们将测试 假设别嘌醇能改善左室舒张功能，就像我们实验室以前所做的那样。目标 2.左室舒张功能受损与运动能力和生活质量下降有关。因此，我们将 在六分钟步行测试和质量测试中验证别嘌醇疗法将提高运动能力的假设 使用堪萨斯城心力衰竭问卷对生活进行评估。

Heart failure (HF) is a leading cause of morbidity, mortality and escalating health care costs within the VA. The type of HF that is increasing disproportionately is HF with a preserved ejection fraction (HFpEF), commonly caused by hypertension and left ventricular (LV) pressure overload. An estimated 10% to 20% of hypertensive patients have resistant hypertension (RHTN), defined as having controlled or uncontrolled blood pressure with the use of ≥ 3 medications that includes a diuretic. We previously reported significant LV hypertrophy and diastolic dysfunction with normal systolic function in persons with RHTN. Hypertension among Black adults in the US has one of the highest prevalence rates in the world and is related to adverse changes in LV structure and function. Hypertension is an underlying factor in >50% of Black adults with HF and is the strongest risk factor for HF in that population.8 Black adults have a 50% increased incidence of HF, due in large part to the greater prevalence and severity of hypertension, and HF occurs 8 years earlier in Black adults as compared with Whites. Although Black adults have the highest death rate for HF, they are consistently underrepresented in clinical trials. The greater HF burden among Black adults calls for further work to discover effective preventive and therapeutic strategies for this higher-risk population. The greater HF burden among Black adults calls for further work to discover effective preventive and therapeutic strategies for this higher-risk population. The long-term goal of this project is to develop an effective strategy to improve the health of African American Veterans with HFpEF. We have recently reported increased plasma xanthine oxidase (XO) activity and mtDNA damage associated molecular products (DAMPs) levels in Black adults with RHTN, compared with White adults with RHTN. This supports the general consensus that oxidative stress is higher in black adults. XO oxidizes hypoxanthine and xanthine to generate hydrogen peroxide and superoxide as a byproduct. These products damage mitochondria leading to bioenergetic dysfunction and further amplification of oxidant generation and production of mtDNA DAMPs. mtDNA DAMPs are potent activators of the innate immune response through several pathways including activation of TLR (toll-like receptor) with promotion of pro- inflammatory cytokine release. We have shown diastolic blood pressure (r=0.876, p<.001), LV end-diastolic mass index (r=0.503, p=0.012), fractional shortening (r=-0.546, p=0.006), wall thickness (r=0.428, p=0.001), mid-wall radius to wall thickness ratio (r=0.354, p=0.008), and early diastolic filling rate (r=-0.422, p=0.04) were related to XO activity at six months among the Blacks but not White RHTN patients. Given the higher level of XO activity and mtDNA DAMPs in blacks, we hypothesize that inhibition of XO improves LV diastolic function in Black African Americans with RHTN. We will address this hypothesis in the following Aims. Aim 1. Impaired LV diastolic function is a major cause of symptoms in HFpEF. Therefore, we will test the hypothesis that allopurinol improves LV diastolic function using CMR as previously performed in our lab. Aim 2. Impaired LV diastolic function is linked to decreased exercise capacity and quality of life. Therefore, we will test the hypothesis that Allopurinol therapy will improve exercise capacity in a six-minute walk test and quality of life using the Kansas City Heart Failure Questionnaire.