Truncated GPNMB, a microglial transmembrane protein, serves as a scavenger receptor for oligomeric ß-amyloid peptide1-42 in primary type 1 microglia.

Glycoprotein non-metastatic melanoma protein B (GPNMB) is up-regulated in one subtype of microglia (MG) surrounding senile plaque depositions of amyloid-beta (Aß) peptides. However, whether the microglial GPNMB can recognize the fibrous Aß peptides as ligands remains unknown. In this study, we report that the truncated form of GPNMB, the antigen for 9F5, serves as a scavenger receptor for oligomeric Aß1-42 (o-Aß1-42) in rat primary type 1 MG. 125I-labeled o-Aß1-42 exhibited specific and saturable endosomal/lysosomal degradation in primary-cultured type 1 MG from GPNMB-expressing wild-type mice, whereas the degradation activity was markedly reduced in cells from Gpnmb-knockout mice. The Gpnmb-siRNA significantly inhibits the degradation of 125I-o-Aß1-42 by murine microglial MG5 cells. Therefore, GPNMB contributes to mouse MG's o-Aß1-42 clearance. In rat primary type 1 MG, the cell surface expression of truncated GPNMB was confirmed by a flow cytometric analysis using a previously established 9F5 antibody. 125I-labeled o-Aß1-42 underwent endosomal/lysosomal degradation by rat primary type 1 MG in a dose-dependent fashion, while the 9F5 antibody inhibited the degradation. The binding of 125I-o-Aß1-42 to the rat primary type 1 MG was inhibited by 42% by excess unlabeled o-Aß1-42, and by 52% by the 9F5 antibody. Interestingly, the 125I-o-Aß1-42 degradations by MG-like cells from human-induced pluripotent stem cells was inhibited by the 9F5 antibody, suggesting that truncated GPNMB also serve as a scavenger receptor for o-Aß1-42 in human MG. Our study demonstrates that the truncated GPNMB (the antigen for 9F5) binds to oligomeric form of Aß1-42 and functions as a scavenger receptor on MG, and 9F5 antibody can act as a blocking antibody for the truncated GPNMB.

Impact of chest subcutaneous fat on the occurrence of central venous port-related infectious complications in cancer patients.

PURPOSE: There is no concrete evidence to support the association between the amount of subcutaneous fat area (SFA) in the central venous port-insertion site (precordium) and port-related complications. We aimed to investigate the relationship between SFA in the midclavicular line and postoperative infectious complications in patients undergoing port-insertion surgery. METHODS: This was a single-institute and historical cohort study of 174 patients who underwent first central venous port implantation surgery for chemotherapy between January 2014 and December 2018. SFA in the midclavicular line was measured using preoperative computed tomography scans. The patients were divided into three groups according to SFA amount tertiles, and we investigated the association of SFA with infectious and all-cause complication events within 1 year. RESULTS: Within a median follow-up of 306 days, the patients with intermediate SFA had significantly higher infection-free survival than those with low and high SFA (low vs. intermediate vs. high: 80.4% vs. 97.7% vs. 83.4%, respectively, p=0.034). In contrast, there was no significant difference in the overall complication-free survival among the groups (low vs. intermediate vs. high: 80.4% vs. 88.9% vs. 81.8%, respectively, p=0.29). Low SFA was independently associated with high risk of infectious complications (hazard ratio, 9.45; 95% confidence interval, 1.07-83.22, p=0.043). CONCLUSION: Low SFA in the midclavicular line was an independent risk factor for infectious complications in the chemotherapy setting. This practical indicator can be useful for optimizing patients' nutritional status and when considering other types of vascular access to support administration of intravenous chemotherapy.

MicroRNA-205-5p inhibits three-dimensional spheroid proliferation of ErbB2-overexpressing breast epithelial cells through direct targeting of CLCN3.

We previously reported that microRNA-205-5p (miR-205-5p) is significantly decreased in the ErbB2-overexpressing breast epithelial cell line MCF10A-ErbB2 compared with control cells. In this study, we identified a direct target of miR-205-5p, chloride voltage-gated channel 3 (CLCN3). CLCN3 expression was induced by ErbB2 overexpression; this induced expression was then reduced to control levels by the transfection of the miR-205-5p precursor. In RNA-binding protein immunoprecipitation with Ago1/2/3 antibody, CLCN3 was significantly enriched in 293T embryonic kidney cells with miR-205-5p mimic transfection compared with negative control mimic transfection. In luciferase reporter assays using CLCN3 3'-UTR constructs, the miR-205-5p mimic significantly decreased reporter activity of both wild-type and partial mutant constructs in MCF10A-ErbB2 cells. In contrast, no inhibitory effects of the miR-205-5p mimic were detected using the complete mutant constructs. Since miR-205-5p expression in exosomes derived from MCF10A-neo cells was substantially higher than in exosomes derived from MCF10A-ErbB2 cells, we next investigated whether an exosome-mediated miR-205-5p transfer could control CLCN3 expression. To this end, exosomal miR-205-5p derived from MCF10A-neo cells was functionally transferred to MCF10A-ErbB2 cells, which served to decrease the expression of CLCN3. To assess the roles of CLCN3 in breast cancer, we next performed three-dimensional (3D) spheroid proliferation analyses using MCF10A-ErbB2 cells treated with MCF10A-neo-derived exosomes or CLCN3 shRNA stably expressing SKBR3 and MDA-MB-453 breast cancer cells. Our results showed that both treatment with MCF10A-neo-derived exosome and CLCN3 shRNA expression suppressed 3D spheroid proliferation. Collectively, these novel findings suggest that CLCN3 may be a novel direct target of miR-205-5p and this CLCN3/miR-205-5p interaction may serve a pivotal role in regulating breast cancer cellular proliferation under physiological conditions.

Independent Prognostic Value of Pulmonary Diffusing Capacity in Nonsmoking Patients with Chronic Heart Failure.

The diffusing capacity of the lung for carbon monoxide (DLCO) is indicative of the alveolar-capillary membrane function. A reduced DLCO is associated with poor prognosis in chronic heart failure (HF). However, the significance of DLCO as an independent prognostic predictor has not been established. Here, we aimed to determine the prognostic value of DLCO in patients with chronic HF.We enrolled 214 patients (139 females, mean age: 63 ± 16 years, left ventricular ejection fraction [LVEF]: 45 ± 21%) with stable chronic HF who underwent pulmonary function tests. Only never smokers were included in the analysis because smoking can decrease DLCO.During a median follow-up period of 2.1 years, 52 patients (24.3%) experienced cardiac events, including unplanned HF admissions, left ventricular assist device (LVAD) implantations, all-cause deaths, and cardiopulmonary arrests (CPAs). The median percent predicted DLCO (%DLCO) was 87.3%. In a Cox regression analysis, a %DLCO of ≤87.3% was independently associated with the cardiac events, even after adjusting for age, sex, systolic blood pressure (SBP), LVEF, anemia, brain natriuretic peptide, estimated glomerular filtration rate (eGFR), and prior HF admission (hazard ratio [HR]: 1.87, 95% confidence interval: 1.03-3.53, P = 0.030).A reduced DLCO is an independent predictor of poor prognosis in nonsmoking patients with chronic HF.

Prognostic impact of peak mitral inflow velocity in asymptomatic degenerative mitral regurgitation.

OBJECTIVE: Appropriate timing of mitral valve surgery in asymptomatic mitral regurgitation (MR) remains controversial. Peak mitral inflow velocity (peak E wave velocity) has been reported as a simple and easy predictor of quantitative MR severity; however, its prognostic significance in asymptomatic MR remains unclear. Therefore, we sought to investigate the prognostic impact of peak E wave velocity in asymptomatic MR. METHODS: Among 529 consecutive patients with degenerative MR of grade 3+ (moderate to severe) or 4+ (severe), 188 asymptomatic patients in sinus rhythm without left ventricular (LV) dysfunction (end-systolic dimension ≥40 mm or ejection fraction <60%) or pulmonary hypertension were studied. Cardiovascular events were defined as a composite endpoint of cardiovascular death or events that indicated mitral surgery including congestive heart failure, atrial fibrillation, LV dysfunction or pulmonary hypertension. RESULTS: Average peak E wave velocity was 1.05±0.26 m/s, and was significantly higher in grade 4+ than grade 3+ (1.20±0.28 vs 0.98±0.21 m/s, p<0.001). Peak E wave velocity was associated with quantitative MR severity, as well as clinical characteristics of advanced MR (higher brain natriuretic peptide, larger LV and left atrium, higher tricuspid regurgitation pressure gradient and dilated inferior vena cava). During a median follow-up of 4.3 years, 66 (35%) patients developed cardiovascular events. Multivariate Cox proportional hazards analysis showed that peak E wave velocity was an independent predictor of cardiovascular events (adjusted HR 1.245 (95% CI 1.126 to 1.378) per 0.1 m/s, p<0.001). CONCLUSIONS: Peak E wave velocity was an independent predictor of cardiovascular events in asymptomatic degenerative MR with preserved LV function.

Monitoring treatment response to tafamidis by serial native T1 and extracellular volume in transthyretin amyloid cardiomyopathy.

Tafamidis meglumine, a transthyretin (TTR) stabilizer, is effective in delaying the progression of neuropathy in TTR amyloidosis with Val30Met mutations. However, its efficacy in TTR amyloid cardiomyopathy is not fully elucidated. Herein, we report a 73-year-old Japanese man with a diagnosis of TTR amyloid cardiomyopathy with Val30Met mutation treated with tafamidis. To evaluate treatment response, cardiac magnetic resonance imaging was performed before and after 12 months of tafamidis treatment. Native T1, extracellular volume, and left ventricular mass showed no obvious worsening, and findings of other diagnostic studies also supported the efficacy of tafamidis to delay the progression of amyloid cardiomyopathy. Our case suggests that serial native T1 and extracellular volume may be novel non-invasive imaging methods to monitor the treatment response to TTR stabilizers in cardiac amyloidosis and also that tafamidis may be effective in suppressing cardiac progression in TTR amyloid cardiomyopathy with Val30Met mutation.

Feasibility of transcatheter prosthetic paravalvular leakage closure: a single-center, exploratory safety evaluation study of transcatheter closure of prosthetic paravalvular regurgitation in Japan (STOP PARA study).

OBJECTIVE: The standard treatment of prosthetic paravalvular leakage (PVL) accompanied by heart failure or hemolytic anemia is repeat open surgery. Although favorable outcomes for transcatheter prosthetic PVL closure in patients with a high surgical risk for repeat open surgery have been reported, procedural feasibility has not been examined in Japan. METHODS: From March 2015 to November 2015, transcatheter PVL closure in mitral position was performed in four patients (age range 41-78, three females) with high surgical risk due to history of repeated surgeries, chest radiation and reconstruction of the mitral annulus after debridement of abscess owing to infective endocarditis. All procedures were performed via a transapical approach under general anesthesia. RESULTS: Of four patients, the indications for PVL closure of two patients were heart failure, and those of the others were hemolytic anemia. There were no major complications, mortalities, or prolonged intensive care unit or hospital stays. Technical success was achieved in two patients. Moderate paravalvular regurgitation persisted in one patient, although regurgitation reduction of one grade was obtained. In one patient, occluder devices were not deployed because the wire could not cross the defect. Improvement in New York Heart Association functional class compared with that at baseline was observed in two patients. CONCLUSIONS: The safety and acute technical success rates of transcatheter mitral PVL closure via a transapical approach were confirmed in Japanese patients. In Japan, transcatheter PVL closure may be an alternative option for patients with PVL who have a high surgical risk.

Left ventricular myxoma with Carney complex.

The left ventricle is a less frequent location of cardiac myxomas overall. Meanwhile, cardiac myxomas related to Carney complex (CNC), which is a multiple neoplasia syndrome involving cardiac, endocrine, neural, and cutaneous tumours, more frequently occur in the left ventricle compared with sporadic cardiac myxomas. Herein, we report a case of a 20-year-old woman with CNC who underwent complete surgical excision of a large and mobile left ventricular myxoma. In our case, echocardiography performed 4 years earlier was normal. This case highlights the importance of annual follow-up by echocardiography in patients with CNC, because early diagnosis of cardiac myxomas might improve their prognosis. Besides, we should bear in mind the possibility of CNC if the patients have cardiac myxoma in a cardiac chamber other than the left atrium at a younger age.

Increased serum Wisteria floribunda agglutinin positive Mac-2 binding protein (Mac-2 binding protein glycosylation isomer) in chronic heart failure: a pilot study.

BACKGROUND: Serum Wisteria floribunda agglutinin positive Mac-2 binding protein (WFA+-M2BP) or Mac-2 Binding Protein Glycosylation Isomer (M2BPGi) is a novel biomarker currently applied for evaluating hepatic fibrosis. The aim of this study was to evaluate the utility of serum WFA+-M2BP level as a biomarker in chronic heart failure (HF) patients with abnormal liver function. METHODS AND RESULTS: Fifty chronic HF patients who underwent measurement of serum WFA+-M2BP were evaluated. The median value of serum WFA+-M2BP was 0.88 (interquartile range 0.48-1.29) cut-off index, and positive WFA+-M2BP (≥ 1.00 cut-off index) was observed in 22 (44%). Elevated WFA + -M2BP was associated with longer HF history, older age, female sex, valvular heart disease, decreased estimated glomerular filtration rate (eGFR), albumin, and cholinesterase. Stepwise multiple regression analysis showed that HF history, eGFR, and albumin were independent determinants of serum WFA+-M2BP values. Repeated measurements of serum WFA+-M2BP suggested association between the decrease of WFA+-M2BP and improvement of New York Heart Association (NYHA) functional class. CONCLUSIONS: Elevation of serum WFA+-M2BP showed a high prevalence in chronic HF patients with abnormal liver function with relation to HF history, decreased hepatic protein synthesis, and renal dysfunction. Our results suggest that serum WFA+-M2BP may be a novel biomarker of chronic HF.

Contrast-enhanced computed tomography with myocardial three-dimensional printing can guide treatment in symptomatic hypertrophic obstructive cardiomyopathy.

Both surgical myectomy and percutaneous transluminal septal myocardial ablation are effective treatments for drug-refractory symptomatic hypertrophic obstructive cardiomyopathy (HOCM). However, in some cases, it is not easy to elucidate the abnormal structure of left ventricular outflow obstruction to adopt these treatments. Here, we presented a young female patient with drug-refractory symptomatic HOCM. In this case, contrast-enhanced computed tomography enabled us to assess the suitability of percutaneous transluminal septal myocardial ablation. By creating three-dimensional printed models using computed tomography data, we could also visualize intracardiac structure and simulate the surgical procedure. A multimodality assessment strategy is useful for evaluating patients complicated with drug-refractory symptomatic HOCM.

ErbB2 signaling epigenetically suppresses microRNA-205 transcription via Ras/Raf/MEK/ERK pathway in breast cancer.

We previously reported that microRNA-205 (miR-205) is downregulated by overexpression of the receptor tyrosine kinase ErbB2 and that ectopic transfection of miR-205 precursor decreases ErbB2 tumorigenicity in soft agar. In this study, we further analyzed the regulatory mechanisms linking ErbB2 overexpression and miR-205 downregulation. In ErbB2-overexpressing breast epithelial cells, miR-205 expression was significantly increased by treatment with MEK inhibitor U0126 or PD98059, Raf-1 inhibitor ZM-336372, and ERK inhibitor SCH772984, but PI3K inhibitor LY294002 and p38 MAPK inhibitor SB203580 had no effect. We established breast epithelial cells overexpressing RafCAAX, a constitutively active form of Raf-1, and showed that overexpression of RafCAAX dramatically reduced miR-205 expression. In RafCAAX-overexpressing cells, miR-205 expression was also significantly increased by SCH772984. Moreover, miR-205 expression was significantly increased by treatment with DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine and expression of several DNMT family members was increased in both ErbB2- and RafCAAX-overexpressing cells. DNA methylation analysis by bisulfite sequencing revealed that the putative miR-205 promoters were predominantly hypermethylated in both ErbB2- and RafCAAX-overexpressing cells. Reporter activity of the putative miR-205 promoters was reduced in both ErbB2-overexpressing and RafCAAX-overexpressing cells. Together, these findings indicate that ErbB2 signaling epigenetically suppresses miR-205 transcription via the Ras/Raf/MEK/ERK pathway.

Multimodality assessment of left ventricular dysfunction in Takayasu arteritis and familial hypercholesterolaemia.

Although left ventricular (LV) systolic dysfunction in patients suffering from Takayasu arteritis (TA) has been reported, little is known regarding the development of heart failure in these patients. We report a novel finding of active TA and familial hypercholesterolaemia presenting with severe LV dysfunction through multimodality assessments of LV systolic dysfunction.

Effect of Mitral Valve Surgery in Patients With Dilated Cardiomyopathy and Severe Functional Mitral Regurgitation.

BACKGROUND: Surgical treatment of functional mitral regurgitation (FMR) improves ventricular remodeling in patients with dilated cardiomyopathy (DCM). However, it is unclear whether surgical treatment improves long-term outcomes. We investigated the effects of mitral valve (MV) surgery in patients with DCM and FMR.Methods and Results:Of 525 patients with DCM hospitalized due to heart failure between January 1996 and September 2014, 70 who had severe FMR despite receiving optimal medical therapy were enrolled in the study. Of these patients, 16 underwent surgery for FMR (surgery group; repair=14, replacement=2); the remaining 54 who refused or decided not to undergo surgery were classified as the medication group. There were no differences in age, sex, medication, or echocardiographic parameters between the 2 groups (P>0.05). During the mean follow-up period of 53.6±43.6 months, the occurrence of clinical outcomes (i.e., all-cause death or left ventricular assist device implantation) was 54.3%; the occurrence of clinical outcomes was lower in the surgery group (P=0.008, log-rank test). Multivariate Cox regression analysis using clinical data revealed that MV surgery (hazard ratio [HR] 0.257, 95% confidence interval [CI] 0.103-0.640; P=0.004) and diabetes mellitus (HR 2.924, 95% CI 1.243-6.876; P=0.014) were independent predictors of clinical outcomes after adjusting for age and sex. CONCLUSIONS: Surgery for severe FMR provides better long-term outcomes in patients with DCM.

Does the pathophysiology of heart failure prime the incidence of cancer?

Both chronic heart failure (CHF) and cancer are among the most frequent causes of death in developed countries. Given that CHF activates neurohumoral factors, such as cytokines, the pathophysiology of CHF could prime the onset or progression of cancer. We consecutively enrolled 5238 patients with CHF who had been hospitalized in the Department of Cardiovascular Medicine in our institute between 2001 and 2013. We followed these patients until April 2015. We examined the cohort of patients from our hospital and compared it with a control cohort derived from the 2008 cancer database 'Monitoring of Cancer Incidence in Japan' from the National Cancer Center, Japan. The incidence of cancer in CHF patients (198 cases out of the 5238 patients) was approximately four times higher than that in control patients (2.27% vs 0.59%, P<0.0001; 95% confidence interval, 1.89-2.71). When we omitted the patients whose cancer diagnosis occurred prior to their diagnosis of CHF, we still observed a significantly higher incidence of cancer in patients with CHF than in controls. Based on our results, we suggest that there is a strong correlation between the pathophysiology of CHF and cancer. Given that CHF could prime the onset of cancers, we recommend that clinicians should be vigilant regarding cancer comorbidity in patients with CHF.

Pathohistological Evidence of Smoldering Inflammation in Rheumatic Heart Disease with Massive Left Atrial Calcification.

A 74-year-old man, who had a history of a mitral valve replacement for rheumatic heart disease (RHD) 30 years previously, was admitted with progressive heart failure. Massive calcification was observed around the left atrium on multidetector CT, in addition to a late gadolinium enhancement (LGE)-positive layer adjacently outside of the calcification on MRI. He underwent a second mitral valve replacement for the prosthetic valve failure. Pathohistological analyses of a tissue section of the left atrial wall from a surgical specimen revealed lymphocyte and macrophage infiltration that coincided with the LGE-positive layer on MRI, suggesting the existence of sustained active inflammation even after the long period of RHD.

First Case Report of the Antemortem Diagnosis of Nonbacterial Thrombotic Endocarditis of a Mechanical Prosthetic Valve.

A 67-year-old man with a history of aortic mechanical valve replacement exhibited an abnormal mass on the sewing ring of the prosthesis on echocardiography. Despite receiving strong anticoagulation, he developed acute cerebral infarction due to the formation of emboli resulting from the thrombus and underwent urgent re-aortic valve replacement. Based on the microscopic findings of the resected mass, he was finally diagnosed as having nonbacterial thrombotic endocarditis (NBTE) of the mechanical prosthetic valve, which was thought to be associated with colorectal cancer. We herein report the first known case of an antemortem diagnosis of NBTE on a mechanical heart valve.

Intracardiac echocardiography to diagnose pannus formation after aortic valve replacement.

A 66-year-old female, under regular follow-up for 20 years after aortic valve replacement (19-mm Carbomedics), presented dyspnea on effort and hypotension during hemodialysis. A transthoracic echocardiogram showed elevation of transvalvular velocity up to 4 m/s, but the structure around the aortic prosthesis was difficult to observe due to artifacts. Fluoroscopy revealed normal motion of the leaflets of the mechanical valve. Intracardiac echocardiography (ICE) revealed a pannus-like structure in the left ventricular outflow tract. Transesophageal echocardiogram also revealed this structure. ICE can visualize structural abnormalities around a prosthetic valve after cardiac surgery even in patients in whom conventional imaging modalities failed.

Prognostic significance of late gadolinium enhancement quantification in cardiac magnetic resonance imaging of hypertrophic cardiomyopathy with systolic dysfunction.

Hypertrophic cardiomyopathy (HCM) with systolic dysfunction carries a poor prognosis. Although late gadolinium enhancement (LGE) on cardiac magnetic resonance is associated with adverse cardiac events in HCM and is inversely related to left ventricular ejection fraction (LVEF), it is unknown whether LGE or LVEF more accurately predicts adverse cardiac events in HCM with systolic dysfunction. We retrospectively assessed the extent of LGE with a threshold of 6 standard deviations in 46 consecutive HCM patients with systolic dysfunction defined as LVEF <50 % (average 35 ± 12 %) who underwent cardiac magnetic resonance (35 males, mean age 59 ± 14 years). They were followed up over 1755 ± 594 days. The composite adverse cardiac events end point included cardiovascular death, lethal arrhythmia, cardioembolic stroke, and unplanned heart failure hospitalization. LGE was detected in all patients, and the mean extent was 30 ± 15 %. Twenty-nine patients developed adverse cardiac events. Multivariate Cox proportional hazard analysis revealed the extent of LGE as a good independent predictor of adverse cardiac events. Risk increased with the extent of LGE (hazard ratio = 1.62/10 % increase in LGE, 95 % confidence interval = 1.23-2.15, p < 0.001). LVEF was inversely related to the extent of LGE (r = -0.44; p = 0.002) and was also an independent predictor of adverse cardiac events. Risk decreased with LVEF (hazard ratio = 0.68/10 % increase in LVEF, 95 % confidence interval = 0.51-0.91, p = 0.010). The Akaike information criterion evaluating the fit of a model demonstrated that the extent of LGE was a better independent predictor of MACE than LVEF (Akaike information criterion = 172.20 and 178.09, respectively).The extent of LGE was a good independent predictor of adverse cardiac events and reflected mortality and morbidity more precisely than LVEF in HCM with systolic dysfunction.

Late aneurysm formation of Valsalva sinus after aortic valve replacement due to Takayasu's arteritis.

Takayasu's arteritis (TA) is an inflammatory disease of unknown etiology involving the aorta and its branches, and also causes aortic regurgitation (AR). One of the most serious but rare complications after aortic valve replacement (AVR) in TA is aneurysm formation of the sinus of Valsalva. A 64-year-old woman had undergone AVR with a prosthetic valve for AR due to TA 4 years earlier and had received an implanted permanent pacemaker for complete atrioventricular block (AVB) 2 years later. Aortography 4 years postoperatively demonstrated aneurysm formation (47 mm in diameter) at the sinus of Valsalva although preoperative aortography showed severe AR without dilatation of the sinus of Valsalva. We recommended reoperation for the aneurysm but the patient refused. The perioperative histopathological examination revealed extensive destruction of the medial elastic fibers. Both the fragility of the sinus of Valsalva and the residual inflammation could have caused the patient's aneurysm formation. Moreover, extension of TA into the ventricular septum or mechanical compression of the aneurysm against the conduction system might have caused her progressive AVB. Close and lifelong follow-up for patients with TA regarding development of aneurysm after surgical treatment is indispensable when fragility of the aortic root had been confirmed.