Decrease in density of INa is in the common final pathway to heart block in murine hearts overexpressing calcineurin

Area of Science:

• Cardiology
• Molecular Biology
• Physiology

Background:

• Calcineurin (CN) overexpression in mice leads to cardiac hypertrophy and sudden death.
• Sudden deaths are linked to heart block (asystole) and decreased action potential upstroke velocity (dV/dt(max)).

Purpose of the Study:

• To investigate the hypothesis that decreased sodium channel activity contributes to heart block in CN-overexpressing mice.
• To explore potential therapeutic interventions for restoring sodium channel function.

Main Methods:

• Assessed sodium currents (I(Na)) and protein expression in CN-overexpressing mice.
• Utilized in vitro treatments (BAPTA-AM, thapsigargin, ryanodine, bisindolylmaleimide I) to evaluate rescue of I(Na).
• Administered encainide and propranolol in vivo to assess the contribution of sodium channel activity to sudden death.

Main Results:

• Profound, age-dependent decreases in I(Na) were observed, correlating with action potential changes.
• Sodium channel protein expression remained unchanged, suggesting post-translational regulation.
• In vitro treatments and a PKC inhibitor rescued I(Na) function.
• Encainide administration induced asystolic death in CN mice, while propranolol triggered death in older CN mice.

Conclusions:

• Decreased sodium channel activity is a critical factor in the development of asystole in CN-overexpressing mice.
• This reduction in sodium channel function represents a common final pathway leading to sudden cardiac death.