2022 Volume 86 Issue 3 Pages 464-471
Background: Cardiovascular complications of coronavirus disease 2019 (COVID-19) are critical for prognosis but have not been elucidated in Japan.
Methods and Results: The COVID-19 Registry Japan, which included data from 19,853 individuals at the end of 2020, was analyzed. The incidences of cardiovascular complications were 0.098% for myocarditis/pericarditis/cardiomyopathy, 0.48% for ventricular tachycardia/fibrillation, 0.17% for myocardial ischemia, 0.062% for endocarditis, 0.59% for deep vein thrombosis, 0.19% for pulmonary embolism, and 0.37% for cerebral infarction/hemorrhage. Excluding endocarditis, all complications were associated with increased in-hospital mortality.
Conclusions: Cardiovascular complications of COVID-19 were infrequent in Japan but were associated with poor prognosis.
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has extended worldwide.1 The most common symptom cluster involves the respiratory system: cough, sputum, shortness of breath, and fever. Musculoskeletal symptoms, including myalgia, arthralgia, headache, and fatigue, can also occur, as well as enteric symptoms such as abdominal pain, vomiting, diarrhea, and mucocutaneous symptoms. Cardiovascular complications are not rare and are critical prognostic factors.2
The first case of COVID-19 in Japan was reported in January 2020. Case numbers increased with time, and a nationwide COVID-19 inpatient registry, the “COVID-19 Registry Japan” (COVIREGI-JP), was established on March 2, 2020.3 Clinical epidemiological characteristics of COVID-19 inpatients in Japan have been reported using data from COVIREGI-JP.4,5 In the present study, we investigated the cardiovascular complications of COVID-19 in hospitalized patients in Japan by analyzing the data from the COVIREGI-JP.
This retrospective observational study enrolled patients from healthcare facilities that participated in the COVIREGI-JP. The inclusion criteria for enrollment were: (1) positive SARS-CoV-2 test and (2) inpatient treatment at a healthcare facility. Data from the COVIREGI-JP were used with permission for the analysis of baseline characteristics, comorbidities, cardiovascular complications, and prognosis.
Data CollectionThe research team of the COVIREGI-JP project modified the case report form of the International Severe Acute Respiratory and Emerging Infection Consortium for the collection of clinical epidemiological and treatment data.6 The study data were collected and managed using Research Electronic Data Capture, a web-based data-capture application hosted at the Joint Center for Researchers, Associates, and Clinicians Data Center of the National Center for Global Health and Medicine.7
Baseline CharacteristicsData on baseline characteristics, including age, sex, ethnicity, body temperature, body weight, height, systolic and diastolic blood pressure, heart rate, respiratory rate, and oxygen saturation, were collected. The first data obtained within 24 h of hospitalization were used.
Cardiovascular ComplicationsCardiovascular complications were predetermined by the research team of the COVIREGI-JP project and included myocarditis, pericarditis, cardiomyopathy, ventricular tachycardia/fibrillation (VT/VF), myocardial ischemia, endocarditis, deep vein thrombosis (DVT), pulmonary embolism (PE), and cerebral infarction/hemorrhage.
ComorbiditiesMedical doctors diagnosed old myocardial infarction (OMI) and congestive heart failure (CHF). Peripheral arterial disease (PAD) included intermittent claudication, post-bypass surgery, necrosis, and aortic aneurysm. Cerebrovascular disease (CVD) included a history of CVD without symptoms or transient ischemic attack. Hemiparesis included paresis without CVD, such as paraplegia. Chronic respiratory disease involved dyspnea caused by light exercise, excluding chronic obstructive pulmonary disease (COPD). Mild liver disease included chronic hepatitis or mild liver cirrhosis without portal hypertension. Moderate-to-severe liver dysfunction included liver cirrhosis and portal hypertension. Mild diabetes mellitus (DM) included DM without the 3 major complications (retinopathy, nephropathy, and neuropathy), excluding DM requiring diet therapy only. Severe DM included at least 1 of the 3 major complications. Moderate-to-severe renal dysfunction involved creatinine level ≥3 mg/dL and requiring treatment with hemodialysis or peritoneal dialysis. Solid cancer excluded metastasis at >5 years after diagnosis. Leukemia included acute and chronic leukemia and polycythemia vera. Lymphoma included lymphosarcoma, macroglobulinemia, and multiple myeloma. Acquired immunodeficiency syndrome was caused by human immunodeficiency virus, with a CD4 count <200/µL.
Supportive care included intensive care unit (ICU) admission, oxygen therapy (cannula, mask, and reservoir) or oxygen therapy (high-flow nasal cannula), non-invasive respiratory support (bilevel positive airway pressure and continuous positive airway pressure), invasive mechanical ventilation, prone position, nitric oxide inhalation, tracheostomy, extracorporeal membrane oxygenation, cardiac stimulant/vasoconstrictor administration, renal replacement therapy/hemodialysis, plasmapheresis/plasma exchange, transfusion/blood products, and intravenous immunoglobulin.
Dispositions included in-hospital death, discharge to home, transfer to other hospitals, isolation in a healthcare facility, and nursing home care.
DatasetWe used data from cases including the following items as of December 31, 2020: demographic and epidemiological characteristics, vital signs, comorbidities at admission, supportive care, outcome at discharge, and in-hospital cardiovascular complications.
Statistical AnalysisCategorical variables were compared between the yes and no/null/unknown groups using the chi-square test. Continuous variables are expressed as medians and interquartile ranges and were compared between groups using the Kruskal-Wallis test. All statistical analyses were performed using R version 3.5.1 (R Foundation for Statistical Computing, Vienna, Austria) and SAS version 9.4 (SAS Institute, Cary, NC, USA).
EthicsThis study was approved by the National Center for Global Health and Medicine Ethics Review Board (NCGM-G-004037-01), and the requirement for informed consent was waived. The procedures followed were in accordance with the Declaration of Helsinki.
Data on 19,853 cases from 471 facilities (university, public, and private hospitals) were included in the analysis. Additionally, secondary and tertiary emergency care centers and non-emergency institutes (e.g., cancer centers, rehabilitation centers for muscular dystrophy, psychiatric hospitals) were included. Both critically ill patients and those exhibiting mild or no symptoms were registered. The available number of cases differed between parameters because of missing data.
The median age of patients was 53.0 years (Table 1). The median age of patients with the following cardiovascular complications was significantly higher in the yes group than in the no/null/unknown group: VT/VF (73.0 years, P<0.0001), myocardial ischemia (70.0 years, P<0.0001), DVT (70.0 years, P<0.0001), PE (64.5 years, P=0.0074), and cerebral infarction/hemorrhage (78.5 years, P<0.0001). Less than half of the patients were women (41.8%). The majority of patients were Japanese (95.2%); ethnicity did not show a statistically significant association with any cardiovascular complication because of the low incidence rate and small number of non-Japanese patients.
| Baseline characteristics | All registries (n=19,853) |
Myocarditis/pericarditis/ cardiomyopathy (n=19) |
VT/VF (n=92) |
Myocardial ischemia (n=33) |
Endocarditis (n=12) |
DVT (n=114) |
PE (n=36) |
Cerebral infarction/ hemorrhage (n=72) |
|---|---|---|---|---|---|---|---|---|
| Age, years; median (IQR) | 53.0 (34.0–70.0) | 64.0 (42.0–75.0) | 73.0 (64.0–79.5)†† | 70.0 (63.0–82.0)†† | 58.5 (50.0–71.5) | 70.0 (59.0–82.0)†† | 64.5 (52.0–72.5)** | 78.5 (66.5–84.5)†† |
| <50, n (%) | 8,610 (43.4%) | 5 (0.1%) | 6 (0.1%) | 2 (0.0%) | 3 (0.0%) | 9 (0.1%) | 8 (0.1%) | 4 (0.0%) |
| 50–59, n (%) | 3,111 (15.7%) | 2 (0.1%) | 12 (0.4%) | 4 (0.1%) | 3 (0.1%) | 20 (0.7%) | 7 (0.2%) | 6 (0.2%) |
| 60–69, n (%) | 2,521 (12.7%) | 4 (0.2%) | 17 (0.7%) | 9 (0.3%) | 2 (0.1%) | 27 (1.1%) | 9 (0.4%) | 14 (0.5%) |
| 70–79, n (%) | 2,649 (13.3%) | 6 (0.2%) | 34 (1.3%) | 8 (0.3%) | 4 (0.2%) | 19 (0.8%) | 5 (0.2%) | 18 (0.7%) |
| ≥80, n (%) | 2,412 (12.1%) | 2 (0.1%) | 23 (1.0%) | 10 (0.4%) | 0 (0.0%) | 39 (1.7%) | 7 (0.3%) | 30 (1.3%) |
| Sex: female, n (%) | 8,303 (41.8%) | 5 (26.3%) | 24 (26.1%)** | 10 (30.3%) | 3 (25.0%) | 44 (38.6%) | 10 (27.8%) | 32 (44.4%) |
| Ethnicity: Japanese, n (%) | 18,843 (95.2%) | 17 (94.4%) | 91 (98.9%) | 33 (100.0%) | 12 (100.0%) | 109 (97.3%) | 33 (91.7%) | 68 (94.4%) |
| Physical status | ||||||||
| Body weight, kg; median (IQR) | 63.0 (52.2–74.0) | 70.5 (56.7–78.0) | 65.0 (55.5–72.8) | 57.1 (49.7–66.9) | 68.0 (55.5–85.7) | 65.0 (53.0–75.0) | 71.0 (65.0–75.9)** | 55.2 (50.0–67.7)* |
| Height, cm; median (IQR) | 164.5 (156.0–171.0) | 167.0 (161.0–170.0) | 165.1 (160.0–170.0) | 163.4 (155.0–168.0) | 166.0 (156.5–173.0) | 162.5 (155.0–169.0) | 168.0 (160.0–173.5) | 160.0 (153.0–165.5)† |
| Body temperature, ℃; median (IQR) | 36.9 (36.5–37.5) | 37.6 (36.5–38.3) | 37.2 (36.6–37.9)* | 37.3 (36.9–38.0)* | 37.0 (36.4–37.7) | 37.2 (36.5–38.2)* | 38.0 (37.0–38.8)†† | 37.1 (36.6–37.5) |
| Systolic BP, mmHg; median (IQR) | 126.0 (113.0–140.0) | 129.5 (113.0–141.0) | 128.0 (112.0–142.0) | 127.0 (109.5–145.0) | 119.0 (110.5–136.5) | 130.0 (116.0–142.0) | 125.0 (114.0–142.0) | 132.5 (118.5–150.0)** |
| Diastolic BP, mmHg; median (IQR) | 79.0 (70.0–88.0) | 74.0 (68.0–89.0) | 73.0 (65.0–88.0)** | 74.0 (66.5–89.0) | 73.0 (69.0–83.5) | 76.0 (67.0–86.0) | 77.0 (64.0–83.0) | 77.5 (66.5–89.5) |
| Heart rate; median (IQR) | 85.0 (75.0–96.0) | 82.5 (76.0–102.0) | 87.5 (77.0–101.0) | 86.5 (71.5–98.5) | 85.5 (77.5–111.0) | 82.5 (74.0–95.5) | 89.0 (80.0–102.0) | 86.0 (73.0–100.0) |
| Respiratory rate; median (IQR) | 18.0 (16.0–20.0) | 20.0 (18.0–26.0)** | 20.0 (18.0–26.0)†† | 23.5 (18.5–27.5)†† | 23.0 (16.0–32.0)* | 18.0 (16.0–22.0) | 20.0 (17.0–24.0)* | 20.0 (16.0–24.0)* |
| SpO2, %; median (IQR) | 97.0 (96.0–98.0) | 96.0 (95.0–98.0) | 95.0 (93.0–97.0)†† | 94.5 (92.5–97.0)† | 96.5 (94.5–98.0) | 95.0 (93.0–98.0)†† | 96.0 (91.5–98.0)** | 96.0 (92.0–98.0)†† |
Significant differences are shown as *P<0.05, **P<0.01, †P<0.001, ††P<0.0001. BP, blood pressure; DVT, deep vein thrombosis; IQR, interquartile range; PE, pulmonary embolism; SpO2, oxygen saturation; VT/VF, ventricular tachycardia/fibrillation.
Myocarditis/pericarditis/cardiomyopathy occurred at a rate of 0.098% (Supplementary Table A) and was significantly associated with a high respiratory rate (P=0.0030), CHF (P=0.0001), mild DM (P=0.0012), metastatic tumor (P<0.0001), and collagen disease (P<0.0001) (Table 2). Except for plasmapheresis/plasma exchange, the rate of supportive care for myocarditis/pericarditis/cardiomyopathy was significantly higher in the yes group than in the no/null/unknown group, as was the mortality rate (26.3%, P<0.0001) (Table 3).
| Comorbidities | All registries (n=19,853) |
Myocarditis/pericarditis/ cardiomyopathy (n=19) |
VT/VF (n=92) |
Myocardial ischemia (n=33) |
Endocarditis (n=12) |
DVT (n=114) |
PE (n=36) |
Cerebral infarction/ hemorrhage (n=72) |
|---|---|---|---|---|---|---|---|---|
| OMI | 326 (1.6%) | 0 (0.0%) | 7 (7.6%)†† | 7 (21.2%)†† | 0 (0.0%) | 2 (1.8%) | 0 (0.0%) | 8 (11.1%)†† |
| CHF | 472 (2.4%) | 3 (15.8%)† | 14 (15.2%)†† | 4 (12.1%)† | 1 (8.3%) | 9 (7.9%)†† | 1 (2.8%) | 8 (11.1%)†† |
| PAD | 222 (1.1%) | 1 (5.3%) | 3 (3.3%) | 1 (3.0%) | 0 (0.0%) | 5 (4.4%)† | 1 (2.8%) | 1 (1.4%) |
| CVD | 1,022 (5.1%) | 1 (5.3%) | 13 (14.1%)†† | 5 (15.2%)** | 0 (0.0%) | 10 (8.8%) | 1 (2.8%) | 27 (37.5%)†† |
| Hemiparesis | 227 (1.1%) | 0 (0.0%) | 4 (4.3%)** | 1 (3.0%) | 0 (0.0%) | 2 (1.8%) | 1 (2.8%) | 6 (8.3%)†† |
| Dementia | 1,185 (6.0%) | 0 (0.0%) | 9 (9.8%) | 5 (15.2%)* | 0 (0.0%) | 13 (11.4%)** | 3 (8.3%) | 16 (22.2%)†† |
| COPD | 393 (2.0%) | 0 (0.0%) | 4 (4.3%) | 0 (0.0%) | 0 (0.0%) | 5 (4.4%) | 2 (5.6%) | 5 (6.9%)** |
| Chronic respiratory disease other than COPD | 275 (1.4%) | 0 (0.0%) | 3 (3.3%) | 1 (3.0%) | 0 (0.0%) | 4 (3.5%) | 1 (2.8%) | 7 (9.7%)†† |
| Bronchial asthma | 966 (4.9%) | 0 (0.0%) | 6 (6.5%) | 2 (6.1%) | 0 (0.0%) | 5 (4.4%) | 2 (5.6%) | 4 (5.6%) |
| Mild liver disease | 367 (1.8%) | 0 (0.0%) | 4 (4.3%) | 1 (3.0%) | 0 (0.0%) | 3 (2.6%) | 0 (0.0%) | 2 (2.8%) |
| Moderate-to-severe liver dysfunction | 53 (0.3%) | 0 (0.0%) | 1 (1.1%) | 1 (3.0%)** | 0 (0.0%) | 1 (0.9%) | 0 (0.0%) | 0 (0.0%) |
| Peptic ulcer | 146 (0.7%) | 0 (0.0%) | 2 (2.2%) | 0 (0.0%) | 1 (8.3%)** | 1 (0.9%) | 0 (0.0%) | 2 (2.8%)* |
| Hypertension | 4,770 (24.0%) | 6 (31.6%) | 47 (51.1%)†† | 10 (30.3%) | 4 (33.3%) | 56 (49.1%)†† | 9 (25.0%) | 30 (41.7%)† |
| Dyslipidemia | 2,323 (11.7%) | 4 (21.1%) | 21 (22.8%)† | 7 (21.2%) | 1 (8.3%) | 28 (24.6%)†† | 11 (30.6%)† | 11 (15.3%) |
| Mild DM | 2,458 (12.4%) | 7 (36.8%)** | 24 (26.1%)†† | 5 (15.2%) | 3 (25.0%) | 24 (21.1%)** | 8 (22.2%) | 20 (27.8%)†† |
| Severe DM | 380 (1.9%) | 0 (0.0%) | 6 (6.5%)** | 3 (9.1%)* | 1 (8.3%) | 5 (4.4%) | 2 (5.6%) | 2 (2.8%) |
| Obesity | 1,070 (5.4%) | 2 (10.5%) | 8 (8.7%) | 2 (6.1%) | 1 (8.3%) | 13 (11.4%)** | 3 (8.3%) | 3 (4.2%) |
| Moderate-to-severe renal dysfunction | 225 (1.1%) | 0 (0.0%) | 8 (8.7%)†† | 1 (3.0%) | 1 (8.3%)* | 1 (0.9%) | 1 (2.8%) | 1 (1.4%) |
| Hemodialysis | 124 (0.6%) | 0 (0.0%) | 4 (4.3%)†† | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Peritoneal dialysis | 7 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 1 (1.4%)†† |
| Solid cancer | 537 (2.7%) | 0 (0.0%) | 11 (12.0%)†† | 3 (9.1%)* | 0 (0.0%) | 6 (5.3%) | 0 (0.0%) | 6 (8.3%)** |
| Leukemia | 48 (0.2%) | 0 (0.0%) | 2 (2.2%)† | 1 (3.0%)** | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Lymphoma | 77 (0.4%) | 0 (0.0%) | 1 (1.1%) | 1 (3.0%)* | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Metastatic cancer | 160 (0.8%) | 2 (10.5%)†† | 3 (3.3%)** | 2 (6.1%)† | 0 (0.0%) | 2 (1.8%) | 0 (0.0%) | 1 (1.4%) |
| Collagen disease | 216 (1.1%) | 2 (10.5%)†† | 2 (2.2%) | 2 (6.1%)** | 0 (0.0%) | 3 (2.6%) | 2 (5.6%)** | 2 (2.8%) |
| HIV infection | 38 (0.2%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| AIDS | 4 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Congenital heart disease | 24 (0.1%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
| Congenital malformations | 18 (0.1%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) | 0 (0.0%) |
Significant differences are shown as *P<0.05, **P<0.01, †P<0.001, ††P<0.0001. AIDS, acquired immunodeficiency syndrome; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CVD, cerebrovascular disease; DM, diabetes mellitus; HIV, human immunodeficiency virus; OMI, old myocardial infarction; PAD, peripheral arterial disease. Other abbreviations as in Table 1.
| Supportive care and disposition | All registries (n=19,853) |
Myocarditis/pericarditis/ cardiomyopathy (n=19) |
VT/VF (n=92) |
Myocardial ischemia (n=33) |
Endocarditis (n=12) |
DVT (n=114) |
PE (n=36) |
Cerebral infarction/ hemorrhage (n=72) |
|---|---|---|---|---|---|---|---|---|
| Supportive care | ||||||||
| Intensive care unit, n (%) | 1,357 (7.0%) | 10 (52.6%)†† | 44 (47.8%)†† | 15 (45.5%)†† | 6 (50.0%)†† | 61 (54.0%)†† | 20 (55.6%)†† | 27 (39.1%)†† |
| Oxygen (cannula, mask, and reservoir), n (%) | 5,717 (29.6%) | 15 (78.9%)†† | 75 (81.5%)†† | 27 (81.8%)†† | 8 (66.7%)** | 95 (84.1%)†† | 30 (83.3%)†† | 51 (73.9%)†† |
| Oxygen (high-flow nasal cannula), n (%) | 544 (2.8%) | 2 (10.5%)* | 15 (16.5%)†† | 4 (12.5%)† | 1 (8.3%) | 17 (15.0%)†† | 3 (8.3%)* | 7 (10.1%)† |
| Non-invasive respiratory support (BIPAP, CPAP), n (%) | 308 (1.6%) | 2 (10.5%)** | 12 (13.0%)†† | 6 (18.2%)†† | 3 (25.0%)†† | 13 (11.5%)†† | 2 (5.6%) | 4 (5.8%)** |
| Invasive mechanical ventilation, n (%) | 958 (5.0%) | 8 (42.1%)†† | 41 (44.6%)†† | 15 (45.5%)†† | 4 (33.3%)†† | 51 (45.1%)†† | 19 (52.8%)†† | 26 (37.7%)†† |
| Prone position, n (%) | 321 (2.0%) | 4 (33.3%)†† | 16 (19.8%)†† | 5 (18.5%)†† | 2 (25.0%)†† | 22 (22.7%)†† | 8 (26.7%)†† | 7 (12.3%)†† |
| Nitric oxide inhalation, n (%) | 21 (0.1%) | 1 (8.3%)†† | 3 (3.7%)†† | 0 (0.0%) | 0 (0.0%) | 5 (5.2%)†† | 1 (3.3%)†† | 2 (3.5%)†† |
| Tracheostomy, n (%) | 164 (1.0%) | 1 (8.3%)* | 15 (18.5%)†† | 3 (11.1%)†† | 1 (12.5%)** | 21 (21.6%)†† | 5 (16.7%)†† | 9 (15.8%)†† |
| Muscle relaxants, n (%) | 443 (2.8%) | 4 (33.3%)†† | 20 (27.0%)†† | 8 (32.0%)†† | 2 (25.0%)† | 30 (30.9%)†† | 13 (43.3%)†† | 8 (15.4%)†† |
| Extracorporeal membrane oxygenation, n (%) | 110 (0.6%) | 2 (10.5%)†† | 13 (14.1%)†† | 3 (9.1%)†† | 1 (8.3%)† | 15 (13.3%)†† | 6 (16.7%)†† | 7 (10.1%)†† |
| Cardiac stimulant/vasoconstrictor administration, n (%) | 485 (2.5%) | 7 (36.8%)†† | 33 (35.9%)†† | 15 (45.5%)†† | 4 (33.3%)†† | 31 (27.4%)†† | 11 (30.6%)†† | 17 (24.6%)†† |
| Renal replacement therapy/hemodialysis, n (%) | 237 (1.2%) | 2 (10.5%)† | 16 (17.6%)†† | 6 (18.2%)†† | 3 (25.0%)†† | 12 (10.6%)†† | 7 (19.4%)†† | 6 (8.7%)†† |
| Plasmapheresis/plasma exchange, n (%) | 14 (0.1%) | 0 (0.0%) | 1 (1.1%)† | 0 (0.0%) | 0 (0.0%) | 1 (0.9%)** | 0 (0.0%) | 0 (0.0%) |
| Transfusion/blood products, n (%) | 412 (2.1%) | 5 (26.3%)†† | 29 (31.5%)†† | 12 (36.4%)†† | 2 (16.7%)† | 34 (30.4%)†† | 13 (36.1%)†† | 12 (17.4%)†† |
| Immunoglobulin, n (%) | 169 (0.9%) | 3 (15.8%)†† | 10 (10.9%)†† | 2 (6.1%)** | 1 (8.3%)** | 11 (9.7%)†† | 3 (8.3%)†† | 3 (4.3%)** |
| Disposition | ||||||||
| In-hospital death, n (%) | 761 (4.0%) | 5 (26.3%)†† | 33 (35.9%)†† | 14 (42.4%)†† | 1 (9.1%) | 22 (19.6%)†† | 6 (17.6%)†† | 22 (31.9%)†† |
| Discharge to home, n (%) | 14,661 (76.3%) | 9 (47.4%)** | 26 (28.3%)†† | 8 (24.2%)†† | 6 (54.5%) | 54 (48.2%)†† | 18 (52.9%)** | 7 (10.1%)†† |
| Transfer to other hospitals, n (%) | 2,151 (11.2%) | 4 (21.1%) | 31 (33.7%)†† | 9 (27.3%)** | 4 (36.4%)* | 30 (26.8%)†† | 8 (23.5%)* | 34 (49.3%)†† |
| Isolation in a healthcare facility, n (%) | 1,168 (6.1%) | 1 (5.3%) | 0 (0.0%)* | 1 (3.0%) | 0 (0.0%) | 1 (0.9%)* | 0 (0.0%) | 1 (1.4%) |
| Nursing home care, n (%) | 465 (2.4%) | 0 (0.0%) | 2 (2.2%) | 1 (3.0%) | 0 (0.0%) | 5 (4.5%) | 2 (5.9%) | 5 (7.2%)** |
| Missing data, n | 647 | 0 | 0 | 0 | 1 | 2 | 2 | 3 |
Significant differences are shown as *P<0.05, **P<0.01, †P<0.001, ††P<0.0001. BIPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure. Other abbreviations as in Table 1.
VT/VF showed an incidence of 0.48% (Supplementary Table B) and affected significantly more men than women (73.9%, P=0.0022). VT/VF was associated with an increased body temperature (P=0.0448), decreased diastolic blood pressure (P=0.0098), increased respiratory rate (P<0.0001), and decreased oxygen saturation (P<0.0001) (Table 1), as well as with OMI (P<0.0001), CHF (P<0.0001), CVD (P<0.0001), hemiparesis (P=0.0038), hypertension (P<0.0001), dyslipidemia (P<0.0009), mild DM (P<0.0001), severe DM (P=0.0012), moderate-to-severe renal dysfunction (P<0.0001), hemodialysis (P<0.0001), solid cancer (P<0.0001), leukemia (P=0.0002), and metastatic tumor (P=0.0083) (Table 2). VT/VF was significantly associated with supportive care and had a high mortality rate of 35.9% (P<0.0001) (Table 3).
The incidence of myocardial ischemia (0.17%) increased with age (Table 1). Myocardial ischemia was associated with a high body temperature (P=0.0189), high respiratory rate (P<0.0001), and low oxygen saturation (P=0.0002) (Supplementary Table C), as well as with OMI (P<0.0001), CHF (P=0.0002), CVD (P=0.0092), dementia (P=0.0259), moderate-to-severe liver dysfunction (P=0.0021), severe DM (P=0.0026), solid cancer (P=0.0236), leukemia (P=0.0011), lymphoma (P=0.0145), metastatic tumor (P<0.0007), and collagen disease (P=0.0059) (Table 2). Except for plasmapheresis/plasma exchange, supportive care was more frequently required in patients with myocardial ischemia than in the no/null/unknown group, and the mortality rate of myocardial ischemia (42.4%) was the highest among all cardiovascular complications (P<0.0001) (Table 3).
Endocarditis was rare, occurring at a rate of 0.062% (Supplementary Table D). Endocarditis was associated with an increased respiratory rate (P=0.0170), peptic ulcer (P=0.0021), moderate-to-severe renal dysfunction (P=0.0184), ICU admission (P<0.0001), oxygen therapy (cannula, mask, and reservoir; P=0.0050), non-invasive respiratory support (P<0.0001), invasive mechanical ventilation (P<0.0001), prone position (P<0.0001), tracheostomy (P=0.0012), muscle relaxants (P=0.0001), extracorporeal membrane oxygenation (P=0.0004), cardiac stimulant/vasoconstrictor administration (P<0.0001), renal replacement therapy/hemodialysis (P<0.0001), transfusion/blood products (P=0.0005), and intravenous immunoglobulin (P=0.0056) (Tables 2,3). The mortality rate of endocarditis (9.1%) was not significantly higher than that of other cardiovascular complications or the study population (Table 3).
The incidence of DVT (0.59%) increased with age (Table 1, Supplementary Table E). DVT was associated with a high body temperature (P=0.0255), low oxygen saturation (P<0.0001), and comorbidities such as CHF (P=0.0001), PAD (P=0.0009), dementia (P=0.0140), hypertension (P<0.0001), dyslipidemia (P<0.0001), mild DM (P=0.0048), and obesity (P=0.0043) (Tables 2,3). Patients with DVT required more supportive care and showed a high mortality rate (19.6%, P<0.0001) (Table 3).
The incidence of PE (0.19%) increased with age (Table 1, Supplementary Table F). PE was associated with an increased body weight (P=0.0028), increased body temperature (P<0.0001), increased respiratory rate (P=0.0249), and decreased oxygen saturation (P=0.0026) (Table 1), as well as with dyslipidemia (P=0.0004), collagen disease (P=0.0097), and supportive care, except for plasmapheresis/plasma exchange (Tables 2,3). The mortality rate of PE was high at 17.6% (P<0.0001).
The incidence of cerebral infarction/hemorrhage (0.37%) increased with age (Table 1, Supplementary Table G). Cerebral infarction/hemorrhage was associated with a low body weight (P=0.0193), short height (P=0.0006), high systolic blood pressure (P=0.0064), increased respiratory rate (P=0.0127), and low oxygen saturation (P<0.0001) (Table 1), as well as with OMI (P<0.0001), CHF (P<0.0001), CVD (P<0.0001), hemiparesis (P<0.0001), dementia (P<0.0001), COPD (P=0.0024), other chronic respiratory diseases (P<0.0001), peptic ulcer (P=0.0422), hypertension (P=0.0004), mild DM (P<0.0001), peritoneal dialysis (P<0.0001), and solid cancer (P=0.0032) (Table 2). Patients with cerebral infarction/hemorrhage required more supportive care, except for plasmapheresis/plasma exchange. The mortality rate of cerebral infarction/hemorrhage was high at 31.9% (P<0.0001) (Table 3).
The COVIREGI-JP, which is the largest registry thus far that describes the clinical epidemiological characteristics of hospitalized COVID-19 patients in Japan, includes thousands of COVID-19 inpatients in Japan. Nonetheless, there might have been a selection bias attributable to the manual input of data. The dataset represented 8.4% (19,853/235,908) of confirmed COVID-19 cases in Japan as of December 31, 2020.3 This registration rate was almost the same as that of the CLAVIS-COVID registry supported by the Japanese Circulation Society (9.0%).8 The CLAVIS-COVID registry focused on major acute-care hospitals and analyzed 693 patients. The COVIREGI-JP involved 471 facilities, which were university, public, and private hospitals, including acute-care hospitals. The mean patient age in the CLAVIS-COVID registry was 68 years, which was much higher than the median patient age of 53.0 years in the COVIREGI-JP. The CLAVIS-COVID registry reported data obtained from January 1, 2020, to May 31, 2020 (i.e., the first wave in Japan), whereas in the present study the COVIREGI-JP reported data from January 1, 2020, to December 31, 2020 (i.e., the first, second, and third waves in Japan). This might elucidate why the CLAVIS-COVID registry included more severely infected patients and had a higher in-hospital mortality rate than the COVIREGI-JP (9.2% vs. 4.0%).
Several comorbidities were found to increase with age, including myocardial infarction, CHF, PAD, CVD, hemiparesis, dementia, COPD, other chronic respiratory diseases, hypertension, lipid disorder, DM, and renal dysfunction. In COVID-19 patients, the prevalence of pre-existing hypertension was 29.3% across 15 studies, whereas the prevalence of CVD was 14.6% across 16 studies.9 Increased numbers of comorbidities are associated with higher mortality rates.1,10,11
The frequency of cardiovascular complications in this study was lower than that reported by previous studies. A study in Wuhan, China, reported that 12% of COVID-19 patients were diagnosed with acute myocarditis, as indicated by elevated high-sensitivity troponin (hsTn) I levels.1 Subsequent studies reported acute cardiac injury in 7.2–17% of hospitalized COVID-19 patients.11,12 Troponin levels are associated with age, duration of hospitalization, comorbidities, complications, mechanical ventilation, and death.2,11 In the COVIREGI-JP, hsTn was not routinely measured, and the prevalence of myocarditis/pericarditis/cardiomyopathy was 0.098%. The CAPACITY-COVID registry, an international patient registry, revealed that 0.10% and 0.033% of patients had myocarditis and pericarditis, respectively,13 which is similar to our results. The diagnosis of myocarditis or pericarditis differs from that of myocardial injury based on hsTn levels. In previous studies, the hsTn T level was elevated in 64.6% of recovered COVID-19 patients,14 and a slight decrease in the left ventricular global longitudinal strain was reported in Japan.15 Myocarditis/pericarditis/cardiomyopathy was associated with CHF, mild DM, metastatic tumor, and collagen disease, suggesting poor prognosis.
Mechanisms underlying arrhythmogenicity include acute myocardial injury, myocarditis, hypoxia, systemic inflammation, autonomic imbalance, electrolyte abnormalities, QT-prolonging drugs, drug–drug interactions, and cardiovascular comorbidities. Approximately 6–17% of COVID-19 patients develop arrhythmias.16 Wang et al reported that critically ill COVID-19 patients were at high risk for arrhythmias (44.4% in ICU vs. 6.9% in non-ICU).12 Another study reported that 25.9% of patients with cardiac injury had arrhythmias.17 Atrial fibrillation has been reported as the most common arrhythmia;13 nonetheless, atrial fibrillation and bradycardia were not corrected in the COVIREGI-JP. The incidence of VT/VF was 0.48% in this study and 0.46% in the CAPACITY-COVID registry.13 Coronary risk factors and comorbidities, including OMI, CHF, CVD, and renal dysfunction, were associated with arrhythmogenicity, resulting in high mortality rates.
COVID-19 significantly increases the risk of thrombotic complications. In a previous study, 1.3% of hospitalized COVID-19 patients were admitted with anterior ST-segment elevation myocardial infarction.18 A Danish study reported that 0.33% of COVID-19 patients experienced their first-ever acute myocardial infarction within 14 days of diagnosis.19 In the present study, 0.17% had myocardial ischemia; on the other hand, 0.50% in the CAPACITY-COVID registry had acute coronary syndrome.13 Among all cardiovascular complications examined, myocardial ischemia exhibited the highest mortality rate.
In this study, the incidence of endocarditis was 0.062%. On the other hand, 0.13% of patients in the CAPACITY-COVID registry were identified to have bacterial endocarditis.13 In addition to bacterial endocarditis, non-bacterial thrombotic endocarditis with continuous peripheral embolization has been reported in COVID-19 patients. Endocarditis required supportive care; nevertheless, the mortality rate was low.
The incidence of PE in the present study (0.19%) was lower than that found in the CAPACITY-COVID registry (6.6%).13 A meta-analysis revealed that the incidence rates of PE and DVT in COVID-19 patients were 16.5% and 14.8%, respectively.20 D-dimer levels were not routinely measured in the COVIREGI-JP; hence, DVT and PE might have been underdiagnosed.
COVID-19 increases the risk of ischemic stroke. In a previous study of COVID-19 patients, 1.3% developed acute ischemic stroke.21 A Danish study reported that 0.86% had their first-ever ischemic stroke within 14 days of diagnosis.19 Although the incidence of ischemic stroke increased with age, younger people without traditional cardiovascular risk factors also suffered. Cerebral infarction/hemorrhage was associated with well-known risk factors for stroke such as OMI, CHF, CVD, hemiparesis, dementia, respiratory disease, hypertension, mild DM, and solid cancer.
A recent study used data from the largest healthcare organization in Israel to examine adverse events via vaccination and SARS-CoV-2 infection analyses.22 We calculated the incidence of cardiovascular complications in infected patients from the risk ratios and risk differences in the appendix data, which yielded the following results: 0.012% for myocarditis, 0.013% for pericarditis, 0.225% for arrhythmia, 0.032% for myocardial infarction, 0.058% for DVT, 0.067% for PE, 0.025% for cerebrovascular accident, and 0.009% for intracranial hemorrhage. These rates were lower than the complication rates found in the COVIREGI-JP. The median age in the Israeli study was only 34 years, and we suppose that this might be the primary reason for the low cardiovascular complication rate.
Future validation using objective indicators such as troponin and D-dimer levels is necessary. Although the data center provides a data-input manual, an input check function, and inquiries to institutions, the accuracy of data may be lower than that in clinical trials. In addition, data are updated daily in the registry, and it is possible that our findings may diverge from results in the future.
Our study revealed that cardiovascular complications of COVID-19 among hospitalized patients were infrequent in Japan but were associated with poor prognosis in 2020.
We thank the participants, data registrants, and staff of the COVIREGI-JP. The study was supported by funds from NCGM (#19-A-1015).
The authors declare that there are no conflicts of interest.
This study was approved by the National Center for Global Health and Medicine Ethics Review Board (NCGM-G-004037-01).
The deidentified participant data will not be shared; only facilities participating in the COVIREGI-JP have access to the data.
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-21-0687
