External validation of the PE-SARD bleeding score for early major bleeding in patients with acute pulmonary embolism: From the COMMAND VTE Registry-2.

BACKGROUND: There is no established risk score for anticoagulant-related bleeding during the acute phase in patients with pulmonary embolism (PE). The Syncope, Anemia, Renal Dysfunction (PE-SARD) bleeding score was developed to predict early major bleeding, but has not yet been fully externally validated. OBJECTIVES: To externally validate the PE-SARD bleeding score. PATIENTS/METHODS: Using the COMMAND VTE Registry-2 database, which enrolled 5197 consecutive acute symptomatic venous thromboembolism patients among 31 centers in Japan between January 2015 and August 2020, we identified acute PE patients. We divided those into 3 groups by the score: high-risk (>2.5 points), intermediate-risk (1-2.5 points), and low-risk (0 points). The discriminating and calibration performances of the score for 30-day major bleeding were assessed. Subgroup analyses based on active cancer were also performed. RESULTS: Of 2781 eligible patients, the high-risk group accounted for 557 patients (20%), intermediate-risk group for 1412 (51%), and low-risk group for 812 (29%). Major bleeding occurred in 121 patients within 30 days. The cumulative 30-day incidence of major bleeding substantially increased in the higher risk categories by the score (high-risk group: 8.2% [95%CI, 5.9%-10.5%], intermediate-risk group: 4.6% [95%CI, 3.5%-5.7%], and low-risk group: 1.8% [95%CI, 0.8%-2.7%]). The discriminating power of the score was modest with a C-statistic of 0.65 (95%CI, 0.61-0.70) with a good calibration performance with a score of <4 points except for in active cancer patients. CONCLUSIONS: The PE-SARD bleeding score had a modest discriminating performance with a limited calibration performance in acute PE patients without active cancer.

Statins use and recurrent venous thromboembolism in the direct oral anticoagulant era: insight from the COMMAND VTE Registry-2.

Statins were reported to have a potential effect of primary prevention of venous thromboembolism (VTE), although that of secondary prevention remains uncertain. To investigate the association between statins use and recurrent VTE in the current era. The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive VTE patients among 31 centers in Japan between January 2015 and August 2020. We divided the entire cohort into 2 groups according to statins use at the time of discharge; the statins (N = 865) and no statins groups (N = 4332). The statins group was older (72.9 vs. 66.7 years, P < 0.001), and less often had active cancer (22.0% vs. 30.4%, P < 0.001). The cumulative incidence of discontinuation of anticoagulation was significantly lower in the statins group (60.3% vs. 52.6%, Log-rank P < 0.001). The cumulative 5-year incidence of recurrent VTE was significantly lower in the statins group (6.8% vs. 10.1%, Log-rank P = 0.01). Even after adjusting for the confounders, the lower risk of the statins group relative to the no statins group remained significant for recurrent VTE (HR 0.65, 95% CI 0.45-0.91, P = 0.01). The cumulative 5-year incidence of major bleeding was significantly lower in the statins group (12.2% vs. 14.1%, Log-rank P = 0.04), although, after adjusting for the confounders, the risk of the statins group relative to the no statins group turned to be insignificant (HR 0.77, 95% CI 0.59-1.00, P = 0.054). In this large real-world VTE registry, statins use was significantly associated with a lower risk for the recurrent VTE in the current era.

Edoxaban, Rivaroxaban, or Apixaban for Cancer-Associated Venous Thromboembolism in the Real World: Insights from the COMMAND VTE Registry-2.

BACKGROUND: Real-world data on clinical characteristics and outcomes related to the use of different direct oral anticoagulants (DOACs) for cancer-associated venous thromboembolism (VTE) is lacking. METHODS: The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive patients with acute symptomatic VTE from 31 centers in Japan from January 2015 to August 2020. Our study population comprised 1,197 patients with active cancer who were divided into the edoxaban (N = 643, 54%), rivaroxaban (N = 297, 25%), and apixaban (N = 257, 22%) groups. RESULTS: The cumulative 5-year incidence of recurrent VTE (9.3, 10.2, and 8.5%, respectively, p = 0.82) and all-cause death (67.5, 66.8, and 63.8%, respectively, p = 0.22) did not differ among the groups. Despite adjusting for confounders, the risks of recurrent VTE and all-cause death did not differ significantly among the groups. The cumulative 5-year incidence of major and clinically relevant bleeding was significantly lower in the rivaroxaban group than those in the other groups (22.6, 14.0, and 22.8%, p = 0.04; and 37.6, 26.8, and 38.3%, p = 0.01, respectively). After adjusting for confounders, in the rivaroxaban group, the risk for major bleeding was numerically lower (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.40-1.01) and that of clinically relevant all bleeding was significantly lower (HR: 0.67, 95% CI: 0.48-0.92) than those in the edoxaban group. CONCLUSION: The risks of recurrent VTE and all-cause death did not differ significantly among the different DOACs ; however, the risk of bleeding events could differ, with a potentially lower risk of bleeding with rivaroxaban.

A cAMP-biosensor-based assay for measuring plasma arginine-vasopressin levels.

Arginine-vasopressin (AVP), a cyclic peptide hormone composed of nine amino acids, regulates water reabsorption by increasing intracellular cyclic adenosine monophosphate (cAMP) concentrations via the vasopressin V2 receptor (V2R). Plasma AVP is a valuable biomarker for the diagnosis of central diabetes insipidus (CDI) and is commonly measured using radioimmunoassay (RIA). However, RIA has several drawbacks, including a long hands-on time, complex procedures, and handling of radioisotopes with special equipment and facilities. In this study, we developed a bioassay to measure plasma AVP levels using HEK293 cells expressing an engineered V2R and a cAMP biosensor. To achieve high sensitivity, we screened V2R orthologs from 11 various mammalian species and found that the platypus V2R (pV2R) responded to AVP with approximately six-fold higher sensitivity than that observed by the human V2R. Furthermore, to reduce cross-reactivity with desmopressin (DDAVP), a V2R agonist used for CDI treatment, we introduced a previously described point mutation into pV2R, yielding an approximately 20-fold reduction of responsiveness to DDAVP while maintaining responsiveness to AVP. Finally, a comparison of plasma samples from 12 healthy individuals demonstrated a strong correlation (Pearson's correlation value: 0.90) between our bioassay and RIA. Overall, our assay offers a more rapid and convenient method for quantifying plasma AVP concentrations than existing techniques.

Subclass phenotypes in patients with unprovoked venous thromboembolisms using a latent class analysis.

BACKGROUND: Patients with unprovoked venous thromboembolisms (VTEs) can be sub-classified based on the different phenotypes using a latent class analysis (LCA), which might be useful for selecting individual management strategies. METHODS: In the COMMAND VTE Registry-2 database enrolling 5197 VTE patients, the current derivation cohort consisted of 1556 patients with unprovoked VTEs. We conducted clustering with an LCA, and the patients were classified into subgroups with the highest probability. We compared the clinical characteristics and outcomes among the developed subgroups. RESULTS: This LCA model proposed 3 subgroups based on 8 clinically relevant variables, and classified 592, 813, and 151 patients as Class I, II, and III, respectively. Based on the clinical features, we named Class I the younger, Class II the older with a few comorbidities, and Class III the older with many comorbidities. The cumulative 3-year anticoagulation discontinuation rate was highest in the older with many comorbidities (Class III) (39.9 %, 36.1 %, and 48.4 %, P = 0.02). There was no significant difference in the cumulative 5-year incidence of recurrent VTEs among the 3 classes (12.8 %, 11.1 %, and 4.0 % P = 0.20), whereas the cumulative 5-year incidence of major bleeding was significantly higher in the older with many comorbidities (Class III) (7.8 %, 12.7 %, and 17.8 %, P = 0.04). CONCLUSION: The current LCA revealed that patients with unprovoked VTEs could be sub-classified into further phenotypes depending on the patient characteristics. Each subclass phenotype could have different clinical outcomes risks especially a bleeding risk, which could have a potential benefit when considering the individual anticoagulation strategies. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/index.htm COMMAND VTE Registry-2: Unique identifier, UMIN000044816 COMMAND VTE Registry: Unique identifier, UMIN000021132.

Association of left atrial enlargement with heart failure events in non-valvular atrial fibrillation patients with preserved left ventricular ejection fraction.

Aims: Atrial fibrillation (AF) increases the risk of heart failure (HF); however, little is known regarding the risk stratification for incident HF in AF patients, especially with preserved left ventricular ejection fraction (LVEF). Methods and results: The Fushimi AF Registry is a community-based prospective survey of AF patients. From the registry, 3002 non-valvular AF patients with preserved LVEF and with the data of antero-posterior left atrial diameter (LAD) at enrolment were investigated. Patients were stratified by LAD (<40, 40-44, 45-49, and ≥50 mm) with backgrounds and HF hospitalization incidences compared between groups. Of 3002 patients [mean age, 73.5 ± 10.7 years; women, 1226 (41%); paroxysmal AF, 1579 (53%); and mean CHA2DS2-VASc score, 3.3 ± 1.7], the mean LAD was 43 ± 8 mm. Patients with larger LAD were older and less often paroxysmal AF, with a higher CHA2DS2-VASc score (all P < 0.001). Heart failure hospitalization occurred in 412 patients during the median follow-up period of 6.0 years. Larger LAD was independently associated with a higher HF hospitalization risk [LAD ≥ 50 mm: hazard ratio (HR), 2.36; 95% confidence interval (CI), 1.75-3.18; LAD 45-49 mm: HR, 1.84; 95% CI, 1.37-2.46; and LAD 40-44 mm: HR, 1.34; 95% CI, 1.01-1.78, compared with LAD < 40 mm) after adjustment by age, sex, AF type, and CHA2DS2-VASc score. These results were also consistent across major subgroups, showing no significant interaction. Conclusion: Left atrial diameter is significantly associated with the risk of incident HF in AF patients with preserved LVEF, suggesting the utility of LAD regarding HF risk stratification for these patients.

Home Treatment for Active Cancer Patients With Low-Risk Pulmonary Embolism　- A Predetermined Companion Report From the ONCO PE Trial.

BACKGROUND: Patients with appropriately selected low-risk pulmonary embolism (PE) can be treated at home, although it has been controversial whether applies to patients with cancer, who are considered not to be at low risk.Methods and Results: The current predetermined companion report from the ONCO PE trial evaluated the 3-month clinical outcomes of patients with home treatment and those with in-hospital treatment. The ONCO PE trial was a multicenter, randomized clinical trial among 32 institutions in Japan investigating the optimal duration of rivaroxaban treatment in cancer-associated PE patients with a score of 1 using the simplified version of the Pulmonary Embolism Severity Index (sPESI). Among 178 study patients, there were 66 (37%) in the home treatment group and 112 (63%) in the in-hospital treatment group. The primary endpoint of a composite of PE-related death, recurrent venous thromboembolism (VTE) and major bleeding occurred in 3 patients (4.6% [0.0-9.6%]) in the home treatment group and in 2 patients (1.8% [0.0-4.3%]) in the in-hospital treatment group. In the home treatment group, there were no cases of PE-related death or recurrent VTE, but major bleeding occurred in 3 patients (4.6% [0.0-9.6%]), and 2 patients (3.0% [0.0-7.2%]) required hospitalization due to bleeding events. CONCLUSIONS: Active cancer patients with PE of sPESI score=1 could be potential candidates for home treatment.

Development and basic performance verification of a rapid homogeneous bioassay for agonistic antibodies against the thyroid-stimulating hormone receptor.

Graves' disease is a type of autoimmune hyperthyroidism caused by thyroid-stimulating antibodies (TSAb).1 The combination of a porcine thyroid cell bioassay and cyclic adenosine monophosphate (cAMP) immunoassay (TSAb-enzyme immunoassay; EIA) is a clinically approved TSAb measurement method. Due to the requirement of multiple procedures and a long assay time of 6 h in the TSAb-EIA, a simplified and rapid assay is desired. Herein, we developed a rapid homogeneous TSAb bioassay (rapid-TSAb assay) using the human embryonic kidney cell line (HEK293), engineered to express the human thyroid-stimulating hormone receptor (TSHR), along with a cAMP-dependent luminescence biosensor. The measurement consists of three steps: thawing frozen cells, blood sample addition, and luminescence detection. The procedures can be conducted within 1 h. The World Health Organization International Standard TSAb (NIBSC 08/204) stimulated the cells co-expressing TSHR and cAMP biosensor. The intra- and inter-assay coefficients of variance were < 10%. Stimulation activity using wild-type TSHR and chimeric TSHR (Mc4) almost completely correlated with the tested Graves' disease and normal samples. In the rapid-TSAb assay, the evaluation of 39 samples, including TSHR antibody-positive sera, yielded a sensitivity of 100.0% and a specificity of 90.9%, compared to the TSAb-EIA control. The rapid-TSAb assay enables simple and rapid measurement of TSAb and is promising for improving the diagnosis of autoimmune thyroid diseases.

Fragility and long-term clinical outcomes in patients with venous thromboembolism receiving direct oral anticoagulants: From the COMMAND VTE REGISTRY-2.

INTRODUCTION: There is limited data on the safety of direct oral anticoagulants (DOACs) in fragile patients with venous thromboembolism (VTE). MATERIALS AND METHODS: We used the COMMAND VTE Registry-2 enrolling patients with acute symptomatic VTE. The study population consisted of 3928 patients receiving DOACs, who were divided into fragile (2136 patients) and non-fragile groups (1792 patients). Fragility was defined as patients of age ≥ 75 years, creatinine clearance level ≤ 50 ml/min, and/or body weight ≤ 50 kg. RESULTS: The fragile group significantly more often received reduced doses of DOACs compared to the non-fragile group (51 % and 19 %, P < 0.001). The cumulative 5-year incidence of major bleeding was numerically higher in the fragile group than the non-fragile group (15.0 % and 11.1 %, P = 0.052), even with no significant excess risk after adjusting for confounders (HR 1.03, 95%CI 0.81-1.31, P = 0.78). The cumulative 5-year incidence of clinically relevant bleeding was significantly higher in the fragile group than the non-fragile group (28.6 % and 19.6 %, P < 0.001), even after adjusting for confounders (HR 1.28, 95%CI 1.08-1.53, P = 0.005). There was no significant difference in cumulative 5-year incidence of recurrent VTE between the groups (9.6 % and 8.9 %, P = 0.68), which was consistent after adjusting for confounders (HR 1.13, 95%CI 0.84-1.51, P = 0.41). CONCLUSIONS: Among VTE patients receiving DOACs, fragile patients were associated with a numerically higher rate of major bleeding and a significantly increased risk of clinically relevant bleeding, but not an increased risk of recurrent VTE.

Cancer-associated venous thromboembolism in the direct oral anticoagulants era: Insight from the COMMAND VTE Registry-2.

BACKGROUND: There is a paucity of data on real-world management strategies and clinical outcomes of cancer-associated venous thromboembolism (VTE) in the direct oral anticoagulants (DOACs) era. OBJECTIVES: To investigate the status of cancer-associated VTE in the DOAC era. METHODS: This multicenter, retrospective cohort study among 31 centers in Japan between 2015 and 2020 enrolled 5197 consecutive patients with acute symptomatic VTE, who were divided into 1507 patients (29 %) with active cancer and 3690 patients (71 %) without. RESULTS: The cumulative 3-year rate of anticoagulation discontinuation was significantly higher in patients with active cancer than in those without (62.7 % vs. 59.1 %, P < 0.001). The cumulative 5-year incidence of recurrent VTE was higher in patients with active cancer than in those without (10.1 % vs. 9.1 %, P = 0.01), however, after adjusting for the confounders and competing risk of mortality, the excess risk of the active cancer group relative to the no active cancer group was no longer significant (HR: 0.95, 95 % CI: 0.73-1.24). The cumulative 5-year incidence of major bleeding was much higher in the active cancer group (20.4 % vs. 11.6 %, P < 0.001). Even after adjusting for the confounders and competing risk of mortality, the risk of the active cancer group relative to the no active cancer group remained significant (HR: 1.36, 95 % CI: 1.11-1.66). CONCLUSIONS: The current large real-world registry revealed that the risk of major bleeding was still higher in patients with active cancer than in those without, leading to the frequent anticoagulation discontinuation, which has been still a huge challenge to overcome in the DOAC era.

Proteinuria is independently associated with heart failure events in patients with atrial fibrillation: the Fushimi AF registry.

AIMS: Previous studies have shown that proteinuria is independently associated with the incidence of atrial fibrillation (AF), and is also associated with the incidence of cardiovascular events such as stroke and thromboembolism in patients with AF. However, the association of proteinuria with heart failure (HF) events in patients with AF remains unclear. METHODS AND RESULTS: The Fushimi AF Registry is a community-based prospective study of patients with AF. Of the entire cohort of 4489 patients, 2164 patients had available data of proteinuria. We compared the clinical background and outcomes between patients with proteinuria (n = 606, 28.0%) and those without (n = 1558, 72.0%). Patients with proteinuria were older and had a higher prevalence of major co-morbidities. During the median follow-up of 5.0 years, the incidence rates of HF events (composite of cardiac death or HF hospitalization) were higher in patients with proteinuria than those without (4.1% vs. 2.1% person-year, P < 0.01). Multivariate analyses revealed that proteinuria was an independent risk factor of the incidence of HF events [adjusted hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.13-1.74]. This association was consistent among the various subgroups, except for the age subgroup in which there was a significant interaction (P < 0.01) between younger (<75 years) (unadjusted HR: 3.03, 95% CI: 2.12-4.34) and older (≥75 years) patients (unadjusted HR: 1.59, 95% CI: 1.23-2.05). CONCLUSION: Our community-based large prospective cohort suggests that proteinuria is independently associated with the incidence of HF events in Japanese patients with AF.

A case of infective endocarditis mimicking antineutrophil cytoplasmic antibody-associated vasculitis.

Infective endocarditis (IE) is not a common disease, but it remains a serious condition. Antineutrophil cytoplasmic antibodies (ANCA) are often positive in IE, and discrimination between IE and ANCA-associated vasculitis is important because misdirected selection of therapy can lead to catastrophic consequences. We report a case of IE mimicking ANCA-associated vasculitis in which we were able to make a correct diagnosis and perform treatment. This case suggests that it is important to consider IE as a differential diagnosis in ANCA-positive patients. Learning objective: Antineutrophil cytoplasmic antibodies (ANCA) are associated with primary systemic vasculitis. However, ANCA have also been described in other conditions and infective endocarditis (IE) was considered an important cause of ANCA.Discrimination between IE and ANCA-associated vasculitis is important, although it is sometimes difficult. We report a case of IE mimicking ANCA-associated vasculitis. ANCA-positive patients with nonspecific symptoms should be suspected of having IE, checked for heart murmurs, and tested by echocardiography and blood cultures.

Association of Concomitant Coronary Artery Disease With Cardiovascular Events in Patients With Atrial Fibrillation　- The Fushimi AF Registry.

BACKGROUND: Atrial fibrillation (AF) patients often have concomitant coronary artery disease (CAD); however, there are little data on clinical characteristics and outcomes of such patients in daily clinical practice in Japan.Methods and Results: The Fushimi AF Registry is a community-based prospective survey of AF patients in Fushimi-ku, Kyoto, Japan. Follow-up data were available for 4,464 patients, and the median follow up was 5.1 (interquartile range: 2.3-8.0) years. History of CAD was present in 647 patients (14%); of those patients, 267 (41%) had history of myocardial infarction (MI). Patients with CAD were older and had more comorbidities than those without CAD. The crude incidences (% per patient-year) of cardiovascular events were significantly higher in patients with CAD than those without CAD (cardiac death: 1.8 vs. 0.7, stroke or systemic embolism [SE]: 2.9 vs. 2.1, MI: 0.6 vs. 0.1, composite of those events: 5.1 vs. 2.8, respectively, all log-rank P<0.01). After multivariate adjustment, concomitant CAD was associated with incidence of cardiac events, and history of MI was associated with incidence of MI; however, neither history of CAD nor MI was associated with the incidence of stroke/SE. CONCLUSIONS: In Japanese AF patients, concomitant CAD was associated with higher prevalences of major co-morbidities and higher incidences of cardiovascular events; however, history of CAD was not associated with the incidence of stroke/SE.

Multisystem Inflammatory Syndrome in Adults Accompanied with Kikuchi-Fujimoto Disease.

We herein report a case of multisystem inflammatory syndrome in adults (MIS-A) complicated with Kikuchi-Fujimoto disease (KFD). A previously healthy 41-year-old man presented with painful swelling of the cervical lymph nodes, fever, diarrhea, conjunctivitis, edema, and hypotension one month after the onset of asymptomatic coronavirus disease 2019. Laboratory investigations revealed an elevation of CRP, and echocardiography indicated diastolic dysfunction. We diagnosed the patient to have MIS-A. Histopathology of the lymph nodes showed necrotizing lymphadenitis. After the initiation of hydrocortisone and diuretics, his symptoms resolved immediately. This case suggested that post-viral immune dysregulation in MIS-A could play a role in the etiology of KFD.

10-Year Trends of Antithrombotic Therapy Status and Outcomes in Japanese Atrial Fibrillation Patients　- The Fushimi AF Registry.

BACKGROUND: Atrial fibrillation (AF) increases the risk of stroke and death. Oral anticoagulants (OAC) are highly effective in reducing the risk of stroke, and direct oral anticoagulants (DOAC) became available worldwide in 2011.Methods and Results:The Fushimi AF Registry is an on-going prospective survey of AF patients in Fushimi-ku, Kyoto, Japan. The study cohort consisted of 4,489 patients (mean age 73.6 years, 59.6% male, mean CHADS2score 2.03), enrolled in 2011-2017. From 2011 to 2021, antithrombotic therapy has undergone a major transition; the proportion of patients receiving OAC has increased from 53% to 70%, with a steady uptake of DOAC (from 2% to 52%), whereas the proportion of patients receiving antiplatelet agents has decreased from 32% to 14%. Over a median follow-up of 5.1 years, the incidence of stroke/systemic embolism (SE), major bleeding, and all-cause death was 2.2%, 1.9%, and 4.9% per patient-year, respectively. The incidence of stroke/SE (1.6% vs. 2.3%; P<0.01), major bleeding (1.6% vs. 2.0%; P=0.07), and death (4.2% vs. 5.0%; P<0.01) was lower among patients enrolled in 2014-2017 than in 2011-2013, despite comparable baseline characteristics (age 73.2 vs. 73.7 years, CHADS2score 2.03 vs. 2.04, and HAS-BLED score 1.67 vs. 1.77, respectively). CONCLUSIONS: Over the past 10 years, there has been a major transition in antithrombotic therapy and a decline in the incidence of adverse events in AF patients.

Periprocedural management and clinical outcomes of invasive procedures after venous thromboembolism: from the COMMAND VTE registry.

Anticoagulation therapy is prescribed for the prevention of recurrence in patients with venous thromboembolism, which could be temporarily interrupted during invasive procedures. The COMMAND VTE Registry is a multicenter registry enrolling 3027 consecutive patients with acute symptomatic VTE in Japan between January 2010 and August 2014. We identified patients who underwent invasive procedures during the entire follow-up period and evaluated periprocedural managements and clinical outcomes at 30 days after invasive procedures. During a median follow-up period of 1213 (IQR: 847-1764) days, 518 patients underwent invasive procedures with the cumulative incidences of 5.8% at 3 months, 11.1% at 1 year, and 24.0% at 5 years. Among 382 patients in high bleeding-risk category of invasive procedures, anticoagulation therapy had been discontinued already in 62 patients (16%) and interrupted temporarily in 288 patients (75%) during the invasive procedures with bridging anticoagulation therapy with heparin in 214 patients (56%). Among 80 patients in low bleeding-risk category, anticoagulation therapy had been already discontinued in 15 patients (19%) and interrupted temporarily in 31 patients (39%) during invasive procedure with bridging anticoagulation therapy with heparin in 17 patients (21%). At 30 days after the invasive procedures, 14 patients (2.7%) experienced recurrent VTE, while 28 patients (5.4%) had major bleeding. This study elucidated the real-world features of peri-procedural management and prognosis in patients with VTE who underwent invasive procedures during follow-up in the large multicenter VTE registry. The 30-day incidence rates of recurrent VTE and major bleeding events were 2.7% and 5.4%.

Isometric Handgrip Stress Test during Right Heart Catheterization in Patients with Mitral Regurgitation -A Case Series Study.

Objective The severity of mitral regurgitation (MR) dynamically changes during a stress test. Isometric handgrip is a readily-available stress test in daily practice; however, little is known regarding the response to isometric handgrip in MR patients during right heart catheterization. We aimed to evaluate this issue from our case-series study. Methods We retrospectively investigated consecutive MR patients using the isometric handgrip stress test during right heart catheterization at our institution between October 2019 and April 2021. After resting measurements were obtained, sustained maximum-effort hand dynamometer grasping was maintained for about 2-3 minutes. We investigated the differences in right heart catheterization data between at rest and during handgrip, and evaluated the individual response to the isometric handgrip stress test. Results We investigated a total of 15 patients (mean age: 75±6 years, moderate/severe MR: 7/8, primary/secondary MR: 8/7, mean left ventricular ejection fraction: 56±16%, exertional dyspnea: 10). During the handgrip test, the pulmonary capillary wedge pressure (PCWP) significantly increased [9 (8, 13) mmHg at rest to 20 (15, 27) mmHg during handgrip; p<0.001]. PCWP changes varied among individuals (range 2-22 mmHg) and were not correlated with patients' backgrounds including age, the natriuretic peptide levels, left ventricular ejection fraction, left atrial diameter or E/e' (all p>0.05). Patients with PCWP ≥25 mmHg during handgrip had a higher prevalence of exertional dyspnea than those without [6 (100%) vs. 4 (44%); p=0.04]. Conclusion We observed dynamic and varied hemodynamic changes during isometric handgrip in MR patients, suggesting that further research is needed to evaluate the clinical value of this maneuver.

Clinical Characteristics and Outcomes of Very Elderly Patients With Atrial Fibrillation at High Bleeding Risk　- The Fushimi AF Registry.

Background: The ELDERCARE-AF trial demonstrated that low-dose edoxaban prevented stroke or systemic embolism (SE) in very elderly Japanese patients with non-valvular atrial fibrillation (NVAF) in whom standard oral anticoagulant therapy was inappropriate because of high bleeding risk. The aim of this study was to elucidate the characteristics and outcomes of such patients in routine clinical practice. Methods and Results: Data were extracted from the Fushimi AF Registry for ELDERCARE-eligible NVAF patients aged ≥80 years, with a CHADS2 score ≥2 and ≥1 bleeding risk factors, as shown in the ELDERCARE-AF trial. ELDERCARE-eligible patients (n=549; 12.8% of the entire cohort, 52.9% of those aged ≥80 years and with CHADS2 score ≥2) were less often male, were older, had more comorbidity and higher risk scores than non-eligible patients from the entire cohort (n=3,734). The crude incidence (% per patient-year) of adverse events was significantly higher in ELDERCARE-eligible than non-eligible patients (stroke/SE, 4.8% vs. 2.0%; major bleeding, 3.6% vs. 1.9%; all-cause mortality, 15.5% vs. 3.9%; cardiovascular death, 2.7% vs. 0.6%; all log-rank P<0.001). Compared with non-eligible patients aged ≥80 years and with a CHADS2 score ≥2 (n=488), the incidence of stroke/SE, all-cause mortality, and cardiovascular death remained significantly higher in ELDERCARE-eligible patients. Conclusions: Patients with NVAF who met the inclusion criteria of the ELDERCARE-AF trial were common in routine clinical practice, and had poor clinical outcomes.

Characteristics and clinical outcomes in atrial fibrillation patients classified using cluster analysis: the Fushimi AF Registry.

AIMS: The risk of adverse events in atrial fibrillation (AF) patients was commonly stratified by risk factors or clinical risk scores. Risk factors often do not occur in isolation and are often found in multimorbidity 'clusters' which may have prognostic implications. We aimed to perform cluster analysis in a cohort of AF patients and to assess the outcomes and prognostic implications of the identified comorbidity cluster phenotypes. METHODS AND RESULTS: The Fushimi AF Registry is a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto, Japan. Hierarchical cluster analysis was performed on 4304 patients (mean age: 73.6 years, female; 40.3%, mean CHA2DS2-VASc score 3.37 ± 1.69), using 42 baseline clinical characteristics. On hierarchical cluster analysis, AF patients could be categorized into six statistically driven comorbidity clusters: (i) younger ages (mean age: 48.3 years) with low prevalence of risk factors and comorbidities (n = 209); (ii) elderly (mean age: 74.0 years) with low prevalence of risk factors and comorbidities (n = 1301); (iii) those with high prevalence of atherosclerotic risk factors, but without atherosclerotic disease (n = 1411); (iv) those with atherosclerotic comorbidities (n = 440); (v) those with history of any-cause stroke (n = 681); and (vi) the very elderly (mean age: 83.4 years) (n = 262). Rates of all-cause mortality and major adverse cardiovascular or neurological events can be stratified by these six identified clusters (log-rank test; P < 0.001 and P < 0.001, respectively). CONCLUSIONS: We identified six clinically relevant phenotypes of AF patients on cluster analysis. These phenotypes can be associated with various types of comorbidities and associated with the incidence of clinical outcomes. CLINICAL TRIAL REGISTRATION INFORMATION: https://www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000005834.

Iatrogenic ventricular fibrillation caused by inappropriately synchronized cardioversion in a patient with pre-excited atrial fibrillation: A case report.

Direct-current (DC) cardioversion is effective at terminating arrhythmias in an emergency. During treatment, energy delivery synchronizing with the QRS complex is essential to avoid ventricular fibrillation (VF) caused by a shock on the T wave, which is the vulnerable period of ventricular repolarization. However, distinguishing the QRS from the T wave is difficult in some patients with abnormal, irregular, and varying QRS complexes. We report the case of a 45-year-old man who had iatrogenic VF caused by inappropriate synchronization with the T wave during cardioversion of pre-excited atrial fibrillation due to high ventricular rates and varying R wave amplitude affected by an accessory pathway. .