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VA内发病率，死亡率和医疗保健费用升级的主要原因。 HF的类型不成比例地增加了HF，hF具有保留的射血分数（HFPEF），通常是HF 由高血压和左心室（LV）压力超负荷引起。估计高血压的10％至20％ 患者患有耐药性高血压（RHTN），定义为具有控制或不受控制的血压 使用包括利尿剂的≥3种药物。我们以前报道了明显的LV肥大和 RHTN患者的舒张功能障碍具有正常收缩功能。黑人成年人的高血压 美国是世界上最高的患病率之一，与LV结构的不利变化有关 和功能。高血压是> 50％的黑人黑人成年人的潜在因素，是强烈的风险 该人群中HF的因素。8黑人成年人的HF事件增加了50％，这在很大程度上是由于 比较黑人成年人，高血压的患病率和严重程度更高，HF发生在8年前 尽管黑人成年人的死亡率最高，但他们的代表性不足 在临床试验中。黑人成年人的HF燃烧更大，要求进一步工作以发现有效 对于这种高危人群的预防和治疗策略。黑色之间的HF燃烧更大 成年人呼吁进一步工作，以发现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策略来改善非洲的健康 与HFPEF的美国退伍军人。我们最近报道了血浆黄嘌呤氧化物（XO）活性增加 与RHTN的黑人成年人相比 白人成年人患有RHTN。这支持了一般共识，即黑人成年人的氧化应激更高。 XO氧化物低黄嘌呤和黄嘌呤可产生过氧化氢和超氧化物作为副产品。这些 产品损害线粒体导致生物能功能障碍并进一步扩增氧化剂 mtDNA潮湿的产生和生产。 mtDNA潮湿是先天免疫的潜在激活剂 通过多种途径的反应，包括激活TLR（Toll-like受体），并促进促进 炎症细胞因子释放。我们已经显示出舒张压（r = 0.876，p <.001），LV末期舒张 质量指数（r = 0.503，p = 0.012），分数缩短（r ​​= -0.546，p = 0.006），壁厚（r = 0.428，p = 0.001）， 中壁半径与壁厚度比（r = 0.354，p = 0.008）和早期舒张期填充率（r = -0.422，p = 0.04） 与黑人六个月但白色RHTN患者的XO活性有关。考虑到更高的水平 XO活性和黑色的mtDNA潮湿，我们假设抑制XO可改善LV舒张期 与RHTN的黑人非洲裔美国人的功能。我们将在以下目的中解决这一假设。 AIM1。LV舒张功能受损是HFPEF症状的主要原因。因此，我们将测试 假设别嘌呤醇使用CMR改善LV舒张功能，如先前在我们的实验室中所做的。目的 2。左室舒张功能受损与改善运动能力和生活质量有关。因此，我们会的 测试假说，即在六分钟的步行测试和质量中，别嘌呤醇疗法将提高运动能力 使用堪萨斯城心力衰竭问卷的生活。