COVID-19 pandemic and hypertension: an updated report from the Japanese Society of Hypertension project team on COVID-19.

The number of reported cases with coronavirus disease 2019 (COVID-19) has exceeded 620 million worldwide, still having a profound impact on people's health and daily lives since its occurrence and outbreak in December 2019. From the early phase of the COVID-19 pandemic, there has been a concern that the rapid spread of this communicable disease can negatively influence non-communicable diseases. Accumulating data indicate that the restriction on the access to medical care, psychological distress, and life-style changes triggered by the pandemic have indeed affected blood pressure control in hypertensive patients. Since our previous report in 2020 that summarized the findings of the literature related to COVID-19 and hypertension, there has been a considerable progress in our understanding of the association between these two disorders; nonetheless, there are remaining challenges and emerging questions in the field. In this article, we aim to summarize the latest information on the impact of the pandemic on blood pressure control, the use of the renin-angiotensin system inhibitors in patients with COVID-19, and the blood pressure changes as one of the possible post-acute sequelae of COVID-19 (also known as long COVID). We also summarize the evidence of telemedicine and COVID-19 vaccination in hypertensive subjects, based on data available as of June 2022.

Long COVID and hypertension-related disorders: a report from the Japanese Society of Hypertension Project Team on COVID-19.

The coronavirus disease 2019 (COVID-19) affects infected patients even after the acute phase and impairs their health and quality of life by causing a wide variety of symptoms, referred to as long COVID. Although the evidence is still insufficient, hypertension is suspected to be a potential risk factor for long COVID, and the occurrence of cardiovascular diseases seems to be a key facet of multiple conditions observed in long COVID. Nonetheless, there are few reports that comprehensively review the impacts of long COVID on hypertension and related disorders. As a sequel to our previous report in 2020 which reviewed the association of COVID-19 and hypertension, we summarize the possible influences of long COVID on hypertension-related organs, including the cardiovascular system, kidney, and endocrine system, as well as the pathophysiological mechanisms associated with the disorders in this review. Given that the clinical course of COVID-19 is highly affected by age and sex, we also review the impacts of these factors on long COVID. Lastly, we discuss areas of uncertainty and future directions, which may lead to better understanding and improved prognosis of clinical problems associated with COVID-19.

Second Nationwide Survey of Japanese Cardiac Rehabilitation Training Facilities During the Coronavirus Disease 2019 (COVID-19) Outbreak

Background: We previously reported the results of a questionnaire survey of 37 cardiac rehabilitation (CR) training facilities conducted during April 2020, in Japan. Methods and Results: We conducted a second questionnaire survey in 38 CR training facilities to explore the preventive measures against Coronavirus Disease 2019 (COVID-19) after a nationwide state of emergency was declared and to investigate differences between the 2 surveys. No significant differences were observed, except for the requirement for patients to wear surgical masks during CR (P=0.01) in the second survey. Thirty-four facilities (89%) continued CR with innovations, 61% revised their instruction manuals (vs. 46% in the first survey), and, in 39%, patients requested resumption of ambulatory CR and training videos. Conclusions: In the second survey, 74% of facilities were unable to continue conventional group ambulatory CR;however, patients maintained their physical activity and exercise regimens and managed their illnesses with the aid of telephones and mobile devices.

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.

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.

Hospitalizations for Cardiovascular Diseases During the Early Stage of the COVID-19 Pandemic in Japan.

Background: Although reductions in hospitalizations for myocardial infarction and heart failure have been reported during the period of COVID-19 pandemic restrictions, it is unclear how the overall number of hospitalizations for cardiovascular disease (CVD) treatment changed in the early stages of the pandemic. Methods and Results: We analyzed the records of 574 certified hospitals affiliated with the Japanese Circulation Society and retrieved data from April 2015 to March 2020. Records were obtained from the nationwide Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination database. A quasi-Poisson regression model was used to estimate the number of hospitalizations for CVD treatment. Between January and March 2020, when the number of COVID-19 cases was relatively low in Japan, the actual/estimated number of hospitalizations for acute CVD was 18,233/21,634 (84.3%), whereas the actual/estimated number of scheduled hospitalizations was 16,921/19,066 (88.7%). The number of hospitalizations for acute heart failure and scheduled hospitalizations for valvular disease and aortic aneurysm were 81.1%, 84.6%, and 83.8% of the estimated values, respectively. A subanalysis that considered only facilities without hospitalization restrictions did not alter the results for these diseases. Conclusions: The spread of COVID-19 was associated with a decreased number of hospitalizations for CVD in Japan, even in the early stages of the pandemic.

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.

Sex Differences in Clinical Outcomes Among Patients With COVID-19 and Cardiovascular Disease　- Insights From the CLAVIS-COVID Registry.

Background: Male sex is associated with a worse clinical course and outcomes of COVID-19, particularly in older patients. However, studies on COVID-19 patients with cardiovascular disease and/or risk factors (CVDRF), which are representative risk factors of COVID-19, are limited. In this study, we investigated the effect of sex on the outcomes of hospitalized COVID-19 patients with CVDRF. Methods and Results: We analyzed 693 COVID-19 patients with CVDRF. Patients were divided into 2 groups based on sex, and baseline characteristics and in-hospital outcomes were compared between the 2 groups. The mean age of the 693 patients was 68 years; 64.8% were men and 96.1% were Japanese. In a univariate analysis model, sex was not significantly associated with in-hospital mortality (odds ratio [OR] 1.22; 95% confidence interval [CI] 0.74-2.02; P=0.43). However, men had higher in-hospital mortality than women, especially among older (age ≥80 years) patients (OR 2.21; 95% CI 1.11-4.41; P=0.024). After adjusting for age and pivotal risk factors (hypertension, diabetes, heart failure, coronary artery disease, chronic lung disease, and chronic kidney disease), multivariate analysis suggested that male sex was an independent predictor of in-hospital mortality (OR 2.20; 95% CI 1.23-3.92; P=0.008). Conclusions: In this post hoc analysis of a nationwide registry focusing on patients with COVID-19 and CVDRF, men had higher in-hospital mortality than women, especially among older patients.

Collective Knowledge Used to Unveil Cardiovascular Injury Emerged during COVID-19.

Two years have passed since the unprecedented breakout of the global pandemic of the coronavirus disease COVID-19, which began at the end of 2019 [...].

Impact of serum lactate dehydrogenase on the short-term prognosis of COVID-19 with pre-existing cardiovascular diseases.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) and underlying cardiovascular comorbidities have poor prognoses. Our aim was to identify the impact of serum lactate dehydrogenase (LDH), which is associated with mortality in acute respiratory distress syndrome, on the prognoses of patients with COVID-19 and underlying cardiovascular comorbidities. METHODS: Among 1518 patients hospitalized with COVID-19 enrolled in the CLAVIS-COVID (Clinical Outcomes of COVID-19 Infection in Hospitalized Patients with Cardiovascular Diseases and/or Risk Factors study), 515 patients with cardiovascular comorbidities were analyzed. Patients were divided into tertiles based on LDH levels at admission [tertile 1 (T1), <235 U/L; tertile 2 (T2), 235-355 U/L; and tertile 3 (T3); ≥356 U/L]. We investigated the impact of LDH levels on the in-hospital mortality. RESULTS: The mean age was 70.4 ± 30.0 years, and 65.3% were male. There were significantly more in-hospital deaths in T3 than in T1 and T2 [n = 50 (29.2%) vs. n = 15 (8.7%), and n = 24 (14.0%), respectively; p < 0.001]. Multivariable analysis adjusted for age, comorbidities, vital signs, and laboratory data including D-dimer and high-sensitivity troponin showed T3 was associated with an increased risk of in-hospital mortality (adjusted hazard ratio, 3.04; 95% confidence interval, 1.50-6.13; p = 0.002). CONCLUSIONS: High serum LDH levels at the time of admission are associated with an increased risk of in-hospital death in patients with COVID-19 and known cardiovascular disease and may aid in triage of these patients.

Impact of body mass index on the outcome of Japanese patients with cardiovascular diseases and/or risk factors hospitalized with COVID-19 infection.

BACKGROUND: Obesity is reported to be a predictor of adverse clinical events in coronavirus disease 2019 (COVID-19) in Western countries. However, there are limited data reported regarding the prognostic impact of obesity in Asian patients. We investigated the relationship between body mass index (BMI) and in-hospital outcomes in 580 Japanese patients with cardiovascular disease and/or risk factors and who were admitted for COVID-19 infection using data from 49 hospitals in Japan. METHODS: We analyzed data from the Clinical Outcomes of COVID-19 Infection in Hospitalized Patients with Cardiovascular Disease and/or Risk Factors (CLAVIS-COVID) registry. BMI was classified into four groups accordance with the definition of the Japan Society for the Study of Obesity, as follows: underweight, <18.5 kg/m2; normal range, 18.5 to <25 kg/m2; pre-obese, 25 to 30 kg/m2; and obese, ≥30 kg/m2. RESULTS: In-hospital death occurred in 15.0% (n=87) of the patients and intubation was performed for 139 (24.0%) patients. In a multivariate analysis, we found a significant association between higher BMI and in-hospital mortality [underweight: hazard ratio (HR) 0.47, 95% confidence interval (CI) 0.23-0.97; p=0.041; pre-obese: HR 1.46, 95%CI 0.84-2.55; p=0.18; and obese: HR 3.28, 95%CI 1.34-8.02; p=0.009 vs. normal range]. In contrast, the association between BMI and the intubation rate was not statistically significant. CONCLUSIONS: Obesity was associated with a stepwise increase in the risk of in-hospital mortality in Japanese patients with COVID-19 infection. The threshold BMI for the increased risk of a worse outcome was 30, which was much lower in comparison to Western countries.

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.

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.

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.

Nationwide Survey of Japanese Cardiac Rehabilitation Training Facilities During the Coronavirus Disease 2019 Outbreak.

Background: Since the reporting of a cluster outbreak of coronavirus disease 2019 (COVID-19) in sports gyms, the Japanese Association of Cardiac Rehabilitation (CR) shared a common understanding of the importance of preventing patients and healthcare providers from contracting COVID-19. This questionnaire survey aimed to clarify the status of CR in Japan during the COVID-19 outbreak. Methods and Results: An online questionnaire survey was conducted in 37 Japanese CR training facilities after the national declaration of a state of emergency in 7 prefectures. Among these facilities, 70% suspended group ambulatory CR and 43% suspended cardiopulmonary exercise testing (CPX). In contrast, all facilities maintained individual inpatient CR. Of the 37 facilities, 95% required CR staff to wear a surgical mask during CR. In contrast, 50% of facilities did not require patients to wear a surgical mask during CR. Cardiac telerehabilitation was only conducted by a limited number of facilities (8%), because this method was still under development. In our survey, 30% of the facilities not providing cardiac telerehabilitation had specific plans for its future use. Conclusions: Our data demonstrate that ambulatory CR and CPX were suspended to avoid the spread of COVID-19. In the future, we need to consider CR resumption and develop new technologies for cardiovascular patients, including cardiac telerehabilitation.