SARS-CoV-2 infection causes extrapulmonary symptoms, such as acute myocardial infarction or acute coronary syndrome, which affect 1.7% (confidence interval, 0%–3.6%) of patients hospitalized for the virus. Despite the majority of these patients having no history of coronary heart disease, many present with ST-segment elevation myocardial infarction, which is caused by the rupture of vulnerable coronary atherosclerotic plaques, coronary spasm, endothelial dysfunction, and thrombosis. Nevertheless, the number of hospitalizations for acute coronary events and percutaneous interventions registered in the United States, Italy, and Spain during the SARS-CoV-2 pandemic was significantly lower than the preceding period (33–35), possibly because fewer people sought medical care for heart attacks (36).

SARS-CoV-2 infection can contribute to an increase in plasma troponin levels above the 99th percentile, which is indicative of myocardial injury. The major type of injury associated with SARS-CoV-2 is acute myocardial infarction, caused by acute myocardial ischemia, which can be of two types. Type 1 infarction typically results from plaque rupture, ulceration, erosion, dissection, and thrombosis; conversely, type 2 infarction is caused by an imbalance between oxygen supply and demand in heart muscles. To treat this condition, it is crucial to determine the type of infarction (37), both of which can occur in patients infected with SARS-CoV-2 (38). The presence of comorbidities, such as diabetes mellitus, arterial hypertension, and obesity, partially explains the high prevalence of coronary events in patients with COVID-19, as well as the higher incidence in severe cases.

Similar to myocardial injury, Takotsubo syndrome is associated with increased plasma troponin levels. In this syndrome, the segmental contractility of the left ventricular wall is altered, resulting in hypokinesia and akinesia, which lead to sudden heart failure and, in rare cases, can mimic acute myocardial infarction. Although its etiology is unclear, sympathetic hyperstimulation with microvascular involvement caused by stress-induced catecholamines appears to be an underlying cause (39). Takotsubo syndrome is also associated with high-grade inflammation (40–42).

Acute myocardial involvement is the most common cardiac complication associated with SARS-CoV-2 infection. Typical symptoms include acute heart failure (3%–33%), left ventricular dysfunction (10%–41%), right ventricular dysfunction (33%–47%), and biventricular dysfunction (3%–15%) (43, 44); presence of electrocardiogram (ECG) abnormalities and increased cardiac enzymes, such as high-sensitivity cardiac troponin T (hs-cTn) and N-terminal B-type natriuretic peptide (NT-proBNP) are indicators of these clinical complications (45).

Ventricular wall stress caused by pressure or volume overload is the main stimulus for natriuretic peptide synthesis and release, which act in the kidney, inducing natriuresis and diuresis. Other physiological effects include peripheral vasodilation and inhibition of the renin–angiotensin and sympathetic nervous systems. NT-proBNP has a half-life of 120 min and is primarily eliminated by the kidneys (46).

SARS-CoV-2 infection promotes NT-proBNP expression, which is a marker of both cardiac injury and disease severity (47–49). Severe COVID-19 cases display a mean NT-proBNP level of 791 pg/mL, while milder cases have a mean of 160 pg/mL (49). Thus, NT-proBNP levels can be used as a biomarker of cardiac involvement and a prognosis indicator (50). The ventricular myocardium is the primary source of BNP. SARS-CoV-2 infection also causes increased hs-cTn and D-dimer levels, the degree of which is strongly correlated with poor prognosis in hospitalized patients (48, 51). The magnitude of hs-cTn and D-dimer elevation correlates with the final clinical outcome, ranging from hospital discharge to death.

During the SARS-CoV-2 pandemic, hospitalizations for myocarditis increased by 42.3%, compared with the prepandemic period. The risk for myocarditis was 0.146% among patients diagnosed with SARS-CoV-2 during an inpatient or hospital-based outpatient encounter and 0.009% among patients who did not have a confirmed case of SARS-CoV-2 infection. After adjusting for individual and local care factors, the adjusted risk of myocarditis among SARS-CoV-2 carriers was 15.7 (confidence interval, 14.1–17.2) times higher than that of SARS-CoV-2 negative carriers (52).

Endomyocardial biopsy is the gold standard for diagnosing acute and chronic inflammatory cardiomyopathies. Myocardial biopsies are accepted by the European Society of Cardiology (53) as gold standard investigative procedures for patients with myocarditis, using histochemical and viral genome analysis. A major drawback of the SARS-CoV-2 pandemic pertained to the technical difficulties imposed by performing these types of procedures in such conditions. However, magnetic resonance imaging can be a useful diagnostic resource for the identification of patients with cardiac involvement due to viral infection. Magnetic resonance imaging allows the detection of myocardial edema, hyperemia, necrosis, and/or fibrosis (Lake Louise criteria) (54, 55) with perfect correlation with the histological evidence of inflammation observed with endomyocardial biopsy (56–59).

Cardiovascular magnetic resonance imaging (CMR) is useful for the characterization of the myocardial tissue in vivo, providing insights into the pattern and degree of cardiac injury. In patients with SARS-CoV-2, the prevalence of myocardial involvement identified using CMR ranges from 26% to 60%; this variability is attributed to differences between populations, severity of illness, and interval between acute infection and CMR evaluation. The European Society for Cardiovascular Magnetic Resonance Imaging recommends CMR and provides recommendations for its use and reporting metrics, toward improved standardization, uniform data acquisition, and analytical approaches in patients with SARS-CoV-2 infection (56).

Heart failure can occur at different stages of SARS-CoV-2 infection, making it particularly challenging to diagnose and manage. Patients with heart failure alone have a higher chance of contracting SARS-CoV-2 infection because of their weakened immune systems, overall fragility, and reduced hemodynamic tolerance to dangerous infectious processes. Inflammatory cytokine generation, macrophage recruitment, and granulocyte release result in a severe inflammatory storm and increased metabolic demand, leading to acute or chronic decompensation and exacerbation of latent clinical illness. Other contributing factors are as follows: the occurrence of coagulation issues and thrombotic events, which are also associated with renal involvement in 15%–25% of SARS-CoV-2 infections and exacerbate cardiac and renal dysfunction (60); and increased sympathetic activity, which creates an imbalance between energy supply and consumption.

The most prevalent cardiovascular phenotype in hospitalized patients with SARS-CoV-2 infections is acute decompensated heart failure, which is characterized by severe congestion, drastically altered hemodynamic state, and increased biomarkers of myocardial injury (61). Up to 25% of hospitalized patients with COVID-19 develop new cases of heart failure. This complication is presumed to be a direct consequence of the virus or due to systemic inflammation. This causes acute myocarditis and, in some cases, results in cardiogenic shock, dysfunction of multiple organs, and death (62).

Different mechanisms can lead to cardiogenic shock, including fulminant myocarditis, which causes sudden hemodynamic impairment, global hypokinesia, biventricular dysfunction, hypotension, and multiple organ dysfunction syndrome (63). Cardiogenic shock can also be associated with type 1 infarction, in cases of patients with large infarction extension that progresses to the most severe classification on the Killip scale and with mechanical complications.

Right ventricular failure results from the advancement of pulmonary illness, cytokine production, and inflammatory interstitial pneumonia, leading to severe pulmonary embolism or microembolization. Patients may develop secondary right ventricular failure caused by mechanical ventilation–induced pulmonary injury and right ventricular systolic dysfunction (due to precapillary pulmonary hypertension resulting from pulmonary hypoxemia vasoconstriction). In patients with SARS-CoV-2 infection, acute myocarditis or a hypertensive emergency may contribute to the occurrence of right ventricular failure. Sudden changes that can contribute to this complication include the infectious process and hydrostatic modifications with increased capillary permeability and accumulation of fluid in the extravascular space, leading to alveolar edema (64).

Patients with SARS-CoV-2 may develop heart failure with reduced ejection fraction; however, its prevalence remains unclear. Further studies are needed, specifically those including outpatient follow-up, to help uncover the clinical cause of the infection and lingering cardiac involvement (61).

The primary causes of respiratory failure can be distinguished using biomarkers of cardiac injury, such as natriuretic peptides, in diagnostic imaging, which can also help determine the appropriate therapeutic approach.

In this regard, ECG is an excellent research tool for detecting myocardial ischemia because it is a straightforward, accessible, affordable, and low-risk procedure (71).

Plaque rupture, coronary spasm, microthrombosis, endothelial dysfunction, hypoxia, electrolyte changes, and cytokine storms contribute to ECG changes during SARS-CoV-2 infection (72). These ECG alterations occur in 93% of patients hospitalized in the intensive care unit (ICU) with SARS-CoV-2 infection, which highlights the frequent comorbidity between COVID-19 and various arrhythmias and ECG alterations, as will be discussed in the following sections.

The main ECG alterations (73–78), molecular mechanisms of cardiac arrhythmias, and echocardiographic findings observed in patients with SARS-CoV-2 infection are presented in Supplementary Material Figure S2.

The most prevalent supraventricular arrhythmia in patients with SARS-CoV-2 infections is sinus tachycardia, which likely results from hypovolemia, hypoperfusion, hypoxia, and high body temperature. Conversely, AF is the most prevalent type of arrhythmia in patients with SARS-CoV-2-induced inflammatory cardiomyopathy. AF has variable presentations, such as sudden onset, recurrent pre-existing arrhythmia, and persistent or permanent AF with a rapid ventricular response, all of which are predictors of poor disease prognosis (79). Other arrhythmias that have been observed include atrial flutter, atrioventricular nodal reentrant tachycardia, and atrioventricular reentrant tachycardia, which are more common in younger individuals.

Viral cardiomyopathy usually manifests as malignant ventricular arrhythmias, such as ventricular tachycardia and ventricular fibrillation in patients with SARS-CoV-2 infection. These arrhythmias can be caused by metabolic disorders or administration of drugs that prolong the rate-corrected QT (QTc) interval in the ECG. Monomorphic ventricular tachycardia has been observed in patients with structural myocardial diseases, such as acute coronary syndrome, ST-segment elevation myocardial infarction, and myocarditis. Polymorphic tachycardia, including torsade de pointes, results from functional heart diseases, such as drug toxicity, long QT, and Brugada syndrome (80).

Ventricular atrial blocks occur less frequently than tachyarrhythmias. When patients with SARS-CoV-2 infection develop this type of block, an artificial cardiac pacemaker may be required. Cardiac arrest in these patients may be preceded by sinus bradycardia, nodal rhythm, or ventricular tachycardia; thus, bradycardia may be an indicator of cardiovascular collapse risk in patients with SARS-CoV-2 (80).

Patients with SARS-CoV-2 infection frequently present prolonged QT intervals, which is a cause for concern, as these can lead to malignant ventricular arrhythmias and cardiovascular death. At the beginning of the pandemic, a marked prolongation of the QT interval was observed in critically ill patients in ICUs receiving adjuvant therapies, including hydroxychloroquine, with or without concomitant azithromycin (81). This change in the ECG is associated with increased disease severity, serious cardiac injuries, and high mortality rates (82–84). However, a variety of factors can contribute to cardiac repolarization changes and impact the QT interval (85, 86). These include hereditary and acquired factors such as inflammatory processes, medications, treatments, and electrolyte imbalance.

ECG is a readily accessible tool that identifies cardiac involvement and can be used to predict the underlying cause of a disease (87). QRS and QTc intervals are early markers of SARS-CoV-2 disease progression and mortality (88). The exact mechanism by which SARS-CoV-2 infection may induce cardiac conduction abnormalities remains unknown. QT alterations may represent a simple marker reflecting the inflammatory state at the myocardial cellular level of the myocardium (83). The prolonged QTc intervals in ECG may result from the immune-mediated phenomena elicited by the virus infection, involving a cytokine storm with an elevation of IL-6 (89, 90), which blocks the potassium-related ether-a-go-go channel, contributing to increased circulating levels of IL-6.

QTc prolongation is likely more than just a drug-related side effect because the administration of drugs that extend the QTc interval does not impact the hospital mortality in patients with COVID-19 (83, 91). Jiménez-Jáimez et al. (92) analyzed 219 patients with ECG on admission. They reported that outpatients not critically ill with SARS-CoV-2 treated with hydroxychloroquine, azithromycin, and antiretrovirals developed a non-relevant prolongation of the QT interval (92). Significant waves in V1 and V2, ST-segment depression, T-wave inversion in leads II, III, arteriovenous fistula, V1 to V4, right and left branch blocks, and QRS axis deviations were indicative of right ventricular overload (93). Therefore, SARS-CoV-2 can have a deleterious effect on the cardiac conduction system, leading to significant ECG changes (79, 94).

In SARS-CoV-2 infection, there are numerous possible mechanisms that increase the risk of cardiac arrhythmias. These include various forms of myocardial damage and extracardiac processes that may exacerbate arrhythmias in patients with a pre-existing propensity.

Myocarditis can cause arrhythmia in the acute phase as a direct cytopathic effect, resulting in electrical imbalance, ischemia (due to microvascular dysfunction), and junction dysfunction resulting from an impaired myocardial expression of connexins or ion channels. This is particularly common in patients with channelopathies with superimposed inflammation. Viral infections and host-related factors can alter the structural and electrophysiological properties of the myocardium in viral myocarditis, resulting in abnormal calcium movement and a negative regulation of potassium channels, leading to prolonged repolarization and abnormal conduction. Prolonged repolarization can induce deflagrated electrical activity in association with abnormal conduction (reduced conduction velocity and decreased refractoriness). Arrhythmias can also occur in the postinflammatory phase, in which variable degrees of myocardial scarring may exist, thereby promoting reentrant arrhythmias (95).

The systemic inflammatory response syndrome causes indirect myocardial damage. The intensive release of cytokines and chemokines, especially IL-1, IL-6, and TNF-α, is caused by a combination of micro- and macrovascular dysfunction, enhanced thrombogenicity, acidosis, hypoxia, and an imbalance in T-helper 1 and 2 responses. This process is amplified by enhanced catecholaminergic reactions; hyperinflammation due to high IL-6 levels results in a blockade of the hERG potassium channel and lengthening of the QT interval, facilitating the formation of unstable arrhythmias (96).

Inflammatory cytokines are well-studied triggers of arrhythmia, particularly in patients with a long QT syndrome, in which the cardiac sympathetic nervous system is overstimulated by the hypothalamus-mediated inflammatory reflex and peripherally mediated activation of the stellate ganglion pathway (96). Furthermore, IL-6 inhibits cytochrome P450, which increases the bioavailability of drugs that prolong the QT interval (97).

Hypoxia arising from lung injury or myocardial ischemia can activate anaerobic glycolysis, reducing intracellular pH, and thus increasing cytosolic calcium levels. This, in turn, can facilitate early and late depolarization and cause temporal changes in action potential duration. Hypoxia also increases extracellular potassium levels, which decrease the depolarization threshold and accelerate electrical conduction. In addition, hypoxemia can cause reduced electrical coupling and tissue anisotropy owing to the dephosphorylation of connexin 43 at communicating junctions (96).

In a previously published case series, the effects of electrolyte abnormalities on both preexisting and new arrhythmias were studied (3). These findings have been attributed to diarrhea associated with SARS-CoV-2 infection or renal injury (98), and severe electrolyte disorders, such as hypokalemia, hypomagnesemia, and hypophosphatemia, are also linked to atrial arrhythmias (99).

Traditional cardiovascular risk factors such as type II diabetes mellitus, hypertension, and hypercholesterolemia, as well as comorbidities such as ischemic heart disease and chronic renal failure, also contribute to the development of arrhythmia by altering the cardiac structure. Another potential contributor to the development of SARS-CoV-2 infection is the p.Ser1103Tyr variant of the common SCN5A-encoded Nav1.5 sodium channel that results in a lack of “repolarization reserve” (91).

Most research on cardiovascular outcomes during the acute stage of hospitalization, which represents a minority of patients infected with SARS-CoV-2, does not adequately address the long-term cardiovascular sequelae of the infection. However, a database analysis (103) of cardiovascular outcomes after a 12-month follow-up revealed that hospital readmission is associated with a high mortality rate, with multiple organ dysfunction being the primary cause (104). Nevertheless, a persistent elevation of myocardial injury biomarkers, such as hs-cTn, NT-proBNP, and D-dimer, indicates injury or underlying heart disease, and an increased risk of myocarditis, pericarditis, coronary artery disease manifested by acute coronary syndrome, myocardial infarction, angina, and ischemic cardiomyopathy. Other symptoms include heart failure, non-ischemic cardiomyopathy, left ventricular systolic and diastolic dysfunction, deep vein thrombosis, and pulmonary thromboembolism (105).

Also, the post-SARS-CoV-2 group also displays an increased incidence of AF, sinus tachycardia and/or bradycardia, ventricular arrhythmias, and atrial flutter.

In patients with SARS-CoV-2 infection, 12 months after hospital release, there is an increased risk of developing diabetes mellitus, and some prediabetic individuals progress to diabetes after infection (106). One hypothesis is the expression of ACE2 in pancreatic islet cells, where it could promote direct viral infiltration, resulting in inflammation and loss of pancreatic beta cells, and contributing to the development of diabetes mellitus (107).

There is also evidence suggesting a higher risk of developing hypertension in individuals post-SARS-CoV-2 infection, as well as poorer blood pressure control. Although the mechanisms are not fully understood, ACE2 may be involved in reducing the renin–angiotensin–aldosterone system by converting angiotensin 1 and 2 into angiotensin 1–9 and 1–7, respectively. This is accompanied by an increased bioavailability of angiotensin 2 and a subsequent increase in blood pressure (108). Inadequate control of blood pressure in the postinfection stage is suggestive of lifestyle changes; a decrease in physical activity, unhealthy diets, and increased psychosocial stress have been observed as a result of the pandemic (109).

Finally, a prolonged clinical picture of symptoms ranging from weeks to months post-SARS-CoV-2 infection called “long SARS-CoV-2” has been observed, which includes a broad spectrum of symptoms such as fatigue, exertional dyspnea, chest pain, palpitations, headache, nausea, vomiting, skin rashes, joint pain, anxiety, and depression. Although there is no standard universal criterion to characterize this condition, the World Health Organization has proposed that long SARS-CoV-2 should be defined as clinical manifestations lasting more than 3 months and symptoms lasting ≥ 2 months not explained by another disease (110, 111).

The goal of this mini review was to provide an overview of the literature on the relationship between SARS-CoV-2 infection and the clinical manifestations of cardiovascular system involvement in children and adults, including important disorders affecting cardiac rhythm. We summarized the potential mechanisms that could be involved in the expression of the different clinical manifestations and the mechanisms underlying the complications of arrhythmias associated with SARS-CoV-2 infection and discussed the main imaging methods that allow appropriate diagnoses to be made.