Nuclear magnetic resonance-based metabolomics identifies phenylalanine as a novel predictor of incident heart failure hospitalisation: results from PROSPER and FINRISK 1997.

Christian Delles,Aki S Havulinna,Simon P Mooijaart,Charles Boachie,Pasi Soininen,Mika Ala‐Korpela,Peter Würtz,J Wouter Jukema,Paul Welsh,Naomi J Rankin,Naveed Sattar,Antti Kangas,Stella Trompet,Ian Ford,Alex Mcconnachie,Veikko Salomaa,Faiez Zannad

doi:10.1002/ejhf.1076

Abstract

AimsWe investigated the association between quantified metabolite, lipid and lipoprotein measures and incident heart failure hospitalisation (HFH) in the elderly, and examined whether circulating metabolic measures improve HFH prediction.Methods and resultsOverall, 80 metabolic measures from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial were measured by proton nuclear magnetic resonance spectroscopy (n = 5341; 182 HFH events during 2.7‐year follow‐up). We repeated the work in FINRISK 1997 (n = 7330; 133 HFH events during 5‐year follow‐up). In PROSPER, the circulating concentrations of 13 metabolic measures were found to be significantly different in those who were later hospitalised for heart failure after correction for multiple comparisons. These included creatinine, phenylalanine, glycoprotein acetyls, 3‐hydroxybutyrate, and various high‐density lipoprotein measures. In Cox models, two metabolites were associated with risk of HFH after adjustment for clinical risk factors and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP): phenylalanine [hazard ratio (HR) 1.29, 95% confidence interval (CI) 1.10–1.53; P = 0.002] and acetate (HR 0.81, 95% CI 0.68–0.98; P = 0.026). Both were retained in the final model after backward elimination. Compared to a model with established risk factors and NT‐proBNP, this model did not improve the C‐index but did improve the overall continuous net reclassification index (NRI 0.21; 95% CI 0.06–0.35; P = 0.007) due to improvement in classification of non‐cases (NRI 0.14; 95% CI 0.12–0.17; P < 0.001). Phenylalanine was replicated as a predictor of HFH in FINRISK 1997 (HR 1.23, 95% CI 1.03–1.48; P = 0.023).ConclusionOur findings identify phenylalanine as a novel predictor of incident HFH, although prediction gains are low. Further mechanistic studies appear warranted.

Highlights

The prevention of heart failure (HF) is an important clinical issue
In Cox models, two metabolites were associated with risk of heart failure hospitalisation (HFH) after adjustment for clinical risk factors and N-terminal pro-B-type natriuretic peptide (NT-proBNP): phenylalanine [hazard ratio (HR) 1.29, 95% confidence interval (CI) 1.10–1.53; P = 0.002] and acetate (HR 0.81, 95% CI 0.68–0.98; P = 0.026)
Our findings identify phenylalanine as a novel predictor of incident HFH, prediction gains are low

Summary

Introduction

The prevention of heart failure (HF) is an important clinical issue. Patients with HF have a high mortality and impaired quality of life, so identifying those at risk is important.[1,2] The risk of HF increases with age but typical symptoms of HF, such as shortness of breath, may be absent in the elderly (or masked by other co-morbidities); the prognosis of HF is poor, and the mechanisms of HF differ in the elderly.[3] Treatment of hypertension and dyslipidaemia, prevention of diabetes, smoking cessation, increased exercise, weight reduction, and reduced alcohol intake have been associated with lower risks for HF.[4,5,6] At present, symptomatic patients have B-type natriuretic peptide (BNP) or N-terminal proBNP (NT-proBNP) concentrations measured as a rule-out test for HF, a cost-effective strategy to increase the positive predictive value of echocardiography. Studies to improve the understanding of HF aetiology and generate new hypothesis, in the elderly, are needed

Methods

Results

Conclusion