Pro-Arrhythmic Effect of Chronic Stress-Associated Humoral Factors in Human Induced Pluripotent Stem Cell-Derived...

Area of Science:

• Cardiology
• Physiology
• Molecular Biology

Background:

• The pro-arrhythmic effects of circulating factors during chronic stress on human cardiomyocytes are not well understood.
• Chronic stress is a known risk factor for cardiovascular diseases, including arrhythmias.

Purpose of the Study:

• To investigate the impact of serum from chronically stressed mice on the electrical activity of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs).
• To elucidate the mechanisms by which circulating humoral factors induce arrhythmias under chronic stress.

Main Methods:

• Exposure of hiPSC-CMs to serum from mice subjected to chronic unpredictable mild stress (CUMS).
• Electrophysiological recordings (patch clamp) to assess ion channel function (I_to, I_Kr, I_Ks).
• Analysis of ion channel protein expression.
• Assessment of arrhythmias induced by heat-inactivated and deproteinized serum.
• Metabolomics analysis of CUMS serum.

Main Results:

• Serum from CUMS mice induced time- and concentration-dependent arrhythmia-like events in hiPSC-CMs.
• CUMS serum inhibited key potassium currents (I_to, I_Kr, I_Ks) and reduced the expression of related channel proteins.
• Small molecules in the serum were identified as the primary mediators of the arrhythmogenic effect.
• Significant alterations in serum metabolite profiles were observed in CUMS mice.

Conclusions:

• Circulating humoral substances under chronic stress conditions exert direct pro-arrhythmic effects on cardiomyocytes.
• Chronic stress-induced small molecules impair ion channel function, leading to cardiac arrhythmias.
• This study highlights a novel mechanism linking chronic stress, humoral factors, and cardiac electrical instability.