R2-CHA2DS2-VASc Score for Cardiovascular Event Prediction After Bioprosthetic Valve Replacement　- Subanalysis From the BPV-AF Registry.

Background: There are few studies evaluating the prognostic prediction method in atrial fibrillation (AF) patients after bioprosthetic valve (BPV) replacement. The R2-CHA2DS2-VASc score is increasingly used for the prediction of cardiovascular (CV) events in patients with AF, device implantation, and acute coronary syndrome. We aimed to evaluate the predictive value of the R2-CHA2DS2-VASc score for future CV events in AF patients after BPV replacement. Methods and Results: The BPV-AF, an observational, multicenter, prospective registry, enrolled AF patients who underwent BPV replacement. The primary outcome measure was a composite of stroke, systemic embolism, CV events including heart failure requiring hospitalization, and cardiac death. A total of 766 patients was included in the analysis. The mean R2-CHA2DS2-VASc score was 5.7±1.8. Low (scores 0-1), moderate (scores 2-4), and high (scores 5-11) R2-CHA2DS2-VASc score groups consisted of 12 (1.6%), 178 (23.2%), and 576 (75.2%) patients, respectively. The median follow-up period was 491 (interquartile range 393-561) days. Kaplan-Meier analysis showed a higher incidence of the composite CV events in the high R2-CHA2DS2-VASc score group (log rank test; P<0.001). Multivariate Cox proportional hazards regression analysis revealed that the R2-CHA2DS2-VASc score as a continuous variable was an independent predictor of composite CV outcomes (hazard ratio 1.36; 95% confidence interval 1.18-1.55; P<0.001). Conclusions: The R2-CHA2DS2-VASc score is useful for CV risk stratification in AF patients after BPV replacement.

A novel 7-phenoxy-benzimidazole derivative as a potent and orally available BRD4 inhibitor for the treatment of melanoma.

The bromodomain-containing protein 4 (BRD4), which is a key epigenetic regulator in cancer, has emerged as an attractive target for the treatment of melanoma. In this study, we investigate 7-phenoxy-benzimidazole derivative 12, which is a novel BRD4 inhibitor for the treatment of melanoma, by performing scaffold hopping on the previously reported benzimidazole derivative 1. Despite their good oral and intravenous exposure, the compounds obtained by modifying derivate 1 exhibit mutagenicity, which was confirmed by the positive Ames test results. Based on our hypothesis that the cause of the Ames test positivity is the metabolic intermediates generated from those chemical series, we implemented a scaffold hopping strategy to avoid the N-benzyl moiety by relocating the substituent groups to preserve the essential interaction. Based on this strategy, we successfully obtained compound 12; the Ames test results of this compound were negative. Notably, compound 12 not only exhibited a favorable pharmacokinetic (PK) profile but also significant tumor growth inhibition in a mouse melanoma xenograft model, indicating its potential as a therapeutic agent for the treatment of melanoma.

Impact of Dietary Vitamin K Intake on Anticoagulation Therapy in Patients With Left Ventricular Assist Device During the 2018 Osaka Earthquake.

Background: The 2018 Osaka earthquake caused severe damage to the National Cerebral and Cardiovascular Center, and the interruption to the delivery of hospital food in particular had a significant effect on patients with left ventricular assist devices (LVAD). Methods and Results: We retrospectively assessed 10 patients who had been provided with emergency rations on the day of earthquake and the next day for breakfast. Catered foods were provided thereafter. Vitamin K content was largely reduced due to emergency rations; the prothrombin time-international normalized ratio (PT-INR) on day 2 was significantly higher than on day 1. Conclusions: Close monitoring of PT-INR and assessing vitamin K content may be important for preventing complications in patients with a LVAD during a disaster.

Clinical effects of direct oral anticoagulants in elderly patients with a bioprosthetic valve and atrial fibrillation.

BACKGROUND: Current guidelines recommend direct oral anticoagulants (DOACs) and warfarin for patients with atrial fibrillation (AF) who have a bioprosthetic valve (BPV). However, the data related to elderly patients (aged ≥80 years) with BPV replacement and AF are limited. METHODS: This post-hoc subgroup analysis of a BPV-AF Registry enrolled 752 patients with BPV replacement and AF. The primary net outcome was a composite of cardiac death, stroke, systemic embolism, major bleeding, and cardiovascular events. RESULTS: Among 752 patients, 429 (57%) patients were ≥ 80 and 323 (43%) were < 80 years old. The higher risk in patients aged ≥80 than <80 years was significant for the net outcome (hazard ratio [HR], 2.04; 95% confidence interval [CI], 1.31-3.17; P = 0.001). After adjustment for confounders, there was no statistically significant difference between warfarin (reference) and DOAC users in the risk of net outcomes (adjusted HR, 1.26; 95% CI, 0.71-2.24; P = 0.44), stroke and systemic embolism (adjusted HR, 2.01; 95% CI, 0.48-8.38; P = 0.34), and major bleeding (adjusted HR, 0.73; 95% CI, 0.11-4.98; P = 0.75) in patients aged ≥80 years old as well as those aged <80 years. Among 489 warfarin users, the cumulative incidence of net outcomes tended to be higher in patients aged ≥80 than <80 years (12.2% vs. 5.7% at 1 year, log-rank P = 0.002). Among 263 DOAC users, however, it was similar between patients aged ≥80 and < 80 years. CONCLUSIONS: The present study demonstrated that DOAC showed similar efficacy and safety compared with warfarin even in elderly patients aged ≥80 years with BPV replacement and AF.

Successful Implantation of Rapid Deployment Aortic Valve after TAVR Explantation.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) has become widely used in recent years, However, there is also an increasing need for removal of TAVR valves due to prosthetic valve dysfunction (PVD) and the development of infective endocarditis. Surgical aortic valve replacement (AVR) for these patients is risky due to the original patient background and anatomic conditions. Intuity rapid deployment aortic valve (Edwards Lifesciences, Irvine, CA) replacement would be useful for such high risk patients to prevent longer cardiac arrest time and obtain good hemodynamic results. However, there are few reports which present Intuity valve replacement after TAVR explantation. Herein, We report two cases in which we have achieved good hemodynamics with shorter cardiac arrest times by using a rapid deployment valve after TAVR explantation. CASE PRESENTATION: We present 2 cases of successful implantation of the Intuity rapid deployment valve after TAVR explantation. The 84- and 88-year-old female patients had previously received TAVR for severe aortic stenosis with SAPIEN XT (Edwards Lifesciences, Irvine, CA) and developed PVD during follow-up. The TAVR valve was removed carefully, then an Intuity valve was implanted with cardiac arrest times of 69 and 41 min. Both patients had good echocardiographic results with effective orifice area of 2.0 cm2 and 1.2 cm2 and mean trans-aortic plessure gradient of 9 mmHg and 15 mmHg respectively without aortic regurgitation. They were discharged without major complications. CONCLUSIONS: Surgical AVR using a rapid deployment valve is a useful alternative to sutured AVR after TAVR valve explantation. It allows for shorter cardiac arrest times and better postoperative hemodynamics without major complication.

Risk factors for placenta accreta spectrum in pregnancies conceived after frozen-thawed embryo transfer in a hormone replacement cycle.

OBJECTIVE: Assisted reproductive technology (ART), especially frozen-thawed embryo transfer (FET) in a hormone replacement cycle (HRC), is a risk factor for placenta accreta spectrum (PAS). This study aimed to clarify the risk factors for PAS related to the maternal background and ART techniques in pregnancies achieved after FET in an HRC. STUDY DESIGN: We performed a case-control study in two tertiary perinatal centres in Japan. Among 14,028 patients who delivered at ≥24 weeks of gestation or were transferred after delivery to two tertiary perinatal centres between 2010 and 2021, 972 conceived with ART and 13,056 conceived without ART. PAS was diagnosed on the basis of the FIGO classification for the clinical diagnosis of PAS or retained products of conception after delivery at ≥24 weeks of gestation. We excluded women with fresh embryo transfer, FET with a spontaneous ovulatory cycle, a donor oocyte cycle, and missing details of the ART treatment. Finally, among women who conceived after FET in an HRC, 62 with PAS and 340 without PAS were included in this study. Multivariate logistic regression models were used for case-control comparisons, with adjustment for maternal age at delivery, parity, endometriosis or adenomyosis, the number of previous uterine surgeries of caesarean section, myomectomy, endometrial polypectomy or endometrial curettage, placenta previa, the stage of transferred embryos, and endometrial thickness at the initiation of progestin administration. RESULTS: PAS was associated with ≥2 previous uterine surgeries (adjusted odds ratio, 3.57; 95 % confidence interval, 1.60-7.97) and the stage of embryo transfer (blastocysts: adjusted odds ratio, 2.89; 95 % confidence interval, 1.15-7.26). In patients with <2 previous uterine surgeries, PAS was associated with an endometrial thickness of <7.0 mm (adjusted odds ratio, 5.18; 95 % confidence interval, 1.10-24.44). CONCLUSION: Multiple uterine surgeries and the transfer of blastocysts are risk factors for PAS in pregnancies conceived after FET in an HRC. In women with <2 previous uterine surgeries, a thin endometrium before FET is also a risk factor for PAS in these pregnancies.

Alcohol synthesis based on the SN2 reactions of alkyl halides with the squarate dianion.

A convenient method has been developed for transforming alkyl halides into the corresponding alcohols via an SN2 reaction. Treatment of an alkyl halide with the squarate dianion at high temperature produces mono-alkyl squarate, and a one-pot basic hydrolysis of the intermediate affords the alcohol in good yield.

The outcomes of a standardized protocol for extracorporeal mechanical circulatory support selection-left ventricular challenge protocol.

There are no criteria for surgical mechanical circulatory system (MCS) selection for acute heart failure. Since 2021, we have utilized cardiopulmonary bypass system to assess patients' heart and lung condition to inform surgical MCS selection. we aimed to retrospectively analyze the outcomes of treatments administered using our protocol. We analyzed the data of 19 patients who underwent surgical MCS implantation. We compared patients' characteristics across the biventricular-assist device (BiVAD), central Y-Y extracorporeal membrane oxygenation (ECMO), central ECMO, and left VAD (LVAD) systems. Patients' diagnoses included fulminant myocarditis (47.4%), dilated cardiomyopathy (21.1%), acute myocardial infarction (15.8%), infarction from aortic dissection (5.3%), doxorubicin-related cardiomyopathy (5.3%), and tachycardia-induced myocarditis (5.3%). Eight patients (42.1%) underwent LVAD implantation, 1 (5.2%) underwent central ECMO, 4 (21.1%) underwent BiVAD implantation, and 6 (31.6%) underwent central Y-Y ECMO. 48 h after surgery, both the pulmonary arterial and right atrial pressures were effectively controlled, with median values being 19.0 mmHg and 9.0 mmHg, respectively. No patients transitioned from LVAD to BiVAD in the delayed period. Cerebrovascular events occurred in 21.1%. Successful weaning was achieved in 11 patients (57.9%), and 5 patients (26.3%) were converted to durable LVAD. Two-year cumulative survival was 84.2%. Our protocol showed good results for device selection in patients with heart failure, and device selection according to this protocol enabled good control of the pulmonary and systemic circulations.

Can right ventricular endomyocardial biopsy predict left ventricular fibrosis beforehand in dilated cardiomyopathy?

AIMS: Myocardial fibrosis of the left ventricle (LV) is a prognostic factor in dilated cardiomyopathy (DCM). This study aims to evaluate whether fibrosis of right ventricular (RV) endomyocardial biopsy (EMB) can predict the degree of LV fibrosis beforehand in DCM. METHODS AND RESULTS: Fibrosis extent in 70 RV-EMB specimens of DCM diagnosis was compared with that in the whole cross-sectional LV of excised hearts in the same patients (52 explanted hearts for transplant and 18 autopsied hearts). The median interval between biopsy and excision was 4.1 (0.13-19.3) years. The fibrosis area ratio of the EMBs and excised hearts were evaluated via image analysis. The distribution of cardiovascular magnetic resonance-late gadolinium enhancement (LGE) in the intraventricular septum was classified into four quartile categories. The fibrosis area ratio in RV-EMB correlated significantly with that in the short-axis cut of the LV of excised hearts (r = 0.82, P < 0.0001) and with a diffuse pattern of LGE (r = 0.71, P = 0.003). In a multivariate model, after adjusting for the interval between biopsy performance and heart excision, the fibrosis area ratio in RV-EMB was associated with that in LV-excised heart (regression coefficient, 0.82; 95% confidence interval, 0.68-0.95; P < 0.0001). CONCLUSIONS: The fibrosis observed in RV-EMB positively correlated with the extent of fibrosis in the LV of excised hearts in patients with DCM. The study findings may help predict LV fibrosis, considered a prognostic factor of DCM through relatively accessible biopsy techniques.

Safety and efficacy of aortic valvuloplasty for de novo aortic insufficiency in patients with a left-ventricular assist device.

OBJECTIVES: Progression of aortic insufficiency during left-ventricular assist device (LVAD) support is a crucial topic. One treatment option is aortic valvuloplasty (AVP); however, there is controversy regarding its safety and efficacy. We investigated the safety and efficacy of AVP using the coaptation stitch method (Park's stitch) performed for de novo aortic insufficiency. METHODS: Between 2013 and 2020, 175 consecutive patients underwent LVAD implantation, of which 7 patients [men, 2 (28.6%); median age, 55 years] underwent late-stage AVP. Two patients underwent AVP within 2 weeks, and the remaining six patients underwent AVP 3, 19, 24, 28, 42, and 49 months, respectively, after LVAD implantation. RESULTS: Preoperatively, the degree of aortic insufficiency was moderate in 6 (85.7%) patients and severe in 1 (14.3%) patient. AVP was technically successful in 6 (85.7%) patients, while one case of failed plasty was subsequently treated with bioprosthetic valve replacement. A 1-year post-AVP right heart catheterization study revealed a median pulmonary artery wedge pressure of 10.0 mmHg. No deaths or heart failure admissions occurred during the follow-up (median, 38.0 months). There was no aortic insufficiency in 2 (28.6%) patients; however, trivial AI was observed in 3 (42.8%) patients, and mild AI was observed in 1 (14.3%) patient 2 years postoperatively. However, at the 3-year follow-up, two patients developed an increase in AI grade from trivial to mild. CONCLUSIONS: AVP using Park's stitch was safe. It is critical to carefully observe the aortic valve during AVP surgery to ensure that AVP is appropriate.

Cost-effective analysis of transcatheter aortic valve replacement in patients with severe symptomatic aortic stenosis: A prospective multicenter study.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) for severe symptomatic aortic stenosis (AS) does not benefit all patients. We performed a prospective multicenter study to investigate the cost-effectiveness of TAVR in a Japanese cohort. METHODS AND RESULTS: We prospectively enrolled 110 symptomatic patients with severe AS who underwent TAVR from five institutions. The quality of life measurement (QOL) was performed for each patient before and at 6 months after TAVR. Patients without an improvement in QOL at 6 months after TAVR were defined as non-responders. Pre-TAVR higher QOL, higher clinical frailty scale predicted the non-responders. Three models, 1) conservative treatment for all patients strategy, 2) TAVR for all patients strategy, and 3) TAVR for a selected patient strategy who is expected to be a responder, were simulated. Lifetime cost-effectiveness was estimated using incremental cost-effectiveness ratio (ICER) and cost per quality-adjusted life-year (QALY) gained. In comparison to conservative therapy for all patients, ICER was estimated to be 5,765,800 yen/QALY for TAVR for all patients and 2,342,175 yen/QALY for TAVR for selected patient strategy patients, which is less than the commonly accepted ICER threshold of 5,000,000 yen/QALY. CONCLUSIONS: TAVR for selected patient strategy model is more cost-effective than TAVR for all patient strategy without reducing QOL in the Japanese healthcare system. TAVR for selected patient strategy has potential benefit for optimizing the TAVR treatment in patients with high frailty and may direct our resources toward beneficial interventions.

[Asymptomatic Ball Thrombus in Right Atrium Under Anticoagulant Therapy:Report of a Case].

A rare case of isolated right atrial thrombus under anticoagulant therapy for atrial fibrillation is reported herein. The patient was an 81-year-old man undergoing anticoagulant therapy with oral warfarin for atrial fibrillation. During preoperative screening for eye surgery, echocardiography revealed a mobile mass in the right atrium, and emergency hospital admission was indicated. Excision of the right atrial thrombus was performed, and no residual thrombus was detected on postoperative imaging studies. This case was considered a good indication for surgical resection because of potential risk of fatal embolism.

Successful echocardiography-guided medical management of severe early post-implant right ventricular failure in a patient with left ventricular assist device support: a case report.

BACKGROUND: Post-implant right heart failure (RHF) has been recognized as a crucial prognostic factor in patients receiving left ventricular assist devices (LVADs), and its management has long attracted attention from cardiologists and surgeons. CASE PRESENTATION: This report described an 18-year-old female with acutely deteriorating heart failure due to dilated cardiomyopathy who underwent paracorporeal pulsatile-flow LVAD and developed early post-implant RHF. At postoperative day (POD) six, she was almost asymptomatic at rest on 2.5 mg/kg/min of dobutamine; however, the echocardiogram, performed as part of the daily postoperative care, revealed a severely enlarged right ventricle with a decompressed left ventricle, implying the development of post-implant RHF. Bolus infusion of saline and reduction of pump flow (6.0 L/min to 3.0 L/min) led to normalization of both ventricular shapes in 30 s, suggesting that RHF could be managed without surgical interventions. Milrinone was started on POD six, followed by sildenafil administration on POD seven. Fluid balance was strictly adjusted under the close observation of daily echocardiograms. Milrinone and dobutamine were discontinued on PODs 18 and 21, respectively. The patient was listed for a heart transplant on POD 40. Despite reduced right ventricular function (right ventricular stroke work index of 182.34 mmHg*ml/m- 2, body surface area 1.5 m2), she was successfully converted to implantable LVAD on POD 44 with no recurrence of post-implant RHF thereafter for four years. CONCLUSIONS: In post-implant RHF management, early detection, together with proper and prompt medical management, is crucial to avoiding any surgical intervention. Close observation of daily echocardiograms might be helpful in detecting subclinical RHF and is useful for post-implant medical management.

Outcomes and residual gap analysis after the modified cryomaze procedure performed via right minithoracotomy versus sternotomy.

Objectives: Developments in both technique and technology have enabled surgeons to perform the maze procedure via right minithoracotomy (RMT) to treat atrial fibrillation (AF). This study aimed to clarify the outcomes of the modified cryomaze procedure via the RMT approach compared with the sternotomy approach. Methods: The study cohort comprised 803 consecutive patients who underwent a modified cryomaze procedure (130 via RMT and 673 via sternotomy) for paroxysmal AF and persistent AF from January 2001 to March 2022. The Gray test was applied to compare the incidence of recurrent atrial tachyarrhythmias. Additionally, residual electrical gaps were investigated in the patients who underwent additional catheter ablation for recurrent atrial tachyarrhythmias. Results: The respective 1-, 2-, and 3-year cumulative incidences of recurrent atrial tachyarrhythmias were 13.1%, 19.5%, and 23.1% in the RMT group, and 9.3%, 10.9%, and 12.8% in the sternotomy group (Gray test P = .036). All 31 patients with recurrent atrial tachyarrhythmias underwent additional catheter ablation, comprising 14 (10.8%) in the RMT group and 17 (2.5%) in the sternotomy group. There was a significant intergroup difference in the site of residual electrical gaps; the RMT group more frequently had residual gaps in the tricuspid annulus than the sternotomy group (6.2% vs 0.4%; P < .001). Conclusions: In the modified cryomaze procedure via the RMT approach, ablation failure is more likely to occur at the tricuspid annulus, where the surgical field of view is relatively poor compared with the sternotomy approach. Therefore, surgical ablation should be performed with caution when the RMT approach is used.

Discovery of a potent, orally available tricyclic derivative as a novel BRD4 inhibitor for melanoma.

The epigenetic regulation of the protein bromodomain-containing protein 4 (BRD4) has emerged as a compelling target for cancer treatment. In this study, we outline the discovery of a novel BRD4 inhibitor for melanoma therapy. Our initial finding was that benzimidazole derivative 1, sourced from our library, was a powerful BRD4 inhibitor. However, it exhibited a poor pharmacokinetic (PK) profile. To address this, we conducted a scaffold-hopping procedure with derivative 1, which resulted in the creation of benzimidazolinone derivative 5. This new derivative displayed an improved PK profile. To further enhance the BRD4 inhibitory activity, we attempted to introduce hydrogen bond acceptors. This indeed improved the activity, but at the cost of decreased membrane permeability. Our search for a potent inhibitor with desirable permeability led to the development of tricyclic 18. This compound demonstrated powerful inhibitory activity and a favorable PK profile. More significantly, tricyclic 18 showed antitumor efficacy in a mouse melanoma xenograft model, suggesting that it holds potential as a therapeutic agent for melanoma treatment.

Prognostic impact of lung computed tomography density in cardiogenic shock patients with veno-arterial extracorporeal membrane oxygenation.

BACKGROUND: Pulmonary complications often occur in patients receiving veno-arterial extracorporeal membrane oxygenation (VA ECMO). However, the prognostic impact of lung damage has not been fully elucidated. METHODS: This single-center retrospective observational study targeted patients with cardiogenic shock who received VA ECMO between 2012 and 2021. This study included 65 patients who underwent chest computed tomography (CT) on VA ECMO, followed by escalation to central mechanical circulatory support (MCS) with left ventricular venting. The average density of lung CT images was measured using region-of-interest methods, and the primary endpoint was 180-day all-cause death after escalation to the central MCS. RESULTS: Twenty-two patients (34%) developed 180-day all-cause death. According to the Cox regression analysis, age (hazard ratio [HR], 1.08; 95% confidence interval [CI], 1.03-1.14; p = 0.001), ischemic etiology (HR, 5.53; 95% CI, 2.09-14.62; p < 0.001), duration of VA ECMO support (HR, 1.19; 95% CI, 1.00-1.40; p = 0.045), and lung CT density (≥ -481 Hounsfield unit [HU]) (HR, 6.33; 95% CI, 2.26-17.72; p < 0.001) were independently associated with all-cause death. Receiver operating characteristic curve analysis determined that lung CT density ≥ -481 HU is an optimal cutoff value for predicting all-cause death (area under the curve [AUC], 0.72). The 180-day overall survival rate for patients with high lung CT density (≥ -481 HU) was significantly lower than that for those with low lung CT density (< -481 HU) (44.4% vs. 81.6%, respectively, p = 0.002). CONCLUSIONS: Higher lung CT density could be a useful predictor of death in patients with VA ECMO requiring central MCS escalation.

Decreased pregnancy rate per embryo transfer in women undergoing assisted reproductive technology after abdominal trachelectomy: A retrospective study.

OBJECTIVE: Abdominal trachelectomy (AT) is a fertility-preservation surgery for patients with early-stage cervical cancer. Few studies have reported the outcomes of assisted reproductive technology (ART) in patients after AT. The aim of this study was to evaluate the outcomes of ART after AT. STUDY DESIGN: In this retrospective study, we compared the ART outcomes of 13 patients who underwent AT at another hospital prior to undergoing ART at our clinic (T group) and 52 control patients (non-T group) who did not undergo AT prior to ART, selected on the basis of age, time of treatment onset, and serum anti-Müllerian hormone concentrations, matched 1:4, respectively. RESULTS: Cumulative live birth rates were 62% (8/13) and 65% (34/52) in the T and non-T groups, respectively (p = 0.795). The total number of oocyte retrieval cycles was 34 in the T group and 95 in the non-T group. In all oocyte retrieval cycles, no significant differences were noted in the number of oocyte retrievals, rate of fertilization, and presence of good-quality blastocysts (Gardner classification ≥ BB). The total number of embryo transfer (ET) cycles was 55 in the T group and 109 in the non-T group. The pregnancy and live birth rates per ET were lower in the T group than those in the non-T group (pregnancy rate, 20% vs. 39%, p = 0.017; live birth rate, 15% vs. 30%, p = 0.028; respectively). Endometrial thickness before ET was lower in the T group vs. the non-T group: median (range): 7.4 (3.5-14.3) mm vs. 9.0 (5.5-14.9) mm, respectively; p < 0.0001. Multivariate logistic regression models showed that age at oocyte retrieval (adjusted odds ratio [OR], 0.76; 95% confidence interval [CI], 0.66-0.87), use of good-quality blastocysts (adjusted OR, 3.23; 95% CI, 1.20-8.67), and history of AT (adjusted OR, 0.28; 95% CI, 0.11-0.72) were associated with the pregnancy rate per ET. CONCLUSION: The pregnancy rate per ET was lower in patients with vs. without a history of AT. Clinicians should be aware of the longer time to pregnancy in patients who undergo ART after AT.