Metabolic Profiling Associates with Disease Severity in Nonischemic Dilated Cardiomyopathy

Abstract

Background: Metabolomic profiling may have diagnostic and prognostic value in heart failure. This study investigated whether targeted blood and urine metabolomics reflects disease severity in patients with nonischemic dilated cardiomyopathy (DCM) and compared its incremental value on top of N-terminal prohormone of brain natriuretic peptide (NT-proBNP). Methods and Results: A total of 149 metabolites were measured in plasma and urine samples of 273 patients with DCM and with varying stages of disease (patients with DCM and normal left ventricular reverse remodeling, n = 70; asymptomatic DCM, n = 72; and symptomatic DCM, n = 131). Acylcarnitines, sialic acid and glutamic acid are the most distinctive metabolites associated with disease severity, as repeatedly revealed by unibiomarker linear regression, sparse partial least squares discriminant analysis, random forest, and conditional random forest analyses. However, the absolute difference in the metabolic profile among groups was marginal. A decision-tree model based on the top metabolites did not surpass NT-proBNP in classifying stages. However, a combination of NT-proBNP and the top metabolites improved the decision tree to distinguish patients with DCM and left ventricular reverse remodeling from symptomatic DCM (area under the curve 0.813 § 0.138 vs 0.739 § 0.114; P = 0.02). Conclusion: Functional cardiac recovery is reflected in metabolomics. These alterations reveal potential alternative treatment targets in advanced symptomatic DCM. The metabolic profile can complement NT-proBNP in determining disease severity in nonischemic DCM.

Metabolomic profiling of patients with high gradient aortic stenosis undergoing transcatheter aortic valve replacement

“…The development of high-throughput metabolomic technologies has allowed to investigate large patient cohorts of different disease states and to achieve new inputs for putative diagnostic, prognostic or therapy surveillance markers. Thus, independent studies previously reported metabolic alterations in the failing heart [25,31,32]. Aortic stenosis belongs to the most frequent clinical causes of hospitalization and mortality in elderly people and TAVR, being the preferred option for elderly patients, is a well-established interventional therapy for permanent improvement.…”

Machine-learning facilitates selection of a novel diagnostic panel of metabolites for the detection of heart failure

“…To our knowledge, this is the first study that implemented untargeted metabolomics analysis combined with ML algorithms in order to select metabolites creating the top performing diagnostic model for HFrEF. Recently, Verdonschot et al 18 www.nature.com/scientificreports www.nature.com/scientificreports/ have shown that the NT pro-BNP-based determination of the dilated cardiomyopathy (DCM) severity might be complemented by the combination of metabolites. In contrast to our study, authors have applied targeted metabolomics approach which might limit objective analysis of changes occurring in the blood/urine metabolites' profile.…”

Long-Chain Acylcarnitines and Cardiac Excitation-Contraction Coupling: Links to Arrhythmias

“…Others have found a greater level in early stage HFpEF relative to HFrEF; however, this may be due to discrepancies in HFrEF severity and cohort sizes ( Zordoky et al, 2015 ; Bedi et al, 2016 ). Significant circulating LCAC upregulation occurs in both ischemic and non-ischaemic HF etiologies, although the upregulation is significantly greater in ischaemic HF patients ( Lanfear et al, 2017 ; Verdonschot et al, 2019 ). Importantly, circulating LCAC levels were found to normalize to non-failing levels following left ventricular assist device implantation of aortic valve replacement ( Ahmad et al, 2016 ; Elmariah et al, 2018 ).…”

“…LCACs are intermediates of intracellular fatty acid metabolism. High LCAC levels have been associated with key CVDs, including heart failure (HF), coronary artery disease (CAD), and cardiac arrhythmias ( Shah et al, 2010 ; Kalim et al, 2013 ; Rizza et al, 2014 ; Zordoky et al, 2015 ; Krause et al, 2018 ; Verdonschot et al, 2019 ). Moreover, the LCAC-CVD association has been reported to be proportional to disease severity in many studies ( Lai et al, 2014 ; Ahmad et al, 2016 ).…”

“…A growing body of evidence has correlated circulating LCACs with total CVD risk and CVD prognosis ( Kalim et al, 2013 ; Cheng et al, 2015 ; Ruiz-Canela et al, 2017 ). LCACs have been independently associated with HF and indices of left ventricle (LV) remodeling and function in a manner proportional to disease stage and severity ( Lai et al, 2014 ; Rizza et al, 2014 ; Zordoky et al, 2015 ; Ahmad et al, 2016 ; Hunter et al, 2016 ; Lanfear et al, 2017 ; Ruiz et al, 2017 ; Elmariah et al, 2018 ; Verdonschot et al, 2019 ). In some epidemiological cohorts, LCAC levels are reported to be increased in HF with reduced ejection fraction (HFrEF) relative to either non-failing controls or patients with HF with preserved ejection fraction (HFpEF) ( Ahmad et al, 2016 ; Hunter et al, 2016 ; Lanfear et al, 2017 ; Verdonschot et al, 2019 ).…”