Crosstalk between coagulation and complement activation promotes cardiac dysfunction in arrhythmogenic right...

Area of Science:

• Cardiology
• Immunology
• Pathophysiology

Background:

• Complement components are upregulated in arrhythmogenic right ventricular cardiomyopathy (ARVC) myocardium.
• Inhibition of complement receptor C5aR ameliorates disease severity in a mouse model of ARVC.
• The precise mechanism of complement activation in ARVC requires further elucidation.

Purpose of the Study:

• To investigate the mechanism of complement activation in ARVC.
• To explore the interplay between complement and coagulation systems in ARVC pathogenesis.
• To identify potential therapeutic targets for ARVC.

Main Methods:

• Detection of complement and coagulation factors using immunostaining, RT-PCR, and western blot.
• Generation of C3 knockout in desmin-deficient mice (ARVC model) to assess complement pathway independence.
• Evaluation of coagulation system interventions and assessment of plasma sC5b9 levels in ARVC patients.

Main Results:

• Complement system activation in ARVC myocardium, potentially mediated by autoantibodies.
• Evidence of C5 activation independent of the conventional pathway, linked to the coagulation system.
• Crosstalk between complement and coagulation exacerbates myocardial injury, reduced by thrombin inhibition; elevated sC5b9 and thrombin correlate with mortality in ARVC patients.

Conclusions:

• Crosstalk between coagulation and complement systems plays a critical role in ARVC cardiac dysfunction.
• This interaction represents a potential therapeutic target for ARVC.
• Understanding this crosstalk has significant clinical implications for ARVC diagnosis and treatment.