Evaluation of the Cardiovascular Safety of Sofosbuvir and/or Daclatasvir in Rats: Evidence of Cardiac Autonomic Neuropathy

Abstract

The combination of sofosbuvir and daclatasvir is a highly effective antiviral regimen that has been used in the treatment of hepatitis C for over a decade. Despite wide clinical use, data on the cardiovascular safety of these antivirals remain limited and inconsistent. Here, we evaluated the cardiovascular and autonomic profiles of rats treated for two weeks with oral sofosbuvir (5, 20, or 40 mg/kg/day), daclatasvir (5, 15, or 30 mg/kg/day), or their combined regimen (sofosbuvir-20/daclatasvir-15). Cardiovascular functions were subsequently assessed in conscious rats, pre-instrumented 24-hour earlier with femoral indwelling catheters. The data showed that blood pressure, heart rate, and indices of left ventricular systolic and diastolic functions were largely unaffected by any of these treatments. Contrarily, analysis of heart rate variability in the time and frequency domains demonstrated that sofosbuvir-20, daclatasvir-15, or their combination decreased indices of cardiac sympathetic and total autonomic activity, and shifted cardiac autonomic balance toward parasympathetic dominance as evidenced by the reduction in the low-frequency/high-frequency ratio of the spectral profile. The measurement of arterial baroreceptor activity with the vasoactive method indicated that combined, but not isolated, treatments impaired reflex bradycardic responses to the vasopressor phenylephrine. Molecularly, the sofosbuvir-20/dacltasvir-15 regimen (i) increased the expression of the proinflammatory NFκB, but not the membrane-bound oxidase NOX-4, in the heart and neuronal pools of the hypothalamic paraventricular nucleus, (ii) reduced the antioxidant transcription factor Nrf2, and (iii) caused no changes in serum TNF-α, IL-1β, or caspase-3. Overall, short-term sofosbuvir-20/daclatasvir-15 regimen does not alter baseline hemodynamics but compromises cardiac autonomic regulation and baroreceptor responsiveness, likely through inflammatory and oxidative shifts in cardiac and hypothalamic tissues. Further preclinical and clinical investigations are warranted to substantiate these observations. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.