Acute Adenoviral Infection Elicits an Arrhythmogenic Substrate Prior to Myocarditis

Area of Science:

• Cardiology
• Virology
• Molecular Biology

Background:

• Viral cardiac infections, including myocarditis, are a significant cause of sudden cardiac death, particularly in young adults.
• Current understanding of myocarditis focuses on later disease stages and immune responses, with limited knowledge of acute infection mechanisms.
• Adenovirus is a common cause of myocarditis, but species specificity has hindered the development of effective infection models and understanding of its role in sudden cardiac arrest.

Purpose of the Study:

• To establish a mouse adenovirus type-3 infection model for investigating acute cardiac infection.
• To identify molecular alterations in the heart during acute viral infection before significant immune responses or cardiomyopathy development.

Main Methods:

• Developed a mouse model using mouse adenovirus type-3 to study acute cardiac infection.
• Utilized optical mapping to assess cardiac function and Cx43 phosphorylation in infected hearts.
• Performed patch-clamp electrophysiology on infected cardiomyocytes to analyze ion channel function.
• Investigated human adenovirus type-5 in human induced pluripotent stem cell-derived cardiomyocytes to assess conserved mechanisms.

Main Results:

• Adenovirus infection led to decreased conduction velocity and increased Cx43^Ser368 phosphorylation, impacting gap junction function.
• Hearts with a phospho-null mutation at Cx43^Ser368 were protected against conduction velocity slowing.
• Infected cardiomyocytes showed prolonged action potential duration due to reduced I_K1 and I_Ks currents.
• Human adenovirus type-5 replicated these findings in human cardiomyocytes, showing increased Cx43^Ser368 phosphorylation and disrupted synchrony.

Conclusions:

• Adenoviral infection directly induces an arrhythmogenic substrate by targeting cardiac gap junction and ion channel function.
• These molecular alterations are critical in precipitating arrhythmias and likely contribute to sudden cardiac death in acute viral myocarditis.
• The established mouse model provides a platform for further mechanistic studies of acute viral cardiac infections.