Allopurinol Improves Diastolic Function in African Americans with Resistant Hypertension

别嘌呤醇可改善患有难治性高血压的非裔美国人的舒张功能

• 批准号: 10701217
• 负责人: Louis J. Dell'Italia
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701217
• 关键词: Adult; African American; African American population; Allopurinol; Bioenergetics; Black Populations; Black race; Blood Pressure; Calcium; Cardiac; Cardiac Myocytes; Cities; Clinical Trials; Consensus; Death Rate; Diastolic blood pressure; Diuretics; EFRAC; Functional disorder; Generations; Goals; Grant; Health; Health Care Costs; Heart failure; High Prevalence; Hydrogen Peroxide; Hypertension; Hypoxanthines; Impairment; Incidence; Inflammatory; Innate Immune Response; Kansas; Left; Left Ventricular Dysfunction; Left Ventricular Function; Left Ventricular Hypertrophy; Left Ventricular Mass; Left Ventricular Remodeling; Left ventricular structure; Link; Magnetic Resonance; Measures; Mitochondria; Mitochondrial DNA; Molecular; Morbidity - disease rate; Myofibrils; Oxidants; Oxidative Stress; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Physiologic intraventricular pressure; Plasma; Population; Prevalence; Preventive; Production; Quality of life; Questionnaires; Radial; Reporting; Resistant Hypertension; Risk Factors; Severities; Shortening Fraction; Spironolactone; Superoxides; Symptoms; Testing; Therapeutic; Thick; Toll-like receptors; Ventricular; Veterans; Walking; Work; Xanthine Oxidase; Xanthines; cardiac magnetic resonance imaging; cytokine; depressive symptoms; exercise capacity; high risk population; hypertensive; improved; indexing; mortality; preservation

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.

心力衰竭 (HF) 是退伍军人管理局发病率、死亡率和医疗费用不断上升的主要原因。这 不成比例增加的 HF 类型是射血分数保留 (HFpEF) 的 HF，通常 由高血压和左心室（LV）压力超负荷引起。估计有 10% 至 20% 患有高血压 患者患有难治性高血压（RHTN），定义为血压受控或不受控制 使用 ≥ 3 种药物，其中包括利尿剂。我们之前报道过明显的左室肥厚 RHTN 患者的舒张功能障碍和收缩功能正常。黑人成人高血压 美国是世界上患病率最高的国家之一，这与左室结构的不利变化有关 和功能。高血压是超过 50% 的黑人成人心力衰竭的潜在因素，也是最大的风险 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 与相比，黑人成年人的高血压患病率和严重程度更高，心力衰竭发生时间早 8 年 与白人。尽管黑人成年人的心力衰竭死亡率最高，但他们的代表性始终不足 在临床试验中。黑人成年人的心力衰竭负担更大，需要进一步努力寻找有效的方法 针对这一高危人群的预防和治疗策略。黑人的高频负担更大 成年人呼吁进一步努力寻找针对这种高风险的有效预防和治疗策略 人口。该项目的长期目标是制定有效的战略来改善非洲人的健康 患有 HFpEF 的美国退伍军人。我们最近报告血浆黄嘌呤氧化酶 (XO) 活性增加 与 RHTN 黑人成年人相比，mtDNA 损伤相关分子产物 (DAMP) 水平 患有 RHTN 的白人成年人。这支持了黑人成年人氧化应激更高的普遍共识。 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物。这些 产品会损害线粒体，导致生物能功能障碍并进一步放大氧化剂 mtDNA DAMP 的生成和生产。 mtDNA DAMP 是先天免疫的有效激活剂 通过多种途径进行反应，包括激活 TLR（Toll 样受体）并促进 pro- 炎症细胞因子释放。我们显示了舒张压 (r=0.876, p<.001)、左心室舒张末期 质量指数（r=0.503，p=0.012），缩短分数（r=-0.546，p=0.006），壁厚（r=0.428，p=0.001）， 中壁半径与壁厚之比（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 活动相关，但与白人 RHTN 患者无关。鉴于较高水平 黑人中的 XO 活性和 mtDNA DAMP，我们假设抑制 XO 可以改善 LV 舒张压 RHTN 在非裔美国人中发挥作用。我们将在以下目标中解决这一假设。 目标 1. 左心室舒张功能受损是 HFpEF 症状的主要原因。因此，我们将测试 假设别嘌呤醇使用我们实验室之前进行的 CMR 改善左室舒张功能。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。因此，我们将 检验别嘌呤醇疗法将提高六分钟步行测试中的运动能力和质量的假设 使用堪萨斯城心力衰竭问卷来了解生活。