Familial hypercholesterolemia and cardiovascular disease in older individuals


      • Older familial hypercholesterolemia (FH) individuals had higher frequencies of cardiovascular disease than non-affected hypercholesterolemic counterparts.
      • There was a predominance of women in the study population suggesting a survival bias.
      • Male sex was independently associated with previous cardiovascular disease among FH elders.
      • Results emphasize monogenic defects as important markers of cardiovascular disease.


      Background and aims

      Familial hypercholesterolemia (FH) is characterized by high LDL-cholesterol (LDL-C) and early atherosclerotic cardiovascular disease (ASCVD). With a lipid lowering therapy (LLT), most individuals with FH may have a longer ASCVD-free survival. However, there is scant data about older individuals with FH.


      We compared characteristics of genetically defined FH older individuals with age-matched non-FH counterparts.


      From 4111 genotyped individuals, 462 older than 60 years were included (198 positive and 264 negative for FH variants). There were no differences regarding median age [%25; 75%] 66.0 (62.0; 71.0) and 66.0 (62.2; 71.0) years, p = 0.68 for FH and non-FH, respectively. In both groups, there was a higher frequency of females, however, there were more males in the FH group 37.4% vs. 24.2%, p = 0.002. No differences were seen between FH and non-FH in LLT use: 88.5% vs. 91.5%, p = 0.29. Despite a longer LLT duration in FH patients (with 11.0 (7.0; 20.0) vs. 7.0 (3.0; 13.0) years, p < 0.001), treatment was started late in both groups: at 54.0 (47.0; 61.0) and 59.0 (52.0; 64.0) years, p < 0.001, in FH and non-FH, respectively. FH had greater frequencies of previous and early ASCVD (40.9% vs. 27.3%, p = 0.002, and 22.2% vs. 9.0%, p < 0.001). In FH, male sex [HR (95%CI)] 2.67 (1.50–4.73), p = 0.001, and LLT onset age 0.96 (0.93–0.99), p = 0.009, were independently associated with ASCVD.


      Among hypercholesterolemic older individuals participating in a cascade screening program, the genetic diagnosis of FH was associated with higher ASCVD rates, emphasizing the relevance of a monogenic defect as the cause of long-lasting hypercholesterolemia and ASCVD risk, particularly in men.

      Graphical abstract


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        • Defesche J.C.
        • Gidding S.S.
        • Harada-Shiba M.
        • Hegele R.A.
        • Santos R.D.
        • Wierzbicki A.S.
        Familial hypercholesterolaemia.
        Nat Rev Dis Primers. 2017; 3: 17093
        • Mundal L.J.
        • Igland J.
        • Veierod M.B.
        • et al.
        Impact of age on excess risk of coronary heart disease in patients with familial hypercholesterolaemia.
        Heart. 2018; 104: 1600-1607
        • Slack J.
        Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states.
        Lancet. 1969; 2: 1380-1382
        • Austin M.A.
        • Hutter C.M.
        • Zimmern R.L.
        • Humphries S.E.
        Familial hypercholesterolemia and coronary heart disease: a HuGE association review.
        Am. J. Epidemiol. 2004; 160: 421-429
      1. Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific Steering Committee on behalf of the Simon Broome Register Group.
        Atherosclerosis. 1999; 142: 105-112
        • Perak A.M.
        • Ning H.
        • de Ferranti S.D.
        • Gooding H.C.
        • Wilkins J.T.
        • Lloyd-Jones D.M.
        Long-term risk of atherosclerotic cardiovascular disease in US adults with the familial hypercholesterolemia phenotype.
        Circulation. 2016; 134: 9-19
        • Grundy S.M.
        • Stone N.J.
        • Bailey A.L.
        • et al.
        AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of cardiology/American heart association task force on clinical practice guidelines.
        J. Am. Coll. Cardiol. 2018; 73 (2019): e285-e350
        • Miname M.H.
        • Bittencourt M.S.
        • Moraes S.R.
        • et al.
        Coronary artery calcium and cardiovascular events in patients with familial hypercholesterolemia receiving standard lipid-lowering therapy.
        JACC Cardiovascular imaging. 2019; 12: 1797-1804
        • Santos R.D.
        • Gidding S.S.
        • Hegele R.A.
        • et al.
        Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel.
        Lancet Diabetes Endocrinol. 2016; 4: 850-861
        • Miname M.H.
        • Santos R.D.
        Reducing cardiovascular risk in patients with familial hypercholesterolemia: risk prediction and lipid management.
        Prog. Cardiovasc. Dis. 2019; 62: 414-422
        • Versmissen J.
        • Oosterveer D.M.
        • Yazdanpanah M.
        • et al.
        Efficacy of statins in familial hypercholesterolaemia: a long term cohort study.
        BMJ. 2008; 337: a2423
        • Hyttinen L.
        • Kekalainen P.
        • Vuorio A.F.
        • Sintonen H.
        • Strandberg T.E.
        Health-related quality of life in elderly patients with familial hypercholesterolemia.
        Int. J. Technol. Assess. Health Care. 2008; 24: 228-234
        • Murano S.
        • Shinomiya M.
        • Shirai K.
        • Saito Y.
        • Yoshida S.
        Characteristic features of long-living patients with familial hypercholesterolemia in Japan.
        J. Am. Geriatr. Soc. 1993; 41: 253-257
        • Johnson K.W.
        • Dudley J.T.
        • Bobe J.R.
        A 72-year-old patient with longstanding, untreated familial hypercholesterolemia but no coronary artery calcification: a case report.
        Cureus. 2018; 10e2452
        • Lacaze P.
        • Sebra R.
        • Riaz M.
        • et al.
        Familial hypercholesterolemia in a healthy elderly population.
        Circ Genom Precis Med. 2020; 13: 337-339
        • Khera A.V.
        • Won H.H.
        • Peloso G.M.
        • et al.
        Diagnostic yield and clinical utility of sequencing familial hypercholesterolemia genes in patients with severe hypercholesterolemia.
        J. Am. Coll. Cardiol. 2016; 67: 2578-2589
        • Shetty P.
        Grey matter: ageing in developing countries.
        Lancet. 2012; 379: 1285-1287
        • Silva P.R.S.
        • Jannes C.E.
        • Oliveira T.G.M.
        • et al.
        Evaluation of clinical and laboratory parameters used in the identification of index cases for genetic screening of familial hypercholesterolemia in Brazil.
        Atherosclerosis. 2017; 263: 257-262
        • Jannes C.E.
        • Santos R.D.
        • de Souza Silva P.R.
        • et al.
        Familial hypercholesterolemia in Brazil: cascade screening program, clinical and genetic aspects.
        Atherosclerosis. 2015; 238: 101-107
        • Richards S.
        • Aziz N.
        • Bale S.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of medical genetics and Genomics and the association for molecular pathology.
        Genet. Med. 2015; 17: 405-424
        • Jojo Genetics Database
        • American Academy of Family Physicians AdA
        National Council on the Aging, American Academy of Family Physicians ADA, National Council on the Aging. Nutrition screening e intervention resources for healthcare professionals working with older adults. Nutrition Screening Initiative.
        in: American Dietetic Association Washington. 2002
        • Besseling J.
        • Hovingh G.K.
        • Huijgen R.
        • Kastelein J.J.P.
        • Hutten B.A.
        Statins in familial hypercholesterolemia: consequences for coronary artery disease and all-cause mortality.
        J. Am. Coll. Cardiol. 2016; 68: 252-260
        • Hamczyk M.R.
        • Nevado R.M.
        • Barettino A.
        • Fuster V.
        • Andres V.
        Biological versus chronological aging: JACC focus seminar.
        J. Am. Coll. Cardiol. 2020; 75: 919-930
        • Besseling J.
        • Kindt I.
        • Hof M.
        • Kastelein J.J.
        • Hutten B.A.
        • Hovingh G.K.
        Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14,000 mutation carriers.
        Atherosclerosis. 2014; 233: 219-223
        • Perez de Isla L.
        • Alonso R.
        • Mata N.
        • et al.
        Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART registry (Spanish familial hypercholesterolemia cohort study).
        Circulation. 2017; 135: 2133-2144
        • Paquette M.
        • Dufour R.
        • Baass A.
        The Montreal-FH-SCORE: a new score to predict cardiovascular events in familial hypercholesterolemia.
        J Clin Lipidol. 2017; 11: 80-86
        • Gallo A.
        • Giral P.
        • Carrie A.
        • et al.
        Early coronary calcifications are related to cholesterol burden in heterozygous familial hypercholesterolemia.
        J Clin Lipidol. 2017; 11 (e702): 704-711
        • Sharifi M.
        • Higginson E.
        • Bos S.
        • et al.
        Greater preclinical atherosclerosis in treated monogenic familial hypercholesterolemia vs. polygenic hypercholesterolemia.
        Atherosclerosis. 2017; 263: 405-411
        • Trinder M.
        • Li X.
        • DeCastro M.L.
        • et al.
        Risk of premature atherosclerotic disease in patients with monogenic versus polygenic familial hypercholesterolemia.
        J. Am. Coll. Cardiol. 2019; 74: 512-522
        • Trinder M.
        • Francis G.A.
        • Brunham L.R.
        Association of monogenic vs polygenic hypercholesterolemia with risk of atherosclerotic cardiovascular disease.
        JAMA Cardiol. 2020;
        • Perez de- Isla L.
        • Alonso R.
        • Watts G.F.
        • et al.
        Attainment of LDL cholesterol treatment goals in patients with familial hypercholesterolemia at 5-year follow-up: SAFEHEART registry.
        J. Am. Coll. Cardiol. 2016; 67: 1278-1285
        • deGoma E.M.
        • Ahmad Z.S.
        • O'Brien E.C.
        • et al.
        Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: data from the CASCADE-FH registry.
        Circulation Cardiovascular genetics. 2016; 9: 240-249
        • Mach F.
        • Baigent C.
        • Catapano A.L.
        • et al.
        ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
        Eur. Heart J. 2019; 41 (2020): 111-188
        • Santos R.D.
        • Stein E.A.
        • Hovingh G.K.
        • et al.
        Long-term evolocumab in patients with familial hypercholesterolemia.
        J. Am. Coll. Cardiol. 2020; 75: 565-574
        • Ridker P.M.
        • Rose L.M.
        • Kastelein J.J.
        • et al.
        Cardiovascular event reduction with PCSK9 inhibition among 1578 patients with familial hypercholesterolemia: results from the SPIRE randomized trials of bococizumab.
        Journal of clinical lipidology. 2018; 12: 958-965
        • Shaw L.J.
        • Bairey Merz C.N.
        • Pepine C.J.
        • et al.
        Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study: Part I: gender differences in traditional and novel risk factors, symptom evaluation, and gender-optimized diagnostic strategies.
        J. Am. Coll. Cardiol. 2006; 47: S4-S20
        • Vrablik M.
        • Vaclova M.
        • Tichy L.
        • et al.
        Familial hypercholesterolemia in the Czech Republic: more than 17 years of systematic screening within the MedPed project.
        Physiol. Res. 2017; 66: S1-S9
        • Ek S.
        Gender differences in health information behaviour: a Finnish population-based survey.
        Health Promot. Int. 2015; 30: 736-745
        • Bertakis K.D.
        • Azari R.
        • Helms L.J.
        • Callahan E.J.
        • Robbins J.A.
        Gender differences in the utilization of health care services.
        J. Fam. Pract. 2000; 49: 147-152
        • Dewey F.E.
        • Gusarova V.
        • Dunbar R.L.
        • et al.
        Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease.
        N. Engl. J. Med. 2017; 377: 211-221
        • Khera A.V.
        • Emdin C.A.
        • Drake I.
        • et al.
        Genetic risk, adherence to a healthy lifestyle, and coronary disease.
        N. Engl. J. Med. 2016; 375: 2349-2358
        • Luirink I.K.
        • Wiegman A.
        • Kusters D.M.
        • et al.
        20-Year follow-up of statins in children with familial hypercholesterolemia.
        N. Engl. J. Med. 2019; 381: 1547-1556
        • Alonso R.
        • Andres E.
        • Mata N.
        • et al.
        Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation.
        J. Am. Coll. Cardiol. 2014; 63: 1982-1989