Rajeev Malhotra1, Christopher J Nicholson1, Dongyu Wang1, Vijeta Bhambhani1, Samantha Paniagua1, Charles Slocum1, Haakon H Sigurslid1, Christian L Lino Cardenas1, Rebecca Li1, Sophie L Boerboom1, Yin-Ching Chen2,3, Shih-Jen Hwang4,5, Chen Yao4, Fumito Ichinose6, Donald B Bloch6,7,8, Mark E Lindsay1, Gregory D Lewis1, Jayashri R Aragam9, Udo Hoffmann10, Gary F Mitchell11, Naomi M Hamburg12, Ramachandran S Vasan13,14, Emelia J Benjamin4,13,14, Martin G Larson4,15, Warren M Zapol6, Susan Cheng4,16, Jason D Roh1, Christopher J O'Donnell17, Christopher Nguyen1,2,3, Daniel Levy4, Jennifer E Ho1,18. 1. Cardiovascular Research Center and Corrigan Minehan Heart Center, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Boston (R.M., C.J.N., D.W., V.B., S.P., C.S., H.H.S., C.L.L.C., R.L., S.L.B., M.E.L., G.D.L., J.D.R., C.N., J.E.H.). 2. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown (Y.C.C., C.N.). 3. Schepens Eye Research Institute/Massachusetts Eye and Ear Infirmary, Harvard Medical School, Cambridge (Y.C.C., C.N.). 4. Framingham Heart Study, MA (S.J.H., C.Y., E.J.B., M.G.L., S.C., D.L.). 5. Population Sciences Branch, Division of Intramural Research, National Institutes of Health, Bethesda, MD (S.J.H., C.Y., D.L.). 6. Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston (F.I., D.B.B., W.M.Z.). 7. Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Boston (D.B.B.). 8. Department of Medicine, Massachusetts General Hospital, Boston (D.B.B.). 9. West Roxbury VA Hospital, Harvard Medical School, Boston, MA (J.R.A.). 10. Department of Radiology, Massachusetts General Hospital, Boston (U.H.). 11. Cardiovascular Engineering, Inc, Norwood, MA (G.F.M.). 12. Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, MA (N.M.H.). 13. Department of Epidemiology, Boston University School of Public Health & Sections of Preventive Medicine and Epidemiology and Cardiology (R.S.V., E.J.B.), Boston University School of Public Health, MA. 14. Department of Medicine (R.S.V., E.J.B.), Boston University School of Public Health, MA. 15. Department of Biostatistics (M.G.L.), Boston University School of Public Health, MA. 16. Barbara Streisand Women's Heart Center, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (S.C.). 17. U.S. Department of Veterans Affairs, Boston, MA (C.J.O.). 18. Now with Cardiovascular Institute and Division of Cardiology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA (J.E.H.).
Abstract
OBJECTIVE: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp+/- mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp+/- mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation. CONCLUSIONS: This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.
OBJECTIVE: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp+/- mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp+/- mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation. CONCLUSIONS: This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.
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