Disturbed Repolarization-Relaxation Coupling During Acute Myocardial Ischemia Permits Systolic...

Area of Science:

• Cardiovascular Physiology
• Cardiac Electrophysiology
• Arrhythmogenesis Research

Background:

• Mechanical forces in the heart influence electrical activity, potentially causing arrhythmias.
• Repolarization-relaxation coupling (RRC) normally protects against systolic mechano-arrhythmogenesis.
• Ischemia's impact on late-systolic mechano-arrhythmogenesis and RRC remains unclear.

Purpose of the Study:

• To investigate the hypothesis that ischemia-induced alterations in RRC create a vulnerable period for mechano-arrhythmogenesis.
• To elucidate the mechanisms underlying late-systolic mechano-arrhythmogenesis in ischemic myocardium.

Main Methods:

• Induction of acute regional ischemia in Langendorff-perfused rabbit hearts with controlled mechanical load.
• Assessment of mechanical activity, arrhythmia incidence, and cardiomyocyte stretch responses.
• Simultaneous voltage-[Ca2+]i fluorescence imaging to evaluate RRC and pharmacological testing of mechano-arrhythmogenesis mechanisms.

Main Results:

• Acute regional ischemia disrupted RRC at the ischemic border, leading to systolic stretch and arrhythmias.
• Arrhythmias were reduced by mechanical unloading, electro-mechanical uncoupling, or [Ca2+]i buffering.
• Prolonged RRC in ischemic cardiomyocytes created a vulnerable period for systolic mechano-arrhythmogenesis, mitigated by interventions targeting [Ca2+]i, TRPA1 channels, or reactive oxygen species.

Conclusions:

• Prolonged RRC in acute ischemia enables late-systolic mechano-arrhythmogenesis.
• Elevated intracellular calcium ([Ca2+]i), TRPA1 channel activity, and reactive oxygen species contribute to this process.
• These factors represent potential therapeutic targets for preventing ischemia-induced arrhythmias.