Huerta Ana, López Begoña, Ravassa Susana, San José Gorka, Querejeta Ramón, Beloqui Óscar, Zubillaga Elena, Rábago Gregorio, Brugnolaro Cristina, Díez Javier, González Arantxa
aDepartment of Internal Medicine, University of Navarra Clinic bProgram of Cardiovascular Diseases, Center for Applied Medical Research, University of Navarra cIdiSNA, Navarra Institute for Health Research, Pamplona dDivision of Cardiology, Donostia University Hospital, University of the Basque Country, San Sebastián eDivision of Internal Medicine, Donostia University Hospital, University of the Basque Country, San Sebastián fDepartment of Cardiology and Cardiac Surgery, University of Navarra Clinic, Pamplona, Spain *Javier Díez and Arantxa González contributed equally to the study.
J Hypertens. 2016 Jan;34(1):130-8. doi: 10.1097/HJH.0000000000000757.
Cystatin C has been shown to be associated with heart failure with preserved ejection fraction (HFPEF). In addition, myocardial fibrosis has been involved in diastolic dysfunction in HFPEF. Therefore, we hypothesized that increased cystatin C levels may be associated with altered collagen metabolism, contributing to diastolic dysfunction in patients with HFPEF.
One hundred and forty-one elderly hypertensive patients with HFPEF were included. Cardiac morphology and function was assessed by echocardiography. Circulating levels of cystatin C, biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I) and degradation [matrix metalloproteinase-1 (MMP-1) and its inhibitor TIMP-1] and osteopontin were analyzed by ELISA. Twenty elderly sex-matched patients with no identifiable cardiac disease were used as controls. In-vitro studies were performed in human cardiac fibroblasts.
Compared with controls, cystatin C was increased (P < 0.001) in patients with HFPEF, even in those with a normal estimated glomerular filtration rate (eGFR; P < 0.05). Cystatin C was directly correlated with the estimated pulmonary capillary wedge pressure (P < 0.01), TIMP-1 and osteopontin (P < 0.001) and inversely correlated with MMP-1:TIMP-1 (P < 0.01), but not with carboxy-terminal propeptide of procollagen type I or MMP-1 in all patients with HFPEF. These associations were independent of eGFR. In vitro, osteopontin (P < 0.01) and TIMP-1 (P < 0.001) increased in the supernatant of cardiac fibroblasts exposed to cystatin C.
In patients with HFPEF of hypertensive origin, cystatin C is increased and associated with diastolic dysfunction and alterations in collagen metabolism independently of eGFR. An excess of cystatin C might contribute to diastolic dysfunction in HFPEF by facilitating myocardial fibrosis via accumulation of osteopontin and TIMP-1.
胱抑素C已被证明与射血分数保留的心力衰竭（HFpEF）相关。此外，心肌纤维化参与了HFpEF的舒张功能障碍。因此，我们假设胱抑素C水平升高可能与胶原代谢改变有关，导致HFpEF患者出现舒张功能障碍。
纳入141例老年HFpEF高血压患者。通过超声心动图评估心脏形态和功能。采用酶联免疫吸附测定法分析胱抑素C、I型胶原合成生物标志物（I型前胶原羧基末端前肽）和降解标志物[基质金属蛋白酶-1（MMP-1）及其抑制剂TIMP-1]以及骨桥蛋白的循环水平。选取20例无明显心脏病的老年性别匹配患者作为对照。在人心脏成纤维细胞中进行体外研究。
与对照组相比，HFpEF患者的胱抑素C升高（P<0.001），即使在估算肾小球滤过率（eGFR）正常的患者中也是如此（P<0.05）。胱抑素C与估算的肺毛细血管楔压直接相关（P<0.01）、与TIMP-1和骨桥蛋白直接相关（P<0.001），与MMP-1:TIMP-1呈负相关（P<0.01），但在所有HFpEF患者中与I型前胶原羧基末端前肽或MMP-1无关。这些关联独立于eGFR。在体外，暴露于胱抑素C的心脏成纤维细胞上清液中骨桥蛋白（P<0.01）和TIMP-1（P<0.001）增加。
在高血压源性HFpEF患者中，胱抑素C升高，且与舒张功能障碍和胶原代谢改变相关，独立于eGFR。胱抑素C过量可能通过骨桥蛋白和TIMP-1的积累促进心肌纤维化，从而导致HFpEF患者出现舒张功能障碍。
