Prospective Associations of Obesity and Obesity Severity With 9 Cardiovascular Outcomes: The Cross-Cohort Collaboration

Zeina A. Dardari; Zhiqi Yao; Jianjun Zhang; Giorgos Bakoyannis; Hongmei Nan; Lisa K. Staten; Kunal K. Jha; Erfan Tasdighi; Yara Jelwan; Semenawit Burka; Kunihiro Matsushita; Eleanor M. Simonsick; Joao A.C. Lima; Bruce M. Psaty; Debbie L. Cohen; Lawrence J. Appel; Amit Khera; Amil M. Shah; Michael E. Hall; Suzanne E. Judd; Shelley A. Cole; Ramachandran S. Vasan; Emelia J. Benjamin; Peggy M. Cawthon; Eric Orwoll; Michael J. LaMonte; Charles B. Eaton; Samar R. El Khoudary; Rebecca C. Thurston; Carol A. Derby; Paulo A. Lotufo; Isabela M. Bensenor; Márcio Sommer Bittencourt; Michael J. Blaha

doi:10.1161/CIRCULATIONAHA.125.075327

Prospective Associations of Obesity and Obesity Severity With 9 Cardiovascular Outcomes: The Cross-Cohort Collaboration

Zeina A. Dardari
, Zhiqi Yao
, Jianjun Zhang
, Giorgos Bakoyannis
, Hongmei Nan
, Lisa K. Staten
, Kunal K. Jha
, Erfan Tasdighi
, Yara Jelwan
, Semenawit Burka
, Kunihiro Matsushita
, Eleanor M. Simonsick
, Joao A.C. Lima
, Bruce M. Psaty
, Debbie L. Cohen
, Lawrence J. Appel
, Amit Khera
, Amil M. Shah
, Michael E. Hall
, Suzanne E. Judd

Shelley A. Cole, Ramachandran S. Vasan, Emelia J. Benjamin, Peggy M. Cawthon, Eric Orwoll, Michael J. LaMonte, Charles B. Eaton, Samar R. El Khoudary, Rebecca C. Thurston, Carol A. Derby, Paulo A. Lotufo, Isabela M. Bensenor, Márcio Sommer Bittencourt, Michael J. Blaha

Department of Epidemiology and Environmental Health

Johns Hopkins University
Indiana University-Purdue University Indianapolis
University of Louisville
Rutgers - The State University of New Jersey, New Brunswick
National Institutes of Health
University of Washington
University of Pennsylvania
University of Texas Southwestern Medical Center
University of Mississippi
American Heart Association
University of Alabama at Birmingham
Southwest Foundation for Biomedical Research
University of Texas School of Public Health San Antonio
Boston University
University of California at San Francisco
Oregon Health and Science University
Brown University
University of Pittsburgh
Albert Einstein College of Medicine
Universidade de São Paulo

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

BACKGROUND: – Obesity is an established risk factor for cardiovascular disease (CVD); however, the overall and sex-specific relationships across the full spectrum of body mass index (BMI), particularly severe obesity defined as class 2 (BMI 35 to <40.0 kg/m²) and class 3 (BMI ≥40 kg/m²), and long-term CVD outcomes remain incompletely described. METHODS: – We included 289 875 participants (mean age, 60.3 years; 79.2% women) from 21 cohorts of the Cross-Cohort Collaboration enrolled between 1948 and 2015 with harmonized BMI data, a BMI ≥18.5 kg/m², and at least one of nine adjudicated outcomes: time to first fatal and non-fatal myocardial infarction (MI), fatal and nonfatal stroke, heart failure (HF), atrial fibrillation (AF), total coronary heart disease (CHD), total CVD, CHD mortality, CVD mortality, and all-cause mortality. Multivariable Cox proportional hazard models with restricted cubic splines were used to estimate the hazard ratio (HR) of BMI for each outcome, adjusting for demographic and clinical risk factors. RESULTS: – Over 19.2 median years (25th, 11.6; 75th, 23.5 percentile) of follow-up, there were a total of 15 542 incident MI events, 15 467 incident stroke events, 14 172 incident HF events, 9066 diagnosed AF, and 113 918 total deaths, of which 14 647 were CHD-related and 28 879 were CVD-related. Overall, compared with individuals with normal weight, those with class 2 and class 3 obesity had the highest risk of HF (HR, 2.1, 95% CI, 2.0–2.3, and HR, 3.0, 95% CI, 2.7–3.2, respectively) and AF (HR, 1.8, 95% CI 1.7–2.0, and HR, 2.8, 95% CI, 2.5–3.1, respectively). Compared with men, women experienced higher relative increases in the risk associated with severe obesity for outcomes stroke, CVD, and all-cause mortality (P for interaction: <0.001, 0.003, and <0.001, respectively). Furthermore, in men, no increase in stroke risk was observed with higher BMI categories (P trend=0.49), whereas in women, the risk of stroke plateaued across obesity subclasses (compared with normal weight) yet remained significantly increased. CONCLUSIONS: – Higher BMI was robustly associated with increased risk for most outcomes, particularly HF and AF, even after adjusting for traditional risk factors. Observed sex differences in the relative hazard of higher BMI categories and stroke, total CVD, and all-cause mortality suggest potential differences in underlying biological mechanisms.

Original language	English
Journal	Circulation
Volume	Publish Ahead of Print
DOIs	https://doi.org/10.1161/CIRCULATIONAHA.125.075327
State	Published - Feb 12 2026

Keywords

cardiovascular disease
cross-cohort collaboration
obesity

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10.1161/CIRCULATIONAHA.125.075327

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Dardari, Z. A., Yao, Z., Zhang, J., Bakoyannis, G., Nan, H., Staten, L. K., Jha, K. K., Tasdighi, E., Jelwan, Y., Burka, S., Matsushita, K., Simonsick, E. M., Lima, J. A. C., Psaty, B. M., Cohen, D. L., Appel, L. J., Khera, A., Shah, A. M., Hall, M. E., ... Blaha, M. J. (2026). Prospective Associations of Obesity and Obesity Severity With 9 Cardiovascular Outcomes: The Cross-Cohort Collaboration. Circulation, Publish Ahead of Print. https://doi.org/10.1161/CIRCULATIONAHA.125.075327

@article{c787e98113bc4a4b9783f59083b4929d,

title = "Prospective Associations of Obesity and Obesity Severity With 9 Cardiovascular Outcomes: The Cross-Cohort Collaboration",

abstract = "BACKGROUND: – Obesity is an established risk factor for cardiovascular disease (CVD); however, the overall and sex-specific relationships across the full spectrum of body mass index (BMI), particularly severe obesity defined as class 2 (BMI 35 to <40.0 kg/m2) and class 3 (BMI ≥40 kg/m2), and long-term CVD outcomes remain incompletely described. METHODS: – We included 289 875 participants (mean age, 60.3 years; 79.2\% women) from 21 cohorts of the Cross-Cohort Collaboration enrolled between 1948 and 2015 with harmonized BMI data, a BMI ≥18.5 kg/m2, and at least one of nine adjudicated outcomes: time to first fatal and non-fatal myocardial infarction (MI), fatal and nonfatal stroke, heart failure (HF), atrial fibrillation (AF), total coronary heart disease (CHD), total CVD, CHD mortality, CVD mortality, and all-cause mortality. Multivariable Cox proportional hazard models with restricted cubic splines were used to estimate the hazard ratio (HR) of BMI for each outcome, adjusting for demographic and clinical risk factors. RESULTS: – Over 19.2 median years (25th, 11.6; 75th, 23.5 percentile) of follow-up, there were a total of 15 542 incident MI events, 15 467 incident stroke events, 14 172 incident HF events, 9066 diagnosed AF, and 113 918 total deaths, of which 14 647 were CHD-related and 28 879 were CVD-related. Overall, compared with individuals with normal weight, those with class 2 and class 3 obesity had the highest risk of HF (HR, 2.1, 95\% CI, 2.0–2.3, and HR, 3.0, 95\% CI, 2.7–3.2, respectively) and AF (HR, 1.8, 95\% CI 1.7–2.0, and HR, 2.8, 95\% CI, 2.5–3.1, respectively). Compared with men, women experienced higher relative increases in the risk associated with severe obesity for outcomes stroke, CVD, and all-cause mortality (P for interaction: <0.001, 0.003, and <0.001, respectively). Furthermore, in men, no increase in stroke risk was observed with higher BMI categories (P trend=0.49), whereas in women, the risk of stroke plateaued across obesity subclasses (compared with normal weight) yet remained significantly increased. CONCLUSIONS: – Higher BMI was robustly associated with increased risk for most outcomes, particularly HF and AF, even after adjusting for traditional risk factors. Observed sex differences in the relative hazard of higher BMI categories and stroke, total CVD, and all-cause mortality suggest potential differences in underlying biological mechanisms.",

keywords = "cardiovascular disease, cross-cohort collaboration, obesity",

author = "Dardari, \{Zeina A.\} and Zhiqi Yao and Jianjun Zhang and Giorgos Bakoyannis and Hongmei Nan and Staten, \{Lisa K.\} and Jha, \{Kunal K.\} and Erfan Tasdighi and Yara Jelwan and Semenawit Burka and Kunihiro Matsushita and Simonsick, \{Eleanor M.\} and Lima, \{Joao A.C.\} and Psaty, \{Bruce M.\} and Cohen, \{Debbie L.\} and Appel, \{Lawrence J.\} and Amit Khera and Shah, \{Amil M.\} and Hall, \{Michael E.\} and Judd, \{Suzanne E.\} and Cole, \{Shelley A.\} and Vasan, \{Ramachandran S.\} and Benjamin, \{Emelia J.\} and Cawthon, \{Peggy M.\} and Eric Orwoll and LaMonte, \{Michael J.\} and Eaton, \{Charles B.\} and \{El Khoudary\}, \{Samar R.\} and Thurston, \{Rebecca C.\} and Derby, \{Carol A.\} and Lotufo, \{Paulo A.\} and Bensenor, \{Isabela M.\} and Bittencourt, \{M{\'a}rcio Sommer\} and Blaha, \{Michael J.\}",

note = "Publisher Copyright: {\textcopyright} 2026 American Heart Association, Inc.",

year = "2026",

month = feb,

day = "12",

doi = "10.1161/CIRCULATIONAHA.125.075327",

language = "English",

volume = "Publish Ahead of Print",

journal = "Circulation",

issn = "0009-7322",

publisher = "Lippincott Williams and Wilkins",

}

Dardari, ZA, Yao, Z, Zhang, J, Bakoyannis, G, Nan, H, Staten, LK, Jha, KK, Tasdighi, E, Jelwan, Y, Burka, S, Matsushita, K, Simonsick, EM, Lima, JAC, Psaty, BM, Cohen, DL, Appel, LJ, Khera, A, Shah, AM, Hall, ME, Judd, SE, Cole, SA, Vasan, RS, Benjamin, EJ, Cawthon, PM, Orwoll, E, LaMonte, MJ, Eaton, CB, El Khoudary, SR, Thurston, RC, Derby, CA, Lotufo, PA, Bensenor, IM, Bittencourt, MS & Blaha, MJ 2026, 'Prospective Associations of Obesity and Obesity Severity With 9 Cardiovascular Outcomes: The Cross-Cohort Collaboration', Circulation, vol. Publish Ahead of Print. https://doi.org/10.1161/CIRCULATIONAHA.125.075327

TY - JOUR

T1 - Prospective Associations of Obesity and Obesity Severity With 9 Cardiovascular Outcomes

T2 - The Cross-Cohort Collaboration

AU - Dardari, Zeina A.

AU - Yao, Zhiqi

AU - Zhang, Jianjun

AU - Bakoyannis, Giorgos

AU - Nan, Hongmei

AU - Staten, Lisa K.

AU - Jha, Kunal K.

AU - Tasdighi, Erfan

AU - Jelwan, Yara

AU - Burka, Semenawit

AU - Matsushita, Kunihiro

AU - Simonsick, Eleanor M.

AU - Lima, Joao A.C.

AU - Psaty, Bruce M.

AU - Cohen, Debbie L.

AU - Appel, Lawrence J.

AU - Khera, Amit

AU - Shah, Amil M.

AU - Hall, Michael E.

AU - Judd, Suzanne E.

AU - Cole, Shelley A.

AU - Vasan, Ramachandran S.

AU - Benjamin, Emelia J.

AU - Cawthon, Peggy M.

AU - Orwoll, Eric

AU - LaMonte, Michael J.

AU - Eaton, Charles B.

AU - El Khoudary, Samar R.

AU - Thurston, Rebecca C.

AU - Derby, Carol A.

AU - Lotufo, Paulo A.

AU - Bensenor, Isabela M.

AU - Bittencourt, Márcio Sommer

AU - Blaha, Michael J.

PY - 2026/2/12

Y1 - 2026/2/12

N2 - BACKGROUND: – Obesity is an established risk factor for cardiovascular disease (CVD); however, the overall and sex-specific relationships across the full spectrum of body mass index (BMI), particularly severe obesity defined as class 2 (BMI 35 to <40.0 kg/m2) and class 3 (BMI ≥40 kg/m2), and long-term CVD outcomes remain incompletely described. METHODS: – We included 289 875 participants (mean age, 60.3 years; 79.2% women) from 21 cohorts of the Cross-Cohort Collaboration enrolled between 1948 and 2015 with harmonized BMI data, a BMI ≥18.5 kg/m2, and at least one of nine adjudicated outcomes: time to first fatal and non-fatal myocardial infarction (MI), fatal and nonfatal stroke, heart failure (HF), atrial fibrillation (AF), total coronary heart disease (CHD), total CVD, CHD mortality, CVD mortality, and all-cause mortality. Multivariable Cox proportional hazard models with restricted cubic splines were used to estimate the hazard ratio (HR) of BMI for each outcome, adjusting for demographic and clinical risk factors. RESULTS: – Over 19.2 median years (25th, 11.6; 75th, 23.5 percentile) of follow-up, there were a total of 15 542 incident MI events, 15 467 incident stroke events, 14 172 incident HF events, 9066 diagnosed AF, and 113 918 total deaths, of which 14 647 were CHD-related and 28 879 were CVD-related. Overall, compared with individuals with normal weight, those with class 2 and class 3 obesity had the highest risk of HF (HR, 2.1, 95% CI, 2.0–2.3, and HR, 3.0, 95% CI, 2.7–3.2, respectively) and AF (HR, 1.8, 95% CI 1.7–2.0, and HR, 2.8, 95% CI, 2.5–3.1, respectively). Compared with men, women experienced higher relative increases in the risk associated with severe obesity for outcomes stroke, CVD, and all-cause mortality (P for interaction: <0.001, 0.003, and <0.001, respectively). Furthermore, in men, no increase in stroke risk was observed with higher BMI categories (P trend=0.49), whereas in women, the risk of stroke plateaued across obesity subclasses (compared with normal weight) yet remained significantly increased. CONCLUSIONS: – Higher BMI was robustly associated with increased risk for most outcomes, particularly HF and AF, even after adjusting for traditional risk factors. Observed sex differences in the relative hazard of higher BMI categories and stroke, total CVD, and all-cause mortality suggest potential differences in underlying biological mechanisms.

AB - BACKGROUND: – Obesity is an established risk factor for cardiovascular disease (CVD); however, the overall and sex-specific relationships across the full spectrum of body mass index (BMI), particularly severe obesity defined as class 2 (BMI 35 to <40.0 kg/m2) and class 3 (BMI ≥40 kg/m2), and long-term CVD outcomes remain incompletely described. METHODS: – We included 289 875 participants (mean age, 60.3 years; 79.2% women) from 21 cohorts of the Cross-Cohort Collaboration enrolled between 1948 and 2015 with harmonized BMI data, a BMI ≥18.5 kg/m2, and at least one of nine adjudicated outcomes: time to first fatal and non-fatal myocardial infarction (MI), fatal and nonfatal stroke, heart failure (HF), atrial fibrillation (AF), total coronary heart disease (CHD), total CVD, CHD mortality, CVD mortality, and all-cause mortality. Multivariable Cox proportional hazard models with restricted cubic splines were used to estimate the hazard ratio (HR) of BMI for each outcome, adjusting for demographic and clinical risk factors. RESULTS: – Over 19.2 median years (25th, 11.6; 75th, 23.5 percentile) of follow-up, there were a total of 15 542 incident MI events, 15 467 incident stroke events, 14 172 incident HF events, 9066 diagnosed AF, and 113 918 total deaths, of which 14 647 were CHD-related and 28 879 were CVD-related. Overall, compared with individuals with normal weight, those with class 2 and class 3 obesity had the highest risk of HF (HR, 2.1, 95% CI, 2.0–2.3, and HR, 3.0, 95% CI, 2.7–3.2, respectively) and AF (HR, 1.8, 95% CI 1.7–2.0, and HR, 2.8, 95% CI, 2.5–3.1, respectively). Compared with men, women experienced higher relative increases in the risk associated with severe obesity for outcomes stroke, CVD, and all-cause mortality (P for interaction: <0.001, 0.003, and <0.001, respectively). Furthermore, in men, no increase in stroke risk was observed with higher BMI categories (P trend=0.49), whereas in women, the risk of stroke plateaued across obesity subclasses (compared with normal weight) yet remained significantly increased. CONCLUSIONS: – Higher BMI was robustly associated with increased risk for most outcomes, particularly HF and AF, even after adjusting for traditional risk factors. Observed sex differences in the relative hazard of higher BMI categories and stroke, total CVD, and all-cause mortality suggest potential differences in underlying biological mechanisms.

KW - cardiovascular disease

KW - cross-cohort collaboration

KW - obesity

UR - https://www.scopus.com/pages/publications/105032994438

U2 - 10.1161/CIRCULATIONAHA.125.075327

DO - 10.1161/CIRCULATIONAHA.125.075327

M3 - Article

C2 - 41674444

AN - SCOPUS:105032994438

SN - 0009-7322

VL - Publish Ahead of Print

JO - Circulation

JF - Circulation

ER -

Prospective Associations of Obesity and Obesity Severity With 9 Cardiovascular Outcomes: The Cross-Cohort Collaboration

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