Synergism between arrhythmia and hyperhomocysteinemia in structural heart disease

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

Research output: Contribution to journalArticle

13 Scopus citations

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 Hcydependent endothelial-myocyte uncoupling in cardiac arrhythmia and failure, and have therapeutic ramifications for sudden cardiac death.

Original languageEnglish (US)
Pages (from-to)107-119
Number of pages13
JournalInternational Journal of Physiology, Pathophysiology and Pharmacology
Volume3
Issue number2
StatePublished - 2011

Keywords

  • A-V fistula
  • Calpain
  • Connexin
  • Endothelial myocyte coupling
  • Heart failure
  • MMP-9
  • Mitochondria
  • NO
  • NOX4
  • PVC
  • Peroxiredoxin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Physiology
  • Physiology (medical)

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