Proteomic Analysis of Coronary Sinus Serum Reveals Leucine-Rich α2-Glycoprotein as a Novel Biomarker of Ventricular Dysfunction and Heart Failure

Abstract

Background-Heart failure (HF) prevention strategies require biomarkers that identify disease manifestation. Increases in B-type natriuretic peptide (BNP) correlate with increased risk of cardiovascular events and HF development. We hypothesize that coronary sinus serum from a high BNP hypertensive population reflects an active pathological process and can be used for biomarker exploration. Our aim was to discover differentially expressed disease-associated proteins that identify patients with ventricular dysfunction and HF. Methods and Results-Coronary sinus serum from 11 asymptomatic, hypertensive patients underwent quantitative differential protein expression analysis by 2-dimensional difference gel electrophoresis. Proteins were identified using mass spectrometry and then studied by enzyme-linked immunosorbent assay in sera from 40 asymptomatic, hypertensive patients and 105 patients across the spectrum of ventricular dysfunction (32 asymptomatic left ventricular diastolic dysfunction, 26 diastolic HF, and 47 systolic HF patients). Leucine-rich ␣2-glycoprotein (LRG) was consistently overexpressed in high BNP serum. LRG levels correlate significantly with BNP in hypertensive, asymptomatic left ventricular diastolic dysfunction, diastolic HF, and systolic HF patient groups (PՅ0.05). LRG levels were able to identify HF independent of BNP. LRG correlates with coronary sinus serum levels of tumor necrosis factor-␣ (Pϭ0.009) and interleukin-6 (Pϭ0.021). LRG is expressed in myocardial tissue and correlates with transforming growth factor-␤R1 (PϽ0.001) and ␣-smooth muscle actin (Pϭ0.025) expression. Conclusions-LRG was identified as a serum biomarker that accurately identifies patients with HF. Multivariable modeling confirmed that LRG is a stronger identifier of HF than BNP and this is independent of age, sex, creatinine, ischemia, ␤-blocker therapy, and BNP. (Circ Heart Fail. 2011;4:188-197.)Key Words: heart failure Ⅲ hypertension Ⅲ natriuretic peptides Ⅲ leucine-rich ␣2-glycoprotein A lthough therapies for heart failure (HF) have improved, it is clear that effective prevention strategies will have the most important impact on the concerning epidemiology of this syndrome. In this regard, it is essential to complement effective risk factor control with the earliest possible identification of those at risk for progressive ventricular dysfunction and HF. Hypertensive heart disease (HHD) is a welldescribed example of progressive ventricular dysfunction. Currently, it is not known why a certain proportion of patients with hypertension develop diastolic dysfunction (DD) and others do not. Furthermore, the early diagnosis of the transition to HF is critical and can be clinically challenging. A better understanding of the pathophysiological signals at play may allow for more precise diagnostic tests to define the onset of HF. This natural history is not simply explained by the degree of blood pressure control and probably involves complex disease mechanisms still not fully understood. The ability to identify which asymptom...

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