Amanda M Perak1, Hongyan Ning1, Sarah D de Ferranti1, Holly C Gooding1, John T Wilkins1, Donald M Lloyd-Jones2. 1. From Division of Cardiology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago (A.M.P.), Department of Preventive Medicine (A.M.P., H.N., J.T.W., D.M.L.-J.), and Division of Cardiology, Department of Medicine (J.T.W., D.M.L.-J.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Cardiology, Boston Children's Hospital, Harvard Medical School, MA (S.D.d.F.); and Division of Adolescent and Young Adult Medicine, Boston Children's Hospital, Harvard Medical School, MA (H.C.G.). 2. From Division of Cardiology, Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago (A.M.P.), Department of Preventive Medicine (A.M.P., H.N., J.T.W., D.M.L.-J.), and Division of Cardiology, Department of Medicine (J.T.W., D.M.L.-J.), Northwestern University Feinberg School of Medicine, Chicago, IL; Department of Cardiology, Boston Children's Hospital, Harvard Medical School, MA (S.D.d.F.); and Division of Adolescent and Young Adult Medicine, Boston Children's Hospital, Harvard Medical School, MA (H.C.G.). dlj@northwestern.edu.
Abstract
BACKGROUND: Heterozygous familial hypercholesterolemia (FH) affects up to 1 in 200 individuals in the United States, but atherosclerotic cardiovascular disease (ASCVD) outcomes of FH in the general US population have not been described. We therefore sought to evaluate long-term coronary heart disease (CHD) and total ASCVD risks in US adults with an FH phenotype. METHODS: Using individual pooled data from 6 large US epidemiological cohorts, we stratified participants by low-density lipoprotein cholesterol level at index ages from 20 to 79 years. For the primary analysis, low-density lipoprotein cholesterol levels ≥190 and <130 mg/dL defined the FH phenotype and referent, respectively. Sensitivity analyses evaluated the effects of varying the FH phenotype definition. We used Cox regression models to assess covariate-adjusted associations of the FH phenotype with 30-year hazards for CHD (CHD death or nonfatal myocardial infarction) and total ASCVD (CHD or stroke). RESULTS: We included 68 565 baseline person-examinations; 3850 (5.6%) had the FH phenotype by the primary definition. Follow-up across index ages ranged from 78 985 to 308 378 person-years. After covariate adjustment, the FH phenotype was associated with substantially elevated 30-year CHD risk, with hazard ratios up to 5.0 (95% confidence interval, 1.1-21.7). Across index ages, CHD risk was accelerated in those with the FH phenotype by 10 to 20 years in men and 20 to 30 years in women. Similar patterns of results were found for total ASCVD risk, with hazard ratios up to 4.1 (95% confidence interval, 1.2-13.4). Alternative FH phenotype definitions incorporating family history, more stringent age-based low-density lipoprotein cholesterol thresholds, or alternative lipid fractions decreased the FH phenotype prevalence to as low as 0.2% to 0.4% without materially affecting CHD risk estimates (hazard ratios up to 8.0; 95% confidence interval, 1.0-61.6). CONCLUSIONS: In the general US population, the long-term ASCVD burden related to phenotypic FH, defined by low-density lipoprotein cholesterol ≥190 mg/dL, is likely substantial. Our finding of CHD risk acceleration may aid efforts in risk communication.
BACKGROUND: Heterozygous familial hypercholesterolemia (FH) affects up to 1 in 200 individuals in the United States, but atherosclerotic cardiovascular disease (ASCVD) outcomes of FH in the general US population have not been described. We therefore sought to evaluate long-term coronary heart disease (CHD) and total ASCVD risks in US adults with an FH phenotype. METHODS: Using individual pooled data from 6 large US epidemiological cohorts, we stratified participants by low-density lipoprotein cholesterol level at index ages from 20 to 79 years. For the primary analysis, low-density lipoprotein cholesterol levels ≥190 and <130 mg/dL defined the FH phenotype and referent, respectively. Sensitivity analyses evaluated the effects of varying the FH phenotype definition. We used Cox regression models to assess covariate-adjusted associations of the FH phenotype with 30-year hazards for CHD (CHD death or nonfatal myocardial infarction) and total ASCVD (CHD or stroke). RESULTS: We included 68 565 baseline person-examinations; 3850 (5.6%) had the FH phenotype by the primary definition. Follow-up across index ages ranged from 78 985 to 308 378 person-years. After covariate adjustment, the FH phenotype was associated with substantially elevated 30-year CHD risk, with hazard ratios up to 5.0 (95% confidence interval, 1.1-21.7). Across index ages, CHD risk was accelerated in those with the FH phenotype by 10 to 20 years in men and 20 to 30 years in women. Similar patterns of results were found for total ASCVD risk, with hazard ratios up to 4.1 (95% confidence interval, 1.2-13.4). Alternative FH phenotype definitions incorporating family history, more stringent age-based low-density lipoprotein cholesterol thresholds, or alternative lipid fractions decreased the FH phenotype prevalence to as low as 0.2% to 0.4% without materially affecting CHD risk estimates (hazard ratios up to 8.0; 95% confidence interval, 1.0-61.6). CONCLUSIONS: In the general US population, the long-term ASCVD burden related to phenotypic FH, defined by low-density lipoprotein cholesterol ≥190 mg/dL, is likely substantial. Our finding of CHD risk acceleration may aid efforts in risk communication.
Authors: John T Wilkins; Kunal N Karmali; Mark D Huffman; Norrina B Allen; Hongyan Ning; Jarett D Berry; Daniel B Garside; Alan Dyer; Donald M Lloyd-Jones Journal: Int J Epidemiol Date: 2015-08-14 Impact factor: 7.196
Authors: Roberta E Goldman; Donna R Parker; Charles B Eaton; Jeffrey M Borkan; Robert Gramling; Rebecca T Cover; David K Ahern Journal: Ann Fam Med Date: 2006 May-Jun Impact factor: 5.166
Authors: Emil M deGoma; Zahid S Ahmad; Emily C O'Brien; Iris Kindt; Peter Shrader; Connie B Newman; Yashashwi Pokharel; Seth J Baum; Linda C Hemphill; Lisa C Hudgins; Catherine D Ahmed; Samuel S Gidding; Danielle Duffy; William Neal; Katherine Wilemon; Matthew T Roe; Daniel J Rader; Christie M Ballantyne; MacRae F Linton; P Barton Duell; Michael D Shapiro; Patrick M Moriarty; Joshua W Knowles Journal: Circ Cardiovasc Genet Date: 2016-03-24
Authors: Anne C Goldberg; Jennifer G Robinson; William C Cromwell; Joyce L Ross; Paul E Ziajka Journal: J Clin Lipidol Date: 2011-04-08 Impact factor: 4.766
Authors: Børge G Nordestgaard; M John Chapman; Steve E Humphries; Henry N Ginsberg; Luis Masana; Olivier S Descamps; Olov Wiklund; Robert A Hegele; Frederick J Raal; Joep C Defesche; Albert Wiegman; Raul D Santos; Gerald F Watts; Klaus G Parhofer; G Kees Hovingh; Petri T Kovanen; Catherine Boileau; Maurizio Averna; Jan Borén; Eric Bruckert; Alberico L Catapano; Jan Albert Kuivenhoven; Päivi Pajukanta; Kausik Ray; Anton F H Stalenhoef; Erik Stroes; Marja-Riitta Taskinen; Anne Tybjærg-Hansen Journal: Eur Heart J Date: 2013-08-15 Impact factor: 29.983
Authors: Jorie Versmissen; Daniëlla M Oosterveer; Mojgan Yazdanpanah; Joep C Defesche; Dick C G Basart; Anho H Liem; Jan Heeringa; Jacqueline C Witteman; Peter J Lansberg; John J P Kastelein; Eric J G Sijbrands Journal: BMJ Date: 2008-11-11
Authors: Emily M Bucholz; Angie Mae Rodday; Katherine Kolor; Muin J Khoury; Sarah D de Ferranti Journal: Circulation Date: 2018-03-26 Impact factor: 29.690
Authors: Katrina L Ellis; Jing Pang; David Chieng; Damon A Bell; John R Burnett; Carl J Schultz; Graham S Hillis; Gerald F Watts Journal: Clin Cardiol Date: 2018-02-26 Impact factor: 2.882
Authors: Salim S Virani; Kevin F Kennedy; Julia M Akeroyd; Pamela B Morris; Vera A Bittner; Frederick A Masoudi; Neil J Stone; Laura A Petersen; Christie M Ballantyne Journal: Circ Cardiovasc Qual Outcomes Date: 2018-05
Authors: Donna K Arnett; Roger S Blumenthal; Michelle A Albert; Andrew B Buroker; Zachary D Goldberger; Ellen J Hahn; Cheryl Dennison Himmelfarb; Amit Khera; Donald Lloyd-Jones; J William McEvoy; Erin D Michos; Michael D Miedema; Daniel Muñoz; Sidney C Smith; Salim S Virani; Kim A Williams; Joseph Yeboah; Boback Ziaeian Journal: J Am Coll Cardiol Date: 2019-03-17 Impact factor: 24.094