PMC:7796041 / 22853-33081 JSONTXT

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Discussion\nCardiac arrhythmias were the most common cardiac event associated with hospitalization for COVID-19. Age and cardiovascular disease were identified as risk factors for the incidence of arrhythmias. Arrhythmia was associated with elevated cardiac biomarkers suggesting myocardial injury, need for ICU/IMC care and mechanical ventilation as well as mortality, and constituted an independent predictor of prolonged hospitalization and need for mechanical ventilation.\nThis is the first multicenter study including both tertiary care centers and regional hospitals focusing on the role of arrhythmias in hospitalization for COVID-19, considering both clinical and biomarker profiles. With respect to age, baseline parameters and the overall incidence of arrhythmias, our cohort corresponds to previously described COVID-19 patient populations [7,8,17,20].\nIn accordance with prior results, AF was the most common incident arrhythmia both in the entire cohort and in the subgroup of patients without any previous history of arrhythmia. An elevated risk for AF has been described in association with other respiratory virus infections, in particular influenza [21], however, with a lower incidence compared to our cohort of COVID-19-patients [22]. The present analyses of the patient subgroup with newly diagnosed AF revealed not only a relevant increase in cardiac biomarkers hinting at myocardial injury but also significantly elevated inflammatory biomarkers. This may point to an association between the degree of inflammatory state caused by COVID-19 and susceptibility to AF, which is in line with previous findings regarding inflammatory mechanisms promoting the development of atrial fibrillation [23].\nWith respect to risk factors for arrhythmia incidence during hospitalization for COVID-19, we could identify age and previous cardiovascular disease as predictors for the occurrence of any arrhythmia. These baseline characteristics have previously been shown to predispose for the development of arrhythmia in the general population without association with infectious diseases [24]. Thus, they may reflect a subgroup of greater general susceptibility to additional proarrhythmic effects. In patients with arrhythmia in our cohort, QTc duration was longer at admission, albeit within normal range in the majority of patients. Dynamic changes of the QTc interval under therapy with hydroxychloroquine and azithromycin cannot be evaluated as repeated ECGs during hospital stay were not systematically available in all patients. Thus, proarrhythmic effects of these drugs cannot be excluded in this cohort. Previous reports point towards significant prolongation of the QTc interval by hydroxychloroquine in COVID-19 which is even more enhanced in combination with azithromycin therapy [25,26]. However, the rate of associated ventricular arrhythmia has been low in these studies. Similarly, no typical “torsades des pointes” were seen in our cohort: in three of five patients with ventricular arrhythmias pre-existent cardiovascular disease was present, and only one of the remaining two patients received QTc-prolonging medication. Thus, rather than induced by direct effects of administered medication, ventricular arrhythmias may have been due to other predisposing risk factors in our cohort.\nPatients with arrhythmias during hospitalization showed elevated cardiac biomarkers and elevated levels of IL-6. Myocardial injury in COVID-19 has been reported by multiple studies, however, the underlying mechanisms have yet to be elucidated [2,4]. In our cohort, arrhythmia itself may have promoted a more pronounced increase in hsTNT and NTproBNP by an additional shift in myocardial oxygen demand under a restricted respiratory function and by increasing atrial and ventricular load. In particular, among patients with pre-existent cardiovascular disease a myocardial supply-demand-imbalance of oxygen may become evident during arrhythmia. On the other hand, myocardial injury or ischemia-especially in the light of a higher prevalence of cardiovascular disease in this subgroup-may have exerted proarrhythmic effects in addition to the inflammatory state. Such additional inflammatory influences are implicated by the pronounced increase in IL-6 in patients with arrhythmias in our cohort. In COVID-19 a state of hyperinflammation is commonly observed and correlates with both respiratory failure and myocardial injury [27]. Based on our observations, it may additionally constitute a risk factor for the incidence of arrhythmia but distinct molecular mechanisms have yet to be investigated in experimental studies and larger, prospective patient cohorts. Estimating optimal cut-off values is associated with uncertainty and is affected by the study population. Therefore, the calculated cut-offs for the biomarkers in this study should be interpreted with caution.\nWith respect to clinical outcome, an association of incident arrhythmia with the need for ICU/IMC-care was identified, which is in line with the previous observations from Pennsylvania [8]. However, age and cardiac co-morbidities have been identified as potential confounders in our analyses regarding ICU/IMC admission. Furthermore, rates of NIV- or high-flow oxygen-therapy and need for vasopressors were increased in this group. These observations, together with the results from biomarker analyses, reflect an association of the severity of disease with the incidence of cardia arrhythmia in our cohort.\nMore specifically, we show that mechanical ventilation is associated with the occurrence of arrhythmias, even when correcting for age and cardiovascular disease as potential confounders. Additionally, overall duration of hospitalization was significantly increased in patients with incident arrhythmia in multiple regression analyses, which has not been reported by previous studies. This result points towards a potentially independent prognostic role of arrhythmia in COVID-19. In light of limited ventilator- and hospital-capacity during peak episodes of the COVID-19-pandemic, these aspects are of particular relevance. In this context, our exploratory univariate analysis of patients with atrial fibrillation shows that not only ventricular arrhythmias but also supraventricular arrhythmias may have implications on the clinical course during hospitalization COVID-19 patients.\nArrhythmia during hospitalization for COVID-19 was associated with increased in-hospital mortality in the univariate analysis. However, in multiple regression analyses, pre-existent cardiovascular disease had a stronger prognostic implication than incident cardiac arrhythmia regarding this aspect, even though the majority of fatal cases were due to respiratory failure. This is in line with observations from large multicenter cohorts identifying risk factors for in-hospital death in COVID-19 [28]. With respect to a wide range of symptoms and prognostic severity associated with an infection with SARS-CoV-2, further studies aiming at individualized risk stratification are crucial.\n\nLimitations\nDue to its retrospective design, this study carries inherent limitations. Despite thorough analysis of clinical records and use of different source documents (e.g., discharge notes, nurses’ reports, daily doctors’ documentation) underreporting of arrhythmia events cannot be excluded. Not all arrhythmic events during the clinical course may have been documented in written reports. Asymptomatic arrhythmias in patients without continuous ECG-monitoring may also have been missed. However, clinically relevant arrhythmias leading to medical interventions are documented as part of the participating centers’ standards.\nBaseline and outcome data recorded in this study were prespecified and screened for in the available clinical documents. Missing parameters were specifically inquired from the participating centers. Due to different admission protocols and diagnostic standards, there are remaining missing values with regard to certain baseline parameters or biomarker measurements. However, we clearly indicate this limitation in the respective tables whenever information was available only in a subgroup of patients. QTc-duration was available at baseline in the majority of patients, however, due to different standards of ECG-based follow-up, QTc-duration in the course of hospitalization, e.g., during therapy with QT-prolonging drugs, could not be systematically analyzed.\nInclusion of both tertiary and secondary-level hospitals may lead to treatment bias due to different standards of care or available facilities. Importantly, in our study, all contributing centers provide intermediate and intensive care units and operate according to national and international guidelines. Cardiorespiratory monitoring, non-invasive and mechanical ventilation are carried out according to guidelines in all participating centers. All centers treated both moderate and severe cases of COVID-19. Patients requiring extracorporeal life support were primarily treated at tertiary centers but constituted a minority of subjects in this study cohort. Therefore, we do not expect significant bias due to differences in center size. However, due to the limited number of patients in the respective subgroups a comprehensive analysis of this aspect was not feasible. In order to provide further insight, we present an overview into the types and individual contribution of participating centers (Table S1). Additionally, individual specific therapy attemps with respect to COVID-19, e.g., hydroxochloroquine administration, were specified (Table 1). Left ventricular ejection fraction (LVEF) may have constituted an additional predictor for arrhythmia, however, the value was not provided in a relevant number of patients in this cohorts. In order to account for this limitation, we attempted imputation of these values (Supplementary Materials) hinting at a potential role of reduced LVEF as a risk factor for arrhythmia during hospitalization for COVID-19. However, these results are exploratory and have to be interpreted with caution due to the high number of missing values. Further efforts should be made to study this specific aspect in COVID-19 patients."}

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Discussion\nCardiac arrhythmias were the most common cardiac event associated with hospitalization for COVID-19. Age and cardiovascular disease were identified as risk factors for the incidence of arrhythmias. Arrhythmia was associated with elevated cardiac biomarkers suggesting myocardial injury, need for ICU/IMC care and mechanical ventilation as well as mortality, and constituted an independent predictor of prolonged hospitalization and need for mechanical ventilation.\nThis is the first multicenter study including both tertiary care centers and regional hospitals focusing on the role of arrhythmias in hospitalization for COVID-19, considering both clinical and biomarker profiles. With respect to age, baseline parameters and the overall incidence of arrhythmias, our cohort corresponds to previously described COVID-19 patient populations [7,8,17,20].\nIn accordance with prior results, AF was the most common incident arrhythmia both in the entire cohort and in the subgroup of patients without any previous history of arrhythmia. An elevated risk for AF has been described in association with other respiratory virus infections, in particular influenza [21], however, with a lower incidence compared to our cohort of COVID-19-patients [22]. The present analyses of the patient subgroup with newly diagnosed AF revealed not only a relevant increase in cardiac biomarkers hinting at myocardial injury but also significantly elevated inflammatory biomarkers. This may point to an association between the degree of inflammatory state caused by COVID-19 and susceptibility to AF, which is in line with previous findings regarding inflammatory mechanisms promoting the development of atrial fibrillation [23].\nWith respect to risk factors for arrhythmia incidence during hospitalization for COVID-19, we could identify age and previous cardiovascular disease as predictors for the occurrence of any arrhythmia. These baseline characteristics have previously been shown to predispose for the development of arrhythmia in the general population without association with infectious diseases [24]. Thus, they may reflect a subgroup of greater general susceptibility to additional proarrhythmic effects. In patients with arrhythmia in our cohort, QTc duration was longer at admission, albeit within normal range in the majority of patients. Dynamic changes of the QTc interval under therapy with hydroxychloroquine and azithromycin cannot be evaluated as repeated ECGs during hospital stay were not systematically available in all patients. Thus, proarrhythmic effects of these drugs cannot be excluded in this cohort. Previous reports point towards significant prolongation of the QTc interval by hydroxychloroquine in COVID-19 which is even more enhanced in combination with azithromycin therapy [25,26]. However, the rate of associated ventricular arrhythmia has been low in these studies. Similarly, no typical “torsades des pointes” were seen in our cohort: in three of five patients with ventricular arrhythmias pre-existent cardiovascular disease was present, and only one of the remaining two patients received QTc-prolonging medication. Thus, rather than induced by direct effects of administered medication, ventricular arrhythmias may have been due to other predisposing risk factors in our cohort.\nPatients with arrhythmias during hospitalization showed elevated cardiac biomarkers and elevated levels of IL-6. Myocardial injury in COVID-19 has been reported by multiple studies, however, the underlying mechanisms have yet to be elucidated [2,4]. In our cohort, arrhythmia itself may have promoted a more pronounced increase in hsTNT and NTproBNP by an additional shift in myocardial oxygen demand under a restricted respiratory function and by increasing atrial and ventricular load. In particular, among patients with pre-existent cardiovascular disease a myocardial supply-demand-imbalance of oxygen may become evident during arrhythmia. On the other hand, myocardial injury or ischemia-especially in the light of a higher prevalence of cardiovascular disease in this subgroup-may have exerted proarrhythmic effects in addition to the inflammatory state. Such additional inflammatory influences are implicated by the pronounced increase in IL-6 in patients with arrhythmias in our cohort. In COVID-19 a state of hyperinflammation is commonly observed and correlates with both respiratory failure and myocardial injury [27]. Based on our observations, it may additionally constitute a risk factor for the incidence of arrhythmia but distinct molecular mechanisms have yet to be investigated in experimental studies and larger, prospective patient cohorts. Estimating optimal cut-off values is associated with uncertainty and is affected by the study population. Therefore, the calculated cut-offs for the biomarkers in this study should be interpreted with caution.\nWith respect to clinical outcome, an association of incident arrhythmia with the need for ICU/IMC-care was identified, which is in line with the previous observations from Pennsylvania [8]. However, age and cardiac co-morbidities have been identified as potential confounders in our analyses regarding ICU/IMC admission. Furthermore, rates of NIV- or high-flow oxygen-therapy and need for vasopressors were increased in this group. These observations, together with the results from biomarker analyses, reflect an association of the severity of disease with the incidence of cardia arrhythmia in our cohort.\nMore specifically, we show that mechanical ventilation is associated with the occurrence of arrhythmias, even when correcting for age and cardiovascular disease as potential confounders. Additionally, overall duration of hospitalization was significantly increased in patients with incident arrhythmia in multiple regression analyses, which has not been reported by previous studies. This result points towards a potentially independent prognostic role of arrhythmia in COVID-19. In light of limited ventilator- and hospital-capacity during peak episodes of the COVID-19-pandemic, these aspects are of particular relevance. In this context, our exploratory univariate analysis of patients with atrial fibrillation shows that not only ventricular arrhythmias but also supraventricular arrhythmias may have implications on the clinical course during hospitalization COVID-19 patients.\nArrhythmia during hospitalization for COVID-19 was associated with increased in-hospital mortality in the univariate analysis. However, in multiple regression analyses, pre-existent cardiovascular disease had a stronger prognostic implication than incident cardiac arrhythmia regarding this aspect, even though the majority of fatal cases were due to respiratory failure. This is in line with observations from large multicenter cohorts identifying risk factors for in-hospital death in COVID-19 [28]. With respect to a wide range of symptoms and prognostic severity associated with an infection with SARS-CoV-2, further studies aiming at individualized risk stratification are crucial.\n\nLimitations\nDue to its retrospective design, this study carries inherent limitations. Despite thorough analysis of clinical records and use of different source documents (e.g., discharge notes, nurses’ reports, daily doctors’ documentation) underreporting of arrhythmia events cannot be excluded. Not all arrhythmic events during the clinical course may have been documented in written reports. Asymptomatic arrhythmias in patients without continuous ECG-monitoring may also have been missed. However, clinically relevant arrhythmias leading to medical interventions are documented as part of the participating centers’ standards.\nBaseline and outcome data recorded in this study were prespecified and screened for in the available clinical documents. Missing parameters were specifically inquired from the participating centers. Due to different admission protocols and diagnostic standards, there are remaining missing values with regard to certain baseline parameters or biomarker measurements. However, we clearly indicate this limitation in the respective tables whenever information was available only in a subgroup of patients. QTc-duration was available at baseline in the majority of patients, however, due to different standards of ECG-based follow-up, QTc-duration in the course of hospitalization, e.g., during therapy with QT-prolonging drugs, could not be systematically analyzed.\nInclusion of both tertiary and secondary-level hospitals may lead to treatment bias due to different standards of care or available facilities. Importantly, in our study, all contributing centers provide intermediate and intensive care units and operate according to national and international guidelines. Cardiorespiratory monitoring, non-invasive and mechanical ventilation are carried out according to guidelines in all participating centers. All centers treated both moderate and severe cases of COVID-19. Patients requiring extracorporeal life support were primarily treated at tertiary centers but constituted a minority of subjects in this study cohort. Therefore, we do not expect significant bias due to differences in center size. However, due to the limited number of patients in the respective subgroups a comprehensive analysis of this aspect was not feasible. In order to provide further insight, we present an overview into the types and individual contribution of participating centers (Table S1). Additionally, individual specific therapy attemps with respect to COVID-19, e.g., hydroxochloroquine administration, were specified (Table 1). Left ventricular ejection fraction (LVEF) may have constituted an additional predictor for arrhythmia, however, the value was not provided in a relevant number of patients in this cohorts. In order to account for this limitation, we attempted imputation of these values (Supplementary Materials) hinting at a potential role of reduced LVEF as a risk factor for arrhythmia during hospitalization for COVID-19. However, these results are exploratory and have to be interpreted with caution due to the high number of missing values. Further efforts should be made to study this specific aspect in COVID-19 patients."}

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Discussion\nCardiac arrhythmias were the most common cardiac event associated with hospitalization for COVID-19. Age and cardiovascular disease were identified as risk factors for the incidence of arrhythmias. Arrhythmia was associated with elevated cardiac biomarkers suggesting myocardial injury, need for ICU/IMC care and mechanical ventilation as well as mortality, and constituted an independent predictor of prolonged hospitalization and need for mechanical ventilation.\nThis is the first multicenter study including both tertiary care centers and regional hospitals focusing on the role of arrhythmias in hospitalization for COVID-19, considering both clinical and biomarker profiles. With respect to age, baseline parameters and the overall incidence of arrhythmias, our cohort corresponds to previously described COVID-19 patient populations [7,8,17,20].\nIn accordance with prior results, AF was the most common incident arrhythmia both in the entire cohort and in the subgroup of patients without any previous history of arrhythmia. An elevated risk for AF has been described in association with other respiratory virus infections, in particular influenza [21], however, with a lower incidence compared to our cohort of COVID-19-patients [22]. The present analyses of the patient subgroup with newly diagnosed AF revealed not only a relevant increase in cardiac biomarkers hinting at myocardial injury but also significantly elevated inflammatory biomarkers. This may point to an association between the degree of inflammatory state caused by COVID-19 and susceptibility to AF, which is in line with previous findings regarding inflammatory mechanisms promoting the development of atrial fibrillation [23].\nWith respect to risk factors for arrhythmia incidence during hospitalization for COVID-19, we could identify age and previous cardiovascular disease as predictors for the occurrence of any arrhythmia. These baseline characteristics have previously been shown to predispose for the development of arrhythmia in the general population without association with infectious diseases [24]. Thus, they may reflect a subgroup of greater general susceptibility to additional proarrhythmic effects. In patients with arrhythmia in our cohort, QTc duration was longer at admission, albeit within normal range in the majority of patients. Dynamic changes of the QTc interval under therapy with hydroxychloroquine and azithromycin cannot be evaluated as repeated ECGs during hospital stay were not systematically available in all patients. Thus, proarrhythmic effects of these drugs cannot be excluded in this cohort. Previous reports point towards significant prolongation of the QTc interval by hydroxychloroquine in COVID-19 which is even more enhanced in combination with azithromycin therapy [25,26]. However, the rate of associated ventricular arrhythmia has been low in these studies. Similarly, no typical “torsades des pointes” were seen in our cohort: in three of five patients with ventricular arrhythmias pre-existent cardiovascular disease was present, and only one of the remaining two patients received QTc-prolonging medication. Thus, rather than induced by direct effects of administered medication, ventricular arrhythmias may have been due to other predisposing risk factors in our cohort.\nPatients with arrhythmias during hospitalization showed elevated cardiac biomarkers and elevated levels of IL-6. Myocardial injury in COVID-19 has been reported by multiple studies, however, the underlying mechanisms have yet to be elucidated [2,4]. In our cohort, arrhythmia itself may have promoted a more pronounced increase in hsTNT and NTproBNP by an additional shift in myocardial oxygen demand under a restricted respiratory function and by increasing atrial and ventricular load. In particular, among patients with pre-existent cardiovascular disease a myocardial supply-demand-imbalance of oxygen may become evident during arrhythmia. On the other hand, myocardial injury or ischemia-especially in the light of a higher prevalence of cardiovascular disease in this subgroup-may have exerted proarrhythmic effects in addition to the inflammatory state. Such additional inflammatory influences are implicated by the pronounced increase in IL-6 in patients with arrhythmias in our cohort. In COVID-19 a state of hyperinflammation is commonly observed and correlates with both respiratory failure and myocardial injury [27]. Based on our observations, it may additionally constitute a risk factor for the incidence of arrhythmia but distinct molecular mechanisms have yet to be investigated in experimental studies and larger, prospective patient cohorts. Estimating optimal cut-off values is associated with uncertainty and is affected by the study population. Therefore, the calculated cut-offs for the biomarkers in this study should be interpreted with caution.\nWith respect to clinical outcome, an association of incident arrhythmia with the need for ICU/IMC-care was identified, which is in line with the previous observations from Pennsylvania [8]. However, age and cardiac co-morbidities have been identified as potential confounders in our analyses regarding ICU/IMC admission. Furthermore, rates of NIV- or high-flow oxygen-therapy and need for vasopressors were increased in this group. These observations, together with the results from biomarker analyses, reflect an association of the severity of disease with the incidence of cardia arrhythmia in our cohort.\nMore specifically, we show that mechanical ventilation is associated with the occurrence of arrhythmias, even when correcting for age and cardiovascular disease as potential confounders. Additionally, overall duration of hospitalization was significantly increased in patients with incident arrhythmia in multiple regression analyses, which has not been reported by previous studies. This result points towards a potentially independent prognostic role of arrhythmia in COVID-19. In light of limited ventilator- and hospital-capacity during peak episodes of the COVID-19-pandemic, these aspects are of particular relevance. In this context, our exploratory univariate analysis of patients with atrial fibrillation shows that not only ventricular arrhythmias but also supraventricular arrhythmias may have implications on the clinical course during hospitalization COVID-19 patients.\nArrhythmia during hospitalization for COVID-19 was associated with increased in-hospital mortality in the univariate analysis. However, in multiple regression analyses, pre-existent cardiovascular disease had a stronger prognostic implication than incident cardiac arrhythmia regarding this aspect, even though the majority of fatal cases were due to respiratory failure. This is in line with observations from large multicenter cohorts identifying risk factors for in-hospital death in COVID-19 [28]. With respect to a wide range of symptoms and prognostic severity associated with an infection with SARS-CoV-2, further studies aiming at individualized risk stratification are crucial.\n\nLimitations\nDue to its retrospective design, this study carries inherent limitations. Despite thorough analysis of clinical records and use of different source documents (e.g., discharge notes, nurses’ reports, daily doctors’ documentation) underreporting of arrhythmia events cannot be excluded. Not all arrhythmic events during the clinical course may have been documented in written reports. Asymptomatic arrhythmias in patients without continuous ECG-monitoring may also have been missed. However, clinically relevant arrhythmias leading to medical interventions are documented as part of the participating centers’ standards.\nBaseline and outcome data recorded in this study were prespecified and screened for in the available clinical documents. Missing parameters were specifically inquired from the participating centers. Due to different admission protocols and diagnostic standards, there are remaining missing values with regard to certain baseline parameters or biomarker measurements. However, we clearly indicate this limitation in the respective tables whenever information was available only in a subgroup of patients. QTc-duration was available at baseline in the majority of patients, however, due to different standards of ECG-based follow-up, QTc-duration in the course of hospitalization, e.g., during therapy with QT-prolonging drugs, could not be systematically analyzed.\nInclusion of both tertiary and secondary-level hospitals may lead to treatment bias due to different standards of care or available facilities. Importantly, in our study, all contributing centers provide intermediate and intensive care units and operate according to national and international guidelines. Cardiorespiratory monitoring, non-invasive and mechanical ventilation are carried out according to guidelines in all participating centers. All centers treated both moderate and severe cases of COVID-19. Patients requiring extracorporeal life support were primarily treated at tertiary centers but constituted a minority of subjects in this study cohort. Therefore, we do not expect significant bias due to differences in center size. However, due to the limited number of patients in the respective subgroups a comprehensive analysis of this aspect was not feasible. In order to provide further insight, we present an overview into the types and individual contribution of participating centers (Table S1). Additionally, individual specific therapy attemps with respect to COVID-19, e.g., hydroxochloroquine administration, were specified (Table 1). Left ventricular ejection fraction (LVEF) may have constituted an additional predictor for arrhythmia, however, the value was not provided in a relevant number of patients in this cohorts. In order to account for this limitation, we attempted imputation of these values (Supplementary Materials) hinting at a potential role of reduced LVEF as a risk factor for arrhythmia during hospitalization for COVID-19. However, these results are exploratory and have to be interpreted with caution due to the high number of missing values. Further efforts should be made to study this specific aspect in COVID-19 patients."}