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Int J Physiol Pathophysiol Pharmacol 2011;3(2):107-119.

Original Article
Synergism between arrhythmia and hyperhomocysteinemia in structural heart

Srikanth Givvimani, Natia Qipshidze, Neetu Tyagi, Paras K.Mishra, Utpal Sen, Suresh C.Tyagi

Department of Physiology and Biophysics, University of Louisville School of Medicine, Louisville, Kentucky, USA.

Received May 5, 2011; accepted May 23, 2011; Epub May 29, 2010; Published June 30, 2011

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.  (IJPPP1105001).

Key words: A-V fistula, MMP-9, connexin, NO, endothelial myocyte coupling, PVC, mitochondria, calpain, NOX4, peroxiredoxin, heart

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Address all correspondence to:
Suresh C Tyagi, PhD,
Department of Physiology & Biophysics,   
University of Louisville School of Medicine,
500 South Preston Street,
Louisville, KY 40202
Tel: 502-852-3381, Fax: 502-852-6239,