PREDICTION OF OUTCOMES IN HEART FAILURE WITH PRESERVED EJECTION FRACTION (HFPEF): A NEW PLASMA BIOMARKER

摘要 心力衰竭伴保留射血分数(HFpEF)影响着美国约290万患者 各州。HFpEF既是一种致命性疾病，也是一种致命疾病。它住院后的五年死亡率为60%-65%， 这比大多数癌症都要糟糕。不幸的是，医生不能直接解决极高的 发病率和死亡率，因为目前还没有提高存活率的治疗方法。还有一位亲戚 缺乏关于生物标志物在本病预后或治疗中的作用的数据，尤其是在比较中 心力衰竭，射血分数降低。此外，HFpEF患者经常合并几种疾病。 条件，如肥胖和肾功能障碍，可以影响标准的心力衰竭生物标记物，如 利钠肽及其解释。 来自我们小组的最新流行病学数据显示，一种新的生物标志物，特定脂类在 血浆神经酰胺24：0/神经酰胺16：0(C24：0/C16：0)预测心力衰竭事件和全因死亡 在两个以社区为基础的队列中的5000名受试者：Framingham后代队列和健康研究 在波美拉尼亚，即使考虑了标准的心血管危险因素。此外，血浆C24：0/C16：0 改变了预测全因死亡率的c统计量。这一新的生物标记物是否也可以预测所有原因 已知的HFpEF患者的死亡率和其他次要事件尚不清楚。特定的基因 参与这一新的生物标志物的表达和调控也是未知的。这项研究将解决这些问题 差距。我们已获得BioLINCC存储库的批准，可以使用已有的数据以及血浆和基因 样本来自TOPCAT临床试验，该试验在HFpEF患者中进行，目的如下。 我们将利用一种独特的、经过充分验证的液体色谱-串联质谱仪(LC/MS-MS)脂组 化验，这是由我们研究所开发的。此外，我们还将纳入新的统计基因组 实现以下目标的方法： 1.评价血浆C24：0/C16：0神经酰胺比值在预测脑出血继发危险中的作用。 TOPCAT试验中已知HFpEF的患者。全因死亡率将成为主要终点。一个 心血管死亡、心力衰竭住院、心脏骤停流产和心肌梗塞的联合终点 脑梗塞将被评估为次要终点，所有出现的单个组件 次要结果也将被评估。 2.研究HFpEF患者血浆C24：0/C16：0比值和死亡风险的遗传因素 并使用TOPCAT的数据和遗传样本来确定这一比率的潜在因果影响， 以及包括孟德尔随机化在内的新的统计基因组方法。

ABSTRACT Heart failure with preserved ejection fraction (HFpEF) affects approximately 2.9 million patients in the United States. HFpEF is both a morbid and mortal disease. It has a 60-65% five-year mortality rate after hospitalization, which is worse than most cancers. Unfortunately, physicians cannot directly address the extremely high rates of morbidity and mortality, as currently there are no treatments that improve survival. There is a also a relative paucity of data on the utility of biomarkers in prognosis or treatment of this disease, especially in comparison with heart failure with reduced ejection fraction. Moreover, patients with HFpEF often have several co-morbid conditions, such as obesity, and renal dysfunction, which can affect standard heart failure biomarkers such as natriuretic peptides and their interpretation. Recent epidemiologic data from our group showed that a new biomarker, the ratio of specific lipids in the plasma, i.e., ceramide 24:0/ceramide 16:0 (C24:0/C16:0) predicted incident heart failure and all-cause mortality in >5,000 subjects in two community-based cohorts: the Framingham Offspring cohort and the Study for Health in Pomerania even after accounting for standard cardiovascular risk factors. Moreover, the plasma C24:0/C16:0 altered the c-statistic for prediction of all-cause mortality. Whether this novel biomarker also predicts all-cause mortality and other secondary events in patients with known HFpEF is, as yet, unknown. The specific genes involved in the expression and regulation of this new biomarker is also not known. This study will address these gaps. We have approval from the BioLINCC repository to use already available data and plasma and genetic samples from the TOPCAT clinical trial, which was performed in patients with HFpEF for the Aims listed below. We will utilize a unique, well-validated liquid chromatography-tandem mass spectrometry (LC/MS-MS) lipidomic assay, which was developed at our institution. In addition, we will incorporate novel statistical genomic methodology to achieve the following Aims: 1. To assess the utility of the plasma C24:0/C16:0 ceramide ratio for secondary risk prediction in patients with known HFpEF from the TOPCAT trial. All-cause mortality will be the primary endpoint. A combined endpoint of cardiovascular death, heart failure hospitalizations, aborted cardiac arrest, and myocardial infarction will be evaluated as a secondary endpoint and all occurrences of the individual components of the secondary outcome will also be evaluated. 2. To characterize the genetic contributions to the plasma C24:0/C16:0 ratio and risk of death in HFpEF and to determine the potential causal impact of this ratio using data and genetic samples from TOPCAT, as well as novel statistical genomic methods including Mendelian Randomization.