Cardiac spheroids as a human model for inflammation induced cardiac dysfunction.

Area of Science:

• Cardiovascular Biology
• Immunology
• Biomedical Engineering

Background:

• Inflammatory signaling critically impacts cardiac dysfunction in sepsis, myocarditis, and heart failure.
• Current in vitro models lack the multicellular complexity for accurate human cardiac pathology recapitulation.

Purpose of the Study:

• To utilize human cardiac spheroids as a physiologically relevant model for studying lipopolysaccharide (LPS)-induced cardiac inflammation.
• To assess the impact of inflammation on mitochondrial metabolism and contractile function in a multicellular cardiac model.

Main Methods:

• Human cardiac spheroids composed of cardiomyocytes, fibroblasts, and endothelial cells were developed.
• Lipopolysaccharide (LPS) was used to induce inflammation, followed by assessment of cytotoxicity (LDH release).
• Transcriptional and protein levels of inflammatory markers (TLR2, IL6, TNF, CXCL8, CCL2), mitochondrial function, and contractility were analyzed.

Main Results:

• LPS stimulation induced a robust inflammatory response without significant cytotoxicity.
• Significant upregulation and secretion of key inflammatory mediators were observed.
• Mitochondrial respiration, ATP production, and maximal capacity were significantly reduced.
• Cardiac spheroid contractility was impaired, showing reduced beat rate and altered contraction/relaxation dynamics.

Conclusions:

• Human cardiac spheroids provide a physiologically relevant platform for studying multicellular inflammatory responses in the heart.
• This model demonstrates that inflammation compromises mitochondrial metabolism and mechanical performance.
• The spheroid model is valuable for investigating innate immune activation and screening anti-inflammatory therapies for cardiac dysfunction.