Association of low total cholesterol level with clinical outcomes in patients with atrial fibrillation: the Fushimi AF registry
Authors: Iguchi M , Masunaga N , Ishii M , An Y , Fujino A , Hamatani Y , Doi K , Esato M , Wada H , Hasegawa K , Ogawa H , Abe M , Akao M ,   FAF investigators
Published: October 2021

Abstract

Background
Hyperlipidemia is a well-established risk factor for cardiovascular disease. However, low cholesterol is also reported to be associated with poor outcome in patients with chronic disease, which is called “cholesterol paradox”, and the association of cholesterol level with the incidence of clinical outcomes in patients with atrial fibrillation (AF) remains unclear.

Methods
In the Fushimi AF Registry, a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto, Japan, follow-up data and baseline total cholesterol levels were available in 3,054 patients. We excluded 767 patients who were taking statins, and 2,267 patients were included in the analyses. We defined low cholesterol as total cholesterol &lt;150 mg/dl, and examined the incidence of all-cause death, stroke/systemic embolism (SE), heart failure (HF) hospitalization, and major bleeding.

Results
Patients with low cholesterol (N=464 (20.4%)) were older, more often male, and had higher prevalence of low body weight (&lt;50 kg), permanent/persistent AF, prior stroke/SE, HF, chronic kidney disease, and anemia (hemoglobin &lt;11 g/dl). CHA2DS2-VASc score was higher in patients with low cholesterol (low cholesterol vs others; 3.6±1.6 vs 3.2±1.7: P&lt;0.001). Prescription of oral anti-coagulants was comparable between the groups (50.0% vs 54.5%: P=0.09). During the median follow-up of 1,805 days, the incidence of all-cause death, stroke/SE, HF hospitalization, and major bleeding was significantly higher in patients with low cholesterol (all-cause death, 10.9 vs 3.8 /100 person-years; stroke/SE, 3.4 vs 1.9 /100 person-years; HF hospitalization, 4.7 vs 2.5 /100 person-years; major bleeding, 2.7 vs 1.4 /100 person-years) (Figure 1). After adjustment for the components of CHA2DS2-VASc score, low body weight, permanent/persistent AF, chronic kidney disease, anemia, and prescription of oral anti-coagulants, low cholesterol was significantly associated with the incidence of all-cause death and stroke/SE, but not with that of HF hospitalization or major bleeding (Figure 2, model 3). Total cholesterol levels were still significantly and inversely associated with the incidence of all-cause death (hazard ratio, 0.94; 95% confidence interval, 0.92–0.96 for 10 mg/dl increase) and stroke/SE (hazard ratio, 0.96; 95% confidence interval, 0.92–0.999 for 10 mg/dl increase), when analyzed as continuous variables. Subgroup analysis revealed that the risk of low cholesterol for all-cause death was more pronounced in female (interaction P, 0.049), patient without prior stroke/SE (interaction P, 0.01), those without HF (interaction P, 0.01), and those without vascular disease (interaction P, 0.001). The risk for stroke/SE was more pronounced in patients without vascular disease (interaction P, 0.01).

Conclusion
Low total cholesterol level was significantly associated with the incidence of all-cause and stroke/SE in AF patients not taking statins, suggesting the existence of cholesterol paradox in AF.

Funding Acknowledgement
Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Boehringer Ingelheim, Bayer Healthcare, Pfizer, Bristol-Myers Squibb, Astellas Pharma, AstraZeneca, Daiichi-Sankyo, Novartis Pharma, MSD, Sanofi-Avent