Open access peer-reviewed chapter - ONLINE FIRST

Impairment of the Cardiovascular System during SARS-CoV-2 Infection

Written By

Cristina Tudoran, Mariana Tudoran, Voichita Elena Lazureanu, Adelina Raluca Marinescu, Dorin Novacescu and Talida Georgiana Cut

Submitted: February 12th, 2022 Reviewed: February 27th, 2022 Published: May 13th, 2022

DOI: 10.5772/intechopen.103964

RNA Viruses Edited by Yogendra Shah

From the Edited Volume

RNA Viruses [Working Title]

Ph.D. Yogendra Shah

Chapter metrics overview

4 Chapter Downloads

View Full Metrics


Although the infection with the severe acute respiratory syndrome (SARS-CoV-2) virus affects primarily the respiratory system, it became evident from the very beginning that the coronavirus disease 2019 (COVID-19) is frequently associated with a large spectrum of cardiovascular involvements such as myocarditis/pericarditis, acute coronary syndrome, arrhythmias, or thromboembolic events, explained by a multitude of pathophysiological mechanisms. Individuals already suffering of significant cardiovascular diseases were more likely to be infected with the virus, had a worse evolution during COVID-19, with further deterioration of their basal condition and increased morbidity and mortality, but significant cardiac dysfunctions were diagnosed even in individuals without a history of heart diseases or being at low risk to develop such a pathology. Cardiovascular complications may occur anytime during the course of COVID-19, persisting even during recovery and, potentially, explaining many of the persisting symptoms included now in terms as subacute or long-COVID-19. It is now well accepted that in COVID-19, the occurrence of cardiovascular impairment represents a significant negative prognostic factor, immensely rising the burden of cardiovascular pathologies.


  • COVID-19
  • inflammation
  • cytokine storm
  • myocardial injury
  • heart failure
  • thromboembolic events
  • arrhythmias

1. Introduction

Since the end of 2019, when the first cases were documented in Wuhan (China), the corona virus disease 2019 (COVID-19), a zoonotic infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread rapidly and rampantly, raising major concerns regarding public health, while applying an unprecedented, continuous strain, on the global medical infrastructure. COVID-19 was officially declared a pandemic by the World Health Organization on 11 March 2020 [1], and since then it has affected over 400 million people worldwide, with a cumulative mortality rate of under 2% [2] and recent alleviation of clinical outcomes due to the development and widespread implementation of efficient vaccination. Taking into account the extreme polymorphism of clinical presentations, ranging from asymptomatic to severe systemic effects, mainly involving the respiratory and cardiovascular systems, and fatal, rapidly progressing, acute respiratory distress syndrome (ARDS), the containment of transmission, at least in the pre-vaccination era, and the therapeutic management of COVID-19 and its systemic complications, has proven to be quite a challenge for clinicians, especially in the case of high-risk patients [3].

A novel member of the β-coronavirus genus, group 2, the enveloped, positive-sense RNA single-stranded SARS-CoV-2, has established itself as the third emerging, highly pathogenic coronavirus, to infect humans and cause a large-scale outbreak since the early 2000s, after severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) [4]. Even though mortality rates are lower for SARS-CoV2 than for previous related coronavirus outbreaks (>35% for MERS-CoV and > 10% for SARS-CoV), contagiousness is much higher (MERS-CoV and SARS-CoV had only 10000 cumulative cases between them), as transmission is mainly airborne (via respiratory droplets), with multiple alternative mechanisms being reported (aerosols, direct contact with contaminated surfaces, and fecal-oral transmission [4]).

From a genomic viewpoint, SARS-CoV-2 shares ~80% sequence identity with SARS-CoV and ~ 50% with MERS-CoV, encoding 16 nonstructural proteins (that make up the replicase complex), 9 accessory proteins, and 4 structural proteins – spike (S), envelope (E), membrane (M), and nucleocapsid (N). The SARS-CoV-2 life cycle revolves around the envelope S protein. Direct contact between the Spike receptor-binding domain and the innate cellular receptor (angiotensin-converting enzyme 2 – ACE2), if provided adequate cleavage of the viral Spike S1/S2 polybasic cleavage site by host-cell proteolytic enzymes, will ensure Spike activation in endosomes and virus-cell membrane fusion (cell surface and endosomal compartments), allowing viral RNA to be released into the host-cell cytosol. Viral replication ensues, with subsequent expulsion into the intercellular space [4]. In fact, the S gene of SARS-CoV-2 represents the distinguishing genomic feature from SARS-CoV, sharing <75% nucleotide identity [4].

The main tissue tropism of SARS-CoV-2 is pulmonary, targeting high ACE2 expression cells (airway/alveolar epithelial cells, vascular endothelial cells, and alveolar macrophages) [5]. Even so, higher levels of ACE2 messenger RNA expression can be found in many extra-pulmonary tissues as well and nearly undetectable amounts of ACE2 still support viral host-cell entry. Therefore, additional, underappreciated, cell-intrinsic factors must also be involved in host-cell entry [4]. Noteworthy, a subpopulation of human type II alveolar cells has been documented, which manifest abundant ACE2 expression, and concomitant high levels of messenger RNA, specific to certain cellular proviral genes (coding elements of the, SARS-CoV-2 cell entry facilitating, and endosomal transport system) [6]. Also, ACE2 expression regulation must be considered, as, during viral infection, ACE2 gene expression in human airway epithelial cells is upregulated by type I and II interferons [5].

Considering the multitude of the medical literature written on the topic of multisystem impairment occurred during the infection with the SARS-CoV-2 virus, the purpose of our research was to summarize the opinions of experts concerning the cardiovascular alterations associated with COVID-19, and for this aim we reviewed the most significant articles published on PubMed, Medline, and Research gate on these topics and provided individualized summaries of expert opinions.


2. Effects of the SARS-CoV-2 virus on the cardiovascular system

The COVID-19 pandemic greatly challenged clinicians, both due to the sheer number of patients, but also because of the lack of therapeutic consensus and incomplete understanding of disease pathogenesis. Most fatal cases of COVID-19 relate to a severe atypical pneumonia, accompanied by a sudden systemic deterioration, despite therapeutic intervention in the hospital setting.

The infection with the SARS-CoV-2 virus primarily affects the respiratory structures, but the involvement of the cardiovascular system is also frequent. Cardiovascular complications in addition to respiratory disease may develop in all phases of COVID-19, which can start with the dramatic picture of acute heart failure (ACF), acute coronary syndrome (ACS), pulmonary venous thromboembolism (VTE), or even sudden cardiac death, as shown in Figure 1. The pathophysiological mechanisms underlying these disproportionate effects of the SARS-CoV-2 infection on patients with cardiovascular comorbidities, however, remain incompletely understood [7]. Thromboembolic events, usually accompanied by violent, pulmonary, and/or systemic complications, have been described from early on, since the beginning of the pandemic, with infectious inflammatory response patterns rapidly shifting into a typical systemic inflammatory response syndrome (SIRS) or ARDS, which could potentially induce multi-organ failure (MOF) and, subsequently, death. As we enter the third year of the pandemic, COVID-19 pathophysiology is slowly unraveling as we begin to better comprehend the complex interplay between the direct cytotoxic effects of SARS-CoV-2 on pneumocytes and endothelial cells, the emerging local and systemic inflammatory response, and the ways in which these responses interact with hemostatic homeostasis, a mechanism which has been deemed as central and, at least to this extent, unprecedented [8].

Figure 1.

Main COVID-19-associated cardiovascular complications and underlying pathophysiological mechanisms.

2.1 Cardiac tissue damage

COVID-19 was initially considered to be solely a respiratory disease, yet clinical outcomes quickly revealed that, undeniably, this infection implies multi-organ involvement. Perhaps most notably, the heart has been shown to represents a target organ for SARS-CoV-2-related pathogenesis, with a high prevalence of cardiac injury following COVID-19, often diagnosed only through biomarker evaluation. Beyond subclinical myocardial damage, SARS-CoV-2 infection may also cause more aggressive, clinically apparent modifications, such as myocarditis, accompanied by a subsequent diastolic dysfunction or severe reduction of left ventricle ejection fraction, not to mention the fact that heart failure may represent a short−/long-term consequence of COVID-19-related inflammatory cardiomyopathy, with dramatic consequences regarding prognosis [9].

Regarding myocardial damage in COVID-19, although the full pathophysiology is still incompletely understood, multiple mechanisms are most likely incriminated (see Figure 2), which, globally, can be divided into two main groups: direct, specific modifications, related to the cytopathic effects of SARS-CoV-2 infection, and indirect, general modifications, commonly seen in other severe infections, as well [10].

Figure 2.

Pathophysiology of COVID-19-related myocardial injury [15,16].

2.1.1 Direct cytopathic myocardial injury

The aforementioned ACE2, a type I transmembrane protein, highly expressed in different organs (heart, lungs, gut, and kidneys), mediates SARS-CoV-2 entry into the host cells, with different clinical implications, depending on the targeted organ, and represents the key molecular entity involved in the direct cytopathic effects of SARS-CoV-2 infection within the cardiac tissue. After entering the host cell through the host ACE2 receptor, SARS-CoV-2 utilizes the host’s RNA-dependent RNA polymerase to replicate its own structural proteins, which are then assembled, and the newly formed virions are released from the infected cells, perpetuating the viral life cycle. Theoretically, as a consequence of this process, infected cells may become damaged/destroyed [11].

This idea is supported by a recent autopsy study, analyzing cardiac tissue from 39 consecutive patients who died as a consequence of COVID-19, which found viral genome in the myocardial tissue, yet in situ hybridization showed that the most likely localization of SARS-CoV-2 not to be in the cardiomyocytes, but rather in interstitial cells or macrophages invading the myocardial tissue [12]. Even so, in engineered heart tissue models of COVID-19 myocardial pathology, SARS-CoV-2 demonstrated the ability to directly infect cardiomyocytes through ACE2, resulting in contractile deficits, cytokine production, sarcomere disassembly, and cell death [9].

Furthermore, ACE2 must not be viewed as a mere bystander in the pathophysiology of COVID-19 myocardial injury, seeing as, besides being the host cell receptor of SARS-CoV-2, ACE2 is an enzyme involved in the renin-angiotensin-aldosterone system (RAAS). Specifically, ACE2 cleaves angiotensin II, a very potent vasoconstrictor, into angiotensin 1–7, which manifests vasodilator and anti-inflammatory effects. ACE2 also demonstrates a weak affinity for angiotensin I (or proangiotensin, formed by the action of renin on angiotensinogen), competitively limiting angiotensin II synthesis by ACE. Angiotensin I is converted by ACE2 into the nonapeptide angiotensin 1–9, which will manifest vasodilator effects through subsequent angiotensin type 2 (AT2) receptor stimulation. Therefore, ACE2 can counteract the undesirable effects of angiotensin II, demonstrating vasodilator, antioxidant, and anti-fibrotic effects [13]. In the context of SARS-CoV-2 infection, after S protein binding is complete, the virus attaches ACE2 through membrane fusion and invagination, causing a downregulation of ACE2 enzymatic activity [13]. Additionally, ACE2 also demonstrates immunomodulatory properties, both directly, via its interactions with macrophages, and indirectly, as it reduces expression of angiotensin II, which stimulates inflammation [14]. Thus, ACE2 downregulation in the context of SARS-CoV-2 infection may increase angiotensin II levels, favoring AT1 receptor activity, with a subsequent vasoconstriction, fibrotic, proliferative, and pro-inflammatory effects [10].

2.1.2 Indirect mechanisms of myocardial injury

As is the case with all severe respiratory infections, COVID-19 has a general deleterious effect on the cardiovascular system, with fever and sympathetic activation causing tachycardia and implicitly increasing myocardial oxygen consumption [9, 10], while prolonged bed rest and systemic inflammation will favor coagulation disorders, as supported by clinical findings – both venous and atypical arterial thromboembolic events have been documented in COVID-19 patients (see subchapter 3.4. Thromboembolic events and bleeding risk). Hypoxemia, another hallmark of COVID-19, will determine enhanced oxidative stress and increased production of reactive oxygen species, with subsequent intracellular acidosis, mitochondrial damage, and cell death [7, 9].

Moreover, another series of indirect mechanisms for COVID-19-related myocardial damage appears as a result of the abnormal inflammatory response which may be elicited by SARS-CoV-2 infection (i.e. a pro-inflammatory surge, the so-called “cytokine storm,” which may occur as early as 1 week after the initial exposure and infection) [15].

Indeed, individual immune response is the cardinal element behind SARS-CoV-2 infection progression. Upon viral genome expulsion into the host cytosol, SARS-CoV-2 viral replication begins, with aberrant RNA sequences, byproducts of replication, being, in turn, detected by intracellular receptors, which activate the cellular antiviral response, involving enhanced leukocyte chemotaxis and transcriptional induction of type I and III interferons (IFN-I/-III), followed by under-regulation of IFN-stimulated genes [16]. Lung cell damage incurred during replication will also activate the local immune response, resulting in monocyte/macrophage recruitment [16], while chemokines will induce specific leukocyte subset recruitment and coordination [16]. Circulating immune cell relocation in the pulmonary tissue will determine additional cytokine/chemokine production, while also creating multiple imbalances in immune cell populations – increased leukocyte count and neutrophil-lymphocyte ratio, with decreased lymphocytes (especially T cells [17]), thus setting the scene for immune response dysregulation [3].

In fact, the relationship between SARS-CoV-2 infection and extensive activation of inflammation signaling pathways has been well documented, representing the main immunopathological mechanism through which severe forms occur, in susceptible individuals. During the acute phase of the infection, a disproportionate response occurs between T helper cell populations (types 1 and 2), characterized by high circulating levels of interleukin (IL)-1β, IL-1RA, IL-2, IL-6, IL-7, IL-8, IL-9 IL-10, interferon gamma-induced protein-10 (CXCL10), monocyte chemoattractant protein-1 (CCL2), macrophage inflammatory protein 1α (CCL3) and 1β (CCL4), granulocyte colony-stimulating factor, vascular endothelial growth factor (VEGF), and tumor necrosis factor (TNF) α [16, 18, 19], which mediate widespread lung inflammation, in an attempt to eradicate the pathogen [3]. The resulting hyper-inflammatory status, as well as the individual excessive levels of certain circulating cytokine species, have been independently associated with an unfavorable evolution and increased mortality [20]. This hyper-inflammatory state seems, at least intuitively, to be pivotal in the development of cardiac injury, seeing as positive correlations have been established between the increase in inflammatory markers and myocardial damage in COVID-19 [21, 22]. Indeed, this idea is additionally supported by previous studies, in other septic conditions, evidencing that the release of pro-inflammatory cytokines such as TNFα and IL-1β, were responsible for myocardial cells depression through modulation of calcium channel activity and nitric oxide production [23].

It may also be the case that the cytokine storm following SARS-CoV-2 infection determines the AHF, recurrently seen in severe COVID-19, as the inflammatory activation and oxidative stress background are similarly expressed generally in heart failure, predisposing to a more severe clinical course [24].

Lastly, the aforementioned marked inflammatory changes will also take place in the endothelium, as shown in postmortem histological studies, evidencing lymphocytic endotheliitis with apoptotic bodies and viral inclusion in multiple organs [7, 25]. Endotheliitis can lead to disseminated intravascular coagulation, with small or large vessels thrombosis and infarction, and will determine significant new vessel growth through a mechanism of intussusceptive angiogenesis [25].

2.2 Coagulation disturbances

After becoming infected, roughly 20% of COVID-19 patients will be incapable of controlling/halting viral replication through their initial immune response, which may be aberrant/insufficient or overwhelmed by a high initial viral load, or both [26]. This subgroup of patients will thus progress to a more severe disease phenotype, with aggravating symptomatology secondary to uncontrolled viral replication, leading to host pneumocyte and endothelial cell apoptosis, which in turn will activate platelets, induce procoagulant factor expression (fibrinogen, factors V, VII, VIII, X, and von Willebrand), and increase inflammatory response, as the body tries and fails to keep the infection localized to the lungs [27]. This sequence of host responses will additionally damage the pulmonary parenchyma (through further destruction of pneumocytes, microangiopathy, and inflammatory microthrombi), causing even more severe symptoms and hindering oxygenation, thus imposing the need for an additional oxygen supply. Even so, at this point, a relative balance between procoagulant and anticoagulant (but also pro-inflammatory/anti-inflammatory) factors is still maintained. In only approximately 5% of symptomatic patients, the pro-inflammatory processes involved in the immune response to SARS-CoV-2 infection will derail into the so-called “cytokine storm,” which will fuel pro-inflammatory and pro-coagulatory processes even further, resulting in systemic endotheliitis and capillary leakage, cellular dysfunction, organ dysfunction (including ARDS), and overt activation of the (systemic) coagulation cascade resulting in the need for critical organ support [28]. In fact, SARS-CoV-2 infection may trigger endothelial dysfunction not only through the direct cytopathic effect of invasion on vascular endothelial cells but also through indirect mechanisms, such as hypoxia and the induced inflammatory response [27]. Moreover, some patients have also manifested antiphospholipid antibodies [28].

Therefore, all factors of the classic Virchow triad are influenced during the course of COVID-19, and they contribute synergically to the risk of thromboembolic events: hemodynamic changes (increased blood viscosity due to elevated fibrinogen, but also venous stasis due to hospitalization and disease-related immobilization); hypercoagulability (due to an overwhelming inflammatory state, occurring early after infection); and endothelial injury/dysfunction (ACE2 receptor expression on endothelial cells allows viral entry and cytopathic effects – endotheliitis) [3].


3. Acute cardiovascular complications of COVID-19

3.1 Myocarditis/pericarditis

It is generally accepted that viral infections, and corona viruses even more, are a common cause of myocarditis, frequently associated with congestive heart failure (CHF), and an increased risk to sudden death due to ventricular arrhythmias [29]. Emerging data suggest an increased association between myocarditis and COVID-19, observed more frequently in hospitalized patients, associated with an increased risk of adverse outcome, including higher mortality rates [30].

According to Dallas criteria, acute myocarditis is defined as “inflammatory infiltrate of the myocardium with necrosis and/or degeneration of adjacent myocytes not typical for the ischemic damage associated with coronary artery disease.” Proposed pathophysiological pathways are myocardial injury due to the direct action of the virus, mediated via ACE2 receptors, and an intense, prolonged inflammatory response resulting in the release of high amounts of cytokines [29, 31, 32] together with additional factors such as hypoxia, increased metabolic demands, and physiological stress. At biopsy, myocyte and interstitial cells necrosis and mononuclear cell infiltrates were detected.

The real prevalence of acute myocarditis in patients infected with the SARS-CoV-2 virus is difficult to establish. In the medical literature, in these patients, the estimated incidence of acute myocarditis ranges from 12–17% or even 22–31% in ICU patients [33]. The symptoms vary from mild, nonspecific ones: palpitations, breathlessness, chest pain, common in influenza, to the dramatic picture of AHF with dyspnea, arrhythmias, or even sudden cardiac death. On the electrocardiogram (ECG), there are nonspecific ST, PR, and T-wave abnormalities, but signs mimicking an ACS, tachyarrhythmias, and conduction disturbances associated or not with left ventricular echocardiographic alterations and elevated levels of high sensitive troponins are also frequently seen [31, 33]. Another aspect is that the main diagnostic criteria require endomyocardial biopsy and cardiac magnetic resonance imaging (MRI), which are sometimes difficult or even impossible to access in COVID-19 patients due to the increased risk of contamination [33, 34]. It has been discussed that the prevalence of myocarditis rose parallel with the evolving strains of the SARS-CoV-2 virus being higher in patients infected in 2021 than in 2020 [30].

The incidence of pericarditis in COVID-19 patients ranges from 3% to 4.8% [35, 36]. It is often associated with myocarditis in COVID-19 patients with pneumonia and elevated inflammatory markers, as demonstrated by Diaz et al. in a meta-analysis performed on 33 studies, mainly case reports. The principal mechanism seems to be an autoreactive, inflammatory response [36].

Pericarditis manifests itself with a variety of symptoms, such as chest pain, fever, and dyspnea [36]. Pericardial friction rub is seldom encountered (9.3%) [36]. The predominant characteristic of this type of pericarditis is pericardial thickening observed at transthoracic echocardiography (TTE) persisting several weeks during recovery [37]. Over 50% of patients have pericardial effusion, mostly small to moderate in size, with 34% having large pericardial effusion, and even pericardial tamponade developed in about half of this last subset of patients [36]. On the ECG, 60% of patients present the typical four-stage evolution: diffuse ST elevation with depression of the PR segment, normalization of ST elevation, diffuse T-wave inversion, and in the end, normalization of the ECG [66]. Some patients presented unspecific signs, such as diffuse ST elevation, PR depression, and focal T-wave inversion [36].

The treatment of acute pericarditis consists in high doses of nonsteroidal anti-inflammatory drugs (NSAIDs) such as Ibuprofen, Indomethacin, or Naproxen recommended until symptom relief is achieved, and in addition, colchicine is recommended to be used for 3 to 6 months. Aspirin may be an alternative to NSAIDs [36]. Although low to moderate doses of steroids could be recommended in patients with SARS-CoV-2 infection, in most cases, this therapy is started sooner because of the associated viral myocarditis [36]. Furthermore, steroids can also be added to NSAIDs and colchicine as triple therapy for patients with an incomplete response. In the case of cardiac tamponade, pericardial drainage represents the standard of care [36]. Usually, the evolution of pericarditis associated with COVID-19 is benign.

3.2 Acute coronary syndrome

An increased incidence of ACS has been reported in several viral infections such as influenza, SARS, and MERS, being associated with a 3- to 10-fold increased risk, but in COVID-19 exact data are lacking [31, 32]. As principal potential pathophysiological pathways are considered: destabilization of atherosclerotic plaques due to systemic inflammation with an increased release of pro-inflammatory cytokines, the “cytokine storm,” associated microangiopathy, activation of prothrombotic factors, as well as other specific changes of immune cell polarization toward more unstable phenotypes. Contributing factors also are myocardial oxygen supply/demand mismatch in the context of increased metabolic demands due to tachycardia/arrhythmias, fever, and hypoxia. These factors probably represent also the best explanation for the increased troponin levels observed in many patients with acute COVID-19 in the absence of typical cardiovascular manifestations (chest pain, specific ischemic electrocardiographic modification, and parietal hypokinesia at TTE) [31, 32], the more so as some other complications such as myopericarditis may have similar symptoms, and often patients with COVID-19 may not have typical angina symptoms.

Patients already suffering with coronary artery disease and heart failure may be exposed in a greater extent to ACS as a consequence of coronary plaque rupture or stent thrombosis in the context of systemic inflammation [31, 32]. For this reason, it is strongly recommended that in patients with a previous history of coronary artery disease and especially in those with coronary interventions, antiplatelet therapy should be continued, eventually even intensified, together with other plaque stabilizing agents such as statins, beta-blockers, and angiotensin-converting enzyme inhibitors [27, 30, 38, 39].

In this global health systems crisis, an adequate diagnosis and management of ACS is complicate and health care institutions worldwide have reexamined their protocols considering the increased risk of contamination of healthcare personal and the high requirements for protective equipment [34, 40, 41]. However, risk stratification is difficult due to limited bedside approach for an accurate ECG and TTE examination [31, 42]. The treatment of acute myocardial infarction (AMI) in COVID-19 patients is even more controversial. While in patients diagnosed with non-ST elevation myocardial infarction (non-STEMI), the result of a PCR testing could be expected prior to cardiac catheterization, in cases with ST elevation myocardial infarction (STEMI), the American College of Cardiology (ACC) recommends reconsidering fibrinolysis in patients with “low-risk STEMI” such as inferior without right ventricular extension, or lateral STEMI without altered hemodynamic. Thus percutaneous coronary intervention (PCI) remains the most indicated therapy, remaining the best option also in non-STEMI patients who are hemodynamically unstable [34, 42, 43].

In a large meta-analysis, DeLuca et al. concluded that COVID-19 pandemic has significantly impacted the therapy of patients with STEMI, with a 19% reduction in PCI procedures leading to increased morbidity and mortality, aspects evidenced also in other studies [34, 40, 43].

3.3 Increased risk of arrhythmias

Arrhythmias were observed precociously in COVID-19 patients worldwide, several centers reporting a large spectrum of electrocardiographic abnormalities [31, 32]. In most cases, sinus tachycardia due to multiple, concomitant causes (hypoperfusion, fever, hypoxia, and anxiety) was observed, but also atrial tachycardia and fibrillation (AF), and less frequently atrioventricular block (AVB) and polymorphic ventricular tachycardia (VT), significantly increasing the morbidity and mortality, and explaining at least in part, the increased number of cardiac arrests noticed in out-of-hospital patients [44, 45]. It was considered that underlying mechanisms are myocardial injury, inflammation, coexisting hypoxia, electrolytic (especially hypokalemia) and acid–base imbalances, and activation of the sympathetic nervous system, which is contributing the medication used to treat this disease such as hydroxychloroquine, azithromycin, and antivirals that prolong the QT interval [46, 47].

Perhaps the most comprehensive study written on this topic is the one of Coromilas et al. who analyzed data collected from over 4000 patients with COVID-19 and arrhythmias, from 4 continents and 12 countries, and concluded that the majority of them (81.8%) developed supraventricular arrhythmias including AF and atrial flutter, 21% of subjects had ventricular arrhythmias, and 22.6% developed bradyarrhythmias [47]. They also observed that arrhythmias were more frequent in patients over 60 years old, male gender prevailed, and frequently systemic hypertension and diabetes mellitus were associated comorbidities [33, 46, 47].

Treatment of arrhythmias should follow the standard guidelines for the management of arrhythmias focusing on the underlying pathophysiological mechanisms, and addressing as much as possible the reversible causes, especially electrolyte abnormalities. In the case of recurrent, uncontrolled ventricular arrhythmias not responding to antiarrhythmic therapy, implantable cardioverter defibrillators may be recommended, and for persistent high-degree AVB transvenous pacemaker insertion [48].

3.4 Thromboembolic events and bleeding risk

As the pandemic unravels, medical literature has provided robust insight into the unique mechanisms of and specific propensity for COVID-19 thrombogenicity, identified as considerably different from other severe infectious and non-infectious diseases. The relationship between SARS-CoV-2 infection and subsequent dysregulation of coagulation homeostasis is reflected in the various rates of occurrence of major venous and arterial thromboembolic/thrombotic events, which, in more extreme cases, have been documented to occur concomitantly. A recent comparative study, which retrospectively evaluated thromboembolic risk in large patient cohorts of COVID-19 and Influenza, found that COVID-19 was independently associated with a higher 90-day risk for venous thrombosis, but not arterial thrombosis, as compared to Influenza, with secondary analysis showing a similar risk for ischemic stroke and myocardial infarction, and a higher risk for deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with COVID-19 [49].

In spite of early thromboprophylaxis, most frequently, VTE negatively impacts clinical outcomes in COVID-19 hospitalized patients, and the risk seems to be greatest in the intensive care unit (ICU) setting, among the critically ill [50]. Major arterial thrombotic events and VTE have been reported at a higher frequency, in COVID-19 ICU patients, as compared to non-ICU patients, over a 30-day period, despite a thromboprophylaxis rate of 85–90% [51]. Moreover, a recent meta-analysis of 12 studies, in which all patients were under thromboprophylaxis, with either low molecular weight or unfractionated heparin, still showed a 31% pooled prevalence of VTE for ICU admissions [52]. Very recently, an overall incidence of 17.3% for VTE among hospitalized COVID-19 has been reported (~2/3 DVT), with significant discrepancies between pooled incidences of VTE for ICU admissions as compared to general ward patients (27.9% vs. 7.1%, respectively), while including catheter-associated thromboembolism, isolated distal DVT, and isolated pulmonary emboli reached the highest incidence rates. Even so, VTE incidence was higher when assessed within a screening strategy (33.1% vs. 9.8% by clinical diagnosis), meaning that, in clinical practice, it is very likely that many COVID-19 patients with subclinical VTE remain undiagnosed [53]. Moreover, VTE prevalence in COVID-19 patients varies widely depending on the subpopulation evaluated, seemingly correlating well with disease severity and preexisting metabolic and cardiovascular comorbidities, a statement reflected by the variability of occurrence rates reported: <3% in non-ICU patient [51], >30% for ICU cases, with DVT and subsequent PE representing the most common thrombotic complication in the ICU setting [54], while autopsy findings of COVID-19 fatalities suggest it may reach nearly 60% [55].

Interestingly, amounting data suggest that the majority of so-called PE diagnoses occur without a recognizable source of venous embolism and may be better defined as primary in situ pulmonary arterial thrombosis, a direct consequence of the SARS-CoV-2 pulmonary disease, entailing thrombotic occlusion of small−/mid-sized pulmonary arteries, which will result in the infarction of afferent lung parenchyma [56]. This may explain why PE is the most prevalent thrombotic event seen in COVID-19 patients [54] and why screening yielded a higher incidence of VTE than clinical evaluation of asymptomatic patients. In a recent investigation, duplex ultrasound was performed for clinical suspicion of DVT, reporting 41.58% confirmed DVT, 6.93% superficial thrombophlebitis and, surprisingly, 23.76% PE (mostly involving distal pulmonary vessels), yet only 7.92% had PE and concomitant, associated DVT, meaning that 2/3 of PE occurred in the absence of a recognizable DVT, suggesting a causal mechanism of primary thrombosis rather than embolism [56]. Additionally, postmortem analyses of COVID-19 fatalities have frequently documented thrombosis of small- and mid-sized pulmonary arteries, a lesion capable of causing hemorrhagic necrosis, fibrosis, disruption of pulmonary circulation, acute pulmonary hypertension (PH), and ultimately death [55]. Other severe morphopathological modifications of pulmonary tissue architecture have also been frequently reported in COVID-19 autopsy reports, such as severe endothelial injury, with disruption of cell membranes, rampant vascular thrombosis, and significant angiogenesis [25], while other organs also showed microthrombotic lesions on autopsy, but at a lower rate (cardiac thrombi, epicardial coronary artery thrombi and microthrombi in myocardial capillaries, arterioles, and small muscular arteries) [55].

An aforementioned study, analyzing 184 COVID-19 ICU cases, all receiving thromboprophylaxis, demonstrated a 31% cumulative incidence of the defined vascular complication composite outcome (PE, DVT, ischemic stroke, ACS, or systemic arterial embolism). The main independent predictors of thrombotic complications identified were age, with an adjusted hazard ratio (aHR) of 1.05/per year, and coagulopathy [54]. Conversely, regarding VTE, an extensive meta-analysis (44 studies/14,866 hospitalized COVID-19 patients), on the topic acute complications and mortality, reported a much lower prevalence of 15% for VTE, than previously reported. This value may be influenced not only by cohort size but also by other factors such as heterogeneous reporting between the studies evaluated and increased risk of bias, resulting in very low-quality evidence [57].

On the other hand, as seen in the above-mentioned studies, VTE can still occur in noncritically ill COVID-19 patients; therefore, rigorous elaboration of adequate screening and risk stratification protocols for VTE, especially for mild and moderate COVID-19 phenotypes, will be essential, as these patients are much less likely to undergo tromboprophylaxis.

Regarding arterial thromboembolism (ATE), incidence rates among COVID-19 diagnosed patients have consistently been reported as being much lower than for VTE, since the early days of the pandemic (3.7%) to date [54]. Unsettlingly, large-vessel strokes in young and generally healthy people, which became infected with SARS-CoV-2, have been consistently reported [25, 55]. Early retrospective studies, seemingly corroborated these findings, claiming that acute, new-onset, cerebrovascular disease was not uncommon in COVID-19 patients – out 219 consecutive COVID-19 patients, 10 (4.6%) developed acute ischemic stroke and 1 (0.5%) had intracerebral hemorrhage [58] –,and that SARS-CoV-2 infection carried an increased risk of ACS, especially via coronary stent thromboses [59]. Nevertheless, investigations involving a much larger sample size showed that the actual incidence of ATE (thrombotic/embolic) is, in fact, much lower than initially reported in earlier studies [51, 60]. A large cohort retrospective study, evaluating 1114 COVID-19 patients with independently adjudicated thrombotic/embolic events, found stroke and ACS incidence were 0.1% (1/1114) and 1.3% (14/1114), respectively [51]. Most authors agree that thrombotic events occur early in the evolution of COVID-19, and in order to combat the hypercoagulable and prothrombotic state, administration of anticoagulants is recommended to reduce this risk [27].

Of great importance is the fact that, due to several factors such as thrombocytopenia, hyperfibrinolytic state, consumption of coagulation factors, which initiate their action later on, after 1 to 3 weeks, COVID-19 patients may also become prone to bleeding. This must be taken into account, especially in severe COVID-19 cases, where concomitant administration of anticoagulants as thromboprophylaxis is very likely to occur [61]. Additionally, critically ill COVID-19 patients have an even more increased bleeding risk, due to thrombocytopenia/platelet dysfunction or coagulation factor deficiencies, or both [62], which are frequent occurrences in this clinical population. Thus, it has become increasingly difficult to establish an adequate, integrative, anticoagulant prophylaxis strategy for COVID-19.

As opposed to the numerous investigations debating over thromboembolic events, there are much fewer articles focusing on major bleedings and just a few case reports on hematomas in COVID-19. Al-Shamkary et al. reported an overall incidence of 4.8–8% referring to bleeding events, and of 3.5% for major bleedings [62], being mostly associated with advanced age, comorbidities and apparently, more frequent in males.

All in all, thromboembolic events are a frequent morbidity encountered in COVID-19 patients, especially in those with severe forms and comorbidities. For their prophylaxis/treatment anticoagulant therapy is recommended, thus increasing the risk of bleedings. Both thromboembolic events and hemorrhagic complications aggravate the evolution of these patients, representing significant negative prognostic factors and increasing the morbidity and mortality associated with COVID-19.


4. Subacute and long-term cardiovascular sequels following the infection with the SARS-CoV-2 virus

The important contribution of COVID-19 in the pathogenesis of acute cardiovascular involvements is now well established, but because this pandemic is a new disease, long-term data on post-COVID-19 complications were not available [63, 64]. However, more and more studies revealed that the infection with the SARS-CoV-2 virus also causes chronic cardiac complications, even when the viral load is normalized [63, 64], explaining the persistence of symptoms during recovery observed in an increasing number of individuals [65]. In some patients, myocarditis, subacute pericarditis, persisting arrhythmias, pulmonary hypertension, or heart failure have been observed raising serious concerns and indicating that in symptomatic patients, a comprehensive evaluation and a regular long-term follow-up are needed for effective therapeutic regime and to prevent a worse evolution of these cardiovascular complications.

4.1 Pulmonary hypertension

It is well known that pulmonary hypertension (PH) may occur during the acute phase of the SARS-CoV-2 infection as a consequence of extensive lung injury and of altered pulmonary circulation, frequently leading to right heart failure (RHF), shearing common pathophysiological mechanisms with other complications encountered in this illness, and significantly increasing the mortality [66, 67].

In COVID-19 patients, the prevalence of PH varies wildly, depending on the studied population, ranging from 7.69% to 12–13,4% or even 22% in severe COVID-19 cases [67, 68]. While this topic was largely debated in the medical literature, information over its outcome is less available. It has been observed that some patients are predisposed to develop interstitial lung disease (ILD) frequently associated with persisting PH and explaining, at least partially, the persisting symptoms observed in patients with subacute and long COVID-19 [69, 70]. The backgrounds of this disease are complex and multifactorial, including a large variety of pathophysiological types, ranging from arterial PH (group 1), PH of group 3 – due to ILD, to chronic thromboembolism (group 4 PH) or even of group 2 PH (secondary left heart disease) [70, 71]. In their study, Suzuki et al., observed a unique hystopathological finding identified only at the autopsy of COVID-19 patients, namely thickened pulmonary vascular walls, considered an important hallmark of arterial PH [71]. This finding suggests that COVID-19, depending on the severity of the lung injury and the inflammatory responses, could favor the development of PH, and some of these patients may develop in the future signs and symptoms of PH and RHF [71].

The diagnosis of PH is difficult and implies right heart catheterization, which is limited during the pandemic considering the risk of contamination and shortness of personal and resources. In patients infected with SARS-CoV-2, TTE allows an accurate estimation of the systolic pressure in the pulmonary artery, being the most utilized method for the diagnostic and follow-up of these patients. A specific therapy for this type of PH has not been described, and future studies are needed to clarify its management.

4.2 Heart failure

AHF may appear precocious in the evolution of the SARS-CoV-2 infection, in some cases being even the first manifestations. Since COVID-19 and AHF/worsening of CHF shear similar symptoms, distinguishing these two pathologies is challenging, the more so as these two conditions may coexist. Some studies describe an increased prevalence of ACH (23% or even 33%) in patients hospitalized for COVID-19 being associated with an increased risk of mortality [63]. In many cases, it is difficult to establish if AHF is the consequence of a new myocarditis/cardiomyopathy or it represents the exacerbation of previously undiagnosed CHF. Responsible pathophysiological mechanisms of AHF in COVID-19 may include acute myocardial injury due to inflammation (myocarditis), tachyarrhythmia or ischemia, or to acute respiratory failure, acute kidney injury, and hypervolemia [9, 29, 31]. Importantly, RHF may also be present especially in patients with severe pulmonary injury and PE contributing to the increased mortality of these patients [37].

Diagnosis may be difficult, but clinical presentation, history of preexisting cardiovascular comorbidities, evidence of cardiomegaly, and/or bilateral pleural effusion on chest radiography are suggestive. Increased levels of B-type natriuretic peptide (BNP)/N-terminal B-type natriuretic peptide (NT-proBNP) could be an important clue for AHF/worsened CHF, although elevated BNP/NT-proBNP values were also found in COVID-19 patients in the absence of AHF. An important contribution offers TTE demonstrating enlarged cardiac cavities, impaired systolic performance, and other important signs [34, 49, 72].

Therapy of AHF in COVID-19 patients should be performed according to guidelines [63] based on the same recommendation as in subjects without COVID-19, with special attention to early detection and treatment of complications, especially hypoxia, thrombotic/bleeding events, and cardiac arrhythmias. It is important to consider AHF/CHF when administering intravenous fluids avoiding excessive fluid replacement and to be conscious on the cardiac adverse effects of medications used in the treatment of COVID-19 [9, 31, 64].

Referring to patients already diagnosed with CHF, it is well known that they are predisposed to develop more severe forms of COVID-19, being predisposed to a higher mortality. The SARS-CoV-2 infection may also unmask a latent CHF, particularly heart failure with preserved ejection fraction (HFpEF) which is common among elderly overweight, hypertensive patients. In addition, as a consequence of myocardial injury, cardiac fibrosis may occur, explaining the increased frequency of diastolic dysfunction identified on TTE. The risk to develop overt CHF is present both during the acute phase of COVID-19 and during the recovery from the acute illness in survivors [31, 33, 72, 73].

Another aspect is that the COVID-19 pandemic negatively impacted the outcome of patients with CHF who avoided or delayed hospital controls or admissions due to fear of contamination. They presented themselves to the hospital only when their condition was severe, which lead to an increased mortality worldwide [9, 74].

4.3 New onset or aggravation of systemic hypertension

The relationship between the infection with the SARS-CoV-2 virus and systemic hypertension is very complicated and difficult to establish. While it is generally accepted that COVID-19 patients with a history of cardiovascular diseases, especially systemic hypertension, have a worse outcome and increased mortality [29, 75], it is very difficult to establish if there is a new onset or a worsening of a chronic hypertension in the context of this illness, since a previous comprehensive evaluation is not available in the majority of cases. A meta-analysis of Lippi et al. evidenced a nearly 2.5-fold increase of severity and mortality of severe COVID-19 in patients with associated systemic hypertension, especially in those older than 60 years with other comorbidities [75].

Other large meta-analyses focused on the impact of hypertension’s severity and its control and the outcomes but failed to document significant connections [76]. It was concluded that hypertension is associated with endothelial dysfunction strongly impacted in COVID-19, and patients with more severe forms have more advanced atherosclerosis and consecutive complications, thus increasing the morbidity and mortality. As the concerns regarding therapy with ACE inhibitors were not found to be justified, treatment should be given according to guidelines to optimize blood pressure values [77].

4.4 Postural orthostatic tachycardiac syndrome

The postural tachycardia syndrome (POTS) is the result of an autonomic dysregulation which determines increased vasoconstriction when standing, resulting in blood pooling within the splanchnic vasculature and limbs, with reduced venous return to the heart. An excessive compensatory tachycardia and increased plasma noradrenaline levels contribute to symptoms, the commonest of which are fatigue, palpitations, light-headedness, headache, and nausea symptoms reported by many of patients with long-COVID (between 15% and 50% according to some studies) [78]. Although orthostatic intolerance is common among patients recovering from a COVID-19 infection, not all have POTS, some of them have only orthostatic hypotension [78].

The exact pathophysiological mechanism of POTS is not fully clarified, and there are several mechanisms involved, including hypovolemia, autonomic denervation, hyperadrenergic stimulation, and autoimmune pathology. It is not well established whether the same recognized pathophysiology of POTS is also present in patients with long COVID further studies being necessary [78].

4.5 Aggravation of preexisting cardiovascular pathologies

From the early stages of the infection with the SARS-CoV-2 virus, it became evident that underlying cardiovascular diseases, obesity, diabetes mellitus, and more advanced age are associated with a higher risk for severe COVID-19 infection [34]. Individuals already suffering from cardiovascular diseases were more likely to be infected with the virus, and the virus infection was likely to determine the deterioration of basic heart disease [79]. Apparently, among COVID-19 patients, there were almost 50% diagnosed with chronic diseases, 40% of them with cardiovascular and cerebrovascular disorders, chronic kidney failure, and chronic obstructive pulmonary disease, having an increased risk of morbidity or even death related to this infection. A large study from the USA reported that the most common comorbidities among patients with COVID-19 were systemic hypertension (56.6%), obesity (41.7%), diabetes (33.8%), coronary artery disease (11.1%), and CHF (6.9%) [33], and a retrospective cohort study in China conducted on patients with cardiovascular comorbidities evidenced a fivefold higher mortality risk (10.5%). Based on these results, hypertension and cardiovascular comorbidities can be considered as risk factors for persons with severe symptoms of the disease.

In COVID-19 cases, it is important to recognize the clinical characteristics of infected persons to identify and effectively treat the associated comorbidities and the newly developed cardiovascular complications as well to reduce patients’ morbidity and mortality. Since many antiviral drugs may determine cardiac insufficiency, arrhythmia or other cardiovascular disorders, therefore, during the therapy of this illness, especially with antiviral therapy, the risk of cardiac toxicity needs to be closely monitored [79].

Another aspect is that of the long-term outcome of patients who suffered from a SARS-CoV-2 infection. In a recent and comprehensive study realized on over 150000 individuals recovering from COVID-19 [80], Xie et al. highlighted that beyond the first month after infection, people with COVID-19 experienced at 12 months an increased morbidity risks and burdens of cardiovascular diseases, including cerebrovascular disorders, dysrhythmias, inflammatory heart disease, ischemic heart disease, heart failure, thromboembolic disease, and other cardiac disorders [80]. These risks were obvious regardless of age, race, gender, and associated cardiovascular risk factors, including obesity, hypertension, diabetes, chronic kidney disease, and hyperlipidemia, being evident even in individuals without history of cardiovascular pathology before the SARS-CoV-2 virus infection, raising concerns that these risks might be present even in people at low risk of cardiovascular disease [80]. These risks and associated burdens increased parallel to the severity of the acute phase of COVID-19: from non-hospitalized individuals – who were the majority – to hospitalized patients, especially to those admitted to the intensive care units [80].

4.6 Cardiovascular effects of medication used to treat COVID-19

It has been observed that many of the medications used for the treatment of COVID-19 strongly interfere with other medications used in the therapy of cardiovascular diseases, such as anticoagulants, antiplatelets, statins, antihypertensives, and especially antiarrhythmics favoring the occurrence of arrhythmias [31]. Some antibiotics (azithromycin), corticosteroids, antimalarials (chloroquine, hydroxychloroquine), newly developed therapies, still under study such as antivirals (remdesivir, ribavirin, lopinavir/ritonavir, and favipiravir), and biologics (tocilizumab) determine cardiotoxicity, interact with electrolyte metabolism, and many of them, especially Lopinavir/ritonavir, may cause QT and PR prolongation favoring the occurrence of arrhythmias or conduction disturbances, mainly in patients already treated with drugs prolonging the QT interval. Data over the mechanism of action and potential effects of main medication used in the treatment of COVID-19 is presented in Table 1 [31].

MedicationMechanism of actionCardiovascular effects and drug interactions
AzithromycinInteracts with the synthesis of proteins and binds to 50s ribosome
  • Interferes with statins, anticoagulants, and antiarrhythmics, prolonging QT interval and favoring arrhythmias (torsades de pointes).

Chloroquine and HydroxychloroquineAlterations in the pH of endosomal/organelle
  • May induce direct myocardial toxicity worsening myocarditis and cardiomyopathy.

  • Alter intracardiac conduction resulting in bundle branch block, AV block.

  • Interact with antiarrhythmics favoring ventricular arrhythmias, torsades de pointes.

  • Determines fluid retention, hypertension, and dyselectrolytemia.

  • Interacts with anticoagulants.

RemdesivirInhibitor of RNA polymerases
  • May cause hypotension and arrhythmias.

RibavirinInhibits RNA and DNA virus replication
  • Interacts with anticoagulants.

  • May cause severe hemolytic anemia.

Lopinavir/RitonavirLopinavir inhibits protease and Ritonavir inhibits CYP3A metabolism
  • Interacts with anticoagulants, antiplatelets, statins, and antiarrhythmics.

  • May determine prolonged QT interval, AV blocks, and torsades de pointes.

FavipiravirInhibits RNA-dependent RNA polymerases
  • Interacts with anticoagulants, statins, and antiarrhythmics.

InterferonImmune system activation
  • May determine direct myocardial toxicity.

  • Worsens cardiomyopathy; alters intracardiac conduction.

  • Causes hypotension or cardiac ischemia.

TocilizumabInhibits IL-6
  • May interfere with some medication metabolism such as statins.

  • May determine hypertension.

Table 1.

Interactions of medications used in the treatment of COVID-19.

4.7 Cardiovascular effects related to vaccination

After the introduction of mRNA COVID-19 vaccines a higher incidence of myocarditis in vaccine recipients. A study performed on the data basis from an Israeli national database concluded that the incidence of myocarditis after two doses of the BNT162b2 mRNA vaccine was reduced (risk ratio = 3.24), significantly lower than after COVID-19 (risk ratio = 18.28), but higher than in unvaccinated individuals. The risk of myocarditis was higher after the second dose of vaccine and in young male recipients [81].

Similar results were also reported by other researcher, with an elevated risk of myocarditis, pericarditis, and myopericarditis observed particularly among young males with 39–47 expected cases of per million second mRNA COVID-19 vaccine doses administered [82]. They reported an increased risk of myocarditis after the first dose of ChAdOx1 and BNT162b2 vaccines and the first and second doses of the mRNA-1273 vaccine [82].


5. Conclusions

The impairment of the cardiovascular system in COVID-19 comprises a wide spectrum of dysfunctions, ranging from mild to severe, or even life-threatening forms, often having an acute onset, sometimes continuing during recovery or even resulting in chronic pathologies. Individuals are affected regardless of age, race, gender, and associated cardiovascular risk factors, but those with a history of cardiovascular pathology prior to the SARS-CoV-2 virus infection have a worse outcome. Therefore, a comprehensive cardiologic evaluation, including TTE, is justified to assess the involvement of the cardiovascular system, for initiating a proper therapy as soon as possible and to schedule a follow-up program particularly in patients at high risk.


  1. 1. WHO Director-General’s Opening Remarks at the Media Briefing on COVID-19-11 March 2020. [cited April 27, 2021]. Available from:
  2. 2. COVID Live—Coronavirus Statistics—Worldometer. [cited February 11, 2022]. Available from:
  3. 3. Dumache R, Daescu E, Ciocan V, Mureşan C, Talida C, Gavrilita D, et al. Molecular testing of SARS-CoV-2 infection from blood samples in disseminated intravascular coagulation (DIC) and elevated D-dimer levels. Clinical Laboratory. 2021;67(1):187-192
  4. 4. Harrison AG, Lin T, Wang P. Mechanisms of SARS-CoV-2 Transmission and Pathogenesis. Trends in Immunology. 2020;41(12):1100-1115
  5. 5. Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, et al. SARS-CoV-2 Receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell. 2020;181(5):1016-1035
  6. 6. Zhao Y, Zhao Z, Wang Y, Zhou Y, Ma Y, Zuo W. Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. American Journal of Respiratory and Critical Care Medicine. 2020;202(5):756-759
  7. 7. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. Endothelial cell infection and endotheliitis in COVID-19. Lancet. 2020;395(10234):1417-1418
  8. 8. Leentjens J, van Haaps TF, Wessels PF, Schutgens REG, Middeldorp S. COVID-19-associated coagulopathy and antithrombotic agents—lessons after 1 year. The Lancet Haematology. 2021;8(7):e524-e533
  9. 9. Italia L, Tomasoni D, Bisegna S, Pancaldi E, Stretti L, Adamo M, et al. COVID-19 and Heart Failure: From Epidemiology During the Pandemic to Myocardial Injury, Myocarditis, and Heart Failure Sequelae. Frontiers in Cardiovascular Medicine. 2021;8:1-14
  10. 10. Tomasoni D, Italia L, Adamo M, Inciardi RM, Lombardi CM, Solomon SD, et al. COVID-19 and heart failure: From infection to inflammation and angiotensin II stimulation. Searching for evidence from a new disease. European Journal of Heart Failure. 2020;22(6):957-966
  11. 11. Zheng Y-Y, Ma Y-T, Zhang J-Y, Xie X. COVID-19 and the cardiovascular system. Nature Reviews: Cardiology. 2020;17(5):259-260
  12. 12. Lindner D, Fitzek A, Bräuninger H, Aleshcheva G, Edler C, Meissner K, et al. Association of cardiac infection with SARS-CoV-2 in confirmed COVID-19 autopsy cases. JAMA Cardiology. 2020;5(11):1-5
  13. 13. Patel VB, Zhong J-C, Grant MB, Oudit GY. Role of the ACE2/Angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circulation Research. 2016;118(8):1313-1326
  14. 14. Madjid M, Safavi-Naeini P, Solomon SD, Vardeny O. Potential effects of coronaviruses on the cardiovascular system: A review. JAMA Cardiology. 2020;5(7):831-840
  15. 15. Ragab D, Salah Eldin H, Taeimah M, Khattab R, Salem R. The COVID-19 cytokine storm; what we know so far. Frontiers in Immunology. 2020;11:1446
  16. 16. Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LFP. The trinity of COVID-19: Immunity, inflammation and intervention. Nature Reviews. Immunology. 2020;20(6):363-374
  17. 17. Guo Y-R, Cao Q-D, Hong Z-S, Tan Y-Y, Chen S-D, Jin H-J, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – An update on the status. Military Medical Research. 2020;7(1):11
  18. 18. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet. 2020;395(10223):497-506
  19. 19. Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y, et al. Pathogenic T cells and inflammatory monocytes incite inflammatory storm in severe COVID-19 patients. National Science Review. 2020;7(6):998-1002
  20. 20. Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. The Lancet Respiratory Medicine. 2020;8(5):475-481
  21. 21. Shi S, Qin M, Shen B, Cai Y, Liu T, Yang F, et al. Association of cardiac injury with mortality in hospitalized patients with COVID-19 in Wuhan, China. JAMA Cardiology. 2020;5(7):802-810
  22. 22. Arévalos V, Ortega-Paz L, Rodríguez-Arias JJ, Calvo M, Castrillo L, Salazar A, et al. Myocardial injury in COVID-19 patients: Association with inflammation, coagulopathy and in-hospital prognosis. Journal of Clinical Medicine. 2021;10(10):2096
  23. 23. Joulin O, Petillot P, Labalette M, Lancel S, Neviere R. Cytokine profile of human septic shock serum inducing cardiomyocyte contractile dysfunction. Physiological Research. 2007;56(3):291-297
  24. 24. Unudurthi SD, Luthra P, Bose RJC, McCarthy JR, Kontaridis MI. Cardiac inflammation in COVID-19: Lessons from heart failure. Life Sciences. 2020;260:118482
  25. 25. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19. The New England Journal of Medicine. 2020;383(2):120-128
  26. 26. Fajnzylber J, Regan J, Coxen K, Corry H, Wong C, Rosenthal A, et al. SARS-CoV-2 viral load is associated with increased disease severity and mortality. Nature Communications. 2020;11(1):5493
  27. 27. Bikdeli B, Madhavan MV, Jimenez D, Chuich T, Dreyfus I, Driggin E, et al. COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow-up: JACC State-of-the-Art Review. Journal of the American College of Cardiology. 2020;75(23):2950-2973
  28. 28. Singhania N, Bansal S, Nimmatoori DP, Ejaz AA, McCullough PA, Singhania G. Current overview on hypercoagulability in COVID-19. American Journal of Cardiovascular Drugs. 2020;20(5):393-403
  29. 29. Farshidfar F, Koleini N, Ardehali H. Cardiovascular complications of COVID-19. JCI Insight. 2021;6(13):1-15
  30. 30. Lewek J, Jatczak-Pawlik I, Maciejewski M, Jankowski P, Banach M. COVID-19 and cardiovascular complications – The preliminary results of the LATE-COVID study. Archives of Medical Science. 2021;17(3):818-822
  31. 31. Long B, Brady WJ, Koyfman A, Gottlieb M. Cardiovascular complications in COVID-19. The American Journal of Emergency Medicine. 2020;38(7):1504-1507
  32. 32. Ranard LS, Fried JA, Abdalla M, Anstey DE, Givens RC, Kumaraiah D, et al. Approach to acute cardiovascular complications in COVID-19 infection. Circulation. 2020;13(7):e007220
  33. 33. Guzik TJ, Mohiddin SA, Dimarco A, Patel V, Savvatis K, Marelli-Berg FM, et al. COVID-19 and the cardiovascular system: Implications for risk assessment, diagnosis, and treatment options. Cardiovascular Research. 2020;116(10):1666-1687
  34. 34. The Task Force for the management of COVID-19 of the European Society of Cardiology, Baigent C, Windecker S, Andreini D, Arbelo E, Barbato E, et al. ESC guidance for the diagnosis and management of cardiovascular disease during the COVID-19 pandemic: Part 2—care pathways, treatment, and follow-up. European Heart Journal. 2021;43(11):1033-1058
  35. 35. Tung-Chen Y. Acute pericarditis due to COVID-19 infection: An underdiagnosed disease? Medicina Clínica (Barcelona). 2020;155(1):44-45
  36. 36. Diaz-Arocutipa C, Saucedo-Chinchay J, Imazio M. Pericarditis in patients with COVID-19: A systematic review. Journal of Cardiovascular Medicine. 2021;22(9):693-700
  37. 37. Tudoran C, Tudoran M, Pop GN, Giurgi-Oncu C, Cut TG, Lazureanu VE, et al. Associations between the Severity of the Post-Acute COVID-19 Syndrome and Echocardiographic Abnormalities in Previously Healthy Outpatients Following Infection with SARS-CoV-2. Biology. 2021;10(6):469
  38. 38. Ashraf S, Ilyas S, Alraies MC. Acute coronary syndrome in the time of the COVID-19 pandemic. European Heart Journal. 2020;41(22):2089-2091
  39. 39. Mafham MM, Spata E, Goldacre R, Gair D, Curnow P, Bray M, et al. COVID-19 pandemic and admission rates for and management of acute coronary syndromes in England. The Lancet. 2020;396(10248):381-389
  40. 40. Zaleski AL, Taylor BA, McKay RG, Thompson PD. Declines in acute cardiovascular emergencies during the COVID-19 pandemic. The American Journal of Cardiology. 2020;129:124-125
  41. 41. Mahmud E, Dauerman HL, Welt FGP, Messenger JC, Rao SV, Grines C, et al. Management of acute myocardial infarction during the COVID -19 pandemic: A Consensus Statement from the Society for Cardiovascular Angiography and Interventions (SCAI), the American College of Cardiology (ACC), and the American College of Emergency Physicians (ACEP). Catheterization and Cardiovascular Interventions. 2020;96(2):336-345
  42. 42. Fileti L, Vecchio S, Moretti C, Reggi A, Aquilina M, Balducelli M, et al. Impact of the COVID-19 pandemic on coronary invasive procedures at two Italian high-volume referral centers. Journal of Cardiovascular Medicine. 2020;21(11):869-873
  43. 43. De Luca G, Verdoia M, Cercek M, Jensen LO, Vavlukis M, Calmac L, et al. Impact of COVID-19 pandemic on mechanical reperfusion for patients with STEMI. Journal of the American College of Cardiology. 2020;76(20):2321-2330
  44. 44. Kochav SM, Coromilas E, Nalbandian A, Ranard LS, Gupta A, Chung MK, et al. Cardiac arrhythmias in COVID-19 infection. Circulation: Arrhythmia and Electrophysiology. 2020;13(6):e008719
  45. 45. Kochi AN, Tagliari AP, Forleo GB, Fassini GM, Tondo C. Cardiac and arrhythmic complications in patients with COVID-19. Journal of Cardiovascular Electrophysiology. 2020;31(5):1003-1008
  46. 46. Patel NH, Rutland J, Tecson KM. Arrhythmias and intraventricular conduction disturbances in patients hospitalized with coronavirus disease 2019. The American Journal of Cardiology. 2022;162:111-115
  47. 47. Coromilas EJ, Kochav S, Goldenthal I, Biviano A, Garan H, Goldbarg S, et al. Worldwide survey of COVID-19–associated arrhythmias. Circulation: Arrhythmia and Electrophysiology. 2021;14(3):e009458
  48. 48. Lakkireddy DR, Chung MK, Gopinathannair R, Patton KK, Gluckman TJ, Turagam M, et al. Guidance for cardiac electrophysiology during the COVID-19 pandemic from the Heart Rhythm Society COVID-19 Task Force; Electrophysiology Section of the American College of Cardiology; and the Electrocardiography and Arrhythmias Committee of the Council on Clinical Cardiology. American Heart Association. Heart Rhythm. 2020;17(9):e233-e241
  49. 49. Ward A, Sarraju A, Lee D, Bhasin K, Gad S, Beetel R, et al. COVID-19 is associated with higher risk of venous thrombosis, but not arterial thrombosis, compared with influenza: Insights from a large US Cohort. PLoS One. 2022;17(1):e0261786
  50. 50. Fontana P, Casini A, Robert-Ebadi H, Glauser F, Righini M, Blondon M. Venous thromboembolism in COVID-19: Systematic review of reported risks and current guidelines. Swiss Medical Weekly. 2020;150:w20301
  51. 51. Piazza G, Campia U, Hurwitz S, Snyder JE, Rizzo SM, Pfeferman MB, et al. Registry of arterial and venous thromboembolic complications in patients with COVID-19. Journal of the American College of Cardiology. 2020;76(18):2060-2072
  52. 52. Hasan SS, Radford S, Kow CS, Zaidi STR. Venous thromboembolism in critically ill COVID-19 patients receiving prophylactic or therapeutic anticoagulation: A systematic review and meta-analysis. Journal of Thrombosis and Thrombolysis. 2020;50(4):814-821
  53. 53. Jiménez D, García-Sanchez A, Rali P, Muriel A, Bikdeli B, Ruiz-Artacho P, et al. Incidence of VTE and bleeding among hospitalized patients with coronavirus disease 2019. Chest. 2021;159(3):1182-1196
  54. 54. Klok FA, Kruip MJHA, van der Meer NJM, Arbous MS, Gommers DAMPJ, Kant KM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thrombosis Research. 2020;191:145-147
  55. 55. Wichmann D, Sperhake J-P, Lütgehetmann M, Steurer S, Edler C, Heinemann A, et al. Autopsy findings and venous thromboembolism in patients with COVID-19. Annals of Internal Medicine. 2020;6:M20
  56. 56. Marone EM, Bonalumi G, Curci R, Arzini A, Chierico S, Marazzi G, et al. Characteristics of venous thromboembolism in COVID-19 patients: A multicenter experience from Northern Italy. Annals of Vascular Surgery. 2020;68:83-87
  57. 57. Potere N, Valeriani E, Candeloro M, Tana M, Porreca E, Abbate A, et al. Acute complications and mortality in hospitalized patients with coronavirus disease 2019: A systematic review and meta-analysis. Critical Care. 2020;24:389
  58. 58. Li Y, Li M, Wang M, Zhou Y, Chang J, Xian Y, et al. Acute cerebrovascular disease following COVID-19: A single center, retrospective, observational study. Stroke Vascular Neurology. 2020;5(3):279-284
  59. 59. Prieto-Lobato A, Ramos-Martínez R, Vallejo-Calcerrada N, Corbí-Pascual M, Córdoba-Soriano JG. A case series of stent thrombosis during the COVID-19 pandemic. JACC Case Reports. 2020;2(9):1291-1296
  60. 60. Bilaloglu S, Aphinyanaphongs Y, Jones S, Iturrate E, Hochman J, Berger JS. Thrombosis in hospitalized patients with COVID-19 in a New York City Health System. Journal of the American Medical Association. 2020;324(8):799-801
  61. 61. Becker RC. COVID-19 update: Covid-19-associated coagulopathy. Journal of Thrombosis and Thrombolysis. 2020;50(1):54-67
  62. 62. Al-Samkari H, Karp Leaf RS, Dzik WH, Carlson JCT, Fogerty AE, Waheed A, et al. COVID-19 and coagulation: Bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood. 2020;136(4):489-500
  63. 63. Szekely Y, Lichter Y, Taieb P, Banai A, Hochstadt A, Merdler I, et al. Spectrum of cardiac manifestations in COVID-19: A Systematic Echocardiographic Study. Circulation. 2020;142(4):342-353
  64. 64. MVB| NW| CN|. Research Reveals Heart Complications in COVID-19 Patients. CIDRAP; 2020 [cited October 31, 2020]. Available from:
  65. 65. Iqubal A, Iqubal MK, Hoda F, Najmi AK, Haque SE. COVID-19 and cardiovascular complications: An update from the underlying mechanism to consequences and possible clinical intervention. Expert Review of Anti Infective Therapy.19(9):1083-1092
  66. 66. Mishra A, Lal A, Sahu KK, George AA, Martin K, Sargent J. An update on pulmonary hypertension in coronavirus disease-19 (COVID-19): Pulmonary hypertension and COVID -19. Acta Bio-Medica. 2020;91(4):e2020155
  67. 67. Khan AW, Ullah I, Khan KS, Tahir MJ, Masyeni S, Harapan H. Pulmonary arterial hypertension post COVID-19: A sequala of SARS-CoV-2 infection? Respiratory Medicine Case Reports. 2021;33:101429
  68. 68. Pagnesi M, Baldetti L, Beneduce A, Calvo F, Gramegna M, Pazzanese V, et al. Pulmonary hypertension and right ventricular involvement in hospitalised patients with COVID-19. Heart. 2020;106(17):1324-1331
  69. 69. Aronson KI, Podolanczuk AJ. Lungs after COVID-19: Evolving knowledge of post–COVID-19 interstitial lung disease. Annals ATS. 2021;18(5):773-774
  70. 70. Potus F, Mai V, Lebret M, Malenfant S, Breton-Gagnon E, Lajoie AC, et al. Novel insights on the pulmonary vascular consequences of COVID-19. American Journal of Physiology. Lung Cellular and Molecular Physiology. 2020;319(2):L277-L288
  71. 71. Suzuki YJ, Nikolaienko SI, Shults NV, Gychka SG. COVID-19 patients may become predisposed to pulmonary arterial hypertension. Medical Hypotheses. 2021;147:110483
  72. 72. Tudoran M, Tudoran C, Lazureanu VE, Marinescu AR, Pop GN, Pescariu AS, et al. Alterations of left ventricular function persisting during post-acute COVID-19 in subjects without previously diagnosed cardiovascular pathology. Journal of Personalized Medicine. 2021;11:225-232
  73. 73. Baycan OF, Barman HA, Atici A, Tatlisu A, Bolen F, Ergen P, et al. Evaluation of biventricular function in patients with COVID-19 using speckle tracking echocardiography. International Journal of Cardiovascular Imaging. 2020;37(1):135-144
  74. 74. Rey JR, Caro-Codón J, Rosillo SO, Iniesta ÁM, Castrejón-Castrejón S, Marco-Clement I, et al. Heart failure in COVID-19 patients: Prevalence, incidence and prognostic implications. European Journal of Heart Failure. 2020;22(12):2205-2215
  75. 75. Lippi G, Wong J, Henry BM. Hypertension in patients with coronavirus disease 2019 (COVID-19): A pooled analysis. Polish Archives of Internal Medicine. 2020;130(4):304-309
  76. 76. Sheppard JP, Nicholson BD, Lee J, McGagh D, Sherlock J, Koshiaris C, et al. Association between blood pressure control and coronavirus disease 2019 outcomes in 45 418 symptomatic patients with hypertension: An Observational Cohort Study. Hypertension. 2021;77(3):846-855
  77. 77. World Health Organization. Guideline for the Pharmacological Treatment of Hypertension in Adults. Geneva: World Health Organization; 2021 [cited February 8, 2022]. Available from:
  78. 78. Kavi L. Postural tachycardia syndrome and long COVID: An update. The British Journal of General Practice. 2022;72(714):8-9
  79. 79. Naeini MB, Sahebi M, Nikbakht F, Jamshidi Z, Ahmadimanesh M, Hashemi M, et al. A meta-meta-analysis: Evaluation of meta-analyses published in the effectiveness of cardiovascular comorbidities on the severity of COVID-19. Obesity Medicine. 2021;22:100323
  80. 80. Xie Y, Xu E, Bowe B, Al-Aly Z. Long-term cardiovascular outcomes of COVID-19. Nature Medicine. 2022
  81. 81. Mevorach D, Anis E, Cedar N, Bromberg M, Haas EJ, Nadir E, et al. Myocarditis after BNT162b2 mRNA vaccine against Covid-19 in Israel. The New England Journal of Medicine. 2021;385(23):2140-2149
  82. 82. Patone M, Mei XW, Handunnetthi L, Dixon S, Zaccardi F, Shankar-Hari M, et al. Risks of myocarditis, pericarditis, and cardiac arrhythmias associated with COVID-19 vaccination or SARS-CoV-2 infection. Nature Medicine. 2021

Written By

Cristina Tudoran, Mariana Tudoran, Voichita Elena Lazureanu, Adelina Raluca Marinescu, Dorin Novacescu and Talida Georgiana Cut

Submitted: February 12th, 2022 Reviewed: February 27th, 2022 Published: May 13th, 2022