New-Onset Atrial Fibrillation in Patients With Coronavirus Disease 2019 (COVID-19) and Cardiovascular Disease　- Insights From the CLAVIS-COVID Registry.

BACKGROUND: Both pre-existing atrial fibrillation (AF) and new-onset AF (NOAF) are observed in patients with coronavirus disease 2019 (COVID-19); however, the effect of AF on clinical outcomes is unclear. This study aimed to investigate the effect of AF, especially NOAF, on the outcomes of hospitalized patients with COVID-19.Methods and Results: This study analyzed 673 COVID-19 patients with cardiovascular diseases and risk factors (CVDRF). Patients were divided into 3 groups; pre-existing AF (n=55), NOAF (n=28), and sinus rhythm (SR) (n=590). The baseline characteristics and in-hospital outcomes were evaluated. The mean age of the patients was 68 years, 65.4% were male, and the in-hospital mortality rate was 15.6%. The NOAF group demonstrated a higher in-hospital mortality rate (42.9%) than the pre-existing AF (30.9%) and SR (11.2%) groups (P<0.001). Patients with NOAF had a higher incidence of acute respiratory syndrome, multiple organ disease, hemorrhage, and stroke than those with pre-existing AF and NOAF. NOAF was independently associated with in-hospital mortality after adjusting for pre-existing AF and 4C mortality score (odds ratio [95% confidence interval]: 4.71 [1.63-13.6], P<0.001). CONCLUSIONS: Patients with NOAF had significantly worse outcomes as compared to patients with pre-existing AF and SR. The incidence of NOAF would be a useful predictor of clinical outcomes during hospitalization.

Early initiation of tolvaptan is associated with early discharge in patients with heart failure regardless of age.

BACKGROUND: Elderly patients with heart failure (HF) have been observed to decrease activities of daily living (ADL) during hospitalization. Prevention of ADL decline from shortening of hospital stays is especially important in the elderly, because decreasing ADL is associated with poor prognosis. We investigated the relationship between the early initiation of tolvaptan (TLV) after hospitalization and the length of hospital stay in patients with HF aged younger than 80 years and aged 80 years and older. METHODS: We analyzed 146 patients younger than 80 years (< 80) and 101 patients aged 80 years and older (≥ 80) who were hospitalized with HF from February 2011 to June 2016 and had initiated TLV. The relationship between the time until commencement of TLV and the length of hospital stay was assessed. Additionally, a comparison made between the TLV early start group (within the median) and the delayed start group (over the median) for both groups. Multivariate analysis was also performed on factors that required hospital stays below the median. RESULTS: A significant correlation was observed between time to TLV initiation and the length of hospital stay (< 80: r = 0.382, P < 0.001; ≥ 80: r = 0.395, P < 0.001). The length of hospital stay in the early group was significantly longer than that in the delayed group for both groups (< 80: early 21.0 ± 13.0 days and 33.0 ± 22.7 days, respectively, P < 0.001; ≥ 80: early 21.3 ± 12.5 days and 32.9 ± 17.9 days, respectively, P < 0.001). Conversely, no statistically significant difference found in the length of hospital stay after initiation of TLV. Moreover, no increase in adverse events in the elderly observed. A multivariate analysis revealed that a predictive factor for short-term hospitalization was early administration of TLV regardless of age. CONCLUSIONS: The early initiation of TLV after hospitalization was associated with a shorter length of hospital stay in patients with HF regardless of age.

Multiple Cardiovascular Diseases or Risk Factors Increase the Severity of Coronavirus Disease 2019.

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.

Association Between Statin Use Prior to Admission and Lower Coronavirus Disease 2019 (COVID-19) Severity in Patients With Cardiovascular Disease or Risk Factors.

BACKGROUND: Cardiovascular diseases and/or risk factors (CVDRF) have been reported as risk factors for severe coronavirus disease 2019 (COVID-19).Methods and Results:In total, we selected 693 patients with CVDRF from the CLAVIS-COVID database of 1,518 cases in Japan. The mean age was 68 years (35% females). Statin use was reported by 31% patients at admission. Statin users exhibited lower incidence of extracorporeal membrane oxygenation (ECMO) insertion (1.4% vs. 4.6%, odds ratio [OR]: 0.295, P=0.037) and septic shock (1.4% vs. 6.5%, OR: 0.205, P=0.004) despite having more comorbidities such as diabetes mellitus. CONCLUSIONS: This study suggests the potential benefits of statins use against COVID-19.

Clinical and Biomarker Profiles and Prognosis of Elderly Patients With Coronavirus Disease 2019 (COVID-19) With Cardiovascular Diseases and/or Risk Factors.

BACKGROUND: This study investigated the effects of age on the outcomes of coronavirus disease 2019 (COVID-19) and on cardiac biomarker profiles, especially in patients with cardiovascular diseases and/or risk factors (CVDRF).Methods and Results:A nationwide multicenter retrospective study included 1,518 patients with COVID-19. Of these patients, 693 with underlying CVDRF were analyzed; patients were divided into age groups (<55, 55-64, 65-79, and ≥80 years) and in-hospital mortality and age-specific clinical and cardiac biomarker profiles on admission evaluated. Overall, the mean age of patients was 68 years, 449 (64.8%) were male, and 693 (45.7%) had underlying CVDRF. Elderly (≥80 years) patients had a significantly higher risk of in-hospital mortality regardless of concomitant CVDRF than younger patients (P<0.001). Typical characteristics related to COVID-19, including symptoms and abnormal findings on baseline chest X-ray and computed tomography scans, were significantly less prevalent in the elderly group than in the younger groups. However, a significantly (P<0.001) higher proportion of elderly patients were positive for cardiac troponin (cTn), and B-type natriuretic peptide (BNP) and N-terminal pro BNP (NT-proBNP) levels on admission were significantly higher among elderly than younger patients (P<0.001 and P=0.001, respectively). CONCLUSIONS: Elderly patients with COVID-19 had a higher risk of mortality during the hospital course, regardless of their history of CVDRF, were more likely to be cTn positive, and had significantly higher BNP/NT-proBNP levels than younger patients.

Cardio-ankle vascular index predicts the 1-year prognosis of heart failure patients categorized in clinical scenario 1.

The sudden increase in blood pressure by vascular dysfunction is associated with the development of acute decompensated heart failure (ADHF) categorized in clinical scenario (CS) 1. However, the relationship between vascular function and prognosis in ADHF patients with CS1 is unclear. 3239 consecutive ADHF patients between January 2012 and June 2018 were enrolled. ADHF patients with CS1 undergoing ankle brachial index/cardio-ankle vascular index (CAVI) were included and patients with peripheral artery disease were excluded. Finally, 113 patients were analyzed. The primary endpoint of the present study was composite endpoint at 1 year (the cardiac death or re-hospitalization by ADHF). Cox proportional hazard analysis was conducted to identify independent predictors of composite endpoint. 25 patients (22.1%) were developed composite endpoint. CAVI in patients who have composite endpoint were significantly higher than without non-composite endpoint (composite endpoint group: 9.9 ± 1.3 non-composite endpoint group 8.7 ± 1.7, P = 0.001). The composite endpoint group was elderly and had higher ejection fraction, lower hemoglobin, and less used beta blockers, and renin angiotensin aldosterone system inhibitors. After adjustment by these confounding factors, CAVI was independently associated with the occurrence of composite endpoint (hazard ratio 1.69, 95% CI 1.05-2.73, P = 0.032). A cut-off value of CAVI for predicting composite endpoint was 8.65 (sensitivity 0.444, specificity 0.920, area under the curve 0.724, 95% CI 0.614-0.834). High CAVI was associated with the occurrence of composite endpoint after CS1 ADHF.

Bisoprolol transdermal patch improves orthostatic hypotension in patients with chronic heart failure and hypertension.

ß blockers (BBs) play an important role in heart failure (HF) treatment. However, orthostatic hypotension (OH) is sometimes caused by BBs. The bisoprolol transdermal patch works more slowly and is long acting compared with the bisoprolol fumarate tablet. The risk of OH may be reduced by using the bisoprolol transdermal patch. We evaluated 57 consecutive patients who were taking the bisoprolol fumarate tablet for chronic HF with hypertension from November 2016 to September 2017. We switched the patients to the bisoprolol transdermal patch. Because 12 of 57 subjects could not continue using the bisoprolol transdermal patch, we analyzed the remaining 45 patients. We investigated BP, blood tests, and changes in BP from supine to standing positions before and after 6 months of switching from tablet to patch. OH was diagnosed by observing a systolic/diastolic BP drop of at least 20/10 mmHg or an absolute systolic BP (sBP) of <90 mmHg from the standing position. No significant changes were observed in the BP and BPs from supine to standing positions, whereas log brain natriuretic peptide was significantly reduced after switching from patch to tablet (2.102 to 2.070pg/dl, P = .039). OH, which occurred in originally 17 patients, showed improvement and eventually appeared in 4 patients. In these patients, changes in BP from supine to standing positions were also significantly improved (changes in sBP, -11 to -6mmHg, P = .016). This study demonstrated that switching from the bisoprolol fumarate tablet to transdermal patch reduced the morbidity of OH in HF patients.

Right Bundle Branch Block and Rehospitalization in Patients With Heart Failure.

OBJECTIVE: The most important aspect of managing heart failure (HF) is preventing rehospitalization. Bundle branch block (BBB), particularly left BBB (LBBB), has been a known risk factor for worsening prognosis, whereas no such consideration has been made for right BBB (RBBB). However, recent research has shown that RBBB was associated with increased mortality. This study evaluated the effects of RBBB on prognosis, especially rehospitalization, in patients with HF. MATERIALS: This study included 698 patients admitted for HF. Those who died in the hospital (n = 31) and dropped out during observation (n = 143) were excluded. After one year of observation, the patients were divided into a control group (n = 361) and a major adverse cardiovascular event (MACE) group (n = 163). After further excluding according to electrocardiography findings, patients were categorized as having no BBB (n = 307), pure RBBB (n = 37), and LBBB (n = 56), and then the characteristics, clinical data, and prognosis of the remaining patients were evaluated. RESULTS: Patients were compared to no BBB, pure RBBB, and LBBB was associated with a risk for HF rehospitalization (p = 0.007). Furthermore, pure RBBB was independently associated with HF rehospitalization even after adjusting for confounders (hazard ratio: 2.40 (95% confidence interval: 1.26-4.58; p = 0.008). CONCLUSION: Pure RBBB was independently associated with HF rehospitalization, highlighting the need for vigilance against the risk of HF rehospitalization among those with pure RBBB.

A case of constrictive pericarditis with a milk of calcium pericardial effusion undergoing surgical treatment.

Milk of calcium (MOC) pericardial effusion (PE) is extremely rare and has rarely been reported. A 78-year-old man was referred to our institution because of breathlessness and bilateral leg edema. Echocardiography revealed mild PE. In addition, abrupt posterior motion of the ventricular septum in early diastole was observed. A non-contrast chest computed tomography revealed a hyperdense PE, with Hounsfield units of 130, suggestive of MOC PE. Right heart catheterization (RHC) revealed that the right ventricular pressure had a dip and plateau pattern. We diagnosed the patient with constrictive pericarditis (CP) with MOC PE. As the right heart failure secondary to CP was refractory to medical therapy, we decided to perform surgical treatment. During pericardiectomy, a highly viscous PE, of which the color was pale and reddish brown, was aspirated. Chemical analysis of the PE revealed a very high calcium content of 39.2 mmol/L. The clinical symptoms secondary to CP improved. RHC performed postoperatively confirmed the disappearance of a dip and plateau pattern in the right ventricular pressure. In conclusion, we experienced a of CP with MOC PE and surgical treatment contributed to the improvement of the clinical symptoms and pericardial constriction secondary to CP. Learning objective: Because constrictive pericarditis (CP) with milk of calcium (MOC) pericardial effusion (PE) can cause severe morbidity and even mortality, the early diagnosis of CP is important in patients suspected of having MOC PE. MOC PE has hyperdensity on computed tomography, so its findings could be helpful in the diagnosis of MOC PE. Pericardiectomy for CP with MOC PE may contribute to the improvement of the clinical symptoms and pericardial constriction secondary to CP.

Assessment of thromboembolism risk in COVID-19 patients with cardiovascular disease risk factors: Analysis of a Japanese Nationwide Registry.

INTRODUCTION: Patients with COVID-19 and cardiovascular disease risk factors (CVDRF) have been reported to develop coagulation abnormalities frequently. However, there are limitations in conventional predictive models for the occurrence of thromboembolism in patients with COVID-19 and CVDRF. METHODS: Among data on 1518 hospitalized patients with COVID-19 registered with CLAVIS-COVID, a Japanese nationwide cohort study, 693 patients with CVDRF were subjected to least absolute shrinkage and selection operator (LASSO) analysis; a method of shrinking coefficients for reducing variance and minimizing bias to increase predictive accuracy. LASSO analysis was performed to identify risk factors for systemic thromboembolic events; occurrence of arterial and venous thromboembolism during the index hospitalization as the primary endpoint. RESULTS: LASSO analysis identified a prior systemic thromboembolism, male sex, hypoxygenemia requiring invasive mechanical ventilation support, C-reactive protein levels and D-dimer levels at admission, and congestion on chest X-ray at admission as potential risk factors for the primary endpoint. The developed risk model consisting of these risk factors showed good discriminative performance (AUC-ROC: 0.83, 95 % confidence interval [CI]: 0.77-0.90), which was significantly better than that shown by D-dimer (AUC-ROC: 0.70, 95 % CI: 0.60-0.80) (p < 0.001). Furthermore, systemic embolic events were independently associated with in-hospital mortality (adjusted odds ratio: 3.29; 95 % CI: 1.31-8.00). CONCLUSIONS: Six parameters readily available at the time of admission were identified as risk factors for thromboembolic events, and these may be capable of stratifying the risk of in-hospital thromboembolic events, which are associated with in-hospital mortality, in patients with COVID-19 and CVDRF.

Predictive value of neutrophil-to-lymphocyte ratio for the fatality of COVID-19 patients complicated with cardiovascular diseases and/or risk factors.

Previous studies have reported that a high neutrophil-to-lymphocyte ratio (NLR) is associated with disease severity and poor prognosis in COVID-19 patients. We aimed to investigate the clinical implications of NLR in patients with COVID-19 complicated with cardiovascular diseases and/or its risk factors (CVDRF). In total, 601 patients with known NLR values were selected from the CLAVIS-COVID registry for analysis. Patients were categorized into quartiles (Q1, Q2, Q3, and Q4) according to baseline NLR values, and demographic and clinical parameters were compared between the groups. Survival analysis was conducted using the Kaplan-Meier method. The diagnostic performance of the baseline and follow-up NLR values was tested using receiver operating characteristic (ROC) curve analysis. Finally, two-dimensional mapping of patient characteristics was conducted using t-stochastic neighborhood embedding (t-SNE). In-hospital mortality significantly increased with an increase in the baseline NLR quartile (Q1 6.3%, Q2 11.0%, Q3 20.5%; and Q4, 26.6%; p < 0.001). The cumulative mortality increased as the quartile of the baseline NLR increased. The paired log-rank test revealed significant differences in survival for Q1 vs. Q3 (p = 0.017), Q1 vs. Q4 (p < 0.001), Q2 vs. Q3 (p = 0.034), and Q2 vs. Q4 (p < 0.001). However, baseline NLR was not identified as an independent prognostic factor using a multivariate Cox proportional hazards regression model. The area under the curve for predicting in-hospital death based on baseline NLR was only 0.682, whereas that of follow-up NLR was 0.893. The two-dimensional patient map with t-SNE showed a cluster characterized by high mortality with high NLR at follow-up, but these did not necessarily overlap with the population with high NLR at baseline. NLR may have prognostic implications in hospitalized COVID-19 patients with CVDRF, but its significance depends on the timing of data collection.

Intensive Care Unit Admission for Moderate-to-Severe COVID-19 Patients With Known Cardiovascular Diseases or Their Risk Factors　- Insights From a Nationwide Japanese Cohort Study.

Background: The COVID-19 pandemic has challenged healthcare systems, at times overwhelming intensive care units (ICUs). We aimed to describe the length and rate of ICU admission, and explore the clinical variables influencing ICU use, for COVID-19 patients with known cardiovascular diseases or their risk factors (CVDRF). Methods and Results: A post hoc analysis was performed of 693 Japanese COVID-19 patients with CVDRF enrolled in the nationwide CLAVIS-COVID registration system between January and May 2020 (mean [±SD] age 68.3±14.9 years; 35% female); 199 patients (28.7%) required ICU management. The mean (±SD) ICU length of stay (LOS) was 19.3±18.5 days, and the rate of in-hospital death and hospital LOS were significantly higher (P<0.001) and longer (P<0.001), respectively, in the ICU than non-ICU group. Logistic regression analysis revealed that clinical variables reflecting impaired general condition (e.g., high C-reactive protein, low Glasgow Coma Scale score, SpO2, albumin level), male sex, and previous use of ß-blockers) were associated with ICU admission (all P<0.001). Notably, age was inversely associated with ICU admission, and this was particularly prominent among elderly patients (OR 0.97, 95% confidence interval 0.95-0.99; P=0.0018). Conclusions: One-third of COVID patients with CVDRF required ICU care during the first phase of the pandemic in Japan. Other than anticipated clinical variables, such as hypoxia and altered mental status, age was inversely associated with the use of the ICU, warranting further investigation.

External validation of the 4C Mortality Score for patients with COVID-19 and pre-existing cardiovascular diseases/risk factors.

OBJECTIVES: Predictive algorithms to inform risk management decisions are needed for patients with COVID-19, although the traditional risk scores have not been adequately assessed in Asian patients. We aimed to evaluate the performance of a COVID-19-specific prediction model, the 4C (Coronavirus Clinical Characterisation Consortium) Mortality Score, along with other conventional critical care risk models in Japanese nationwide registry data. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Hospitalised patients with COVID-19 and cardiovascular disease or coronary risk factors from January to May 2020 in 49 hospitals in Japan. MAIN OUTCOME MEASURES: Two different types of outcomes, in-hospital mortality and a composite outcome, defined as the need for invasive mechanical ventilation and mortality. RESULTS: The risk scores for 693 patients were tested by predicting in-hospital mortality for all patients and composite endpoint among those not intubated at baseline (n=659). The number of events was 108 (15.6%) for mortality and 178 (27.0%) for composite endpoints. After missing values were multiply imputed, the performance of the 4C Mortality Score was assessed and compared with three prediction models that have shown good discriminatory ability (RISE UP score, A-DROP score and the Rapid Emergency Medicine Score (REMS)). The area under the receiver operating characteristic curve (AUC) for the 4C Mortality Score was 0.84 (95% CI 0.80 to 0.88) for in-hospital mortality and 0.78 (95% CI 0.74 to 0.81) for the composite endpoint. It showed greater discriminatory ability compared with other scores, except for the RISE UP score, for predicting in-hospital mortality (AUC: 0.82, 95% CI 0.78 to 0.86). Similarly, the 4C Mortality Score showed a positive net reclassification improvement index over the A-DROP and REMS for mortality and over all three scores for the composite endpoint. The 4C Mortality Score model showed good calibration, regardless of outcome. CONCLUSIONS: The 4C Mortality Score performed well in an independent external COVID-19 cohort and may enable appropriate disposition of patients and allocation of medical resources.Trial registration number UMIN000040598.