Selective serotonin reuptake inhibitors induce cardiac toxicity through dysfunction of mitochondria and sarcomeres

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Pharmacology

Background:

• Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed during pregnancy.
• Maternal SSRI use is associated with an increased risk of congenital heart defects in newborns.
• The precise mechanisms underlying SSRI-induced cardiotoxicity remain incompletely understood.

Purpose of the Study:

• To investigate the toxic effects of SSRIs on cardiac development and function.
• To elucidate the underlying molecular mechanisms of SSRI-induced cardiotoxicity.
• To evaluate the impact of specific SSRIs (fluoxetine, paroxetine, sertraline) on cardiomyocytes.

Main Methods:

• Utilized human pluripotent stem cells to create 2D-monolayer cardiomyocyte and 3D-cardiac organoid models.
• Assessed the effects of SSRI exposure on cardiomyocyte differentiation, mitochondrial function, and sarcomere organization.
• Quantified ATP production, mitochondrial respiration, and evaluated cardiac development and angiogenesis in organoid models.

Main Results:

• SSRI exposure significantly inhibited ATP production and mitochondrial respiration in differentiating cardiomyocytes.
• Observed disruption of mitochondrial homeostasis and sarcomere structure, leading to cardiomyocyte dysfunction.
• Cardiac organoid models showed reduced mitochondrial respiration, impaired ATP production, and potential effects on cardiac development and angiogenesis.

Conclusions:

• SSRIs induce mitochondrial dysfunction and sarcomeric disorganization in developing cardiomyocytes.
• These cellular defects highlight potential risks to the fetal cardiac system associated with SSRI exposure.
• The findings underscore the need for further investigation into SSRI safety during pregnancy.