Cardiac Manifestations Of Coronavirus (COVID-19)

Article Author:
Indranill Basu-Ray
Article Author:
Nureddin Almaddah
Article Author:
Adedayo Adeboye
Article Editor:
Michael Soos
Updated:
4/23/2020 9:26:33 PM
PubMed Link:
Cardiac Manifestations Of Coronavirus (COVID-19)

Introduction

Coronaviruses are a large family of single positive-stranded, enveloped RNA viruses that can infect many animal species and humans. Human coronaviruses can be divided based on their pathogenicity. The types with high pathogenicity including SARS-CoV, MERS-CoV, and current novel SARS-CoV2.[1] Cross-species transmission is the most likely model of the initial transmission from bat to human. The initial transfer believed to have happened in Wuhan, China.[2][3]

Etiology

As early as December 2019, cases of unusual pneumonia were presented in Wuhan, China. A novel SARS-CoV2 virus was identified as the cause of the new Corona disease 2019 (COVID-19).[4]

Epidemiology

The majority of initial COVID-19 cases were associated with travel to Hubei Province, China; however, a growing number of cases due to person-to-person transmission have been reported both in and outside of China.[4] Up to 94% of COVID-19 cases were reported to originate from Hubei Province in December 2019; as of March 2020, the greatest number of new cases are now being reported in Italy, Spain, Germany, and the United States (U.S.) which is believed to be predominantly through community transmission. Thousands of death has been reported the world over. There are currently more than one million cases confirmed with more than 113,296 deaths around the world. (updated on 04/12/2020). Based on the latest data, the U.S. had become the country with the largest number of COVID positive cases.

Pathophysiology

COVID-19 is an acute disease that targets the respiratory system primarily. SARS-CoV2 uses its S-spike to bind ACE2 receptors as an entry point to the cell. ACE 2 receptor expressed in both type1 and type 2 pneumocytes but also expressed in other types of cells, including endothelial cells. ACE2 is an inverse regulator of the renin-angiotensin system.[4][5][6]

Droplet transmission is the primary mode of transmission. The virus (SARS-CoV2) is released in respiratory secretions. A person can get infected by contact of mucus membrane (nose, eyes, or mouth) with the respiratory secretions of an actively infected person discharging virus particles. There is growing evidence that the disease may have an airborne spread, which has led many countries to recommend following appropriate precautions.

Accumulated evidence suggests that cardiac involvement is common, particularly in a patient hospitalized with COVID-19 disease. While if the same is true for all infected, symptomatic and asymptomatic people are unclear due to lack of vigilance on this cohort given the violent outburst of the disease forcing concentration of resources on hundreds if not thousands of hospitalized patients. Most of the meager available resources were also geared towards that cohort due to the sudden rise of cases world over with severe sickness and deaths that were noted.[4][7][8]

Patients with cardiac risk factors and established cardiovascular disease (CVD) seem to have a heightened vulnerability to develop COVID-19 and tend to have more severe disease with worse clinical outcomes. In a case report of 138 hospitalized COVID-19 patients (Wang et al.). 14.1% had baseline cardiovascular disease, and 31.1% had hypertension. In another smaller study of 41 patients (Huang et al.). 14.6% with baseline cardiovascular disease, 14.6% with hypertension. While in a larger cohort of 416 patients (Shaobo Shi, Mu Qin, Bo Shen, et al.), 30.5% had hypertension, 10.6% had coronary artery disease, and 5.3% had cardiovascular disease. Prognostic significance of CVD was amply illustrated with a cohort of 191 patients (Zhou et al.), where 30% had hypertension and constituted 48% of non-survivors, whereas CVD was present in 8% who constituted13% of non-survivors.[4][7][8][9]

A meta-analysis of six published studies from China, including 1527 patients with COVID-19, reported 9.7%, 16.4%, and 17.1% prevalence of diabetes, cardio-cerebrovascular disease, and hypertension, respectively. The overall case fatality rate (CFR) was 2.3% in the entire cohort but significantly higher (6%, 7.3%, and 10.5% respectively) in patients with hypertension, diabetes, and CVD.[10][11]

Multiple mechanisms have been suggested for cardiac damage based on studies on previous SARS and MERS epidemic and the currently ongoing COVID-19[5][6][12][13]:

As a part of the systemic inflammatory response of severe COVID-19 disease, a high level of cytokine surge, which can result in injury to multiple organs, including cardiac myocytes, has been documented. Studies have shown elevated levels of proinflammatory cytokines in patients with severe COVID-19 disease.[12]

Direct myocardial cells injury; the SARS-CoV2 virus uses ACE2 receptors as an entry point to the cell. ACE 2 receptor expressed in both type1 and type 2 pneumocytes but also expressed in other types of cells, including endothelial cells. ACE2 is an inverse regulator of the Renin-Angiotensin System. This interaction of SARS-CoV2 with ACE2 can result in changes of ACE2 pathways leading to acute injury to the lung, heart, and endothelial cells.[12]

Myocardial oxygen supply/demand mismatch; As a result of increased cardiometabolic demand associated with the systemic infection and ongoing hypoxia caused by severe pneumonia or acute respiratory distress syndrome can lead to increased demand in the face of inadequate supply leading to myocardial damage.[12]

Acute plaque rupture leading to acute coronary syndrome as a part of systemic inflammation and catecholamine surge inherent in this disease; increased plaque vulnerability could be associated. This will precipitate plaque rupture resulting in acute coronary syndrome.[12][14]

There are other possibilities, including medications side effects of corticosteroids, antiviral medications, and immunological agents. Electrolyte disturbance can occur in any critical systemic illness and trigger arrhythmias with a higher risk of arrhythmia in patients with underlying cardiac disease. There is particular concern about hypokalemia in COVID-19 disease; as a result interaction of SARS-CoV2 with the RAS system. Hypokalemia is well known to increases vulnerability to various kinds of arrhythmia.[12]

Histopathology

No virus RNA could be isolated from cardiac myocytes in the cardiac biopsies that performed for patients with COVID-19 in China. Cardiac biopsy was performed on a 50-year-old COVID-19 patient, and infiltration of cardiac myocytes by interstitial mononuclear inflammatory cells was noticed.[5][12]

History and Physical

COVID-19 disease mostly affects middle-aged and elderly patients. Children seem to be asymptomatic or get a mild form of the disease. The mean incubation period is about 5 days from exposure but ranges between 2 to 14 days. A higher risk of infection has been noticed in older patients, male sex, patients with medical comorbidities, patients with chronic pulmonary or chronic cardiac or chronic kidney disease, and patients with diabetes.[4][15] U.S experience indicates that up to one-fifth of infected people are between the age of  20 to 44 years who have been hospitalized, including 2% to 4% who required intensive care unit admission. The symptoms of COVID-19 are akin to other viral upper respiratory illnesses. Initial presentation can, however, be vague.  GI symptoms are present in 10% of cases, including nausea, vomiting, or diarrhea. Patients may also experience rarely headaches and confusion. Atypical presentations of infection may be more common in the elderly and immunocompromised, who may not mount a febrile response. Alteration of taste and smell, anosmia, is suspected as an early symptom of COVID-19 and is occasionally reported as a phenomenon of upper respiratory viral infection. Presently it is unclear how common it is in COVID-19. In current literature, no known reports exist in which the presenting symptoms were exclusively cardiac.[9][15]Three major trajectories for COVID-19 have been described: a mild disease with upper respiratory symptoms, non-severe pneumonia, and severe pneumonia complicated by acute respiratory distress syndrome (ARDS), necessitating aggressive resuscitative measures. Based on current reports which could be biased by available data, only hospitalized patients were noted to have cardiac involvement. Though, as alluded to earlier, this number is significant and did correlate with increased morbidity and mortality several notches higher than those without ARDS.[9]

Evaluation

Anemia, lymphopenia, hypoxemia, abnormal kidney and liver function, elevated creatine kinase and D-dimer, thrombocytopenia, and increased lactate dehydrogenase can be present. Inflammatory markers like serum ferritin and C-reactive protein were elevated. Troponin and brain natriuretic peptide may be elevated in patients with COVID-19 with cardiac involvement and should be obtained in patients with such a suspicion.[7][16]

The standard test to confirm the presence of the virus has been discussed elsewhere.[17] Certain laboratory anomalies have corresponded to cardiovascular involvement and worse outcomes. These include lymphopenia, acute kidney injury, as well as elevated lactate dehydrogenase (LDH), liver enzymes, inflammatory markers (ferritin and C-reactive protein), prothrombin time, troponin, creatine phosphokinase, and D-dimer (>1 mcg/mL).[9][18]

New studies are evaluating potential abnormal coagulation cascade in severe COVID-19 cases that may lead to microthrombi in many end organs. In those patients, high D-dimer was associated with poor prognosis and a high mortality rate. The trend of worsening lymphopenia with an attendant elevation of d dimer was seen in non-survivors than survivors.[4][19]

In a new study published in the Journal of Thrombosis and Haemostasis by Tang, N. et al., investigators utilized the finding of elevated INR, thrombocytopenia, and elevated SOFA score to calculate a sepsis-induced coagulopathy (SIC) score. Authors observed a reduction in the 28-day mortality of patients prescribed 40-60 mg enoxaparin/day or unfractionated heparin 10000-15000 U/day with SIC score greater than 4 (40.0% vs 64.2%, P=0.029), or D-dimer > 6 fold of upper limit of normal (32.8% vs 52.4%, P=0.017). 

Image finding includes:

Chest x-ray: pneumonia finding. There is no specific finding differentiate COVID-19 pneumonia from other causes of pneumonia on chest x-ray. Chest CT: Most finding includes typical peripheral distribution of ground-glass opacities, most commonly bilateral and involves the lower lobes. The current recommendation by the American College of Radiology and CDC not to use chest CT as a screening method to diagnose COVID-19.[15][20][21]

Transthoracic echocardiography is recommended for an inpatient with heart failure, arrhythmia, ECG changes, or newly diagnosed cardiomegaly on chest x-ray or CT-chest. Cardiac MRI has been used to diagnose myocarditis in a case report. However, most radiology societies have warned undue CT/MRI imaging again for cardiovascular disease purposes as it can lead to unwanted exposure of the radiology staff and add to the disease burden. Appropriate prudence is thus warranted.[22][23]

Treatment / Management

There is no approved treatment for COVID-19 disease yet. The main treatment is currently supportive. Certain drug treatments have been tried in the field without appropriate trials forced by overloaded sick patients and death in confirmed cases with COVID-19 disease. The decision of home or hospital management should be based on 3 main categories; Vital signs, laboratory data, and preexisting risk factors. Patients with severe disease usually would require oxygen support therapy that requires hospitalization and close monitoring for their clinical condition. Some severe patients will develop ARDS that would lead to respiratory failure and the requirement of ventilation support.

Patients on ACE inhibitors for hypertension and or diabetes: Given the fact that patients who are hypertensives and are on a group of drugs called ACE inhibitors who express excess ACE receptors as a reason, it has been postulated that these people may be at increased risk of contacting COVID-19. However, multiple cardiac societies, including ACC, AHA, and ESC currently recommended in patients with COVID-19 to not start ACE inhibitors or ARB but to continue prior ACE inhibitors or ARB in otherwise normal patients if there is no contraindication.[24] Patients on these drugs admitted with serious COVID infection needs to be handled on a case by case basis by the treating specialists. It is still unknown whether active treatment with ACE inhibitors alone or Hypertension perse is the cause of the increased risk of getting and developing moderate to severe disease.[9] The current recommendation is to continue patient chronic cardiac medication if there is no contraindication with close monitoring of potential side effects and drug-drug interaction. Also, in medications that affect QTC to close monitor of QTC and electrolytes (including magnesium and potassium) before and after starting medications.[23][25][26]

Non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen use, have been reported with clinical deterioration in some patients with severe COVID-19. The current recommendation to avoid NSAID use in patients with COVID-19 disease.[27] 

Potential Cardiac Side Effects of Currently Medications Being Tried for COVID-19 Management

Due to the emerging nature of COVID-19 and the urgency of management, no randomized controlled trials are showing the efficacy of specific therapy to eradicate SARS-CoV2. Some existing and some newer agents may exhibit antiviral property against this coronavirus, but most of them have to be tried in a randomized clinical trial setting to gauge their efficacy. Many of these drugs exhibit serious cardiovascular side effects which clinicians must be aware of:

azithromycin has been combined with chloroquine products with improved recovery of symptoms. Azithromycin is a macrolide has it's known to prolong QTc. Combining azithromycin with hydroxychloroquine theoretically would increase the risk of QTc prolongation and potential risk for torsade de pointes. The current recommendation to assess QTc before starting medication and close monitoring in patients with additional risk factors or patients using other medications that could enhance the QTc prolongation.[28] The ACC now provides an easy to use risk calculator to help guide providers in decided which patients are at higher risk for ventricular arrhythmia when prescribing these medications. There is particular concern about hypokalemia in COVID-19, due to the interaction of SARS-CoV2 with the renin-angiotensin-aldosterone system.[5][6][12][13]  Hypokalemia increases vulnerability to various tachyarrhythmias, and for that specific reason, we should closely monitor electrolytes and QTC in patients with COVID-19 when we start medications like azithromycin and also chloroquine.

Chloroquine has also been noted to cause AV blocks and prolonged QTc. Hydroxychloroquine, which is the more potent synthetic form of chloroquine, is being used for empirical management of COVID-19 based on a small French trial along with azithromycin, a macrolide antibiotic.[29][30] Hydroxychloroquine can similarly produce conduction defects in the heart. Additive effects of concomitant use of beta-blockers or calcium channel blockers can induce severe bradycardia leading to cerebral hypoperfusion with syncope and or fall.[31]

Lopinavir/ritonavir: These are protease inhibitors that the FDA has approved for HIV-1 infection. It has been shown to prolong PR and QT intervals leading to reports of high-grade AV blocks and rarely torsade de Pointes. They can increase serum lipid levels, and they also inhibit CYP3A4 activity, thereby decreasing serum concentration of active metabolites of clopidogrel, prasugrel while increasing that of ticagrelor as well as increasing statins levels with risk of rhabdomyolysis. A recent clinical trial did not show any added benefit of this medication, but it is still part of the protocol in many countries. Lopinavir/ritonavir potentiates the effects of factor Xa inhibitors such as apixaban and rivaroxaban through the inhibition of CYP3A4, thereby increasing bleeding risk. Thus, extreme caution is warranted in patients on multiple CVD related medicines.[32] In a recent study published in the New England Journal of Medicine, "A trial of lopinavir-ritonavir in adults hospitalized with severe COVID-19" by Cao B, et al. researchers observed no survival benefit following treatment with lopinavir/ritonavir in hospitalized adult patients with severe COVID-19. At this time, this is not currently a recommended treatment option for COVID patients.

Ribavirin is sometimes combined with lopinavir/ritonavir, it is not known to cause cardiac abnormalities directly but can indirectly by increasing the levels of lopinavir/ritonavir. It has also been reported to reduce the effect of warfarin and to have non-cardiac side effects.[33]

Methylprednisolone causes fluid retention, electrolyte derangement, and hypertension. In general, using corticosteroids in patients with COVID-19 should be avoided because of potential harm, as we learned from SARS data that indicated an increase of viral shedding.[34][35]

Interferon can cause direct cardiac myocytes toxicity and disorders of the cardiac conduction tissue.[36]

Remdesivir is an investigational drug being studied in COVID-19. There is limited information on adverse effects, but there was a patient who developed hypotension and bradycardia when this medication was used to treat Ebola.[37]

Tocilizumab an anti-IL-6R antibody and is on trials and hospital COVID-19 protocol for its potential efficacy in reducing inflammatory response including the cytokine storm contributing to ARDS and even death.[7] It is known to increase cholesterol levels, but there are conflicting reports on its effect on long term cardiac morbidity and mortality.[38]

Differential Diagnosis

The differential diagnosis for COVID-19 should be tailored to the patient and their presenting symptoms and comorbidities. Influenza, respiratory syncytial virus (RSV), other viral illnesses, and bacterial pneumonia should be considered, as well as other pulmonary diseases. Given the well-known epidemiology, antecedent travel or other sources of exposure, if present, must be elicited.[9] Cardiac presentation includes cardiac injury, heart failure, and myocarditis also are not specific and already been reported with other virus infections, including influenza.[21][39][40]

Pertinent Studies and Ongoing Trials

Multiple studies have currently been conducted investigating the potential cure effect, including hydroxychloroquine, tocilizumab, ivermectin, and other antiviral medications. Initial results using convalescent plasma of cured patients with COVID-19 in critically ill patients with COVID-19 seems promising.[41]

Prognosis

Most of the patients (80%) will get a mild form of the disease. The severe form of the disease occurs in about 15% of patients requiring hospitalization and critical form occurs in about 5% of patients requiring intensive care. The current mortality rate ranges between 2% to 5% of all patients with COVID-19 but is much higher in patients requiring invasive mechanical ventilation. The major cause of death in COVID-19 is acute respiratory distress (ARDS), but there is also significant other vital organ involvement, including the cardiovascular system and shock.[4][5][6] In the presence of chronic cardiac diseases or cardiac involvement will have a higher mortality rate in comparison to patients without cardiovascular disease.[11][26]

Complications

In a case report of 138 hospitalized patients with COVID-19 (Wang et al.), 7.2% had acute cardiac injury, and 16.7% had arrhythmia.[4] In a smaller cohort of 41 patients (Huang et al.), 12.1% had acute cardiac injury.[7] In another bigger cohort study of 416 patients (Shaobo shi, Mu Qin, Bo Shen, et al.), cardiac injury occurred in 19.7% of patients during hospitalization.[8] In another cohort (Zhou et al.) of 191 patients with COVID-19, 17.2% of patients had cardiac injury.[9] A meta-analysis of six published studies from China, including 1527 patients with COVID-19 (Li et al.) reported 8% of the patients had cardiac injury.[11]Cardiac complications of COVID-19 includes:

Myocardial cell death leading to elevated enzymes: myocardial injury is a common condition in patients hospitalized with COVID-19 disease. It is defined by an increase in the troponin level.[42] From current literature, it is noted that 12% of patients with COVID-19 disease have elevated troponin to above 0.028 ng/ml. As alluded to earlier, this is probably secondary to decrease oxygen availability compared to an increased need in the presence of cytokine storm that severe COVID 19 elucidates. Various advisories have been provided by different cardiovascular institutions; however, it is generally accepted that troponin should only be measured if acute myocardial infarction is being suspected.[7]

Myocarditis

Myocarditis defined as an inflammatory disease of the cardiac myocytes and pathologically defined by mononuclear cells infiltration of the myocytes. Patients with myocarditis should be distinguished clinically to identify high-risk fulminant myocarditis cases as those would have higher mortality.[39] The association between coronavirus infection and myocarditis is not new, as it was also noticed during MERS-CoV.[40] There has been a case report of fulminant myocarditis in a patient with COVID-19 disease with complete recovery of left ventricular ejection fraction. As a part of the treatment regimen for this patient, methylprednisolone was used.[39] Another case report of myocarditis in a COVID-19 patient was reported (Richard M. Inciardi et al.) Cardiac MRI was used to help with diagnosis, and the patient also received corticosteroids.[22] In general, using corticosteroids in patients with COVID-19 should be avoided because of potential harm, as we learned from SARS data that indicated an increase of viral shedding.[35] There is a recent case report from England of a COVID-19 patient complicated with myopericarditis causing pericardial fluid accumulation and life-threatening cardiac tamponade requiring pericardiocentesis. She was 47-year-old and did not have any cardiovascular risk factors.[43]

Heart Failure

Newly diagnosed cardiomyopathy vs. acute on chronic heart failure exacerbation have been experienced in patients with COVID-19. In a cohort of 21 intensive care severely sick patients with COVID-19, one third developed cardiomyopathy.[44] Also, patients should be monitored for signs of right-side heart failure secondary to pulmonary hypertension as a result of hypoxia and ARDS.[42] A cohort of 191 patients with COVID-19 (Zhou et al.) 44 patients (23%) had new or worsening heart failure, 28 patients survived, and 16 died.[9] Presence/absence and degree of cardiomyopathy is crucial in managing patients in shock status and also to determine the need for circulatory support and type of extracorporeal membranous oxygenation (ECMO). There is no data available about using a Swan-Ganz catheter for hemodynamic monitoring in patients with COVID-19 in shock.[42] Management of heart failure using current guidelines is recommended.[45]

Arrhythmia

Relationship of COVID-19 to induction of arrhythmia can be due to acute cardiac injury from different etiologies such as hypoxia-mediated, worsening of coronary perfusion, direct tissue damage, a product of hyperacute systemic inflammatory response syndrome or it could be due to the effects of medications used in the management of COVID-19. In a study, about 16.7% of people had arrhythmia, with an increase to 44.4% of those admitted to the ICU.[23] There is particular concern about hypokalemia in COVID-19 disease; as a result interaction of SARS-CoV2 with the RAS system.[12] Hypokalemia is well known to increases vulnerability to various kinds of arrhythmia. Recommendations for the management of arrhythmias follows a similar pattern for non-COVID patients with optimization of electrolytes, avoiding triggers including medication modification and EKG monitoring for patients with long QTc or on medications known to prolong QTc interval.[46]

Deterrence and Patient Education

During this pandemic time patients should avoid close contact with another patient with suspected or confirmed COVID-19 or having signs and symptoms of respiratory infection. Hand washing and social distancing is a principle to reduce the risk of infection. Patients with underlying cardiac disease, hypertension, cardiac transplant patients, or patients taking immunosuppressive medications should take extra caution to avoid getting infected taking into consideration data we already explained above. These recommendations also supported by CDC.

Enhancing Healthcare Team Outcomes

This is an ongoing pandemic. Health care workers should take all recommended precautions recommended by the CDC and their local hospital to avoid and prevent the spreading of the disease. As a response to COVID-19 society of cardiovascular computed tomography published recommendation (updated March 26, 2020) to minimize risk spreading of infection to health care workers including reduce the use of transesophageal echocardiogram in a patient with CAVID-19 and use cardiac CT when it is appropriate including to rule-out left atrial appendage and intracardiac thrombus before cardioversion. Also, consideration of using Cardiac CT to rule out coronary disease, which will both decrease health care worker and patient exposure. American Society of Echocardiography also released a statement on the protection of patients and echocardiography service providers during the outbreak. Managing COVID-19 patients with ACS is challenging, taking into consideration the risk of spreading infection of this highly contagious virus. Cardiovascular societies in different countries have come out with guidelines in this regard. One of the important suggestions has been to go in favor of thrombolytic therapy in STEMI patients with COVID-19 if they present within the therapeutic interval contrary to the dominant practice in the pre-COVID era. In the U.S., primary angioplasty is the standard of care, particularly in medical facilities, where it is feasible to be performed within the door to the ballon window. If percutaneous intervention is not available, patients diagnosed with COVID-19 pneumonia should be considered for medical thrombolysis if STEMI or conservatively managed with medications if not. Detailed consideration is beyond the scope of this article but available. The general agreement also prohibits the performance of complex interventions or electrophysiological procedures that are non-urgent and planned.[47]



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