Association and its population heterogeneities between low-density lipoprotein cholesterol and all-cause and cardiovascular mortality:A population-based cohort study

Background:The association and its population heterogeneities between low-density lipoprotein cholesterol(LDL-C)and all-cause and cardiovascular mortality remain unknown.We aimed to examine the dose-dependent associations of LDL-C levels with specific types of cardiovascular disease(CVD)mortality and heterogeneities in the associations among different population subgroups.Methods:A total of 2,968,462 participants aged 35-75 years from China Health Evaluation And risk Reduction through nationwide Teamwork(ChinaHEART)(2014-2019)were included.Cox proportional hazard models and Fine-Gray subdistribution hazard models were used to estimate associations between LDL-C categories(<70.0,70.0-99.9,100.0-129.9[reference group],130.0-159.9,160.0-189.9,and≥190.0 mg/dL)and all-cause and cause-specific mortality.Results:During a median follow-up of 3.7 years,57,391 and 23,241 deaths from all-cause and overall CVD were documented.We observed J-shaped associations between LDL-C and death from all-cause,overall CVD,coronary heart disease(CHD),and ischemic stroke,and an L-shaped association between LDL-C and hemorrhagic stroke(HS)mortality(P for non-linearity<0.001).Compared with the reference group(100.0-129.9 mg/dL),very low LDL-C levels(<70.0 mg/dL)were significantly associated with increased risk of overall CVD(hazard ratio[HR]:1.10,95%confidence interval[CI]:1.06-1.14)and HS mortality(HR:1.37,95%CI:1.29-1.45).Very high LDL-C levels(≥190.0 mg/dL)were associated with increased risk of overall CVD(HR:1.51,95%CI:1.40-1.62)and CHD mortality(HR:2.08,95%CI:1.92-2.24).The stronger associations of very low LDL-C with risk of CVD mortality were observed in individuals with older age,low or normal body mass index,low or moderate 10-year atherosclerotic CVD risk,and those without diagnosed CVD or taking statins.Stronger associations between very high LDL-C levels and all-cause and CVD mortality were observed in younger people.Conclusions:People with very low LDL-C had a higher risk of all-cause,CVD,and HS mortality;those with very high LDL-C had a higher risk of all-cause,CVD,and CHD mortality.On the basis of our findings,comprehensive health assessment is needed to evaluate cardiovascular risk and implement appropriate lipid-lowering therapy for people with very low LDL-C.