Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France.
Department of Cardiology, Tokyo Medical University Hospital, Tokyo, Japan.
Eur J Heart Fail. 2024 May;26(5):1231-1241. doi: 10.1002/ejhf.3202. Epub 2024 Mar 25.
High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables.
In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population-based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase-2 (MMP-2), insulin-like growth factor binding protein-2 (IGFBP-2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP-2 and NT-proBNP, regardless of baseline LAVi (p > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C-terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (p > 0.10).
In individuals without heart failure, LAVi was associated with MMP-2, IGFBP-2 and NT-proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size.
左心室充盈压升高会增加左心房容积并导致心肌纤维化，而螺内酯可能会降低这种情况的发生。我们研究了与左心房容积指数（LAVi）相关的临床和蛋白质组学特征，以及 LAVi 是否会影响螺内酯对生物标志物表达和临床变量的反应。
在心力衰竭高危人群的 HOMAGE 试验中，我们将参与者随机分为螺内酯组或对照组，分析了基线时、第 1 个月和第 9 个月有 LAVi 数据和 276 项蛋白质组学测量数据（Olink）的 421 名参与者（平均年龄 73±6 岁；女性占 26%；LAVi 为 32±9ml/m²）。我们还在一个基于人群的队列（STANISLAS）中评估了与无症状个体的 LAVi 相关的循环蛋白（n=1640；平均年龄 49±14 岁；女性占 51%；LAVi 为 23±7ml/m²）。在这两项研究中，更大的 LAVi 与更大的左心室质量和容积显著相关。在 HOMAGE 研究中，经过调整和多重检验校正后，更大的 LAVi 与更高浓度的基质金属蛋白酶-2（MMP-2）、胰岛素样生长因子结合蛋白-2（IGFBP-2）和 N 末端 pro-B 型利钠肽（NT-proBNP）相关（错误发现率[FDR] <0.05）。这些关联在 STANISLAS 中得到了外部验证（所有 FDR<0.05）。在这些生物标志物中，螺内酯降低了 MMP-2 和 NT-proBNP 的浓度，与基线 LAVi 无关（p>0.10）。螺内酯还显著降低了 LAVi，改善了左心室射血分数，降低了 E/e'、血压和血清原胶原 I C 端前肽（PICP）浓度，这是一种胶原蛋白合成标志物，与基线 LAVi 无关（p>0.10）。
在没有心力衰竭的个体中，LAVi 与 MMP-2、IGFBP-2 和 NT-proBNP 相关。螺内酯降低了这些生物标志物的浓度以及 LAVi 和 PICP，而与左心房大小无关。
