Supplementation with a Probiotic Formula Having ß-Glucuronidase Activity Modulates Serum Estrogen Levels in Healthy Peri- and Postmenopausal Women.

Declines in estrogen levels occur in women transitioning to menopause. Estrogen hormones play important roles in multiple systems of the body, and estrogen loss is associated with a variety of symptoms that can decrease quality of life. The gut microbiota is involved in regulating endogenous estrogen levels. A portion of estrogen glucuronides can be reactivated in the gut by the microbial enzyme ß-glucuronidase, and the resulting free estrogens can return to the bloodstream. Here, we carried out in vitro screening of ß-glucuronidase activities for 84 strains belonging to 16 different species of lactic acid bacteria and bifidobacteria and found that one and three strains of Levilactobacillus brevis and Lacticasebacillus rhamnosus, respectively, can deconjugate estrogens. Among these strains, L. brevis KABP052 had the highest ß-glucuronidase activity. Moreover, in an exploratory, randomized, double-blind, placebo-controlled trial, we demonstrated that serum estrogen levels in healthy peri- and postmenopausal women given a probiotic formula containing KABP052 were maintained over time, whereas levels significantly decreased in the group given a placebo. Significantly higher levels of estradiol (31.62 ± 7.97 pg/mL vs. 25.12 ± 8.17 pg/mL) and estrone (21.38 ± 8.57 pg/mL vs. 13.18 ± 8.77 pg/mL) were observed in the probiotic versus placebo group after 12 weeks of intervention. This clinical study demonstrated for the first time the estrogen modulation capacity of a probiotic formula containing a bacterial strain having ß-glucuronidase activity in women during the menopausal transition and formed the basis for future investigations using probiotics in the menopausal population.

Left ventricular assist device temporary explantation as a strategy for infection control in a pediatric patient.

We report a case of temporary Berlin Heart EXCOR® explantation in a pediatric patient with idiopathic dilated cardiomyopathy who suffered an uncontrollable inflow cannulation site infection while on bridge-to-transplantation. Despite failure to thrive and catheter-related infections, once free of the device, the patient was cured of infection using systemic antibiotics and surgical debridement. The patient underwent EXCOR® reimplantation after four months, and is awaiting heart transplantation in stable condition. A life-threatening ventricular assist device-related infection may require device explantation under conditions that may not fulfill conventional explantation criteria despite risks. Temporary explantation can be an effective strategy if isolated systolic dysfunction is managed carefully.

Modified procedures of subcutaneous implantable cardioverter defibrillator implantation for a child with small body size.

Modified procedures of subcutaneous implantable cardioverter defibrillator (S-ICD) implantation for a child with a small body size are presented. This report demonstrates the feasibility of novel diagonal S-ICD lead implantation method.

Impact of the Rudimentary Chamber on Outcomes in Fontan Patients.

Background: We sought to evaluate the influence of the rudimentary ventricle on long-term outcomes after the Fontan operation, focusing on exercise capacity and cardiac performance. Methods: Between 1995 and 2021, 290 patients underwent a total cavopulmonary connection. "Two-ventricle" Fontan circulation was defined as a rudimentary ventricle >30% of the dominant ventricle or >50% of its predicted normal value. This cohort was compared with patients with single-ventricle Fontan circulation. The primary endpoint was Fontan failure, and the secondary endpoints were VO2 and cardiac catheterization data at ten years postoperatively. Results: The median follow-up after the Fontan operation was 7.9 years (interquartile range: 1.9-13.9). No significant difference was found in Fontan failure-free survival between the "two-ventricle" Fontan circulation group and the single-ventricle Fontan circulation group (83/91, 93% vs 156/199, 78%), respectively at 20 years; P = .11). No significant difference was found in VO2 or cardiac performance except cardiac index, with 2.9 (2.3-4.8) versus 2.5 (2.3-4.3) L/min/m2 (P = .047). Fifty-one patients in the "two-ventricle" Fontan circulation group were followed up for over ten years after the Fontan operation. In the subgroup analysis of this cohort, the rudimentary ventricular end-diastolic volume/dominant ventricular end-diastolic volume ratio showed a significant positive correlation with dominant ventricular end-diastolic pressure (r = 0.58 [95% CI 0.35-0.74], P = .002) and a significant negative correlation with VO2 (r = -0.61 [95% CI -0.80 to -0.28], P = .001). Conclusions: The rudimentary ventricle was not significantly associated with any clinical disadvantages regarding Fontan failure. However, a large rudimentary ventricle was significantly associated with higher end-diastolic pressure and lower exercise capacity.

Pleiotropic effects of extracellular vesicles from induced pluripotent stem cell-derived cardiomyocytes on ischemic cardiomyopathy: A preclinical study.

BACKGROUND: Stem cell-secreted extracellular vesicles (EVs) play essential roles in intercellular communication and restore cardiac function in animal models of ischemic heart disease. However, few studies have used EVs derived from clinical-grade stem cells and their derivatives with stable quality. Moreover, there is little information on the mechanism and time course of the multifactorial effect of EV therapy from the acute to the chronic phase, the affected cells, and whether the effects are direct or indirect. METHODS: Induced pluripotent stem cell-derived cardiomyocytes (iPSCM) were produced using a clinical-grade differentiation induction system. EVs were isolated from the conditioned medium by ultracentrifugation and characterized in silico, in vitro, and in vivo. A rat model of myocardial infarction was established by left anterior descending artery ligation and treated with iPSCM-derived EVs. RESULTS: iPSCM-derived EVs contained microRNAs and proteins associated with angiogenesis, antifibrosis, promotion of M2 macrophage polarization, cell proliferation, and antiapoptosis. iPSCM-derived EV treatment improved left ventricular function and reduced mortality in the rat model by improving vascularization and suppressing fibrosis and chronic inflammation in the heart. EVs were uptaken by cardiomyocytes, endothelial cells, fibroblasts, and macrophages in the cardiac tissues. The pleiotropic effects occurred due to the direct effects of microRNAs and proteins encapsulated in EVs and indirect paracrine effects on M2 macrophages. CONCLUSIONS: Clinical-grade iPSCM-derived EVs improve cardiac function by regulating various genes and pathways in various cell types and may have clinical potential for treating ischemic heart disease.

Risk factors for atrial arrhythmia recurrence after atrial arrhythmia surgery with pulmonary valve replacement.

Objectives: Atrial arrhythmias are a significant cause of late morbidity and mortality in patients after tetralogy of Fallot repair. However, reports on their recurrence following atrial arrhythmia surgery are limited. We aimed to identify the risk factors for atrial arrhythmia recurrence after pulmonary valve replacement (PVR) and arrhythmia surgery. Methods: We reviewed 74 patients with repaired tetralogy of Fallot who underwent PVR for pulmonary insufficiency at our hospital between 2003 and 2021. Twenty-two patients (mean age, 39 years) underwent PVR and atrial arrhythmia surgery. A modified Cox-maze III was performed in 6 patients with chronic atrial fibrillation, and a right-sided maze was performed in 12 with paroxysmal atrial fibrillation, 3 with atrial flutter, and 1 with atrial tachycardia. Atrial arrhythmia recurrence was defined as any documented sustained atrial tachyarrhythmia requiring intervention. The influence of preoperative parameters on recurrence was assessed with the Cox proportional-hazards model. Results: The median follow-up period was 9.2 years (interquartile range, 4.5-12.4). Cardiac death and redo-PVR due to prosthetic valve dysfunction were not observed. Eleven patients had atrial arrhythmia recurrence after discharge. Atrial arrhythmia recurrence-free rates were 68% at 5 years and 51% at 10 years after PVR and arrhythmia surgery. Multivariable analysis revealed that right atrial volume index (hazard ratio, 1.04; 95% confidence interval, 1.01-1.08, P = .009) was a significant risk factor for atrial arrhythmia recurrence after arrhythmia surgery and PVR. Conclusions: Preoperative right atrial volume index was associated with atrial arrhythmia recurrence, which may assist in planning the timing of atrial arrhythmia surgery and PVR.

Cardiomyocyte deoxyribonucleic acid damage and cardiac recovery in paediatric dilated cardiomyopathy.

OBJECTIVES: The goal of this study was to identify the clinical significance of the deoxyribonucleic acid (DNA) damage response marker, phosphorylated H2A histone variant X, on the bridge to recovery in low-weight paediatric patients with dilated cardiomyopathy (DCM) after having a Berlin Heart EXCOR implanted. METHODS: Consecutive paediatric patients with DCM who had an EXCOR implanted for DCM at our hospital between 2013 and 2021 were reviewed. Patients were classified into 2 groups according to the degree of DNA damage in the left ventricular cardiomyocytes-the low DNA damage group and the high DNA damage group-using the median value as the threshold. We examined and compared the preoperative factors and histologic findings associated with cardiac functional recovery following the explant procedure in the 2 groups. RESULTS: Competing outcome analysis of 18 patients (median body weight, 6.1 kg) showed that the incidence of an EXCOR explant was 40% at 1 year after the implant procedure. Serial echocardiography revealed significant left ventricular functional recovery in the low DNA damage group 3 months after the implant. The univariable Cox proportional hazards model revealed that the percentage of phosphorylated H2A histone variant X-positive cardiomyocytes was the significant factor associated with cardiac recovery and the EXCOR explant (hazard ratio, 0.16; 95% confidence interval, 0.027-0.51; P = 0.0096). CONCLUSIONS: The degree of DNA damage response to the EXCOR implant may aid in predicting the bridge to recovery with EXCOR among low-weight paediatric patients with DCM.

Influence of Bovine Arch Anatomy on Surgical Outcomes of Coarctation of the Aorta.

This study aimed to evaluate the outcome of coarctation of the aorta (CoA) repair with a special interest in bovine arch anatomy. Fifty-six patients who underwent CoA repair between 2010 and 2021 were included in this retrospective study. Of these, 11 patients had bovine arch anatomy. Surgical outcomes were reviewed. Computed tomography was used to analyze aortic arch geometry for all cases preoperatively. The gap between anastomotic sites was calculated at the linear region of the lesser curvature of the aortic arch between the distal ascending aorta and the proximal descending aorta. CoA repair was performed at a median age of 39 days (median body weight 3.3 kg). Thirty-two patients underwent extended direct anastomosis, 22 patients underwent direct anastomosis, and two patients underwent lesser curvature patch augmentation. The median follow-up period was 47 months. There were no early deaths. In patients who underwent direct and extended direct anastomosis, nine recoarctation and one left pulmonary venous obstruction events occurred. Moreover, freedom from these adverse events was 81% in normal arch and 50% in bovine arch patients at 10 years (P = 0.04). Two patients with a bovine arch anatomy who underwent lesser curvature patch augmentation had good outcomes. The distal arch was narrower and longer, and the gap between anastomotic sites was longer in patients with a bovine arch anatomy than with a normal arch (P < 0.01). In CoA with a bovine arch anatomy, the gap between anastomotic sites was long. This adversely influenced the outcomes of the CoA repairs.

Univentricular Conversion for Acquired Severe Right Ventricular Failure.

In a 14-year-old boy, prolonged right ventricular (RV) dysfunction due to postmyocarditis cardiomyopathy developed, whereas left ventricular function recovered with conservative treatment. On catheterization, the RV end-diastolic volume index was 184 mL/m2, and mean pulmonary artery pressure was 16 mm Hg. Despite one-and-a-half ventricle repair, RV dilation continued to worsen; therefore, 3 years after the operation, RV exclusion and extracardiac total cavopulmonary connection were performed. Postoperatively, left ventricular function was maintained, and no further RV dilation was observed. Univentricular conversion may be an effective procedure for the treatment of acquired severe isolated right-sided heart failure.

A probiotic blend improves defecation, mental health, and productivity in healthy Japanese volunteers under stressful situations.

We investigated whether a blend of probiotics (KABP-021, KABP-022, and KABP-023) improved diarrhea-related problems in healthy Japanese adults who routinely lived under stressful conditions. Twenty-six females and 34 males were divided randomly into the probiotic and placebo groups in this double-blind, placebo-controlled, parallel-group comparison study. All participants ingested 1 capsule of probiotics or placebo per day for 4 weeks. Intervention with probiotics significantly reduced diarrhea-related problems assessed by the Izumo scale compared with placebo treatment (P < 0.001). In the Short Form-8 questionnaire, probiotic intervention improved mental component scores (P = 0.002), role emotional scores (P = 0.002), and mental health scores (P < 0.001). Treatment with probiotics also reduced the effects of diarrhea on daily activities (P < 0.001) and overall working habits (P = 0.010), including missing work (absenteeism) and impaired productivity (presenteeism), as assessed by the Work Productivity and Activity Impairment Questionnaire: General Health. Furthermore, there was a correlation between improved scores for diarrhea on the Izumo scale and increased abundance of Faecalibacterium, a butyric acid-producing bacterium, in the gut in the probiotic group (P = 0.047), whereas no such a correlation or trend was found in the placebo group. Our strategy of supplementation for 4 weeks with a specific blend of probiotics reduced diarrhea-related symptoms and may improve the mental health and daily activities of healthy individuals under stress.

Benefits of Laparoscopic Surgery for Bleeding Events in Patients with Implantable Left Ventricular Assist Devices during Antithrombotic Therapy.

Hemorrhagic ovarian cysts (HOCs), a common gynecological disease causing intraabdominal bleeding, can be life threatening in patients undergoing antithrombotic therapy, especially those with left ventricular assist device (LVAD) implantation under strong antithrombotic therapy. We encountered three postLVAD implantation cases with intraabdominal bleeding due to suspected HOCs, which required surgery for hemostasis. Such patients are not only at a higher risk of bleeding but also have restrictions in available surgical incision sites to avoid damaging the LVAD driveline located underneath the abdominal wall. Laparoscopic surgery, which can be performed through minute incisions with flexible site selection, may benefit intraabdominal hemorrhage patients with LVADs.

Successful bridge to transplantation with long-term support using Berlin heart EXCOR in a child with failing Fontan.

A 2-year-old girl underwent the Fontan operation for aortic valve stenosis, mitral valve stenosis, a hypo-plastic left ventricle, and a non-compacted right ventricle. The patient's cardiac function reduced gradually thereafter, mainly due to systemic ventricular dysfunction. A Berlin Heart EXCOR (BHE) ventricular assist device with a 10-mL pump was implanted at 4 years of age. After 465 days, BHE support without major complications, the patient underwent heart transplantation. A safe and long-term BHE support was achieved with proper case selection and repeated examinations.

Infective endocarditis in an adult with unrepaired corrected transposition.

We report a case of a 28-year-old man with unrepaired congenitally corrected transposition of the great arteries, ventricular septal defect, and pulmonary stenosis who presented with septic shock due to infective endocarditis by Abiotrophia defectiva. The cardiac catheterization had the risk of vegetation scattering. Without invasive hemodynamic assessment, the degree of pulmonary stenosis and left ventricle preparation as a systemic ventricle could not be accurately determined, making surgical planning difficult. We chose a staged approach with pulmonary valve replacement first for source control, followed by a more definitive operation following recovery from endocarditis.

Clinical significance of diastolic dysfunction on outcomes of pulmonary valve replacement for pulmonary insufficiency.

OBJECTIVES: According to the current guidelines of pulmonary valve replacement (PVR) for pulmonary insufficiency, the age at the time of PVR is becoming younger. However, recent studies have shown that the improvements in mortality have leveled off, making it important to suppress the cumulative lifetime risk of morbidity. In this study we aimed to identify the risk factors for morbidity late after PVR. METHODS: Sixty-three patients who underwent PVR for pulmonary insufficiency after intracardiac repair of tetralogy of Fallot or pulmonary atresia with ventricular septal defect at our hospital from 2003 to 2019 were included in this study. Morbidity of PVR included arrhythmia requiring treatment and hospitalization for heart failure. The influence of hemodynamic parameters before PVR was analyzed using the Cox proportional hazards model. RESULTS: The median postoperative follow-up period was 6.5 years. Cardiac death and redo PVR because of prosthetic valve dysfunction were not observed. Twenty-two patients suffered cardiovascular adverse events, including 16 supraventricular tachycardia, 3 sick sinus syndrome/atrioventricular block, 2 sustained ventricular tachycardia, and 1 heart failure hospitalization as first events. In the multivariable analysis, pulmonary end diastolic forward flow (hazard ratio [HR], 7.8; 95% CI, 2.6-23; P < .001), right atrial volume index (HR, 1.02; 95% CI, 1.01-1.04; P = .005), and right atrial pressure (HR, 1.2; 95% CI, 1.01-1.45; P = .042) were significant risk factors for adverse events late after PVR. CONCLUSIONS: End diastolic forward flow, large right atrial volume index, and high right atrial pressure before PVR, which are considered markers of diastolic dysfunction, were significant risk factors for cardiovascular adverse events after PVR.

Inferior-to-Superior Vena Cava Bypass for Baffle Stenosis After Atrial Switch.

An atrial switch operation was successfully performed in an 11-month-old patient with transposition of the great arteries. Good cardiac function was noted on regular follow-ups. A severe inferior vena cava baffle stenosis was detected after a ruptured hepatocellular carcinoma at the age of 39 years. Liver cirrhosis and hepatocellular carcinoma could have been associated with liver congestion resulting from the stenosis. After partial hepatectomy, inferior vena cava-to-superior vena cava bypass was performed without cardiopulmonary bypass. The patient's postoperative course was uneventful, liver enzyme levels decreased to normal limits, and distant recurrence of hepatocellular carcinoma has not been observed.

Risk factors of gynecological bleeding in female patients with left-ventricular assist device.

Women with implantable left-ventricular assist devices (LVADs) experience gynecological bleeding (GYN-bleeding). However, a few studies have investigated female-specific problems. Therefore, this study aimed to identify the risk factors for adverse GYN-bleeding after LVAD implantation. We retrospectively analyzed 59 women (mean age: 41 ± 15 years) with long-term implantable LVAD support (≥ 6 months) at our institution between 2005 and 2018. The history of GYN-bleeding before implantation was defined as abnormal utero-ovarian bleeding, excessive menstruation, uterine fibroids, and endometrial lesions. GYN-bleeding after implantation was defined as a requirement of emergency outpatient visits and/or hospitalization, blood transfusions, hormonal therapy, and/or surgery. Additionally, risk factors for GYN-bleeding were identified using the Cox regression model. Twenty-four GYN-bleeding cases were seen in 15 patients (two times: five patients, three times: two patients, 0.18 events per patient-year). The 1- and 2-year GYN-bleeding-free rates were 84% and 73%, respectively. Twelve patients (17 events) required RBC ≥ 4 units, and five patients (7 events) required FFP ≥ 4 units. Seven patients required pseudomenopausal treatment after blood transfusion, and four patients required surgical treatment. Fifteen patients with GYN-bleeding after implantation were significantly younger than the remaining 44 patients without GYN-bleeding (34 ± 12 years vs. 43 ± 16 years, P = 0.02). Multivariable risk analysis showed a history of GYN-bleeding before implantation was a significant risk factor (hazard ratio 3.7 [1.2-10.6], P = 0.004). Patients with a history of GYN-bleeding before LVAD implantation have a high risk of developing GYN-bleeding after implantation. We should identify the high-risk population and prepare for the management of GYN-bleeding.

Persistent end-diastolic forward flow after pulmonary valve replacement in patients with repaired tetralogy of Fallot.

OBJECTIVES: The clinical significance of persistent end-diastolic forward flow (EDFF) after pulmonary valve replacement (PVR) remains unclear in patients with repaired tetralogy of Fallot. This study aimed to identify the characteristics of these patients and the impact of persistent EDFF on outcomes. METHODS: Of 46 consecutive patients who underwent PVR for moderate to severe pulmonary regurgitation between 2003 and 2019, 23 (50%) did not show EDFF before PVR [group (-)]. In the remaining 23 patients with EDFF before PVR, EDFF was diminished after PVR in 13 (28%) [group (+, -)] and persisted in 10 (22%) [group (+, +)]. The following variables were compared between these 3 groups: (i) preoperative right ventricular (RV) and right atrial volumes measured by magnetic resonance imaging, haemodynamic parameters measured by cardiac catheterization and the degree of RV myocardial fibrosis measured by RV biopsy obtained at PVR and (ii) the post-PVR course, development of atrial arrhythmia and need for intervention. RESULTS: A high RV end-diastolic pressure, a greater right atrial volume index and a greater RV end-systolic volume index before PVR and a high degree of RV fibrosis were significantly associated with persistent EDFF 1 year after PVR. Persistent EDFF was a significant risk factor for postoperative atrial tachyarrhythmia, and catheter ablation and pacemaker implantation were required more frequently in these patients. CONCLUSIONS: Persistent EDFF after PVR could predict a worse prognosis, especially an increased risk of arrhythmia. Close follow-up is required in patients with persistent EDFF for early detection of arrhythmia and prompt reintervention if necessary. CLINICAL TRIAL REGISTRATION NUMBER: Institutional review board of Osaka University Hospital, number 16105.

External compression due to seroma of ventricular assist device outflow graft.

A 45-year-old woman with repaired complex congenital heart disease, who underwent placement of Jarvik 2000, a ventricular assist device (VAD) for 4 years, experienced abdominal pain due to outflow graft compression caused by seroma formation between the outflow graft and ringed Gore-Tex graft. We exchanged the pump of Jarvik 2000 and punched several small holes in the new ringed Gore-Tex graft. Seroma formation between the two grafts should be considered as a cause of outflow graft obstruction in patients with the long-term support of VAD, and additional surgical interventions to the ringed Gore-Tex graft may prevent this complication.

Total percutaneous biventricular assist device implantation for fulminant myocarditis.

We report an effective therapeutic approach of mechanical circulatory support for a patient with cardiogenic shock and respiratory insufficiency due to fulminant myocarditis. An Impella® 5.0 was utilized as a left ventricular assist device (VAD) and percutaneous veno-pulmonary extracorporeal membrane oxygenation (ECMO) as a right VAD. These devices were implanted without sternotomy or thoracotomy. Although a combination of Impella and veno-arterial ECMO has been reported as percutaneous biventricular support, there are concerns that this combination is not beneficial for myocardial recovery in patients with respiratory insufficiency, because Impella expels insufficiently oxygenated blood from the left ventricle to the coronary arteries. Our approach took advantage of percutaneous implantation of ECMO and temporary VAD, eliminating the drawbacks of both devices, thus providing a more effective and less invasive form of temporary biventricular support.

Pediatric patient with restrictive cardiomyopathy on staged biventricular assist device support with Berlin Heart EXCOR® underwent heart transplantation successfully: the first case in Japan.

Pure restrictive cardiomyopathy is a strong risk factor for poor outcomes in children with cardiomyopathy on ventricular assist devices. Owing to concomitant right heart failure, children with end-staged restrictive cardiomyopathy who are supported with a ventricular assist device often require a biventricular assist device, which is another risk factor for waitlist mortality in heart transplantation candidates. Herein, we report the case of a 3-year-old boy with pure restrictive cardiomyopathy who successfully underwent heart transplantation after 12 months of support with staged biventricular assist devices. Owing to the progression of diastolic dysfunction, the left ventricular assist device could not provide adequate circulation support. Despite the provision of biventricular assist device support, the patient required a complex management strategy that involved balancing the left and right ventricular assist device supports. We were able to stabilize the patient by careful synchronization of the supports and proceeded to heart transplantation. TRIAL REGISTRATION: Clinical Registration No.: Institutional Review Board of Osaka University Hospital, approval no. 16105.