Interleukin-1β Drives Disease Progression in Arrhythmogenic Cardiomyopathy

Area of Science:

• Cardiovascular Biology
• Genetics
• Immunology

Background:

• Arrhythmogenic cardiomyopathy (ACM) is a genetic heart failure caused by desmosomal gene mutations, leading to arrhythmias and sudden cardiac death.
• Current treatments are limited, with heart transplantation often being the primary option for affected individuals.

Purpose of the Study:

• To investigate the molecular and cellular mechanisms underlying arrhythmogenic cardiomyopathy (ACM).
• To identify potential therapeutic targets for ACM by analyzing myocardial tissue from patients and a mouse model.

Main Methods:

• Single nucleus RNA sequencing and spatial transcriptomics on human ACM patient and control myocardial samples.
• Analysis of homozygous Dsg2 mutant mice to identify analogous disease mechanisms.
• Treatment of Dsg2 mutant mice with an anti-IL1B neutralizing antibody.

Main Results:

• Identified disease-associated spatial niches in ACM characterized by fibrosis, inflammation, and failing cardiac myocytes.
• Discovered increased inflammatory macrophage subsets with high Il1b expression in ACM.
• Anti-IL1B treatment in mice attenuated fibrosis, reduced inflammation, preserved cardiac function, and diminished arrhythmogenic mechanisms.

Conclusions:

• IL1B (interleukin-1 beta) plays a significant role in the pathogenesis of arrhythmogenic cardiomyopathy (ACM).
• Targeting IL1B or IL1 signaling with existing therapeutics shows promise for improving outcomes in ACM patients.