Association of Growth Differentiation Factor 15 with Arterial Stiffness and Endothelial Function in Subpopulations of Patients with Coronary Artery Disease: A Proof-of-Concept Study.

Konstantinos Mourouzis, Gerasimos Siasos, Nikoleta Bozini, Evangelos Oikonomou, Marina Zaromitidou, Vasiliki Tsigkou, Eleni Kokkou, Evanthia Bletsa, Panagiota Stampouloglou, Manolis Vavuranakis, Dimitrios Tousoulis
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Abstract

Background: Growth-differentiation factor-15 (GDF-15) is a biomarker belonging to the transforming growth factor-beta cytokine superfamily, which is linked to many pathological conditions, including inflammation and myocardial injury. Pulse wave velocity (cfPWV) and augmentation index (AIx) are indices of arterial stiffness, which are associated with the severity of coronary artery disease (CAD). Flow-mediated dilatation (FMD) is a well-studied surrogate marker of endothelial-dependent dysfunction and systemic inflammation.

Objective: In this proof-of-concept study, we aimed to investigate the relationship between circulating GDF-15, endothelial dysfunction, and indices of arterial stiffness in different settings of coronary artery disease and myocardial injury.

Methods: In this cross-sectional single-center study, we enrolled patients (n = 22) after interventional treatment for acute myocardial infarction (AMI), patients (n = 11) admitted with chest pain and elevated cardiac enzymes but without evidence of obstructing CAD (MI-NOCAD) in percutaneous coronary angiography (CAG), and patients (n = 20) who underwent CAG according to indications without evident obstructive CAD in CAG (NOCAD). FMD was assessed at the brachial artery. AIx of the central aortic pressure and cfPWV were estimated by applanation tonometry at the radial and carotid-femoral site, respectively, with a validated acquisition system (Sphygmo- Cor, AtCor Medical, Sydney (NSW), Australia). ELISA was used to determine circulating GDF- 15 serum levels (R&D Systems, Minneapolis, MN). Clinical and demographic data and values of routine biochemical biomarkers were obtained. The highest high-sensitive cardiac Troponin I (hsTpnI) value during hospitalization was also recorded. Left ventricular ejection fraction (LVEF) was assessed with a transthoracic echocardiogram.

Results: Patients with AMI were older, had worse LVEF, higher values of hsTpnI and increased circulating GDF-15 levels. Importantly, AMI patients had increased cfPWV values, deteriorated AIx values, blunted FMD and worse serum creatinine levels compared to MI-NOCAD and NOCAD patients, respectively, whereas MI-NOCAD and NOCAD did not differ from each other significantly on these biomarkers. Both AMI and MI-NOCAD patients presented a higher but comparable white blood cell count than NOCAD patients. A strong linear correlation between GDF-15 and cfPWV, hsTpnI, AIx, white blood cell count and creatinine but not with FMD was demonstrated in the general study population.

Conclusion: This proof-of-concept study showed that higher circulating levels of GDF-15, an inflammatory biomarker, were associated significantly with increased arterial stiffness only in AMI patients, whereas elevated GDF-15 demonstrated a linear relationship with the severity of the myocardial injury.

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冠状动脉疾病患者亚群中生长分化因子15与动脉僵硬和内皮功能的关联:一项概念验证研究
背景:生长分化因子-15 (growth -differentiation factor-15, GDF-15)是一种生物标志物,属于转化生长因子-细胞因子超家族,与许多病理状况有关,包括炎症和心肌损伤。脉搏波速度(cfPWV)和增强指数(AIx)是动脉硬度的指标,与冠状动脉疾病(CAD)的严重程度相关。血流介导的扩张(FMD)是内皮依赖性功能障碍和全身性炎症的一个被充分研究的替代标志物。目的:在这项概念验证性研究中,我们旨在探讨不同冠状动脉疾病和心肌损伤情况下循环GDF-15、内皮功能障碍和动脉僵硬指数之间的关系。方法:在这项横断面单中心研究中,我们招募了22例急性心肌梗死(AMI)介入治疗后的患者,11例胸痛和心肌酶升高但经皮冠状动脉造影(CAG)无阻塞性CAD (MI-NOCAD)证据的患者,以及20例根据适应症行CAG的患者,CAG中无明显阻塞性CAD (NOCAD)证据。在肱动脉处评估FMD。采用经过验证的采集系统(Sphygmo- Cor, AtCor Medical, Sydney (NSW), Australia),分别通过桡动脉和颈动脉-股动脉部位的压平血压计估计中央主动脉压的AIx和cfPWV。ELISA检测血清循环GDF- 15水平(R&D Systems, Minneapolis, MN)。获得临床和人口统计学资料及常规生化生物标志物值。同时记录住院期间高敏感心肌肌钙蛋白I (hsTpnI)值的最高值。左心室射血分数(LVEF)经胸超声心动图评估。结果:AMI患者年龄较大,LVEF较差,hsTpnI值较高,循环GDF-15水平升高。重要的是,与MI-NOCAD和NOCAD患者相比,AMI患者的cfPWV值升高,AIx值变差,FMD变钝,血清肌酐水平变差,而MI-NOCAD和NOCAD在这些生物标志物上没有显著差异。AMI和MI-NOCAD患者的白细胞计数均高于NOCAD患者。在一般研究人群中,GDF-15与cfPWV、hsTpnI、AIx、白细胞计数和肌酐之间存在很强的线性相关性,但与口蹄疫无关。结论:这项概念验证性研究表明,较高的循环GDF-15水平(一种炎症生物标志物)仅在AMI患者中与动脉僵硬度增加显著相关,而升高的GDF-15与心肌损伤的严重程度呈线性关系。
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