Several antivirals, including remdesivir, Paxlovid, molnupiravir, and monoclonal antibodies like tixagevimab and cilgavimab, have been repurposed to treat the coronavirus disease 2019 (COVID-19) or received emergency use authorization (EUA). Antimalarial and antiparasitic drugs like ivermectin, hydroxychloroquine, and chloroquine have also been investigated for their potential activity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
A recent review published in the journal Acta Pharmacologica Sinica discusses the cardiovascular adverse effects associated with antiviral drugs used to treat COVID-19.
About the virus
SARS-CoV-2 is a single-stranded ribonucleic acid (RNA) virus enclosed in a protein envelope comprising the membrane, spike, and envelope proteins. Viral RNA is stored within the nucleocapsid, comprised of the nucleocapsid protein.
The SARS-CoV-2 spike protein recognizes and subsequently binds to the angiotensin-converting enzyme 2 (ACE2) receptor present on the surface of the host cell. The S1 subunit of the spike protein consists of an N-terminal domain (NTD) and receptor-binding domain (RBD).
RBD-ACE2 binding causes the S2 subunit to dissociate from the ACE2 molecule, which subsequently causes the virus to transition from a pre to post-fusion state. Thereafter, the virus and host cell membranes fuse together, thereby allowing viral entry into the cell.
ACE2 and cardiovascular adverse effects
ACE2 regulates the vasoactive effects of ACE, which converts angiotensin I to angiotensin II, a potent vasoconstrictor and pro-inflammatory agent. Angiotensin II induces hyperinflammation due to the dysregulated release of cytokines, leading to severe tissue damage and multi-organ failure, which is often characteristic of severe COVID-19.
Pre-pandemic antivirals and cardiovascular effects
Idoxuridine was the first antiviral approved in 1963 for feline herpesvirus-1 eye infections; since then, 37 antivirals have been approved to treat a wide range of infections caused by the human immunodeficiency virus (HIV), hepatitis B virus (HBV), cytomegalovirus (CMV), influenza virus, respiratory syncytial virus (RSV), and hepatitis C virus (HCV).
Among the drugs used to treat HIV include protease inhibitors like lopinavir/ritonavir, which increase lipid levels in the blood, liver, and heart, in addition to weakening heart pumping activity. Endothelial damage has also been observed, which may cause atherosclerosis with its cardiovascular sequelae. Interferon-α, which is used in the treatment of multiple viral infections and cancers, has also been associated with adverse cardiac effects.
Remdesivir
Remdesivir is a prodrug that converts to an analog of the nucleotide adenosine, thereby disrupting viral replication. The vasodilation activity of adenosine can induce the release of catecholamines like epinephrine, thereby increasing the risk of ventricular tachycardia, ventricular fibrillation, and atrial fibrillation.
When administered intravenously, remdesivir can trigger QT prolongation and the potentially deadly arrhythmia torsade de pointes. Thus, continuous heart monitoring is essential for COVID-19 patients being treated with remdesivir, especially those with pre-existing cardiac disease or electrolyte abnormalities.
Paxlovid
Paxlovid, which consists of nirmatrelvir and ritonavir, may cause bradycardia and sinus dysfunction. However, it remains unclear which component of Paxlovid is responsible and what mechanisms are involved in this adverse side effect.
The toxicity of Paxlovid, when combined with tacrolimus, an immunosuppressant, has been reported in several cases. Paxlovid may also increase the risk of bleeding when used in combination with ticagrelor, warfarin, or rivaroxaban.
Paxlovid may also interact with other drugs to cause skeletal muscle breakdown and myopathy.
Molnupiravir
Esterases in host plasma activate molnupiravir to its active antiviral nucleoside analog EIDD-1931. Molnupiravir can increase oxidant stress, which may cause tissue damage. However, like Paxlovid, the use of molnupiravir can reduce the risk of severe COVID-19, particularly among those with diabetes and patients 65 years of age and older.
Other drugs
Hydroxychloroquine (HCQ) acidifies intracellular endosomes and affects the viral life cycle at multiple stages. Its therapeutic effects may be synergistic with those of azithromycin.
Nevertheless, both HCQ and azithromycin can cause prolonged QTc or cardiac arrhythmias. Thus, the combination of these drugs may not be ideal for severe COVID-19 or patients at an increased risk of QT prolongation.
Ivermectin
Ivermectin inhibits interactions between the virus and host cell, thereby preventing nuclear transport of viral proteins. However, preclinical data suggests the accumulation of ivermectin in the heart and inhibition of potassium currents. Patients with COVID-19 who are treated with ivermectin should be monitored for arrhythmias or QT prolongation.
Antibodies
Both monoclonal antibodies (mAbs) and plasma have been used to treat COVID-19. Cardiac arrhythmias have been reported with mAb, particularly following treatment with tixagevimab or cilgavimab.
The combination of cilgavimab and tocilizumab may cause thromboembolic events. Hypertension is most commonly reported with mAbs like casirivimab and imdevimab, bamlanivimab alone or with etesevimab, and sotrovimab.
Conclusions
The potential cardiovascular side effects of COVID-19 therapeutics must be carefully considered before prescribing these agents to high-risk patients. Despite reported observations of cardiotoxicity, additional studies are needed to differentiate the cardiovascular effects of SARS-CoV-2 infection from those of antivirals.
Future antiviral drug development assisted with the newest artificial intelligence platform may improve the accuracy to predict the structures of biomolecules of antivirals and therefore to mitigate their associated cardiovascular adversities.”
- Chen, E., & Xi, L. (2024). Cardiovascular adverse effects of antiviral therapies for COVID-19: Evidence and plausible mechanisms. Acta Pharmacologica Sinica. doi:10.1038/s41401-024-01382-w.
News
New mRNA therapy targets drug-resistant pneumonia
Bacteria that multiply on surfaces are a major headache in health care when they gain a foothold on, for example, implants or in catheters. Researchers at Chalmers University of Technology in Sweden have found [...]
Current Heart Health Guidelines Are Failing To Catch a Deadly Genetic Killer
New research reveals that standard screening misses most people with a common inherited cholesterol disorder. A Mayo Clinic study reports that current genetic screening guidelines overlook most people who have familial hypercholesterolemia, an inherited disorder that [...]
Scientists Identify the Evolutionary “Purpose” of Consciousness
Summary: Researchers at Ruhr University Bochum explore why consciousness evolved and why different species developed it in distinct ways. By comparing humans with birds, they show that complex awareness may arise through different neural architectures yet [...]
Novel mRNA therapy curbs antibiotic-resistant infections in preclinical lung models
Researchers at the Icahn School of Medicine at Mount Sinai and collaborators have reported early success with a novel mRNA-based therapy designed to combat antibiotic-resistant bacteria. The findings, published in Nature Biotechnology, show that in [...]
New skin-permeable polymer delivers insulin without needles
A breakthrough zwitterionic polymer slips through the skin’s toughest barriers, carrying insulin deep into tissue and normalizing blood sugar, offering patients a painless alternative to daily injections. A recent study published in the journal Nature examines [...]
Multifunctional Nanogels: A Breakthrough in Antibacterial Strategies
Antibiotic resistance is a growing concern - from human health to crop survival. A new study successfully uses nanogels to target and almost entirely inhibit the bacteria P. Aeruginosa. Recently published in Angewandte Chemie, the study [...]
Nanoflowers rejuvenate old and damaged human cells by replacing their mitochondria
Biomedical researchers at Texas A&M University may have discovered a way to stop or even reverse the decline of cellular energy production—a finding that could have revolutionary effects across medicine. Dr. Akhilesh K. Gaharwar [...]
The Stunning New Push to Protect the Invisible 99% of Life
Scientists worldwide have joined forces to build the first-ever roadmap for conserving Earth’s vast invisible majority—microbes. Their new IUCN Specialist Group reframes conservation by elevating microbial life to the same urgency as plants and [...]
Scientists Find a Way to Help the Brain Clear Alzheimer’s Plaques Naturally
Scientists have discovered that the brain may have a built-in way to fight Alzheimer’s. By activating a protein called Sox9, researchers were able to switch on star-shaped brain cells known as astrocytes and turn them into [...]
Vision can be rebooted in adults with amblyopia, study suggests
Temporarily anesthetizing the retina briefly reverts the activity of the visual system to that observed in early development and enables growth of responses to the amblyopic eye, new research shows. In the common vision [...]
Ultrasound-activated Nanoparticles Kill Liver Cancer and Activate Immune System
A new ultrasound-guided nanotherapy wipes out liver tumors while training the immune system to keep them from coming back. The study, published in Nano Today, introduces a biodegradable nanoparticle system that combines sonodynamic therapy and cell [...]
Magnetic nanoparticles that successfully navigate complex blood vessels may be ready for clinical trials
Every year, 12 million people worldwide suffer a stroke; many die or are permanently impaired. Currently, drugs are administered to dissolve the thrombus that blocks the blood vessel. These drugs spread throughout the entire [...]
Reviving Exhausted T Cells Sparks Powerful Cancer Tumor Elimination
Scientists have discovered how tumors secretly drain the energy from T cells—the immune system’s main cancer fighters—and how blocking that process can bring them back to life. The team found that cancer cells use [...]
Very low LDL-cholesterol correlates to fewer heart problems after stroke
Brigham and Women's Hospital's TIMI Study Group reports that in patients with prior ischemic stroke, very low achieved LDL-cholesterol correlated with fewer major adverse cardiovascular events and fewer recurrent strokes, without an apparent increase [...]
“Great Unified Microscope” Reveals Hidden Micro and Nano Worlds Inside Living Cells
University of Tokyo researchers have created a powerful new microscope that captures both forward- and back-scattered light at once, letting scientists see everything from large cell structures to tiny nanoscale particles in a single shot. Researchers [...]
Breakthrough Alzheimer’s Drug Has a Hidden Problem
Researchers in Japan found that although the Alzheimer’s drug lecanemab successfully removes amyloid plaques from the brain, it does not restore the brain’s waste-clearing system within the first few months of treatment. The study suggests that [...]
