Left ventricular diastolic function in relation to the urinary proteome: A proof-of-concept study in a general population

Abstract

BackgroundIn previous studies, we identified two urinary proteomic classifiers, termed HF1 and HF2, which discriminated subclinical diastolic left ventricular (LV) dysfunction from normal. HF1 and HF2 combine information from 85 and 671 urinary peptides, mainly up- or down-regulated collagen fragments. We sought to validate these classifiers in a population study.MethodsIn 745 people randomly recruited from a Flemish population (49.8 years; 51.3% women), we measured early and late diastolic peak velocities of mitral inflow (E and A) and mitral annular velocities (e' and a') by conventional and tissue Doppler echocardiography, and the urinary proteome by capillary electrophoresis coupled with mass spectrometry.ResultsIn the analyses adjusted for sex, age, body mass index, blood pressure, heart rate, LV mass index and intake of medications, we expressed effect sizes per 1-SD increment in the classifiers. HF1 was associated with 0.204 cm/s lower e' peak velocity (95% confidence interval, 0.057–0.351; p = 0.007) and 0.145 higher E/e' ratio (0.023–0.268; p = 0.020), while HF2 was associated with a 0.174 higher E/e' ratio (0.046–0.302; p = 0.008). According to published definitions, 67 (9.0%) participants had impaired LV relaxation and 96 (12.9%) had elevated LV filling pressure. The odds of impaired relaxation associated with HF1 was 1.38 (1.01–1.88; p = 0.043) and that of increased LV filling pressure associated with HF2 was 1.38 (1.00–1.90; p = 0.052).ConclusionsIn a general population, the urinary proteome correlated with diastolic LV dysfunction, proving its utility for early diagnosis of this condition.

Novel Urinary Biomarkers For Improved Prediction Of Progressive eGFR Loss In Early Chronic Kidney Disease Stages And In High Risk Individuals Without Chronic Kidney Disease

“…Specific CKD diagnoses were biopsy-proven for glomerulonephritides, while diabetic nephropathy was diagnosed clinically when diabetic patients showed clinical parameters (urinary albumin, eGFR) consistent with kidney disease during follow-up in the absence of evidence for a different nephropathy. Out of 2422 patients from previous studies with available baseline and follow-up eGFR 13,17,18,38–43 , 1482 met the definitions of either rapid progressor (sustained decline in eGFR of 5 ml/min/1.73 m 2 /year or more) or non-rapid progressor/stable renal function (change between −1.5 and +5 ml/min/1.73 m 2 /year), as detailed below. The choice of the 5 ml/min/1.73 m 2 /year was not arbitrary.…”

“…Sample collection and analysis of urine samples using capillary electrophoresis-mass spectrometry (CE-MS) have been previously reported 17,18,41–43 . Normalized signal intensity was used as a measure for relative abundance for peptide quantification.…”

Diastolic Left Ventricular Function in Relation to Urinary and Serum Collagen Biomarkers in a General Population

“…Our previous studies revealed a unique urinary proteomic signature, which in case-control studies [9] and in the general population [10] was reproducibly associated with subclinical diastolic LV dysfunction and which predicted the incidence of adverse cardiovascular outcomes over and beyond traditional cardiovascular risk factors [11]. We hypothesised that jointly linking diastolic LV dysfunction to urinary and serum markers of collagen turnover might increase our understanding of LV dysfunction.…”

“…We hypothesised that jointly linking diastolic LV dysfunction to urinary and serum markers of collagen turnover might increase our understanding of LV dysfunction. With the aim to generalise observations in patients with diastolic heart failure [2–5] to the early still asymptomatic stage of the disease in the population at large, we analysed the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO) [10]. First, we searched for association of diastolic LV function with individual urinary peptides with known amino-acid sequence, thereby identifying collagen types as the parent proteins.…”

Utilizing proteomics to understand and define hypertension: where are we and where do we go?

“…The urinary peptide markers have been further shown to be differentially regulated also in patients with overt heart failure, indicating a molecular pathophysiological continuum from subclinical damage to overt disease [72]. These data have been further confirmed in a larger study in the general population demonstrating correlations between left ventricular dysfunction and the urinary proteome [73]. The urinary proteome can also provide information on cardiovascular endpoints in hypertensive patients where it has been found to predict coronary events in a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) [74].…”