Novel Urinary Peptidomic Classifier Predicts Incident Heart Failure

Abstract

BackgroundDetection of preclinical cardiac dysfunction and prognosis of left ventricular heart failure (HF) would allow targeted intervention, and appears to be the most promising approach in its management. Novel biomarker panels may support this approach and provide new insights into the pathophysiology.Methods and ResultsA retrospective comparison of urinary proteomic profiles generated by mass spectrometric analysis from 49 HF patients, 36 patients who progressed to HF within 2.6±1.6 years, and 192 sex‐ and age‐matched controls who did not progress to HF enabled identification of 96 potentially HF‐specific peptide biomarkers. Based on these 96 peptides, the classifier called Heart Failure Predictor (HFP) was established by support vector machine modeling. The incremental prognostic value of HFP was subsequently evaluated in urine samples from 175 individuals with asymptomatic diastolic dysfunction from an independent population cohort. Within 4.8 years, 17 of these individuals progressed to overt HF. The area under receiver‐operating characteristic curve was 0.70 (95% CI, 0.56–0.82); P=0.0047 for HFP and 0.57 (0.42–0.72; P=0.62) for N‐terminal pro b‐type natriuretic peptide. Hazard ratios were 1.63 (CI, 1.04–2.55; P=0.032) per 1‐SD increment in HFP and 0.70 (CI, 0.35–1.41; P=0.32) for a doubling of the logarithmically transformed N‐terminal pro b‐type natriuretic peptide.Conclusions HFP is a novel biomarker derived from the urinary proteome and might serve as a sensitive tool to improve risk stratification, patient management, and understanding of the pathophysiology of HF.

Urinary Proteomics in Predicting Heart Transplantation Outcomes (uPROPHET)—Rationale and database description

“…HF1 [ 5 – 7 ], HF2 [ 6 ], HFrEF103 [ 39 ], and HFP [ 40 ] are multidimensional UP classifiers, respectively consisting of 85, 671, 103 and 96 urinary peptide fragments, which were developed for diagnosis and risk stratification in the framework of subclinical diastolic left ventricular dysfunction (HF1) or symptomatic heart failure (HF2, HFrEF103 and HFP). CAD238 [ 11 ] and ACSP75 [ 11 ], consisting of 238 and 75 peptide fragments have been designed for diagnostic and prognostic use in coronary heart disease.…”

“…uPROPHET builds on previously identified biomarkers and classifiers [ 5 – 9 , 11 , 39 , 40 ]. HF1 was originally designed in a case-control study nested within the Flemish Study on Environment, Genes and Health Outcomes (FLEMENGHO) [ 5 ] with the goal to identify potentially discriminating urinary biomarkers for diastolic LV dysfunction.…”

“…The odds of impaired relaxation associated with HF1 was 1.38 ( P = 0.043) and that of increased LV filling pressure associated with HF2 was 1.38 ( P = 0.052). HFP was originally designed in the Generation Scotland study and was subsequently validated in a cohort of FLEMENGHO participants with diastolic LV dysfunction at risk of HF [ 40 ]. HFrEF103 accurately (area under the curve, 0.972) discriminated between HF patients with reduced ejection fraction and control individuals with or without impaired renal function and hypertension (sensitivity, 93.6%) [ 39 ].…”

“…Very recently, we demonstrated that CKD273 predicts progression to stage-3 CKD, defined as a decrease in estimated glomerular filtration by 10 mL/min/1.73 m2 or more to less than 60 mL/min/1.73 m2 over approximately 5 years [ 52 ]. In the initial stages of uPROPHET, these established urinary biomarkers [ 5 – 9 , 11 , 39 , 40 ] will be tested to detect worsening of right heart hemodynamic conditions (HF1 and HF2), coronary vasculopathy (CAD238 and ACSP75) or to predict decline in renal function (CKD273). Analyses of single sequenced urinary peptides, allowing to identify the parent proteins, will be pursued, as described elsewhere [ 7 , 10 ], as a way to gain insight in the underlying disease processes and molecular pathways.…”

Ups and downs in heart failure: the case of proteomics

“…Several studies have hitherto been published concerning, among other issues, protein alterations in conditions such as dilated cardiomyopathy, myocardial hypertrophy, atherosclerosis, atrial fibrillation and myocardial stunning, the identification of biomarkers in ischaemic heart disease and the acquisition of mechanistic insights into myocardial protection during ischaemia and reperfusion . In heart failure (HF), proteome analyses have revealed changes concerning proteins of the extracellular matrix, cardiomyocyte cytoskeleton, contractile apparatus, energy production and cardiomyocyte protection that are up‐ or down‐regulated ( Table ) …”