Cardiac complications associated with SARS-CoV-2 (COVID-19)


Background

On March 11, 2020 the World Health Organization declared the global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or COVID-19, a pandemic, making this novel coronavirus the third pandemic of the twenty-first century.1 Two days later, on March 13, 2020, the United States declared a national emergency to contain the spread of this potentially life-threatening virus. An estimated two million cases have been confirmed worldwide, with over one hundred thousand deaths. COVID-19 is a positive, single-stranded RNA virus that can ultimately lead to systemic inflammation causing acute respiratory distress syndrome (ARDS).2 Due to regulatory function disruptions within the immune system, heightened metabolic rate, and entering a hypercoagulable state, individuals are also more likely to experience cardiac complications associated with COVID-19. These complications have been shown to not only put individuals with preexisting cardiovascular disease (CVD) at an increased risk of developing a more severe disease but also lead to significantly higher mortality.3 Furthermore, patients with pre-existing CVD have a much higher risk of acquiring COVID-19.

Clinical manifestations of COVID-19 present on a spectrum ranging from mild symptoms, such as fever, cough, fatigue, myalgias, and diarrhea, to more severe symptoms, such as shortness of breath, persistent chest pain, confusion, and excessive fatigue.3 Although there is no definitive evidence, it is thought that angiotensin-converting enzyme 2 (ACE2) plays a protective role in lung injury. ACE2 has demonstrated to be responsible for decreasing angiotensin II, leading to decreased inflammation and lung injury caused by angiotensin II. The 2019 novel coronavirus disrupts this protective mechanism. Similar to SARS coronaviruses, it enters a host’s cell via ACE2 by binding to its spike protein. Once the virus enters the cell, it begins replicating, which then leads to the deregulation of lung protection.

Cardiovascular Complications

Cardiovascular (CV) complications of COVID-19 include, but are not limited to, myocardial injury and myocarditis, acute myocardial infarction, heart failure and cardiomyopathy, arrythmias, cardiogenic shock, cardiac arrest, and venous thromboembolic events.2,3 Delays in care may exacerbate CV complications associated with COVID-19.3 Risk factors associated with developing these severe complications include age > 65 years, systemic inflammation, coagulation abnormalities, severe illness, multiorgan dysfunction, and immobility. Comorbidities, such as CVD, diabetes, renal impairment, and lung impairment all predispose a patient to worse outcomes associated with COVID-19.

Myocarditis

Myocarditis associated with COVD-19 can present with a multitude of symptoms, such as persistent chest pain, dyspnea, dysthymia, and acute left ventricular dysfunction.2,3 Cardiac labs often present as abnormal highlighted by elevated troponin levels. These elevated levels have been directly correlated to an increase in patients’ risk of severe infection and higher mortality.2 In addition, electrocardiogram (ECG) changes similar to those seen in acute coronary syndrome, such as ST segment abnormalities, T wave inversion, and PR and ST segment variations (depression and elevation), have been observed. These ECG changes are due to the inflammation within the cardiac myocytes. The ECG abnormalities and elevated troponin levels in patients with COVID-19 project a more severe illness and can lead to worse outcomes. In a case series consisting of 150 patients infected with COVID-19, seven percent of the total 68 deaths were associated with myocarditis and circulatory system failure.3 One third of these deaths are thought to have played a major role in putting patients at a much higher risk of developing more severe cardiac complications resulting in death.

In the setting of COVID-19, patients with atherosclerotic disease are at risk of experiencing acute myocardial infarction (MI) due to the severity of inflammation spreading throughout the body.2 Pro-inflammatory cytokines mediate the disruption of atherosclerotic plaque, which results in plaque rupture and increases inflammation that induces procoagulant factors. This puts the body in a hypercoagulable state which predisposes these patients to ischemia and thrombosis and can lead to a higher risk of experiencing an acute MI.5 Currently, treatment of acute MI in patients with COVID-19 is being debated between the use of fibrinolysis or percutaneous coronary intervention (PCI). PCI is the preferred treatment as it is routine treatment for patients presenting with ST elevations. With the use of proper personal protective equipment (PPE), healthcare workers may carry out the procedure in order to contain the spread of the virus to clinicians.2,4 For patients with non-ST elevation (NSTEMI), conservative therapy will need to be followed.4

Heart Failure

Heart failure is another CV complication that occurs in patients with COVID-19, but the underlying mechanism is unknown.2,4 Heart failure is hypothesized to be a result of either pre-existing left ventricular dysfunction exacerbation or cardiomyopathy due to stress or inflammation. Right ventricular heart failure is also thought to be associated with pulmonary hypertension in the setting of severe parenchymal lung disease and ARDS.2

A retrospective, multicenter cohort study conducted by Zhou et al., observed that therapies under investigation for COVID-19 may have significant drug-drug interactions with CV medications to treat various CV conditions, such as heart failure and hypertension.5 Sepsis is the most frequent complication associated with COVID-19 infection, with heart failure following right after. This led to secondary infections, including ventilator associated pneumonia and death, in over half of the 23% of individuals who developed heart failure.

Venous Thromboembolic Events

Patients infected with SARS-CoV-2 are at an extremely high risk of developing venous thromboembolic events due to increased inflammation, hypoxia, immobilization, and diffuse intravascular coagulation (DIC).2,6-7 Potential risk factors include systemic inflammation, abnormal coagulation status, multiorgan dysfunction, and critical illness. In a study that treated 184 patients admitted to the ICU with confirmed COVID-19 associated pneumonia, there was a 31% incidence of thromboembolic events observed in patients admitted into the intensive care unit (ICU).7 This incidence was significantly higher compared to VTE incidences in other categories. None of these patients developed disseminated intravascular coagulation (DIC), but these findings supported the hypothesis that all patients with COVID-19 admitted into the ICU should be given an adequate dose of thrombosis prophylaxis, such as enoxaparin 40 mg twice daily. Furthermore, these patients should also be monitored for signs and symptoms associated with thrombotic complications.

CVD Complications associated with Drug Therapies

Many medications used for the treatment of SARS-CoV-2 may interact with the drug therapies used to treat CVD.3 In addition, they also come with their own set of CV toxicities. Currently, there is no definitive treatment for COVID-19; however, it is important to keep in mind the potential drug-drug interactions and adverse events associated with medications used to treat the cardiovascular system and COVID-19 investigational medications. Possible therapies currently being utilized include, but are not limited to, antivirals, antimalarials, corticosteroids, azithromycin, and other investigational treatment modalities such as tocilizumab and similar biologics.2,3

Antivirals

Using antivirals as a potential treatment option is at the forefront of treating patients infected with SAR-CoV-2. Protease inhibitors, such as lopinavir and ritonavir, have been used in combination as an investigational therapy for COVID-19.2 Ritonavir inhibits the metabolism of lopinavir, thus helping maintain adequate blood levels of lopinavir. However, lopinavir and ritonavir both interact with many medications that patients with pre-existing CVD may already be on, such as anticoagulants, antiplatelets, statins, and antiarrhythmics. For example, ritonavir is a CYP3A inhibitor which can affect the metabolism of clopidogrel despite the fact that its active metabolite is formed via CYP2C19.2 By inhibiting the active metabolite, clopidogrel may not be able to provide adequate P2Y12 inhibition, resulting in decreased platelet inhibition and increased risk of clot formation. In addition, the U.S. Preventive Services Task Force recommends that those with no prior history of CVD, such as symptomatic coronary artery disease or ischemic stroke, should still be on a low to moderate intensity statin to prevent CVD events and mortality.8 However, increased statin levels were observed when used with ritonavir and lopinavir, which resulted in patients experiencing myopathy.3 Ritonavir can also potentially cause QTc prolongation, AV node blockade, and torsades de pointes when used in combination with a statin.

Antimalarials

Antimalarials, such as chloroquine and hydroxychloroquine, were widely utilized at the beginning of this pandemic.2,3 These immune modulating therapies work by increasing the pH within the endosome which is required for SARS-CoV-2 and other viral entry into the cell.3 Although it has been demonstrated to exert inhibitory activity against SARS-CoV-2 in vitro, there is a potential risk for myocardial toxicity. Risk factors include long-term exposure (greater than 3 months), higher weight-based dose, renal insufficiency, and pre-existing cardiac issues. Moreover, these agents may also worsen cardiomyopathy by altering cardiac conduction and disturbing electrolyte balances, which may result in bundle branch block, AV block, ventricular arrhythmias, and torsades de pointes.2 Lastly, many patients infected with SARS-CoV-2 may also be on beta-blockers, which are metabolized via CYP2D6, an enzyme inhibited by these antimalarials. With an increased blood concentration of beta-blockers, the risk of developing adverse effects associated with these agents increases as well, such as bradycardia.3

Antibiotics, Steroids, and Biologics

As the pandemic progresses, alternate therapies have been considered to treat COVID-19; however, they have not been employed as frequently. These options include azithromycin, a macrolide antibiotic that interferes with bacterial protein synthesis, and methylprednisolone, a glucocorticoid that reduces inflammation.2 Additionally, azithromycin interacts with many commonly prescribed CV medications, such as antiarrhythmics, anticoagulants, and statins. It also has many adverse effects associated with its use, such as dysrhythmias, QTc prolongation, and torsades de pointes. Although the mechanism is unknown, anticoagulants are the most concerning when combined with methylprednisolone. Methylprednisolone is associated with adverse events that could lead to increased mortality in infected patients. These complications include fluid retention, electrolyte disturbances, and hypertension.2,3 Finally, tocilizumab, a biologic which inhibits IL-6, has been thought to play a role in treating COVID-19. However, it may lead to hypertension and may increase statin metabolism, thus putting patients at increased risk of developing myopathy and other statin toxicities.2

Conclusion

The COVID-19 pandemic has swept the globe and resulted in hundreds of thousands of deaths. This virus poses a huge threat to the respiratory system and the CV system. Several CV complications, such as, myocarditis, heart failure, and venous thromboembolic events may occur because of the COVID-19 infection. Moreover, many medications currently being used to manage COVID-19 have been shown to have adverse cardiac events. Thus, it is critical for clinicians to be aware of potential complications, adverse events, and drug-drug interactions. Cardiovascular management will be key in managing patients with current CVD disease and ensuring appropriate treatment and precautions are taken in patients with underlying CV complications.

References

  1. WHO Timeline - COVID-19. World Health Organization. Updated April 27, 2020. Accessed June 23, 2020. https://www.who.int/news-room/detail/27-04-2020-who-timeline---covid-19
  2. Long B, Brady WJ, Koyfman A, Gottlieb M. Cardiovascular complications in COVID-19. Am J Emerg Med. 2020;S0735-6757(20)30277-1. doi:10.1016/j.ajem.2020.04.048
  3. Driggin E, Madhavan MV, Bikdeli B, et al. Cardiovascular considerations for patients, health care workers, and health systems during the COVID-19 pandemic. J Am Coll Cardiol. 2020;75(18):2352-2371. doi:10.1016/j.jacc.2020.03.031
  4. Welt F.G.P., Shah P.B., Aronow H.D, et al. Catheterization laboratory considerations during the coronavirus (COVID-19) pandemic: from ACC’s Interventional Council and SCAI. J Am Coll Cardiol. 2020; 75(18):2372-2375. doi:10.1016/j.jacc.2020.03.021
  5. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062. doi:10.1016/s0140-6736(20)30566-3
  6. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18(4):844-847. doi:10.1111/jth.14768
  7. Klok F, Kruip M, Meer NVD, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res. 2020;191:145-147. doi:10.1016/j.thromres.2020.04.013
  8. Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Statin use for the primary prevention of cardiovascular disease in adults. JAMA. 2016;316(19):1997-2007. doi:10.1001/jama.2016.15450
Prepared by:
Rawan Zayed, PharmD Candidate 2021
Nerissa Caballes, PharmD, MS, CRC
Rucha Patel, PharmD
University of Illinois at Chicago
College of Pharmacy

The information presented is current as of August 2020. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.