Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been responsible for the worst pandemic in the past 100 years. Initially thought to be primarily a respiratory system disease, Coronavirus Disease 2019 (Covid-19) has generally been accepted as a disease with systemic manifestations. Understanding the pathophysiology of this disease makes us realize that SARS-CoV-2 targets and utilizes angiotensin-converting enzyme 2 (ACE-2) receptors as the initial point of invasion into the human body, which eventually results in the devastating cascade that has become the hallmark of this disease. ACE-2 receptors are expressed not only in type 1 and type 2 pneumocytes but also in endothelial cells, vascular smooth muscle cells, and migratory angiogenic cells in the vascular system and cardiac fibroblasts, cardiomyocytes, and endothelial cells, pericytes, and epicardial adipose cells in the heart. Therefore, it becomes very evident that SARS-CoV-2 targets the entire cardiovascular system characterized by a cytokine storm that is distinct in patients with COVID-19, which results in endothelial dysfunction, endothelial inflammation, microvascular thrombosis, and multiorgan failure,1 in addition to the lungs, thereby not limited to being a respiratory disease causing pneumonia and respiratory failure.2–5 Myocardial injury, defined as elevated cardiac troponin levels, is present in almost one in four hospitalized COVID-19 patients.6–9 The mortality rate of COVID-19 among all patients was deemed to be about 3.4 and 1.4% among patients without underlying disease.2 However, in patients with pre-existing cardiovascular disease (CVD), the mortality rate was 13.2%.2 The cardiovascular complications covered in this chapter are summarized in Fig. 6.1.
Fig. 6.1 Cardiovascular complications of Covid-19 and associated risk of mortality. Licensed under creative commons licenseCreative Commons—Attribution 4.0 International—CC BY 4.0. Lee CCE, Ali K, Connell D, Mordi IR, George J, Lang EM, Lang CC. COVID-19-associated cardiovascular complications. Diseases 2021;9:47. https://doi.org/10.3390/diseases9030047144
Pathophysiology
Cardiovascular manifestations of COVID-19 are due to both direct infection and invasion of myocardial cells and endothelial dysfunction and inflammation, and microvascular thrombosis resulting in indirect injury to the cardiovascular system.
Direct Myocardial Injury
SARS-Cov-2 is a single-stranded ribonucleic acid (RNA) virus. The Spike protein (S) of SARS-CoV-2 binds to the ACE-2 receptors, allowing the virus to enter the cells. Cell entry of the virus requires priming the spike protein by cellular serine protease transmembrane protease series 2 (TMPRSS2) or other proteases such as cathepsin L, cathepsin B, factor X, trypsin, elastase, and furin.10,11 Patients with pre-existing CVD are associated with more severe COVID-19 disease because they have higher plasma levels of ACE-2.12 After gaining entry into the host cell, the virus uses the cell’s machinery to translate RNA to polypeptides, including an RNA-dependent RNA polymerase that the virus uses to replicate its own RNA.13 Thereafter, a new virus is released from the cell by exocytosis. Host cells subsequently are disabled or destroyed, potentially triggering an innate immune response.14 However, only a few reports confirm the presence of viral inclusion bodies or SARS-CoV-2 genomic RNA from myocardial tissue in biopsy-proven COVID-19 myocarditis cases that are associated with typical features of myocarditis, including intramyocardial inflammation, microvascular thrombosis, and myocardial necrosis.15–20 An autopsy series of consecutive patients showed SARS-CoV-2 in cardiac tissues in 61.5% of those patients.21
Indirect Injury by SARS-CoV-2
ACE-2 converts angiotensin II (Ang II) to angiotensin (Ang)-(1-7), which in turn acts by activating its receptor MAS—a G-protein-coupled receptor (GPCR).22 This ACE-2/Ang-(1-7)/Mas axis counteracts and is an inverse regulator of the renin-angiotensin-aldosterone system (RAAS) counterbalancing the vasoconstrictive and proinflammatory actions of classical RAAS, which includes renin, ACE, Ang II, and its receptors AT1 and AT2 while acting as the protective arm of the RAAS.22 The interaction between the Spike protein of SARS-CoV-2 and ACE-2 extracellular domains leads to downregulation of surface ACE-2 expression while allowing SARS CoV-2 into cells.23 Downregulation of ACE-2 activity leads to an increase in the accumulation of Ang II since it is responsible for the conversion of Ang II to Ang-(1-7).13
ACE-2 and Inflammation
A disintegrin and metalloproteinase domain 17 (ADAM-17), a transmembrane protease, which is also responsible for the proteolysis and ectodomain shedding of ACE-2, spurs the activation of macrophages which are integral to the immune system and are a source of inflammatory cytokine tumor necrosis factor alpha (TNF-α).24,25 Downregulation of ACE-2 results in an increase in Ang-II/angiotensin 1 receptor (AT1R) at the expense of ACE-2/Ang-1-7/Mas axis, which is the protective arm of the RAAS, and is essential in maintaining the physiological and pathophysiological equilibrium of the body.23 Accumulation of Ang II leads to increased binding of Ang II to Ang II type I receptor, triggering a signaling cascade that leads to ADAM-17 phosphorylation and enhanced catalytic activity.5,24 Activated ADAM-17 increases ACE-2 shedding, resulting in further reductions of Ang II clearance, increased Ang II-mediated inflammatory responses, and a vicious positive feedback cycle.13 This deleterious imbalance leads to comprehensive negative consequences, including aldosterone secretin, fibrosis, proinflammation, hypertrophy, vasoconstriction, enhanced reactive oxygen species and vascular permeability, cardiac remolding, gut dysbiosis, and multiple organ dysfunction syndrome (MODS).5,23,26 Downregulation of ACE-2 expression has been seen in myocardial cells in both SARS-CoV-2-infected mice and humans.27 A positive correlation between elevated circulating Ang II levels in COVID-19 patients and lung injury and increased viral load has also been seen.23 Therefore, it has been surmised that a direct link between tissue ACE-2 downregulation and upregulation of Ang II is at least partially responsible for the development of cardiovascular complications or multiorgan failure following SARS-Cov-2 infection.28,29
Endothelial Inflammation, Endothelial Dysfunction, and Thrombosis
It is known that the endothelium of both venous and arterial vasculature express ACE-2.30 Microscopic evidence of SARS-CoV-2 viral particles in endothelial cells of the kidney and endotheliitis characterized by activated neutrophils and macrophages in numerous organs, including the lung, intestine, and heart, has been obtained from histopathological studies.31,32 The release of interleukin-1β (IL-1β) and IL-6 causes endothelial activation and the expression of cell adhesion molecules. Endothelial inflammation and subsequent endothelial dysfunction make it proadhesive and prothrombotic with an increased expression of tissue factor and plasminogen activator inhibitor-1.32 It has also been shown that von Willebrand factor (vWF), a circulating blood coagulation glycoprotein associated with endothelial dysfunction, is significantly elevated in COVID-19 patients compared with normal individuals, indicating ongoing endothelial activation and dysfunction.33–35 vWF, being a carrier of coagulation factor VIII, can trigger platelet aggregation and blood coagulation36 (Fig. 6.2). Evidence of endotheliitis caused by SARS-CoV-2 infection has been shown by histological studies.31 Interaction of platelets and neutrophils and macrophage activation thereafter can then lead to proinflammatory responses, including cytokine storm and the formation of neutrophil extracellular traps (NETs).37 NETs then damage the endothelium and stimulate both extrinsic and intrinsic coagulation pathways, which result in microthrombus formation and microvascular dysfunction. High levels of NETs were reportedly seen in hospitalized patients with COVID-19, which correlated positively with disease severity.38
Fig. 6.2 Inflammatory response at the endothelial level direct viral injury and cytokine-mediated factors activate endothelial cell resulting in local release of cytokines, netosis (NET), and endotheliitis associated microthrombosis. Modified from Farshidfar F, Koleini N, Ardehali H. Cardiovascular complications of COVID-19. https://doi.org/10.1172/jci.insight.148980 http://creativecommons.org/licenses/by/4.0/
Both indirect generation of inflammation and prothrombotic conditions resulting in vasculopathy and the direct invasion of endothelial cells by SARS-CoV-2 infection contribute to the pathophysiological mechanisms of COVID-19.30,31,39 Hyperinflammation and the cytokine storm are hallmarks of severe COVID-19. Rapid viral replication, interference with interferon signaling, and recruitment of inflammatory cells (neutrophils and monocytes/macrophages) are mediators of hyperinflammation as per previous studies with human coronaviruses.40 White blood cells, neutrophils, lymphocyte subtypes, and inflammation parameters (CRP and procalcitonin), which are measurements of immunity, were independently related to acute cardiac injury in patients with COVID-19.41
A sharp rise in levels of multiple proinflammatory cytokines triggered by infection has been observed following infection with H1N1 (44), SARS,40,42 and MERS, and is characteristic of a cytokine storm.40,42–44 The SARS-CoV-2 infection causes an increase in chemokines, high levels of interleukin-6 (IL-6), and decreased levels of type I and III interferons, resulting in an atypical inflammatory reaction. A reduction in innate antiviral defenses and raised proinflammatory responses contribute to COVID-19 pathology. SARS-CoV-2 infection results in pathogenic T-helper 1 cells, and inflammatory CD14, CD16 monocytes induce high granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-6 expression. IL-6 is known to activate coagulation, induce thrombosis, inhibit heart function, cause endothelial dysfunction leading to vascular leakage, tissue ischemia, and hypoxia, resulting in a drop in blood pressure, disseminated intravascular coagulation (DIC), and MODS.45–49 Higher serum levels of IL-6 have been linked to worse prognosis and have been found to correlate with fibrinogen levels in patients with COVID-19.50–54
Since hypoxemia is the preeminent clinical manifestation of COVID-19, an oxygen supply–demand mismatch resulting in myocardial injury is frequently seen.55 The pathophysiology of cardiac injury among many COVID-19 patients does not involve the acute disruption of atheromatous plaque. It is similar to type 2 myocardial infarction resulting from an imbalance of oxygen supply and demand caused by cytokine storm and endothelial dysfunction.56,57 The cytokine storm causes the release of IL-6 and catecholamines that increase core body temperature, heart rate, and cardiac oxygen consumption.23 In addition, endothelial dysfunction and cytokine storm cause pathological changes such as coronary artery spasm and thrombosis, which lead to decreased coronary artery blood flow.23 Reflex tachycardia, severe hypoxemia, hypotension, and anemia in critically ill COVID-19 patients with increased cardiometabolic demand further compromise oxygen supply. Therefore, an oxygen supply and demand mismatch due to the confluence of factors in COVID-19 patients leads to acute cardiac injury.23
Clinical Cardiovascular Manifestations of COVID-19
Understanding the wide-ranging manifestations of the pathophysiology of COVID-19 affecting the cardiovascular system brings the realization that clinical cardiovascular manifestations of COVID-19 would involve a broad spectrum of disease. Pre-existing CVD could worsen, or COVID-19 could precipitate new cardiovascular complications. This would include ischemic and nonischemic myocardial injury (based upon elevation of cardiac biomarkers), arrhythmias, venous thromboembolism, acute heart failure and cardiomyopathy, and shock. A clear and established association of severity of COVID-19 with cardiovascular manifestations of the disease makes it incumbent to recognize and understand the spectrum of clinical cardiovascular expressions of the disease process.
According to the definition of myocardial injury in the Fourth Universal Definition of Myocardial Infarction, myocardial injury has been clinically identified by the presence of at least one cardiac troponin value above the 99th percentile upper reference limit (URL).58 Myocardial injury is generally identified by elevation of cardiac troponin, including all conditions that cause cardiomyocyte death with or without accompanying electrocardiographic or echocardiographic evidence of acute ischemia.6,7,58–61 Even after controlling for other comorbidities, increased levels of hs-cTn correlate with disease severity and mortality rate in COVID-19.27,62
With abnormal serum troponins, it could be challenging. However, it is essential to differentiate type I myocardial infarction (MI), which is due to plaque rupture or thrombosis, type II myocardial infarction, which is due to supply–demand mismatch, myocardial injury in disseminated intravascular coagulation (DIC), acute myocarditis, and Takotsubo (stress) cardiomyopathy.
Ischemic Myocardial Injury
Ischemic myocardial injury can be caused by epicardial coronary artery disease (CAD) due to plaque rupture or demand ischemia, cardiac microvascular dysfunction, small vessel cardiac vasculitis, and endotheliitis.31,63
The Fourth Universal Definition of MI also provides clinical classification based upon the cause of myocardial ischemia.58
Acute Coronary Syndrome (Type 1 MI)
The acute coronary syndrome includes patients with either ST-elevation myocardial infarction (STEMI) or non-ST-elevation myocardial infarction (NSTEMI), or unstable angina. The Fourth Universal Definition of MI states that the term “acute MI” should be used when there is an acute myocardial injury with clinical evidence of acute myocardial ischemia and with detection of a rise or fall of cardiac troponin values with at least one value above the 99th percentile URL and at least one of the following58:
Symptoms of myocardial ischemia.
New ischemic electrocardiographic (ECG) changes.
Development of pathological Q waves.
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology.
Identification of a coronary thrombus by angiography or autopsy (not for type II or III MI).
Type I acute myocardial infarction (AMI) due to plaque rupture or erosion can result from the systemic inflammation and catecholamine surge inherent to COVID-19 disease.64,65 Coronary thrombosis has been identified as a possible cause of acute coronary syndrome in COVID-19 patients.66 Severe viral infections can cause a systemic inflammatory response syndrome that increases the risk of plaque rupture and thrombus formation, resulting in AMI.65,67,68 Viral products known as pathogen-associated molecular patterns entering the systemic circulation activate immune receptors on cells in existing atherosclerotic plaques and predispose them to plaque rupture.65,69 They are also believed to activate the inflammasome and convert nascent procytokines into biologically active cytokines.70 In addition, viral infection and inflammation may also lead to dysregulation of coronary vascular endothelial function and cause vasoconstriction and thrombosis.71 Extensive inflammation, endothelial dysfunction, and hypercoagulability in patients with COVID-19 may increase the risk of AMI.42,72 Some studies have shown an increased risk of AMI in patients with COVID-19.73–75 However, the actual incidence of AMI in COVID-19 patients is unknown so far. Newly diagnosed AMI was reported in 5.3% of cases in an electrocardiographic study of COVID-19.76 AMI was seen in 2.9% in an echocardiography study.77 However, in 33.3 to 39.3% of patients with COVID-19 who had STEMI were found to have nonobstructive coronary artery disease.74,78
The American College of Cardiology (ACC) recommendations for AMI in COVID-19 patients gives the option of fibrinolysis for patients with low-risk STEMI defined as inferior wall STEMI with no right ventricular involvement or lateral AMI without hemodynamic compromise while recognizing that the treatment of choice remains percutaneous coronary intervention (PCI).42 The ACC recommends that hemodynamically unstable COVID-19 patients with NSTEMI be managed similarly to those with STEMI.42 Real-time reverse transcriptase polymerase chain reaction (RT-PCR) assays for testing for COVID-19 should be readily and easily available, as waiting for test results in patients with uncertain COVID-19 status would exceed the time frame within which primary revascularization is beneficial for myocardial salvage. As the airborne transmission of SARS-CoV-2 is no longer a mystery, it goes without saying that staff should don appropriate personal protective equipment (PPE), and full decontamination of the catheterization laboratory should be performed following each procedure. According to the ACC for COVID-19 patients with NSTEMI, diagnostic testing before catheterization is recommended, and conservative therapy may be sufficient.42
Supply–Demand Mismatch (Type 2 MI)
As stated, type 2 MI is due to myocardial oxygen supply–demand mismatch, also known as demand ischemia. With the understanding of the pathophysiology of COVID-19, four specific mechanisms in the context of COVID-19 have been proposed.13 They are:
Fixed coronary atherosclerosis limiting myocardial perfusion.
Endothelial dysfunction within the coronary microcirculation.
Severe systemic hypertension resulting from elevated circulating Ang-II levels and intense arteriolar vasoconstriction.
Hypoxemia resulting from acute respiratory distress syndrome (ARDS) or from in situ pulmonary vascular thromboses.
It has been seen that patients with underlying atherosclerosis are susceptible to myocardial infarction or injury in conditions such as systemic inflammatory response syndrome (SIRS), coronavirus pneumonia, and HINI influenza.79,80 It has been seen in conditions involving severe physiological stress such as respiratory failure, sepsis, and lung injury that biomarkers of myocardial injury are elevated even in the absence of atherosclerotic plaques.81–83 Inflammatory profile in patients with cardiomyopathy associated with sepsis exhibits high serum levels of cytokines that include IL-6 and TNF-α.79,80,84
The Suspicion of Death due to MI in CVD (Type 3 MI)
This unfortunate clinical scenario explains unexplained sudden cardiac death among patients with known coronary artery disease suspected of having COVID-19.85–89 In these patients, there is a suspicion of MI as the cause of death without obtaining cardiac biomarker confirmation. During the multiple surges of COVID-19, many patients avoided hospital care, some of whom died without confirmation of either COVID-19 or myocardial infarction.85–89
Stress-Induced (Takotsubo) Cardiomyopathy
Patients with stress-induced cardiomyopathy have elevated cardiac troponin with echocardiographic findings. It has been observed that the incidence of Takotsubo cardiomyopathy significantly increased from 1.5 to 1.8% during prepandemic periods to 7.8% during the COVID-19 pandemic.90 It appears that in addition to the pathophysiology of COVID-19 resulting in a hypersympathetic state, cytokine storm, endotheliitis, and microvascular dysfunction, a rise in social, mental, and financial stress may have contributed to an association between Takotsubo cardiomyopathy and COVID-19.
A single-center study in New York City with 118 consecutive laboratory-confirmed COVID-19 patients who underwent transthoracic echocardiographic evaluation showed imaging features compatible with the diagnosis of Takotsubo cardiomyopathy (e.g., circumferential hypokinesis or akinesis of the apical and midwall segments without a discrete epicardial coronary artery distribution) in 4.2% of these patients.91 These patients with Takotsubo cardiomyopathy had higher degrees of cardiac troponin elevation than patients with myocardial injury who did not have features of Takotsubo cardiomyopathy on transthoracic echocardiography. Patients with myocardial injury and features of Takotsubo cardiomyopathy had higher rates of in-hospital mortality and major complications from COVID-19 compared with patients without myocardial injury.13
Acute Myocarditis
Patients with acute myocarditis can present as a diagnostic challenge in the COVID-19 era. These patients can present with chest pain, shortness of breath, along with abnormal serum troponins levels. The ECG findings can be nonspecific ST-segment changes, ST-segment depression or elevation, and PR segment deviation. COVID-19 patients with acute myocarditis may also present with a third-degree atrioventricular block.76 In COVID-19 patients, pericardial involvement with cardiac tamponade and acute myopericarditis with elevated levels of cardiac biomarkers have been reported.2,64,92–94 In one study, myocarditis was thought to be the cause of 7% of COVID-19-related deaths.51 Echocardiographic evaluation could help differentiate acute myocarditis from an acute coronary syndrome, with focal wall motion abnormalities being present more in acute coronary syndrome. Acute myocarditis would either have no wall motion abnormality or will have global wall motion dysfunction.42,72 Both direct injury to the cardiomyocytes by SARS-CoV-2 and immune-mediated hyperinflammation are considered the causes of acute myocarditis (Fig. 6.3). COVID-19-related myocarditis cases have been confirmed by cardiac magnetic resonance (CMR) imaging.15,95 SARS-CoV-2 particles were found in interstitial cells of the myocardium.18 Endomyocardial biopsy found evidence of lymphocytic inflammatory infiltrates in the myocardium.96 In a prospective cohort study conducted in Germany of 100 patients who recovered from COVID-19 and underwent CMR imaging at a median time interval of 71 days since infection, CMR revealed cardiac involvement in nearly 80% of patients and ongoing myocardial inflammation in 60%. CMR abnormalities included low left ventricular ejection fraction, greater left ventricular volumes, raised native T1 and T2, late gadolinium enhancement, and pericardial enhancement.97 These findings correlated with higher levels of high-sensitivity troponin and active lymphocytic inflammation on endomyocardial biopsy specimens.13 It appears that myocardial injury in acute myocarditis is more because of systemic effects of COVID-19 and less due to direct viral injury to cardiomyocytes.38
Fig. 6.3 Summary of mechanisms involved in Covid-19-associated myocarditis. (a) Direct viral injury to cardiac myocytes and (b) endotheliitis. (c) Cytokine-mediated injury and inflammation may also predominate. Modified from Farshidfar F, Koleini N, Ardehali H. Cardiovascular complications of COVID-19. https://doi.org/10.1172/jci.insight.148980 http://creativecommons.org/licenses/by/4.0
Incidence and Outcomes of Myocardial Injury in COVID-19
Elevated cardiac troponin levels were seen in about 10 to 30% of hospitalized COVID-19 patients and are associated with higher mortality.7,50,59,98 The prevalence of acute myocardial injury is higher in patients admitted to the intensive care unit (ICU) at 22.2 versus 2% in patients who are not.6 Also, acute cardiac injury is seen in 59% of nonsurvivors versus 1% among survivors.50 One early observational study showed that acute myocardial injury as determined by elevated troponin levels exhibited a strong association of CVD (CAD, hypertension, or cardiomyopathy) and mortality.59 In this study, a history of CVD was present in 35% of patients, and troponin was elevated in 28% of all patients. Troponin elevation was seen in 55% of patients with CVD. The mortality rate was 69% in patients with CVD who had elevated troponin. Among patients without CVD and normal troponin, the mortality rate was 7.6%. The mortality rate was 13.3% among patients with CVD and normal troponin. Patients without CVD and elevated troponin had a mortality rate of 37.5%. The mortality rate of 69.4% was the highest among patients who had both CVD and elevated troponin. A higher troponin level was associated with increase in mortality. It has been shown that the pattern in the rise of cTn levels is significant from a prognostic standpoint. Higher levels of cTn elevation with continued rise until death (mean time from symptom answer to death was 18.5 days) were seen in nonsurvivors, while in survivors, cTn levels remained unchanged.50 Therefore, trending off cTn levels in hospitalized COVID-19 patients would be significant.
Many patients with COVID-19 who have elevated cardiac troponin, or ECG cardiac abnormalities, or cardiac imaging abnormalities do not have classic anginal symptoms of heart disease, especially in the initial stages, including among hospitalized patients. Most patients with myocardial injury do not have previously diagnosed CVD and frequently present without chest pain.59,60 It is also seen that myocardial injury and other manifestations of end-organ damage appeared to occur later (greater than 14 days) after the onset of initial symptoms.13 There are only small-sized studies that have echocardiographic findings in patients with COVID-19. The most common echocardiographic abnormality found was right ventricular dilatation and right ventricular dysfunction, with only a small percentage of patients having left lenticular systolic dysfunction.13,99–101 The true incidence of type 1 MI is still unknown in COVID-19 patients. Troponin and D-dimer levels were higher in COVID-19 patients with type 1 MI, but these type 1 MI patients had lower in-hospital mortality than COVID-19 patients who had a nonischemic myocardial injury.13 Nonobstructive CAD in patients with COVID-19 presenting with STEMI had a high prevalence, as seen in an extensive series of 28 patients who underwent invasive coronary angiography in northern Italy.78
A multicenter retrospective analysis in New York City is the largest available outcome study of myocardial injury.7 In this study, a total of 2,736 patients were included, of whom 36% had evidence of myocardial injury at the time of presentation based on the elevation of cardiac troponin. Only 30% of patients who had myocardial injury had a history of coronary artery disease. Patients who had troponin elevations (signifying myocardial injury) were associated with increased risk of in-hospital mortality (adjusted odds ratio [OR]: 1.75; 95% confidence interval [CI]: 1.37–2.24 and adjusted OR: 3.03; 95% CI: 2.42–3.80, respectively). Cardiac troponin elevation has shown a correlation with higher levels of inflammatory biomarkers (e.g., ferritin, IL-6, C-reactive protein), coagulation biomarkers (e.g., D-dimer), and severity of hypoxemia and respiratory illness (e.g., need for mechanical ventilation).13
Arrhythmias in COVID-19 Patients
Acute myocardial injury is seen in about 10 to 27.8% of admitted COVID-19 patients.6–8,59,60,102 With a myocardial injury, the incidents of arrhythmias increase substantially. Arrhythmias were reported in 17.3% of hospitalized COVID-19 patients with myocardial injury and 1.5% of patients with no myocardial injury.59,60 In another study, arrhythmias were present in 16.7% of hospitalized COVID-19 patients, with an increased prevalence of 44.4% among patients admitted to the ICU versus 6.9% in non-ICU hospitalized COVID-19 patients.6 Ventricular arrhythmias were seen in 17.3% of COVID-19 patients with acute myocardial injury compared to 1.5% COVID-19 patients without acute myocardial injury.59 Atrial arrhythmias were seen in 17.7% of COVID-19 patients who required mechanical ventilation compared to 1.9% of hospitalized COVID-19 patients who did not require mechanical ventilation.103 In a New York cohort of hospitalized COVID-19 patients, prolonged corrected QT (500 ms) was found in 6% of 4,250 patients.95 Asystole was the most common initial rhythm reported in 89.7% of hospitalized COVID-19 patients who suffered cardiac arrest compared to shockable rhythms in 5.9% of such patients.104 Third-degree atrioventricular block has also been reported in a COVID-19 patient with acute myocarditis.76
In addition to the increased risk of incidence of arrhythmias associated with myocardial injury, other mechanisms for arrhythmias in COVID-19 patients should be considered, especially seen in patients with worsening renal function.105,106 These include arrhythmias that may develop due to electrolyte abnormalities, including hypokalemia, hypomagnesemia, hypoxemia, and QT-prolonging medications. COVID-19 patients with previously present myocardial scar could experience monomorphic ventricular tachycardia due to the prevalence of hyperadrenergic state in such patients.13 Arrhythmias in hospitalized COVID-19 patients have also been found to be due to the direct electrophysiological effects of cytokines on the myocardium due to the hyperinflammatory state that is characteristic of COVID-19.13 The ventricular action potential duration is prolonged due to the modulation of the expression/activity of cardiomyocyte K+ and Ca++ ion channels by the inflammatory cytokines upregulated in patients with COVID-19. In such patients with increased expression of inflammatory cytokines, IL-6 inhibits the human ether-a-go-go-related gene (hERG)-K+ channel resulting in the prolongation of the ventricular action potential.107 IL-6 also inhibits cytochrome 450 (CYP) 3A4, increasing the bioavailability of several QT-prolonging medications. In addition to the direct cardiac effects of inflammatory cytokines, cardiac sympathetic system hyperactivation is also provoked centrally (an inflammatory reflex mediated by the hypothalamus) and peripherally (by activating the left stellate ganglia), which can then trigger life-threatening arrhythmias in the setting of long QT.108
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