Vanderbilt Translational and Clinical Research Center, Cardiology Division Vanderbilt University Medical Center Nashville TN.
Population Sciences Branch, Division of Intramural Research National Heart, Lung, and Blood Institute, National Institutes of Health Bethesda MD.
J Am Heart Assoc. 2023 Nov 7;12(21):e029980. doi: 10.1161/JAHA.122.029980. Epub 2023 Oct 27.
While exercise impairments are central to symptoms and diagnosis of heart failure with preserved ejection fraction (HFpEF), prior studies of HFpEF biomarkers have mostly focused on resting phenotypes. We combined precise exercise phenotypes with cardiovascular proteomics to identify protein signatures of HFpEF exercise responses and new potential therapeutic targets.
We analyzed 277 proteins (Olink) in 151 individuals (N=103 HFpEF, 48 controls; 62±11 years; 56% women) with cardiopulmonary exercise testing with invasive monitoring. Using ridge regression adjusted for age/sex, we defined proteomic signatures of 5 physiological variables involved in HFpEF: peak oxygen uptake, peak cardiac output, pulmonary capillary wedge pressure/cardiac output slope, peak pulmonary vascular resistance, and peak peripheral O extraction. Multiprotein signatures of each of the exercise phenotypes captured a significant proportion of variance in respective exercise phenotypes. Interrogating the importance (ridge coefficient magnitude) of specific proteins in each signature highlighted proteins with putative links to HFpEF pathophysiology (eg, inflammatory, profibrotic proteins), and novel proteins linked to distinct physiologies (eg, proteins involved in multiorgan [kidney, liver, muscle, adipose] health) were implicated in impaired O extraction. In a separate sample (N=522, 261 HF events), proteomic signatures of peak oxygen uptake and pulmonary capillary wedge pressure/cardiac output slope were associated with incident HFpEF (odds ratios, 0.67 [95% CI, 0.50-0.90] and 1.43 [95% CI, 1.11-1.85], respectively) with adjustment for clinical factors and B-type natriuretic peptides.
The cardiovascular proteome is associated with precision exercise phenotypes in HFpEF, suggesting novel mechanistic targets and potential methods for risk stratification to prevent HFpEF early in its pathogenesis.
虽然运动障碍是射血分数保留型心力衰竭（HFpEF）的症状和诊断的核心，但之前对 HFpEF 生物标志物的研究主要集中在静息表型上。我们将精确的运动表型与心血管蛋白质组学相结合，以确定 HFpEF 运动反应的蛋白质特征和新的潜在治疗靶点。
我们分析了 151 名个体（N=103 例 HFpEF，48 例对照；62±11 岁；56%为女性）在心肺运动试验中使用 Olink 分析了 277 种蛋白。使用调整了年龄/性别因素的脊回归，我们确定了与 HFpEF 相关的 5 个生理变量的蛋白质特征：峰值摄氧量、峰值心输出量、肺毛细血管楔压/心输出量斜率、峰值肺血管阻力和峰值外周 O 提取。每个运动表型的多蛋白特征捕获了各自运动表型的显著比例的变化。在每个特征中，研究特定蛋白质的重要性（脊系数大小）突出了与 HFpEF 病理生理学（如炎症、纤维化蛋白）有潜在联系的蛋白质，以及与不同生理学相关的新蛋白质（如涉及多器官[肾脏、肝脏、肌肉、脂肪]健康的蛋白质）与 O 提取受损有关。在另一个样本（N=522，261 例 HF 事件）中，峰值摄氧量和肺毛细血管楔压/心输出量斜率的蛋白质特征与 HFpEF 的发生相关（比值比，0.67 [95%置信区间，0.50-0.90]和 1.43 [95%置信区间，1.11-1.85]），调整了临床因素和 B 型利钠肽。
心血管蛋白质组与 HFpEF 的精确运动表型相关，提示了新的机制靶点和潜在的风险分层方法，以在 HFpEF 发病早期预防 HFpEF。
