COVID-19 is a multiorgan systemic inflammatory disease caused by SARS-CoV-2 virus. Patients with COVID-19 often exhibit cardiac dysfunction and myocardial injury, but imaging evidence is lacking. In the study we detected and evaluated the severity of myocardial dysfunction in COVID-19 patient population using two-dimensional speckle-tracking echocardiography (2-D STE). A total of 218 consecutive patients with confirmed diagnosis of COVID-19 who had no underlying cardiovascular diseases were enrolled and underwent transthoracic echocardiography. This study cohort included 52 (23.8%) critically ill and 166 noncritically ill patients. Global longitudinal strains (GLSs) and layer-specific longitudinal strains (LSLSs) were obtained using 2-D STE. Changes in GLS were correlated with the clinical parameters. We showed that GLS was reduced (<−21.0%) in about 83% of the patients. GLS reduction was more common in critically sick patients (98% vs. 78.3%, P < 0.001), and the mean GLS was significantly lower in the critically sick patients than those noncritical (−13.7% ± 3.4% vs. −17.4% ± 3.2%, P < 0.001). The alteration of GLS was more prominent in the subepicardium than in the subendocardium (P < 0.001). GLS was correlated to mean serum pulse oxygen saturation (SpO2, RR = 0.42, P < 0.0001), high-sensitive C-reactive protein (hsCRP, R = −0.20, P = 0.006) and inflammatory cytokines, particularly IL-6 (R = −0.21, P = 0.003). In conclusions, our results demonstrate that myocardial dysfunction is common in COVID-19 patients, particularly those who are critically sick. Changes in indices of myocardial strain were associated with indices of inflammatory markers and hypoxia, suggesting partly secondary nature of myocardial dysfunction.
To our knowledge, this is the first comprehensive analysis of cardiac function using 2-D STE in a large COVID-19 cohort. We found that almost all critically ill COVID-19 patients (98%) and most noncritical patients (78.3%) had detectable abnormalities of cardiac function using deformation analysis by 2-D STE. These findings demonstrated for the first time the presence of widespread cardiac dysfunction that might contribute to the prognosis of COVID-19 patients. Our results suggest that myocardial deformation indices are sensitive indicators of cardiac injury and seemingly superior to biomarkers cTnI and NT-proBNP in COVID-19 patients. We further found that a reduction in strain was predominantly detected in the subepicardium rather than the subendocardium, which was consistent with known features of myocardial damage from myocarditis. Moreover, the GLS parameters were significantly associated with the serum levels of inflammatory cytokines and SpO2, underscoring the potential mechanisms involved in the pathogenesis of COVID-19-induced cardiac injury and dysfunction.
Hypersensitive cTnI was found to be elevated in 10.8% of the COVID-19 cohort, a level comparable to that observed in a previous report . Elevated NT-proBNP (900-pg/mL cutoff value) levels were observed in 15.3% of COVID-19 patients, slightly lower than the 22.2% reported in a previous study from Wuhan . In addition, 22% of patients had a reduced LV EF (<50%), a commonly used indicator of LV function. In contrast, 83% of the COVID-19 patients had reduced GLS, which was more common than the prevalence of reduced LV EF or elevated cTnI and NT-proBNP. These data indicate that most hospitalized COVID-19 patients developed subclinical LV dysfunction, despite preserved EF and normal levels of cTnI and/or NT-proBNP. Our findings offer the first clinical evidence that cardiac abnormalities are a common finding in COVID-19, and their prevalence is much higher than that previously reported. New imaging tools, such as myocardial strain analysis by 2-D STE, provide a valuable approach to detect the full spectrum of cardiac abnormalities and may be considered as part of the diagnostic evaluation of patients with COVID-19, particularly critically ill patients. Patients in this study were mostly in the mid- or late-phase of their disease course; therefore, symptoms such as fever and cough had resolved. The most common symptom among the cohort was shortness of breath, which could have been caused by either respiratory distress or cardiac dysfunction or both. However, the typical symptoms of heart failure, including orthopnea, paroxysmal nocturnal dyspnea, and ankle swelling, were largely absent in the study subjects. Likewise, in 94.5% of patients with cTnI elevation, the absolute cTnI level was lower than 100 pg/mL. The asymptomatic presentation of cardiac dysfunction and the low-grade elevation of cTnI were in line with the subclinical state of the cardiac dysfunction associated with COVID-19. GLS reduction was more common in critically ill patients (98%) than in noncritical patients (78.3%). Likewise, the absolute levels of GLS were significantly lower in the critical cases than in the noncritical cases. This correlation suggests that cardiac dysfunction may have a significant contribution to disease progression and adverse outcomes in patients with COVID-19. Histologic evidence of inflammatory cell infiltrates by EMB is the gold standard criterion for diagnosing myocarditis . Likewise, CMR is an alternative noninvasive imaging tool . However, EMB and CMR have not been routinely available during the COVID-19 pandemic, raising a major challenge for proper diagnosis of the state of cardiac health in patients with COVID-19. Myocardial deformation analysis by 2-D STE, particularly layer-specific quantification, provides a novel tool for detecting cardiac dysfunction in COVID-19 patients. Indices of longitudinal strains are known to strongly correlate with the levels of lymphocytic infiltrates in EMB samples  and with the amount of edema detected by CMR . Moreover, the diagnostic performance of LSLSs in acute myocarditis has been validated by showing preferential alteration of subepicardial deformation that was consistent with tissue characteristics established by CMR . In the present study, the reduction in longitudinal strains in the subepicardium was more severe than that in the subendocardium, suggesting that cardiac dysfunction was located predominantly in the subepicardial layer of the myocardium, an important feature consistent with the manifestation of myocarditis. Indeed, 18 patients from the present study cohort had CMR imaging after their discharge (data not shown), of whom 8 showed evidence of myocardial edema. Therefore, the findings of the present study of a large cohort provided additional evidence, based on echo imaging, to support the potential involvement of myocarditis in COVID-19. Myocardial inflammation involves pericardial remodeling, and vice versa. In this study, we noted that 11.5% of COVID-19 patients developed pericardial effusion; however, most cases were mild, and only a few had moderate effusion. Large effusion was not detected, and no difference in the incidence of pericarditis was observed in the critical vs. the noncritical patients. Whether SARS-CoV-2 can directly cause primary myocardial injury through myocardial inflammation is still controversial, though it has been widely speculated based on previous knowledge of other viral-induced cardiac injuries . To date, there have been only two case reports indicating the presence of myocarditis by showing the presence of myocardial edema using CMR imaging [23, 24] and one case report detected the presence of SARS-CoV-2 in EMB sample tissue . However, neither inflammatory infiltrates nor substantial myocardial damage was found in a patient who died from severe COVID-19 infection . There was also no direct evidence of myocarditis in the COVID-19 cohorts at this moment. In addition to myocardial inflammation, systemic inflammation and hypoxemia may also contribute to cardiac injury under different pathological conditions [27,28,29,30,31]. The systemic inflammatory response has been found to be associated with early cardiac dysfunction in patients with traumatic brain injury and in perioperative myocardial injury in patients undergoing noncardiac surgery [27, 29]. Inflammatory cytokines, such as IL-6, IL-10, and TNF-α, have been associated with cardiovascular dysfunction in patients with cardiac arrest . Hypoxemia may also lead to cardiac injury via inflammation, metabolic acidosis, and mitochondrial abnormalities, as suggested by previous studies [30, 31]. However, their roles in cardiac injury and dysfunction in COVID-19 are not known. In the present study, the levels of serum inflammatory cytokines, such as IL-6, IL-10, and TNF-α, as well as inflammation markers, such as ESR and CRP, were all significantly elevated, especially in the critically ill patients. Hypoxemia was also particularly common in the critically ill patients. Therefore, we suspected that systemic inflammation and hypoxemia may cause secondary myocardial injury in COVID-19. By multivariable regression analysis, we found that systemic inflammatory cytokines, particularly IL-6 and SpO2, were closely associated with a reduction in GLS in COVID-19 patients. Therefore, we speculated that systemic inflammation and hypoxemia may contribute to cardiac injury in patients with COVID-19. Regarding the effects of medical treatment on myocardial injury, only the intravenous use of corticosteroids was associated with improvement in GLS, indicating the potential beneficial effect of systemic corticosteroid treatment. However, further evidence is needed to assess the value of corticosteroids in COVID-19.
Limitations There are some notable limitations in the present study. First, patients with underlying cardiovascular diseases were excluded, and important comorbidities, such as hypertension and diabetes, were not investigated. In addition, the normal cohort in this study consisted of only 23 subjects, which is modest and may complicate the interpretation of the findings on the effects of COVID-19 on cardiac function. The TTE scans in the study were performed at the time when most of the enrolled patients had passed the critical period of COVID-19 disease progression; most patients were generally toward the end of their hospitalization period. Therefore, the echocardiographic features obtained in the study may be subject to survival bias and may not be adequate to predict the outcome. Meanwhile, critically ill patients who died earlier than March 15 were not included in this study, which explained the low mortality in the present study and may affect the outcome analysis. Moreover, EMB data were absent in the present study. Therefore, although the study raised the possibility that COVID-19 was associated with highly prevalent cardiac abnormalities and could potentially cause myocarditis, direct evidence remains lacking. Fourth, different treatments may be significant confounding factors of the disease outcome and may have further complicated the statistical analysis and the conclusions of the study. Fifth, repeated echo and with serum markers were not performed at the end of hospitalization to determine the changes in cardiac injury. Last, whether COVID-19 could cause chronic cardiomyopathy was not addressed in this study, and long-term follow-up is needed.
Conclusions This study provides imaging evidence of the high prevalence of myocardial dysfunction in a large population of patients with COVID-19. Myocardial deformation analysis by 2-D STE detected a broad range of cardiac abnormalities in COVID-19 patients. The preferential alteration of strains in the subepicardium supports possible myocarditis as the underpinning cardiac pathology in COVID-19. Likewise, inflammatory storms and hypoxemia may be important mechanisms leading to cardiac injury in COVID-19 patients.
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