The Cardiovascular Complications of COVID-19

by William Zhang

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused an ongoing global pandemic known as the coronavirus disease 2019 (COVID-19). While initially thought to be a pulmonary virus, scholars have recently argued that the virus may primarily affect the cardiovascular system instead. [1, 2] As such, SARS-CoV-2 remains a pathological mystery for the most part. This paper aims to review the interactions between SARS-CoV-2 and the cardiovascular system as well as how potential SARS-CoV-2 treatments can affect pre-existing cardiovascular complications by looking at the results of published studies. One specific study, published by Shi et al. in the March 2020 issue of JAMA Cardiology, retrospectively assessed the cardiovascular characteristics of 416 COVID-19 patients at the Renmin Hospital of Wuhan University. It was found that approximately one-fifth of the study cohort suffered from COVID-related cardiac injuries. Those who suffered cardiac injuries were of older age, and were associated with increased mortality, necessity for mechanical ventilation, and more severe complications such as acute respiratory distress syndrome (ARDS). [3] On a cellular level, COVID-19 causes cardiac damage through its affinity to the ACE2 protein that is highly expressed in cardiomyocytes. [3,4] Ultimately, a stronger understanding of COVID-19’s cardiovascular pathology is essential for the development of more effective countermeasures and treatments as well as a more specific identification of COVID-19 risk groups. 

Introduction

Since the reporting of its first case in Wuhan, China in December 2019, the novel coronavirus COVID-19 caused over a million confirmed deaths globally. The coronavirus outbreak was declared a pandemic by the World Health Organization on March 11, 2020 and continues to spread rapidly throughout the world with over 122 million confirmed cases as of March 19, 2021. [5] On a macroscopic level, the COVID-19 pandemic has caused global economic downturns due to businesses temporarily shutting down to comply with quarantine. For the average person, the COVID-19 pandemic not only poses physiological risks due to its high mortality rate, but also psychological dangers that can arise through prolonged quarantine and concern for loved ones that may be part of the COVID risk group. As such, an increased pathological understanding of COVID-19 is essential for the development of stronger preventative as well as curative approaches in order for our daily lives to return to normalcy.

COVID-19 is a member of a broader category of viruses known as coronaviruses, which are RNA viruses coated in layers of proteins that typically infect avians and mammals. According to the World Health Organization, COVID-19 is primarily spread through the respiratory tract. When an infected person expels viral droplets through coughing or sneezing, the virus remains in the air. When the airborne virus comes into contact with open orifices such as the eyes, mouth, or nose, it can enter an uninfected person and initiate a new viral infection. [6] While self-diagnosis is possible through detection of critical symptoms such as bluish lips and an inability to stay awake, confirmative diagnosis is performed through real-time reverse transcriptase polymerase chain reaction (RT-PCR) tests on nasopharyngeal swab specimens to detect viral RNA fragments. [7]

Due to COVID-19’s extensive interactions with the human respiratory system, the American Lung Association has classified it as a primarily pulmonary disease. [8] However, the pathology of COVID-19 remains mostly unknown and needs further research. In a recently published study by Reynolds et al., it was found that some COVID-19 patients exhibit hypoxemia due to abnormal vasodilation leading to ventilation-perfusion mismatches, which differs from acute respiratory distress syndrome-induced hypoxemia, where patients receive less oxygenated blood due to alveolar collapse. [9] Researchers began to suspect cardiovascular involvement because the primary receptor for COVID-19 viral entry, angiotensin-converting enzyme 2 (ACE2), is heavily expressed in cardiomyocytes, which renders them susceptible to viral infection and cellular damage. [4] Existing clinical studies also support this approach. One study, conducted by Klok et al., shows that 31% of the 184 Dutch ICU patients enrolled in the study suffered from thromboembolic complications such as ischemic stroke and deep-vein thrombosis. [10] This suggests that COVID-19 has significant cardiovascular effects, and a deeper understanding of its cardiovascular pathology can be groundbreaking for advancing COVID-19 countermeasures.

This paper focuses on the study published by Shi et al. in JAMA Cardiology in order to demonstrate how COVID-19 damages the cardiovascular system as well as how it exacerbates the patients’ pre-existing comorbidities. In this study, approximately 82 of the 416 enrolled patients suffered from cardiovascular complications. Patients with cardiac injury had higher mortality rates (51.2% vs. 4.2%), more need for mechanical ventilation (noninvasive 46.3% vs. 3.9%, invasive 22.0% vs. 4.2%), but also higher median age (74 vs. 60). [3] From these data, it can be seen that the cardiovascular factors that affect a COVID-19 patient’s health are complex, which warrants further investigation. With a stronger understanding of COVID-19’s cardiovascular complications, healthcare professionals can treat risk groups more effectively and therefore lessen the severity of COVID-19 infections in demographics such as elders and patients with pre-existing medical conditions. In addition, we can also better grasp the long-term effects of COVID-19 infections and more readily prepare against them.

Methods

The following methods are paraphrased and taken from the study published by Shi et al. in JAMA Cardiology. [3]

Participants

The study was conducted with COVID-19 patients admitted to the Renmin Hospital in Wuhan, China between January 20, 2020 and February 10, 2020. These patients were diagnosed with COVID-19 with the guidance of the World Health Organization. For the purposes of this study, the enrolled patients who did not present cardiac damage biomarkers such as high-sensitivity troponin I (hs-TNI) and creatine kinase (CK-MB), which are substances that are released into the bloodstream when the heart is under stress, were excluded from the study.

Data Collection

Metrics relevant to the study were collected by researchers from electronic medical records. The data includes: demographics, clinical history, lab test results, and results from cardiac investigations (biomarkers and EKG). Cardiac damage biomarkers were measured upon patient admission, while radiologic data were collected through chest radiography and CT scans. Patients were divided into two groups, one with cardiac injury and another without cardiac injury, where cardiac injury is defined as the expression of hs-TNI above the 99th-percentile upper reference limit. The clinical outcomes of the patients were monitored until February 15, 2020, which was the final date of the follow-up.

COVID-19 diagnoses were confirmed with the Viral Nucleic Acid Kit (Health), which extracted viral nucleic acids. The nucleic acids were then subjected to the 2019-nCoV kit (Bioperfectus), which tests for the N gene and the ORF1ab gene via RT-PCR. Positivity in both tests determine a successful diagnosis of COVID-19.

Statistical Analysis

Categorical variables involved in the study were compared to each other using the Fisher exact test or the χ2 test, while continuous variables were compared to each other using the t-test or the Mann-Whitney U-test. Continuous data were expressed as means (with standard deviation) or medians (with interquartile range), and categorical data were presented as proportions. Survival data were presented as Kaplan-Meier curves, and the survival of patients with cardiac injury versus patients without cardiac injury were analyzed through the log-rank test. Multivariate Cox regression models were used to determine the independent risk factors for death during hospitalization. For all the statistical analyses, P < .05 was considered significant.

Results

The data, figures, and results as presented in this section are all paraphrased and taken from the work of Shi et al. as published in JAMA Cardiology. [3]

Table 1. Baseline Characteristics and Laboratory and Radiographic Findings of 416 Patients With COVID-19. [3]

The retrospective chart study conducted by Shi et al. yielded a large set of patient data demonstrating the interactions between COVID-19 and the cardiovascular system (Table 1). Shi et al. separated the patients into two categories: with cardiac damage and without cardiac damage, and the two patient groups are compared against each other. For this study, cardiac injury was defined as the presence of the cardiac biomarker, hs-TNI, above the 99th percentile.

Statistical analyses show a significantly higher median age for the former group (74 vs. 60, p < 0.001), which implies stronger vulnerability for the elderly against the cardiovascular effects of COVID-19. The statistics for signs and symptoms upon admission are similar between the two groups, but it should be noted that patients who present with chest pain, a common sign of cardiovascular distress, are much more likely to experience cardiac damage from COVID-19 (13.4% vs. 0.9%, p < 0.001). 

Patients with COVID-19 comorbidities appear to have a higher risk of suffering cardiac damage. For example, a higher proportion of patients with cardiac damage suffer from hypertension as opposed to those that are infected by COVID-19 but did not experience cardiovascular symptoms (59.8% vs. 23.4%, p < 0.001). This phenomenon seems to remain consistent in this patient population across most other severe comorbidities known to medical professionals with the exception of pregnancy (0% vs. 2.1%).

Figure 1. Kaplan-Meier survival curves for COVID-19 patients. Mortality over time for patients are graphed from A. time of symptom onset and B. time of admission. In B, the maximum number was 16 days for the population with cardiac injury. C. A comparison of outcomes between patients with and without cardiac injury through log-rank test both starting from time of symptom onset and time of admission.

After analyzing the patients’ pre-admission statistics, Shi et al. also studied the progression of COVID-19 in the two patient populations by plotting their mortality against time (Fig. 1). Patients who suffered from cardiovascular damage from COVID-19 were seen as more severe cases, as it had taken them significantly shorter time to go from symptom onset to follow-up (mean, 15.6 [range 1-37] days vs. 16.9 [range 3-37] days, p < 0.001) as well as admission to follow-up (mean, 6.3 [range 1-16] days vs. 7.8 [range 1-23] days, p < 0.001). Mortality rate was also higher among the patients that experienced cardiac injury as opposed to the non-cardiac injury group (51.2% vs. 4.5%, p < 0.001). 

Table 2. Multivariate Cox Regression Analysis on the Risk Factors Associated With Mortality in Patients With COVID-19

In order to further determine the risk behind cardiovascular damage behind COVID-19, Shi et al. performed a Cox regression analysis on various risk factors and their impact on patient mortality (Table 2). The Cox regression analysis is a model that determines the the effect of multiple variables on a given event through the hazard ratio, and as seen from Shi et al.’s data, the leading risk factor of COVID-19 mortality is ARDS with an average hazard ratio of 7.89 (p < 0.001), followed by cardiac injury with an average hazard ratio of 4.26 (p < 0.001). 

Discussion

Shi et al.’s work shows that despite COVID-19’s nature as a primarily pulmonary disease, its cardiovascular complications are severe and cannot be overlooked. Even though ARDS overshadows cardiac injury as the primary risk factor for COVID-19 mortality, Shi et al. reports that patients with cardiac injury are more likely to need advanced intervention such as noninvasive and invasive mechanical ventilation. [3] Other researchers’ works have agreed with these observations, bringing the cardiovascular complications of COVID-19 to the attention of emergency care workers and even discussing the potential of chronic cardiovascular damage. [2, 11] Zheng et al. have also noted the complex interactions between COVID-19 antivirals and the cardiovascular system, citing “cardiac insufficiency, arrhythmia” among other forms of antiviral-induced cardiac toxicity as a cause for concern for patients with pre-existing cardiovascular complications. [11] While much of COVID-19’s pathophysiology remains unexplored, current research is bringing light to the importance of long-term care for COVID-19 patients even after discharge as well as the necessity for more effective treatment plans that address the severity of cardiovascular damages.

The main observation from Shi et al.’s publication is the association between cardiovascular damage from COVID-19 and its risk of mortality; two risks correlated with COVID-related cardiac injuries are comorbidities and old age. Shi et al.’s findings bring a new understanding as to how the elderly are a risk group beyond their possession of a generally weaker immune system that renders them more vulnerable to viral infections. [12] As the human body ages, so does its organs, and a weaker heart is more likely to be exploited by COVID-19 specifically. While the precise interaction between COVID-19 comorbidities and the virus itself remains unclear, Shi et al. has also cemented a strong association between the two through a cardiovascular perspective. Alongside other present research such as Klok et al.’s study on thromboembolic crises in COVID-19 patients, [10] the results highlighted in this paper will encourage further research to be done on the cardiovascular pathophysiology of COVID-19 in order to better serve known risk groups beyond knowing that the elderly and those with underlying illnesses are more susceptible to severe COVID-19 symptoms.

However, it must be noted that Shi et al. acknowledged the limitations of the study. The ongoing nature of the clinical observations may lead to further conclusions being drawn in the future, and larger patient populations must be observed in order to draw more general conclusions. [3] While the work of Shi et al. supports theories that COVID-19 can directly damage the heart due to its affinity for ACE2, [13] there have also been studies that disagree with the potential for COVID-19 to directly damage the heart. For instance, a study by Xu et al. shows that signs of cellular inflammation have been found in COVID-19 patients without significant cardiac injury, and Shi et al. cited Xu et al.’s work as a potential indication of COVID-19’s indirect involvement in cardiac injuries. [3, 14] As such, the cardiac pathophysiology of COVID-19 remains a mystery, but is certainly an aspect of the disease that necessitates further research. 

Conclusion

Shi et al.’s study was conducted in order to gain a better understanding of the pathophysiology of COVID-19 after observing potential cardiovascular correlations in the patient body. Through clinical observations as well as retrospective chart studies, Shi et al. have found that not only does COVID-19 worsen with pre-existing cardiovascular comorbidities, the presentation of new cardiac injury in COVID-19 patients is strongly associated with mortality. Despite the virus’s tendency to primarily attack the pulmonary system, Shi et al. has shown that the cardiovascular system is also a risk factor to consider, as patients with cardiovascular symptoms typically need more intensive care and intervention. These results are in agreement with existing studies showing that COVID-19 cell entry is dependent on the ACE2 protein that is heavily expressed in cardiomyocytes, which implies that cardiomyocytes are at great risk of being a target for COVID-19. Overall, Shi et al.’s findings suggest that the human heart is an important subject of study in COVID-19 pathophysiology due to its association with increased severity of symptoms. As research progresses, cardiovascular breakthroughs can help with the treatment and control of COVID-19 in the long term. 

Works Cited

[1] Kavanaugh, K. Is COVID-19 Primarily a Heart and Vascular Disease? Infection Control Today, Sep. 8, 2020, https://www.infectioncontroltoday.com/view/is-covid-19-primarily-a-heart-and-vascular-diseases

[2] Long, B et al. Am. J. Emerg. Med. 2020, 38, 1504-1507

[3] Shi, S et al. JAMA Cardiol. 2020, 5, 802-810

[4] Pérez-Bermejo, JA et al. bioRxiv. [Online] 2020. https://www.biorxiv.org/content/10.1101/2020.08.25.265561v1.full. (Accessed October 31st, 2020)

[5] COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6. (Accessed October 31st, 2020)

[6]: Coronavirus disease (COVID-19): How is it transmitted? https://www.who.int/news-room/q-a-detail/coronavirus-disease-covid-19-how-is-it-transmitted. (Accessed October 31st, 2020)

[7]: Country & Technical Guidance - Coronavirus disease (COVID-19). https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance-publications. (Accessed October 31st, 2020)

[8]: Coronavirus Disease (COVID-19). https://www.lung.org/lung-health-diseases/lung-disease-lookup/covid-19#:~:text=COVID%2D19%20is%20a%20lung,other%20than%20supportive%20care%20available. (Accessed October 31st, 2020)

[9]: Reynolds, AS et al. Am. J. Respir. Crit. Care Med. 2020, 202, 1037-1039

[10]: Klok, FA et al. Thromb. Res. 2020, 191, 145-147

[11]: Zheng, Y et al. Nat. Rev. Cardiol. 2020, 17, 259-260

[12]: Meng, H et al. Psychiatry Res. 2020, 289, 112983

[13]: South, AM. et al. Am. J. Physiol. Heart Circ. Physiol. 2020, 318, H1084-H1090 

[14]: Xu, Z et al.Lancet Respir. Med. 2020, 8, 420-422