2021 Volume 85 Issue 11 Pages 2111-2115
Background: This study aimed to determine whether disease severity varied according to whether coronavirus disease 2019 (COVID-19) patients had multiple or single cardiovascular diseases and risk factors (CVDRFs).
Methods and Results: COVID-19 patients with single (n=281) or multiple (n=412) CVDRFs were included retrospectively. Multivariable logistic regression showed no significant difference in the risk of in-hospital death between groups, but patients with multiple CVDRFs had a significantly higher risk of acute respiratory distress syndrome (odds ratio: 1.75, 95% confidence interval: 1.09–2.81).
Conclusions: COVID-19 patients with multiple CVDRFs have a higher risk of complications than those with a single CDVRF.
Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first reported in December 2019,1 and the COVID-19 pandemic is currently a serious problem worldwide. SARS-CoV-2 infects the alveolar epithelium and causes viral pneumonia, and severe COVID-19 is often fatal due to complications such as acute respiratory distress syndrome (ARDS).2 Therefore, a better understanding of the characteristics of patients with COVID-19 is desirable for optimal disease management.
Some comorbidities, such as diabetes mellitus and cardiovascular disease, are associated with worse clinical outcomes of COVID-19.3–7 In a Japanese nationwide study,8 the incidence of in-hospital death was significantly higher in COVID-19 patients with cardiovascular diseases and risk factors (hypertension, diabetes mellitus, dyslipidemia: CVDRFs) than in those without CVDRFs (15.6% vs. 3.9%; P<0.001). The presence of CVDRFs was associated with severe COVID-19. However, there is limited evidence of the presence of multiple CVDRFs further increaing the risk, especially in East Asian countries other than China. Additionally, the contribution of CVDRFs in Asian countries appears to differ from that in Western countries.9 Therefore, we evaluated the effect of multiple CVDRFs on the severity of COVID-19 in a Japanese nationwide study.
This study was conducted in accordance with the Declaration of Helsinki. The Ethics Committee of Osaka Medical College (Osaka, Japan) approved the study design (protocol no. 2020-060). The requirement for consent was waived.
Study DesignCLAVIS-COVID was a Japanese nationwide multicenter retrospective study of the clinical outcomes in patients hospitalized with COVID-19 between January 1 and May 31, 2020.8 Patients with a positive SARS-CoV-2 polymerase chain reaction (PCR) test result during the study period were included. Patients aged under 20 years, and those who refused to participate in the study were excluded. Of the 1,518 COVID-19 patients enrolled from 49 acute care hospitals, 693 patients with CVDRFs (46%) who were discharged by November 8, 2020, the date on which data collection was censored, were included in the study.
Data CollectionThe 693 COVID-19 patients with CVDRFs were divided into 2 groups based on whether they had single or multiple CVDRFs. The presence of a single CVDRF was defined as a patient with 1 CVDRF factor, and possession of multiple CVDRFs was defined as a patient with ≥2 CVDRF factors.
The primary outcome was in-hospital death, and the secondary outcomes were intensive care unit (ICU) admission, ARDS, intubation, sepsis, septic shock, acute kidney injury, liver dysfunction, multiple organ failure, hemorrhage, embolism, cardiopulmonary arrest, renal replacement therapy, and plasma apheresis.
DefinitionsA positive SARS-CoV-2 PCR test result was defined as infection with COVID-19. CVDRF was defined as the presence of underlying cardiovascular disease or risk factors. Cardiovascular diseases included heart failure, coronary artery disease, myocardial infarction, peripheral artery disease, valvular heart disease, cardiac arrhythmia, pericarditis, myocarditis, congenital heart disease, pulmonary hypertension, deep vein thrombosis, pulmonary embolism, aortic dissection, aortic aneurysm, cerebral infarction/transient ischemic attack, the use of cardiac devices (pacemaker, implantable cardioverter defibrillator, cardiac resynchronization therapy, and left ventricular assist device), heart transplantation, and cardiac arrest. Cardiovascular risk factors included hypertension, diabetes mellitus, and dyslipidemia.
Statistical AnalysisThe characteristics of patients with single and multiple CVDRFs were compared using Fisher’s exact test for categorical variables, and Student’s t-test for continuous variables. The frequency of outcomes among the groups was compared using Fisher’s exact test. Multivariable logistic regression was performed to identify risk factors for the outcomes. In addition to the presence of multiple CVDRFs, other risk factors for severe COVID-19 were included in the multivariable logistic regression model (male sex,10 age ≥65 years,2 cancer,11 chronic obstructive pulmonary disease (COPD),12 chronic kidney disease (CKD) including dialysis,13 and obesity6). Odds ratios (ORs), 95% confidence intervals (CIs), and P values were calculated. The threshold for statistical significance was P<0.05 in all analyses. Two reviewers (TY and KM) performed the statistical analyses independently and confirmed the reproducibility of the results. All analyses were performed using JMP® Pro 14 (SAS Institute Inc., Cary, NC, USA).
Of the 693 COVID-19 patients with CVDRFs, 281 were assigned to the single CVDRF group, and 412 were assigned to the multiple CVRDF group (Table 1). None of the study patients were vaccinated against COVID-19. In the multiple CVDRF group, the most common CVDRF combinations of risk factors were hypertension and diabetes mellitus (n=82) followed by hypertension and dyslipidemia (n=80); hypertension, diabetes mellitus, and dyslipidemia (n=38); and diabetes mellitus and dyslipidemia (n=30) (Supplementary Table 1).
| No. of cases |
Total | Single CVDRF (n=281) |
Multiple CVDRF (n=412) |
P value | |
|---|---|---|---|---|---|
| Age (years) | 693 | 68.3±14.9 | 65.8±15.7 | 70.0±14.0 | <0.01 |
| Sex (male) | 693 | 449 (64.8) | 180 (64.1) | 269 (65.3) | 0.75 |
| Height (cm) | 588 | 163.0±10.6 | 163.5±11.0 | 162.6±10.3 | 0.34 |
| Weight (kg) | 580 | 64.8±17.6 | 63.9±17.4 | 65.3±17.8 | 0.37 |
| Body mass index (kg/m2) | 580 | 24.3±5.1 | 23.8±4.8 | 24.6±5.2 | 0.06 |
| Smoking | 655 | 270 (41.2) | 102 (38.5) | 168 (43.1) | 0.26 |
| Heart failure | 693 | 60 (8.7) | 1 (0.4) | 59 (14.3) | <0.01 |
| Coronary artery disease | 693 | 70 (10.1) | 5 (1.8) | 65 (15.8) | <0.01 |
| Myocardial infarction | 693 | 30 (4.3) | 3 (1.1) | 27 (6.6) | <0.01 |
| Valvular heart disease | 693 | 19 (2.7) | 1 (0.4) | 18 (4.4) | <0.01 |
| Cardiac arrhythmia | 693 | 70 (10.1) | 9 (3.2) | 61 (14.8) | <0.01 |
| Heart transplant, LV assist device | 693 | 1 (0.1) | 1 (0.4) | 0 (0.0) | 0.41 |
| Use of cardiac device | 693 | 9 (1.3) | 1 (0.4) | 8 (1.9) | 0.09 |
| Cardiac arrest | 693 | 3 (0.4) | 0 (0.0) | 3 (0.7) | 0.28 |
| Pericarditis, myocarditis, CHD, pulmonary hypertension |
693 | 2 (0.3) | 0 (0.0) | 2 (0.5) | 0.52 |
| CI/TIA | 693 | 52 (7.5) | 5 (1.8) | 47 (11.4) | <0.01 |
| Hypertension | 693 | 513 (74.0) | 168 (59.8) | 345 (83.7) | <0.01 |
| Diabetes mellitus | 693 | 266 (38.4) | 42 (14.9) | 224 (54.4) | <0.01 |
| Dyslipidemia | 693 | 269 (38.8) | 40 (14.2) | 229 (55.6) | <0.01 |
| Deep vein thrombosis | 693 | 1 (0.1) | 0 (0.0) | 1 (0.2) | 1.00 |
| Pulmonary embolism | 693 | 7 (1.0) | 3 (1.1) | 4 (1.0) | 1.00 |
| Aortic dissection | 693 | 6 (0.9) | 1 (0.4) | 5 (1.2) | 0.41 |
| Aortic aneurysm | 693 | 10 (1.4) | 1 (0.4) | 9 (2.2) | 0.06 |
| Peripheral artery disease | 693 | 5 (0.7) | 0 (0.0) | 5 (1.2) | 0.08 |
| Obesity | 693 | 47 (6.8) | 14 (5.0) | 33 (8.0) | 0.13 |
| Asthma | 693 | 34 (4.9) | 10 (3.6) | 24 (5.8) | 0.21 |
| COPD | 693 | 35 (5.1) | 12 (4.3) | 23 (5.6) | 0.48 |
| CKDa | 693 | 56 (8.1) | 12 (4.3) | 44 (10.7) | <0.01 |
| Liver cirrhosis | 693 | 1 (0.1) | 1 (0.4) | 0 (0.0) | 0.41 |
| Chronic neurologic condition | 693 | 6 (0.9) | 4 (1.4) | 2 (0.5) | 0.23 |
| Cancer | 693 | 67 (9.7) | 26 (9.3) | 41 (10.0) | 0.79 |
| Autoimmune disease | 693 | 15 (2.2) | 6 (2.1) | 9 (2.2) | 1.00 |
Values were presented as mean±standard deviation or numbers (%). aIncludes dialysis patients. CHD, congenital heart disease; CI, cerebral infarction; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; COVID-19, coronavirus disease 2019; CVDRF, cardiovascular disease or risk factors; LV, left ventricular; TIA, transient ischemic attack.
The risk of in-hospital death was not significantly different in the multiple CVDRF group (Table 2) using Fisher’s exact test. In the multivariable logistic regression analysis, male sex, age ≥65 years, CKD, and COPD were significantly associated with in-hospital death (Table 3). However, the presence of multiple CVDRFs was not associated with a significant increase in the risk of in-hospital death (Table 3).
| Total (n=693) |
Single CVDRF (n=281) |
Multiple CVDRFs (n=412) |
OR (95%CI) |
P value | |
|---|---|---|---|---|---|
| In-hospital death | 108 (15.6) | 39 (13.9) | 69 (16.8) | 1.25 (0.82–1.91) | 0.34 |
| ICU admission | 199 (28.7) | 67 (23.8) | 132 (32.0) | 1.51 (1.07–2.12) | 0.02 |
| ARDS | 97 (14.0) | 28 (10.0) | 69 (16.8) | 1.82 (1.14–2.90) | 0.01 |
| Intubation | 152 (21.9) | 50 (17.8) | 102 (24.8) | 1.52 (1.04–2.22) | 0.03 |
| ECMO | 25 (3.6) | 11 (3.9) | 14 (3.4) | 0.86 (0.39–1.93) | 0.84 |
| Sepsis | 55 (7.9) | 18 (6.4) | 37 (9.0) | 1.44 (0.80–2.59) | 0.25 |
| Septic shock | 34 (4.9) | 14 (5.0) | 20 (4.9) | 0.97 (0.48–1.96) | 1.00 |
| AKI | 61 (8.8) | 19 (6.8) | 42 (10.2) | 1.57 (0.89–2.75) | 0.13 |
| Liver dysfunction | 72 (10.4) | 28 (10.0) | 44 (10.7) | 1.08 (0.66–1.78) | 0.80 |
| Multiple organ failure | 42 (6.1) | 16 (5.7) | 26 (6.3) | 1.12 (0.59–2.12) | 0.87 |
| Hemorrhage | 24 (3.5) | 8 (2.9) | 16 (3.9) | 1.38 (0.58–3.27) | 0.53 |
| Embolism | 30 (4.3) | 11 (3.9) | 19 (4.6) | 1.19 (0.56–2.53) | 0.71 |
| CPA | 93 (13.4) | 32 (11.4) | 61 (14.8) | 1.35 (0.86–2.14) | 0.21 |
| RRT | 45 (6.5) | 15 (5.3) | 30 (7.3) | 1.39 (0.73–2.64) | 0.35 |
| Plasma apheresis | 1 (0.14) | 0 (0.0) | 1 (0.24) | – | 1.00 |
AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; CPA, cardiopulmonary arrest; CVDRF, cardiovascular disease or risk factors; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; RRT, renal replacement therapy.
| In-hospital death/total, n (%) |
OR (95% CI) | |||
|---|---|---|---|---|
| Crude | Adjusted | P value* | ||
| Female | 30/244 (12.30%) | 1 [Ref.] | 1 [Ref.] | |
| Male | 78/449 (17.37%) | 1.50 (0.95–2.36) | 1.80 (1.11–2.93) | 0.02 |
| Age <65 years | 10/275 (3.64%) | 1 [Ref.] | 1 [Ref.] | |
| Age ≥65 years | 98/418 (23.44%) | 8.12 (4.15–15.90) | 7.73 (3.82–15.6) | <0.01 |
| Without CKD | 87/637 (13.66%) | 1 [Ref.] | 1 [Ref.] | |
| With CKD | 21/56 (37.50%) | 3.79 (2.11–6.82) | 3.04 (1.61–5.71) | <0.01 |
| Without COPD | 94/658 (14.29%) | 1 [Ref.] | 1 [Ref.] | |
| With COPD | 14/35 (40.00%) | 4.00 (1.97–8.14) | 2.29 (1.07–4.90) | 0.03 |
| Without obesity | 103/646 (15.94%) | 1 [Ref.] | 1 [Ref.] | |
| With obesity | 5/47 (10.64%) | 0.63 (0.24–1.62) | 1.44 (0.49–4.22) | 0.50 |
| Without cancer | 88/626 (14.06%) | 1 [Ref.] | 1 [Ref.] | |
| With cancer | 20/67 (29.85%) | 2.60 (1.47–4.60) | 1.56 (0.84–2.91) | 0.16 |
| Single CVRDF | 39/281 (13.88%) | 1 [Ref.] | 1 [Ref.] | |
| Multiple CVRDFs | 69/412 (16.75%) | 1.25 (0.82–1.91) | 0.97 (0.61–1.54) | 0.90 |
*Calculated using multivariable logistic regression. CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.
The incidence of ICU admission, ARDS, and intubation was significantly higher in the multiple CVDRF group than in the single CVDRF group (Table 2). In the multivariable logistic regression analysis, multiple CVDRFs were associated with a significantly higher incidence of intubation (Table 4), ICU admission (OR, 1.46; 95% CI, 1.02–2.08, P=0.04; Supplementary Table 2), and ARDS (OR, 1.75; 95% CI, 1.09–2.81, P=0.02; Supplementary Table 3). Other outcomes did not differ significantly between the single and multiple CVDRF groups (Table 2).
| Intubation/total, n (%) |
OR (95% CI) | |||
|---|---|---|---|---|
| Crude | Adjusted | P value* | ||
| Female | 27/244 (11.07%) | 1 [Ref.] | 1 [Ref.] | |
| Male | 125/449 (27.84%) | 3.10 (1.98–4.86) | 3.14 (1.98–4.99) | <0.01 |
| Age <65 years | 62/275 (22.55%) | 1 [Ref.] | 1 [Ref.] | |
| Age ≥65 years | 90/418 (21.53%) | 0.94 (0.65–1.36) | 1.15 (0.77–1.73) | 0.50 |
| Without CKD | 139/637 (21.82%) | 1 [Ref.] | 1 [Ref.] | |
| With CKD | 13/56 (23.21%) | 1.08 (0.57–2.07) | 1.07 (0.55–2.10) | 0.84 |
| Without COPD | 141/658 (21.43%) | 1 [Ref.] | 1 [Ref.] | |
| With COPD | 11/35 (31.43%) | 1.68 (0.80–3.51) | 1.47 (0.68–3.19) | 0.33 |
| Without obesity | 136/646 (21.05%) | 1 [Ref.] | 1 [Ref.] | |
| With obesity | 16/47 (34.04%) | 1.94 (1.03–3.64) | 1.83 (0.94–3.57) | 0.08 |
| Without cancer | 140/626 (22.36%) | 1 [Ref.] | 1 [Ref.] | |
| With cancer | 12/67 (17.91%) | 0.76 (0.39–1.45) | 0.64 (0.32–1.27) | 0.20 |
| Single CVRDF | 50/281 (17.79%) | 1 [Ref.] | 1 [Ref.] | |
| Multiple CVRDFs | 102/412 (24.76%) | 1.52 (1.04–2.22) | 1.48 (1.001–2.188) | 0.0495 |
*Calculated using multivariable logistic regression. Abbreviations as in Tables 1,3.
The incidence of in-hospital death did not differ significantly between the single and multiple CVDRF groups, but the incidence of ICU admission, ARDS, and intubation was significantly higher in the multiple CVDRF group than in the single CVDRF group. The multiple CVDRF group had a higher rate of ARDS, which may have resulted in the higher incidence of ICU admission and intubation. Additionally, the multivariable logistic regression analyses showed that multiple CVDRFs were associated with a greater risk of ICU admission, ARDS, and intubation. These results suggested that the presence of multiple CVDRFs complicates the respiratory status of patients with COVID-19 compared with having a single CVDRF.
A single-center retrospective study by Motaib et al showed that very-high-risk patients, who had a high prevalence of multiple CVDRFs, had higher mortality rates than other risk categories.14 Henein et al reported the results of a retrospective cohort study of Coptic clergy, which found that a combination of systolic blood pressure ≥160 mmHg, diabetes mellitus, obesity, and history of coronary artery disease was an independent predictor of COVID-19-related death.15 Moreover, Mok et al reported that a history of venous thromboembolism was associated with higher mortality rates in COVID-19 patients with heart failure.16 However, our study did not show a significant difference in the risk of in-hospital death between the multiple CVDRF and single CVDRF groups. One of the reasons for this difference could be the difference in the patient characteristics. The comparison group in the study by Motaib et al included patients without CVDRF,14 and in the study by Henein et al, the mean age was 49.6 years, and the mean body mass index was 31.9 m/kg2 (overweight 34.7%, obesity 57.3%),15 which were lower and higher than in our report (mean age, 68.3 years; body mass index, 24.3 m/kg2), respectively. Additionally, there were very few cases of venous thromboembolism (deep vein thrombosis, 1/693 (0.1%); pulmonary embolism, 7/693 (1.0%), among the patients in our study. Motaib et al reported that very-high-risk status was an independent risk factor for ICU admission,14 which was similar to our study. Therefore, proper control of CVDRFs is important to prevent severe COVID-19. Additionally, patients with multiple CVDRFs should be prioritized to receive COVID-19 vaccination in order to reduce COVID-19 severity.
Metabolic syndrome is associated with low immune function.17,18 Diabetes mellitus decreases the production of pro-inflammatory cytokines such as interferon-gamma and interleukins, functionally compromising the host’s innate and humoral immune systems.17 Hypertension and diabetes mellitus are associated with an angiotensin-converting enzyme 2 (ACE2) deficiency.19 Because SARS-COV-2 binds to ACE2, it is hypothesized that this can reduce the physiological function of ACE2.5 A reduction in the function of ACE2 leads to increased activation of the ACE/angiotensin-II/angiotensin-II type 1 receptor axis, which may cause severe manifestations of COVID-19 such as ARDS.5,19 As SARS-CoV-2 infection induces endothelial inflammation in multiple organs and accelerates the host inflammatory response,20 the effect on patients with vascular endothelial disorders is likely to be significant. As mentioned above, multiple factors may contribute to the severity of COVID-19. Individuals with multiple CVDRFs are potentially at a higher risk of low immune function, ACE2 deficiency, and endothelial dysfunction, and thus ARDS than individuals with a single CVDRF.
The current study has several limitations. First, this study was conducted retrospectively, so there is a risk of bias. Second, the severity and duration of each CVDRF illness and the COVID-19 treatment were not considered in the analysis. Finally, the patient data in this study were collected during the early stage of the COVID-19 pandemic in Japan. Nevertheless, the results provide information about factors associated with complicated COVID-19.
In conclusion, although a well-controlled, prospective study is desirable, the current study results suggest that COVID-19 patients with multiple CVDRFs are more likely to experience severe COVID-19 than COVID-19 patients with a single CDVRF.
The authors acknowledge all the investigators who participated in CLAVIS-COVID and the Japanese Circulation Society.
A. Ukimura, Infection Control Center, Osaka Medical and Pharmaceutical University Hospital, is the principal investigator responsible for this research and analysis.
T. Yonetsu belongs to endowed departments of Abbott Vascular Japan, Boston Scientific Japan, Japan Lifeline, WIN International, and Takeyama KK. S. Kohsaka received unrestricted research grants from the Department of Cardiology, Keio University School of Medicine provided by Daiichi Sankyo Co., Ltd. and Bristol-Meyers Squibb, and lecture fees from AstraZeneca and Bristol-Meyers Squibb. Y. Matsue is affiliated with a department endowed by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi, received an honorarium from Otsuka Pharmaceutical Co. and Novartis Japan, received a consultant fee from Otsuka Pharmaceutical Co., and joint research funds from Otsuka Pharmaceutical Co. and Pfizer Inc. K. Node is a member of Circulation Journal’s Editorial Team.
The Ethics Committee of Osaka Medical College (Osaka, Japan) approved the study design (protocol no. 2020-060).
This study received financial support from the Japanese Circulation Society.
All authors met the ICMJE authorship criteria.
Conceptualization: A. Ukimura, T. Yamada
Data Curation: A. Ukimura, M. Hoshiga, T. Sano, T. Kitai, T. Yonetsu, S. Torii, S. Kohsaka, S. Kuroda, K. Node, Y. Matsue, S. Matsumoto
Data Analysis: T. Yamada, T. Ogawa, K. Minami, Y. Kusaka
Methodology: T. Yamada, T. Ogawa, K. Minami, Y. Kusaka
Project Administration: A. Ukimura, M. Hoshiga
Supervision: T. Sano, T. Kitai, T. Yonetsu, S. Torii, S. Kohsaka, S. Kuroda, K. Node, Y. Matsue, S. Matsumoto
Writing – Original Draft: T. Yamada
Writing – Review & Editing: T. Ogawa, K. Minami, Y. Kusaka, M. Hoshiga, A. Ukimura, T. Sano, T. Kitai, T. Yonetsu, S. Torii, S. Kohsaka, S. Kuroda, K. Node, Y. Matsue, S. Matsumoto
All authors contributed to writing the final manuscript.
Due to the nature of this research, the study participants did not agree for their data to be shared publicly or upon request. Hence, the data are not available.
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-21-0684
