CRYAB stop-loss variant causes rare syndromic dilated cardiomyopathy with congenital cataract: expanding the phenotypic and mutational spectrum of alpha-B crystallinopathy.

Missense mutations in the alpha-B crystallin gene (CRYAB) have been reported in desmin-related myopathies with or without cardiomyopathy and have also been reported in families with only a cataract phenotype. Dilated cardiomyopathy (DCM) is a disorder with a highly heterogeneous genetic etiology involving more than 60 causative genes, hindering genetic diagnosis. In this study, we performed whole genome sequencing on 159 unrelated patients with DCM and identified an unusual stop-loss pathogenic variant in NM_001289808.2:c.527A>G of CRYAB in one patient. The mutant alpha-B crystallin protein is predicted to have an extended strand with addition of 19 amino acid residues, p.(Ter176TrpextTer19), which may contribute to aggregation and increased hydrophobicity of alpha-B crystallin. The proband, diagnosed with DCM at age 32, had a history of bilateral congenital cataracts but had no evidence of myopathy or associated symptoms. He also has a 10-year-old child diagnosed with bilateral congenital cataracts with the same CRYAB variant. This study expands the mutational spectrum of CRYAB and deepens our understanding of the complex phenotypes of alpha-B crystallinopathies.

Diagnostic Pitfall and Clinical Characteristics of Variant Versus Wild-Type Transthyretin Amyloid Cardiomyopathy in Asian Population: The Korean Nationwide Cohort Study.

BACKGROUND: Transthyretin amyloidosis cardiomyopathy (ATTR-CM) is an under-recognized cause of heart failure (HF) with clinical phenotypes that vary across regions and genotypes. We sought to characterize the clinical characteristics of ATTR-CM in Asia. METHODS: Data from a nationwide cohort of patients with ATTR-CM from six major tertiary centres in South Korea were analysed between 2010 and 2021. All patients underwent clinical evaluation, biochemical laboratory tests, echocardiography, and transthyretin (TTR) genotyping at the time of diagnosis. The study population comprised 105 Asian ATTR-CM patients (mean age: 69 years; male: 65.7%, wild-type ATTR-CM: 41.9%). RESULTS: Among our cohort, 18% of the patients had a mean left ventricular (LV) wall thickness < 12 mm. The diagnosis of ATTR-CM increased notably during the study period (8 [7.6%] during 2010-2013 vs. 22 [21.0%] during 2014-2017 vs. 75 [71.4%] during 2018-2021). Although the duration between symptom onset and diagnosis did not differ, the proportion of patients with HF presenting mild symptoms increased during the study period (25% NYHA class I/II between 2010-2013 to 77% between 2018-2021). In contrast to other international registry data, male predominance was less prominent in wild-type ATTR-CM (68.2%). The distribution of TTR variants was also different from Western countries and from Japan. Asp38Ala was the most common mutation. CONCLUSION: A nationwide cohort of ATTR-CM exhibited less male predominance, a proportion of patients without increased LV wall thickness, and distinct characteristics of genetic mutations, compared to cohorts in other parts of the world. Our results highlight the ethnic variation in ATTR-CM and may contribute to improving the screening process for ATTR-CM in the Asian population.

Clinical Implication of Left Atrial Appendage Emptying Velocity in Thoracoscopic Ablation of Atrial Fibrillation.

BACKGROUND: There are limited data about predictors of atrial fibrillation (AF) recurrence after totally thoracoscopic ablation (TTA). This study investigated the clinical implication of left atrial appendage emptying velocity (LAAV) in patients undergoing TTA.Methods and Results: Patients who underwent TTA between 2012 and 2015 at a tertiary hospital were prospectively enrolled in this study. LAAV was measured and averaged over five heart beats from preoperative transesophageal echocardiography. The primary outcome was a freedom from recurrent AF or atrial flutter (AFL) detected on 24-h Holter monitoring or an electrocardiogram over a 3-year period after TTA. In all, 129 patients were eligible for analysis in this study. The mean (±SD) patient age was 54.4±8.8 years, and 95.3% were male. During the 3 years after TTA, the overall event-free survival rate was 65.3%. LAAV was an independent predictor of recurrent AF/AFL during the 3-year period after TTA (per 1-cm/s increase, adjusted hazard ratio [aHR] 0.95; 95% confidence interval [CI] 0.91-0.99; P=0.016). Event-free survival was significantly lower among patients with a low LAAV (<20 cm/s; n=21) compared with those with a normal (≥40 cm/s; n=38; aHR 6.11; 95% CI 1.42-26.15; P=0.015) or intermediate (LAAV ≥20 and <40 cm/s; n=70; aHR 2.74, 95% CI 1.29-5.83; P=0.009) LAAV. CONCLUSIONS: In patients with AF, LAAV was significantly associated with the risk of long-term recurrence of AF after TTA.

Direct comparison of diagnostic and clinical values between Tc-99 m DPD and Tc-99 m PYP scintigraphy in patients with cardiac amyloidosis.

BACKGROUND: Technetium-99 m 3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) and technetium-99 m sodium pyrophosphate (PYP) are the two most commonly used radiotracers for cardiac amyloidosis (CA), but no studies have directly compared them. Therefore, in this study, we directly compared the diagnostic and clinical utility of DPD and PYP scintigraphy in patients with CA. METHODS: Ten patients with CA were enrolled. Eight clinical variables and 12 scintigraphic parameters were used. Clinical variables were age, sex, estimated glomerular filtration rate (eGFR), N-terminal pro brain natriuretic peptide (NT-proBNP), and the results of electromyography (EMG), a sensory test, electrocardiogram, and echocardiography (EchoCG). Four heart retention ratios (heart/whole-body profile, heart/pelvis, heart/skull, and heart/contralateral lung) were calculated from the DPD and PYP scans and two visual scoring systems (Perugini and Dorbala systems) were used. Comparative analyses were performed between radiotracers and between visual scoring systems using clinical variables and scintigraphic parameters. RESULTS: Twenty DPD parameters and nine PYP parameters had significant associations with age, eGFR, NT-proBNP, EchoCG, and EMG. DPD parameters had more frequent significant associations with clinical variables than PYP parameters. Compared to visual scores in the DPD scan, the proportion of patients with higher visual scores in the PYP scan was relatively greater than those with lower visual scores, and there were more patients with a visual score of 2 or higher in PYP scans than DPD scans. CONCLUSIONS: DPD scintigraphy may reflect the disease severity of CA better than PYP scintigraphy, whereas PYP scintigraphy may be a more sensitive imaging modality for identifying CA involvement.

The impact of preoperative kidney replacement therapy on kidney outcome and survival in patients with left ventricular assist device.

Left ventricular assist device (LVAD) has been highlighted as a new treatment option in the end-stage heart failure (HF). Kidney outcome after LVAD in severe cardiorenal syndrome (CRS) patients requiring kidney replacement therapy (KRT) is unclear. We investigated the impact of preoperative KRT on kidney function and survival in LVAD patients with severe CRS. A total of 50 patients followed up for at least 1 year after LVAD implantation was analyzed. The primary outcomes were estimated glomerular filtration rate and survival rate. Patients were divided into two groups depending on in-hospital KRT before LVAD implantation: the control group (n = 33) and the KRT group (n = 17). Postoperative KRT was performed for 76.5% of patients in the KRT group, and all of them discontinued KRT before discharge. There were no statistically significant differences in the degree of eGFR decline in survivors according to preoperative KRT. Although there were no statistically significant differences in the degree of eGFR decline in survivors regardless of preoperative KRT, old age (ß -0.94, p < 0.01), preexisting chronic kidney disease (ß -21.89, p < 0.01), and high serum creatinine (ß -13.95, p < 0.01) were identified as independent predictors of post-LVAD eGFR decline. Mortality rate was higher, and more patients progressed to end-stage kidney disease in KRT group than control group. However, LVAD still can be considered as the treatment option in end-stage HF patients with severe CRS requiring KRT, especially in those with young age and previous normal kidney function.

Coronary Microcirculatory Dysfunction and Acute Cellular Rejection After Heart Transplantation.

BACKGROUND: Acute cellular rejection is a major determinant of mortality and retransplantation after heart transplantation. We sought to evaluate the prognostic implications of coronary microcirculatory dysfunction assessed by index of microcirculatory resistance (IMR) for the risk of acute cellular rejection after heart transplantation. METHODS: The present study prospectively enrolled 154 heart transplant recipients who underwent scheduled coronary angiography and invasive coronary physiological assessment 1 month after transplantation. IMR is microcirculatory resistance under maximal hyperemia. By measuring hyperemic mean transit time using 3 injections (4 mL each) of room-temperature saline under maximal hyperemia, IMR was calculated as hyperemic distal coronary pressure×hyperemic mean transit time. The primary end point was biopsy-proven acute cellular rejection of grade ≥2R during 2 years of follow-up after transplantation and was compared by using multivariable Cox proportional hazards regression according to IMR. The incremental prognostic value of IMR, in addition to the model with clinical factors, was evaluated by comparison of C-index, net reclassification index, and integrated discrimination index. RESULTS: The mean age of recipients was 51.2±13.1 years (81.2% male), and the cumulative incidence of acute cellular rejection was 19.0% at 2 years. Patients with acute cellular rejection had significantly higher IMR values at 1 month than those without acute cellular rejection (23.1±8.6 versus 16.8±11.1, P=0.002). IMR was significantly associated with the risk of acute cellular rejection (per 5-U increase: adjusted hazard ratio, 1.18 [95% CI, 1.04-1.34], P=0.011) and the optimal cutoff value of IMR to predict acute cellular rejection was 15. Patients with IMR≥15 showed significantly higher risk of acute cellular rejection than those with IMR<15 (34.4% versus 3.8%; adjusted hazard ratio, 15.3 [95% CI 3.6-65.7], P<0.001). Addition of IMR to clinical variables showed significantly higher discriminant and reclassification ability for risk of acute cellular rejection (C-index 0.87 versus 0.74, P<0.001; net reclassification index 1.05, P<0.001; integrated discrimination index 0.20, P<0.001). CONCLUSIONS: Coronary microcirculatory dysfunction assessed by IMR measured early after heart transplantation showed significant association with the risk of acute cellular rejection. In addition to surveillance endomyocardial biopsy, early stratification using IMR could be a clinically useful tool to identify patients at higher risk of future acute cellular rejection after heart transplantation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02798731.

Characteristics and outcomes of heart transplant recipients with a pretransplant history of malignancy.

We aimed to investigate the characteristics and outcomes of HTx recipients with a history of pretransplant malignancy (PTM). Among 1062 HTx recipients between 1997 and 2013, 73 (7.1%) patients had PTMs (77 cancer cases). We analyzed post-HTx outcome, recurrence of PTM, and development of de novo malignancies. Post-HTx outcome included overall survival, 10-year survival, 10-year freedom from cardiac allograft vasculopathy (CAV), non-fatal major adverse cardiac events (NF-MACE), any treated rejection (ATR), acute cellular rejection (ACR), and antibody-mediated rejection (AMR). Four most common PTMs were lymphoproliferative disorders (18.2%), prostate cancers (18.2%), non-melanoma skin cancers (18.2%), and breast cancers (13.0%). Median time from PTM and HTx was 9.0 years. During a median follow-up of 8.6 years after HTx, patients with PTM, compared to those without, showed significantly higher incidence of posttransplant malignancies (43.8% vs. 20.8%, p < .001) including 9.6% (n = 7) of PTM recurrences. However, patients with PTM, compared to those without, showed comparable overall survival, 10-year survival, 10-year freedom from CAV, NF-MACE, ATR, ACR, and AMR. Therefore, a history of PTM should not disqualify patients from HTx listing, while further research is necessary for early detection of posttransplant malignancies in these patients.

Dapagliflozin attenuates diabetes-induced diastolic dysfunction and cardiac fibrosis by regulating SGK1 signaling.

BACKGROUND: Recent studies have reported improved diastolic function in patients administered sodium-glucose cotransporter 2 inhibitors (SGLT2i). We aimed to investigate the effect of dapagliflozin on left ventricular (LV) diastolic function in a diabetic animal model and to determine the molecular and cellular mechanisms underlying its function. METHODS: A total of 30 male New Zealand white rabbits were randomized into control, diabetes, or diabetes+dapagliflozin groups (n = 10/per each group). Diabetes was induced by intravenous alloxan. Cardiac function was evaluated using echocardiography. Myocardial samples were obtained for histologic and molecular evaluation. For cellular evaluation, fibrosis-induced cardiomyoblast (H9C2) cells were obtained, and transfection was performed for mechanism analysis (serum and glucocorticoid-regulated kinase 1 (SGK1) signaling analysis). RESULTS: The diabetes+dapagliflozin group showed attenuation of diastolic dysfunction compared with the diabetes group. Dapagliflozin inhibited myocardial fibrosis via inhibition of SGK1 and epithelial sodium channel (ENaC) protein, which was observed both in myocardial tissue and H9C2 cells. In addition, dapagliflozin showed an anti-inflammatory effect and ameliorated mitochondrial disruption. Inhibition of SGK1 expression by siRNA decreased and ENaC and Na+/H+ exchanger isoform 1 (NHE1) expression was confirmed as significantly reduced as siSGK1 in the diabetes+dapagliflozin group. CONCLUSIONS: Dapagliflozin attenuated left ventricular diastolic dysfunction and cardiac fibrosis via regulation of SGK1 signaling. Dapagliflozin also reduced macrophages and inflammatory proteins and ameliorated mitochondrial disruption.

OCULAR MANIFESTATIONS OF ASP38ALA AND THR59LYS FAMILIAL TRANSTHYRETIN AMYLOIDOSIS.

PURPOSE: To describe the ophthalmic manifestations of familial transthyretin amyloidosis (FTA) mutations, including Asp38Ala and Thr59Lys, which have not been previously reported to have ocular involvement. METHODS: This is an observational case series of prospectively collected data of 16 patients with FTA who were taking tafamidis for mild peripheral neuropathy and underwent a comprehensive ophthalmic examination at a single tertiary center, between January 2013 and March 2020. The ocular involvement of each FTA mutation type and the specific manifestations were the main outcome measures. RESULTS: Six of 16 patients with FTA manifested ocular involvement. Ocular involvement was noted in two of three patients with Glu89Lys mutations having retinal deposits, retinal hemorrhages, and corneal opacity. Three of nine patients with Asp38Ala mutations and one of two patients with Thr59Lys mutations showed ocular involvement that had not been previously described. The ophthalmic findings included glaucoma, anterior lens capsule opacity, vitreous opacity, and retinal deposits. The decrease in vascular flow due to perivascular cuffing of the amyloid deposits was detected by optical coherence tomography angiography. CONCLUSION: The current study newly described that two transthyretin mutation types of FTA, Asp38Ala and Thr59Lys, may manifest with ocular findings such as anterior lens capsule opacity and retinal deposits.

Determinants of Exercise Capacity in Patients With Hypertrophic Cardiomyopathy.

BACKGROUND: Reduced exercise capacity reflects symptom severity and clinical outcomes in patients with hypertrophic cardiomyopathy (HCM). The present study aimed to identify factors that may affect exercise capacity in patients with HCM. METHODS: In 294 patients with HCM and preserved left ventricular (LV) ejection fraction, we compared peak oxygen consumption (peak VO2) evaluated by cardiopulmonary exercise testing as a representative parameter of exercise tolerance with clinical and laboratory data, including N-terminal pro-hormone of brain natriuretic peptide (NT-proBNP), diastolic parameters on echocardiography, and the grade of myocardial fibrosis on cardiac magnetic resonance imaging (CMR). RESULTS: Median peak VO2, was 29.0 mL/kg/min (interquartile range [IQR], 25.0-34.0). Age (estimated ß = -0.140, P < 0.001), female sex (ß = -5.362, P < 0.001), NT-proBNP (ß = -1.256, P < 0.001), and E/e' ratio on echocardiography (ß = -0.209, P = 0.019) were significantly associated with exercise capacity. Peak VO2 was not associated with the amount of myocardial fibrosis on CMR (mean of late gadolinium enhancement 12.25 ± 9.67%LV). CONCLUSION: Decreased exercise capacity was associated with age, female sex, increased NT-proBNP level, and E/e' ratio on echocardiography. Hemodynamic changes and increased filling pressure on echocardiography should be monitored in this population for improved outcomes.

tipNrich: A Tip-Based N-Terminal Proteome Enrichment Method.

The mass spectrometry-based analysis of protein post-translational modifications requires large amounts of sample, complicating the analysis of samples with limited amounts of proteins such as clinical biopsies. Here, we present a tip-based N-terminal analysis method, tipNrich. The entire procedure is processed in a single pipette tip to minimize sample loss, which is so highly optimized to analyze small amounts of proteins, even femtomole-scale of a single protein. With tipNrich, we investigated various single proteins purified from different organisms using a low-resolution mass spectrometer and identified several N-terminal peptides with different Nt-modifications such as ragged N-termini. Furthermore, we applied matrix-assisted laser desorption ionization time-of-flight mass spectrometry to our method for shortening the analysis time. Moreover, we showed that our method could be utilized in disease diagnosis as exemplified by the characterization of wild-type transthyretin amyloidosis patients compared to the healthy individuals based on N-terminome profiling. In summary, tipNrich will satisfy the need of identifying N-terminal peptides even with highly scarce amounts of proteins and of having faster processing time to check the quality of protein products or to characterize N-terminal proteoform-related diseases.

Clinical Factors Associated with Renal Outcome After Heart Transplantation.

Cardiorenal syndrome (CRS) frequently occurs in end-stage heart failure patients waiting for heart transplantation (HT). Decision-making regarding simultaneous heart and kidney transplantation is an unresolved issue in these patients. We investigated clinical factors associated with renal outcome after HT. A total of 180 patients who received HT from 1996 to 2015 were included. Factors associated with early post-HT chronic kidney disease (CKD, estimated glomerular filtration rate [eGFR] < 60 mL/minute/1.73 m2 within 1 year post-HT), post-HT end-stage kidney disease (ESKD), and significant renal function improvement (%ΔeGFR > 15%) at 1 year post-HT were analyzed. Early post-HT CKD and post-HT ESKD developed in 61 (33.9%) and 8 (4.4%) of 180 patients, respectively. Old age was only independently associated with early post-HT CKD and preexisting CKD tended to be associated with early post-HT CKD. Old age and preexisting CKD were independently associated with post-HT ESKD. Low pre-HT eGFR and preoperative renal replacement therapy were not associated with early post-HT CKD or post-HT ESKD. Young age, low pre-HT eGFR, and high %ΔeGFR 1 month post-HT were independently associated with significant renal function improvement. Preoperative renal function, including preoperative RRT, was not associated with post-HT mortality. In conclusion, preexisting CKD may impact renal outcomes after HT, but preoperative severe renal dysfunction, even that severe enough to require RRT, may not be a contraindication for HT alone. Our data suggest the necessity of early HT in end-stage heart failure patients with CRS and the importance of careful management during the early postoperative period.

Clinical Outcomes of Early Extubation Strategy in Patients Undergoing Extracorporeal Membrane Oxygenation as a Bridge to Heart Transplantation.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) might be considered a bridge therapy in patients who are expected to have short waiting times for heart transplantation. We investigated the clinical outcomes of patients who underwent VA-ECMO as a bridge to heart transplantation and whether the deployment of an early extubation ECMO strategy is beneficial. METHODS: Between November 2006 and December 2018, we studied 102 patients who received VA-ECMO as a bridge to heart transplantation. We classified these patients into an early extubation ECMO group (n = 24) and a deferred extubation ECMO group (n = 78) based on the length of the intubated period on VA-ECMO (≤ 48 hours or > 48 hours). The primary outcome was in-hospital mortality. RESULTS: The median duration of early extubation VA-ECMO was 10.0 (4.3-17.3) days. The most common cause for patients to be put on ECMO was dilated cardiomyopathy (65.7%) followed by ischemic cardiomyopathy (11.8%). In-hospital mortality rates for the deferred extubation and early extubation groups, respectively, were 24.4% and 8.3% (P = 0.147). During the study period, in the deferred extubation group, 60 (76.9%) underwent transplantation, while 22 (91.7%) underwent transplantation in the early extubation group. Delirium occurred in 83.3% and 33.3% of patients from the deferred extubation and early extubation groups (P < 0.001) and microbiologically confirmed infection was identified in 64.1% and 41.7% of patients from the two groups (P = 0.051), respectively. CONCLUSION: VA-ECMO as a bridge therapy seems to be feasible for deployment in patients with a short waiting time for heart transplantation. Deployment of the early extubation ECMO strategy was associated with reductions in delirium and infection in this population.

Differences in Flow-Gradient Patterns Between Severe Bicuspid Aortic Stenosis and Severe Tricuspid Aortic Stenosis　- Mechanistic Insight From Multimodal Imaging.

BACKGROUND: We investigated the flow-gradient pattern characteristics and associated factors in severe bicuspid aortic stenosis (AS) compared with severe tricuspid AS.Methods and Results:A total of 252 patients with severe AS (115 bicuspid vs. 137 tricuspid) who underwent aortic valve (AV) replacement were retrospectively analyzed. Patients were classified into 4 groups according to stroke volume index and mean pressure gradient across the AV [normal-flow-high-gradient (NF-HG), low-flow-high-gradient, normal-flow-low-gradient, low-flow-low-gradient (LF-LG)]. In 89 patients who underwent cardiac computed tomography (CT), influential structural parameters of the left ventricular outflow tract (LVOT), AV and ascending aorta were assessed. Bicuspid AS was more likely to present a NF-HG pattern (83.5% vs. 64.2%, P<0.001), and significantly fewer presented a LF-LG pattern compared with tricuspid AS. In bicuspid AS, there was a significant mismatch between geometric orifice area (GOA) on CT planimetry and effective orifice area (EOA) calculated using the echocardiographic continuity equation. Bicuspid AS presented with a larger angle between the LVOT-AV and aorta. Multivariate analysis of bicuspid AS revealed that systemic arterial compliance (ß=-0.350, P=0.031) and the LVOT-AV-aorta angle (ß=-0.538, P=0.001), and stroke volume index (ß=0.409, P=0.008) were associated with a discrepancy between GOA and EOA. CONCLUSIONS: Flow-gradient patterns in bicuspid AS differ from those of tricuspid AS and are associated with the structural and functional characteristics of the aorta.

Infective Endocarditis in Cancer Patients　- Causative Organisms, Predisposing Procedures, and Prognosis Differ From Infective Endocarditis in Non-Cancer Patients.

BACKGROUND: Infective endocarditis (IE) in cancer patients is increasing, but because little is known about it in these patients, we analyzed patient characteristics and outcomes and compared these factors in IE patients with and without cancer. Methods and Results: This retrospective cohort study included 170 patients with IE newly diagnosed between January 2011 and December 2015. Among 170 patients, 30 (17.6%) had active cancer. The median age of IE patients with cancer was higher than that of non-cancer patients. Nosocomial IE was more common in cancer patients. Non-dental procedures, such as intravenous catheter insertion and invasive endoscopic or genitourinary procedures, were more frequently performed before IE developed in cancer patients. Staphylococcus was the most common pathogen in cancer patients, whereas Streptococcus was the most common in non-cancer patients. In-hospital mortality was significantly higher in cancer patients with IE (34.4% vs. 12.4%, P<0.001). IE was an important reason for discontinuing antitumor therapy and withholding additional aggressive treatment in nearly all deceased cancer patients. CONCLUSIONS: IE is common in cancer patients and is associated with poorer outcomes. Patients with IE and cancer have different clinical characteristics. Additional studies regarding antibiotic prophylaxis before non-dental invasive procedures in cancer patients are needed, as cancer patients are not considered to be at higher risk of IE.

Effects of continuous positive airway pressure therapy on left ventricular diastolic function: a randomised, sham-controlled clinical trial.

Continuous positive airway pressure (CPAP) therapy may decrease left ventricular (LV) loads and improve myocardial oxygenation. In this study, we investigated the effect of CPAP on LV diastolic function compared with sham treatment in patients with severe obstructive sleep apnoea (OSA).This 3-month prospective single-centre randomised sham-controlled trial analysed 52 patients with severe OSA. Patients were randomly assigned (1:1) to receive either CPAP or sham treatment for 3 months. The main investigator and patients were masked to the trial randomisation. The primary end-point was change of early diastolic mitral annular (e') velocity over the 3-month period. Secondary end-points were pulse wave velocity (PWV), 24-h ambulatory blood pressure (BP) and variables of ventricular-vascular coupling at 3 months.After 3 months of follow-up, CPAP treatment significantly increased the e' velocity, and was greater than the sham treatment (0.65±1.70 versus -0.61±1.85 cm·s-1, p=0.014). The PWV, 24-h mean diastolic BP, night-time diastolic BP, arterial elastance index and ventricular-vascular coupling index after 3 months of follow-up decreased significantly in the CPAP group.In patients with severe OSA, CPAP treatment for 3 months improved LV diastolic function more than sham treatment, and was accompanied by improvements in arterial stiffness and ventricular-vascular coupling.

Different Characteristics, Clinical Outcomes, and Left Atrial Reverse Remodeling in Patients with Mitral Stenosis Maintaining Sinus Rhythm for at Least 10 Years after Successful Percutaneous Mitral Valvuloplasty.

BACKGROUND: We aimed to investigate the characteristics and echocardiographic changes in patients with severe mitral stenosis (MS) who maintained sinus rhythm (SR) for at least 10 years after successful percutaneous mitral balloon valvuloplasty (PMV). METHODS: We retrospectively reviewed 107 patients who had successful PMV and follow-up echocardiography for at least 10 years without mitral valve surgery. Preprocedural, immediate postprocedural (PMV), and long-term follow-up echocardiography (at least 10 years after PMV) data were reviewed. RESULTS: The mean follow-up time after PMV was 15 ± 4 years for SR patients (n = 50) and 16 ± 4 years (p = 0.172) for atrial fibrillation (AF) patients (n = 57). The left atrial diameter was significantly decreased in SR patients in the follow-up echocardiography images compared to its pre-PMV value (46.7 ± 6.3 vs. 43.3 ± 6.2 mm, respectively), whereas it was significantly increased in patients with AF (53.9 ± 7.1 vs. 58.1 ± 8.7 mm). In multivariate analysis, preprocedural AF (odds ratio [OR] 14.50, p = 0.001) and LA diameter ≥50 mm (OR 8.81, p < 0.001) were independently associated with increased risk for the presence of AF after successful PMV. CONCLUSION: Very long-term maintenance of SR after successful PMV was associated with preprocedural SR and LA diameter < 50 mm.

Clinical Implications and Determinants of Left Atrial Mechanical Dysfunction in Patients With Stroke.

BACKGROUND AND PURPOSE: The evaluation of sources of cardioembolism with transesophageal echocardiography (TEE) in patients with stroke is crucial but semi-invasive. We hypothesized that the size and mechanical function of the left atrium (LA) assessed by transthoracic echocardiography (TTE) could provide useful information on high risk of cardioembolism on TEE in patients with stroke. Furthermore, we sought to define the determinants of LA mechanical dysfunction in these patients. METHODS: A total of 248 patients with acute ischemic stroke (147 men; 64±13 years) who underwent 2-dimensional and speckle tracking TTE followed by TEE were analyzed. RESULTS: LA appendage emptying velocity, prevalence of LA or LA appendage thrombus, prevalence of aortic plaques, and incidence of embolic stroke showed significant differences among the 4 groups classified according to the median values of the LA volume index and global LA longitudinal strain (LALS). Patients at high risk of cardioembolism evidenced by TEE revealed significantly larger LA volume index and lower global LALS than those without. Global LALS (cutoff, 11.5%; area under the curve, 0.947; sensitivity, 100%; specificity, 91%; P<0.001) revealed a significantly better diagnostic power (P=0.04) for LA or LA appendage thrombus than LA volume index (cutoff, 36.2 mL/m(2); area under the curve, 0.823; sensitivity, 88%; specificity, 75%; P=0.002). Age, left ventricular systolic function, LA volume index, and pulse wave velocity were independent determinants for global LALS. CONCLUSIONS: LA mechanical dysfunction is closely associated with high risks of cardioembolism. Global LALS assessed by speckle tracking TTE well discriminates the presence of LA or LA appendage thrombus on TEE in patients with acute ischemic stroke.

Overexpression of reactive oxygen species scavenger enzymes is associated with a good prognosis in triple-negative breast cancer.

OBJECTIVE: The aim of this study was to investigate the expression of redox proteins in triple-negative breast cancer (TNBC), a breast cancer type which harbors an aggressive phenotype, and to demonstrate the relationships between the expression of reactive oxygen species (ROS) markers and clinical outcome. METHODS: From 2000 to 2005, we analyzed tissue samples from 135 cases of TNBC obtained from curative surgeries at the Severance Hospital, Seoul, South Korea. Immunochemical staining for redox proteins was performed. RESULTS: The median patient age was 48 (range 27-76) years. TNM staging was as follows: T1 (n = 52, 38.5%), T2 (n = 81, 60%), T3 (n = 2, 1.5%), N0 (n = 88, 65.2%), N1 (n = 35, 25.9%), N2 (n = 8, 5.9%) and N3 (n = 4, 3.0%). Median follow-up was 59 (range 12-99) months. The high-expression catalase group tended to have a lower N stage (p = 0.016), lower tumor recurrence (p = 0.02) as well as longer overall survival rates (p = 0.05). After adjusting for patient age as well as tumor and nodal stage, we found that primary breast cancers with high catalase expression levels did not have an improved clinical outcome. A high MTC4 expression in the stroma was strongly associated with increased manganese superoxide dismutase expression (p = 0.015) and a significantly longer overall survival (p = 0.032). CONCLUSION: Considering the lack of targeted molecules as well as molecular heterogeneity of TNBC, ROS markers may provide clues to clinical outcome in TNBC.

Synthesis of 3'-O-fluorescently mono-modified reversible terminators and their uses in sequencing-by-synthesis.

Next-generation sequencing (NGS) technologies recently developed are now used for study of genomes from various organisms. Sequencing-by-synthesis (SBS) is a key strategy in the NGS. The SBS uses nucleotides so-called dual-modified reversible terminators (DRTs) in which bases are labeled with fluorophores and 3'-OH is protected with a reversibly cleavable chemical group, respectively. In this study, we examined the possibility of performing SBS with mono-modified reversible terminators (MRTs), in which the reversible blocking group on the 3'-OH plays a dual role as a fluorescent signal report as well as a chemical protection. We studied cyclic reversible termination by using two MRTs (dA and dT), wherein the modifications were two different fluorophores and cleavable to regenerate a free 3'-OH. We here demonstrated that SBS could be achieved with incorporation of MRTs by a DNA polymerase and correct base-calls based on the two different colors from the fluorophores.