Epidemiological and histological findings implicate matrix Gla protein in diastolic left ventricular dysfunction

Area of Science:

• Cardiology
• Biochemistry
• Vascular Biology

Background:

• Diastolic left ventricular (LV) dysfunction is increasingly recognized, with novel paradigms suggesting microcirculatory involvement.
• Matrix Gla Protein (MGP), a Vitamin K-dependent protein, is crucial for maintaining microcirculatory integrity.
• Inactive desphospho-uncarboxylated MGP (dp-ucMGP) is a marker of MGP activity.

Purpose of the Study:

• To investigate the association between plasma dp-ucMGP levels and LV filling pressure, a marker of diastolic LV dysfunction.
• To examine the distribution of active and inactive MGP within human myocardial tissue.

Main Methods:

• Echocardiographic assessment of diastolic LV function and plasma dp-ucMGP levels were measured in 668 Flemish and 386 Swiss individuals.
• Cardiac biopsies from patients with cardiomyopathy and healthy controls were analyzed for MGP distribution using conformation-specific antibodies.

Main Results:

• Higher plasma dp-ucMGP levels were significantly associated with increased E/e' (a measure of LV filling pressure) in both cohorts.
• Odds of elevated E/e' (≥ 8.5) were significantly higher with increased dp-ucMGP.
• Inactive MGP was more prevalent in the perivascular and interstitial spaces of diseased hearts, while active MGP was found in capillaries and interstitial cells.

Conclusions:

• The findings support a role for activated MGP in preserving myocardial integrity and diastolic LV function.
• These results suggest that MGP may be a therapeutic target for managing diastolic LV dysfunction and preventing heart failure.