The coronavirus disease of 2019 (COVID-19) is caused by coronavirus-2, which can lead to severe acute respiratory distress syndrome (SARS-CoV2).1 The rapid spread of the virus has created a huge burden on the healthcare systems throughout the world. Given the rapid spread and the number of the affected countries, the World Health Organization declared COVID-19 a pandemic on March 11, 2020. As of May 2, 2020, there have been 3,421,834 confirmed cases and 243,355 deaths, with the numbers expected to increase.2,3
The death rate of COVID-19 is believed to be considerably higher than the seasonal influenza mortality (3–4% versus 0.1%, respectively), with a reported mortality among the elderly up to 14.8%.4,5 Although COVID-19 can affect all age groups, the mortality is higher in the elderly, in patients with comorbidities, and in those who are immunocompromised. Conversely, there are very few children with significant mortality and morbidity.
SARS-CoV2 is a member of the Coronaviridae family. It is an enveloped virus, with a nonsegmented, single-stranded positive-sense ribonucleic acid (RNA) genome.6,7 Studies have demonstrated that SARS-CoV2, as well as other coronaviruses, can use the angiotensin-converting enzyme 2 receptor protein (ACE-2) for cell entry. ACE-2 is expressed in lung alveolar cells. It provides the main entry site for the virus into human hosts and also serves a role in lung protection.1 ACE-2 has a vital role in cardiovascular and immune systems and is involved in heart function and the development of hypertension and diabetes mellitus.8,9 Thus, viral binding to this receptor deregulates a long protective pathway contributing to viral pathogenicity.1
There appear to be different stages of the illness that patients may experience.
Replicative Stage: viral replication occurs over several days, and an innate immune response symptom occurs which fails to contain the virus. This is usually characterized by mild symptoms.
Adaptive Immunity Stage: an adaptive immune response eventually kicks into gear, which leads to falling titers of virus. However, this leads to increased levels of inflammatory cytokines, which leads to tissue damage and clinical deterioration.
The primary presentation of severe clinical cases is ARDS, which is characterized by diffuse alveolar damage. Pneumocytes with viral cytopathic effects are seen, implying direct virus damage.10 Emerging evidence suggests that some patients respond to COVID-19 with an exuberant “cytokine storm” reaction (with features of bacterial sepsis).11
The clinical presentation of COVID-19 is variable. Many infected individuals can be asymptomatic (as many as 20%) or show mild (81.4%), severe (13.9%), and critical (4.7%) symptoms. The symptoms include cough (60–80%), fever (45% on presentation and 85% during illness), dyspnea (30–40%), upper respiratory infection–like symptoms (15%), and gastrointestinal symptoms (10%).4,12,13 The manifestations of symptoms vary between patients. The initial symptoms of chest tightness and palpitations have also been reported in several patients.9
While the implication of COVID-19 on cardiovascular disease (CVD) and vice versa has yet to be fully described, current disease trends indicate that preexisting CVD is associated with higher morbidity and mortality among infected patients. COVID-19 can lead to CVD, including arrhythmias, myocardial infarction (MI), myocarditis, and heart failure (HF). Furthermore, cardiac involvement is often seen in the more severe cases of COVID-19, indicating that cardiac involvement is associated with higher morbidity and mortality among infected patients.
This review aims to describe the effects of COVID-19 on CVD and its impact on the management of the patients with CVD.
PREVALENCE OF CVD IN COVID-19 PATIENTS
The reported prevalence of CVD in patients with COVID-19 continues to change. Current studies from China have suggested that there is an association between preexisting CVD and COVID-19. In a meta-analysis of 6 studies including 1527 patients with COVID-19, the prevalence of hypertension, cardiac and cerebrovascular disease, and diabetes was 17.1%, 16.4%, and 9.7%, respectively.1,14 CVD comorbidities also seem to be more prevalent in the more severe cases that require admission to the intensive care unit (ICU), compared to non-ICU patients. In an analysis of 44,672 patients, an increase in case-fatality was noticed in patients with CVD (10.5%), diabetes (7.3%), and hypertension (6.0%).1,15 In another retrospective cohort study that treated 191 hospitalized COVID-19 patients, the most common comorbidities included hypertension (30%), diabetes (19%), and coronary artery disease (8%).13 Blood pressure levels were significantly higher in patients treated in the ICU than in those not treated in the ICU (mean systolic blood pressure 145 mm Hg versus 122 mm Hg; P < 0.001).6 In another study of patients with severe symptoms of COVID-19, 58% had hypertension, 25% had heart disease, and 44% had arrhythmias.16 According to mortality data released by the National Health Commission of China, 35% of patients with SARS-Co-V2 infection had a history of hypertension and 17% had a history of coronary artery disease.17
The International Society of Hypertension has released a statement indicating that there is no clear evidence that hypertension increases susceptibility to COVID-19 infection.18
A summary of risk factors, mechanisms, and cardiac complications is provided in Figure 1. Viral-related cardiac complications are not unique to COVID-19, and many other respiratory viruses have been associated with cardiac complications (Table 1).6,16,19–40
In a cohort of 137 patients, palpitations were reported in 7.3% of patients.41 In a recent study of 191 patients, 2% presented with a heart rate >125, even though the authors do not specify the rhythm the patients presented with.13 In a recent study of 138 hospitalized patients, 16.7% of patients developed arrhythmias. The arrhythmias were more present in the ICU patients (44.4%) and only in 6.9% of non-ICU patients.16 However, this study does not elaborate on the type, duration, or fatality of the arrhythmias.
In patients with ARDS, it has been reported that the development of arrhythmias is associated with an increase in mortality. In a study of 282 patients with ARDS, 28% developed atrial fibrillation (AF).42 New-onset AF (NoAF) during ARDS was associated with an increased 90-day mortality [NoAF 43% versus no NoAF 19%; APACHE-adjusted odds ratio, 3.09; 95% confidence interval (CI) 1.24–7.72; P = 0.02].42 The development of new-onset arrhythmias was described in 21% of 1051 patients in the ICU. Risk factors associated with it included ARDS, severe sepsis, septic shock, acute renal dysfunction, electrolyte disturbances, and patients on ventilator and vasopressors.43 Even though the rates of arrhythmias and their effect on mortality remain unknown, it can be expected that arrhythmias can be a frequent finding in patients with COVID-19, especially with severe disease.
Myocardial Injury, Myocarditis
Among patients with COVID-19, myocardial injury has been reported in 7–17% of patients from several studies in China.1,6,13,16 It is unclear if the cause of the myocardial injury is due to demand ischemia (tissue hypoxia, sepsis, hypotension, anemia, tachycardia) or direct viral involvement of the heart, leading to myocarditis. The rates of myocardial injury are significantly more common in patients admitted to the ICU (22.2% versus 2.0%; P < 0.0001)16 and those who died (59% versus 1%; P < 0.0001).13 Hui et al44 performed a retrospective single-center study of 41 consecutive patients using cardiac computed tomographic imaging of epicardial adipose tissue to demonstrate cardiac inflammation from COVID-19. The results showed that cardiac injury due to COVID-19 was rare in mild cases and common in severe patients, with the computed tomography scan showing low epicardial adipose tissue density in severe cases.
The National Health Commission of China reported that among the people who died from COVID-19, 11.8% of patients without underlying CVD had either elevated levels of troponin enzymes or cardiac arrest during hospitalization.9 This indicates that cardiovascular complications in COVID-19 patients can be high despite baseline cardiovascular risk factors, most likely due to the systemic inflammatory response.9
Elevated biomarkers are reported in several studies. The levels of biomarkers of myocardial injury were significantly higher in patients treated in the ICU than in those not treated in the ICU (median creatine kinase-MB level, 18 versus 14 U/L; high-sensitivity troponin level, 11.0 versus 5.1 pg/mL; P = 0.004).16 Troponin elevation was reported in 17% of patients in one study and was higher in patients who died (46% versus 1%; P < 0.0001).13 Elevated troponins are common in patients with ARDS and are associated with worse clinical outcomes (adjusted hazard ratio, 1.45; 95% CI, 1.17–1.81; P = 0.01).45 Given the frequency and nonspecific nature of abnormal troponin results among patients with COVID-19 infection, the American College of Cardiology (ACC) recommends clinicians to only measure troponin if the diagnosis of acute MI is being considered on clinical grounds, and an abnormal troponin should not be considered evidence for an acute MI without corroborating evidence.46
Myocarditis can be caused by direct infiltration of the virus but can also be secondary to severe hypoxia and cytokine storm in response to systemic infection. In a case series of 150 patients with COVID-19, 7% of deaths were attributed to myocardial damage with circulatory failure and in 33% of cases of combined respiratory failure and myocardial damage.11 In patients with myocarditis, higher levels of C-reactive protein (CRP) have been associated with worse outcomes.47 Although CRP was more elevated in patients who died versus discharged (126.6 versus 34.1; P < 0.001) in this study, no study thus far has specifically looked at CRP correlation in patients with COVID-19 and myocarditis.11 Cases of fulminant myocarditis have been reported. Hu et al48 describe the case of a 37-year-old male patient who received methylprednisolone (200 mg/d, 4 days), immunoglobulin (20 g/d, 4 days), vasopressors, norepinephrine, milrinone, and diuretic therapy. The patient made a full recovery.48
Pericarditis has yet to be described but is often associated with myocarditis. Pericardial effusion is considered a rare complication but has been described in the literature.49
The mechanism of acute myocardial injury caused by SARS-CoV2 infection might be related to ACE-2, which is widely spread in the cardiovascular system and may have a role in heart injury. Other proposed mechanisms include a cytokine storm triggered by an imbalanced response of type 1 and type 2 helper T cells and respiratory dysfunction with hypoxemia caused by COVID-19, resulting in damage to myocardial cells.9
Acute Coronary Syndrome
Patients with COVID-19 can be at risk for developing acute coronary syndrome (ACS).1 Published data on COVID-19 and ACS are still lacking; however, there is evidence from other respiratory illnesses, which suggest an association.
A link between acute infection and MI has been previously described.50 During the influenza epidemic, an increase in deaths due to CVD had been observed. The risk of having an MI has been associated with influenza infections, pneumonia, acute bronchitis, and other chest infections.51 The risk of MI after confirmed infection with influenza virus and respiratory syncytial virus or other viruses is 6, 4, and 3 times higher, respectively, than that in the year before or after infection.51,52 This pattern might be similar in COVID-19 patients, but currently the association between COVID-19 and ACS remains to be investigated.
ACS is caused by atherosclerotic plaque rupture, which contains inflammatory cells, which can be activated by an infection elsewhere in the body. Patients with ACS also have reduced cardiac reserve, and infection can lead to ischemia and clinical deterioration.51 Furthermore, patients with acute MI do worse when they require respiratory support. Approximately 1 in 23 patients hospitalized with ST-segment elevation myocardial infarction (STEMI) will require respiratory support in the form of invasive mechanical ventilation or noninvasive ventilation. STEMI patients who require respiratory support have a higher risk of death.53 This can become particularly significant in patients with COVID. Figure 2 summarizes considerations for patients with elevated troponin and ACS.
Heart Failure and Shock
HF can be a risk factor of mortality in patients with COVID-19, as well as a consequence of sepsis. Sepsis is a primary cause of death in chronic HF patients, accounting for 23.5% of deaths.54 However, HF can also be seen as a complication of sepsis.
An overproduction of immune cells called a cytokine storm can impede oxygen use by mitochondria, which can lead to acute HF even in young adults with no other cardiac risk factors or coronary artery abnormalities.51
HF has been reported in 23% of patients with COVID-19. It remains unknown if these cases included the exacerbation of a preexisting condition versus new HF. This finding was common in patients who did not survive hospitalization compared with those who did survive it (51.9% versus 11.7%; P < 0.0001).13 Elevated pro-B-type natriuretic peptide (pro-BNP) levels, which are often measured in HF patients, have also been reported in COVID-19 patients. In a study of 150 patients, elevated pro-BNP levels were reported in 22.2% of patients, with 79% in critically ill cases (P < 0.0001)55 However, pro-BNP is frequently elevated among patients with severe respiratory illnesses, typically in the absence of elevated filling pressures or clinical HF. Patients with COVID-19 often demonstrate significant elevation of BNP or NT-pro-BNP. Given the uncertainty of the significance of elevated pro-BNP, the ACC recommends not to trigger evaluation or treatment for HF, unless there is clear clinical evidence for the diagnosis.
Right-sided HF might also become a significant complication in COVID-19 patients. Acute cor pulmonale is an independent risk factor that is associated with increased 28-day mortality in ARDS patients.56 There are still no data on right-sided HF, complicating patients with severe COVID-19.
Patients requiring extracorporeal membrane oxygenation (ECMO) have been reported in several studies. In 2 studies including 138 and 1099 patients, 5 and 4 patients required ECMO, respectively, but no data on mortality were reported.4,16
In the study by Yang et al,57 5 of the 6 patients who were on ECMO died. In a study by Zhou et al13 that included 191 patients, 3 patients required ECMO and then later died. While ECMO can serve as a lifesaving rescue intervention in the setting of ARDS, there have been concerns regarding the potential harms of ECMO therapy for COVID-19 patients.58 Lymphopenia has been associated with increasing disease severity in COVID-19. Patients who died from COVID-19 have been reported to have significantly lower lymphocytes count than those who survive.11,59 ECMO can decrease the number and function of some population lymphocytes and possibly contribute to COVID-19 severity.60 ECMO is also a resource and personnel intensive intervention.
Multiple studies have also shown that interleukin (IL)-6 concentration differs significantly between survivors and nonsurvivors of COVID-19, with nonsurvivors having up to 7 times higher values.11 During ECMO, IL-6 concentrations are consistently elevated and inversely correlated to survival in children and adults.61 Those patients who survived ECMO were able to normalize their IL-6 concentrations, whereas those who died had persistently elevated values.62
Left Ventricular Assist Devices and Heart Transplant
No cases of patients requiring advanced circulatory support have been reported. Patients with left ventricular assist devices might present a challenge if infected with COVID-19. Lymphopenia and elevated IL-6, which are common among patients with severe COVID-19,11,59 are associated with worse outcomes in left ventricular assist device candidates.63,64 However, at this point, no data exist on this patient population.
The information on the predilection, presentation, and prognosis of COVID-19 in solid organ transplantation is sparse and has not been adequately reported.65 Heart transplant patients represent a vulnerable patient population to COVID-19. Whether transplantation-related immunosuppression alters the predilection for acquiring the disease, or if disease implications are modified for better or worse, remains uncertain.65
Li et al66 reported on 2 cases of patients with heart transplant, one with mild and the other with a more severe manifestation. Both patients survived the events. Their clinical presentations and laboratory findings (elevated CRP and lymphopenia) were not different from the nonimmunocompromised patient. The treatment for the patient with severe disease included withholding baseline immunosuppression and treating with high-dose corticosteroids and pooled immunoglobulin infusions. A “kitchen-sink” approach to the cases also included the use of a fluoroquinolone along with ganciclovir, but whether this therapy was useful cannot be determined by this limited reporting. The patient recovered to discharge without incurring immunological consequences on the cardiac allograft and remained rejection-free.65,66 It is unclear if lymphopenia is a manifestation of a more severe form of the disease or if it predisposes to severe disease.4,13 Many transplant-recipient patients have medication-induced lymphopenia.67 Particularly, close attention should be paid to transplant patients with suspected or confirmed coronavirus infection, who are lymphopenic. Such situations may require admission or careful monitoring of home oxygen saturation.67
The rate of venous thromboembolism (VTE) complications in COVID-19 patients remains yet to be determined. In one study, elevated D-dimer (>0.5 mg/L) was associated with more severe cases (59.6% versus 46.4%).4 In a study by Zhou et al,13 elevated D-dimers (>1 g/L) were found in 81% of patients with COVID-19 who died. Elevated D-dimer levels (>1 g/L) were strongly associated with in-hospital death, even after multivariable adjustment (odds ratio, 18.4; 95% CI, 2.6–128.6; P = 0.003).13 Two cases from Wuhan China were reported to be complicated by pulmonary embolism.68 Both patients presented with elevated levels of D-dimers. One case was diagnosed on the 10th day of admission, and the other one was diagnosed on the 6th day.
Data from other respiratory viruses have described VTE as a potential complication. A study in ICU patients with H1N1 and ARDS indicated that these patients were 33 times more likely to develop VTE.69
While the rate of VTE complicating coronavirus infections remains unknown, pulmonary embolism must be suspected, especially in patients with respiratory deterioration. It is also important to follow prophylactic measures to avoid VTE complications in COVID-19 patients.
LONG-TERM CARDIAC CONSEQUENCES
The impact of patients with COVID-19 on long-term cardiovascular outcomes remains unknown. A 12-year follow-up survey of 25 patients who recovered from SARS-CoV270 showed that 68% had hyperlipidemia, 44% had cardiovascular system abnormalities, and 60% had abnormal glucose metabolism. Metabolomics analysis revealed that lipid metabolism was dysregulated in patients with a history of SARS-COV infection, and concentrations of free acids were significantly increased.70 SARS-CoV2 has a similar structure to SARS-COV and can cause chronic damage to the cardiovascular system.9 While long-term outcomes will require further study, aggressive cardiovascular risk factor modification may have an important role after the treatment of COVID-19.
Currently, no studies have looked at the specific cardiac medications and outcomes in patients with COVID-19. A summary of considerations for cardiac medications is provided in Figure 3.
ACE-I and Angiotensin Receptor Blockers
COVID-19 binds to their target cells through ACE-2.71 Fang et al suggested that having increased levels of ACE-2 can facilitate infection with COVID-19. ACE-2 levels are increased in patients with type 1 and type 2 diabetes, in patients taking ACE-I and angiotensin receptor blockers (ARB), as well as in patients taking thiazolidinediones and ibuprofen.71,72 Fang et al72 hypothesized that the use of ACE-I and ARB can increase the risk of developing severe and fatal COVID-19, given this proposed mechanism of COVID-19.
Despite the possible upregulation of ACE-2 by the renin–angiotensin–aldosterone system (RAAS) inhibitors, there are currently no data providing a causal relationship between ACE activity and SARS-CV2–associated mortality.73 Furthermore, ACE-2 expression may not necessarily correlate with the degree of infection. Although ACE-2 is thought to be mandatory for SARS-CoV2 infection, the absence of SARS-CoV2 was observed in some ACE-2–expressing cell types, whereas infection was present in cells lacking ACE-2, suggesting that additional co-factors might be needed for efficient cellular infection.74
On the other hand, studies done in mice suggest that the SARS-CoV2 spike protein led to downregulation of ACE-2 and more severe lung injury in mice that could be attenuated by administration of an ARB, suggesting that primary activation of the RAAS in the cardiovascular patient rather than its inhibition renders them more prone to a deleterious outcome.75,76
In experimental studies, ACE-I and ARB were shown to reduce severe lung injury in certain viral pneumonia, and it has been speculated that these agents might be beneficial to COVID-19 patients.77
A Joint Statement from the ACC/Heart Failure Society of America/American Heart Association recommends against stopping ACE-I and ARB. ACE and ARB therapy are cornerstone therapies in mortality reduction in CVD and congestive HF patients, and their discontinuation can lead to deterioration of cardiac function and HF within days to weeks.77 The statement recommends individualized treatment decisions according to a patient’s hemodynamic status and the addition or removal of any RAAS-related treatments based on standard clinical practice.77
In studies conducted in China, elevated creatinine levels have been reported in 1.6–4.5% of the cases,4,13 with higher creatinine levels recorded in ICU patients and those who died.4,11,13,16 Discontinuation of ACE/ARB in these patients should be evaluated based on the degree of kidney injury.
The anti-inflammatory properties of statins have been previously discussed for their potential role in patients with acute viral infections.78 Some reports show that statins reduce CRP level reduction by 60%.79 Some observational studies have suggested that statin therapy is associated with a reduction in various cardiovascular outcomes and possible mortality in patients with influenza or pneumonia. It is conceivable that patients admitted with viral respiratory illness, including COVID-19, could derive a beneficial effect of their statin therapy. However, there is limited, mixed evidence.80 One randomized controlled trial (RCT) showed possible beneficial effects of statin administration in reducing mortality in patients with ventilator-associated pneumonia,81 while in contrast, another RCT did not support the use of statins.82
A comment from the ACC recommends the use of statins in patients with COVID-19, given their risk of cardiac injury from the virus.80 However, others have suggested that the continuation of statins can have several negative effects, including an impact on the immune system, hepatocellular injury, and an effect on muscle cells.83 Both liver dysfunction and rhabdomyolyses have been reported as possible complications in patients with COVID-19.4,13 The use of statins in ARDS also has mixed data. In a study of 128 patients who were admitted to the ICU for sepsis, it was concluded that patients who were taking a statin before the development of sepsis were less likely to develop ARDS (7% versus 29%; P = 0.005).84
In the Hydroxymethylglutaryl-CoA Reductase Inhibition with Simvastatin in Acute Lung Injury to Reduce Pulmonary Dysfunction trial of 540 patients with ARDS (41% from pneumonia), researchers did not find any differences between groups in ventilator-free days, hospital length of stay, or mortality at 28 days.85 However, a secondary analysis of the trial indicated that the hyperinflammatory sub-phenotype of ARDS had improved survival with simvastatin compared with placebo.86 While the continuation of statins in COVID-19 patients is reasonable in more moderate to severe cases, it is prudent to stop statins if liver complications and rhabdomyolysis are present.
The effects of β-blockers in patients with COVID-19 have yet to be investigated. β-blockers are one of the foundations of cardiovascular therapy incurring mortality benefits. The use of β-blockers in septic shock has raised concerns, given the decrease in heart rate as a deleterious effect of β-adrenergic receptors.
In an RCT of 77 patients with septic shock, esmolol was used in patients with a HR ≥95 bpm, who also required norepinephrine to maintain mean arterial pressure ≥65 mm Hg. This study did not show an increase in adverse events with esmolol.87
β-Blockers have also been reported to improve mortality in patients with ARDS. In the BNP for Acute Shortness of Breath Evaluation, a prospective randomized study, β-blocker trial instituted before or after ICU care was associated with improved mortality, both in-hospital and at 1 year in multivariable analyses.88 This association was demonstrated in stratified analyses for both cardiac and noncardiac causes.88
Since β-blockers are an important cardiac therapy, and current data do not suggest any considerations with COVID-19 patients, withholding β-blockers can lead to deleterious cardiac effects and possible arrhythmias, which have been associated with worse outcomes in COVID-19 patients.16 Their administration should follow the same criteria as for standard management of other septic patients. β-Blockers will most likely play an important role in the management of arrhythmias in hospitalized patients.
Antiarrhythmic Drugs and Digoxin
No guidelines exist for the use of antiarrhythmic drugs or digoxin in patients with COVID-19. Although it is probably safe to continue these drugs, several considerations should be considered for patients with more acute disease. Amiodarone has the potential for pulmonary toxicity. There are no data to determine if there is any implication of amiodarone therapy on patients with ARDS, but fulminant ARDS from amiodarone has been reported. Individualization of each specific case should occur to assure the safety of using this drug.
Renal insufficiency has been reported in COVID-19 patients, and dose adjustment of digoxin administration will be necessary. However, given that many patients with severe COVID-19 disease develop arrhythmias, digoxin and other antiarrhythmics will most probably play a key role in the management of these patients.
Nonsteroidal Anti-Inflammatory Drugs, Antiplatelet Therapy, and Anticoagulation
The use of nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin has been speculated to be aggravating factors for COVID-19 patients. NSAIDs inhibit cyclooxygenase (COX-1 and COX-2) enzymes, which are believed to be upregulated in activated human B lymphocytes that are required for optimal antibody synthesis.89 In vitro studies have found that NSAIDs inhibit antibody production at pharmacological doses.89 In a study of 168 children with acute viral infections, NSAIDs use was associated with an increased risk of empyema.90 In contrast, NSAIDs have also been found to have antiviral activity. Indomethacin was studied in vitro and in animal models, and it was found to have potent direct antiviral activity against SARS-COV2.91 This is particularly important in patients who use aspirin for cardiac disease or have a new stent requiring dual antiplatelet therapy. Currently, no data exist regarding the harmful effects of NSAIDs on COVID-19 patients. In a report from the Canadian Pharmacists Association, both NSAIDs and Tylenol are recommended for symptomatic management of patients.92
While the data on VTE and COVID-19 remain to be analyzed, patients with prolonged hospitalization and immobility have a higher risk of VTE. Prophylactic anticoagulation is important in preventing any VTE complications. For patients who develop non-STEMI or STEMI during their hospitalization, the initiation of anticoagulation like heparin is essential for plaque stability and is directly correlated with mortality and outcomes.93–95
Special consideration for antiplatelet and anticoagulation therapy should be given for bleeding patients.
Patients most commonly develop mild thrombocytopenia (rarely <100,000). A lower platelet count is associated with poor prognosis.11 Also, complications of disseminated intravascular coagulation have been reported. In these patients, clinical judgment and an assessment of risk and benefits should be used in the continuation of antiplatelet and anticoagulation therapy.4,96
COVID-19 TREATMENT IMPLICATIONS
Several medications are being studied for the treatment of COVID-19. Antiviral therapy under investigation includes ribavirin and lopinavir/ritonavir. Lopinavir/ritonavir may result in QT and PR interval prolongation, especially if there is a baseline of prolonged QT.1 Another treatment includes bevacizumab (vascular endothelial growth factor inhibitors), which has been associated with direct myocardial toxicity, hypertension, and thromboembolic events. Eculizumab, which inhibits complement activation, has been associated with hypertension, tachycardia, and peripheral edema. Interferon can cause direct myocardial toxicity, exacerbation of underlying cardiomyopathy, hypotension, and arrhythmias. Fingolimod (lymphocyte inhibitor) has been associated with hypertension, QTc prolongation, bradycardia, and atrioventricular block, and is contraindicated in patients with prior MI, unstable angina, atrioventricular block, sick syndrome, and prolonged baseline QTc. Steroids, which are commonly used to decrease inflammation, can lead to fluid retention, electrolyte disturbance, and hypertension. Tocilizumab, an IL-6 receptor inhibitor, is associated with hypertension and increases cholesterol. Chloroquine/hydroxychloroquine, an old antimalarial drug and a commonly used drug for lupus, has gained recent interest in the treatment of the COVID-19. In an open-label, non-randomized clinical trial, hydroxychloroquine treatment was significantly associated with viral load reduction/disappearance in COVID-19 patients, and its effect was reinforced by azithromycin.97 Its known side effects include direct myocardial toxicity, as well as altered cardiac conductivity, leading to bundle branch block, torsade, and ventricular arrhythmias.1,97 Azithromycin, an antibiotic typically used for pneumonia, is associated with QT prolongation.98
Many of the drugs that are being proposed for COVID-19 treatment have interactions with common cardiac drugs.1 Antivirals can interfere with anticoagulation drugs, antiplatelet drugs, statins, and antiarrhythmics. Chloroquine/hydroxychloroquine interacts with β-blockers and antiarrhythmics. If chloroquine emerges as a successful treatment, β-blockers and antiarrhythmics need to be used with caution. A detailed report of side effects and interactions is provided by Driggin et al.1
IMPACT ON MANAGEMENT OF THE CARDIAC PATIENT
The pandemic of COVID-19 has posed a huge clinical challenge and has already overwhelmed many healthcare systems in the world. This new pandemic has raised many concerns about the healthcare resources that are needed to take care of patients and protect healthcare workers. It has also raised unprecedented ethical challenges for modern medicine. Amid this pandemic, we expect the care of the cardiovascular patient to change.
One of the main concerns is that given the shift on resources to take care of COVID-19 patients, suboptimal care will be provided to the other patients. We lay out some of the different challenges that are still to come. Figure 4 summarizes the impact of COVID-19 on management of patients with CVD.
Emergency Response and Emergency Department
Emergency response systems can be overwhelmed by COVID-19–related calls. Many news outlets have reported an increase in 911 calls in regards to COVID-19.99 As the pandemic worsens, first responders are expecting an increase in 911 calls related to COVID-19 and possibly outstretching their capacity.100 This might cause a delay in response time to patients with active chest pain or other cardiac symptoms that can be life-threatening.
Many hospitals have started to experience an increase in waiting times.101 Thus, a delay in diagnosing major cardiac events like arrhythmias, ACS, or HF is of major concern. Furthermore, the long wait can also possibly mean an extended exposure to patients who have COVID-19. Li et al102 reported that 2.4% of patients in the emergency department (ED) leave without being seen by a provider, allowing for unreceived lifesaving treatment.
While anticipating a shortage in ventilators and ICU beds, medications needed in the ICU, including sedation and pain relievers, can also be in short supply. Shock complicates 1.1–20% of COVID-19 hospitalizations.4,12,13,16 Medications like pressors, which are often used for patients with HF or during catheterization, may also be in short supply. The Food and Drug Administration has already reported drug shortages and is predicting that the outbreak will affect the drug supply chains.103 The shortage of drugs is already occurring and directly affecting patients with lupus.104 Furthermore, there have been cases of noninfected patients overdosing on chloroquine in an attempt to protect themselves from COVID-19.105
Hospital and ICU Beds
Multiple reports from developed countries have shown how COVID-19 overwhelms the healthcare system. Different projections calculate that between 160 million and 214 million people in the United States can become infected with the virus; as many as 200,000 to 1.7 million people can die and 2.4 million to 21 million people can become hospitalized.106 The United States has only about 925,000 hospital beds.106 The signs of the system getting overwhelmed are already showing in states like Washington.107 On the other hand, CVD remains one of the top causes of hospitalizations and mortality in the United States and the world, accounting for 1 out of 3 deaths in the United States.108 Primary HF alone accounted for 1.1 million ED visits and 1 million hospitalizations and comorbid HF (4 million ED, 3.4 hospitalizations, and 230,000 deaths) in 2014.109 AF is the principal diagnosis in approximately 450,000 Americans.110 Patients with CVD are at a higher risk of contracting coronavirus and thus probably compose a substantial amount of COVID-19 hospitalizations and patients who die.4,13 Coronavirus has the potential to overwhelm and consume every bed in the hospital, so logistics of bed availability and hospital capacity might become one potential issue in hospitalized patients with a primary cardiovascular diagnosis.
ICU resources are particularly important for the COVID-19 pandemic. The ICU is a resource-intense setting, accounting for 20–35% of all hospital costs.111 Up to 26% of patients have required ICU support with a medial length of stay of 8 days.13,16 Some reports indicate that if this pandemic reaches the Spanish flu level, as many as 2.9 million people can require ICU admission in the United States alone.112 In an American Heart Association report, there are 534,964 staffed (operational) acute care beds, including 96,596 ICU beds, accounting for a median of 16.7% of all hospital beds.113 Currently, there are 62,188 full-featured mechanical ventilators in the United States.114,115 Cardiac patients occupy large ICU resources. One in 5 patients hospitalized with HF will require ICU admission.111 One in 23 patients admitted with a MI will require respiratory support.53 Many hospitals have cardiac and cardiac surgery–dedicated ICU beds that can now be converted into COVID-19–dedicated ICU beds, depending on the specific need of the area. Given the expected surge in the occupation of ICU beds by COVID-19 patients, as well as resources such as ventilators or ECMO, there is a possibility that longer wait times and limited resources will exist for critical cardiac patients.
Human Resources, Risk of Exposure, and Protective Equipment
Another potential issue that can arise given the ongoing pandemic is the limit of human resources. In the United States, there are reportedly 1.1 million physicians,116 2.86 million nurses,117 290,000 nurse practitioners,118 and 115,500 physician assistants.119 The Society of Critical Care Medicine reports there are 512,000 critical care nurses, 29,700 advanced care nurse practitioners, 29,000 privileged intensivists, 130,200 respiratory therapists, and 6000–7000 critical care specialists.120 Given the shortage of medical professionals, noncritical care trained doctors, nurses, and advanced practitioners might find themselves caring for critically ill COVID-19 patients. Given the shortage in providers, Italy allowed their graduating medical students to enter the workforce early to ease the burden on practicing providers.121 With the surge of patients that are expected to come to the hospitals, healthcare providers will be faced with long work hours and will become overworked.
Cardiologists represent a valuable resource in taking care of these patients, given their experience in managing complex and critical care patients. However, because COVID-19 patients will take priority, this creates the possibility of not prioritizing the other “common” cardiac patients and patients who seek care in the outpatient settings.
Reports from the outbreak suggest that transmission occurs most commonly via respiratory droplets produced when an infected individual coughs or sneezes. These droplets can land on exposed mucous membranes or be inhaled into the lungs of those within proximity.1 The virus can also live for many days on different surfaces.122 Wu et al15 demonstrated that health care workers are at elevated risk for contracting this virus, noting 1716 of the 44,672 (3.8%) of infected individuals were healthcare workers. This poses a significant challenge. If tested positive for the virus, they need to be isolated, unable to serve patients, increasing further the shortage of providers. Nonsymptomatic providers can also unknowingly serve as a vector for the infection. Family members of healthcare workers are also at-risk populations.
These facts emphasize the need for self-protection with personal protective equipment, before caring for potentially exposed COVID-19 patients. There is an ongoing concern for shortage of the appropriate medical equipment to protect healthcare workers. In addition to the known shortage of N95 masks, there are emerging shortages of gowns, gloves, and regular masks and scrubs. Many hospitals have mobilized rationing and reuse of their equipment, and a nationwide effort has been made in mobilizing the appropriate equipment to the frontline workers. Healthcare workers must follow the Center of Disease Control and Prevention guidelines for appropriate protection.123
Inpatient Consults and Outpatient Clinics
Given the number of cardiovascular complications from COVID-19, and especially the percentage of patients with elevated troponin, one can expect an increase in the number of cardiology consults, which also might lead to an overwhelmed consult service. Outpatient clinics can also experience an overflow of calls and messages, which could potentially result in a delayed response to patients who have different symptoms of their CVD.
Catheterization Laboratory, ACS Management, and Cardiac Procedures
In general, catheterization laboratories are not configured with positive pressure ventilation.1 If the hospitals have to run at their maximum capacity, there exists the possibility that the catheterization labs will be converted to COVID-19 rooms. An important consideration for the catheterization laboratory is the appropriate postintervention cleaning for all the equipment, which can increase the waiting time between procedures.1 A joint statement from the ACC Interventional Council and the Society of Cardiovascular Angiography and Intervention (SCAI) urges catheterization laboratories to prepare for likely inevitable staff shortages, due to infected/exposed/quarantined staff and/or the downstream impacts of school closings and other workforce issues.124
STEMI is a disease with high morbidity and mortality, and primary percutaneous coronary intervention is the recommended therapy.125 Systems of care have been established to expedite workflow to minimize the ischemic time from symptoms onset to definite treatment in the catheterization laboratory. However, little is known about the impact of public health emergencies on STEMI systems of care. In an observational study, researchers in China observed the care of a group of 7 patients who underwent percutaneous coronary intervention from January 25, 2020, to February 10, 2020. They compared the data with 108 STEMI patients treated in the year prior. These 7 patients were not infected with COVID-19. They had numerically longer median times from symptom onset to first medical contact [318 min (75–458) versus 82.5 min (32.5–195)], door to device [110 min (93–142) versus 84.5 (65.25–109.75)], and catheterization laboratory to device [33 min (21–37) versus 20.5 (16–27.75)].125 The full impact of the pandemic on taking care of STEMI patients has yet to be understood. While fibrinolysis is not the standard of care in the United States for STEMIs, given the COVID-19 public health crisis, ACC/SCAI recommend consideration of fibrinolysis in COVID-19–positive STEMI patients requiring a careful selection of patients. For the patients with COVID-19 for whom the decision is to perform percutaneous coronary intervention, careful management and appropriate protective equipment for all staff are needed.124
The ACC/SCAI recommends careful differentiation between type 2 MI and primary non-STEMI. For suspected COVID-19 patients, timing should allow testing before intervention. They also note that the rapid discharge of patients with non-STEMI would allow for an increase in bed availability.124
Procedures like transesophageal echocardiogram, cardiac resuscitation, and intubations124 are aerosol-generating and pose a higher risk on providers. The ACC/SCAI recommends a low threshold for intubation and avoidance of emergent intubations in the catheterization laboratory. Personal protective equipment should be worn by all staff during these procedures.124 Cardiac imaging societies, including the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, and the Society for Cardiovascular Magnetic Resonance, emphasize in their guidelines postponing nonurgent imaging and supplying appropriate protection for healthcare providers when imaging is necessary in clinical decision making.126–128
Given the predicted surge of COVID-19 patients in the US hospitals, many hospitals are minimizing or canceling elective procedures, which is also supported by the joint statement of ACC/SCAI.124 These procedures may include but are not limited to coronary artery bypass surgery and transvalvular heart catheterization. It is important to keep in mind that these procedures are often done in patients who are symptomatic and have the critical burden of disease, thus, delaying them can potentially result in a decreased quality of life.
Social Distancing and E-Visits
Social distancing is the main strategy in combating the COVID-19 pandemic. E-visits and telemedicine have emerged as the new ways of providing healthcare to patients without having them leave their homes and risk exposure. While the benefits of social distancing and telemedicine are enormous during the pandemic, we want to point out some disadvantages that might impact the care of the cardiac patient.
The main group for concern is the elderly patients who live alone or might rely on family members for food and medical supplies. Unwanted food shortages can lead to malnutrition. For those patients who need to be seen in person, a loss of their usual means of transportations might lead to a missed opportunity of being seen. Some patients with cardiac disease who need to be seen in the doctor’s office for active management of their disease might avoid in-person appointments given their concerns of the epidemic, thus allowing for possible symptom exacerbation and subpar care.
While E-visits and telemedicine are an excellent resource for many patients to avoid the potential of getting exposed to the virus, it relies on the ability to use technology, which may present a challenge for the older populations. While reportedly 70% of elderly use technology,129 a study on internet-based telemedicine reported that the older adults had more difficulty in task completion rate and task completion time.130 As telemedicine expands and becomes more common in healthcare, better training and guidance will be needed.
E-visits can miss crucial points of an in-person doctor’s visit, including a physical examination, which has significant importance in the cardiac patient and often can reveal clinical cues that are not appreciated by just the history, vital signs or relying on patients taking their vital signs, electrocardiograms, and echocardiograms, which are routinely done in the cardiology office.
Heart Transplant Delays
The wait time for heart transplants is usually several months.131 A significant concern to transplant clinicians will involve the testing of donors, decisions on organ suitability from those recently exposed or infected, and the implications of recovery of such organs by procurement teams.65 This will need to be debated and studied rapidly, as more widespread testing becomes available. With transplant teams avoiding transplanting organs from donors with a history of contact with someone at risk or diagnosed with COVID-19, wait times for recipients will increase. Postsurgical care for a heart transplant can also be difficult to manage with shortages of ICU beds.
The public health crisis that came with COVID-19 has caused unprecedented ethical dilemmas in modern medicine.1 Clinical dilemmas include triaging patients by age, comorbidities, or expected diagnosis. Normally, when encountered with ethical dilemmas, dedicated ethical committees, hospital administrators, and healthcare providers can be involved, and long detailed conversations occur between family and healthcare providers to reach a common agreement that best benefits the patient. However, this healthcare crisis has found doctors having to make difficult decisions based on resource availability, without having the ability to respect patient and family wishes on the end-of-life care, which is one of the foundations of modern medicine. These difficult decisions put a huge emotional burden on families and healthcare providers. Patients with heart disease tend to be older, with multiple comorbidities, thus running the risk to be directly affected by the difficult decisions that come with managing the public health crisis of COVID-19.132
CONCLUSIONS AND FUTURE DIRECTIONS
The COVID-19 pandemic has already affected hundreds of thousands of patients and poses a major health threat on an international level. The cardiology community will play a key role in the management and treatment of patients affected by this virus and also provide continued care to noninfected patients with underlying CVD.1
The ongoing epidemic is changing how medicine is being practiced, with doctors and patients facing unprecedented challenges. Patients run the risk of receiving suboptimal care as they might find themselves cared for by an overworked practitioner, not getting prioritized during the triage process, experiencing longer waiting times, not getting the standard of care treatment, and experiencing medication shortages while running the risk of getting exposed to the virus. Healthcare providers are at high risk of getting exposed to the COVID-19 virus, are working longer hours, experiencing burnout, and also putting their families at risk of exposure. Major efforts from healthcare systems and policymakers are currently being made in handling the surge of patients and creating efficient management of COVID-19 patients, while keeping non-COVID patients safe.
Currently, social distancing is the most powerful tool we currently have to keep patients safe, with telemedicine now being at the forefront of connecting patients with their providers. Many possible treatments are currently being investigated; however, they have yet to be confirmed as a reasonable treatment option. While still not accessible, vaccine implementation may ultimately be a powerful tool to protect people from COVID-19. The influenza vaccination was shown to reduce the risk of cardiovascular events in adults by 36%.51,52
While vaccination and treatments are an exciting possibility, they will most likely not be easily accessible during this pandemic. It is currently unknown when the COVID-19 pandemic will come to an end; thus, efforts must be made at an individual, organizational, and national level to “flatten the curve” to avoid overwhelming our healthcare system, so we can provide optimal care for all patients.
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