title: Synergism between arrhythmia and hyperhomo-cysteinemia in structural heart disease.
abstract: Elevated levels of homocysteine (Hcy) known as hyperhomocysteinemia (HHcy) is associated with cardiac arrhythmia and sudden cardiac death (SCD). Hcy increases iNOS, activates matrix metalloproteinase (MMP), disrupts connexin-43 and increases collagen/elastin ratio. The disruption of connexin-43 and accumulation of collagen (fibrosis) interupt cardiac conduction and attenuate NO transport from endothelium to myocyte (E-M) causing E-M uncoupling. We hypothesize that Hcy increases mtNOS, metalloproteinase activity, disrupts connexin-43, exacerbates endothelial-myocyte uncoupling, and induces cardiac failure by activating NMDA-R1 in structural heart disease. Chronic volume overload heart failure was created by aorta-venacava (AV) fistula. HHcy was induced by adminstrering Hcy in drinking water. NMDA-R1 was blocked by dizocilpine (MK-801). EKG and M-mode Echocardiography was performed. The E-M coupling was determined in cardiac rings. LV mitochondria was isolated. Levels of NMDA-R1, peroxiredoxin, NOX4, and mtNOS were measured. The degradation of connexin-43, collagen and elastin was measured by Western blot analysis. Mouse cardiac endothelial cells were cultured with or without Hcy or MK-801. The results suggest systolic and diastolic heart failure in HHcy and AVF mice. The levels of connexin, collagen degradation and MMP-9 were increased. The elastin was decreased in HHcy and AVF hearts. The mitochondrial NOX4 increased and peroxiredoxin was decreased. The mtNOS activity was synergistically increased in HHcy, AVF and HHcy+AVF hearts. The cardiac contraction and endothelial dependent relaxation was attenutated in HHcy and AVF hearts. Interestingly, the treatment with MK-801 mitigated the contractile dysfunction. These studies delineated the mechanism of Hcy-dependent endothelial-myocyte uncoupling in cardiac arrhythmia and failure, and have therapeutic ramifications for sudden cardiac death.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville School of Medicine Louisville, Kentucky.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Givvimani
authors.forename: Natia
authors.initials: N
authors.lastname: Qipshidze
authors.forename: Neetu
authors.initials: N
authors.lastname: Tyagi
authors.forename: Paras K
authors.initials: PK
authors.lastname: Mishra
authors.forename: Utpal
authors.initials: U
authors.lastname: Sen
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi