Myocardial Fibrosis in Hypertensive Adults with and without Chronic Kidney Disease

项目摘要 心肌纤维化在患有慢性肾病（CKD）的个体中非常常见，并且是一种强烈的慢性肾脏疾病。 主要不良心血管（CV）事件和死亡率的独立预测因子。而回归的 心肌纤维化可能会降低随后的CV事件和死亡，与血压无关， 心肌纤维化的因素尚未完全确定。我们的研究团队得出的新数据显示， 由异常血清碳酸氢盐水平引起的心力衰竭风险增加。然而，几个重要的 关于血清碳酸氢盐和不良CV结局之间的因果关系仍存在疑问。 此外，高血压治疗，酸碱平衡，心肌纤维化消退， CV事件的减少尚不清楚。SPRINT研究是有效解决 这些重要的问题。SPRINT是一项随机对照临床试验，旨在确定强化治疗是否 收缩压降低（<120 mmHg）将减少心血管事件， 对照组（<140 mmHg）。拟议的SPRINT-心肌纤维化辅助研究创新性地汇集了 一个理想的资源组合：心肌纤维化的有效心脏生物标志物，最新的 心血管磁共振成像（MRI）技术，一种新的干预措施，和一个大的随机 临床试验它将招募1000名参与者，并通过生物标志物和非造影剂测量心肌纤维化。 基线和18个月随访时的心脏MRI T1标测，以解决以下假设： 假设1：低血清碳酸氢盐水平与评估的心肌纤维化指数高相关 通过循环血清生物标志物和非造影心脏MRI T1标测;假设2：在18个月随访时- 与标准对照组相比， 假设3：18个月随访时心肌纤维化的改善与 CV事件减少。作为一个探索性的目的，我们将测试心肌纤维化是一个假设， 血清碳酸氢盐水平和不良CV结局之间的联系的中介。这将使研究能够 探索潜在的机制，其中密集的收缩压降低，在测试范围内， SPRINT影响心肌纤维化和随后的心血管事件。通过确定 这些更新颖的心脏MRI T1标测和血清生物标志物测量， 此外，它还将为它们在未来试验中的潜在纳入奠定基础。 SPRINT心肌纤维化将测试关键假设，否则将无法解决， 挑战现有的范式，克服先前研究的局限性，提供关键的机制 有助于解释SPRINT结果的信息，并促进我们对心肌纤维化的理解 CKD及其管理。

Project Summary Myocardial fibrosis is very common in individuals with chronic kidney disease (CKD) and is a strong independent predictor of major adverse cardiovascular (CV) events and mortality. While the regression of myocardial fibrosis may reduce subsequent CV events and death independent of blood pressure, the risk factors for myocardial fibrosis are incompletely defined. New data generated by our research team revealed the increased risk of heart failure conferred by abnormal serum bicarbonate levels. However, several essential questions remain regarding the causal relationship between serum bicarbonate and adverse CV outcomes. Also, the critical links between hypertension treatment, acid base balance, myocardial fibrosis regression, and reduction in CV events are not well understood. SPRINT study is a unique opportunity to efficiently address these important questions. SPRINT was a randomized controlled clinical trial to determine whether intensive reduction in systolic blood pressure (<120 mmHg) will reduce cardiovascular events compared to standard control (<140 mmHg). The proposed SPRINT-Myocardial Fibrosis ancillary study innovatively assembles an ideal combination of resources: validated cardiac biomarkers of myocardial fibrosis, the latest cardiovascular magnetic resonance imaging (MRI) techniques, a novel intervention, and a large randomized clinical trial. It will enroll 1000 participants and measure myocardial fibrosis by biomarkers and non-contrast cardiac MRI T1 mapping at baseline and at 18-months follow-up to address the following hypotheses: Hypothesis 1: Low serum bicarbonate level is associated with high indices of myocardial fibrosis as assessed by circulating serum biomarkers and non-contrast cardiac MRI T1 mapping; Hypothesis 2: At 18-months follow- up the intensive blood pressure group will have reduced myocardial fibrosis compared to the standard control group; and Hypothesis 3: The improvements in myocardial fibrosis at 18 months follow-up will be associated with reductions in CV events. As an exploratory aim, we will test the hypothesis that myocardial fibrosis is a mediator in the link between serum bicarbonate levels and adverse CV outcomes. This will enable the study to explore potential mechanisms whereby intensive systolic blood pressure reduction, in the range being tested in SPRINT, influences myocardial fibrosis and subsequent cardiovascular events. By determining the changes of these more novel cardiac MRI T1 mapping and serum biomarkers measurements to the intensive systolic blood pressure reduction, it will also lay the groundwork for their potential inclusion in future trials. SPRINT-Myocardial Fibrosis will test critical hypotheses that would not otherwise be addressable, challenge existing paradigms, overcome limitations of prior studies, provide key mechanistic information to help interpret the SPRINT results, and advance our understanding of myocardial fibrosis in CKD and its management.