Discussion
In this large community-based prospective study of 47 832 Chinese adults, we observed that: (1) participants with the higher cumulative burden of TG, TC, LDL-C and non-HDL-C burden, as compared with those in low group, was more likely to develop stroke. (2) While this relationship did not exist in cumulative burden of HDL-C, higher cumulative burden of TG, TC, LDL-C and non-HDL-C burden, except for cumulative HDL-C burden, was consistently associated with higher subsequent IS risk in participants with low cumulative burden of LDL-C. Primary prevention for IS should not only focus on the magnitude of lipid burden at one time point but also take the prior duration of cumulative lipid profiles exposure into consideration.
Because the natural history of atherosclerosis is prolonged, the risk of clinical events rises exponentially late in life.26 Incorporating both the LDL-C concentration and exposure duration into a single risk parameter for future cardiovascular events is intuitively appealing. A previous study derived from Framingham Offspring Cohort data suggested that cumulative exposure to hyperlipidaemia in young adulthood increases the subsequent risk of coronary heart disease in a dose-dependent fashion.26
Cumulative exposure to hyperlipidaemia in young adulthood increases the subsequent risk of coronary heart disease in a dose-dependent fashion. In patients with systemic lupus erythematosus, first-available TC was not predictive of cardiovascular disease among patients, in whom measures reflecting cumulative exposure over time are better able to quantify cardiovascular disease risk.27 These studies stress the importance of cumulative exposure on lipid levels.
Our study extended the previous works by not only showing the cumulative burden of LDL-C, but also other ApoB-containing lipoproteins.28 However, Mendelian randomisation studies have not indicated any causality between HDL-C and cardiovascular disease.29–31 Cumulative burden of HDL-C also showed no significant relationship with incident IS in the current study.
Moreover, clinical trials evaluating lipid-lowering therapy for primary prevention have mostly been limited to intermediate-risk and high-risk groups32–34; studies evaluating the association of other lipid profiles with incident IS, specifically in the group of low LDL-C burden, are limited despite the fact that this group accounts for a rather high percentage of the population. Clinical evidence suggests that the residual cardiovascular risk observed in patients with well-controlled LDL-C levels can be, in part, explained by residual lipid risk factor.11 35 Residual hypertriglyceridaemia occurs over one-fifth (5.5 million) of US adults with diabetes, including those on statin therapy and well-controlled LDL-C. Over three quarters of adults with diabetes with hypertriglyceridaemia are at moderate or high 10-year risk for atherosclerotic cardiovascular disease.36 Using the database of our Chronic Heart Failure Analysis and Registry in the Tohoku District 2 study, the largest scale cohort study of cardiovascular patients in Japan, a previous study indicates that higher triglyceride levels were associated with higher incidence of recurrent myocardial infarction in patients with LDL <100 mg/dL.37 Our study confirmed the association between cumulative burden of other lipid profiles and IS in individuals with low risk evaluated by LDL-C.
Continued exposure to ApoB-containing lipoproteins leads to additional particles being retained over time in the artery wall, and to the growth and progression of atherosclerotic plaques. Once the size of the total plaque burden exceeds this threshold, a person is at risk of experiencing an acute vascular event.12 Because the risk of cardiovascular events depends on the cumulative lifetime exposure to LDL-C and other ApoB-containing lipoproteins, primary prevention strategies designed to lower lipids closer to optimal levels should be initiated in early adulthood to minimise the cumulative lifetime exposure to atherogenic lipoproteins.
The strengths of this study include its prospective design, the large population with a complete follow-up of stroke and repeated assessment of various lipids measurements. However, our study has several limitations. First of all, in this subanalysis of the Kailuan study, the information on four surveys (2006–2007, 2008–2009, 2010–2011 and 2012–2013) was used to calculate the cumulative burden of lipid profiles. The 6 year prior duration of exposure to cumulative lipid profiles recorded in this study, to a certain extent, may be not quite substantial to represent the effect of exposure duration. Second, the associations of lipids profiles and stroke vary by stroke subtypes according to previous studies2; however, we cannot further explore the potential effect of lipids variability on different subtypes of IS. Finally, the Kailuan Study was not designed to be nationally representative. The study was conducted in Tangshan city, a city of northern China. Therefore, it may limit the generalisability of the conclusions to other settings and populations.