Inflammasome and ventricular arrhythmogenesis: pathogenic interplay and potential targets on the horizon
Maria Lucia Narducci1, Cristina Conte2, Alessandro Telesca2
1Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy.
Trends in Cardiovascular Medicine
|June 13, 2025
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View abstract on PubMed
Summary
Inflammation, cardiac fibrosis, and sympathetic hyperactivity drive life-threatening ventricular arrhythmias (VAs). Targeting the NLRP3 inflammasome pathway and autonomic imbalance offers new therapeutic strategies for managing VAs and sudden cardiac death.
Area of Science:
- Cardiology
- Molecular Medicine
- Electrophysiology
Background:
- Life-threatening ventricular arrhythmias (VAs) contribute significantly to mortality, with sudden cardiac death remaining a concern despite current treatments.
- Existing anti-arrhythmic drugs and catheter ablation offer only partial efficacy, highlighting the need for improved risk stratification and therapeutic targets.
- Ventricular tachycardia (VT) is often associated with myocardial infarction or cardiomyopathy, characterized by fibrotic scars that promote arrhythmogenesis.
Purpose of the Study:
- To explore the interplay between inflammation, cardiac fibrosis, and sympathetic hyperactivity in the pathogenesis of VAs.
- To identify novel therapeutic targets for mitigating adverse ventricular remodeling and reducing the burden of VAs.
- To investigate the role of the NLR family pyrin domain containing 3 (NLRP3) inflammasome in scar development and cardiac electrical instability.
Main Methods:
- Review of evidence linking cardiac fibrosis, identified via late gadolinium enhancement (LGE) or low-voltage mapping, to VAs.
- Examination of the role of inflammation, particularly the NLRP3 inflammasome, in myocardial scar formation and electrical instability.
- Analysis of the contribution of systemic and local sympathetic hyperactivity to electrical instability.
Main Results:
- Cardiac fibrosis, a key substrate for VAs, promotes reentry circuits through structural remodeling.
- Inflammation mediated by the NLRP3 inflammasome is a critical factor in scar development and disease progression.
- Sympathetic hyperactivity exacerbates electrical instability, interacting with fibrosis and inflammation.
Conclusions:
- The NLRP3 inflammasome pathway, autonomic imbalance, and early myocardial fibrosis are promising therapeutic targets for VAs.
- A hypothetical 'Coumel's triangle of arrhythmogenesis' suggests inflammation as a trigger, fibrosis as the substrate, and sympathetic hyperactivity as a modulating factor.
- Understanding this interplay is crucial for developing tailored pharmacological strategies to manage VAs and reduce sudden cardiac death risk.
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