Aldosterone, nitric oxide, myocardial fibrosis, and capillary loss in ESRD

ESRD 中的醛固酮、一氧化氮、心肌纤维化和毛细血管损失

• 批准号: 9333355
• 负责人: Finnian R McCausland
• 金额: $ 48.3万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-22 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333355
• 关键词: Accounting; Address; Aldosterone; Aldosterone Antagonists; Architecture; Arginine; Arrhythmia; Atherosclerosis; Biological Availability; Biology; Blood capillaries; Blood flow; Cardiac; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cessation of life; Chronic; Clinical; Clinical Data; Conduct Clinical Trials; Coronary; Data; Dialysis procedure; Disease; Doppler Echocardiography; Double-Blind Method; Dropout; Echocardiography; End stage renal failure; Event; Expenditure; Failure; Fibrosis; Frequencies; Functional disorder; General Population; Healthcare; Heart; Heart Diseases; Homeostasis; Human; Image; Incidence; Individual; Israel; Kidney Failure; Left Ventricular Hypertrophy; Malignant - descriptor; Measures; Medical center; Medicare; Microvascular Dysfunction; Mineralocorticoid Receptor; Myocardial; Myocardial Infarction; Myocardial perfusion; Nature; Nitric Oxide; Outcome; Oxygen; Pathway interactions; Patients; Pharmaceutical Preparations; Placebo Control; Placebos; Play; Population; Positron-Emission Tomography; Randomized; Renal function; Research; Rest; Risk Factors; Role; Scanning; Spironolactone; Stress; Sudden Death; Testing; Tissues; United States; Ventricular Function; angiogenesis; capillary; cardiovascular risk factor; coronary fibrosis; design; heart function; high risk; high risk population; improved; improved outcome; indexing; insight; mortality; novel; novel marker; novel therapeutics; perfusion imaging; preclinical study; prospective; public health relevance; targeted treatment

DESCRIPTION (provided by applicant): More than 500,000 people in United States have end stage renal disease (ESRD), and these individuals suffer from an extremely high incidence of cardiovascular (CV) death. Treatments that are effective in reducing CV mortality in the general population have been less successful in dialysis-dependent ESRD, and new therapies are sorely needed. Traditional CV risk factors are less important in the setting of advanced kidney failure, and the disappointing results with standard therapies appear to be attributable to important differences in the mechanisms underlying CV disease in individuals with ESRD. Sudden death accounts for the vast majority of CV deaths in individuals with ESRD, with a 5-folder higher frequency than atherosclerotic death or myocardial infarction which more commonly account for CV mortality in other settings. These considerations suggest that targeting ESRD-specific mechanisms for sudden CV death rather than mechanisms underlying atherosclerosis and myocardial infarction may be a particularly potent way to improve outcomes in ESRD. However, there are currently no well-established targets or therapies for this purpose. A wealth of data including studies by the applicants demonstrate that myocardial fibrosis and microvascular dropout are dramatically increased in the hearts of individuals with ESRD, and that non-invasive measures of myocardial fibrosis and microvascular disease are highly predictive of CV death, suggesting that fibrosis and microvascular disease are important determinants of sudden CV death. Additional studies show that abnormalities in the bioavailability of nitric oxide and aldosterone are critical and synergistic contributors to the progression of myocardial fibrosis and microvascular disease and that administration of spironolactone or L-arginine improve NO bioavailability, inhibit the effects of aldosterone, and are safe in ESRD. We therefore hypothesize that administration of L-arginine or the aldosterone antagonist spironolactone to patients with dialysis-dependent ESRD will inhibit myocardial fibrosis and microvascular dropout. We will test our 2 specific aims using a 9-month, randomized, placebo- controlled, 2x2 factorial clinical trial conducted at Partners Health Care and Beth Israel Deaconess Medical Center: Aim 1) To test the hypothesis that blockade of aldosterone using spironolactone improves myocardial fibrosis and microvascular supply in individuals with ESRD as measured using tissue Doppler Echocardiography (TDI) and myocardial perfusion imaging (PET) scans, respectively; Aim 2) To test the hypothesis that L-arginine, an agent which improves NO bioavailability, improves myocardial fibrosis and microvascular supply as measured by TDI and PET.

描述（由申请人提供）：美国有超过 500,000 人患有终末期肾病 (ESRD)，这些人的心血管 (CV) 死亡发生率极高。有效降低普通人群心血管死亡率的治疗方法在治疗依赖透析的终末期肾病 (ESRD) 方面效果较差，因此迫切需要新的治疗方法。传统的心血管危险因素在晚期肾衰竭的情况下不太重要，标准疗法令人失望的结果似乎可归因于终末期肾病患者的心血管疾病机制的重要差异。猝死占 ESRD 患者心血管死亡的绝大多数，其发生率比动脉粥样硬化死亡或心肌梗塞高 5 倍，后者在其他情况下更常见。这些考虑表明，针对心血管猝死的 ESRD 特异性机制，而不是动脉粥样硬化和心肌梗死的潜在机制，可能是改善 ESRD 结局的特别有效的方法。然而，目前尚无用于此目的的明确靶标或疗法。包括申请人的研究在内的大量数据表明，ESRD患者心脏中的心肌纤维化和微血管脱落显着增加，并且心肌纤维化和微血管疾病的非侵入性测量高度预测心血管死亡，这表明纤维化和微血管疾病是心血管猝死的重要决定因素。其他研究表明，一氧化氮和醛固酮的生物利用度异常是心肌纤维化和微血管疾病进展的关键和协同因素，螺内酯或 L-精氨酸的给药可提高一氧化氮的生物利用度，抑制醛固酮的作用，并且在 ESRD 中是安全的。因此，我们假设对依赖透析的 ESRD 患者给予 L-精氨酸或醛固酮拮抗剂螺内酯将抑制心肌纤维化和微血管脱落。我们将使用在 Partners Health Care 和 Beth Israel Deaconess 医疗中心进行的一项为期 9 个月、随机、安慰剂对照、2x2 析因临床试验来测试我们的 2 个具体目标： 目标 1) 测试以下假设：使用螺内酯阻断醛固酮可改善 ESRD 患者的心肌纤维化和微血管供应（使用组织多普勒超声心动图 (TDI) 测量）和 分别进行心肌灌注成像（PET）扫描；目标 2) 检验 L-精氨酸（一种提高 NO 生物利用度的药物）可改善心肌纤维化和微血管供应（通过 TDI 和 PET 测量）的假设。

项目成果

Predialysis serum phosphate and intradialytic hypotension.

透析前血清磷酸盐和透析中低血压。

• DOI: 10.1111/hdi.12971
• 发表时间: 2022
• 期刊: Hemodialysis international. International Symposium on Home Hemodialysis
• 作者: Ravi,KatherineScovner;Reeves,PatrickB;Correa,Simon;Neves,JoãoSérgio;Waikar,SushrutS;Mothi,SurajS;McCausland,FinnianR
• 通讯作者: McCausland,FinnianR

Effects of Spironolactone on Arrhythmias in Hemodialysis Patients: Secondary Results of the SPin-D Randomized Controlled Trial.

• DOI: 10.34067/kid.0000000000000067
• 发表时间: 2023-04-01
• 期刊: Kidney360
• 作者: Mc Causland FR;Hsu JY;Himmelfarb J;Ikizler TA;Raj DS;Mehrotra R;Waikar SS;Kimmel PL;Kliger AS;Dember LM;Charytan DM;Hemodialysis Novel Therapeutics Consortium
• 通讯作者: Hemodialysis Novel Therapeutics Consortium

Risk of Intradialytic Hypotension by Day of the Week in Maintenance Hemodialysis.

维持性血液透析中每周各天的透析中低血压风险。

• DOI: 10.1097/mat.0000000000001576
• 发表时间: 2022-06-01
• 期刊: ASAIO JOURNAL
• 影响因子: 4.2
• 作者: Correa, Simon;Guerra-Torres, Xavier E.;Ravi, Katherine Scovner;Mothi, Suraj S.;Waikar, Sushrut S.;Mc Causland, Finnian R.
• 通讯作者: Mc Causland, Finnian R.

Angiotensin-neprilysin inhibition and renal outcomes across the spectrum of ejection fraction in heart failure.

• DOI: 10.1002/ejhf.2421
• 发表时间: 2022-09
• 期刊: EUROPEAN JOURNAL OF HEART FAILURE
• 影响因子: 18.2
• 作者: Mc Causland, Finnian R.;Lefkowitz, Martin P.;Claggett, Brian;Packer, Milton;Senni, Michele;Gori, Mauro;Jhund, Pardeep S.;McGrath, Martina M.;Rouleau, Jean L.;Shi, Victor;Swedberg, Karl;Vaduganathan, Muthiah;Zannad, Faiez;Pfeffer, Marc A.;Zile, Michael;McMurray, John J., V;Solomon, Scott D.
• 通讯作者: Solomon, Scott D.

How is the heart best protected in chronic dialysis patients?: Between Scylla and Charybdis: what is the appropriate role for percutaneous coronary revascularization and coronary artery bypass grafting in patients on dialysis?

如何最好地保护慢性透析患者的心脏？：Scylla 和 Charybdis 之间：经皮冠状动脉血运重建和冠状动脉旁路移植术在透析患者中​​的适当作用是什么？

• DOI: 10.1111/sdi.12181
• 发表时间: 2014
• 期刊: Seminars in dialysis
• 影响因子: 1.6
• 作者: Charytan,DavidM