The S Protein of SARS-CoV-2 Injures Cardiomyocytes Indirectly through the Release of Cytokines Instead of Direct Action.

BACKGROUND: Emerging evidence has shown that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with cardiac injury, but it remains unclear whether cardiac injury is mainly caused by direct viral infection or is secondary to SARS-CoV-2-induced cytokine storm. METHODS: Through directly treating cardiomyocytes with S protein, a crucial surface protein of SARS-CoV-2, and indirectly treating cardiomyocytes with S protein-derived human T lymphocyte conditioned medium, we compared the intensities of cardiomyocyte injuries caused by either S protein of the virus or S protein of virus-triggered cytokines. RESULTS: The directly treated cardiomyocytes did not show increasing cell apoptosis. In contrast, cardiomyocytes treated with the supernatant medium of S protein pre-conditioned peripheral blood mononuclear cells showed significantly suppressed viability. In addition, using a cardiovascular disease-specific PCR array, genes associated with hypertrophy, apoptosis, inflammation and angiogenesis were observed to be affected by cytokine stress. CONCLUSIONS: Collectively, we found that SARS-CoV-2-induced heart injury may be mainly through the S protein of the virus enhancing host immune responses instead of the S protein of the virus per se. With regards to clinical application, the strategy for treating COVID-19 should not only focus on anti-viral therapy but also on suppressing over-activated immunity.

The impact of COVID-19 on cardio-oncology care in Taiwan.

COVID-19 has not only affected the respiratory but the cardiovascular system. Taiwan has encountered a less severe COVID-19 pandemic. We reported the current situation in Taiwan. In this study, we retrospectively analyzed the data from our cardio-oncology program since October of 2019 to April of 2020 (the initial months of COVID-19 pandemic). In our cardio-oncology program, newly diagnosed breast cancer patients preparing for epirubicin therapy were included. Echocardiography, 6-min walking distance and major adverse cardiovascular events (MACEs) were recorded. To evaluate whether the social atmosphere affects cardio-oncology care, we analyzed the objective (physical) and subjective (emotional) parameters before and after January 21, 2020, when the first case of COVID-19 was confirmed in Taiwan. There was no significant decrease in patients' return ratio and LVEFs. However, there was a trend of subjective shortness of breath reported by the patients but no decline in 6 MWT. Notably, none of the enrolled patients reported MACEs during the COVID pandemic. We observed an impact of anxiety on patients receiving epirubicin but it did not influence their return ratio.

The Impact of COVID-19 on Elective Cardiovascular Procedures in Taiwan - A Single-Center Experience.

COVID-19 has reached a pandemic level and affected both individual's health and global healthcare systems. Although Taiwan has encountered a less severe COVID-19 pandemic than many other countries, it has impacted the workflow of all cardiovascular examinations and procedures. Compared to before January 21st, 2020 (the date of the first confirmed COVID-19 in Taiwan), the number of patients who have received echocardiography and cardiac catheterization has since fallen. However, the number of percutaneous coronary interventions being performed has remained at the usual level. Based on our experience, we suggest that healthcare providers in Taiwan should carefully evaluate the urgency of cardiovascular procedures and deferred non-emergent procedures. Given that the pandemic has not yet plateaued, we should remain prepared for future challenges to maintain our medical service.

Cardiovascular Complications of COVID-19 and Associated Concerns: A Review.

SARS-CoV-2 is the virus that has caused the current coronavirus disease 2019 (COVID-19) pandemic. SARS-CoV-2 is characterized by significantly affecting the cardiovascular system of infected patients. In addition to the direct injuries caused by the virus, the subsequent cytokine storm - an overproduction of immune cells and their activating compounds - also causes damage to the heart. The development of anti-SARS-CoV-2 treatments is necessary to control the epidemic. Despite an explosive growth in research, a comprehensive review of up-to-date information is lacking. Herein, we summarize pivotal findings regarding the epidemiology, complications, and mechanisms of, and recent therapies for, COVID-19, with special focus on its cardiovascular impacts.

Management of acute cardiovascular events in patients with COVID-19.

The pandemic of coronavirus disease 2019 (COVID-19) caused by the newly discovered virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), had been noticed to have high morbidity and mortality. Apart from pneumonia, COVID-19 can also cause damage to the cardiovascular system, and co-occurring with cardiovascular injury leads to a poorer prognosis. Besides, amid the pandemic of COVID-19, the management of critical cardiovascular events needs to further account for the highly infectious coronavirus, prompt and optimal treatments, clinician's safety, and healthcare provider's capacity. This review article aims to provide more comprehensive and appropriate guidance for the management of critical cardiovascular disease, including ST-segment elevation myocardial infarction (STEMI), non-STEMI acute coronary syndrome, cardiogenic shock, acute heart failure, cardiopulmonary resuscitation, and advanced care planning, during the COVID-19 epidemic.

Evidence for the Effectiveness of Remdesivir (GS-5734), a Nucleoside-Analog Antiviral Drug in the Inhibition of I K(M) or I K(DR) and in the Stimulation of I MEP.

Remdesivir (RDV, GS-5734), a broad-spectrum antiviral drug in the class of nucleotide analogs, has been particularly tailored for treatment of coronavirus infections. However, to which extent RDV is able to modify various types of membrane ion currents remains largely uncertain. In this study, we hence intended to explore the possible perturbations of RDV on ionic currents endogenous in pituitary GH3 cells and Jurkat T-lymphocytes. The whole-cell current recordings of ours disclosed that upon membrane depolarization in GH3 cells the exposure to RDV concentration-dependently depressed the peak or late components of I K(DR) elicitation with effective IC50 values of 10.1 or 2.8 µM, respectively; meanwhile, the value of dissociation constant of RDV-induced blockage of I K(DR) on the basis of the first-order reaction was yielded to be 3.04 µM. Upon the existence of RDV, the steady-state inactivation curve of I K(DR) was established in the RDV presence; moreover, the recovery became slowed. However, RDV-induced blockage of I K(DR) failed to be overcome by further addition of either α,ß-methylene ATP or cyclopentyl-1,3-dipropylxanthine. The RDV addition also lessened the strength of M-type K+ current with the IC50 value of 2.5 µM. The magnitude of voltage hysteresis of I K(M) elicited by long-lasting triangular ramp pulse was diminished by adding RDV. Membrane electroporation-induced current in response to large hyperpolarization was enhanced, with an EC50 value of 5.8 µM. Likewise, in Jurkat T-lymphocytes, adding RDV declined I K(DR) amplitude concomitantly with the raised rate of current inactivation applied by step depolarization. Therefore, in terms of the RDV molecule, there appears to be an unintended activity of the prodrug on ion channels. Its inhibition of both I K(DR) and I K(M) occurring in a non-genomic fashion might provide additional but important mechanisms through which in vivo cellular functions are seriously perturbed.

A Double-Edged Sword-Cardiovascular Concerns of Potential Anti-COVID-19 Drugs.

Coronavirus disease 2019 (COVID-19) is a pandemic infection caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). COVID-19 significantly affects multiple systems including the cardiovascular system. Most importantly, in addition to the direct injury from the virus per se, the subsequent cytokine storm, an overproduction of immune cells and their activating compounds, causes devastating damage. To date, emerging anti-SARS-CoV-2 treatments are warranted to control epidemics. Several candidate drugs have been screened and are currently under investigation. These primarily include antiviral regimens and immunomodulatory regimens. However, beyond the anti-SARS-CoV-2 effects, these drugs may also have risks to the cardiovascular system, especially altering cardiac conduction. Herein, we review the cardiovascular risks of potential anti-COVID-19 drugs.

Effective block by pirfenidone, an antifibrotic pyridone compound (5-methyl-1-phenylpyridin-2[H-1]-one), on hyperpolarization-activated cation current: An additional but distinctive target.

Pirfenidone (PFD), a pyridone compound, is well recognized as an antifibrotic agent tailored for the treatment of idiopathic pulmonary fibrosis. Recently, through its anti-inflammatory and anti-oxidant effects, PFD based clinical trial has also been launched for the treatment of coronavirus disease (COVID-19). To what extent this drug can perturb membrane ion currents remains largely unknown. Herein, the exposure to PFD was observed to depress the amplitude of hyperpolarization-activated cation current (Ih) in combination with a considerable slowing in the activation time of the current in pituitary GH3 cells. In the continued presence of ivabradine or zatebradine, subsequent application of PFD decreased Ih amplitude further. The presence of PFD resulted in a leftward shift in Ih activation curve without changes in the gating charge. The addition of this compound also led to a reduction in area of voltage-dependent hysteresis evoked by long-lasting inverted triangular (downsloping and upsloping) ramp pulse. Neither the amplitude of M-type nor erg-mediated K+ current was altered by its presence. In whole-cell potential recordings, addition of PFD reduced the firing frequency, and this effect was accompanied by the depression in the amplitude of sag voltage elicited by hyperpolarizing current stimulus. Overall, this study highlights evidence that PFD is capable of perturbing specific ionic currents, revealing a potential additional impact on functional activities of different excitable cells.