Cardiovascular Considerations during the COVID-19 Pandemic: Implications for Patient Management

Based on currently observed disease patterns, cardiologists will be actively involved in the care of patients with COVID-19. Infection can have a direct impact on cardiovascular diseases (CVD).

Pre-existing cardiovascular disease may predispose to COVID-19 infection. People with CVD who are infected with the virus are at high risk for adverse outcomes; and the infection itself is associated with cardiovascular complications.

Therapeutics for COVID-19 have the potential for adverse cardiovascular effects and physicians providing cardiovascular (CV) care are at risk of developing the disease or becoming vectors for the infection.

The objective of this review is to characterize the CV impact of COVID-19, its potential consequences in patients with established CVD, as well as considerations for individual patients (with and without COVID-19), healthcare workers and healthcare systems. Understanding and addressing these issues will be crucial to optimizing outcomes during the current critical period and beyond.

The authors reviewed the published literature (including multiple MEDLINE search strategies using the PubMed interface) and critically evaluated early reports on medRxiv, a preprint server.

Since the initial epicenter of this outbreak was China, most data on COVID-19 patients comes from this region. Although a systematic attempt was made to include reports and views from other highly affected countries, data related to risk factors or CV presentation were limited.

This selection bias in testing, care, and reporting may lead to differences in prevalence estimates of preexisting risk factors and patient presentation in reports from various countries. Furthermore, most existing analyses, including those related to CV complications of COVID-19, are based on retrospective and often single-center series.

No published or completed prospective cohort studies or randomized controlled trials were found in this literature search. There is an urgent need for high-quality research in this area, but at this point it is useful to review the available data.

SARS-CoV2 is an enveloped virus with a single-stranded, non-segmented, positive-sense RNA genome. Studies have shown that SARS-CoV2 and other coronaviruses can use the angiotensin-converting enzyme 2 (ACE2) protein for cellular entry. ACE2 is a membrane protein that is highly expressed in lung alveolar cells, providing the primary entry site for the virus into human hosts. ACE2 also plays a role in lung protection, and therefore viral binding to this receptor deregulates a lung protective pathway, contributing to viral pathogenicity.

Since initial identification, the disease has spread to more than 100 countries worldwide, with a crude case fatality rate of 3.8%. The infectivity of COVID-19 is higher than that of influenza, with an estimated R0 value (the basic reproduction number, which represents viral infectivity) of 2.28.

Notably, the mortality rate associated with COVID-19 is also considerably higher compared to the most recent WHO estimate of the seasonal influenza mortality rate and may reach much higher rates in elderly patients, those with comorbidities and without efficient intensive care support.

Uncertain and inconsistent determination of disease has resulted in variability in reported case mortality rates for several reasons, including:

1) The disease may be asymptomatic or mildly symptomatic in a large proportion of patients.

2) Inadequate testing capacity in most geographies, leading to frequent underdiagnosis, especially in patients with less severe diseases.

3) Complications and death often occur much later than infection (usually 2 to 3 weeks after infection).

In particular, asymptomatic infection in a considerable portion of individuals (up to 20%) may contribute significantly to the further spread of infection.

The clinical presentation of COVID-19 is quite variable. One large study reported mild disease in 81.4% of cases, severe in 13.9%, and critical in 4.7%. The clinical features of mild COVID-19 appear to include symptoms common to other viral infections (fever, cough, dyspnea, myalgia, fatigue, and diarrhea), as well as laboratory abnormalities such as lymphopenia.

In severe cases, COVID-19 can present as pneumonia, acute respiratory distress syndrome (ARDS), with or without distributive and cardiogenic shock, where elderly populations with pre-existing comorbidities are the most vulnerable. Patients with the most severe clinical presentations are likely at risk for coinfections, and worse outcomes have been observed in such cases.

Children represent the minority of confirmed cases and appear to be less susceptible to severe disease, possibly due to stronger innate immunity, fewer comorbidities, differences in viral receptor maturation, and/or prior exposure to other coronavirus species. However, moderate to severe disease has also been described in children.

The lack of widespread testing, national surveillance, and standardized data collection, as well as potential sampling bias in sick and hospitalized patients with more comorbidities, such as CVD, has complicated efforts to accurately estimate the prevalence of CVD in patients with COVID-19. 19.

Several studies in the available literature suggest an association between pre-existing CVD and severe COVID-19. A meta-analysis of six studies including 1,527 patients examined the prevalence of CVD and reported that the prevalence of hypertension, cardiac and cerebrovascular diseases, and diabetes was 17.1%, 16.4%, and 9.7%, respectively.

Patients requiring intensive care unit (ICU) admission were more likely to have these comorbidities compared to non-ICU patients.

Higher case fatality rates were noted in the analysis of 44,672 confirmed COVID-19 cases from Wuhan, China, in patients with CVD (10.5%), diabetes (7.3%), hypertension (6%), all notably higher higher than the total case fatality rate of 2.3%.

Although reports outside China are limited, data from Italy suggest similar mortality rates and an elevated risk of death in patients with comorbidities.

It is increasingly recognized that the mechanisms leading to cardiovascular disease overlap with pathways regulating immune function. For example, age is the strongest risk factor for CVD and the effect of aging on immune function may be equally important for the susceptibility and severity of COVID-19.

As an example of this, the effect of age on the immune system is exemplified by low protection titers among 50% of adults over 65 years of age who receive the influenza vaccine.

Other traditional CVD risk factors, such as diabetes and hyperlipidemia, affect immune function, and conversely, dysregulated immune status corresponds with elevated CVD risk.

Therefore, prevalent CVD may be a marker of accelerated aging/immune dysregulation and be indirectly related to COVID-19 prognosis. It has been postulated that higher ACE2 expression in patients with hypertension and cardiovascular diseases increases susceptibility to SARS-CoV2, although the data are contradictory and without a clear treatment suggestion.

It is important to consider COVID-19 in the context of an especially vulnerable group of patients, such as individuals awaiting/after a heart transplant .

Two heart transplant patients in China, one with mild disease and one with severe disease, presented with typical symptoms of COVID-19 disease. Both were managed by maintaining baseline immunosuppressive regimens and being treated aggressively with high doses of steroids, intravenous immunoglobulin, and antibiotics, and both survived without evidence of rejection.

Particularly severe infection has been observed in immunocompromised solid organ transplant recipients in previous viral outbreaks.

Organ allocation teams should consider optimal screening strategies to prevent serious infections in recipients, including whether all donor hearts need to be screened, given the existence of asymptomatic COVID-19, rather than limiting screening to patients with a history of symptoms or exposure to COVID -19. Maximum infection control precautions should be taken when interacting with these vulnerable immunocompromised patients.

Several reports suggest that SARS-CoV2 infection leads to CV complications or exacerbation of pre-existing CVD.

> Myocardial injury, myocarditis and acute coronary syndromes

Myocardial injury, defined by an increased troponin level, can occur due to myocardial ischemia or nonischemic myocardial processes, including myocarditis. With severe respiratory infection and hypoxia, especially in the setting of severe infection and ARDS due to COVID-19, several patients are likely to develop such injury.

Elevated serum troponin levels have been described in many patients infected with COVID-19, with significant differences between patients who died and those who survived to discharge. In a meta-analysis, the mean difference in cardiac troponin I levels was significantly greater in those with severe COVID-19-related disease compared to those with non-severe disease.

Reports have also suggested that acute cardiac injury, which also includes electrocardiographic and echocardiographic abnormalities, is highly prevalent in patients with COVID-19 and is associated with more severe disease and worse prognosis.

Cohort studies of hospitalized patients in China estimate that such injury occurs in 7-17% of patients hospitalized with the disease and is significantly more common in patients admitted to the ICU (22.2% vs. 2%) and among those who died (59% vs. 1%).

Previous studies in other coronavirus species have shown evidence of acute myocarditis and inflammation and myocardial damage have been reported with COVID-19 infection. Pericardial involvement has not yet been reported, further studies are needed.

The analysis carried out by Kwong et al. demonstrated that patients with acute respiratory infections are at high risk of developing acute myocardial infarction after influenza (incidence ratio 6.1) and after non-influenza-related viral illnesses. including other coronavirus species (2.8).

The development of care pathways and protocols for COVID-19 patients with STEMI suggests that both within and outside of China, this clinical scenario is highly likely. Additionally, it is important to consider the possible overlapping symptomatology between SCA and COVID-19.

As the virus continues to infect patients with significant CV risk factors or established CVD, cases of ACS are likely to develop in the context of COVID-19.

> Cardiac arrhythmia and cardiac arrest

Cardiac arrhythmias are another common CV manifestation described in patients with COVID-19 infection. Although nonspecific, heart palpitations were part of the presenting symptoms in 7.3% of patients in a cohort of 137 patients admitted for COVID-19.

In patients hospitalized with COVID-19, cardiac arrhythmia was observed in 16.7% in a Chinese cohort and was more common in ICU patients compared to non-ICU patients (44.4% vs. 6.9%).

The high prevalence of arrhythmia could be attributed, in part, to metabolic disorder, hypoxia, neurohormonal or inflammatory stress in the context of a viral infection in patients with or without previous CVD.

> Cardiomyopathy and heart failure

Zhou et al. reported that heart failure was observed in 23% of patients with COVID-19 presentations. Notably, heart failure was seen more frequently than acute kidney injury in this cohort and was more common in patients who did not survive hospitalization compared to those who did survive (51.9% vs 11.7%). .

It is still unclear whether it is due more to exacerbation of preexisting left ventricular dysfunction or new cardiomyopathy. Right heart failure and associated pulmonary hypertension should also be considered, particularly in the setting of severe parenchymal lung disease and ARDS.

> Cardiogenic and mixed shock

The predominant clinical presentation of COVID-19 is acute respiratory illness, which can lead to ARDS manifesting as ground-glass opacities on chest imaging and hypoxemia. However, similar features can be seen in the case of de novo or coexisting cardiogenic pulmonary edema.

As such, it is important to consider mixed cardiogenic or primary pulmonary cardiac causes of respiratory manifestations in COVID-19. The Berlin criteria use the time of symptom onset, imaging with bilateral lung opacities, and lack of volume overload to identify patients with ARDS.

In many cases, serum brain natriuretic peptide (BNP) and echocardiography can help clarify the diagnosis. If these tests are unclear and there remains concern for mixed presentation, pulmonary artery catheterization should be considered in selected cases to evaluate filling pressures, cardiac output, and to guide clinical decision making, given the different approaches. of treatment for ARDS and cardiogenic shock.

Finally, it is crucial to determine whether or not a concomitant cardiogenic component is present when considering mechanical respiratory and circulatory support with extracorporeal membranous oxygenation (ECMO) or other techniques, as this may lead to changes in device selection (e.g. , veno-venous versus veno-arterial ECMO).

In more severe infections with ARDS and necrotizing pneumonias, the patient’s prognosis may be poor even with ECMO support. In a case series of 52 critically ill patients with COVID-19, 83.3% of patients who were treated with ECMO did not survive, warranting additional studies on the utility of ECMO in advanced COVID-19.

> Venous thromboembolic disease

Patients infected with COVID-19 are at increased risk of venous thromboembolic disease (VTE). There are reports of abnormal coagulation parameters in hospitalized patients with severe COVID-19 illness.

In a multicenter retrospective cohort study from China, elevated D-dimer levels (>1g/L) were strongly associated with in-hospital death.

In another study comparing COVID-19 survivors with non-survivors, non-survivors had significantly higher levels of D-dimer and fibrin degradation products (FDP) and 71.4% of non-survivors met clinical criteria for clotting disseminated intravascular (DIC).

In addition to DIC, critically ill patients with prolonged immobilization have an inherently high risk of VTE. The optimal thromboprophylactic regimen for hospitalized patients with COVID-19 is unknown . Low molecular weight heparins or unfractionated heparin with or without mechanical prophylaxis are likely to be the choice in these patients.

Although there are currently no effective therapies specific for COVID-19, several pharmacological agents are under active investigation.

> Antiviral therapy

Ribavirin and lopinavir/ritonavir are under investigation in clinical trials for COVID-19 and have been used for years as components of treatment for hepatitis C and HIV, respectively.

While ribavirin has no characterized direct CV toxicity, lopinavir/ritonavir may cause QT and PR prolongation, especially in patients who have a baseline abnormality (long QT) or those who are at risk for conduction abnormalities, including those taking other QT prolonging medications.

Both ribavirin and lopinavir/ritonavir have the potential to affect anticoagulant dosing.

Lopinavir /ritonavir may also influence the activity of P2Y12 inhibitors through inhibition of CYP3A4, resulting in decreased serum concentrations of the active metabolites of clopidogrel and prasugrel and increased serum concentrations of ticagrelor (in this case the use of ticagrelor is not recommended due to the excess risk of bleeding).

In contrast, clopidogrel may not always provide sufficient platelet inhibition in the context of concomitant lopinavir/ritonavir administration. If P2Y12 inhibition is needed during lopinavir/ritonavir treatment, prasugrel can be used ; however, if contraindicated (history of stroke or TIA, low BMI, or active pathologic bleeding), alternative antiplatelet agents may be considered.

Lovastatin and simvastatin are contraindicated for coadministration with lopinavir/ritonavir due to the risk of rhabdomyolysis. Other statins, such as atorvastatin and rosuvastatin, should be given at the lowest possible dose while taking lopinavir/ritonavir.

Remdesivir is being studied in patients with COVID-19. While extensive CV toxicities and drug interactions have not yet been reported, previous evaluation of this drug during the Ebola outbreak noted the development of hypotension and subsequent cardiac arrest after the loading dose in one patient (among 175 total) .

> Other treatments

Chloroquine blocks virus infection by increasing the endosomal pH required for virus/cell fusion, and has been shown in vitro to have inhibitory activity on SARS-CoV2.

Chloroquine and the closely related hydroxychloroquine have the potential for intermediate to late myocardial toxicity.

Risk factors include exposure > 3 months, higher dose based on weight, preexisting heart disease, and renal failure. Chloroquine cardiac toxicity presents as restrictive or dilated cardiomyopathy or conduction abnormalities.

Additionally, due to inhibition of CYP2D6, beta-blockers metabolized through it (such as metoprolol, carvedilol, propranolol, or labetalol) may have a higher drug concentration that requires careful monitoring of heart rate and changes in blood pressure. Finally, both agents are associated with a conditional risk of torsade des pointes in patients with electrolyte abnormalities or with concomitant use of QT prolonging agents.

Methylprednisolone is another investigational drug currently used to treat severe cases of COVID-19 that are complicated by ARDS . This steroid is known to cause fluid retention, electrolyte disturbance, and hypertension as direct CV effects, and may also interact with warfarin through an undescribed mechanism.

> ACE2 and possible therapeutic implications

Since the ACE2 receptor is the entry mechanism for SARS-CoV2, some data suggest that ACE inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) may upregulate ACE2, thereby increasing susceptibility. to the virus.

Other studies show that ACEI/ARB can enhance the lung protective function of ACE2, which is an angiotensin II inhibitor. Overall, there is insufficient data to suggest any mechanistic connection between therapy with these agents and the acquisition of COVID-19 or the severity of the disease once acquired.

> Protective equipment for CV health workers

Early reports of the outbreak have suggested that transmission most commonly occurs through respiratory droplets produced when an infected person coughs or sneezes. These droplets can land on exposed mucous membranes or enter the lungs of nearby people, and the virus can remain active on surfaces for several days.

While the CDC had previously recommended airborne precautions for the care of patients with COVID-19, this recommendation was recently modified such that only patients undergoing aerosol-generating procedures require airborne isolation.

Recommendations made by the WHO and CDC for personal protective equipment (PPE) agree that standard contact precautions of a mask, eye protection, gown, and gloves are necessary. Additionally, additional PPE may be required when performing aerosol-generating procedures, including controlled or powered air-purifying respirators (CAPR/PAPR).

In the case of cardiac arrest , CPR efforts could result in widespread dissemination of virus particles to doctors, healthcare workers, and other patients. One measure that can help protect healthcare workers in the setting of cardiac arrest is the use of external mechanical compression devices to minimize direct contact with infected patients.

Another important consideration for the cath lab is appropriate post-intervention cleaning of all equipment potentially contaminated with SARS-CoV2. Another consideration is the fact that cath labs and operating rooms are typically configured with positive pressure ventilation, and there have been reports of facilities in China converting such facilities to negative pressure isolation in the COVID-19 environment.

Healthcare workers are at high risk of contracting this virus, as demonstrated by Wu et al., noting that 1,716 of the 44,672 (3.8%) infected people were healthcare workers.

This fact emphasizes the need for self-protection with PPE before caring for COVID-19 or potentially exposed patients, and provides additional justification for delaying elective procedures. Finally, transmission between professionals is also a major concern, especially in the context of suboptimal emergency logistics, or when PPE is in short supply.

> Classification of CV patients and consultations

An important mechanism to help prevent transmission is the use of telemedicine . This technology, already used by numerous large healthcare systems around the world, is ideal in public health crises as it allows patients to be tested while minimizing the exposure of patients and healthcare workers to potential infections.

Other essential principles are to minimize non-essential/non-urgent in-person doctor-patient interactions as much as possible (i.e., social distancing) and limit elective cardiac catheterization, operating room, and echocardiographic procedures. If such procedures are necessary, the number of personnel required should be kept to a minimum.

Recently, due to potential health concerns for cardiovascular health researchers and workers, several medical conferences around the world are being canceled or postponed. Furthermore, given the clear implications of this pandemic on CV care, numerous societies have already intervened with guidance statements.

Statements from the ESC Council on Hypertension and the European Society of Hypertension acknowledge questions about ACEI and ARB therapy in the context of patients with COVID-19. These societies, as well as some others, agree that more data would be vital to inform decisions about adjusting regimens for these agents in the context of this outbreak.

> Prepare for hospital surges and prioritize the care of critically ill patients

A significant increase in patients with COVID-19 should be anticipated. At the same time, provisions for general health services for acute and serious chronic diseases must be maintained.

Specifically, with respect to CV care, as the pandemic escalates, hospitals can prioritize the treatment of severe and high-risk patients and enact policies to prevent people who do not require medical care from visiting the doctor (and crashing the healthcare system). health).

There are reports of individual centers developing alternative pathways in ST-segment elevation myocardial infarction (STEMI) in the context of the COVID-19 crisis, such as the use of fibrinolytic therapy if delays in primary PCI are anticipated when the provision of Cath lab staffing is inadequate.

Additionally, OCUs will likely need to be repurposed as ICUs for the care of COVID-19 patients, which may limit the quality of specialized care for CV patients. Given the need for ICU beds after cardiac surgery, medical management or percutaneous intervention approaches may need to be considered for urgent scenarios that cannot wait, to minimize ICU bed utilization.

> Need for education

Information on the most up-to-date evidence on the management and treatment of patients with COVID-19 should be widely disseminated and freely available, and provided in illustrative formats (e.g., infographics) that improve public knowledge and understanding. The free flow of communication between healthcare workers and hospitals is essential to effectively combat the pandemic.

Caring for patients with COVID-19 will require the expertise of many services, including pulmonology/critical care, infectology, cardiology, surgery, pharmacy and hospital administration, among others. Optimal infection control and treatment strategies for COVID-19 should be shared with the entire medical community.

Consequently, every effort should be made to provide clear and unambiguous information to patients and decision makers, countering myths and fake news that can generate panic or false optimism. The dissemination of accurate information must occur in real time.

> Ethical challenges

COVID-19 has brought new and dramatic ethical dilemmas, from policy issues (e.g., focusing on containment and mitigation versus herd immunity) as well as clinical dilemmas (e.g., considering all patients equally or depending on age, comorbidities and prognosis, similar to other catastrophic circumstances).

Close interaction between patient representatives, government officials, medical associations, hospital administrators and other social leaders will be essential to overcome these ethical challenges.

The COVID-19 pandemic has affected hundreds of thousands of patients and represents a major health threat internationally. The cardiology community will play a key role in the management and treatment of patients affected by this disease and will also provide ongoing care to uninfected patients with underlying CVD.

Efforts to evaluate new therapies will be crucial to the treatment of this virus and, as this process develops, the intricate interplay between COVID-19, CVD and the various stakeholders involved, including patients and healthcare workers, will be further appreciated. health. Prospective randomized clinical trials and cohort studies are ongoing and will be important to help treat patients affected by this virus.

There are several theories regarding the elevated risk of adverse events for CVD patients who develop COVID-19. In particular, a better understanding of the relationship between the ACE2 protein, the use of antihypertensive agents, and the prognosis of COVID-19 will have important implications for patients with COVID-19 and CVD.

An ongoing randomized trial evaluating recombinant ACE2 in the context of COVID-19 may help provide mechanistic information in patients infected with this virus. Outside the scope of individual trials, concerted efforts by all healthcare workers and providers and incisive leadership are required to help mitigate health risk to the general population as well as CV healthcare workers.

Efficient use of resources, including leveraging telemedicine capabilities, and optimal adherence to preventive measures at the population and professional levels will enable the transition from this critical period until the disease outbreak is contained.