Monitoring of COVID-19 sequelae is essential to shedding light on the long-term COVID-19 mortality and morbidity and further developing treatment approaches (10). On this basis, the current study investigated the long-term (i.e., 6 months after the onset of symptoms) echocardiographic alterations of severe and non-severe COVID-19. Our results support that COVID-19, regardless of severity, did not lead to cardiac impairment in an otherwise healthy population. Although there were some patterns of change among echocardiographic indices during the follow-up period, they were all lying within normal reference ranges according to the 2015 ESC echocardiographic cardiac chamber quantification guideline (7).
In both severe and non-severe COVID-19 groups, among systolic indices, 4D-LVEDVI increased significantly along with 4D-LVSVI and LVEF in the follow-up echocardiogram. We hypothesize that these alterations may indicate the higher heart rate (HR) of the participants at the time of the primary echocardiogram to improve oxygenation in response to impaired lung function, which in turn slowed down after the lung recovery. Thus, the stroke volume increases as an expected consequence of slowed-down HR. In line with this hypothesis, an echocardiographic study by Szekely et al. stated that patients with more severe COVID-19 had significantly higher heart rates, and the stroke volume was reported non-significantly lower in the group with more severe COVID-19 (11). Similarly, Racz et al., in a study of echocardiographic follow-up of mild COVID-19 cases compared with non-COVID-19 healthy controls after 59 ± 33 days, showed that 4DLVSVI was significantly lower in the COVID-19 group (12).
In the severe COVID-19 group, 4D-LVGLS increased significantly, demonstrating that LV function has improved over time, and the lower 4D-LVGLS in the primary echocardiogram might have been a consequence of cardiac hyperactivity. It was expressed previously in the ECHOVID study that LVGLS was lower in patients hospitalized for COVID-19 compared to the healthy population (13). Moreover, it was shown in Croft et al. study that the LVGLS in hospitalized COVID-19 patients were lower than the assumed lower limit of the normal range. They hypothesized that the decrease in LVGLS associated with COVID-19 might be attributable to a combination of causes. Direct and indirect processes may cause myocardial damage. Viral invasion of the myocardium directly results in cardiomyocyte death and inflammation. Indirect mechanisms include cardiac stress caused by insults such as respiratory failure and hypoxemia, as well as cardiac inflammation in the presence of substantial systemic hyperinflammation (14–16).
Global RV function indicators demonstrated hyperactivity of RV during the early COVID-19 recovery phase, as the 4D-RVFAC in both non-severe and severe COVID-19 groups decreased significantly in the follow-up echocardiogram in comparison with the primary echocardiogram while it still fell within normal range. Furthermore, RVFWGLS decreased significantly in the non-severe COVID-19 group. Among COVID-19 patients, a cytokine storm has been reported to be prevalent. Cardiac myofibroblasts and cardiomyocytes are the major generators of various proinflammatory cytokines (17). As a result of systemic inflammation in COVID-19, the afterload increases (18); thus, the rise in RVFWGLS in primary echocardiogram among the non-severe COVID-19 group demonstrates hyperactivity of the RV in order to overcome the risen afterload.
A study evaluating the RV in COVID-19 showed that Interleukin 6 serum levels are associated with respiratory dysfunction, ARDS, and poor clinical outcomes. The proinflammatory cytokine cascade may lead to RV dysfunction through adverse inotropic effects on the myocardium. Taken together, reduced RV contractility and abruptly high pulmonary vascular resistance due to ARDS and pulmonary embolism in COVID-19 may be fatal (17). The present study's findings showed no RV failure amongst patients as it was the study of non-critically ill patients. It seems that in non-severe cases of COVID-19, in the absence of a cytokine storm, a healthy heart will increase its contractility in compensation during the acute phase.
In a study of the prognostic value of RV strain, Li et al. stated that non-survivors of COVID-19 had RV enlargement and dysfunction. The COVID-19 infection has been shown to generate both pulmonary and systemic inflammation, which may lead to RV failure via RV overload and direct cardiomyocyte injury. This study revealed that right ventricular longitudinal strain is correlated with COVID-19 severity and is an independent predictor of clinical outcomes in COVID-19 patients. This index may have a more predictive value than other echocardiographic markers (19). In agreement with our findings, the WASE-COVID study, which provided participants with a follow-up echocardiogram, revealed an improvement in 4D-RVGLS in patients with impaired RV function, which may be solid evidence of advancement in lung function between the time of the baseline echocardiogram and the time of the follow-up study (20).
Although TAPSE altered non-significantly in both COVID-19 severity groups, 4DRVFAC decreased significantly on the follow-up echocardiogram in both severe and non-severe COVID-19 groups, suggesting the RV hyperactivity improved oxygenation against the COVID-19-affected lungs in the early recovery phase. Paternoster et al., in a systematic review and meta-analysis, defined the RV dysfunction in COVID-19 patients based on the recommended cut-offs of echocardiographic guidelines that the cut-offs for RV failure determinants were FAC < 35%, TAPSE < 17 mm, and, (PAP) > 25 mmHg, according to which, these indices in our study were not within the range indicating RV failure (7, 21, 22).
Limitations and strengths
There were limitations and strengths in this study's design and running, as follows: The most accurate way to evaluate chambers' volumes and strains is cardiac magnetic resonance imaging (CMR) (23). Although it was better to evaluate the heart condition with CMR, echocardiography is still the most accessible and inexpensive way to carry out the global cardiac status (7). So, in case of having access and enough budgets to perform CMR for research purposes, it would be more reliable to perform this study with CMR, which would probably lead to higher inter-and intra- observer reproducibility. Another noteworthy limitation was the limited sample size. It was a single-center cohort of healthcare workers. The other shortcoming of this study was the absence of electrocardiogram and high-sensitivity troponin among laboratory tests which would provide a better perspective of possible cardiac involvements.
Moreover, as the participants were all healthcare workers and thus aware of the alarm signs and symptoms ending to critically severe COVID-19, they received proper care right away. Consequently, there were fewer patients with cytokine storm and severe COVID-19 pneumonia to measure the impact on the cardiopulmonary system. The bright point of the current study is considering patients without cardiac indication for echocardiography which provides evidence for silent long-term effects of COVID-19 on the cardiovascular system. On the other hand, having a population bare of known cardiac problems excludes the impact of the baseline cardiac complications on the outcomes of the patients. Another novelty of the current study is the duration of the follow-up period (6 months), which is not practiced in most similar studies.