Normal LDL-Cholesterol Levels Are Associated With Subclinical Atherosclerosis in the Absence of Risk Factors

BACKGROUND Absence of cardiovascular risk factors (CVRFs) is traditionally considered low risk for atherosclerosis; however, individuals without CVRFs, as currently defined, still have events. OBJECTIVES This study sought to identify predictors of subclinical atherosclerosis in CVRF-free individuals. METHODS Participants from the PESA (Progression of Early Subclinical Atherosclerosis) study (n 1⁄4 4,184) without conventional CVRFs were evaluated (n1⁄4 1,779; 45.0 4.1 years, 50.3%women). CVRF freedomwas defined as no current smoking and untreated blood pressure <140/90 mm Hg, fasting glucose <126 mg/dl, total cholesterol <240 mg/dl, low-density lipoprotein cholesterol (LDL-C) <160 mg/dl, and high-density lipoprotein cholesterol $40 mg/dl. A subgroup with optimal CVRFs (n 1⁄4 740) was also defined as having blood pressure <120/80 mm Hg, fasting glucose <100 mg/dl, glycosylated hemoglobin <5.7%, and total cholesterol <200 mg/dl. We evaluated ultrasounddetected carotid, iliofemoral, and abdominal aortic plaques; coronary artery calcification; serum biomarkers; and lifestyle. Adjusted odds ratios (with 95% confidence interval) and ordinal logistic regression models were used. RESULTS Subclinical atherosclerosis (plaque or coronary artery calcification) was present in 49.7% of CVRF-free participants. Together with male sex and age, LDL-C was independently associated with atherosclerosis presence and extent, in both the CVRF-free and CVRF-optimal groups (odds ratio [ 10 mg/dl]: 1.14 to 1.18; p < 0.01 for all). Atherosclerosis presence and extent was also associated in the CVRF-free group with glycosylated hemoglobin levels. CONCLUSIONS Many CVRF-free middle-aged individuals have atherosclerosis. LDL-C, even at levels currently considered normal, is independently associated with the presence and extent of early systemic atherosclerosis in the absence of major CVRFs. These findings support more effective LDL-C lowering for primordial prevention, even in individuals conventionally considered at optimal risk. (Progression of Early Subclinical Atherosclerosis [PESA] Study; NCT01410318) (J Am Coll Cardiol 2017;70:2979–91) © 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). From the Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid, Spain; HM Hospitales-Centro Integral de Enfermedades Cardiovasculares, Madrid, Spain; CIBER de enfermedades CardioVasculares, Madrid, Spain; Icahn School of Medicine at Mount Sinai, New York, New York; ISPA-Hospital Universitario Central de Asturias, Oviedo, Spain; Banco de Santander, Madrid, Spain; iþ12 Research Institute and Hospital Universitario 12 de Octubre, Madrid, Spain; London School of Hygiene & Tropical Medicine, London, United Kingdom; IIS-Fundación Jiménez Díaz University Hospital, Madrid, Spain; and the Hospital Clínico San Carlos, Madrid, Spain. The PESA study is cofunded equally by the Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain, and Banco de Santander, Madrid, Spain. The study also has received funding from the Institute of Health Carlos III (PI15/02019) and the European Regional Development Fund. The CNIC is supported by the Ministry of Economy, Industry and Competitiveness (MINECO) and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Vijay Nambi, MD, served as Guest Editor for this paper. Manuscript received September 5, 2017; revised manuscript received October 5, 2017, accepted October 5, 2017. Listen to this manuscript’s audio summary by JACC Editor-in-Chief Dr. Valentin Fuster. J O U R N A L O F T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y V O L . 7 0 , N O . 2 4 , 2 0 1 7 a 2 0 1 7 T H E A U T HO R S . P U B L I S H E D B Y E L S E V I E R O N B E H A L F O F T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F OU N D A T I O N . T H I S I S A N O P E N A C C E S S A R T I C L E U N D E R T H E C C B Y N C N D L I C E N S E ( h t t p : / / c r e a t i v e c o mm o n s . o r g / l i c e n s e s / b y n c n d / 4 . 0 / ) . I S S N 0 7 3 5 1 0 9 7 h t t p s : / / d o i . o r g / 1 0 . 1 0 1 6 / j . j a c c . 2 0 1 7 . 1 0 . 0 2 4