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Background: Echocardiographic indexes of aortic stenosis may not comprehensively reflect disease morbidity. Plasma proteomic profiling may add prognostic value in these patients., Methods and Results: Proximity extension assays (Olink) of 183 circulating cardiovascular and inflammatory proteins were performed in a prospective follow-up study of 122 asymptomatic/minimally symptomatic patients (mean±SD age, 69.1±10.9 years; 61% men) with moderate to severe aortic stenosis and preserved left ventricular ejection fraction. Protein signatures of higher-risk echocardiographic subgroups were determined. Associations of proteins with the primary composite outcome (heart failure hospitalization, progression to New York Heart Association class III-IV, or all-cause mortality) were evaluated using competing risk analyses, with aortic valve replacement being the competing risk. Network analysis unveiled mutually exclusive communities of proteins and echocardiographic parameters, connected only through NT-proBNP (N-terminal pro-B-type natriuretic peptide). Members of the tumor necrosis factor receptor superfamily (TNFRSF1A, TNFRSF1B, and TNFRSF14), and trefoil factor-3 were major hub proteins among the circulating biomarkers. Left ventricular global longitudinal strain >-15% was associated with higher levels of proteins, primarily of inflammation and immune regulation, whereas aortic valve area <1 cm 2 , E/e' >15, and left atrial reservoir strain <20% were associated with higher levels of NT-proBNP. Of 14 proteins associated with the primary end point, phospholipase-C, C-X-C motif chemokine-9, and interleukin-10 receptor subunit β demonstrated the highest hazard ratios after adjusting for clinical factors ( q <0.05)., Conclusions: Plasma proteins involved in inflammation and immune regulation were differentially expressed in patients with aortic stenosis with reduced left ventricular global longitudinal strain, and associated with adverse clinical outcomes. Their incorporation into aortic stenosis risk stratification warrants further assessment.

Background: The role of left atrial (LA) strain as an imaging biomarker in aortic stenosis is not well established. The aim of this study was to investigate the prognostic performance of phasic LA strain in relation to clinical and echocardiographic variables and N-terminal pro-B-type natriuretic peptide in asymptomatic and minimally symptomatic patients with moderate to severe aortic stenosis and left ventricular ejection fraction > 50%., Methods: LA reservoir strain (LASr), LA conduit strain (LAScd), and LA contractile strain (LASct) were measured using speckle-tracking echocardiography. The primary outcome was a composite of all-cause mortality, heart failure hospitalization, progression to New York Heart Association functional class III or IV, acute coronary syndrome, or syncope. Secondary outcomes 1 and 2 comprised the same end points but excluded acute coronary syndrome and additionally syncope, respectively. The prognostic performance of phasic LA strain cutoffs was evaluated in competing risk analyses, aortic valve replacement being the competing risk., Results: Among 173 patients (mean age, 69 ± 11 years; mean peak transaortic velocity, 4.0 ± 0.8 m/sec), median LASr, LAScd, and LASct were 27% (interquartile range [IQR], 22%-32%), 12% (IQR, 8%-15%), and 16% (IQR, 13%-18%), respectively. Over a median of 2.7 years (IQR, 1.4-4.6 years), the primary outcome and secondary outcomes 1 and 2 occurred in 66 (38%), 62 (36%), and 59 (34%) patients, respectively. LASr < 20%, LAScd < 6%, and LASct < 12% were identified as optimal cutoffs of the primary outcome. In competing risk analyses, progressing from echocardiographic to echocardiographic-clinical and combined models incorporating N-terminal pro-B-type natriuretic peptide, LA strain parameters outperformed other key echocardiographic variables and significantly predicted clinical outcomes. LASr < 20% was associated with the primary outcome and secondary outcome 1, LAScd < 6% with all clinical outcomes, and LASct < 12% with secondary outcome 2. LAScd < 6% had the highest specificity (95%) and positive predictive value (82%) for the primary outcome, and competing risk models incorporating LAScd < 6% had the best discriminative value., Conclusions: In well-compensated patients with moderate to severe aortic stenosis and preserved left ventricular ejection fractions, LA strain was superior to other echocardiographic indices and incremental to N-terminal pro-B-type natriuretic peptide for risk stratification. LAScd < 6%, LASr < 20%, and LASct < 12% identified patients at higher risk for adverse outcomes., (Copyright © 2022 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Objective: We investigated the prognostic significance of selected known and novel circulating biomarkers in aortic stenosis (AS)., Methods: N-terminal pro-BNP (NT-proBNP), high-sensitivity troponin-T (hsTnT), growth differentiation factor-15 (GDF-15), suppression of tumorigenicity-2 (ST2), mid-regional proadrenomedullin (MR-proADM) and mid-regional proatrial natriuretic peptide (MR-proANP) were measured in patients with moderate to severe AS, New York Heart Association (NYHA) class I-II and left ventricular ejection fraction ≥50%, recruited consecutively across five centres from 2011 to 2018. Their ability to predict both primary (all-cause mortality, heart failure hospitalisation or progression to NYHA class III-IV) and secondary (additionally incorporating syncope and acute coronary syndrome) outcomes was determined by competing risk analyses., Results: Among 173 patients with AS (age 69±11 years, 55% male, peak transaortic velocity (Vmax) 4.0±0.8 m/s), the primary and secondary outcomes occurred in 59 (34%) and 66 (38%), respectively. With aortic valve replacement as a competing risk, the primary outcome was determined consistently by the comorbidity index and each selected biomarker except ST2 (p<0.05), independent of NYHA class, Vmax, LV-global longitudinal strain and serum creatinine. MR-proADM had the highest discriminative value for both primary (subdistribution HR (SHR) 11.3, 95% CI 3.9 to 32.7) and secondary outcomes (SHR 12.6, 95% CI 4.7 to 33.5). Prognostic assessment of dual-biomarker combinations identified MR-proADM plus either hsTnT or NT-proBNP as the best predictive model for both clinical outcomes. Paired biomarker models were not superior to those including MR-proADM as the sole circulating biomarker., Conclusion: MR-proADM most powerfully portended worse prognosis and should be further assessed as possibly the biomarker of choice for risk stratification in AS., Competing Interests: Competing interests: SHE reports personal fees from Medtronic, Edwards Lifesciences and Abbott Medical, outside the submitted work. ZPD reports personal/speaker fees from GE and Phillips, and non-financial support from Phillips, outside the submitted work. AMR reports grants from National Medical Research Council of Singapore during the conduct of the study, is a long-term collaborator with Roche Diagnostics, the provider of assays central to this submission, and received support in kind, grants, speaker’s honoraria and acted on advisory boards for Roche Diagnostics. LHHL reports grants from National Medical Research Council of Singapore during the conduct of the study., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Left ventricular ejection fraction is the conventional measure used to guide heart failure management, regardless of underlying etiology. Left ventricular global longitudinal strain (LV-GLS) by speckle tracking echocardiography (STE) is a more sensitive measure of intrinsic myocardial function. We aim to establish LV-GLS as a marker of replacement myocardial fibrosis on cardiovascular magnetic resonance (CMR) and validate the prognostic value of LV-GLS thresholds associated with fibrosis. Methods and results: LV-GLS thresholds of replacement fibrosis were established in the derivation cohort: 151 patients (57 ± 10 years; 58% males) with hypertension who underwent STE to measure LV-GLS and CMR. Prognostic value of the thresholds was validated in a separate outcome cohort: 261 patients with moderate-severe aortic stenosis (AS; 71 ± 12 years; 58% males; NYHA functional class I-II) and preserved LVEF ≥50%. Primary outcome was a composite of cardiovascular mortality, heart failure hospitalization, and myocardial infarction. In the derivation cohort, LV-GLS demonstrated good discrimination (c-statistics 0.74 [0.66-0.83]; P < 0.001) and calibration (Hosmer-Lemeshow χ 2 = 6.37; P = 0.605) for replacement fibrosis. In the outcome cohort, 47 events occurred over 16 [3.3, 42.2] months. Patients with LV-GLS > -15.0% (corresponding to 95% specificity to rule-in myocardial fibrosis) had the worst outcomes compared to patients with LV-GLS < -21.0% (corresponding to 95% sensitivity to rule-out myocardial fibrosis) and those between -21.0 and -15.0% (log-rank P < 0.001). LV-GLS offered independent prognostic value over clinical variables, AS severity and echocardiographic LV mass and E/e'. Conclusion: LV-GLS thresholds associated with replacement myocardial fibrosis is a novel approach to risk-stratify patients with AS and preserved LVEF., Competing Interests: The department of Cardiology at Leiden University receives unrestricted research grants from Abbott Vascular, Bayer, Biotronik, BIoventrix, Boston Scientific, Edwards Lifesciences, GE Healthcare, Ionis and Medtronic. VD received speaker fees from Abbott Vascular, Edwards Lifesciences, GE Healthcare, MSD, Medtronic and Novartis. JJB received speaker fees from Abbott Vascular. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Le, Huang, Singh, Toh, Ewe, Tang, Loo, Bryant, Ang, Tay, Soo, Yip, Oon, Gong, Lunaria, Yong, Lee, Yeo, Chai, Goh, Ling, Ong, Richards, Delgado, Bax, Ding, Ling and Chin.)

Objective: To explore the clinical significance of G6PD gene mutation detection in female heterozygote with G6PD deficiency., Methods: G6PD activity and fourteen common G6PD gene mutations in female blood samples were detected by biochemical phenotype detection and PCR-reverse dot blotting, respectively. Unidentified genotype of G6PD positive samples was further ascertained by direct DNA sequencing. The results from two methods were compared and analyzed., Results: A total of 493 unrelated females were enrolled, and the G6PD activity and G6PD mutations was detected. Among them, 473 females were found to be normal in G6PD activity and 20 females with G6PD deficiency, and the detection rate by G6PD activity method was 4.06%. In all enrolled females, G6PD gene mutations, including the mutation of c.1311 C＞T, were identified in 130 females, and the detection rate was 26.3%. Detection rate of the mutations that can lead to G6PD deficiency was 8.11%. The detection rates between the two methods were significantly different (P＜0.01). The misdiagnosis rate of the G6PD activity detection reached 49. 94% for the female heterozygotes. Eight G6PD mutations and 13 mutation patterns were identified in the research, and most of mutation patterns were single nucleotide missense mutation. In addition to c.1311C＞T mutation, the most common mutations were c.1376G＞T, c.1388G＞A and c.95 A＞G. G6PD mutations were identified in 19 of 20 females with G6PD deficiency, and were also detected in 21 of 473 females with normal G6PD activity, of which the rate of heterozygous mutation was 90.88%., Conclusion: The phenotype detection based on G6PD enzyme activity alone is not sufficient for the diagnosis of female heterozygotes. The detection of G6PD mutations that covers the common mutations in specified region can effectively identify the female heterozygotes with normal G6PD activity.

Aim: To investigate the accuracy of cardiac magnetic resonance (CMR) tissue tracking (CMR-TT) and speckle tracking echocardiography (STE) against CMR determined right ventricular (RV) ejection fraction (RVEF) and to identify an optimal cut-off value for STE and CMR-TT to determine RVEF <45% and compare this to other conventional methods for estimating RVEF in dilated cardiomyopathy (DCM) patients., Materials and Methods: Twenty-nine DCM patients were recruited prospectively. CMR and echocardiography were performed within 48 hours and four-chamber views were used for strain analysis. Contoured CMR short axis images provided RVEF. Intraclass correlation coefficient (ICC), bias, levels of agreement, and receiver operating characteristic (ROC) curve analyses were performed., Results: CMR-TT RV free-wall longitudinal strain (FLS) and STE RV global longitudinal strain (GLS) showed the best correlation with RVEF (r=-0.68, r=-0.82, p<0.001 respectively). There was moderate correlation between echocardiography RV GLS and CMR RV FLS (r=0.64, p<0.001). CMR-TT FLS showed excellent intra-observer and interobserver reliability (ICC=0.980; ICC=0.968 respectively). STE GLS correlated better with RVEF than with peak systolic annular velocity (S'; r=0.45), tricuspid annular plane systolic excursion (TAPSE; r=0.56), and fractional area change (FAC; r=0.78). CMR-TT RV FLS had better correlation with RVEF than CMR TAPSE (r=0.69 versus 0.40). ROC analysis demonstrated the optimal cut-off value for CMR-TT RV FLS and STE GLS in detection of RVEF <45% was ≥-24.4% (area under the curve=0.87, 100% sensitivity, 66.7% specificity) and ≥-20.9% (area under the curve=0.88, 100% sensitivity, 60% specificity) respectively., Conclusion: CMR-TT FLS and STE GLS showed potential to provide rapid assessment of RV function and had superior correlation with RVEF compared to conventional parameters., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objective: To investigate the molecular mechanism by which salidroside protects PC12 cells from H 2 O 2 -induced apoptosis., Methods: PC12 cells cultured in DMEM supplemented with 10% horse serum and 5% fetal bovine serum were pretreated with different doses of salidroside for 2 h and then stimulated with H 2 O 2 for different lengths of time. The expression levels of PARP and caspase 3 and the phosphorylation of p38, ERK and JNK were determined with Western blotting. The cell nuclear morphology was observed after DAPI staining. The production of ROS was detected using a ROS detection kit, and the levels of gp91 phox and p47 phox in the membrane and cytoplasm were detected by membrane-cytoplasm separation experiment; the binding between gp91 phox and p47 phox was assayed by coimmunoprecipitation experiment., Results: Salidroside dose-dependently suppressed cell apoptosis, lowered phosphorylation levels of p38, ERK and JNK, inhibited the production of ROS, reduced the binding between gp91 phox and p47 phox , and inhibited the activity of NOX2 in PC12 cells exposed to H 2 O 2 ., Conclusion: Salidroside protects PC12 cells from H 2 O 2 -induced apoptosis at least partly by suppressing NOX2-ROS-MAPKs signaling pathway.

To study the effect of sodium aescinate in inducing human breast cancer MCF-7 cells apoptosis and its possible mechanism. MTT assay was used to detect the inhibitory effect of sodium aescinate on the proliferation of MCF-7 cells. The morphological changes were observed under inverted microscope. DAPI nuclear staining was used to detect the changes in cell nucleus. Annexin V-FITC/PI flow cytometry was adopted to test the apoptosis rate. Changes in apoptosis-related proteins (PARP, cleaved caspase-8 and pro-caspase-3), cell survival-associated signal molecules (AKT and ERK) and their common upstream kinase SRC was detected by Western blotting. The result showed that after different concentrations of sodium aescinate were used to treat breast cancer MCF-7 cells, they inhibited the proliferation of MCF-7 cells in a dose-dependent manner, induced cell apoptosis (typical morphological changes in nucleus, significant increase in cell apoptosis rate). The expressions of cleaved PARP and caspase-8 increased, while the expression of pro-caspase-3 decreased, which further verified sodium aescinate's effect in inducing cell apoptosis. Sodium aescinate significantly inhibited the phosphorylation of cell survival-related signal molecules (AKT, ERK) and down-regulate the activation of their common up-stream kinase SRC. The findings indicated that sodium aescinate can block signals transiting to downstream molecules AKT, ERK, inhibit the proliferation of breast cancer cell MCF-7 cell apoptosis and induced cell apoptosis by suppressing the activation of SRC.

Background: Although the recent surgical treatment of ischemic heart failure substudy reported that revascularization of viable myocardium did not improve survival, these results were limited by the viability imaging technique used and the lack of inducible ischemia information. We examined the relative impact of stress-rest rubidium-82/F-18 fluorodeoxyglucose positron emission tomography identified ischemia, scar, and hibernating myocardium on the survival benefit associated with revascularization in patients with systolic dysfunction., Methods and Results: The extent of perfusion defects and metabolism-perfusion mismatch was measured with an automated quantitative method in 648 consecutive patients (age, 65±12 years; 23% women; mean left ventricular ejection fraction, 31±12%) undergoing positron emission tomography. Follow-up time began at 92 days (to avoid waiting-time bias); deaths before 92 days were excluded from the analysis. During a mean follow-up of 2.8±1.2 years, 165 deaths (27.5%) occurred. Cox proportional hazards modeling was used to adjust for potential confounders, including a propensity score to adjust for nonrandomized treatment allocation. Early revascularization was performed within 92 days of positron emission tomography in 199 patients (33%). Hibernating myocardium, ischemic myocardium, and scarred myocardium were associated with all-cause death (P=0.0015, 0.0038, and 0.0010, respectively). An interaction between treatment and hibernating myocardium was present such that early revascularization in the setting of significant hibernating myocardium was associated with improved survival compared with medical therapy, especially when the extent of viability exceeded 10% of the myocardium., Conclusions: Among patients with ischemic cardiomyopathy, hibernating, but not ischemic, myocardium identifies which patients may accrue a survival benefit with revascularization versus medical therapy.

Background: Accurate assessment of right ventricular (RV) size (RVS) and RV systolic function (RVSF) is vital in the management of various conditions, but their assessment is challenging using echocardiography. The aim of this study was to determine the accuracy and interobserver concordance of qualitative and quantitative RV echocardiography., Methods: Fifteen readers evaluated RV function in 12 patients (360 readings) who underwent echocardiography and cardiac magnetic resonance for RV assessment. Readers qualitatively estimated RVS and RVSF as normal, mild, moderate, or severe and then reassessed quantitatively by adding RV dimensions, fractional area change, S', tricuspid annular plane systolic excursion, and RV index of myocardial performance. Cardiac magnetic resonance was used as the reference standard for grading RVS and RVSF., Results: Quantitative measurements increased accuracy and interreader agreement compared to qualitative assessment alone, especially in normal categories. Readers' accuracy for diagnosing normal and severe RVS increased from 38% to 78% (P = .001) and from 70% to 97% (P = .018), and readers' accuracy for diagnosing normal and mild RVSF increased from 52% to 84% (P < .001) and from 36% to 56% (P = .001). Interreader agreement for classification of the subjects as normal or abnormal improved from a κ value of 0.40 to 0.77 (fair to good agreement) for RVS and from 0.43 to 0.66 (moderate to good agreement) for RVSF., Conclusions: Visual estimation of RVS and RVSF is inaccurate and has wide interobserver variability. Quantitation improves accuracy and reliability, especially in distinction of normal and abnormal. The reliability of mild and moderate grades remains inadequate, and further guidance is needed for the classification of abnormal categories., (Copyright © 2012 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

Background: Uncertainty about long-term effects of surgically unaddressed moderate (2+) secondary tricuspid valve (TV) regurgitation (TR) accompanying left-sided degenerative heart valve disease led us to identify reasons for and factors associated with TV repair, compare safety and clinical effectiveness of relieving TR, and identify factors associated with severe (3/4+) postoperative TR., Methods: From 1997 to 2008, 1,724 patients with 2+ TR underwent 830 mitral, 703 aortic, and 191 double-valve procedures; 91 (5%) had concomitant TV repair. Logistic regression analysis was used to identify factors associated with TV repair and for propensity-matched comparison of safety (in-hospital morbidity, mortality) and effectiveness of TV repair (longitudinal echocardiographic assessment of postoperative TR and New York Heart Association class, TV intervention, survival)., Results: Factors associated with TV repair of 2+ TR included larger right ventricles and left ventricles (p<0.001), greater TV tethering height (p=0.0002), and prior concurrent mitral valve procedures (p≤0.004). In-hospital complications, subsequent TV interventions, and intermediate-term survival were similar for matched patients. The TV repair patients had less 3/4+ TR at discharge (7% versus 15%), sustained out to 3 years. No TV repair (p=0.05), female sex (p<0.0001), and mitral valve replacement (p=0.008) were associated with 3/4+ TR., Conclusions: A TV repair for moderate TR concomitant with surgery for degenerative left-sided heart valve disease is reasonable to provide an opportunity to prevent its progression and development of right ventricle dysfunction, particularly for patients with important right ventricle remodeling and evidence of right ventricular failure, and for patients with advanced left-sided disease requiring mitral valve replacement., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Primary cardiac lymphoma (PCL) is rare and occurs more commonly in immunocompromised patients. It can present in various ways, and diagnosis is particularly challenging, especially for the unsuspecting physician. We report a case of PCL in an immunocompetent 55-year-old man who initially presented with pyrexia of unknown origin, chest pain, dyspnea, and few early clinical signs, but who was later found to have cardiac tamponade and a large cardiac mass on echocardiography and cardiovascular magnetic resonance. A high index of suspicion is needed to diagnose PCL, and echocardiogram remains an important diagnostic tool.

Biotransformation difference between parent strain (MF2) and mutant strain (MF96) of Mycobacterium fortuitum was observed. Biotransformation with resting cells showed that the major products of biotransformation by both parent and mutant strains are delta4-androstenedione(4AD) and testosterone(TS). Experiments with cell-free extract system showed that the proportion of 4AD/TS obtained from parent and mutant strains was almost same when enough NAD+ and NADH were supplied in this system. It was suggested that the difference of the ratio of products transformed by both strains in resting cell system may result from their different ratio of NAD+/NADH. This speculation was verified to be true by determination of the amount of NAD+ and NADH presented in both strains.