Revisiting the cholesterol paradox in heart failure:the impact of heart failure severity and skeletal muscle loss

Introduction Dyslipidemia is among the major risk factors for atherosclerotic cardiovascular disease. Paradoxically, higher cholesterol levels are associated with better survival in patients with heart failure (HF) of any aetiology. Since cholesterol is an integral component of skeletal muscle structure, one possible explanation involves the interplay between lipid metabolism and skeletal muscle health. This study aims to investigate the association between total cholesterol (TC) levels and exercise capacity in patients with chronic HF in the context of HF severity and skeletal muscle mass. Methods A total of 234 patients with chronic HF (67 ± 11 years, 79% male sex, left ventricular ejection fraction 39 ± 13%) were assessed for lipid profile, skeletal muscle mass, and exercise capacity using data from the Studies Investigating Co-morbidities Aggravating HF (SICA-HF). The appendicular skeletal muscle mass index (ASMI) was assessed using dual-energy X-ray absorptiometry scan and classified into high and low ASMI based on the sex-specific median value (men = 7.99 kg/m2, women = 6.79 kg/m2). Exercise capacity was assessed by peak oxygen uptake (peak VO2). Lower exercise capacity was defined as peak VO2 ≤14 mL/min/kg. Severe HF was defined as New York Heart Association (NYHA) class III/Ⅳ. Patients were stratified into four groups based on ASMI values and HF severity. Results Among the patients, 85 (36.3%) presented severe HF. There were significant differences in TC levels and peak VO2 values between the four groups, with both measures being the lowest in the group with low ASMI and severe HF. Overall, TC levels were positively correlated with peak VO2 values (r=0.21, p=0.002). Notably, this correlation was significant and more pronounced only in the group with low ASMI and severe HF (r=0.48, p=0.0005). On multivariable analyses adjusted for clinically relevant covariates, including statin use, lower TC levels were significantly associated with lower exercise capacity (adjusted odds ratio (aOR) 1.77 per 1SD decrease in TC, 95% confidence interval (CI) 1.11-2.82, p=0.02). This association was more evident in patients with severe HF (aOR 2.69 per 1SD decrease in TC, 95%CI 1.24-5.86, p=0.01) but was not significant in those with non-severe HF. Conclusion In patients with chronic HF, lower TC levels were significantly associated with reduced exercise capacity, especially in those with severe HF. This association was more robust in cases of low skeletal muscle mass. Further research is needed to clarify the mechanisms of the cholesterol paradox and optimize lipid-modulating strategies in HF.