Allopurinol Improves Diastolic Function in African Americans with Resistant Hypertension

心力衰竭（HF）是VA内发病率、死亡率和医疗保健费用不断上升的主要原因。的 不成比例增加的HF类型是射血分数保留的HF（HFpEF），通常 由高血压和左心室（LV）压力超负荷引起。估计有10%到20%的高血压患者 患有顽固性高血压（RHTN）的患者，定义为具有控制或不控制的血压， 使用≥ 3种药物，包括利尿剂。我们先前报道了显著的左心室肥大， RHTN患者舒张功能障碍伴收缩功能正常。美国黑人成年人高血压 美国是世界上患病率最高的国家之一，与LV结构的不良变化有关 和功能高血压是>50%的成年黑人HF患者的潜在因素，是最大的风险 8黑人成年人的HF发病率增加了50%，这在很大程度上是由于 高血压的患病率和严重程度更高，与之相比， 与白人虽然黑人成人的HF死亡率最高，但他们的代表性始终不足 在临床试验阶段黑人成年人中更大的HF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。黑人的HF负担更大 成年人呼吁进一步的工作，以发现有效的预防和治疗策略， 人口该项目的长期目标是制定一项有效的战略，以改善非洲人的健康， 美国退伍军人HFpEF我们最近报道了血浆黄嘌呤氧化酶（XO）活性增加 和线粒体DNA损伤相关分子产物（DAMPs）水平在黑人成人RHTN，相比， 患有RHTN的白色成人。这支持了普遍的共识，即氧化应激在黑人成年人中更高。 XO氧化次黄嘌呤和黄嘌呤，产生过氧化氢和超氧化物副产物。这些 产物损伤线粒体，导致生物能功能障碍和氧化剂的进一步放大 mtDNA DAMP的产生和生产。mtDNA DAMPs是先天免疫的有效激活剂， 通过几种途径，包括TLR（toll样受体）的激活，促进促增殖反应， 炎症细胞因子释放。我们显示舒张压（r=0.876，p<0.001），左室舒张末期 质量指数（r=0.503，p=0.012），短轴缩短率（r=-0.546，p=0.006），管壁厚度（r=0.428，p=0.001）， 室壁中径与室壁厚度比值（r=0.354，p=0.008）和舒张早期充盈率（r=-0.422，p=0.04 与黑人RHTN患者六个月时的XO活性相关，但与白色RHTN患者六个月时的XO活性无关。鉴于更高级别的 XO活性和线粒体DAMPs，我们假设抑制XO可以改善左室舒张功能， 在患有RHTN的黑人非裔美国人中发挥作用。我们将在以下目标中讨论这一假设。 目标1。LV舒张功能受损是HFpEF症状的主要原因。因此，我们将测试 假设别嘌呤醇改善左室舒张功能使用CMR在我们的实验室以前进行。目的 2.左心室舒张功能受损与运动能力和生活质量下降有关。所以我们会 在6分钟步行试验中检验别嘌呤醇治疗将改善运动能力和质量的假设。 使用堪萨斯城心力衰竭问卷。

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.