Mitochondrial dysfunction causing cardiac sodium channel downregulation in cardiomyopathy

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Cardiomyopathy is linked to reduced cardiac sodium current (I(Na)), potentially causing arrhythmias.
• Previous research indicated elevated intracellular NADH decreases I(Na) through mitochondrial reactive oxygen species (ROS).

Purpose of the Study:

• To investigate the role of the NADH-mitochondria ROS pathway in I(Na) reduction in nonischemic cardiomyopathy.
• To correlate findings in a mouse model with human failing hearts.

Main Methods:

• Induced nonischemic cardiomyopathy in mice using DOCA hypertension model.
• Assessed cardiac function, NADH/NAD(+) levels, and mitochondrial ROS in mouse myocytes.
• Utilized whole-cell patch clamp, confocal microscopy, and optical mapping in human hearts.

Main Results:

• Myopathic mice exhibited increased blood pressure, cardiac dilation, reduced ejection fraction, elevated NADH, decreased I(Na), and mitochondrial ROS overproduction.
• Treatments including NAD(+), mitoTEMPO, PKC inhibitors, and PKA activators restored I(Na) in myocytes and mice.
• Human failing hearts showed reduced conduction velocity, which improved with NAD(+) administration.

Conclusions:

• Nonischemic cardiomyopathy involves elevated NADH, mitochondrial ROS, and decreased I(Na).
• Targeting mitochondrial ROS with NAD(+), mitoTEMPO, or other agents can restore I(Na).
• NAD(+) shows potential for improving cardiac conduction in human myopathic hearts.