Serum levels of mitochondrial inhibitory factor 1 are independently associated with long-term prognosis in coronary artery disease: the GENES Study

Abstract

BackgroundEpidemiological and observational studies have established that high-density lipoprotein cholesterol (HDL-C) is an independent negative cardiovascular risk factor. However, simple measurement of HDL-C levels is no longer sufficient for cardiovascular risk assessment. Therefore, there is a critical need for novel non-invasive biomarkers that would display prognostic superiority over HDL-C. Cell surface ecto-F1-ATPase contributes to several athero-protective properties of HDL, including reverse cholesterol transport and vascular endothelial protection. Serum inhibitory factor 1 (IF1), an endogenous inhibitor of ecto-F1-ATPase, is an independent determinant of HDL-C associated with low risk of coronary artery disease (CAD). This work aimed to examine the predictive value of serum IF1 for long-term mortality in CAD patients. Its informative value was compared to that of HDL-C.MethodSerum IF1 levels were measured in 577 male participants with stable CAD (age 45–74 years) from the GENES (Genetique et ENvironnement en Europe du Sud) study. Vital status was yearly assessed, with a median follow-up of 11 years and a 29.5 % mortality rate. Cardiovascular mortality accounted for the majority (62.4 %) of deaths.ResultsIF1 levels were positively correlated with HDL-C (rs = 0.40; P < 0.001) and negatively with triglycerides (rs = −0.21, P < 0.001) and CAD severity documented by the Gensini score (rs = −0.13; P < 0.01). Total and cardiovascular mortality were lower at the highest quartiles of IF1 (HR = 0.55; 95 % CI, 0.38–0.89 and 0.50 (0.28–0.89), respectively) but not according to HDL-C. Inverse associations of IF1 with mortality remained significant, after multivariate adjustments for classical cardiovascular risk factors (age, smoking, physical activity, waist circumference, HDL-C, dyslipidemia, hypertension, and diabetes) and for powerful biological and clinical variables of prognosis, including heart rate, ankle-brachial index and biomarkers of cardiac diseases. The 10-year mortality was 28.5 % in patients with low IF1 (<0.42 mg/L) and 21.4 % in those with high IF1 (≥0.42 mg/L, P < 0.02).ConclusionsWe investigated for the first time the relation between IF1 levels and long-term prognosis in CAD patients, and found an independent negative association. IF1 measurement might be used as a novel HDL-related biomarker to better stratify risk in populations at high risk or in the setting of pharmacotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-016-0672-9) contains supplementary material, which is available to authorized users.

Tissue‐specific expression and post‐transcriptional regulation of the ATPase inhibitory factor 1 (IF1) in human and mouse tissues

“…Consistent with these findings, it has been reported that IF1-knockout mice are protected from pressure overload-induced cardiac hypertrophy (37). In the same line, the plasma levels of IF1 have been claimed to provide a biomarker for the risk of experiencing cardiovascular disease (30). Whereas no differences were found in the tissue expression level of IF1 in mice from different genetic backgrounds, a dissimilar expression pattern of IF1 was observed between some human and mouse tissues.…”

Enabling Precision Cardiology Through Multiscale Biology and Systems Medicine

“…Furthermore, despite a plethora of imaging techniques and biomarkers, CAD is still primarily diagnosed and managed symptomatically (93) . Recent advances in characterizing CAD gene networks 94 , 95 could be coupled with advanced imaging 96 , 97 and a wide variety of novel biomarkers 98 , 99 , 100 , 101 , 102 , 103 , 104 to stratify patients with this heterogeneous disease and make more informed treatment decisions.…”

A reference measurement of circulating ATPase inhibitory factor 1 (IF1) in humans by LC-MS/MS: comparison with conventional ELISA

“…Moreover, in clinical studies, circulating IF1 was found to be an independent determinant of HDL-Cholesterol (HDL-C) levels and its mean concentration was lower in coronary heart disease (CHD) patients than in paired control individuals (430 ng/mL and 530 ng/mL, respectively; p <0.001). Later, IF1 levels were found to independently and negatively associate with mortality in CHD patients [3–5]. Recently, higher levels of circulating IF1 were also reported to be significantly associated with greater muscle mass [6].…”