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

Abstract

Objective: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction. 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 heart failure with preserved ejection fraction. 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 heart failure with preserved ejection fraction 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 heart failure with preserved ejection fraction.

Inactive Matrix Gla Protein in Relation to Renal and Cardiac Functions and Cardiac Valvular Calcification Among Type 2 Diabetes Patients

“…22,23 Arterial stiffness is known to be related to higher hypertension prevalence rates, altered remodeling of the myocardial tissues, diastolic dysfunction, and heart failure. 14 In the current study, serum inactive MGP positively correlated with indices of LV hypertrophy. In accordance with our results, Malhotra et al, 14 reported that increased circulating inactive MGP concentrations were associated with increased left atrial diameter and LV relative wall thickness assessed by echocardiography.…”

Serum biomarkers for arterial calcification in humans: A systematic review

“…Nine studies assessed a possible association between uc-MGP and arterial calcification ( Schlieper et al, 2010 ; Torii et al, 2016 ; Rennenberg et al, 2010 ; Zhelyazkova-Savova et al, 2021 ; Dalmeijer et al, 2013a ; Dalmeijer et al, 2013b ; Malhotra et al, 2022 ; Shea et al, 2011 ; Zwakenberg et al, 2018 ) of which two reported a significant negative association ( Schlieper et al, 2010 ; Torii et al, 2016 ) and seven no significant association ( Rennenberg et al, 2010 ; Zhelyazkova-Savova et al, 2021 ; Dalmeijer et al, 2013a ; Dalmeijer et al, 2013b ; Malhotra et al, 2022 ; Shea et al, 2011 ; Zwakenberg et al, 2018 ). Both studies with a significant association did not adjust for possible confounders ( Schlieper et al, 2010 ; Torii et al, 2016 ).…”

Matrix GIa Protein, Large Artery Stiffness, and the Risk of Heart Failure With Preserved Ejection Fraction

“…Interestingly, the authors did not find a relationship between ucMGP and coronary, thoracic aortic, and abdominal aortic calcium measurements made via Vitamin K deficiency (orange arrows) in the vascular wall leads to the formation of uncarboxylated (uc-) MGP and dephosphorylated, uncarboxylated (dpuc-)MGP, which are inactive MGP forms that can be detected in the circulation. As reported by Malhotra et al, 13 MGP also inhibits collagen-1 expression in VSMCs (although the figure shows this as an effect of pc-MGP, it has not been established whether posttranslational MGP carboxylation or phosphorylation are required for this effect). Vascular effects of MGP deficiency can lead to increased large artery stiffening, which, in turn, promotes left ventricular (LV) remodeling and failure via abnormal pulsatile arterial load, and various comorbidities (such as cognitive dysfunction and chronic kidney disease) via transmission of increased arterial pulsatility to low-resistance vascular beds, with subsequent microvascular damage.…”

“…The study by Malhotra et al 13 should be interpreted in the context of its strengths and limitations. Strengths of the study include the large human sample size, adequate methods for the measurement of LAS, the systematic prospective follow-up for adjudication of HF events, and the translational series of studies in a large human community-based cohort, a mouse model of MGP heterozygosity, and ad hoc aortic smooth muscle cell line experiments.…”

“…In this issue of the journal, Malhotra et al 13 examined the association of ucMGP levels with vascular calcification, LAS and incident HF among 7066 Framingham Heart Study Offspring and Third Generation participants, who were free of HF, advanced renal disease and known atrial fibrillation at baseline. Total ucMGP was found to be associated with carotid-femoral pulse wave velocity (a well-validated metric of LAS) and pulse pressure.…”