University of Navarra, CIMA, Program of Cardiovascular Diseases, IdiSNA, Navarra Institute for Health Research, Pamplona, Spain, CIBERCV, Carlos III Institute of Health, Madrid, Spain.
Institute for Internal Medicine and Cardiology, Charité Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany.
Eur J Heart Fail. 2018 Sep;20(9):1290-1299. doi: 10.1002/ejhf.1194. Epub 2018 Apr 30.
Myocardial fibrosis is characterized by excessive cross-linking and deposition of collagen type I and is involved in left ventricular stiffening and left ventricular diastolic dysfunction (LVDD). We investigated whether the effect of spironolactone on LVDD in patients with heart failure with preserved ejection fraction (HFpEF) depends on its effects on collagen cross-linking and/or deposition.
We investigated 381 HFpEF patients from the multicentre, randomized, placebo-controlled Aldo-DHF trial with measures of the E:e' ratio. The ratio of serum carboxy-terminal telopeptide of collagen type I to serum matrix metalloproteinase-1 (CITP:MMP-1, an inverse index of myocardial collagen cross-linking) and serum carboxy-terminal propeptide of procollagen type I (PICP, a direct index of myocardial collagen deposition) were determined at baseline and after 1-year treatment with spironolactone 25 mg once daily or placebo. Patients were classified by CITP:MMP-1 and PICP tertiles at baseline. While CITP:MMP-1 tertiles at baseline interacted (P < 0.05) with spironolactone effect on E:e', PICP tertiles did not. In fact, while spironolactone treatment did not modify E:e' in patients with lower CITP:MMP-1 levels, this ratio was significantly reduced in the remaining spironolactone-treated patients. In addition, PICP was unchanged in patients with lower CITP:MMP-1 levels but was reduced in the remaining spironolactone-treated patients.
A biochemical phenotype of high collagen cross-linking identifies HFpEF patients resistant to the beneficial effects of spironolactone on LVDD. It is suggested that excessive collagen cross-linking, which stabilizes collagen type I fibres, diminishes the ability of spironolactone to reduce collagen deposition in these patients.
心肌纤维化的特征是 I 型胶原的过度交联和沉积，涉及左心室僵硬和左心室舒张功能障碍（LVDD）。我们研究了螺内酯对射血分数保留的心力衰竭（HFpEF）患者 LVDD 的影响是否取决于其对胶原交联和/或沉积的影响。
我们研究了来自多中心、随机、安慰剂对照的 Aldo-DHF 试验的 381 名 HFpEF 患者，测量了 E:e' 比值。在基线和螺内酯 25mg 每日一次或安慰剂治疗 1 年后，测定血清 I 型胶原羧基末端肽与血清基质金属蛋白酶-1（CITP：MMP-1，心肌胶原交联的逆指数）和血清 I 型前胶原羧基末端前肽（PICP，心肌胶原沉积的直接指数）的比值。根据基线时 CITP：MMP-1 和 PICP 的三分位数对患者进行分类。虽然基线时 CITP：MMP-1 的三分位数与螺内酯的作用相互作用（P<0.05），但 PICP 的三分位数没有。事实上，虽然螺内酯治疗并没有改变低 CITP：MMP-1 水平患者的 E:e'，但在其余接受螺内酯治疗的患者中，这一比值显著降低。此外，低 CITP：MMP-1 水平患者的 PICP 不变，但在其余接受螺内酯治疗的患者中则降低。
高胶原交联的生化表型可识别对螺内酯改善 LVDD 作用有抵抗的 HFpEF 患者。这表明，过度的胶原交联稳定 I 型胶原纤维，降低了螺内酯减少这些患者胶原沉积的能力。
