Correspondence to Dr Tarjei Øvrebotten; [email protected]
WHAT IS ALREADY KNOWN ON THIS TOPIC
Multiple studies have indicated an elevated risk of cardiac disease following hospitalisation for COVID-19, but many of these studies lack a suitable control group. Our goal was to determine whether COVID-19 is more strongly linked to cardiac disease compared with viral and bacterial pneumonia.
WHAT THIS STUDY ADDS
We demonstrate that COVID-19 is associated with a lower risk of aggregate cardiac disease following hospitalisation compared to other viral or bacterial pneumonias, and it did not result in an increased number of cardiac investigations.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Our study shows that additional follow-up for cardiac disease is not necessary after being hospitalised with COVID-19 compared with being hospitalised with similar conditions.
Introduction
As early as the 1930s, researchers found an association between respiratory infections and cardiac disease,1 and a causal relationship has been established between influenza and coronary artery disease.2 Community-acquired pneumonia can increase the risk of acute coronary syndrome, arrhythmias, heart failure (HF) and myocarditis.3 4 In particular, viral pneumonias are associated with cardiovascular events, and most events occur in the early phase of the infections.2 5–7 At the start of the COVID-19 pandemic, there was worry that COVID-19 would cause a substantial increase in cardiac disease. In some studies, COVID-19 is associated with cardiovascular complications,8–10 with as many as 78% of patients having cardiac abnormalities when assessed by MRI.11 In contrast, other studies found no increase in cardiac abnormalities or injury due to COVID-19, compared with other pneumonias.12 13 COVID-19 and other pneumonias may influence the heart in several ways, for example, by direct invasion, hypoxaemia, through inflammatory mediators, increased coagulation, damage through angiotensin-converting enzyme 2, increased levels of catecholamines or activation of the sympathetic nervous system.3 14 Additionally, critical illness in itself can lead to cardiac complications, such as septic cardiomyopathy.15 In the realm of infectious diseases and their association with cardiac disease, most research has centred on pneumonia. Consequently, the most intriguing question is whether COVID-19 results in more cardiac disease compared with other pneumonias.
Most studies on the incidence of cardiac pathology following COVID-19 have no appropriate control group, and research on cardiac disease associated with COVID-19 in comparison with other pneumonias is limited. Using data from two national registers with compulsory reporting, this study aimed to determine differences in the hazard of incident cardiac disease following hospitalisation for COVID-19, compared with hospitalisation for other viral or bacterial pneumonias.
Methods
Overall study design and data collection
This was an observational cohort study based on two large-scale national registries in Norway. Data from patients with COVID-19 were collected from the Norwegian Surveillance System for Communicable Diseases (MSIS) register of the Norwegian Institute of Public Health.16 This register contains mandatory reports on all patients in Norway with a positive SARS-CoV-2 PCR test. The Norwegian Patient Registry (NPR) contains codes from the International Classification of Diseases, revision 10 (ICD-10), from admissions and outpatient visits from all hospitals in Norway.17 Since 2008, the reports to NPR have included the national personal identification number, which enables data from MSIS to be linked with data from NPR.
We identified all patients hospitalised with COVID-19 between 21 February and 1 December 2020 (index hospitalisation) from MSIS and cross-linked with data from NPR to obtain information on all hospital stays and procedures in publicly financed hospitals the admission date back to January 2008. Data from hospitalisations before the index hospitalisation were collected to determine comorbid conditions. Cardiac events and procedures were recorded from hospitalisations that occurred after the index hospitalisation. We selected a control population from NPR comprising all patients hospitalised in Norwegian hospitals for viral or bacterial pneumonia in 2018 and 2019 before COVID-19 emerged. Mortality data until February 2022 were collected from NPR and MSIS, with updated information on the date of death from the registers of Statistics Norway.
The Regional Ethics Committee (REK) South-Eastern Norway approved this study (2020/149384). The linkage of registries was performed by NPR; thus, only anonymous data were analysed. Patient consent requirements were waived in accordance with §35 of the Health Research Act. Access to data from MSIS and NPR was granted following the approval process by REK.
Study population
Patients hospitalised with COVID-19 were defined as those having a positive SARS-CoV-2 PCR test ≤14 days before or during the index hospitalisation. We classified other pneumonias by the following ICD-10 codes as the primary diagnosis: viral pneumonias (J09 zoonotic/pandemic influenza, J10 seasonal influenza, J11 unidentified influenza and J12 other viral pneumonias) and bacterial pneumonias (J13 pneumonia, J14 Hemophilus influenza, J15 other specified bacterial pneumonias). Most viral pneumonias were seasonal influenza (69%), and the majority of bacterial pneumonia was coded as ‘other specified bacterial pneumonia’ (88%) (online supplemental table 1).
Outcomes
The primary outcome in this study was incident cardiac disease. We used the following ICD-10 codes to classify cardiac disease: myocarditis (I31.9, I40.0, I41.1, I51.4), acute myocardial infarction (AMI) (I21-I23), atrial fibrillation or flutter (AF) (I48), HF (I50), ischaemic heart disease (IHD) (I20, I24–25) and other cardiac diseases (I31–I51). In addition, we created a composite variable comprising the first event of any cardiac disease (myocarditis, AMI, AF, HF, IHD or other cardiac disease).
Echocardiography and cardiac angiography procedures were identified by the Norwegian Clinical Medical Procedure (NCMP) coding system, which is used nationally for reporting medical procedures. Echocardiography was defined by the following NCMP codes: SFY0HK (comprehensive echocardiography), SFY0GK (standard echocardiography) and SFY0LK (transesophageal echocardiography). We defined coronary angiography by the code SFN0DB and endovascular selective coronary angiography including bypass grafts and percutaneous coronary intervention by Z95.5.
We restricted the follow-up time to 274 days (9 months) after the index hospital admission date for all analyses to harmonise the differences in follow-up time, which was shorter for patients hospitalised for COVID-19 than patients hospitalised for viral and bacterial pneumonia.
Other variables from registers
We obtained data on age and sex from NPR. Comorbidity was classified using ICD-10 codes over the last 10 years preceding the index hospitalisation, in accordance with Charlson Comorbidity Index18 (online supplemental table 2). In addition, we collected data on the number of hospitalisations during 12 months before the index admission, length of stay and respiratory support (non-invasive respiratory support: NCMP GXAV10, GXAV20, GXAV30 or ventilator: NCMP GBB00, GBB03, GBGC05, GBGC10, GXAV01, GXAV23, GXAV24) during the index admission. These variables were considered possible confounders and used in adjusted analyses.
Statistical analysis
We present descriptive statistics for continuous variables as the mean (SD) or median (25th to 75th percentile). Categorical variables are presented as numbers (%).
We calculated crude incidence rates by dividing the number of events occurring during follow-up by the product of follow-up time and total population in each group (COVID-19, viral pneumonia and bacterial pneumonia). Incidence rates are presented per 100 000 person-days with 95% CIs. We considered the admission date as the starting point for all patients, and all patients were followed for a maximum of 274 days. Patients without cardiac events within this time were censored.
We analysed associations between potential predictor variables and cardiac outcomes using Cox regression analysis of time-to-first event, with results presented as HR with 95% CIs and p values. The date of the index hospital admission was used as day 0. The proportional hazard assumption was investigated with log-log plots and a test of the non-zero slope of Schoenfeld residuals and was considered to be fulfilled. Because echocardiography and cardiac angiography following hospitalisation often follow pre-specified protocols for time scheduling at each hospital, we analysed the use of these by multivariable logistic regression instead of time-to-event analysis.
In all multivariable regression analyses, we adjusted for the following a priori selected variables: age, sex, number of hospital admissions during the last 12 months before the index hospitalisation, previous acute myocardial infarction, congestive HF, peripheral vascular disease, cerebrovascular disease (CVD), dementia, chronic obstructive pulmonary disease, rheumatoid disease, renal disease, liver disease, diabetes, cancer and the need of respiratory support during the index hospitalisation. The main analysis was for diagnoses that had not previously been recorded (ie, new-onset cardiac disease). In supplementary analyses, we included diagnoses that had been registered 10 years before the index hospitalisation (ie, recurrent cardiac events). We performed stratified subgroup analyses by age (<70 and ≥70 years) and sex.
In addition to the main analysis with 274 days of follow-up, we performed a sensitivity analysis with censoring at day 90 to account for differences in follow-up. We also did a sensitivity analysis of events occurring within 30 days of admission and beyond 30 days after admission. In a supplementary Cox regression analysis, we also adjusted for a propensity score, ie, the propensity for being hospitalised for COVID-19 vs viral pneumonia, or COVID-19 vs bacterial pneumonia in logistic regression models using all the previously mentioned covariates to derive the propensity score. To account for death as a competing risk for cardiac disease, we also performed a competing risk analysis using the Fine–Gray model.19 All statistical analyses used Stata software version 17 (Stata Corp., College Station, TX, USA). A two-sided P value of <0.05 was considered statistically significant.
Results
Patient characteristics and variables during the index hospitalisation
In total, 30 496 patients with COVID-19 were identified in MSIS; 2083 patients were hospitalised and included in this analysis. We identified 9018 patients hospitalised with a main diagnosis of viral pneumonia and 29 339 with bacterial pneumonia in 2018 and 2019.
Patients with COVID-19 were younger and more often male (mean (SD) 6018 years, 58% males) than patients with viral pneumonia (6919 years, 47% males) or bacterial pneumonia (7217 years, 48% males) (table 1). Patients with COVID-19 had fewer comorbidities and fewer hospitalisations before the index hospitalisation than those with viral or bacterial pneumonia. Established CVD was less common in patients with COVID-19 (7%) than in patients with viral pneumonia (14%) or bacterial pneumonia (15%). Patients with COVID-19 were hospitalised longer than patients with viral pneumonia (median [25th to 75th percentile] 5 [2 to 9] vs 3 [2 to 5] days, p=0.001) and bacterial pneumonia (4 [3 to 7], p=<0.001) and more often required respiratory support during the index hospital stay.
Table 1Characteristics of patients hospitalised with COVID-19, viral pneumonia and bacterial pneumonia
| COVID-19 (n=2082) | Viral pneumonia (n=9018) | P value* | Bacterial pneumonia (n=29 339) | P value* | |
| Male sex, number (%) | 1208 (58) | 4279 (47) | <0.001 | 15 162 (48) | <0.001 |
| Age at index hospitalisation, mean (SD) years | 60 (18) | 69 (19) | 0.001 | 72 (17) | <0.001 |
| Comorbidity, number (%) | |||||
| Acute myocardial infarction | 143 (7) | 1229 (14) | 0.001 | 4303 (15) | <0.001 |
| Congestive heart failure | 143 (7) | 1251 (14) | 0.001 | 4700 (17) | <0.001 |
| Peripheral vascular disease | 120(6) | 1014 (12) | 0.001 | 3903 (14) | <0.001 |
| Cerebrovascular disease | 175 (9) | 1385 (16) | 0.001 | 4894 (17) | <0.001 |
| Dementia | 41 (2) | 361 (4) | 0.001 | 1584 (6) | <0.001 |
| Chronic obstructive pulmonary disease | 250 (13) | 2170 (25) | 0.001 | 8931 (31) | <0.001 |
| Rheumatoid disease | 79 (4) | 559 (6) | 0.001 | 1927 (7) | <0.001 |
| Renal disease | 146 (7) | 1076 (12) | 0.001 | 3735 (13) | <0.001 |
| Liver disease | 73 (4) | 273 (3) | 0.265 | 935 (3) | 0.263 |
| Diabetes | 292 (14) | 1344 (15) | 0.062 | 4252 (15) | 0.315 |
| Cancer | 366 (18) | 2087 (23) | 0.001 | 8082 (28) | <0.001 |
| Hospitalisations last year, number (%) | |||||
| 0 | 1595 (77) | 5401 (60) | <0.001 | 15 974 (55) | <0.001 |
| 1–2 | 367 (18) | 2556 (28) | <0.001 | 8918 (30) | <0.001 |
| ≥3 | 120 (6) | 1061 (12) | <0.001 | 4447 (15) | <0.001 |
| Respiratory support | 336 (16) | 702 (8) | <0.001 | 3274 (11) | <0.001 |
| Length of stay, median (25th to75th percentile) days | 5 (2 to 9) | 3 (2 to5) | <0.001 | 4 (3 to 7) | <0.001 |
| Mortality, number (%) | 226 (11) | 938 (10) | 0.49 | 6523 (22) | <0.001 |
P values were calculated from unadjusted logistic regression and negative binomial regression (length of stay) models.
*Compared to COVID-19.
Incidence of cardiac disease
The median (25th to 75th percentile) follow-up time was 152 (46 to 274) days for patients with COVID-19, 274 (43 to 274) days for patients with viral pneumonia and 274 (234 to 274) days with bacterial pneumonia. The incidence rate of new-onset cardiac disease was 57.6 (95% CI 49.5 to 67.1) per 100 000 person-days for COVID-19, 75.2 (71.2 to 79.4) for viral pneumonia and 102.9 (100.1 to 105.8) for bacterial pneumonia (figure 1; table 2).
Enlarge this image.Figure 1. Incidence of new-onset cardiac disease during 9 months of follow-up in patients hospitalised with COVID-19, viral or bacterial pneumonia, per 100 000 person-days. The bars represent the incidence rate and the lines the corresponding 95% CI.
Cardiac events and cardiac procedures following hospitalisation for COVID-19, viral pneumonia and bacterial pneumonia during 274 days (9 months) of follow-up from admission
| COVID-19 (n=2082) | Viral pneumonia (n=9018) | Bacterial pneumonia (n=29 339) | ||||
| No. (%) | Incidence (95% CI) | No. (%) | Incidence (95% CI) | No. (%) | Incidence (95% CI) | |
| New-onset cardiac disease | ||||||
| Total cardiac disease | 165 (8) | 57.6 (49.5 to 67.1) | 1204 (13) | 75.2 (71.2 to 79.4) | 4596 (16) | 102.6 (99.8 to 105.5) |
| Heart failure | 30 (1) | 9.2 (6.4 to 13.1) | 425 (5) | 20.2 (18.3 to 22.2) | 1950 (7) | 32.2 (30.8 to 33.7) |
| Acute myocardial infarction | 16 (0.8) | 4.8 (3.0 to 7.9) | 153 (2) | 6.7 (5.8 to 7.9) | 696 (2) | 10.6 (9.8 to 11.4) |
| Atrial fibrillation/flutter | 74 (4) | 23.9 (19.0 to 30.0) | 501 (6) | 25.2 (23.1 to 27.5) | 1953 (7) | 34.1 (32.7 to 35.7) |
| Ischaemic disease | 22 (1) | 6.8 (4.5 to 10.3) | 159 (2) | 7.4 (6.3 to 8.6) | 538 (2) | 8.5 (7.8 to 9.2) |
| Myocarditis | 5 (0.2) | 1.5 (0.6 to 3.6) | 10 (0.1) | 0.4 (0.2 to 0.8) | 28 (0.1) | 0.42 (0.3 to 0.6) |
| Other cardiac disease | 125 (6) | 42.7 (35.8 to 50.1) | 636 (7) | 34.9 (32.3 to 37.8) | 2606 (9) | 50.9 (48.9 to 52.8) |
| Recurrent cardiac disease | ||||||
| Total cardiac disease | 344 (16) | 120.1 (108.1 to 133.5) | 2725 (30) | 156.8 (151.0 to 162.8) | 9999 (34) | 204.5 (200.5 to 208.6) |
| Heart failure | 72 (3) | 22.0 (17.5 to 27.7) | 1032 (11) | 49.0 (46.1 to 52.1) | 4104 (14) | 67.8 (65.7 to 69.9) |
| Acute myocardial infarction | 20 (1) | 3.9 (3.9 to 9.3) | 223 (3) | 9.9 (5.0 to 10.6) | 951 (3) | 14.4 (13.5 to 15.4) |
| Atrial fibrillation/flutter | 171 (8) | 55.1 (47.5 to 64.1) | 1466 (16) | 73.8 (70.1 to 77.6) | 5398 (18) | 94.4 (91.9 to 96.9) |
| Ischaemic disease | 87 (4) | 26.8 (21.7 to 33.1) | 752 (8) | 35.0 (32.6 to 37.6) | 2262 (8) | 35.7 (34.3 to 37.2) |
| Myocarditis | 5 (0.2) | 1.5 (0.6 to 3.6) | 13 (0.1) | 0.6 (0.3 to 1.0) | 31 (0.1) | 0.5 (0.3 to 0.7) |
| Other cardiac diseases | 296 (14) | 101.0 (90.2 to 113.2) | 2352 (26) | 129.2 (124.1 to 134.6) | 8828 (30) | 172.3 (168.7 to 175.9) |
| Cardiac procedures | ||||||
| Echocardiography | 314 (15) | 109.1 (97.8 to 122.1) | 1411 (16) | 69.0 (65.5 to 72.7) | 5515 (19) | 95.8 (93.3 to 98.3) |
| Coronary angiography | 24 (1) | 7.2 (4.8 to 10.8) | 198 (2) | 8.7 (7.6 to 10.0) | 494 (2) | 7.4 (6.8 to 8.1) |
AF and other cardiac diseases were the most frequent cardiac events in all three groups. In total, 165 (8%) patients had one or more new-onset cardiac diseases in the COVID-19 group, compared with 1204 (14%) after viral pneumonia, and 4596 (16%) after bacterial pneumonia.
Risk of cardiac disease
In multivariable proportional hazards regression analysis, the hazard of new-onset cardiac disease was lower in COVID-19 than in both viral pneumonia (HR 0.79 [95% CI 0.66 to 0.93], p=0.006) and bacterial pneumonia (0.66 [ 0.57 to 0.78], p<0.001). The hazard of new-onset HF was lower in COVID-19 vs viral pneumonia (0.53 [CI 0.36 to 0.78], p=0.001) and bacterial pneumonia (0.38 [0.27 to 0.54], p<0.001). There were no differences in the hazard of developing new-onset myocarditis, AMI, AF, IHD or other cardiac diseases between patients with COVID-19 and viral pneumonia. Patients with COVID-19 had a lower hazard of AMI (HR 0.54 [95% CI 0.33 to 0.90], p=0.017), AF (0.73 [0.58 to 0.93], p=0.010) and other cardiac disease (0.81 [0.67 to 0.98], p=0.028) compared with patients with bacterial pneumonia (table 3). The results were similar, but less pronounced when recurrent cardiac disease was compared (online supplemental table 3)
Table 3Hazard of incident new-onset cardiac disease in patients hospitalised with COVID-19 vs viral pneumonia and bacterial pneumonia
| COVID-19 (n=2082) vs viral pneumonia* (n=9018) | COVID-19 (n=2082) vs bacterial pneumonia* (n=29 339) | |||
| Hazard ratio (95% CI) | P value | Hazard ratio (95% CI) | P value | |
| Total cardiac disease | 0.79 (0.66 to 0.93) | 0.006 | 0.66 (0.57 to 0.78) | <0.001 |
| Heart failure | 0.53 (0.36 to 0.78) | 0.001 | 0.38 (0.27 to 0.54) | <0.001 |
| Myocardial infarction | 0.67 (0.40 to 1.14) | 0.15 | 0.54 (0.33 to 0.90) | 0.017 |
| Atrial fibrillation/flutter | 0.88 (0.67 to 1.14) | 0.33 | 0.73 (0.58 to 0.93) | 0.010 |
| Ischaemic cardiac disease | 0.90 (0.56 to 1.46) | 0.69 | 0.82 (0.53 to 1.29) | 0.40 |
| Myocarditis | 1.86 (0.57 to 6.0) | 0.30 | 2.03 (0.75 to 5.5) | 0.16 |
| Other cardiac diseases | 1.09 (0.88 to 1.34) | 0.40 | 0.81 (0.67 to 0.98) | 0.028 |
All models were adjusted for age, sex, number of admissions to the hospital the year prior to index hospitalisation, respiratory support and comorbidities (acute myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic obstructive pulmonary disease, rheumatoid disease, renal disease, liver disease, diabetes and cancer).
*Reference category.
Comparison of echocardiography and coronary angiography procedures
During follow-up, 15% of patients with COVID-19, 16% with viral pneumonia and 19% with bacterial pneumonia underwent echocardiography (table 2). In adjusted analysis, the odds of having echocardiography for patients with COVID-19 were comparable to those with viral pneumonia (OR 0.99 [95% CI 0.85 to 1.14], p=0.86), while the odds were lower in COVID-19 than for those with bacterial pneumonia (0.81 [0.72 to 0.93], p=0.003) (table 4).
Table 4Adjusted OR of undergoing echocardiography or cardiac angiography within 274 days in patients hospitalised with COVID-19 vs viral pneumonia and bacterial pneumonia
| COVID-19 (n=2082) vs viral pneumonia* (n=9018) | COVID-19 (n=2082) vs bacterial pneumonia* (n=29 339) | |||
| Odds ratio (95% CI) | P value | Odds ratio (95% CI) | P value | |
| Echocardiography | 0.99 (0.85 to 1.14) | 0.86 | 0.81 (0.72 to 0.93) | 0.003 |
| Coronary angiography | 0.52 (0.33 to 0.81) | 0.004 | 0.66 (0.43 to 1.01) | 0.06 |
All models adjusted for age, sex, number of admissions to the hospital the year prior to index hospitalisation, respiratory support and comorbidities (acute myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic obstructive pulmonary disease, rheumatoid disease, renal disease, liver disease, diabetes and cancer.
*Reference category.
During follow-up, 1.2% of patients with COVID-19, 2.2% of patients with viral pneumonia and 1.7% of patients with bacterial pneumonia underwent coronary angiography. In adjusted analysis, patients with COVID-19 had lower odds of having coronary angiography compared with viral pneumonia (OR 0.52 [95% CI 0.33 to 0.81], p=0.004), but not bacterial pneumonia (0.66 [0.43 to 1.01], p=0.06) (table 4).
Sensitivity analyses
The results were similar when stratifying patients above and below 70 years of age and by sex. Limiting the follow-up time to 90 days resulted in a median (25th to 75th percentile) follow-up of 90 [36 to 90] days for patients with COVID-19, 90 [42 to 90] days for viral and 90 [4 to 90] days for bacterial pneumonia and did not alter the results regarding the risk of total cardiac disease or the odds of echocardiography (online supplemental table 4). In this model, there was no difference in the number of coronary angiographies between patients with COVID-19 and those with viral pneumonia (HR 0.87 [95% CI 0.48 to 1.57]. When excluding the first 30 days after hospital admission in the analysis, the HR for new-onset cardiac disease for COVID-19 compared with viral pneumonia was 1.13 (95% CI 0.79 to 1.58) and 1.00 (0.72 to 1.38) when compared with bacterial pneumonia (online supplemental table 5).
Adjusting for a propensity score did not change the results significantly for COVID-19 compared with viral pneumonia or bacterial pneumonia. When analysing death as a competing risk, the sub-HR of total cardiac disease in COVID-19 was significantly lower for cardiac disease compared with viral and bacterial pneumonia (online supplemental table 6).
Discussion
In this observational nationwide register study, we compared new-onset cardiac disease for patients hospitalised for COVID-19 during the first two waves with patients hospitalised for viral or bacterial pneumonia in 2018–2019. The main finding was that patients hospitalised for COVID-19 had a lower hazard of new-onset HF and aggregated cardiac disease during 9 months of follow-up than patients hospitalised for viral or bacterial pneumonia. The hazard of MI and AF following COVID-19 was similar to other viral pneumonias but lower than for bacterial pneumonias.
In the present study, the crude incidence rate of total cardiac disease was highest for bacterial pneumonia, followed by viral pneumonia, and lowest for COVID-19. The incidence rate for cardiac disease in COVID-19 was slightly higher than reported in some previous studies.20–22 This may be explained by differences in the baseline risk of the population, definition of outcome variables, and analytical methods. Our cohort included a large proportion of patients treated with respiratory support, which is indicative of severe pneumonia. The event rates during the first 30 days in the present study were similar to other studies of viral or bacterial pneumonias.23
In multivariable Cox regression analyses, we found that hospitalisation with COVID-19 was associated with a lower hazard of total cardiac disease compared with viral or bacterial pneumonias. This supports a previous comparison between patients hospitalised for COVID-19 and pneumonia in general.21 Conversely, certain previous studies have shown an increased risk of cardiac disease following hospitalisation with COVID-199 20 24–26 compared with undifferentiated hospitalised patients. The association between community-acquired pneumonia and cardiac disease is well-established, and it is not surprising that this association is also valid for COVID-19.
For specific cardiac outcomes, we found a similar risk of AMI compared with other viral pneumonias but lower than for bacterial pneumonias. This aligns with a prior study that compared COVID-19 to other types of pneumonia21 and is consistent with earlier research that demonstrated a greater risk of AMI after COVID-19,10 22 but still lower than the risk following community-acquired pneumonia.22
HF is associated with both community-acquired pneumonia4 and COVID-19.9 However, in the present study, the risk was lower in COVID-19 compared with both viral and bacterial pneumonias.
Viral infections are a major cause of myocarditis,27 although this is a rather rare event. In the present study, the hazard of myocarditis was higher in COVID-19 compared with other viral or bacterial pneumonias, but the number of events was small. This finding supports a previous study where myocarditis was the only diagnosis with higher prevalence rates in COVID-19 than in other pneumonias.21
Patients with COVID-19 had similar procedure rates as those with other viral pneumonia and lower rates of echocardiography compared with bacterial pneumonia. Furthermore, they had lower rates of coronary angiography compared with both viral and bacterial pneumonias. With the seemingly profound emphasis on cardiovascular complications from COVID-19 during the pandemic and studies showing increased venous and arterial thrombotic tendency,28 29 this finding might be somewhat unexpected. However, it is possible that the number of procedures following COVID-19 was reduced due to infection control measures or reduced capacity during the pandemic.30 We are not aware of other comparisons of the number of procedures following COVID-19 compared with other pneumonias.
Patients with COVID-19 in this study were included before vaccination became available. This could perhaps explain why we found a higher incidence of cardiac disease compared with newer studies. Considering the observed decrease in the rate of cardiac complications following influenza after vaccination,31 further investigations are warranted to ascertain if this phenomenon also extends to COVID-19.
The registry data in this study represents a national cohort of all patients hospitalised for COVID-19, viral or bacterial pneumonias during the respective periods, which strengthens the external validity of the findings. Since events caused by COVID-19 may be better represented by excluding previously diagnosed cardiac disease, we focused on new-onset events in this study. We also conducted several sensitivity analyses, with different follow-up times to account for differences between the pneumonia groups, as well as a competing risk analysis, which supported the findings in the main analysis.
The patients were selected from a registry based on ICD-10 codes; therefore, some patients may have been misclassified. In addition, all patients with COVID-19 had a PCR-verified disease. Because we included patients with COVID-19 from the start of the pandemic, when there was widespread uncertainty about COVID-19, its treatment, prognosis and available hospital capacity, it is possible that the threshold for admitting patients with COVID-19 was lower than for other viral or bacterial pneumonias during the preceding 2 years. In this study, COVID-19 was not necessarily the main diagnosis for those in the COVID-19 group during the hospital stay, unlike viral and bacterial pneumonia. This could have resulted in these groups representing patients with more severe disease than the COVID-19 patients and therefore more susceptible to cardiac complications. We did not have a variable for grading severity, such as clinical measurements during hospitalisation. However, our study indicates that COVID-19 cases had both higher mortality rates and increased use of respiratory support, which may indicate that they were more severely ill. COVID-19 encompasses a wide range of disease entities, ranging from upper respiratory tract infection to ARDS. In the present study, we assume that most patients with COVID-19 were hospitalised for hypoxia, suggesting pneumonia. Therefore, we think patients hospitalised with other pneumonias represent feasible comparison groups. Despite the large number of patients included in our study, the number of cardiac disease events was rather low, especially for myocarditis (n=43), limiting the statistical power of some analyses. In a registry study with a limited number of measurements, and despite adjusting for all relevant covariates such as age and co-morbidity, there will always be a risk of residual confounding.
The risk of cardiac diseases, such as MI or HF exacerbation, is highest shortly after infection.5 26 Therefore, we did not exclude the first 30 days of follow-up from the analysis, like other studies have done,21 but rather performed a sensitivity analysis before and after 30 days, which showed similar results.
Previous studies demonstrating an increased risk of cardiac disease following hospitalisation with COVID-19 have primarily used comparison groups comprising patients hospitalised for causes other than pulmonary infections.9 24–26 In the present study, the risk of cardiac disease following COVID-19 was similar to or lower than those of pneumonias from other viral or bacterial causes. Since this was a registry study with the inherent limitations of such studies, one should be cautious about concluding that there is a weaker association between COVID-19 and heart disease compared with other pneumonias. However, our results suggest that the concern that COVID-19 would lead to significantly more cardiac disease than other similar conditions does not seem to be true. Based on our findings, we do not believe COVID-19 infections warrant additional follow-up and testing to detect cardiac disease, compared with other pneumonias.
Conclusion
In this nationwide register-based study, hospitalisation for COVID-19 was associated with a lower risk of aggregate cardiac disease compared with hospitalisation for other viral or bacterial pneumonias. Additionally, patients with COVID-19 underwent echocardiography at similar rates but had fewer angiography procedures compared with those with other types of pneumonias. These analyses were adjusted for multiple possible confounders. However, it is still possible that there is residual confounding from measurement error, unmeasured or unknown risk factors.
Data availability statement
Data are available upon reasonable request. The data supporting the findings of this study are available on request to the corresponding author. The data are not publicly accessible due to privacy or ethical restrictions.
Ethics statements
Patient consent for publication
Not applicable.
Ethics approval
This study involves human participants and was approved by the Regional Ethics Committee (REK) South-Eastern Norway approved this study (2020/149384). Retrospective registry study.
Contributors BT and KS were responsible for the initial data collection. All authors have been involved in the conceptualisation of the article. TØ had the main responsibility of analysing the data and drafting the article with support from KS. All authors contributed to revision/editing and have approved the final version. KS is the guarantor of the research.
Funding This study was funded by Akershus University Hospital.
Competing interests KS has received consulting fees from UCB Pharma and MSD unrelated to this study. KB reports consulting fees from Boehringer Ingelheim. PLM has served on advisory boards and/or received speaker fees from Amarin, AmGen, AstraZeneca, Bayer, Boehringer Ingelheim, Novartis, Novo Nordisk, Pharmacosmos, Vifor and Us2.ai, unrelated to this work. All other authors report no conflicts of interest.
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Details
; Tholin, Birgitte 2
; Berge, Kristian 1
; Peder Langeland Myhre 1
; Stavem, Knut 3
1 Department of Cardiology, Division of Medicine, Akershus University Hospital, Lørenskog, Norway; University of Oslo, Oslo, Norway
2 University of Oslo, Oslo, Norway; Østfold Hospital Kalnes, Grålum, Norway
3 University of Oslo, Oslo, Norway; Department of Pulmonary Medicine, Akershus University Hospital, Lørenskog, Norway; Health Services Research Unit, Akershus University Hospital, Lørenskog, Norway