Matrix Gla Protein Levels Are Associated With Arterial Stiffness and Incident Heart Failure With Preserved Ejection Fraction

Rajeev Malhotra, Christopher J. Nicholson, Dongyu Wang, Vijeta Bhambhani, Samantha Paniagua, Charles Slocum, Haakon H. Sigurslid, Christian L. Lino Cardenas, Rebecca Li, Sophie L. Boerboom, Yin Ching Chen, Shih Jen Hwang, Chen Yao, Fumito Ichinose, Donald B. Bloch, Mark E. Lindsay, Gregory D. Lewis, Jayashri R. Aragam, Udo Hoffmann, Gary F. MitchellNaomi M. Hamburg, Ramachandran S. Vasan, Emelia J. Benjamin, Martin G. Larson, Warren M. Zapol, Susan Cheng, Jason D. Roh, Christopher J. O'Donnell, Christopher Nguyen, Daniel Levy, Jennifer E. Ho

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)E61-E73
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume42
Issue number2
DOIs
StatePublished - Feb 1 2022
Externally publishedYes

Keywords

  • Arterial stiffness
  • Biomarker
  • Heart failure
  • Hypertension
  • Mice
  • Pulse wave velocity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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