Dephospho-Uncarboxylated Matrix Gla-Protein Is Associated With Adverse Outcomes in Heart Failure

Abstract

Background: MGP (matrix Gla-protein), a known inhibitor of vascular calcification, becomes biologically active by vitamin K-dependent carboxylation. Circulating levels of dpucMGP (dephospho-uncarboxylated matrix Gla-protein), the inactive form of MGP, have been associated with large artery stiffening and reduced skeletal muscle mass in heart failure (HF). Whether dpucMGP is related to adverse outcomes in patients with HF is unknown.

Methods: In this cohort study, we measured plasma dpucMGP among 2247 PHFS (Penn HF Study) participants. We examined the relationship between dpucMGP and ≈5000 other proteins (SomaScan assay) to identify biological pathways associated with dpucMGP. We assessed the association between dpucMGP levels and (1) death or HF-related hospital admission; (2) all-cause death.

Results: Participants' median age was 61 years (interquartile range, 53-70 years), 64% were male, and 71% were White. dpucMGP exhibited prominent proteomic associations with acute phase response, coagulation, complement system, fibrosis, cell signaling, and metabolic pathways. Greater dpucMGP was associated with older age, renal dysfunction, and warfarin use, whereas Black ethnicity was associated with lower dpucMGP. Increased dpucMGP levels were associated with an increased risk of death or HF-related hospital admission (standardized hazard ratio, 1.23 [95% CI, 1.17-1.28]; P<0.0001) and all-cause death (standardized hazard ratio, 1.32 [95% CI, 1.25-1.40]; P<0.0001), particularly among participants with nonischemic HF. Associations between dpucMGP and outcomes were dependent on warfarin use, and higher dpucMGP levels were found to mediate the association between warfarin use and adverse outcomes (death [total effect: P=0.005; indirect effect: P<0.001] and death or HF-related hospital admission [total effect: P<0.001; indirect effect: P=0.002]).

Conclusions: Higher dpucMGP is associated with multiple biological pathways and with an increased risk for adverse outcomes in HF. Greater dpucMGP levels mediated the relationship between warfarin use and adverse outcomes. Further studies are required to determine the role of therapeutic interventions to reduce dpucMGP levels in this patient population.

Keywords: heart failure; hospital; vascular calcification; vitamin K; warfarin.

Figure 1.. Volcano plots showing proteins associated with dephospho-uncarboxylated Matrix Gla-protein (dpucMGP).

Panel A shows the results of unadjusted analyses, whereas panel B shows results of analyses adjusted for age, sex, race, enrollment site, systolic and diastolic blood pressure, history of diabetes, hypertension, dyslipidemia, chronic kidney disease, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) surgery, atrial fibrillation/flutter, current smoking, New York Heart Association (NYHA) class, aspirin, hydralazine, nitrates, statins, warfarin and insulin use. Black dots represent proteins with nonsignificant associations with dpucMGP at the nominal significance level. Blue dots represent proteins with nonsignificant associations with dpucMGP after alpha correction. Yellow dots represent proteins with significant associations with dpucMGP after alpha correction. Refer to Supplemental Files 1 and 2 for additional information.

Figure 1.. Volcano plots showing proteins associated with dephospho-uncarboxylated Matrix Gla-protein (dpucMGP).

Panel A shows the results of unadjusted analyses, whereas panel B shows results of analyses adjusted for age, sex, race, enrollment site, systolic and diastolic blood pressure, history of diabetes, hypertension, dyslipidemia, chronic kidney disease, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) surgery, atrial fibrillation/flutter, current smoking, New York Heart Association (NYHA) class, aspirin, hydralazine, nitrates, statins, warfarin and insulin use. Black dots represent proteins with nonsignificant associations with dpucMGP at the nominal significance level. Blue dots represent proteins with nonsignificant associations with dpucMGP after alpha correction. Yellow dots represent proteins with significant associations with dpucMGP after alpha correction. Refer to Supplemental Files 1 and 2 for additional information.

Figure 2.. Pathways associated with dephospho-uncarboxylated Matrix Gla-protein (dpucMGP).

Panel A shows the results of unadjusted analyses, whereas panel B shows analyses adjusted for age, sex, race, enrollment site, systolic and diastolic blood pressure, history of diabetes, hypertension, dyslipidemia, chronic kidney disease, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) surgery, atrial fibrillation/flutter, current smoking, New York Heart Association (NYHA) class, aspirin, hydralazine, nitrates, statins, warfarin and insulin use. Figure 2B shows only the top 35 pathways associated with dpucMGP in adjusted analyses. For a list of top pathways, please refer to Supplemental Tables 1 and 2. Pathways with z scores significantly different from zero (i.e., clearly directional relationships) are shown in blue and the z score value is shown next to the corresponding bar. The P value represents the overall representation of proteins from a given pathway. The z score takes into account biological function of individual proteins in the pathway to assess whether there is directionality of association.

Figure 2.. Pathways associated with dephospho-uncarboxylated Matrix Gla-protein (dpucMGP).

Panel A shows the results of unadjusted analyses, whereas panel B shows analyses adjusted for age, sex, race, enrollment site, systolic and diastolic blood pressure, history of diabetes, hypertension, dyslipidemia, chronic kidney disease, percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG) surgery, atrial fibrillation/flutter, current smoking, New York Heart Association (NYHA) class, aspirin, hydralazine, nitrates, statins, warfarin and insulin use. Figure 2B shows only the top 35 pathways associated with dpucMGP in adjusted analyses. For a list of top pathways, please refer to Supplemental Tables 1 and 2. Pathways with z scores significantly different from zero (i.e., clearly directional relationships) are shown in blue and the z score value is shown next to the corresponding bar. The P value represents the overall representation of proteins from a given pathway. The z score takes into account biological function of individual proteins in the pathway to assess whether there is directionality of association.

Figure 3.. Multivariable linear regression model showing the independent correlates of dpucMGP.

Standardized regression coefficients for each variable are shown as point estimates along with 95% confidence intervals. BP, blood pressure; CABG, coronary artery bypass grafting; eGFR, estimated glomerular filtration rate; NYHA, New York Heart Association; PCI, percutaneous coronary intervention.

Figure 4.

Kaplan-Meier curves of the incidence of (A) death and (B) death or heart failure-related hospital admission (DHFA) by tertiles of dephospho-uncarboxylated Matrix Gla-protein (dpucMGP).

Figure 4.

Kaplan-Meier curves of the incidence of (A) death and (B) death or heart failure-related hospital admission (DHFA) by tertiles of dephospho-uncarboxylated Matrix Gla-protein (dpucMGP).