Chronic volume/pressure overload-induced
heart failure augments oxidative stress and activates
matrix metalloproteinase which causes endocardial endothelial-myocyte (EM) uncoupling eventually leading to decline in myocardial systolic and diastolic function. The elevated levels of
homocysteine (Hcy),
hyperhomocysteinemia (HHcy), are associated with decline in cardiac performance. Hcy impairs the EM functions associated with the induction of ventricular
hypertrophy leading to cardiac stiffness and
diastolic heart failure. Hcy-induced neurological defects are mediated by the
NMDA-R (
N-methyl-D-aspartate (
NMDA) receptor) activation.
NMDA-R is expressed in the heart. However, the role of
NMDA-R on cardiac function during HHcy is still in its infancy. The blockade of
NMDA-R attenuates
NMDA-agonist-induced increase in the heart rate. Hcy increases intracellular
calcium and activates
calpain and
calpain-associated mitochondrial (mt) abnormalities have been identified in HHcy. Mitochondrial permeabilization and uncoupling in the pathological setting is fueled by redox stress and
calcium mishandling. Recently the role of
cyclophilin D, a component of the mitochondrial membrane permeability transition pore, has been identified in cardiac-
ischemia. Mechanisms underlying the potentiation between
NMDA-R activation and
mitochondrial defects leading to cardiac dysfunction during HHcy remain to be elucidated. This review addresses the mitochondrial mechanism by which Hcy contributes to the decline in mechano-electrical function and arrhythmogenesis via agonizing
NMDA-R. The putative role of mitochondrial
MMP activation,
protease stress and mitochondrial permeability transition in cardiac conduction during HHcy is discussed. The review suggests that Hcy increases
calcium overload and oxidative stress in the mitochondria and amplifies the activation of mtMMP, causing the opening of
mitochondrial permeability transition pore leading to mechano-electrical dysfunction.