A Case of Myocardial Infarction with Non-obstructive Coronary Arteries Complicated by a Ventricular Septal Rupture: The Challenge of Achieving Hemodynamic Stability Using Impella Devices.

The prognosis of myocardial infarction with non-obstructive coronary arteries (MINOCA) is reported to be as worse as myocardial infarction with obstructive coronary arteries. However, its mechanical complications are still poorly understood. A 71-year-old woman developed MINOCA after ascending aortic replacement surgery. During treatment, the patient experienced cardiogenic shock due to a ventricular septal rupture (VSR). The introduction of Impella devices reduced the left-to-right shunt and improved the patient's hemodynamics. Finally, a scheduled surgical repair was performed under stable conditions. In this report, we focused on the pathophysiology of MINOCA-related VSR and discussed the effectiveness of Impella devices as a bridge to surgical repair and circulatory backup during the perioperative period.

Distinctive left ventricular-arterial and right ventricular-pulmonary arterial coupling observed in patients with heart failure and a higher left ventricular ejection fraction range.

AIMS: Higher left ventricular (LV) ejection fraction (EF) is related to unfavourable prognosis in patients with heart failure (HF) with preserved ejection fraction (HFpEF). The cause of this finding needs to be hemodynamically explained. Thus, we investigated this crucial issue from the perspective of LV-arterial (A) and right ventricular (RV)-pulmonary arterial (PA) coupling. METHODS AND RESULTS: Study patients were derived from our prospective cohort study of patients hospitalized due to acute decompensated HF and LVEF>40%. We divided the 255 patients into 3 groups: HF with mildly reduced EF (HFmrEF), HFpEF with 50%≤LVEF<60%, and HFpEF with LVEF≥60%. We compared LV end-systolic elastance (Ees), effective arterial elastance (Ea), and Ees/Ea as a representative of LV-A coupling among groups, and compared the ratio of tricuspid annular plane excursion to peak pulmonary arterial systolic pressure (TAPSE/PASP) as a representative of RV-PA coupling. All-cause death and readmission due to HF-free survival was worse in the group with a higher LVEF range. Ees/Ea was greater in HFpEF patients with LVEF≥60% (2.12±0.57) than in those with 50%≤LVEF<60% (1.20±0.14) and those with HFmrEF (0.82±0.09) (P<0.001). PASP was increased in the groups with higher LVEF; however, TAPSE/PASP did not differ among groups (n=168, P=0.17). In a multivariate Cox proportional-hazard model, TAPSE/PASP but not PASP was significantly related to event-free survival independent of LVEF. CONCLUSION: HFpEF patients with higher LVEF have unfavourable prognosis and distinctive LV-A coupling: Ees/Ea is elevated up to 2.0 or more. Impaired RV-PA coupling also worsens prognosis in such patients.

Evaluation of renal circulation in heart failure using superb microvascular imaging, a microvascular flow imaging system.

PURPOSE: Renal circulation evaluation is essential in understanding the cardiorenal relationship in heart failure (HF), and there is a growing interest in imaging techniques that visualize renal circulation. This study aimed to assess the effectiveness of superb microvascular imaging (SMI) in evaluating renal circulation in HF patients. METHOD: The study included 71 HF patients undergoing cardiac catheterization. Prior to catheterization, renal ultrasound examinations were performed. A control group of 18 subjects without HF was also included. SMI was used to measure the vascular index (VI), which was calculated as the percentage of blood flow signal area in the region of interest. The intrarenal perfusion index (IRPI) was determined as a fluctuation index of VI, reflecting variations in the number of blood cells moving through renal tissue during the cardiac cycle. RESULTS: Using the upper 95% confidence interval of IRPI (0.6) from the control group, HF patients were classified into two groups. Patients with IRPI > 0.6 showed a more congestive profile. Right atrial pressure and biphasic or monophasic Doppler intrarenal flow pattern were independent determinants of IRPI > 0.6. In addition, IRPI remained a significant predictor of estimated glomerular filtration rate (eGFR). CONCLUSION: The parameter IRPI as variations in SMI signal during the cardiac cycle may be a useful evaluation method for renal perfusion impairment in HF.

Simultaneous XIAP and cIAP1/2 inhibition by a dimeric SMAC mimetic AZD5582 induces apoptosis in multiple myeloma.

Overexpression of inhibitor of apoptosis (IAP) proteins is associated with poor prognosis. In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective. Among IAPs, XIAP has the strongest anti-apoptotic function with direct binding activity to caspases and cIAP1 and cIAP2 are positive regulator of NF-κB signaling. Prior IAPi such as LCL161 has high affinity to cIAP1 and cIAP2 resulting in inferior inhibiting activity against XIAP. A novel dimeric IAPi, AZD5582 (C58H78N8O8), have high binding potency to XIAP with EC50 dose of 15 nM, enabling to simultaneous inhibit XIAP and cIAP1/2. AZD5582 monotherapy showed cell growth inhibition for all MM cell lines, MM1S, RPMI8226, U266 and KMS-5 and induced apoptosis. AZD5582 further showed anti-proliferation effect under the IL-6 additional condition and inhibited JAK-STAT signaling triggered by IL-6. AZD5582 combined with carfilzomib therapy showed a synergistic effect. Enhanced apoptosis was also observed in combination therapy. Synergistic effect was further observed with other conventional therapeutics. Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy.

Hemodialysis-induced Myocardial Stunning with No Obstructive Coronary Artery Disease: Pathophysiological Significance of Coronary Microvascular Dysfunction.

Hemodialysis (HD)-induced myocardial stunning, characterized by transient left ventricular systolic dysfunction during HD, has been reported to be common and associated with a poor prognosis. However, the pathophysiology is not fully understood. We herein report a case of HD-induced myocardial stunning without obstructive coronary artery disease complicated by coronary microvascular dysfunction (CMD), suggesting that CMD plays a crucial role in the pathophysiology of this disease.

Development of a Novel CD26-Targeted Chimeric Antigen Receptor T-Cell Therapy for CD26-Expressing T-Cell Malignancies.

Chimeric-antigen-receptor (CAR) T-cell therapy for CD19-expressing B-cell malignancies is already widely adopted in clinical practice. On the other hand, the development of CAR-T-cell therapy for T-cell malignancies is in its nascent stage. One of the potential targets is CD26, to which we have developed and evaluated the efficacy and safety of the humanized monoclonal antibody YS110. We generated second (CD28) and third (CD28/4-1BB) generation CD26-targeted CAR-T-cells (CD26-2G/3G) using YS110 as the single-chain variable fragment. When co-cultured with CD26-overexpressing target cells, CD26-2G/3G strongly expressed the activation marker CD69 and secreted IFNgamma. In vitro studies targeting the T-cell leukemia cell line HSB2 showed that CD26-2G/3G exhibited significant anti-leukemia effects with the secretion of granzymeB, TNFα, and IL-8, with 3G being superior to 2G. CD26-2G/3G was also highly effective against T-cell lymphoma cells derived from patients. In an in vivo mouse model in which a T-cell lymphoma cell line, KARPAS299, was transplanted subcutaneously, CD26-3G inhibited tumor growth, whereas 2G had no effect. Furthermore, in a systemic dissemination model in which HSB2 was administered intravenously, CD26-3G inhibited tumor growth more potently than 2G, resulting in greater survival benefit. The third-generation CD26-targeted CAR-T-cell therapy may be a promising treatment modality for T-cell malignancies.

A Novel Mechanism for Bone Loss: Platelet Count Negatively Correlates with Bone Mineral Density via Megakaryocyte-Derived RANKL.

A potential association between hematopoietic stem cell status in bone marrow and surrounding bone tissue has been hypothesized, and some studies have investigated the link between blood count and bone mineral density (BMD), although their exact relationship remains controversial. Moreover, biological factors linking the two are largely unknown. In our present study, we found no clear association between platelet count and BMD in the female group, with aging having a very strong effect on BMD. On the other hand, a significant negative correlation was found between platelet count and BMD in the male group. As a potential mechanism, we examined whether megakaryocytes, the source of platelet production, secrete cytokines that regulate BMD, namely OPG, M-CSF, and RANKL. We detected the production of these cytokines by megakaryocytes derived from bone marrow mononuclear cells, and found that RANKL was negatively correlated with BMD. This finding suggests that RANKL production by megakaryocytes may mediate the negative correlation between platelet count and BMD. To our knowledge, this is the first report to analyze bone marrow cells as a mechanism for the association between blood count and BMD. Our study may provide new insights into the development and potential treatment of osteoporosis.

DPP8 Selective Inhibitor Tominostat as a Novel and Broad-Spectrum Anticancer Agent against Hematological Malignancies.

DPP8/9 inhibition induces either pyroptotic or apoptotic cell death in hematological malignancies. We previously reported that treatment with the DPP8/9 inhibitor 1G244 resulted in apoptotic cell death in myeloma, and our current study further evaluates the mechanism of action of 1G244 in different blood cancer cell lines. Specifically, 1G244 inhibited DPP9 to induce GSDMD-mediated-pyroptosis at low concentrations and inhibited DPP8 to cause caspase-3-mediated-apoptosis at high concentrations. HCK expression is necessary to induce susceptibility to pyroptosis but does not participate in the induction of apoptosis. To further characterize this DPP8-dependent broad-spectrum apoptosis induction effect, we evaluated the potential antineoplastic role for an analog of 1G244 with higher DPP8 selectivity, tominostat (also known as 12 m). In vitro studies demonstrated that the cytotoxic effect of 1G244 at high concentrations was enhanced in tominostat. Meanwhile, in vivo work showed tominostat exhibited antitumor activity that was more effective on a cell line sensitive to 1G244, and at higher doses, it was also effective on a cell line resistant to 1G244. Importantly, the weight loss morbidity associated with increasing doses of 1G244 was not observed with tominostat. These results suggest the possible development of novel drugs with antineoplastic activity against selected hematological malignancies by refining and increasing the DPP8 selectivity of tominostat.

Association Between Aortic Stiffness and Exercise Tolerance in Patients at the Risk Stage of Heart Failure.

BACKGROUND: The number of patients with heart failure (HF) has increased, and it is crucial to prevent the development of HF in patients at risk of HF. The present study aimed to risk stratify patients in Stage A and B HF based on associations between exercise-induced changes in aortic stiffness and exercise tolerance.Methods and Results: Patients in Stage A and B HF who performed a cardiopulmonary exercise test were enrolled in the study (n=106; median age 65.0 years [interquartile range 52.8-73.0 years]). Exercise tolerance was examined by the percentage of predicted peak oxygen consumption (%V̇O2peak). The ascending aortic pressure waveform was estimated non-invasively. Aortic stiffness was assessed using the augmentation index (AIx) and reflection magnitude (RM). Multivariable regression analysis showed that AIx measured both before and after exercise was significantly associated with %V̇O2peak (ß=-0.221 [P=0.049] and ß=-0.342 [P=0.003], respectively). When participants were divided into %V̇O2peak subgroups using a cut-off value of 60%, RM decreased immediately after exercise and remained lower 5 min after exercise in the group with preserved exercise tolerance, but recovered to baseline levels 5 min after exercise in the group with reduced exercise tolerance. CONCLUSIONS: Exercise-induced increases in aortic stiffness were associated with exercise tolerance in patients at risk of HF, suggesting that exercise-induced changes in aortic stiffness may be useful to stratify high-risk patients.

Malondialdehyde-Modified Low-Density Lipoprotein as a Predictor of Major Adverse Limb Events after Endovascular Therapy in Patients with Lower Extremity Arterial Disease.

AIM: Adverse limb events after endovascular therapy (EVT) are a major concern. This study aimed to investigate the relationship between serum malondialdehyde-modified low-density lipoprotein (MDA-LDL) level, a potentially potent indicator of atherosclerosis, and clinical outcomes after EVT in patients with lower extremity arterial disease (LEAD). METHODS: A total of 208 LEAD patients who underwent EVT and MDA-LDL measurements were retrospectively analyzed. Those with chronic limb-threatening ischemia (CLTI) were included in the CLTI subgroup (n=106). Patients were further categorized into the High or Low MDA-LDL groups according to the cut-off value calculated by receiver operating characteristic analysis. Major adverse limb events (MALE), a composite of cardiovascular death, limb-related death, major amputation, and target-limb revascularization, were evaluated. RESULTS: MALE occurred in 73 (35%) patients. The median follow-up interval was 17.4 months. The MDA-LDL cut-off values were 100.5 U/L (area under the curve [AUC] 0.651) in the overall population and 98.0 U/L (AUC 0.724) in the CLTI subgroup. Overall, the High MDA-LDL group showed significantly higher total cholesterol (189.7±37.5 mg/dL vs. 159.3±32.0 mg/dL, p＜0.01), low-density lipoprotein cholesterol (114.3±29.7 mg/dL vs. 87.3±25.3 mg/dL, p＜0.01), and triglyceride (166.9±91.1 mg/dL vs. 115.8±52.3 mg/dL, p＜0.01) than the Low MDA-LDL group. Multivariate Cox regression analyses revealed that MDA-LDL and C-reactive protein were independent predictors of MALE. In the CLTI subgroup, MDA-LDL was an independent predictor of MALE. The High MDA-LDL group showed worse MALE-free survival rates than the Low MDA-LDL group in overall (p＜0.01) and in the CLTI subgroup (p=0.01). CONCLUSIONS: Serum MDA-LDL level was associated with MALE after EVT.

Postprocedural ascending aortic dissection after transcatheter aortic valve implantation: a case report.

Background: Transcatheter aortic valve implantation (TAVI) has been established as an effective and safe treatment for patients with severe aortic stenosis (AS). It is reported that vascular complications, especially aortic dissection, are rare. However, aortic dissection may be a serious consequence if it occurs. We experienced a case of delayed onset of ascending aortic dissection after TAVI. Case summary: An 82-year-old woman presented with dyspnoea and general fatigue. Echocardiography revealed severe AS and she was diagnosed with heart failure associated with AS. She had difficulty controlling heart failure and required the intervention of the aortic valve. We evaluated the aortic valve and access routes with contrast-enhanced computed tomography (CT), which showed marked dilatation of the ascending aorta. Transcatheter aortic valve implantation was performed and the procedure was completed without major complications. Transoesophageal echocardiography during the procedure did not detect any obvious arterial injury. However, on the second postoperative day, the patient suddenly became unconscious and a CT indicated an ascending aortic dissection. Unfortunately, she passed away. An autopsy revealed the fragility of the ascending aorta. Conclusion: Patients with AS and aortic root dilatation may develop delayed onset of ascending aortic dissection after TAVI.

Massive hyperphosphatemia in clinical tumor lysis syndrome during prophylactic rasburicase use: risk factors and treatment options.

We report the case of a 76-year-old female with diffuse large B cell lymphoma who developed tumor lysis syndrome (TLS) and subsequent acute kidney injury (AKI) due to massive hyperphosphatemia during the prophylactic use of rasburicase. Our case showed no hyperphosphatemia before chemotherapy but had elevated uric acid and creatinine levels and unilateral hydronephrosis due to paraaortic lymphadenopathy. TLS risk was classified as high risk because of bulky mass, LDH elevation, and renal disturbance. With rasburicase use, uric acid was completely controlled but massive hyperphosphatemia and, subsequently, AKI developed. Immediate kidney replacement therapy led to improvement of hyperphosphatemia and AKI. In the rasburicase era, hyperphosphatemia has been a key target for preventing and treating TLS. Renal replacement therapy is the only effective option for lowering hyperphosphatemia and treating AKI.

Unfavourable outcomes in patients with heart failure with higher preserved left ventricular ejection fraction.

AIMS: Newly introduced drugs for heart failure (HF) have been reported to improve the prognosis of HF with preserved ejection fraction (HFpEF) in the lower range of left ventricular ejection fraction (LVEF). We hypothesized that a higher LVEF is related to an unfavourable prognosis in patients with HFpEF. METHODS AND RESULTS: We tested this hypothesis by analysing the data from a prospective multicentre cohort study in 255 patients admitted to the hospital due to decompensated HF (LVEF > 40% at discharge). The primary endpoint of this study was a composite outcome of all-cause death and readmission due to HF, and the secondary endpoint was readmission due to HF. LVEF and the mitral E/e' ratio were measured using echocardiography. In multicovariate parametric survival time analysis, LVEF [hazard ratio (HR) = 1.046 per 1% increase, P = 0.001], concurrent atrial fibrillation (AF) (HR = 3.203, P < 0.001), and E/e' (HR = 1.083 per 1.0 increase, P < 0.001) were significantly correlated with the primary endpoint. In addition to these covariates, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use was significantly correlated with the secondary endpoint (HR = 0.451, P = 0.008). Diagnostic performance plot analysis demonstrated that the discrimination threshold value for LVEF that could identify patients prone to reaching the primary endpoint was ≥57.2%. The prevalence of AF or E/e' ratio did not differ significantly between patients with LVEF ≥ 58% and with 40% < LVEF < 58%. CONCLUSION: A higher LVEF is independently related to poor prognosis in patients with HFpEF, in addition to concurrent AF and an elevated E/e' ratio. ACEI/ARB use, in contrast, was associated with improved prognosis, especially with regard to readmission due to HF. CLINICAL TRIAL REGISTRATION: https://www.umin.ac.jp/ctr/index.htm. UNIQUE IDENTIFIER: UMIN000017725.

Reclassification of Heart Failure with Preserved Ejection Fraction Following Cardiac Sympathetic Nervous System Activation: A New Cutoff Value of 58.

Heart failure (HF) with preserved left ventricular ejection fraction (LVEF) is a heterogeneous syndrome. An LVEF of 50% is widely used to categorize patients with HF; however, this is controversial. Previously, we have reported that patients with an LVEF of ≥ 58% have good prognoses. Further, cardiac sympathetic nervous system (SNS) activation is a feature of HF. In this retrospective, observational study, the cardiac SNS activity of HF patients (n = 63, age: 78.4 ± 9.6 years; male 49.2%) with LVEF ≥ 58% (n = 15) and LVEF < 58% (n = 48) were compared using 123I-metaiodobenzylguanidine scintigraphy. During the follow-up period (median, 3.0 years), 18 all-cause deaths occurred. The delayed heart/mediastinum (H/M) ratio was significantly higher in the LVEF ≥ 58% group than in the LVEF < 58% group (2.1 ± 0.3 vs. 1.7 ± 0.4, p = 0.004), and all-cause mortality was significantly lower in patients in the former than those in the latter group (log-rank, p = 0.04). However, when these patients were divided into LVEF ≥ 50% (n = 22) and LVEF < 50% (n = 41) groups, no significant differences were found in the delayed H/M ratio, and the all-cause mortality did not differ between the groups (log-rank, p = 0.09). In conclusion, an LVEF of 58% is suitable for reclassifying patients with HF according to cardiac SNS activity.

Involvement of activation induced cytidine deaminase in malignant B-cells expressing two distinct M-components as an etiology of biclonal gammopathy.

Biclonal gammopathy (BG) is a rare phenomenon in which 2 M proteins are detected in the same patient, with 2 major hypotheses regarding its etiology. One potential explanation is that completely different malignant B-cell clones produce different M proteins, while the other is that there is a malignant clone that produces both M proteins simultaneously. In this study, we examined 2 cases of B-cell malignancy with BG and found that some cells were double positive for both M proteins by immunofluorescence and flow cytometry. However, most of the remaining cells were single positive cells that produced only one of the M proteins. We hypothesized that double positive cells were in the process of transitioning from 1 single positive cell to another single positive cell, and that class switch recombination (CSR) would be involved as a mechanism. We then examined the expression of activation induced cytidine deaminase (AICDA), which is responsible for CSR, and found that lymphoma/myeloma cells in 2 BG patients were positive for AICDA by immunostaining. Our study is the first report suggesting that AICDA may be involved in the pathogenesis of BG.

Protein-losing Enteropathy Complicated with Primary Intestinal Follicular Lymphoma.

Protein-losing enteropathy (PLE) is a rare syndrome characterized by hypoproteinemia due to gastrointestinal (GI) protein loss. Primary intestinal follicular lymphoma (PIFL), a specific variant of follicular lymphoma with essential only GI involvement, has not been reported as an etiology of PLE. We herein report a case of PLE complicated with PIFL that was successfully treated with rituximab, resulting in rapid improvement of PLE and a complete response of PIFL. Macroscopic findings of ulcerative lesions with diffuse involvement, which were precisely described by capsule and double-balloon enteroscopy at the diagnosis, also improved following the treatment. This case provides a clue suggesting factors that promote PLE in PIFL.

[Successful preoperative replacement of prothrombin with prothrombin complex concentrate for Prothrombin Himi].

Dysprothrombinemia is the rarest inherited bleeding disorder that is characterized by a decrease in the prothrombin activity, but normal antigen levels. In this study, we report the case of a compound heterozygote of two mutations in prothrombin; Met337Thr and Arg388His, which has previously been identified as "Prothrombin Himi." A systemic blood coagulation evaluation revealed a prolonged prothrombin time (39%) and activated partial thromboplastin (64.4 sec), with an isolated severe decrease in the prothrombin activity (8.6%). Preoperative replacement of prothrombin with prothrombin complex concentrate, PPSB-HT "Nichiyaku," successfully prevented abnormal postoperative bleeding after laparoscopic hysterectomy for cervical cancer. This is the second reported case of Prothrombin Himi.