COVID-19’s Consequences on the Cardiovascular System: Immediate, Intermediate, and Long-Term Complications

COVID-19 Consequences on Cardiovascular System: Immediate, Intermediate, and Long-Term Complications covers all the aspects related with the interplay between SARS-COV-2 infection and the cardiovascular system, from bench to bedside and from acute infection to long-term complications. Written by a team of experts, this book is a one-stop-shop reference for both healthcare professionals and researchers who require a comprehensive view into the deleterious effects of COVID-19 on the cardiovascular system, the relationship of cardiovascular risk factors with COVID-19 prognosis, and further insights on the biomarkers that currently make it possible to predict and monitor the evolution of the disease at the cardiovascular level.

Scientific evidence demonstrates that while COVID-19 primarily affects the lungs, it also affects multiple organs, particularly the cardiovascular system, with its most common complications being arrhythmia, cardiac injury, fulminant myocarditis, heart failure and pulmonary embolism.

• Covers all the current scientific pieces of evidence about the effects of COVID-19 on the heart and cardiovascular system from both a basic and a clinical point of view.
• Discusses immediate, intermediate, and long-term complications of COVID-19 on the cardiovascular system.
• Includes studies conducted worldwide by well-known experts in related fields.

• Language: English
• Publisher: Academic Press
• Release date: Apr 4, 2024
• ISBN: 9780443190926

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Introduction

Fabian Sanchis-Gomar¹ and Amer Harky² ¹Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA, United States ²Department of Cardiothoracic Surgery, Liverpool Heart and Chest Hospital, Liverpool, United Kingdom

Introduction

Coronavirus disease 2019 (COVID-19) reached pandemic status, affecting many millions of patients worldwide and causing a very large number of deaths; unfortunately, these numbers will continue to rise. COVID-19 is characterized by a diverse clinical course from direct viral-mediated injury and, in some patients, an exaggerated immune response leading to acute respiratory distress syndrome. COVID-19 causes a wide range of symptoms, including fever, cough, loss of taste and smell, shortness of breath, fatigue, and headache. Although symptoms are usually minor, COVID-19 is associated with severe illness in a number of patients patients, with a case-fatality rate of about 1%. The severity of the disease is worse in the elderly, the immunocompromised, and those with a history of cardiovascular disease. The disease process has been linked to myocardial injury in around 25% of patients, with some developing significant cardiac manifestations, including biventricular heart failure, arrhythmias, and occasionally cardiogenic shock and death. A multifactorial mechanism likely includes cytokine-mediated cardiomyopathy, endothelial inflammation, microemboli, acute coronary events, pulmonary emboli, right ventricular strain, and myocarditis. Concerningly, it has been observed that the recovery process from COVID-19 is extremely long and/or delayed in certain individuals, which has been baptized as post-COVID-19 syndrome, chronic COVID syndrome, or simply long COVID. Accordingly, COVID-19 affects multiple organs and systems, including the heart and cardiovascular system, in the short, middle, and long terms. In this book, we aimed to present the current state of knowledge with respect to immediate, intermediate, and long-term COVID-19-induced consequences and/or complications on the heart and cardiovascular system.

Chapter 1

The pathophysiology of COVID-19 and the cardiovascular system

Nazifa Ahsan¹, Michael O. Adesida², Noorulain Memon³ and Thomas Obemaier³,    ¹Faculty of Medicine, Imperial College London, London, United Kingdom,    ²General Surgery, Princess Royal University Hospital, King’s College Foundation Trust NHS, London, United Kingdom,    ³Emergency Medicine, Princess Royal University Hospital, King’s College Foundation Trust NHS, London, United Kingdom

Abstract

Several studies have shown that COVID-19 is not only a respiratory disease, but also impacts the cardiovascular system. Many mechanisms behind cardiovascular damage secondary to COVID-19 have been elucidated. The primary mechanism stems from SARS-CoV-2 entry via the angiotensin-converting enzyme 2 (ACE2) receptor which is present on the surface of many cell types, including cardiomyocytes, pericardial cells, and endothelial cells. Viral invasion of these cells can result in myocarditis, pericarditis, and endothelial dysfunction. Viral entry via ACE2 can cause ACE2 reduction, through receptor internalization and degradation or shedding. ACE2 functions as a negative regulator of angiotensin II. Therefore ACE2 reduction can lead to increased angiotensin II which is pro-hypertensive, so it can promote heart failure or atherosclerosis development. Furthermore, SARS-CoV-2 invasion into host cells stimulates cytokine release via nuclear factor-κB activation. This effect is heightened by the pro-inflammatory effects of angiotensin II, resulting in a cytokine storm and subsequent organ damage. Pulmonary damage and creation of a hypoxic environment can put strain on the heart, which can be further exacerbated by cardiac muscle damage, leading to heart failure or arrhythmia development. Finally, damage to endothelial cells contributes to endothelial dysfunction, promoting a hypercoagulable state and increasing the risk of thromboembolic events.

Keywords

COVID-19; ACE2; respiratory disease; SARS-CoV-2; cardiovascular disease; heart

Introduction

COVID-19 is classically known as a respiratory disease; however, an interrelationship between COVID-19 and the cardiovascular system has also been shown. Several studies have reported that patients with both COVID-19 and underlying cardiovascular diseases may have a worse prognosis, more critical illness, and higher mortality [1,2]. More specifically, in a retrospective study of 150 patients diagnosed with COVID-19, cardiovascular disease was more prevalent in the patients who died, including 27 due to myocardial damage and circulatory failure [3]. Furthermore, a study with 416 patients affected by COVID-19 showed that cardiac injury during hospitalization occurred in 19.7%. SARS-CoV-2 infection also has vascular impacts, as it appears to generate a profoundly prothrombotic state as evidenced by a surge in global reports of arterial, venous, and catheter-related thrombosis [4]. Many mechanisms behind cardiovascular damage secondary to COVID-19 have been elucidated, which will be discussed in this chapter.

Direct myocardial and pericardial injury by SARS-CoV-2

Postmortem studies have shown that myocardial inflammation, as well as direct SARS-CoV-2 invasion of the cardiac cells, can lead to myocardial necrosis [5]. Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for SARS-CoV-2 [6]. SARS-CoV-2 enters the host cell by binding to the S1 subunit of the ACE2 receptor on the host cell surface. The virus attaches after its S protein is primed by a cellular serine protease called TM protease serine 2 (TMPRSS2). This protease facilitates the fusion of the viral and host membranes through the S2 subunit. ACE2 and TMPRSS2 are both highly expressed in the heart [5]. This makes the heart more vulnerable to COVID-19. Cardiac myocytes, fibroblasts, and, in particular, the pericytes, which are the cells that support the microvasculature throughout the myocardium, highly express this ACE2 receptor. It is through this receptor that SARS-CoV-2 can directly infect and damage cardiac cells. Furthermore, cardiomyocyte-specific upregulation of ACE2 has been noted in failing hearts [7]. A study involving 56 hearts used electron microscopy to show the presence of SARS-CoV-2 in cardiomyocytes (19.6%), cardiac vascular endothelial cells (12.5%), and in cardiac fibroblasts (1.8%) [5].

Autopsy studies have confirmed cellular tropism of SARS-CoV-2 through in situ labeling of SARS-CoV-2 RNA and by electron microscopy detection of virus-like particles within cardiomyocytes, interstitial cells and endothelial cells [8–10]. Further cardiac autopsies (Shaller et al.) have shown that direct infection of the cardiac cells with SARS-CoV-2 can cause cardiomyopathy, myocarditis, pericarditis, endocardial thrombosis, and small vessel thrombosis. These processes can eventually cause acute heart failure, myocardial ischemia or infarction, arrhythmias, and thrombosis secondary to viral-mediated coagulopathy [7]. The mechanisms of how SARS-CoV-2 affects these diseases will be discussed later in this chapter.

Cardiovascular implications of SARS-CoV-2 effect on the renin-angiotensin system

Entry of SARS-CoV-2 via ACE2 results in a reduction of ACE2 on the cell surface via several mechanisms [11]. Firstly, during receptor-mediated endocytosis, the receptors are internalized and degraded; therefore there is a loss of ACE2 from the cell surface [11,12]. Secondly, SARS-CoV-2 internalization via ACE2 triggers disintegrin and metallopeptidase domain 17 (ADAM17) activation [13]. ADAM17 cleaves the ACE2 ectodomain so it is shed from the surface of the cell [14]. Thirdly, as part of the host immune response to viral invasion into host cells, cytokines are released [15]. These cytokines include interleukin-4 (IL-4), which downregulates ACE2 expression from host cell surfaces to reduce susceptibility to viral infection [16,17].

ACE2 functions as a negative regulator of the renin-angiotensin system (RAS) [18]. The primary product of the RAS is angiotensin II, which promotes vasoconstriction and aldosterone secretion via angiotensin II type 1 (AT1) receptor activation [18]. Aldosterone secretion results in increased salt and water reabsorption, which together with vasoconstriction increases blood pressure [18,19]. Therefore overactivation of the RAS can lead to hypertension, which is involved in the development of cardiovascular disease [19]. Hypertension can result in mechanical injury to the endothelial cells, increasing endothelial permeability to lipoproteins which accumulate to form plaque; thus hypertension can accelerate the progression of atherosclerosis [20]. Atherosclerosis is the primary cause of cardiovascular disease [21]. Coronary artery atherosclerosis is responsible for angina and myocardial infarction (MI), which can consequently result in ischemic cardiomyopathy and heart failure [22,23]. Atherosclerosis can also lead to peripheral arterial disease and stroke [21]. In addition to accelerating atherosclerosis, hypertension can have direct impacts on the heart [24]. Hypertension leads to increased left ventricular afterload [24]. Therefore, with prolonged hypertension, the left ventricle hypertrophies in response to having to pump harder against the increased pressure so that it is able to maintain adequate cardiac output [24]. The hypertrophied ventricle is more rigid, so cannot expand while filling, which can result in the development of heart failure with preserved ejection fraction [24].

ACE2 regulates the effects of angiotensin II by converting it into angiotensin 1–7, which can no longer activate the AT1 receptor [18]. However, angiotensin 1–7 is also a biologically active peptide which acts on Mas receptors [18]. In contrast with angiotensin II, angiotensin 1–7 induces vasodilatory effects which lower blood pressure [18]. Therefore the reduction of ACE2 on host cell surfaces by SARS-CoV-2 entry leads to increased angiotensin II and reduced angiotensin 1–7, which may result in increased blood pressure. This is supported by observational studies where patients infected with SARS-CoV-2 were found to have higher levels of angiotensin II and lower levels of angiotensin 1–7 compared to SARS-CoV-2 negative controls [25–27]. In patients with preexisting cardiovascular disease, this increased blood pressure resulting from SARS-CoV-2 infection may aggravate the disease, leading to worsening symptoms or major complications such as MI or stroke resulting from atherosclerotic plaque rupture.

Alongside impacting blood pressure, the balance between angiotensin II and angiotensin 1–7 impacts inflammation and fibrogenesis [28]. Binding of angiotensin II to AT1 receptors can promote inflammation through a variety of mechanisms [29]. Angiotensin II stimulates many pro-inflammatory molecules, one of them being nuclear factor-κB (NF-κB) [29]. NF-κB is a activates the transcription of various genes involved in the inflammatory response including cytokines, chemokines, and adhesion molecules to recruit innate immune cells such as neutrophils, macrophages, and natural killer cells to the site of infection [15,30]. Furthermore, angiotensin II stimulates the enzyme nicotinamide adenine dinucleotide phosphate oxidase, which is a key enzyme in the production of reactive oxygen species (ROS) [29]. Both inflammation and ROS in excess can lead to cardiomyocyte damage [31,32]. Angiotensin II also stimulates the cytokine transforming growth factor-β (TGF-β) expression in cardiac fibroblasts, which stimulates collagen synthesis and excess collagen deposition within the myocardium [28,33]. To counter the action of angiotensin II, angiotensin 1–7 exerts an antiinflammatory and antifibrotic effect through Mas receptor action through inhibition of NF-κB and TGF-β action, respectively [28]. Therefore the increase in angiotensin II with the decrease in angiotensin 1–7 as a result of SARS-CoV-2 infection would lead to a pro-inflammatory and pro-fibrotic phenotype [28]. The combination of cardiomyocyte damage through inflammation and myocardial fibrosis could lead to the development of further cardiac problems such as heart failure and arrhythmias, which are explained in more detail later [31].

Considering how infection with SARS-CoV-2 may result in RAS dysregulation, promoting increased blood pressure, inflammation, and fibrosis, it would make sense to try to counter this to try and avoid the possible implications discussed above. Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are drugs which inhibit RAS activity [34]. ACE inhhibitors work by inhibiting ACE, which converts angiotensin I to angiotensin II [34]. ARBs work by blocking the AT1 receptor that angiotensin II binds to [34]. However, there was found to be increased ACE2 synthesis with ACE inhibitor or ARB treatment [35]. Since ACE2 is an entry route for SARS-CoV-2 into host cells, ACE inhibitor or ARB treatment was thought to increase susceptibility and severity of infection [36]. However, in hospitalized patients with SARS-CoV-2 infection, use of ACE inhibitors or ARBs has been associated with significantly decreased mortality [37]. The mechanisms behind this are unclear but this may be due to the antiinflammatory effects of increased angiotensin 1–7 subsequent to increased ACE2 levels, which protects against multisystem organ damage, as discussed later [38,39].

The role of RAS in the body, the importance of ACE2 in regulating RAS activity, and how these systems may be impacted by SARS-CoV-2 entry into cells and through drug modulation using ACE inhibitors and ARBs are summarized in Fig. 1.1.

Figure 1.1 A summary of the renin-angiotensin system and its counter-regulation by angiotensin-converting enzyme 2 (ACE2).

Processes damaging to the cardiovascular system are shown in red. Cardioprotective processes are shown in green. The purple downward arrow represents ACE2 reduction secondary to SARS-CoV-2 entry via ACE2. The sites of inhibition of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are shown by the blue flat-ended arrows. The blue upward arrow represents increased ACE2 production as a consequence of ACE inhibitor and ARB action. The organs pictured represent sites of production, with ACE and ACE2 being produced in various organs. ADAM17, Disintegrin and metallopeptidase domain 17; AT1, angiotensin II type 1; IL-4, interleukin-4; NF-κB, nuclear factor-κB.

The inflammatory response to SARS-CoV-2 infection

Inflammation is a normal response to injury or infection. However, it is the exaggerated inflammatory response to COVID-19 that results in the enhanced clinical picture. In COVID-19 patients the immune system of the body causes a deadly cycle of inflammation known as the cytokine storm or cytokine release syndrome. The initial entry of the virus into the host cell activates the innate immune response [15]. The SARS-CoV-2 virus is recognized by pattern recognition receptors which then activate downstream transcription factors [15]. A major transcription factor activated is NF-κB which activates the transcription of various genes involved in the inflammatory response including cytokines, chemokines, and adhesion molecules to recruit innate immune cells such as neutrophils, macrophages, and natural killer cells to the site of infection [15,30]. Once recruited and activated, these innate immune cells then release further cytokines and chemokines to amplify the inflammatory response [15]. In addition to this, viral entry via ACE2 results in increased angiotensin II which stimulates various inflammatory mediators including NF-κB, leading to further cytokine release [40]. All these processes together can result in an extremely large amount of cytokine release known as the cytokine storm and consequently systemic hyperinflammation [41].

Tumor necrosis factor-α (TNF-α) is one of the cytokines released and has been shown to induce cardiomyocyte damage by the induction of nitric oxide, generation of oxygen free radicals, and apoptosis [42]. Patients infected with SARS-CoV-2 also have higher levels of interleukin-6 (IL-6), vascular endothelial growth factor, and reduced E cadherin. The latter two compounds cause vascular permeability and leakage leading to the development of shock and acute respiratory distress sydrome (ARDS). IL-6 is associated with respiratory failure and pneumonia. It is released by monocytes, macrophages, and dendritic cells in response to COVID-19 infection. This IL then activates the innate and adaptive immune responses. Subsequently, this leads to the activation of cytotoxic T cells, B cells, and endothelial cells. This immune activation is responsible for the increased vascular permeability, hypotension, shock and ARDS the consequent, multiorgan failure that occurs in COVID-19 [42].

Cardiovascular implications of the cytokine storm

Inflammatory cytokines and ROS released by activated immune cells promote endothelial cell dysfunction, resulting in the endothelial cells becoming activated [43,44]. Once activated, the endothelial cells express adhesion molecules which allow monocyte infiltration [43]. Monocytes differentiate into macrophages and internalize lipoproteins becoming foam cells. This is a key initial step in plaque formation [43,45]. These cytokines can also stimulate the smooth muscle cells to produce a fibrous cap [46]. After COVID-19-induced activation of macrophages and T cells, proteins such as metalloproteinases and peptidases are released [46]. These proteins are responsible for the breakdown of the extracellular matrix and the formation of ROS which in turn can destabilize the plaque [1,2]. When the plaque surface becomes disrupted, thrombogenic elements are released, which lead to the formation of an intravascular thrombus. These thrombi block coronary arteries and lead to Type 1 MI [47]. Inflammation of the coronary arteries also results in decreased fibrinolysis and therefore enhanced fibrin deposition, which is a signficant contributor to thrombosis and hence MI [48]. A review of 50 studies which encompassed 548 COVID-19 patients showed that in 62 cases, cardiac pathologies were identified as the main factor of mortality. The most prevalent acute cardiovascular implications included microvessel thrombi (36.2%), pulmonary embolism (22.2%), large vessel thrombosis (14.3%), and acute MI (11.8%) [5]. Therefore hyperinflammation as part of the host response to SARS-CoV-2 infection may lead to the initiation or progression of atherosclerosis.

Cardiomyocyte damage and death by the host immune response would lead to the replacement of functional tissue with scar tissue [49]. This can impair cardiac function and lead to the development of heart failure [49]. Regions of fibrosis are also associated with slower conduction which can predispose to reentrant arrhythmias [50]. Inflammatory cytokines can also directly promote arrhythmias by interfering with the ionic currents which regulate the cardiac action potential; they can modulate the expression of ion channels resulting in the reduction of outward depolarizing currents and enhancement of inward depolarizing currents and consequently action potential prolongation, posing an arrhythmogenic risk [50]. A Chinese study of 138 COVID-19 patients showed that 16.7% of those patients had arrhythmias. This can also be exacerbated by the hypoxia and electrolyte abnormalities caused during the acute phase of the illness [42].

Viral infections are one of the most common causes of myocarditis. Direct cellular injury and T-cell cytotoxicity of the myocardium by viral infections cause myocarditis [51]. This is a consequence of the cytokine storm. IL-6 is at the center of this process and causes T-lymphocyte and macrophage activation and subsequently a positive feedback loop of immune activation and myocardial damage [52]. Basso et al. did a postmortem study, which showed that 86% of COVID-19 patients presented with nonspecific interstitial macrophage infiltrations in the heart, with 14% of those presenting with multifocal lymphocytic myocarditis [52,53]. Both viral invasion of the cardiomyocytes and the host immune response to viral myocarditis can result in damage to the cardiomyocyte cytoskeleton [54]. This can lead to the development of dilated cardiomyopathy [54].

The inflammatory process can also affect the pericardium, the double-walled sac of the heart. The viruses themselves or the release of cellular debris can promote the formation of the Nod-Like Protein Receptor 3 inflammasome that can fuel a widespread cytokine storm mainly driven by IL-β [55]. Pericardial biopsies of COVID-19 patients have shown a thickened pericardium caused by this cytokine storm, with reactive mesothelial cells, lymphocytes, and histiocytes [56]. The SARS-CoV-2 genome has also been found in the pericardial fluid of covid positive patients [55,57]. Multiple subsequent small pericardial effusions can lead to cardiac tamponade, a lethal condition that creates pressure around the heart and prevents the adequate filling of blood, thus leading to a severe drop in blood pressure and potentially cardiogenic shock. Long-term pericarditis can cause permanent thickening and scarring of the pericardium which can lead to abnormal contraction and relaxation of the heart, ultimately ending in heart failure.

As explained earlier, uncontrolled systemic inflammation can lead to the immune system targeting various host cells including cardiomyocytes [31,41]. Myocardial injury is a unique aspect of COVID-19, as most patients with elevated troponin levels who undergo angiography do not have pericardial coronary artery obstruction but rather Type 2 MI (T2MI) [58]. This is a consequence of the cytokine storm, where a large number of inflammatory cells infiltrate the lungs which release further inflammatory mediators and ROS, leading to alveolar damage and respiratory failure [58]. Furthermore, systemic hyperinflammation can result in hypotension and hemodynamic instability due to increased capillary permeability leading to fluid leakage and hypovolemia [59]. Hypoxia due to ARDS and hypovolemia due to systemic hyperinflammation increase the risk of a myocardial supply and demand mismatch: there would be an increased myocardial oxygen demand due to a need for increased cardiac output, which would likely exceed myocardial oxygen supply [42,60]. This could result in T2MI, which is caused by a myocardial supply and demand mismatch not attributed to coronary artery disease [61]. An observational study by Talanas et al. [62] of 60 patients with T2MI demonstrated a higher incidence of hypoxemia in the patients who were COVID positive as compared to the patients who were COVID negative (67% vs 40%). The severity of T2MI can be determined by the elevations in D-dimer, C-reactive protein (CRP), and procalcitonin levels in blood tests [1,2]. Blood tests from this study also showed significantly higher levels of hemoglobin, ferritin, D-dimer, and CRP in the patients with COVID-19 as compared to those without. In contrast, the patients infected with SARS-CoV-2 had lower peak troponin I levels than those uninfected. Patients with COVID-19-related T2MI also had a twofold higher in-hospital mortality rate as compared to the COVID-negative patients [62].

A summary of the cardiovascular implications of the cytokine storm is shown in Fig. 1.2.

Figure 1.2 A summary of the consequences of the cytokine storm on the heart.

The cytokine storm can lead to myocarditis, arrhythmias, pericarditis, thrombosis (which can concurrently lead to Type 1 myocardial infarction) and acute respiratory distrress syndrome (ARDS), which can result in Type 2 myocardial infarction.

Effect of cytokine storm on systemic vasculature

There are several pathophysiological mechanisms of development of myocarditis, out of which is cytokine storm [63], which has been reported in patients with COVID-19; however, Ackermann et al. [64] reported endothelial cells infiltration in histological studies of COVID-19 patients. Endothelial cell swelling is a result of inflammatory infiltration of the endothelial cells, leading to endothelialitis distorting membrane function and loosening of interendothelial junctions [64]. Varga et al. showed endothelial cell death and dysfunction in patients infected with SARS-CoV-2, which facilitated the induction of endothelialitis in several organs, including cardiac tissue, as a direct consequence of viral involvement and of the host inflammatory response [65].

The presence of endothelialitis demonstrates the activation of endothelial cells, promoting the expression of cell-surface adhesion molecules and thus the binding of inflammatory cells to the endothelium [26,27]. These pathophysiological consequences promote vascular hyperpermeability. Disruption of interendothelial junctions causes endothelial cells to be pulled apart, thus resulting in interendothelial gaps [66], denoting cytoskeletal alterations to the endothelium.

Elevations in cytosolic Ca²+ influx into endothelial cells is a pivotal step in the disruption to interendothelial junctions and thus the progression to increased vascular permeability [67]. A determinant of this increased Ca²+ influx is the upregulation of transient receptor potential channels, which is induced via TNF-α [68], causing a destabilization of microtubules [69]. Evidence supports the notion of a cytokine-induced hyperpermeability response of the vasculature, with Tinsley et al., demonstrating the role of cytokine (TNF-α, IL-1β, and IL-6)-induced vascular hyperpermeability through a protein kinase C (PKC) and myosin light-chain kinase (MLCK)-dependent mechanism in cultured rat heart microvascular endothelial cells [70]. Therefore, translating this to COVID-19 pathophysiology, cytokine storm–induced Ca²+influx into endothelial cells may be a contributing mechanism underpinning the disruption to interendothelial junctions and the promotion of vascular permeability. Furthermore, the cytokine-induced stimulation of PKC and MLCK may promote direct damage to cardiac tissue, which may pose significant deleterious effects upon patients with preexisting CVD, a common comorbidity in the more severe COVID-19 population [71].

Whilst there is a plethora of evidence which suggests that the cytokine storm experienced in COVID-19 patients may promote damage to the vasculature, sustained inflammation directly contributes to progressive cardiomyocyte apoptosis. Elevated TNF-α levels seen in a variety of clinical conditions including COVID-19, drives cardiomyocytes to apoptosis [72]. TNF-α can induce cardiomyocyte apoptosis directly, via the TNF receptor, or indirectly, through stimulation of NO production or ROS, which in turn is induced by pro-inflammatory cytokines such as IL-1, IL-6, TNF-α, and interferon-gamma =[73]. High levels of cardiac troponin are reflective of cardiomyocyte death and injury, and as stated earlier, are associated with COVID-19 disease severity and mortality [74].

In the heart, the acute inflammatory response can expand tissue damage and prolonged inflammation leads to accentuated adverse remodeling. Indeed, pro-inflammatory cytokines and upregulated monocytes/macrophages can inhibit cardiac repair, which is dependent on timely suppression and resolution of pro-inflammatory signaling. Activation of IL-1 signaling induces cytokine expression, promotes matrix-degrading properties, suppresses fibroblast proliferation, and inhibits transdifferentiation of fibroblasts into myofibroblasts, altogether delaying activation of a reparative response [75]. Moreover, a severe or prolonged reparative response is associated with pathological scarring and fibrosis [76].

Hypercoagulable state

Inflammation leads to endothelial activation [43]. In the activated state, endothelial cells express adhesion molecules [43]. This allows the adhesion of neutrophils to the endothelial surface [77]. Cytokines and ROS trigger the production of neutrophil extracellular traps (NETs) which are web-like structures of protein assembled on a scaffold of decondensed chromatin [77,78]. NETs promote coagulation by recruiting factor XIIa [78]. This coagulation factor is involved in the coagulation cascade to promote the formation of a fibrin mesh and also triggers the release of von Willebrand factor (vWF) from endothelial cells [78]. The NETs bind to vWF, and then platelets bind to vWF and recruit more platelets, resulting in platelet aggregation and clot formation [78]. These mechanisms, illustrated in Fig. 1.3, lead to an increased risk of venous thromboembolism in patients infected with SARS-CoV-2, a common manifestation of which is pulmonary embolism [79]. In fact, a large number of clinical observational studies in almost 2000 patients point to an incidence of venous thromboembolism of up to 35% in patients with severe COVID-19 [80]. It is also possible that inflammation and endothelial activation increase the risk of arterial thrombosis, which could result in MI or stroke [79].

Figure 1.3 Illustration of the mechanisms behind the development of a hypercoagulable state secondary to SARS-CoV-2 infection.

FXIIa, Factor XIIa; NETs, neutrophil extracellular traps; vWF, von Willebrand factor.

Disseminated intravascular coagulation

Studies conducted during the COVID-19 pandemic showed that patients with severe forms of COVID-19 showed coagulation disorders that have been associated with respiratory deterioration and death [81,82]. Furthermore, a number of patients diagnosed with COVID-19 infection develop venous thromboembolism which is related to coagulopathy [83]. It has repeatedly been confirmed that pulmonary embolism contributes to a sudden deterioration of pulmonary oxygen exchange that is occasionally seen in patients with COVID-19 infections [80].

Excessively elevated D-dimer level is the most significant abnormal coagulation investigation result in COVID-19 patients [81,82]. A large initial COVID-19 series found abnormally elevated D-dimer levels in 46% of all cases (43% in nonsevere patients versus 60% in critically ill ICU patients) [84]. In another study increased levels of D-dimer were related to a poor outcome [74]. In an investigation of 343 patients it was shown that D-dimer levels of over 2.0 mg/L predicted mortality with a sensitivity of 92% and a specificity of 83%