Metabolomic Profiling Identifies Novel Circulating Biomarkers of Mitochondrial Dysfunction Differentially Elevated in Heart Failure With Preserved Versus Reduced Ejection Fraction: Evidence for Shared Metabolic Impairments in Clinical Heart Failure

Abstract

BackgroundMetabolic impairment is an important contributor to heart failure (HF) pathogenesis and progression. Dysregulated metabolic pathways remain poorly characterized in patients with HF and preserved ejection fraction (HFpEF). We sought to determine metabolic abnormalities in HFpEF and identify pathways differentially altered in HFpEF versus HF with reduced ejection fraction (HFrEF).Methods and ResultsWe identified HFpEF cases, HFrEF controls, and no‐HF controls from the CATHGEN study of sequential patients undergoing cardiac catheterization. HFpEF cases (N=282) were defined by left ventricular ejection fraction (LVEF) ≥45%, diastolic dysfunction grade ≥1, and history of HF; HFrEF controls (N=279) were defined similarly, except for having LVEF <45%. No‐HF controls (N=191) had LVEF ≥45%, normal diastolic function, and no HF diagnosis. Targeted mass spectrometry and enzymatic assays were used to quantify 63 metabolites in fasting plasma. Principal components analysis reduced the 63 metabolites to uncorrelated factors, which were compared across groups using ANCOVA. In basic and fully adjusted models, long‐chain acylcarnitine factor levels differed significantly across groups (P<0.0001) and were greater in HFrEF than HFpEF (P=0.0004), both of which were greater than no‐HF controls. We confirmed these findings in sensitivity analyses using stricter inclusion criteria, alternative LVEF thresholds, and adjustment for insulin resistance.ConclusionsWe identified novel circulating metabolites reflecting impaired or dysregulated fatty acid oxidation that are independently associated with HF and differentially elevated in HFpEF and HFrEF. These results elucidate a specific metabolic pathway in HF and suggest a shared metabolic mechanism in HF along the LVEF spectrum.

Acute and long‐term administration of palmitoylcarnitine induces muscle‐specific insulin resistance in mice

“…Many studies indicate that acylcarnitine accumulation is a result of incomplete FA oxidation [1,2,5,29]. Indeed, during ischemia or heart failure, acylcarnitines accumulate in mitochondria because of a transient or permanent inhibition of FA-dependent oxidative phosphorylation in mitochondria [10,30,31]. However, our results indicate that in certain conditions such as the fasted state, the physiologically important LC acylcarnitine accumulation is a result of their CPT-1-driven overproduction coupled to a high FA oxidation rate.…”

Metabolomic profile of arterial stiffness in aged adults

“…The current wealth of literature pertaining to metabolomics in CVD is largely focused on symptomatic cohorts with clinical CVD. [19][20][21][22] While there are community-based studies that have looked at the association between metabolomic signatures and CVD and function, 23,24 few have studied the elderly. The study by Rizza et al 25 looked at a high-risk cohort of elderly subjects in which over half of the participants had documented coronary artery disease or stroke.…”

Metabolic Profiling Associates with Disease Severity in Nonischemic Dilated Cardiomyopathy

“…8 Furthermore, circulating acylcarnitines are increased in patients with HF and preserved EF and are further increased in patients with HF and reduced EF. 24 Increased circulating acylcarnitines was 1 of the main features in a cohort of principally ischemic patients with HF compared to healthy subjects. 25 As in the latter study, we noted an increase in circulating dicarboxylic acylcarnitines, suggesting that both mitochondrial beta oxidation as well as peroxisomal omega oxidation become implicated.…”