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

Abstract

a b s t r a c t a r t i c l e i n f oBackground: In 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. Methods: In 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. Results: In 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). Conclusions: In a general population, the urinary proteome correlated with diastolic LV dysfunction, proving its utility for early diagnosis of this condition.

Novel Urinary Peptidomic Classifier Predicts Incident Heart Failure

“…The resulting classifier, HFP (threshold level À0.22), allowed correct discrimination of 57 patients with HF at baseline and 38 patients with incident HF versus 192 controls with 100% accuracy upon complete take-1-out cross-validation. HFP had 11 (11.5%) peptide fragments in common with the earlier published classifiers HF1 developed in hypertensive patients with asymptomatic LV diastolic dysfunction 5,6 and shared 22 (22.9%) peptides with HFrEF103 derived in HF patients with reduced ejection fraction. 7 Twenty-two of these common peptides have a known sequence ( Table 2).…”

“…To account for the small sample size in the replication sample (FLEMENGHO 5,6 ), we applied Firth regression. 31 In FLEMENGHO participants, 5,6 we evaluated the discriminatory performance of HFP by constructing the receiver operating characteristic curve and calculating the area under the receiver operating characteristic curve.…”

“…For discovery of the urinary biomarkers, we investigated 95 patients enrolled in the GS (Generation Scotland: Scottish Family Health Study), 8 who had either HF at baseline (n=57) or progressed to HF during follow-up (n=38) and 192 sex-and age-matched healthy controls selected from the same cohort. For validation, we studied 175 patients with asymptomatic diastolic LV dysfunction at baseline enrolled in the FLEMENGHO (Flemish Study on Environment, Genes and Health Outcomes 5,6 ), of whom over a 4.8-year period 17 developed HF during follow-up. The diagnosis of HF was ascertained against the records held by general practitioners or hospitals in the catchment area of the FLEMENGHO study.…”

“…3 In line with this recommendation, we developed multidimensional proteomic biomarkers characterizing distinct molecular manifestations of LV dysfunction that may provide additional diagnostic and prognostic value and identify new targets of treatment. We already identified specific peptide biomarker patterns helping in the diagnosis of coronary artery disease, 4 and asymptomatic LV diastolic 5,6 and systolic 7 dysfunction. The present study aimed to extend the findings 5-7 of these case-control 5,7 and cross-sectional 6 studies and to investigate whether the urinary proteomic signature might predict progression from asymptomatic LV dysfunction to overt symptomatic HF.…”

1.1 Diastolic Left Ventricular Function in Relation to Circulating Metabolic Biomarkers in a General Population

“…11 Findings in symptomatic patients cannot be extrapolated to subclinical disease, in which biomarkers would have the greatest diagnostic or prognostic meaning. 12 In keeping with these considerations, 11,12 we examined the metabolic signature of diastolic LV dysfunction in a random population sample enrolled in the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO). 13 …”