Enterprise AI Analysis
Electrophysiological and Molecular Features of Remdesivir-Induced Cardiac Toxicity in Male and Female Guinea Pigs
The study investigated sex-dependent cardiac toxicity of remdesivir in guinea pigs. Male guinea pigs showed more severe myocardial injury, extensive inflammatory infiltration, marked mitochondrial disruption, and higher incidence of sustained ventricular tachyarrhythmia compared to females. Remdesivir was associated with sex-dependent cardiac toxicity, mitochondrial impairment, and inflammatory activation. Males were more susceptible to electrophysiological instability and mitochondrial dysfunction. Findings suggest careful evaluation of remdesivir's cardiac effects with sex-specific considerations in clinical administration.
Executive Impact & AI Opportunity
Leveraging AI, enterprises can proactively identify drug-induced cardiotoxicity risks, personalize treatment plans, and enhance drug development safety profiles. This study highlights the criticality of sex-specific considerations in pharmacological responses, an area ripe for AI-driven precision medicine.
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Higher QT Prolongation in Males
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Mitochondrial ATP Reduction in Males
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Inflammatory Cytokines (Male vs. Female)
Deep Analysis & Enterprise Applications
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25%
Higher QT Prolongation in Male Guinea Pigs
In vivo ECG monitoring revealed significant alterations in cardiac rhythm. Both sexes showed prolonged QT and RR intervals, and reduced heart rate. Notably, male guinea pigs experienced approximately 25% greater QT prolongation and slower recovery. Ex vivo Langendorff-perfused hearts confirmed dose-dependent electrophysiological changes, with males showing more pronounced and dynamic alterations, especially during drug challenge and recovery. Optical mapping showed prolonged activation time and increased action potential duration (APD50, APD80) in males compared to females, with males exhibiting greater prolongation of repolarization and reduced electrophysiological resilience. At 3 µM remdesivir, male guinea pigs developed significant ventricular tachyarrhythmias, while females maintained a stable rhythm.
Calcium imaging revealed concentration-dependent alterations in Ca2+ handling. At 3 µM remdesivir, males had a modest prolongation of calcium transient duration, while females maintained stable dynamics. At 10 µM, both sexes showed pronounced slowing of calcium reuptake, but the effect was significantly greater in males. These findings indicate remdesivir disrupts calcium homeostasis and prolongs repolarization in a dose- and sex-dependent manner, with males exhibiting greater susceptibility to excitation-contraction coupling dysfunction.
Enterprise Process Flow
Remdesivir Administration
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Mitochondrial Impairment & Inflammation
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Ionic Dysregulation
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Electrophysiological Disturbances
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Cardiac Toxicity (Male Predominant)
Histopathological analysis showed sex-dependent differences in inflammatory and structural injury. Female guinea pigs had mild, focal inflammatory infiltration, mainly perivascular, with preserved myocardial integrity. In contrast, male guinea pigs showed diffuse myocarditis with extensive neutrophil-dominated infiltration, cytoplasmic swelling, enhanced eosinophilia, and focal myofibrillar condensation. These indicate more severe myocardial inflammation and necrosis in males.
Transmission electron microscopy (TEM) revealed prominent mitochondrial damage in male cardiomyocytes, characterized by moderate swelling, disorganized myofibrils, ruptured bundles, indistinct bands, disrupted cristae, and localized matrix rarefaction. Female cardiomyocytes maintained relatively intact cellular and mitochondrial morphology, with uniform matrices and largely preserved cristae. ELISA and Western blot analyses confirmed significantly elevated pro-inflammatory cytokines (IL-6, TNF-α, NF-κB) in remdesivir-treated animals, with male guinea pigs showing markedly higher levels (2-3 times higher). ATP5F1A, a marker of energy metabolism, declined in both sexes, but more significantly in males (45% reduction) than females (30% reduction). These findings demonstrate stronger inflammatory activation and mitochondrial dysfunction in a sex-dependent manner, making males more susceptible to cardiac injury.
| Feature | Male Guinea Pigs | Female Guinea Pigs |
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| Myocardial Injury Severity |
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| Mitochondrial Damage |
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| Electrophysiological Instability |
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| Inflammatory Activation (IL-6, TNF-α, NF-κB) |
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| ATP5F1A Reduction |
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Impact on Male Susceptibility
The study highlights that male guinea pigs are more susceptible to remdesivir-induced cardiac injury due to multiple biological factors. These include higher expression of ACE2, increased propensity for hyperinflammatory responses, and hormonal influences (e.g., testosterone promoting ROS, estrogen's cardioprotective effects in females). These factors collectively contribute to greater electrophysiological instability and mitochondrial dysfunction observed in males.
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