Cardiovascular Implications and Therapeutic Considerations in COVID-19 Infection

Coronavirus disease of 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) and was first reported in Wuhan, China, in December of 2019 [1]. Initial presentations from Wuhan were consistent with viral pneumonia and subsequent deep sequencing confirmed a novel RNA-based virus of the Coronaviridae family. As of June 1, 2020, there are 6.2 million confirmed worldwide cases of COVID-19 with over 375,000 deaths [2]. COVID-19 has become a worldwide pandemic and has mobilized healthcare workers in all disciplines.

Since the initial presentation of COVID-19, much has been learned about the pathophysiology and specific cardiovascular manifestations of the disease. Early in the pandemic, there was evidence that those with preexisting cardiovascular conditions were over-represented in cases of severe infection [3]. Since that time, it has become clear that certain racial and ethnic groups are disproportionately affected by COVID-19 [4]. Additionally, COVID-19 appears to have several unique cardiovascular manifestations that cardiologists must understand, including worsening of heart failure, myocarditis, a proclivity for thrombosis, and arrythmia. Finally, the speed at which clinical trials for COVID-19 are being conducted, using both repurposed and new therapies, means that cardiologists must be aware of potential cardiovascular side effects for agents that are not commonly used in cardiovascular practice.

This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

SARS-CoV-2 is a novel RNA coronavirus that has emerged as the causative infection responsible for the current COVID-19 pandemic. Other viruses from the coronavirus family include the MERS-CoV virus, responsible for the Middle East Respiratory Syndrome (MERS) outbreak, and the SARS-CoV virus, responsible for the Severe Acute Respiratory Syndrome (SARS) outbreak [5‐8]. Initial infection with SARS-CoV-2 is a process that is still being understood but is known to involve viral S proteins and host angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane protease, serine 2 (TMPRSS). SARS-CoV-2 expresses numerous spike (S) proteins on the surface of the viral envelope, which facilitates viral entry into the host cell. TMPRSS, a serine protease expressed on the host cell, primes the viral S proteins to enable interaction with the host ACE2 receptor [9]. The primed S protein then binds the S1 subunit of the host ACE2 receptor allowing for viral entry into the cell [10]. The role of the ACE2 receptor in human physiology remains under investigation but it is believed to provide counter regulation to the renin–angiotensin system [11, 12]. The ACE2 receptor is commonly found in the lungs in type 2 alveolar cells but is also expressed in vascular endothelium, gut epithelium, and in the proximal tubule in the kidneys [13‐15]. The location of the ACE2 receptor is implicated in a multitude of disease presentations associated with SARS-CoV-2 infection. After binding the ACE2 receptor, the virus is internalized, and the viral RNA is released. Immediately, the RNA-dependent RNA polymerase is translated, which allows for viral replication and spread of the infection. The role of the ACE2 receptor expression and blockade within both SARS-CoV-2 infection and disease severity remains controversial, with both protective and deleterious effects hypothesized.

The United States has surpassed other countries worldwide in case numbers with over 1.8 million cases as of June 1, 2020 [16]. The epicenter has spread from China to many European countries and now the USA, with significant clusters around the country. The number of COVID-19-related deaths worldwide has now climbed past 375,000. Due to the heterogeneity of testing strategies and case ascertainment, mortality rates remain controversial, with estimates ranging from 0.7 to 10.8%.

COVID-19 has a broad spectrum of severity and phenotypic presentation. The most typical presentation involves consequences of direct respiratory infection ranging from cough and dyspnea to hypoxia to acute respiratory distress syndrome (ARDS). The initial cohort study of COVID-19 patients included data from 552 hospitals in China with 1099 patients with COVID-19 disease [17]. The study reported that the most common symptoms at presentation were cough (67.8%), fatigue (38.1%), and temperature ≥ 37.5 °C (43.8%). In the largest published cases series of sequential COVID-19 cases from the United States in New York City, of the 5700 patients admitted to 12 different hospitals, 30% of patients presented with an initial fever and 20% presented with hypoxia [18]. Tachypnea was present in 17.3% and tachycardia in 43.1%. Mechanical ventilation was required in 12.2% of patients and early mortality was seen in 24.5%, with 3.2% of patients surviving to discharge and 72.2% remaining in the hospital. Thus, SARS-CoV-2 infection most commonly causes respiratory illness with a wide range of severity and outcomes that is relatively consistent in presentation (cough, dyspnea, fever, and hypoxia) across the globe.

The preexisting burden of comorbid chronic disease is well recognized to contribute to the severity of SARS-CoV-2 infection and there are concerns that underlying comorbid illnesses play a role in the diverse spectrum of phenotypic presentation. The initial study of 41 patients in Wuhan, China, demonstrated a predominance of male patients (73%) with pre-existing comorbidities including diabetes (20%), hypertension (15%), and cardiovascular disease (15%) [1]. The median age of patients in this group was 49 years old. Only 7% of these initial patients had a history of tobacco use. However, since these initial studies, a number of prospective and retrospective studies out of China have demonstrated higher rates of underlying comorbid conditions. Common underlying comorbidities include hypertension (30–32%), diabetes (10–28%), and cardiovascular and coronary artery diseases (11–15%) [19‐21]. Smoking history or obstructive lung disease diagnoses were low, when documented (2–10%). In these studies, these comorbidities were associated with worse severity of illness and mortality. A review of 44,672 confirmed COVID-19 cases from Wuhan, China, demonstrated increased mortality in patients with cardiovascular disease (10.5%), diabetes (7.3%), and hypertension (6%), which was significantly higher than the overall case-fatality rate of 2.3% [22].

In the United States, there are similarities and notable differences from the European and Chinese experience. Among 1482 patients admitted with COVID-19, 54.4% were men and 74.5% were over the age of 50 years, with the majority (17.2%) being over 85 years old [23]. Comorbidities included hypertension (49.7%), obesity (48.3%), diabetes mellitus (28.3%), chronic lung disease (34.6%), cardiovascular disease; including coronary disease and heart failure (27.8%), and, less frequently, renal disease (13.1%) and immunocompromised conditions (9.6%). These initial cases series have shown a similar relationship between underlying cardiac comorbidities with a higher prevalence of hypertension, diabetes, coronary artery disease, and obesity in patients requiring mechanical ventilation [24].

A concerning trend is the alarming rate at which black and Hispanic/Latino Americans are being infected and dying from COVID-19 [25]. There were early data from cities and states across the country indicating higher mortality from COVID19 in black and Hispanic/Latino populations. These included Milwaukee, WI, experiencing a 73% mortality rate in black patients who make up 26% of the population; Chicago, IL (67% of the mortality with 32% of the population); and the states of Louisiana (70% of the mortality with 32% of the population) and Michigan (41% of the mortality with 14% of the population). In the COVID-NET catchment population of the USA, a higher percentage of black patients were infected (33%) compared to the percentage of overall population being black (18%) [23]. This trend has been repeated across the country and has brought into stark reality the devastating impact COVID-19 has had on communities of color [26]. While it is well known that black and Hispanic/Latino patients have a higher incidence of diabetes and hypertension, this alone does not explain the increased infected and mortality rates. Studies during prior epidemics have continued to demonstrate similar healthcare disparities on smaller scales likely related to multiple factors including access to care, racial and ethnical stigmas among medical professionals, crowded living conditions, income instability, and continued rates of exposure and protection [27‐30]. It is crucial to acknowledge the institutionalized barriers to health as a first step to incite change and narrow the outcome gap and improve healthcare for marginalized individuals.

De novo cardiac injury has also been described in patients presenting with COVID-19 disease. Initial studies provide insight into the prevalence and incidence of acute cardiac injury patients presenting with COVID-19. Early studies reported a prevalence of acute cardiac injury of 12% in the entire cohort as defined by either high sensitivity troponin (Hs Tn) or the MB fraction of creatinine kinase (CK-MB) > 99th percentile or new echocardiographic or electrocardiographic abnormalities with greater elevations in cardiac biomarkers among patients requiring ICU care [1, 20]. A meta-analysis further clarified the prevalence of acute cardiac injury among Chinese patients presenting with COVID-19 disease reporting a similar prevalence of acute cardiac injury defined as CK-MB or Hs Tn exceeding the 99th percentile [31]. Case cohort studies included data in patients for whom the outcome and illness course helped further elucidate the role of cardiac injury in COVID-19 disease. Zhou et al. showed that the initial Hs Tn was not dramatically elevated at illness onset, but that in non-survivors there was a rapid rise starting after day 10 that was not seen in survivors [3]. Ruan et al. reported the cause of death in the non-survivors with the majority (53%) due to respiratory failure but a clinically significant number related to combined respiratory/cardiac failure (33%) and cardiac failure (7%) [32]. Based on these studies, the authors hypothesize that myocardial injury occurs frequently in patients with severe COVID disease and that myocardial dysfunction is involved in the pathophysiology of severe disease. As the pandemic progressed and patient outcomes were defined, investigators sought to evaluate the association of myocardial injury with mortality. In a multivariable Cox regression, acute cardiac injury at any point during hospital stay was associated with an increased risk of mortality (HR 4.26, 95% confidence interval 1.92–9.49). Guo et al. examined the association of cardiac comorbidities and acute cardiac injury as defined by Hs Tn above the 99th percentile with mortality in a retrospective cohort of 187 patients [19]. In this cohort, 28% of patients had acute cardiac injury. The proportion of non-survivors was increased in the groups with underlying cardiac comorbidities (hypertension, coronary artery disease, and cardiomyopathy) or myocardial injury and highest in groups with both. The authors did not assess measures of association beyond descriptive statistics. Thus, myocardial injury occurs not infrequently with COVID-19 disease and that the presence of myocardial injury portends both more severe disease and higher mortality.

The mechanism of this acute cardiac injury remains elusive. Data from Zhou et al. and Guo et al. have shown that the rise in troponin typically occurs late in the disease process, typically occurring 10–14 days after the onset of symptoms and coincides with progressive respiratory decline and multiorgan failure [3, 19]. This would suggest that myocardial injury may be a marker for more severe infection and not causally associated. However, there are few reports of systematic cardiac testing of patients with COVID-19 disease, and cardiac injury limited our ability to understand causal associations. A number of mechanisms have been proposed including direct myocardial injury and myocarditis, systemic hyperinflammatory response leading to cytokine storm and myocardial injury, microvascular thromboses, acute plaque rupture physiology, stress cardiomyopathy, and extreme oxygen supply–demand mismatch due to critical illness [33, 34]. The relative mystery surrounding the pathophysiology of acute cardiac injury has resulted in conflicting recommendations regarding the use of troponin to screen and evaluate cardiac dysfunction in patients with COVID-19 disease. A communication by the American College of Cardiology (ACC) recommended against routine cardiac biomarker testing in patients presenting with COVID-19 disease [35]. Subsequent review papers have advocated for systematic use of high-sensitivity troponin as a biomarker of severe illness with proven prognostic value in COVID-19 disease [34, 36]. However, this risk prediction strategy has not yet been evaluated prospectively.

The ongoing COVID-19 pandemic poses an enormous threat globally. Given the high prevalence of existing cardiovascular disease worldwide, it is not surprising that cardiovascular comorbidities significantly impact disease severity. The unique properties of the SARS-CoV-2 infection and pathophysiology further raise concern for de novo cardiac injury with COVID-19. The cardiovascular presentations of COVID-19 are still being elucidated, but appear to at least include decompensated heart failure, myocarditis, ACS, arrhythmia, and thrombosis. The effect of the COVID-19 pandemic on cardiovascular systems of care and whether patients are delaying necessary treatment will be of great importance to understand as the pandemic progresses in the months and years to come. Lastly, emerging therapeutic approaches have expected and unexpected cardiac effects that must be monitored as treatment algorithms expand. Cardiologists will play a vital role in the care of COVID-19 patients worldwide and in the ongoing research into the pathophysiology and population-based effects of the SARS-CoV2 virus.