Muhammad Hammadah1, Ibhar Al Mheid1, Kobina Wilmot1, Ronnie Ramadan1, Naser Abdelhadi1, Ayman Alkhoder1, Malik Obideen1, Pratik M Pimple1, Oleksiy Levantsevych1, Heval M Kelli1, Amit Shah1, Yan V Sun1, Brad Pearce1, Michael Kutner1, Qi Long1, Laura Ward1, Yi-An Ko1, Kareem Hosny Mohammed1, Jue Lin1, Jinying Zhao1, J Douglas Bremner1, Jinhee Kim1, Edmund K Waller1, Paolo Raggi1, David Sheps1, Arshed A Quyyumi1, Viola Vaccarino2. 1. From the Division of Cardiology, Department of Medicine (M.H., I.A.M., K.W., R.R., N.A., A.A., M.O., H.M.K., A.S., K.H.M., A.A.Q., V.V.) and Department of Psychiatry and Behavioral Sciences (J.D.B.), Emory University School of Medicine, Atlanta, GA; Department of Epidemiology, Rollins School of Public Health (P.M.P., O.L., A.S., Y.V.S., B.P., V.V.), Department of Biostatistics and Bioinformatics, Rollins School of Public Health (Y.V.S., M.K., Q.L., L.W., Y.-A.K.), and Department of Hematology and Oncology, Winship Cancer Institute (J.K., E.K.W.), Emory University, Atlanta, GA; Department of Biochemistry and Biophysics, University of California, San Francisco (J.L.); Department of Epidemiology, Tulane University School of Public Health, New Orleans, LA (J.Z.); Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada (P.R.); and Department of Epidemiology, University of Florida, Gainesville (D.S.). 2. From the Division of Cardiology, Department of Medicine (M.H., I.A.M., K.W., R.R., N.A., A.A., M.O., H.M.K., A.S., K.H.M., A.A.Q., V.V.) and Department of Psychiatry and Behavioral Sciences (J.D.B.), Emory University School of Medicine, Atlanta, GA; Department of Epidemiology, Rollins School of Public Health (P.M.P., O.L., A.S., Y.V.S., B.P., V.V.), Department of Biostatistics and Bioinformatics, Rollins School of Public Health (Y.V.S., M.K., Q.L., L.W., Y.-A.K.), and Department of Hematology and Oncology, Winship Cancer Institute (J.K., E.K.W.), Emory University, Atlanta, GA; Department of Biochemistry and Biophysics, University of California, San Francisco (J.L.); Department of Epidemiology, Tulane University School of Public Health, New Orleans, LA (J.Z.); Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada (P.R.); and Department of Epidemiology, University of Florida, Gainesville (D.S.). viola.vaccarino@emory.edu.
Abstract
RATIONALE: Leukocyte telomere length (LTL) is a biological marker of aging, and shorter LTL is associated with adverse cardiovascular outcomes. Reduced regenerative capacity has been proposed as a mechanism. Bone marrow-derived circulating progenitor cells are involved in tissue repair and regeneration. OBJECTIVE: Main objective of this study was to examine the relationship between LTL and progenitor cells and their impact on adverse cardiovascular outcomes. METHODS AND RESULTS: We measured LTL by quantitative polymerase chain reaction in 566 outpatients (age: 63±9 years; 76% men) with coronary artery disease. Circulating progenitor cells were enumerated by flow cytometry. After adjustment for age, sex, race, body mass index, smoking status, and previous myocardial infarction, a shorter LTL was associated with a lower CD34+ cell count: for each 10% shorter LTL, CD34+ levels were 5.2% lower (P<0.001). After adjustment for the aforementioned factors, both short LTL (<Q1) and low CD34+ levels (<Q1) predicted adverse cardiovascular outcomes (death, myocardial infarction, coronary revascularization, or cerebrovascular events) independently of each other, with a hazard ratio of 1.8 and 95% confidence interval of 1.1 to 2.0, and a hazard ratio of 2.1 and 95% confidence interval of 1.3 to 3.0, respectively, comparing Q1 to Q2-4. Patients who had both short LTL (<Q1) and low CD34+ cell count (<Q1) had the greatest risk of adverse outcomes (hazard ratio =3.5; 95% confidence interval, 1.7-7.1). CONCLUSIONS: Although shorter LTL is associated with decreased regenerative capacity, both LTL and circulating progenitor cell levels are independent and additive predictors of adverse cardiovascular outcomes in coronary artery disease patients. Our results suggest that both biological aging and reduced regenerative capacity contribute to cardiovascular events, independent of conventional risk factors.
RATIONALE: Leukocyte telomere length (LTL) is a biological marker of aging, and shorter LTL is associated with adverse cardiovascular outcomes. Reduced regenerative capacity has been proposed as a mechanism. Bone marrow-derived circulating progenitor cells are involved in tissue repair and regeneration. OBJECTIVE: Main objective of this study was to examine the relationship between LTL and progenitor cells and their impact on adverse cardiovascular outcomes. METHODS AND RESULTS: We measured LTL by quantitative polymerase chain reaction in 566 outpatients (age: 63±9 years; 76% men) with coronary artery disease. Circulating progenitor cells were enumerated by flow cytometry. After adjustment for age, sex, race, body mass index, smoking status, and previous myocardial infarction, a shorter LTL was associated with a lower CD34+ cell count: for each 10% shorter LTL, CD34+ levels were 5.2% lower (P<0.001). After adjustment for the aforementioned factors, both short LTL (<Q1) and low CD34+ levels (<Q1) predicted adverse cardiovascular outcomes (death, myocardial infarction, coronary revascularization, or cerebrovascular events) independently of each other, with a hazard ratio of 1.8 and 95% confidence interval of 1.1 to 2.0, and a hazard ratio of 2.1 and 95% confidence interval of 1.3 to 3.0, respectively, comparing Q1 to Q2-4. Patients who had both short LTL (<Q1) and low CD34+ cell count (<Q1) had the greatest risk of adverse outcomes (hazard ratio =3.5; 95% confidence interval, 1.7-7.1). CONCLUSIONS: Although shorter LTL is associated with decreased regenerative capacity, both LTL and circulating progenitor cell levels are independent and additive predictors of adverse cardiovascular outcomes in coronary artery diseasepatients. Our results suggest that both biological aging and reduced regenerative capacity contribute to cardiovascular events, independent of conventional risk factors.
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