**9. Electrocardiographic and echocardiographic changes in COVID-19**

The cardiac involvement in COVID-19 is diverse and as such varying different findings have been observed with diagnostic tools such as the electrocardiogram (ECG) and echocardiography. ECG changes in COVID-19 represent both left and right-sided heart disease [65] and are associated with a higher risk of mortality. In a study of 756 patients, 90 (12%) of which died (**Table 2**); one or more atrial premature contractions right bundle or intraventricular block, ischemic T-wave inversion and nonspecific repolarisation were associated with death [65]. These finding were


**Table 2.**

*Odds ratio for ECG findings significantly associated with mortality. 95%CI, 95% confidence interval [source: McCullough et al. [65]].*

**139**

*Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement…*

further supported by De Vita and colleagues [66] who observed the ECG on admission was a helpful tool to identify COVID-19 patients with increased risk of death. In a retrospective analysis of 319 severe and critically severe COVID-19 cases, Wang and colleagues observed 118 (37%) with normal ECG and 201 (63%) abnormal ECG traces. Differences were observed in ST-T changes, sinus tachycardia, atrial fibrillation, and atrial tachycardia between the group severity. Sinus tachycardia and atrial fibrillation were the independent risk factors of in-hospital death and ventilator use and could be used as an independent predictor of poor outcome [67]. A caveat to ECG induced changes is due to drug therapies given in severe COVID-19 infections. Drug-induced changes associated with chloroquine, hydroxychloroquine and azithromycin can result in a prolonged corrected QT (QTc), however such elongations do not induce arrhythmia-related death [68].

Echocardiographic findings demonstrate Left and right ventricular abnormalities in 39% and 33% of COVID-19 patients respectively [69]. severe ventricular dysfunction or tamponade is observed in approximately 15% of patients. In those without pre-existing cardiac disease the echocardiogram is abnormal in roughly half of COVID-19 patients with approximately 15% demonstrating severe disease. In a study of 90 hospitalised patients with severe (44, 49%) and non-severe (46, 51%) COVID-19; right ventricular (RV) and left ventricular (LV) functions were compared [70]. The RV and LV diameters were larger in severe patients compared to non-severe. Left ventricular ejection fraction (LVEF) were significantly (p = <0.001) lower (54.0% ±9.8%) in the severe-infections compared to the nonsevere (61.9 ± 4.8%). Furthermore, pericardial effusions were observed in 23% of

In a study of 749 known COVID-19 positive patients undergoing transthoracic

Both ECG and echocardiography are useful tools in the identification of left and right-sided cardiac dysfunction in COVID-19. Abnormalities are more frequent as

A number of post-mortem (autopsy) studies have been performed on COVID-19 patients [72–79]. Four main pathological processes are generally observed: (a) Diffuse alveolar infiltration and damage with hyaline membrane formation, (b) thromboembolic disease in pulmonary and cardiac tissue and peripheral deep vein thrombosis, (c) hemophagocytes and (d) depletion of immune related cells [80, 81]. Gross cardiac examination (**Figure 12**) often reveals enlarged hearts [75, 76, 79] and the myocardium appears pale and flabby [76]. Thrombotic pathology is predominantly found in the lung, being present in 90% of cases; in 60% of

In nine community deaths with suspected COVID-19 infections, Youd and colleagues did not observe any cases of myocarditis, however one case of bacterial bronchopneumonia had associated myocarditis. Contraction band necrosis was observed in a 86y Caucasian Male who had an underlying history of hypertension and cardiovascular disease. Cardiac amyloidosis was evident in one case [79].

echocardiography (TTE), 38% were found to have LVEF ≤50% and 14% had moderately reduced right ventricular function. Stress-induced cardiomyopathy as evident by wall motion abnormalities were observed in four patients. A significant inverse relationship between cTnT and LVEF was observed (P = −0.34, P = 0.006). On the basis of the clinical TTE findings, therapeutic management was altered in 24% due to concern for a major cardiac even and in 14% where haemodynamic

infection severity increases and are often associated with poor prognosis.

**10. Gross cardiac pathology and histopathology**

the severe patients with no observed cases in the non-severe patients.

*DOI: http://dx.doi.org/10.5772/intechopen.98210*

instability warranted TTE [71].

hearts and 45% of kidneys [80].

#### *Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement… DOI: http://dx.doi.org/10.5772/intechopen.98210*

further supported by De Vita and colleagues [66] who observed the ECG on admission was a helpful tool to identify COVID-19 patients with increased risk of death.

In a retrospective analysis of 319 severe and critically severe COVID-19 cases, Wang and colleagues observed 118 (37%) with normal ECG and 201 (63%) abnormal ECG traces. Differences were observed in ST-T changes, sinus tachycardia, atrial fibrillation, and atrial tachycardia between the group severity. Sinus tachycardia and atrial fibrillation were the independent risk factors of in-hospital death and ventilator use and could be used as an independent predictor of poor outcome [67].

A caveat to ECG induced changes is due to drug therapies given in severe COVID-19 infections. Drug-induced changes associated with chloroquine, hydroxychloroquine and azithromycin can result in a prolonged corrected QT (QTc), however such elongations do not induce arrhythmia-related death [68].

Echocardiographic findings demonstrate Left and right ventricular abnormalities in 39% and 33% of COVID-19 patients respectively [69]. severe ventricular dysfunction or tamponade is observed in approximately 15% of patients. In those without pre-existing cardiac disease the echocardiogram is abnormal in roughly half of COVID-19 patients with approximately 15% demonstrating severe disease. In a study of 90 hospitalised patients with severe (44, 49%) and non-severe (46, 51%) COVID-19; right ventricular (RV) and left ventricular (LV) functions were compared [70]. The RV and LV diameters were larger in severe patients compared to non-severe. Left ventricular ejection fraction (LVEF) were significantly (p = <0.001) lower (54.0% ±9.8%) in the severe-infections compared to the nonsevere (61.9 ± 4.8%). Furthermore, pericardial effusions were observed in 23% of the severe patients with no observed cases in the non-severe patients.

In a study of 749 known COVID-19 positive patients undergoing transthoracic echocardiography (TTE), 38% were found to have LVEF ≤50% and 14% had moderately reduced right ventricular function. Stress-induced cardiomyopathy as evident by wall motion abnormalities were observed in four patients. A significant inverse relationship between cTnT and LVEF was observed (P = −0.34, P = 0.006). On the basis of the clinical TTE findings, therapeutic management was altered in 24% due to concern for a major cardiac even and in 14% where haemodynamic instability warranted TTE [71].

Both ECG and echocardiography are useful tools in the identification of left and right-sided cardiac dysfunction in COVID-19. Abnormalities are more frequent as infection severity increases and are often associated with poor prognosis.

### **10. Gross cardiac pathology and histopathology**

A number of post-mortem (autopsy) studies have been performed on COVID-19 patients [72–79]. Four main pathological processes are generally observed: (a) Diffuse alveolar infiltration and damage with hyaline membrane formation, (b) thromboembolic disease in pulmonary and cardiac tissue and peripheral deep vein thrombosis, (c) hemophagocytes and (d) depletion of immune related cells [80, 81]. Gross cardiac examination (**Figure 12**) often reveals enlarged hearts [75, 76, 79] and the myocardium appears pale and flabby [76]. Thrombotic pathology is predominantly found in the lung, being present in 90% of cases; in 60% of hearts and 45% of kidneys [80].

In nine community deaths with suspected COVID-19 infections, Youd and colleagues did not observe any cases of myocarditis, however one case of bacterial bronchopneumonia had associated myocarditis. Contraction band necrosis was observed in a 86y Caucasian Male who had an underlying history of hypertension and cardiovascular disease. Cardiac amyloidosis was evident in one case [79].

*Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions*

Giustino and colleagues investigated 305 COVID-19 patients in 7 hospitals in New York City, USA and Milan, Italy. Patients exhibiting myocardial injury has elevated inflammatory markers, electrocardiographic abnormalities as well as transthoracic echocardiographic (TTE) evidence of left ventricular wall motion abnormalities, global left ventricular dysfunction, grade II or III left ventricular diastolic dysfunction, right ventricular dysfunction and pericardial effusion. In-hospital mortality was 32% in patients with myocardial damage and TT abnormalities, 19% with cTn positive myocardial injury only and 5% in those without

Lala and colleagues investigated the degree of myocardial injury in laboratoryconfirmed cases of COVID-19 and correlated findings with outcome [57]. 36% of

Seven studies have investigated the prognostic value of elevated cTn in COVID-19. Five utilised cTnI [57–61], one cTnT [62] and one with combined cTnT and cTnI from different institutions [63]. In all cases, an elevated cTn (cTnI, **Figure 11a**; cTnT **Figure 11b**) was associated with poor outcome; be it in-hospital mortality, or combined endpoints of all-cause mortality and need for mechanical ventilation. Lala and colleagues [57] identified even minor elevations in cTnI (0.03 to 0.09 ng/ml) were associated with mortality (Hazard ratio 1.75; 95%CI = 1.37 to 2.24, p < 0.001). Those with greater cTnI concentrations above 0.09 ng/L conferred

The underlying pathological mechanisms resulting in elevation in cTn in patients with COVID-19 have not been fully elucidated. The vast majority of reported cardiovascular complications in COVID-19 refer to acute cardiac injury, with an incidence of 8–22%. Other mechanisms (% incidence) include pulmonary thrombosis and arterial/venous thromboembolism (16–49%); chronic heart failure (52% in non-survivors, 12% in survivors); Acute coronary syndromes (44% with ST segment elevation myocardial infarction [STEMI]); arrhythmia (17% overall; 44% vs. 9% in severe and mild cases respectively). A few case reports have demon-

**9. Electrocardiographic and echocardiographic changes in COVID-19**

**ECG Abnormality Odds Ratio 95% CI** One or more atrial premature contraction 2.57 1.23 to 5.36 Right bundle branch or intraventricular block 2.61 1.32 to 5.18 Ischemic T-wave inversion 3.49 1.56 to 7.80 Nonspecific repolarisation 2.31 1.27 to 4.21

*Odds ratio for ECG findings significantly associated with mortality. 95%CI, 95% confidence interval [source:* 

The cardiac involvement in COVID-19 is diverse and as such varying different findings have been observed with diagnostic tools such as the electrocardiogram (ECG) and echocardiography. ECG changes in COVID-19 represent both left and right-sided heart disease [65] and are associated with a higher risk of mortality. In a study of 756 patients, 90 (12%) of which died (**Table 2**); one or more atrial premature contractions right bundle or intraventricular block, ischemic T-wave inversion and nonspecific repolarisation were associated with death [65]. These finding were

evidence of cardiac involvement [56].

2,736 patients had an elevated cTnI (>0.03 ng/mL).

greater risk (Hazard ratio 3.03, 95% CI 2.42 to 3.80).

strated myocarditis and pericardial disease [64].

**138**

**Table 2.**

*McCullough et al. [65]].*

#### **Figure 12.**

*Gross macroscopic cardiac pathology in COVID-19. (a) Fibrinous myocarditis; (b) cardiac hypertrophy with pale flabby myocardium; (c) macroscopic right coronary artery thrombosis (green arrow); (d) contained aortic dissection (green arrow) and fibrinous pericarditis (red arrow and H&E histology inset) in a 22y male; (e) gross marantic endocarditis with associated H&E histology inset; (f) extreme right ventricular dilatation with intraventricular septum straightening in a formalin fixed heart; (g) transverse sections demonstrating extensive right ventricular dilation of (i) 2.9:1.7 cm, (ii) 4.0:0.9 cm, (iii) 3.6:3.4 cm. [sources: Adapted from Youd et al. [79], Hanley et al. [80], Fox et al. [82, 83]].*

An Italian study of 22 autopsies (18 with comorbid conditions, 4 without) demonstrated significant pulmonary and cardiovascular pathologies. All 22 deaths were reported as cardiorespiratory failure [76]. Cardiovascular pathologies are reported in **Table 3**.

A systematic review of histopathological findings by physiological system have identified cardiovascular findings such as focal lymphocytic inflammation, acute cardiomyocyte necrosis, presence of inflammatory cells and apoptotic bodies [74].

A multicentre study of 21 autopsy examinations by Basso and colleagues [73] examined cardiac tissue. Lymphocytic myocarditis was present in 3 (14%) cases, two of which were CD4 predominant T-cells, and one CD8 prominent. 86% of cases demonstrated interstitial macrophage infiltration. Mild pericarditis was evident in 4 cases. Common histological findings from cardiac tissue are presented in **Figure 13**.

Although the underlying mechanisms of cardiac involvement in COVID-19 infection remain to be fully elucidated, cardiac fibrosis occurs in tandem with local and systemic inflammatory responses [84]. Whilst these mechanisms are designed to facilitate healing following tissue damage, an excess of the inflammatory response along with the development of fibrotic tissue are pathological drivers for global organ damage. Overt inflammation and fibrosis in the heart can result in abnormal cardiac remodelling potentiating the development of acute and chronic heart failure. Anti-inflammatory and anti-fibrotic therapies are in general unsuccessful in improving damaged cardiac tissue function. With respect to COVID-19,

**141**

**11. Conclusion**

**Figure 13.**

*Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement…*

**conditions (n = 18) (%)**

Myocarditis 9 (50.0) 3 (75.0) Vasculitis 5 (27.8 3 (75.0) Inflammatory infiltrate 13 (72.3) 3 (75.0) Focal necrosis 6 (33.4) 2 (50.0) Pericarditis 9 (50.0) 4 (100) Vascular fibrosis 4 (22.3) 2 (50.0)

*Cardiovascular histopathological findings in COVID-19 cadavers with and without comorbid conditions* 

**COVID-19 deaths without comorbid conditions (n = 4) (%)**

**Histopathological findings COVID-19 deaths with comorbid** 

further work is required to identify potential therapeutic targets of regulation and moderation of cardiac fibroblast function and thus reduce the burden of inflamma-

*(a and b) Myocarditis. Biventricular multifocal and diffuse lymphocytic myocarditis (arrows) with extensive myocyte injury and previously undiagnosed cardiac amyloidosis (H&E) x50 in an 86y male; (c and d) Biventricular multifocal lymphocytic myocarditis (arrows) with myocyte injury (H&E x100). Atrial fibrillation developed 2 d before death, 64y male; (e) Increased interstitial macrophage H&E x400) in a 60y male; (f) Increased macrophage cells within the myocardial interstitum (H&E x100) in a 73y female; (g) Focal lymphocytic pericarditis (arrows, H&E, x400) comprised of (h) CD8+ lymphocytes associated with focal myocardial inflammation in the absence of myocyte injury (arrowhead, CD8 immunostaining x400); (I and j) Small vessel changes. Microthrombus in a small myocardial artery (a, arrow H&E x100) and organised venous thrombosis (b, arrow H&E x100) in a 70y male; (k) Thrombus in a small myocardial vein (arrow, H&E x200) in a 71y male; (l) Leucocyte aggregates of eosinophils and mononuclear cells in capillaries and small* 

*veins (arrow, H&E x400) in a 64y male.[Source: Adapted from Basso et al., [73]].*

The novel Coronavirus disease, COVID-19 that emerged just over one year ago has caused substantial disruption to everyday life for every human on the

tory-responsive fibrotic-based heart failure.

*DOI: http://dx.doi.org/10.5772/intechopen.98210*

**Table 3.**

*[source: Falasca et al. [76]].*

*Coronavirus Disease: Epidemiology, Aetiology, Pathophysiology and Involvement… DOI: http://dx.doi.org/10.5772/intechopen.98210*


#### **Table 3.**

*Cardiac Diseases - Novel Aspects of Cardiac Risk, Cardiorenal Pathology and Cardiac Interventions*

An Italian study of 22 autopsies (18 with comorbid conditions, 4 without) demonstrated significant pulmonary and cardiovascular pathologies. All 22 deaths were reported as cardiorespiratory failure [76]. Cardiovascular pathologies are reported

*Gross macroscopic cardiac pathology in COVID-19. (a) Fibrinous myocarditis; (b) cardiac hypertrophy with pale flabby myocardium; (c) macroscopic right coronary artery thrombosis (green arrow); (d) contained aortic dissection (green arrow) and fibrinous pericarditis (red arrow and H&E histology inset) in a 22y male; (e) gross marantic endocarditis with associated H&E histology inset; (f) extreme right ventricular dilatation with intraventricular septum straightening in a formalin fixed heart; (g) transverse sections demonstrating extensive right ventricular dilation of (i) 2.9:1.7 cm, (ii) 4.0:0.9 cm, (iii) 3.6:3.4 cm. [sources: Adapted from* 

A systematic review of histopathological findings by physiological system have identified cardiovascular findings such as focal lymphocytic inflammation, acute cardiomyocyte necrosis, presence of inflammatory cells and apoptotic bodies [74]. A multicentre study of 21 autopsy examinations by Basso and colleagues [73] examined cardiac tissue. Lymphocytic myocarditis was present in 3 (14%) cases, two of which were CD4 predominant T-cells, and one CD8 prominent. 86% of cases demonstrated interstitial macrophage infiltration. Mild pericarditis was evident in 4 cases. Common histological findings from cardiac tissue are presented in

Although the underlying mechanisms of cardiac involvement in COVID-19 infection remain to be fully elucidated, cardiac fibrosis occurs in tandem with local and systemic inflammatory responses [84]. Whilst these mechanisms are designed to facilitate healing following tissue damage, an excess of the inflammatory response along with the development of fibrotic tissue are pathological drivers for global organ damage. Overt inflammation and fibrosis in the heart can result in abnormal cardiac remodelling potentiating the development of acute and chronic heart failure. Anti-inflammatory and anti-fibrotic therapies are in general unsuccessful in improving damaged cardiac tissue function. With respect to COVID-19,

**140**

in **Table 3**.

*Youd et al. [79], Hanley et al. [80], Fox et al. [82, 83]].*

**Figure 12.**

**Figure 13**.

*Cardiovascular histopathological findings in COVID-19 cadavers with and without comorbid conditions [source: Falasca et al. [76]].*

#### **Figure 13.**

*(a and b) Myocarditis. Biventricular multifocal and diffuse lymphocytic myocarditis (arrows) with extensive myocyte injury and previously undiagnosed cardiac amyloidosis (H&E) x50 in an 86y male; (c and d) Biventricular multifocal lymphocytic myocarditis (arrows) with myocyte injury (H&E x100). Atrial fibrillation developed 2 d before death, 64y male; (e) Increased interstitial macrophage H&E x400) in a 60y male; (f) Increased macrophage cells within the myocardial interstitum (H&E x100) in a 73y female; (g) Focal lymphocytic pericarditis (arrows, H&E, x400) comprised of (h) CD8+ lymphocytes associated with focal myocardial inflammation in the absence of myocyte injury (arrowhead, CD8 immunostaining x400); (I and j) Small vessel changes. Microthrombus in a small myocardial artery (a, arrow H&E x100) and organised venous thrombosis (b, arrow H&E x100) in a 70y male; (k) Thrombus in a small myocardial vein (arrow, H&E x200) in a 71y male; (l) Leucocyte aggregates of eosinophils and mononuclear cells in capillaries and small veins (arrow, H&E x400) in a 64y male.[Source: Adapted from Basso et al., [73]].*

further work is required to identify potential therapeutic targets of regulation and moderation of cardiac fibroblast function and thus reduce the burden of inflammatory-responsive fibrotic-based heart failure.
