Association Between Cigarette Smoking and Subclinical Markers of Cardiovascular Harm

Zhiqi Yao¹, Erfan Tasdighi¹, Zeina A Dardari¹, Kunal K Jha¹, Ngozi Osuji¹, Tanuja Rajan¹, Ellen Boakye², Carlos J Rodriguez³, Kunihiro Matsushita⁴, Eleanor M Simonsick⁵, Joao A C Lima⁶, Rachel Widome⁷, Debbie L Cohen⁸, Lawrence J Appel⁴, Amit Khera⁹, Michael E Hall¹⁰, Suzanne E Judd¹¹, Shelley A Cole¹², Ramachandran S Vasan¹³, Emelia J Benjamin¹⁴, Paulo A Lotufo¹⁵, Isabela M Benseñor¹⁶, Samar R El Khoudary¹⁷, Emma Barinas-Mitchell¹⁷, Imke Janssen¹⁸, Bruce M Psaty¹⁹, Charles B Eaton²⁰, Michael J LaMonte²¹, Peggy M Cawthon²², Eric S Orwoll²³, Marguerite R Irvin²⁴, Aruni Bhatnagar²⁵, Andrew P DeFilippis²⁶, Omar El-Shahaway²⁷, Michael J Blaha²⁸

Affiliations

¹ Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, Maryland, USA.
² Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, Maryland, USA; American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA.
³ American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA; Division of Cardiovascular Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
⁴ Department of Epidemiology, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁵ Intramural Research Program, National Institute on Aging, Baltimore, Maryland, USA.
⁶ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
⁷ Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota, USA.
⁸ Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁹ Division of Cardiology, UT Southwestern Medical Center, Dallas, Texas, USA.
¹⁰ American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.
¹¹ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹² Population Health Program, Texas Biomedical Research Institute, San Antonio, Texas, USA.
¹³ University of Texas School of Public Health San Antonio, San Antonio, Texas, USA.
¹⁴ American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA; Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USA.
¹⁵ Center for Clinical and Epidemiological Research, Universidade de São Paulo, São Paulo, Brazil; Department of Internal Medicine, Universidade de São Paulo, São Paulo, Brazil.
¹⁶ Department of Internal Medicine, Universidade de São Paulo, São Paulo, Brazil.
¹⁷ Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹⁸ Department of Family and Preventive Medicine, Rush University Rush Medical Center, Chicago, Illinois, USA.
¹⁹ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, Washington, USA.
²⁰ Center for Primary Care and Prevention, Department of Family Medicine and Department of Epidemiology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
²¹ Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, USA.
²² California Pacific Medical Center Research Institute, San Francisco, California, USA.
²³ Division of Endocrinology, Diabetes and Clinical Nutrition, School of Medicine, Oregon Health & Science University, Portland, Oregon, USA.
²⁴ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA.
²⁵ American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA; University of Louisville School of Medicine, Louisville, Kentucky, USA.
²⁶ American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁷ Department of Population Health, Grossman School of Medicine, New York University, New York, New York, USA; School of Global Public Health, New York University, New York, New York, USA.
²⁸ Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, Maryland, USA; American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA. Electronic address: mblaha1@jhmi.edu.

PMID: 40074467
DOI: 10.1016/j.jacc.2024.12.032

Association Between Cigarette Smoking and Subclinical Markers of Cardiovascular Harm

Zhiqi Yao et al. J Am Coll Cardiol. 2025.

. 2025 Mar 18;85(10):1018-1034.

doi: 10.1016/j.jacc.2024.12.032.

Authors

Affiliations

¹ Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, Maryland, USA.
² Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, Maryland, USA; American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA.
³ American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA; Division of Cardiovascular Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.
⁴ Department of Epidemiology, Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
⁵ Intramural Research Program, National Institute on Aging, Baltimore, Maryland, USA.
⁶ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
⁷ Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis, Minnesota, USA.
⁸ Renal-Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁹ Division of Cardiology, UT Southwestern Medical Center, Dallas, Texas, USA.
¹⁰ American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA; Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA.
¹¹ Department of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹² Population Health Program, Texas Biomedical Research Institute, San Antonio, Texas, USA.
¹³ University of Texas School of Public Health San Antonio, San Antonio, Texas, USA.
¹⁴ American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA; Department of Epidemiology, School of Public Health, Boston University, Boston, Massachusetts, USA.
¹⁵ Center for Clinical and Epidemiological Research, Universidade de São Paulo, São Paulo, Brazil; Department of Internal Medicine, Universidade de São Paulo, São Paulo, Brazil.
¹⁶ Department of Internal Medicine, Universidade de São Paulo, São Paulo, Brazil.
¹⁷ Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹⁸ Department of Family and Preventive Medicine, Rush University Rush Medical Center, Chicago, Illinois, USA.
¹⁹ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, Washington, USA.
²⁰ Center for Primary Care and Prevention, Department of Family Medicine and Department of Epidemiology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.
²¹ Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University at Buffalo, Buffalo, New York, USA.
²² California Pacific Medical Center Research Institute, San Francisco, California, USA.
²³ Division of Endocrinology, Diabetes and Clinical Nutrition, School of Medicine, Oregon Health & Science University, Portland, Oregon, USA.
²⁴ Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA.
²⁵ American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA; University of Louisville School of Medicine, Louisville, Kentucky, USA.
²⁶ American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
²⁷ Department of Population Health, Grossman School of Medicine, New York University, New York, New York, USA; School of Global Public Health, New York University, New York, New York, USA.
²⁸ Ciccarone Center for Prevention of Cardiovascular Disease, Johns Hopkins Medicine, Baltimore, Maryland, USA; American Heart Association Tobacco Regulation and Addiction Center, Dallas, Texas, USA. Electronic address: mblaha1@jhmi.edu.

PMID: 40074467
DOI: 10.1016/j.jacc.2024.12.032

Abstract

Background: Cigarette smoking is a strong risk factor for cardiovascular harm.

Objectives: The study sought to explore the detailed relationships between smoking intensity, pack-years, and time since cessation with inflammation, thrombosis, and subclinical atherosclerosis markers of cardiovascular harm.

Methods: We included 182,364 participants (mean age 58.2 years, 69.0% female) from 22 cohorts of the Cross Cohort Collaboration with self-reported smoking status, including smoking intensity and/or pack-years, and concurrent subclinical marker measurements. Markers were categorized into 3 domains: inflammation (high-sensitivity C-reactive protein, interleukin-6, glycoprotein acetylation), thrombosis (fibrinogen, D-dimer), and subclinical atherosclerosis (coronary artery calcium, carotid intima-media thickness, carotid plaque, and ankle-brachial index). Utilizing multivariate regression models and restricted cubic splines, we assessed associations of smoking status, intensity, pack-years, time since cessation, and subclinical markers.

Results: A total of 15.3% of participants currently smoke (mean 16.7 cigarettes/day, mean 30.0 pack-years), and 34.6% of participants formerly smoked (median 19.0 years since quitting, mean 22.4 pack-years). Participants with a history of smoking showed higher levels of all subclinical markers compared with those who have never smoked, with stronger associations observed in those currently smoke. Among participants who currently smoke, smoking intensity showed a clear dose-response relationship with all markers, except for D-dimer, specifically with incremental 1% to 9% higher levels of subclinical markers per 10 cigarettes. After 20 cigarettes, the patterns appeared to plateau for blood markers, while they continued to increase for atherosclerosis markers. Among those who have ever smoked, robust dose-response relationships were observed for pack-years with all subclinical markers, with incremental 1% to 9% higher levels per 10 pack-years. The dose-response effects persisted after 20 pack-years for all markers, though with a milder slope. Among participants who smoked formerly, there were substantially lower levels of biomarkers with longer time since quitting, and most markers were not different compared with those who have never smoked by 30 years, except for the coronary artery calcium score, which remained 19% higher even beyond quitting after 30 years.

Conclusions: Smoking-relevant parameters show strong and dose-response relationships across 3 domains of subclinical markers of cardiovascular harm. The sensitivity of the tested subclinical markers to small increments in cigarette exposure suggests potential value in the regulation of new and existing tobacco products.

Keywords: cardiovascular harm; cigarette smoking; inflammation; subclinical atherosclerosis; subclinical marker; thrombosis.

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Conflict of interest statement

Funding Support and Author Disclosures CCC-Tobacco is funded by National Heart, Lung, and Blood Institute (NHLBI) and the Food and Drug Administration Center for Tobacco Products, award U54HL120163. The Atherosclerosis Risk in Communities study has been funded in whole or in part with federal funds from the NHLBI, National Institutes of Health (NIH), Department of Health and Human Services (contract nos. 75N92022D00001, 75N92022D00002, 75N92022D00003, 75N92022D00004, 75N92022D00005). The Baltimore Longitudinal Study of Aging was supported in part by the Intramural Research Program of the National Institute on Aging (NIA). The Baltimore Longitudinal Study of Aging protocol number was 03-AG-0325. The Coronary Artery Risk Development in Young Adults Study is supported by the NHLBI in collaboration with the University of Alabama at Birmingham (75N92023D00002 and 75N92023D00005), Northwestern University (75N92023D00004), University of Minnesota (75N92023D00006), and Kaiser Foundation Research Institute (75N92023D00003). The Cardiovascular Health Study was supported by contracts HHSN268201200036C, HHSN268200800007C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and 75N92021D00006, and grants U01HL080295 and U01HL130114 from the NHLBI, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided by R01AG023629 from the NIA. A full list of principal Cardiovascular Health Study investigators and institutions can be found at CHS-NHLBI.org. Funding for the Chronic Renal Insufficiency Cohort was obtained under a cooperative agreement from National Institute of Diabetes and Digestive and Kidney Diseases (U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902 and U24DK060990). In addition, this work was supported in part by the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award NIH/National Center for Advancing Translational Sciences (NCATS) (UL1TR000003), Johns Hopkins University (UL1 TR-000424), the University of Maryland General Clinical Research Center (M01 RR-16500), Clinical and Translational Science Collaborative of Cleveland (UL1TR000439) from the NCATS component of the NIH and NIH roadmap for Medical Research, the Michigan Institute for Clinical and Health Research (UL1TR000433), the University of Illinois at Chicago (Clinical and Translational Science Award UL1RR029879), Tulane COBRE for Clinical and Translational Research in Cardiometabolic Diseases (P20 GM109036), Kaiser Permanente NIH/National Center for Research Resources UCSF Clinical and Translational Science Institute (UL1 RR-024131), and the Department of Internal Medicine of the University of New Mexico School of Medicine (R01DK119199). The Dallas Heart Study received support from grants provided by the Donald W. Reynolds Foundation and the NCATS, specifically under grant number UL1TR001105. The Framingham Heart Study (FHS), encompassing the FHS Offspring study, and the third-generation study, receives support through contracts NO1-HC-25195, HHSN268201500001I, and 75N92019D00031 from the NHLBI and R01 HL076784. The ELSA-Brasil (Brazilian Longitudinal Study of Adult Health) baseline study was supported by the Brazilian Ministry of Health (Science and Technology Department) and the Brazilian Ministry of Science and Technology (Financiadora de Estudos e Projetos and CNPq National Research Council) (grants 01 06 0010.00 RS, 01 06 0212.00 BA, 01 06 0300.00 ES, 01 06 0278.00 MG, 01 06 0115.00 SP, 01 06 0071.00 RJ). The GOLDN (Genetics of Lipid Lowering Drugs and Diet Network Lipidomics) study was funded by grant HL091357 from the National Heart, Lung, and Blood Institute. The HAPI Heart Study was supported by research grants P30DK072488, U01HL072515, and U01HL084756 from the NIH. The Health, Aging and Body Composition Study was funded by the American Diabetes Association–Association of Subspecialty Professors Young Investigator Innovation Award in Geriatric Endocrinology, sponsored by the Atlantic Philanthropies, the American Diabetes Association, the John A. Hartford Foundation, and the Association of Subspecialty. Additionally, funding was provided by an American Heart Association Fellow to Faculty Transition Award and contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106, along with support from the Intramural Research Program of the NIA. The Hispanic Community Health Study/Study of Latinos is a collaborative study supported by contracts from the NHLBI to the University of North Carolina (HHSN268201300001I/N01-HC-65233), University of Miami (HHSN268201300004I/N01-HC-65234), Albert Einstein College of Medicine (HHSN268201300002I/N01-HC-65235), University of Illinois at Chicago (HHSN268201300003I/N01-HC-65236 Northwestern University), and San Diego State University (HHSN268201300005I/N01-HC-65237). The Jackson Heart Study is supported and conducted in collaboration with Jackson State University (HHSN268201800013I), Tougaloo College (HHSN268201800014I), Mississippi State Department of Health (HHSN268201800015I), and University of Mississippi Medical Center (HHSN268201800010I, HHSN268201800011I, and HHSN268201800012I) contracts from the NHLBI and the National Institute on Minority Health and Health Disparities. The MESA (Multi-Ethnic Study of Atherosclerosis) study received support from contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the NHLBI, supplemented by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the NCATS. The MrOS (Osteoporotic Fractures in Men Study) study is supported by NIH funding. The following institutes provide support the NIA, the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the NCATS (grant nos. U01 AG027810, U01 AG042124, U01 AG042139, U01 AG042140, U01 AG042143, U01 AG042145, U01 AG042168, U01 AR066160, R01 AG066671, and UL1 TR002369). The REGARDS (REasons for Geographic and Racial Differences in Stroke) study is sustained through a cooperative agreement (U01 NS041588) co-funded by the National Institute of Neurological Disorders and Stroke and the NIA. The Rancho Bernardo Study obtained funding from research grants AG028507 and AG07181 from the NIA, along with grant DK31801 from the National Institute of Diabetes and Digestive and Kidney Diseases. The Strong Heart Study has received funding, either wholly or partially, from federal allocations provided by the NHLBI, NIH, and Department of Health and Human Services, identified by contract numbers 75N92019D00027, 75N92019D00028, 75N92019D00029, and 75N92019D00030. Previously, the study benefited from research grants, including R01HL109315, R01HL109301, R01HL109284, R01HL109282, and R01HL109319, as well as from cooperative agreements such as U01HL41642, U01HL41652, U01HL41654, U01HL65520, and U01HL65521. The Study of Osteoporotic Fractures is supported by NIH funding. The NIA provides support under the following grant numbers: R01 AG005407, R01 AR35582, R01 AR35583, R01 AR35584, R01 AG005394, R01 AG027574, and R01 AG027576. The SWAN (Study of Women's Health Across the Nation) study has grant support from the NIH, Department of Health and Human Services, through the NIA, the National Institute of Nursing Research, and the NIH Office of Research on Women's Health (grants U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG 012553, U01AG012554, U01AG012495, and U19AG063720), and the SWAN repository (U01AG017719). The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIA, National Institute of Nursing Research, Office of Research on Women's Health, or NIH. The Women Health Initiative program is funded by the NHLBI, NIH, and Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Dr Blaha has served on advisory board for Novo Nordisk, Bayer, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Genentech, Idorsia, Agepha, Vectura, and New Amsterdam. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

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Association Between Cigarette Smoking and Subclinical Markers of Cardiovascular Harm

Affiliations

Association Between Cigarette Smoking and Subclinical Markers of Cardiovascular Harm

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Research Materials