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Intra-individual variability of total cholesterol is associated with cardiovascular disease mortality: A cohort study

  • Yao Zhu
    Affiliations
    Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, Hangzhou, China
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  • Jie-Ming Lu
    Affiliations
    Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, Hangzhou, China
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  • Zhe-Bin Yu
    Affiliations
    Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, Hangzhou, China
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  • Die Li
    Affiliations
    Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, Hangzhou, China
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  • Meng-Yin Wu
    Affiliations
    Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, Hangzhou, China
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  • Peng Shen
    Affiliations
    Department of Chronic Disease and Health Promotion, Yinzhou District Center for Disease Control and Prevention, Ningbo, China
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  • Hong-Bo Lin
    Affiliations
    Department of Chronic Disease and Health Promotion, Yinzhou District Center for Disease Control and Prevention, Ningbo, China
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  • Jian-Bing Wang
    Correspondence
    Corresponding author. Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China.
    Affiliations
    Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, Hangzhou, China

    Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, China
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  • Kun Chen
    Correspondence
    Corresponding author. Department of Epidemiology and Health Statistics, School of Public Health, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China.
    Affiliations
    Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, Hangzhou, China

    Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, China

    Cancer Institute, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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      Highlights

      • Both too low and too high baseline TC level were associated with higher risk of total, CVD and cancer mortality.
      • Intra-individual variability of TC could be a risk factor of cardiovascular mortality, irrespective of mean TC level.
      • Maintaining the stability of serum cholesterol could help prevent cardiovascular events and mortality.

      Abstract

      Background and aims

      The relationship between serum total cholesterol (TC) and mortality remains inconsistent. Additionally, intra-individual variability of cholesterol has been of increasing interest as a new indicator for health outcomes. We aimed to examine the association between TC and its variability and risk of mortality.

      Methods and results

      We performed a retrospective cohort study with 122,645 individuals aged over 40 years in Ningbo, China. The intra-individual variability was calculated using four metrics including standard deviation, coefficient variation, variation independent of mean and average successive variability. Hazard ratios and 95% confidence intervals were estimated for the associations of baseline and variability in TC with risk of mortality by Cox proportional hazards regression models. During 591,585.3 person-years of follow-up, 4563 deaths (including 1365 from cardiovascular disease, 788 from stroke and 1514 from cancer) occurred. A U-shaped association was observed for baseline TC level and risk of total, cardiovascular and cancer mortality, with lowest mortality at 5.46 mmol/L, 5.04 mmol/L and 5.51 mmol/L, respectively. As compared with subjects with TC variability in the lowest quartile, individuals in the highest quartile had 21% higher risk of all-cause mortality (HR = 1.21, 95% CI: 1.05 to 1.40), and 41% higher risk of CVD mortality (HR = 1.41, 95%CI: 1.10 to 1.81).

      Conclusion

      Both too low and too high baseline TC level were associated with higher risk of total, cardiovascular disease and cancer mortality. Variability of TC could be a risk factor of total and CVD mortality, independent of mean TC level. Future studies are needed to confirm these findings.

      Keywords

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      References

        • Law M.R.
        • Wald N.J.
        • Thompson S.G.
        By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease?.
        BMJ. 1994; 308: 367-372
        • Stamler J.
        • Wentworth D.
        • Neaton J.D.
        Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded?: findings in 356 222 primary screenees of the multiple risk factor intervention trial (MRFIT).
        JAMA. 1986; 256: 2823-2828
        • Stamler J.
        • Daviglus M.L.
        • Garside D.B.
        • Dyer A.R.
        • Greenland P.
        • Neaton J.D.
        Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity.
        JAMA. 2000; 284: 311-318
        • Anderson K.M.
        • Castelli W.P.
        • Levy D.
        Cholesterol and mortality: 30 Years of follow-up from the framingham study.
        JAMA. 1987; 257: 2176-2180
        • Lewington S.
        • Whitlock G.
        • Clarke R.
        • Sherliker P.
        • Emberson J.
        • Halsey J.
        • et al.
        Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths.
        Lancet. 2007; 370: 1829-1839
        • Casiglia E.
        • Spolaore P.
        • Ginocchio G.
        • Colangeli G.
        • Di Menza G.
        • Marchioro M.
        • et al.
        Predictors of mortality in very old subjects aged 80 years or over.
        Eur J Epidemiol. 1993; 9: 577-586
        • Liang Y.
        • Vetrano D.L.
        • Qiu C.
        Serum total cholesterol and risk of cardiovascular and non-cardiovascular mortality in old age: a population-based study.
        BMC Geriatr. 2017; 17: 294
        • Newson R.S.
        • Felix J.F.
        • Heeringa J.
        • Hofman A.
        • Witteman J.C.
        • Tiemeier H.
        Association between serum cholesterol and noncardiovascular mortality in older age.
        J Am Geriatr Soc. 2011; 59: 1779-1785
        • Weverling-Rijnsburger A.W.
        • Blauw G.J.
        • Lagaay A.M.
        • Knook D.L.
        • Meinders A.E.
        • Westendorp R.G.
        Total cholesterol and risk of mortality in the oldest old.
        Lancet. 1997; 350: 1119-1123
        • Schatz I.J.
        • Masaki K.
        • Yano K.
        • Chen R.
        • Rodriguez B.L.
        • Curb J.D.
        Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study.
        Lancet. 2001; 358: 351-355
        • Nago N.
        • Ishikawa S.
        • Goto T.
        • Kayaba K.
        Low cholesterol is associated with mortality from stroke, heart disease, and cancer: the Jichi Medical School Cohort Study.
        J Epidemiol. 2011; 21: 67-74
        • Iso H.
        • Naito Y.
        • Kitamura A.
        • Sato S.
        • Kiyama M.
        • Takayama Y.
        • et al.
        Serum total cholesterol and mortality in a Japanese population.
        J Clin Epidemiol. 1994; 47: 961-969
        • Bae J.M.
        • Yang Y.J.
        • Li Z.M.
        • Ahn Y.O.
        Low cholesterol is associated with mortality from cardiovascular diseases: a dynamic cohort study in Korean adults.
        J Korean Med Sci. 2012; 27: 58-63
        • Yi S.W.
        • Yi J.J.
        • Ohrr H.
        Total cholesterol and all-cause mortality by sex and age: a prospective cohort study among 12.8 million adults.
        Sci Rep. 2019; 9: 1596
        • Bangalore S.
        • Breazna A.
        • DeMicco D.A.
        • Wun C.C.
        • Messerli F.H.
        • Committee T.N.T.S.
        • et al.
        Visit-to-visit low-density lipoprotein cholesterol variability and risk of cardiovascular outcomes: insights from the TNT trial.
        J Am Coll Cardiol. 2015; 65: 1539-1548
        • Waters D.D.
        • Bangalore S.
        • Fayyad R.
        • DeMicco D.A.
        • Laskey R.
        • Melamed S.
        • et al.
        Visit-to-visit variability of lipid measurements as predictors of cardiovascular events presented in part at the American heart association annual scientific sessions, November 2017.
        J Clin Lipidol. 2018; 12: 356-366
        • Bangalore S.
        • Fayyad R.
        • Messerli F.H.
        • Laskey R.
        • DeMicco D.A.
        • Kastelein J.J.
        • et al.
        Relation of variability of low-density lipoprotein cholesterol and blood pressure to events in patients with previous myocardial infarction from the IDEAL trial.
        Am J Cardiol. 2017; 119: 379-387
        • Boey E.
        • Gay G.M.
        • Poh K.K.
        • Yeo T.C.
        • Tan H.C.
        • Lee C.H.
        Visit-to-visit variability in LDL- and HDL-cholesterol is associated with adverse events after ST-segment elevation myocardial infarction: a 5-year follow-up study.
        Atherosclerosis. 2016; 244: 86-92
        • Kim M.K.
        • Han K.
        • Kim H.S.
        • Park Y.M.
        • Kwon H.S.
        • Yoon K.H.
        • et al.
        Cholesterol variability and the risk of mortality, myocardial infarction, and stroke: a nationwide population-based study.
        Eur Heart J. 2017; 38: 3560-3566
        • Smit R.A.J.
        • Jukema J.W.
        • Postmus I.
        • Ford I.
        • Slagboom P.E.
        • Heijmans B.T.
        • et al.
        Visit-to-visit lipid variability: clinical significance, effects of lipid-lowering treatment, and (pharmaco) genetics.
        J Clin Lipidol. 2018; 12: 266-276 e3
        • Wang J.B.
        • Huang Q.C.
        • Hu S.C.
        • Zheng P.W.
        • Shen P.
        • Li D.
        • et al.
        Baseline and longitudinal change in blood pressure and mortality in a Chinese cohort.
        J Epidemiol Community Health. 2018; 72: 1083-1090
        • Rothwell P.M.
        • Howard S.C.
        • Dolan E.
        • O'Brien E.
        • Dobson J.E.
        • Dahlof B.
        • et al.
        Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension.
        Lancet. 2010; 375: 895-905
        • Rothwell P.M.
        Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension.
        Lancet. 2010; 375: 938-948
        • Eisen E.A.
        • Agalliu I.
        • Thurston S.W.
        • Coull B.A.
        • Checkoway H.
        Smoothing in occupational cohort studies: an illustration based on penalised splines.
        Occup Environ Med. 2004; 61: 854-860
        • Meira-Machado L.
        • Cadarso-Suarez C.
        • Gude F.
        • Araujo A.
        smooth HR: an R package for pointwise nonparametric estimation of hazard ratio curves of continuous predictors.
        Comput Math Methods Med. 2013; 2013: 745742
        • Wolbers M.
        • Koller M.T.
        • Stel V.S.
        • Schaer B.
        • Jager K.J.
        • Leffondre K.
        • et al.
        Competing risks analyses: objectives and approaches.
        Eur Heart J. 2014; 35: 2936-2941
        • Corti M.C.
        • Guralnik J.M.
        • Salive M.E.
        • Harris T.
        • Ferrucci L.
        • Glynn R.J.
        • et al.
        Clarifying the direct relation between total cholesterol levels and death from coronary heart disease in older persons.
        Ann Intern Med. 1997; 126: 753-760
        • National Cholesterol Education Program
        Expert panel on detection, E. And A. Treatment of high blood cholesterol in, third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report.
        Circulation. 2002; 106: 3143-3421
      1. 2016 Chinese guidelines for the management of dyslipidemia in adults.
        J Geriatr Cardiol. 2018; 15: 1-29
        • Yi S.W.
        • Shin D.H.
        • Kim H.
        • Yi J.J.
        • Ohrr H.
        Total cholesterol and stroke mortality in middle-aged and elderly adults: a prospective cohort study.
        Atherosclerosis. 2018; 270: 211-217
        • Chen Z.
        • Ichetovkin M.
        • Kurtz M.
        • Zycband E.
        • Kawka D.
        • Woods J.
        • et al.
        Cholesterol in human atherosclerotic plaque is a marker for underlying disease state and plaque vulnerability.
        Lipids Health Dis. 2010; 9: 61
        • Vedre A.
        • Pathak D.R.
        • Crimp M.
        • Lum C.
        • Koochesfahani M.
        • Abela G.S.
        Physical factors that trigger cholesterol crystallization leading to plaque rupture.
        Atherosclerosis. 2009; 203: 89-96
        • Grover-Paez F.
        • Zavalza-Gomez A.B.
        Endothelial dysfunction and cardiovascular risk factors.
        Diabetes Res Clin Pract. 2009; 84: 1-10
        • Davignon J.
        Beneficial cardiovascular pleiotropic effects of statins.
        Circulation. 2004; 109: Iii39-Iii43
        • Chen H.
        • Ren J.Y.
        • Xing Y.
        • Zhang W.L.
        • Liu X.
        • Wu P.
        • et al.
        Short-term withdrawal of simvastatin induces endothelial dysfunction in patients with coronary artery disease: a dose-response effect dependent on endothelial nitric oxide synthase.
        Int J Cardiol. 2009; 131: 313-320