Heart failure (HF) is currently considered a systemic multi-organ syndrome fundamentally driven by metabolic failure, and carnitines, a crucial metabolite in fatty acid metabolism, transport long-chain fatty acids into myocardial mitochondria to produce energy as a source of ATP generation [1] (Fig. 1). Harada et al. conducted the present pilot study [2] to examine the ratio of acylcarnitines to free carnitines (AC/FC), a biomarker of cardiomyocyte carnitine insufficiency and impaired β-oxidation [3], either in symptomatic HF with reduced left ventricular ejection fraction (LVEF) HFrEF or HF with preserved LVEF (HFpEF), and demonstrated that AC/FC levels in admission were significantly higher than in asymptomatic staged HF, decreasing to comparable levels at discharge.

Fig. 1
Fig. 1The alternative text for this image may have been generated using AI.
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Carnitine cycle and fatty acid oxidation. OCTN2 organic cation/carnitine transporter 2, LCFA long chain fatty acids, LCAS long chain acyl-CoA synthesis, CPT carnitine palmitoyltransferase, CACT carnitine-acylcarnitine translocase, TCA tricarboxylic acid, MM mitochondrial membrane

Under normal conditions, the primary source of energy in the heart is mainly oxidative phosphorylation of fatty acids in the mitochondria. On the other hand, in HF patients, cardiac energy metabolism is shifted from fatty acid oxidation to glucose, and carnitine insufficiency in the failing myocardium is caused by the leakage of carnitine through damaged cardiomyocyte membranes [4]. Carnitine insufficiency, represented by increased AC/FC, in HF, especially in HFpEF, have also been previously reported by Yoshihisa et al. and Ahmed et al. [5, 6], consistent with current research. Moreover, Ahmed et al. reported acylcarnitine metabolite levels were reduced with mechanical circulatory support [6]. Taken together with AC/FC reduction by HF treatments in this study, carnitine metabolic changes might be not only distinct prognostic biomarkers, but also be therapeutic targets for HF.

Furthermore, current study demonstrates that AC/FC reduction is associated with LVEF improvement through HF treatment particularly in HFpEF with hypertension. This suggests that there might be different lipid metabolic pathways in the two subtypes of HF, and inhibiting myocardial energy deficiency, by restoring ATP-dependent LV relaxation and contraction, might cause beneficial effects in HFpEF [7]. HFpEF exhibits more complexity and has more associated-comorbidities including hypertension compared to HFrEF, and systemic inflammation and its-induced metabolic injury are closely associated with the pathogenesis of HFpEF. Because many previous reports demonstrated that hypertension alone induces a shift from fatty acid oxidation toward increased glucose utilization in cardiac muscle, hypertension complicated with HFpEF might have additive effects on energy metabolic failure in heart.

Several previous studies have investigated serum free carnitine levels in HFpEF and HFrEF, blood long‐chain acylcarnitines levels are higher in HFpEF than those in HFrEF patients, suggesting that an acylcarnitine increase might imply inefficient β‐oxidation, correlating significantly with better survival rates only in HFpEF [8, 9]. Furthermore, L‐carnitine treatment improves diastolic dysfunction estimated by echocardiography and HF symptoms in HFpEF patients [10]. Taken together, the effect of carnitine metabolism on the pathogenesis of HFpEF could be greater than that of HFrEF.

Clarifying the difference of metabolic profiles and of molecular mechanisms between HFrEF and HFpEF might provide clinical significance of carnitine metabolism as new therapeutic target for metabolic disorder in hypertensive HFpEF, remaining unmet medical needs in cardiovascular medicine.