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Precision medicine, which among other aspects includes an individual's genomic data in diagnosis and management, has become the standard-of-care for Mendelian cardiovascular disease (CVD). However, early identification and management of asymptomatic patients with potentially lethal and manageable Mendelian CVD through screening, which is the promise of precision health, remains an unsolved challenge. The reduced costs of genomic sequencing have enabled the creation of biobanks containing in-depth genetic and health information, which have facilitated the understanding of genetic variation, penetrance, and expressivity, moving us closer to the genotype-first screening of asymptomatic individuals for Mendelian CVD. This approach could transform health care by diagnostic refinement and facilitating prevention or therapeutic interventions. Yet, potential benefits must be weighed against the potential risks, which include evolving variant pathogenicity assertion or identification of variants with low disease penetrance; costly, stressful, and inappropriate diagnostic evaluations; negative psychological impact; disqualification for employment or of competitive sports; and denial of insurance. Furthermore, the natural history of Mendelian CVD is often unpredictable, making identification of those who will benefit from preventive measures a priority. Currently, there is insufficient evidence that population-based genetic screening for Mendelian CVD can reduce adverse outcomes at a reasonable cost to an extent that outweighs the harms of true-positive and false-positive results. Besides technical, clinical, and financial burdens, ethical and legal aspects pose unprecedented challenges. This review highlights key developments in the field of genotype-first approaches to Mendelian CVD and summarizes challenges with potential solutions that can pave the way for implementing this approach for clinical care.

Aims: Tafamidis improves clinical outcomes in transthyretin amyloid cardiomyopathy (ATTR-CM), yet how tafamidis affects cardiac structure and function remains poorly described. This study prospectively analysed the effect of tafamidis on 12-month longitudinal changes in cardiac structure and function by cardiac magnetic resonance (CMR) compared with the natural course of disease in an untreated historic control cohort., Methods and Results: ATTR-CM patients underwent CMR at tafamidis initiation and at 12 months. Untreated patients with serial CMRs served as reference to compare biventricular function, global longitudinal strain (GLS), LV mass and extracellular volume fraction (ECV). Thirty-six tafamidis-treated (n = 35; 97.1% male) and 15 untreated patients (n = 14; 93.3% male) with a mean age of 78.3 ± 6.5 and 76.9 ± 6.5, respectively, and comparable baseline characteristics were included. Tafamidis was associated with preserving biventricular function (LVEF (%): 50.5 ± 12 to 50.7 ± 11.5, P = 0.87; RVEF (%): 48.2 ± 10.4 to 48.2 ± 9.4, P = 0.99) and LV-GLS (-9.6 ± 3.2 to -9.9 ± 2.4%; P = 0.595) at 12 months, while a significantly reduced RV-function (50.8 ± 7.3 to 44.2 ± 11.6%, P = 0.028; P (change over time between groups) = 0.032) and numerically worsening LVGLS (-10.9 ± 3.3 to -9.1 ± 2.9%, P = 0.097; P (change over time between groups) = 0.048) was observed without treatment. LV mass significantly declined with tafamidis (184.7 ± 47.7 to 176.5 ± 44.3 g; P = 0.011), yet remained unchanged in untreated patients (163.8 ± 47.5 to 171.2 ± 39.7 g P = 0.356, P (change over time between groups) = 0.027). Irrespective of tafamidis, ECV and native T1-mapping did not change significantly from baseline to 12-month follow-up (P > 0.05)., Conclusions: Compared with untreated ATTR-CM patients, initiation of tafamidis preserved CMR-measured biventricular function and reduced LV mass at 12 months. ECV and native T1-mapping did not change significantly comparable to baseline in both groups., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background : Tafamidis reduces cardiovascular morbidity and mortality in transthyretin amyloid cardiomyopathy (ATTR-CM), yet availability and access to therapy vary. Objective : To determine how availability and access to tafamidis impact time-to-diagnosis, time-to-therapy, and cardiovascular outcomes in ATTR-CM. Methods : Ninety-one consecutive ATTR-CM (~97% wt-TTR) patients diagnosed between June 2019 and June 2021 were evaluated for tafamidis. Access to therapy was regulated by compassionate use [n(CU) = 42] prior to, and insurance [n(IA) = 49] after regulatory approval. Results : Tafamidis was started in 37/42 (88.1%), and 39/49 (79.6%) patients, respectively. At diagnosis, ATTR-CM disease stage (≤stage 2: 88.2% vs. 90.9%, p = 0.92) was similar between groups. Timely access (after tafamidis approval) reduced the median time from first presentation to diagnosis from 6.2 (IQR: 1.3-28.9) to 2.4 (0.7-21.7) months, and from first presentation to therapy from 24.4 (10.7-46.8) to 11.8 (6.4-32.4) months. While RV function significantly worsened between diagnosis and therapy initiation in CU patients diagnosed before tafamidis approval (S'-velocity 10.0 ± 2.2 to 9.2 ± 2.2 cm/s; p = 0.018; TAPSE 17.3 ± 4.7 to 15.7 ± 3.9 mm, p = 0.008), it remained unchanged in IA patients (S'-velocity 9.6 ± 2.6 to 9.4 ± 2.3 cm/s; p = 0.83; TAPSE 15.6 ± 4.2 to 16.3 ± 3.1 mm, p = 0.45). After a median follow-up of 42.3 and 24.9 months in CU and IA patients, respectively, timely availability was associated with a reduction in annual heart failure hospitalizations (0.40 vs. 0.16 per patient, p < 0.001) and improved MACE-free survival (HR = 0.51; 95%CI: 0.26-1.00; p = 0.051). Timely diagnosis (<12-months) prolonged MACE-free survival (HR = 0.424; 95%CI: 0.22-0.81; p = 0.004), and reduced HFH (HR = 0.40; 95%CI: 0.19-0.81); p = 0.011) and all-cause mortality (HR = 0.29; 95%CI: 0.11-0.74); p = 0.009). Conclusions : Availability of tafamidis improves diagnostic efficacy in ATTR-CM patients. Timely diagnosis and initiation of therapy reduces adverse cardiovascular events.

Aims: The 2021 European Society of Cardiology (ESC) screening recommendations for individuals carrying a pathogenic transthyretin amyloidosis variant (ATTRv) are based on expert opinion. We aimed to (i) determine the penetrance of ATTRv cardiomyopathy (ATTRv-CM) at baseline; (ii) examine the value of serial evaluation; and (iii) establish the yield of first-line diagnostic tests (i.e. electrocardiogram, echocardiogram, and laboratory tests) as per 2021 ESC position statement., Methods and Results: We included 159 relatives (median age 55.6 [43.2-65.9] years, 52% male) at risk for ATTRv-CM from 10 centres. The primary endpoint, ATTRv-CM diagnosis, was defined as the presence of (i) cardiac tracer uptake in bone scintigraphy; or (ii) transthyretin-positive cardiac biopsy. The secondary endpoint was a composite of heart failure (New York Heart Association class ≥II) and pacemaker-requiring conduction disorders. At baseline, 40/159 (25%) relatives were diagnosed with ATTRv-CM. Of those, 20 (50%) met the secondary endpoint. Indication to screen (≤10 years prior to predicted disease onset and absence of extracardiac amyloidosis) had an excellent negative predictive value (97%). Other pre-screening predictors for ATTRv-CM were infrequently identified variants and male sex. Importantly, 13% of relatives with ATTRv-CM did not show any signs of cardiac involvement on first-line diagnostic tests. The yield of serial evaluation (n = 41 relatives; follow-up 3.1 [2.2-5.2] years) at 3-year interval was 9.4%., Conclusions: Screening according to the 2021 ESC position statement performs well in daily clinical practice. Clinicians should adhere to repeating bone scintigraphy after 3 years, as progressing to ATTRv-CM without signs of ATTRv-CM on first-line diagnostic tests or symptoms is common., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background : Despite being the most commonly performed valvular intervention, risk prediction for aortic valve replacement in patients with severe aortic stenosis by currently used risk scores remains challenging. The study aim was to develop a biomarker-based risk score by means of a neuronal network. Methods : In this multicenter study, 3595 patients were divided into test and validation cohorts (70% to 30%) by random allocation. Input variables to develop the ABC-AS score were age, the cardiac biomarker high-sensitivity troponin T, and a patient history of cardiac decompensation. The validation cohort was used to verify the scores' value and for comparison with the Society of Thoracic Surgery Predictive Risk of Operative Mortality score. Results : Receiver operating curves demonstrated an improvement in prediction by using the ABC-AS score compared to the Society of Thoracic Surgery Predictive Risk of Operative Mortality (STS prom) score. Although the difference in predicting cardiovascular mortality was most notable at 30-day follow-up (area under the curve of 0.922 versus 0.678), ABC-AS also performed better in overall follow-up (0.839 versus 0.699). Furthermore, univariate analysis of ABC-AS tertiles yielded highly significant differences for all-cause ( p < 0.0001) and cardiovascular mortality ( p < 0.0001). Head-to-head comparison between both risk scores in a multivariable cox regression model underlined the potential of the ABC-AS score (HR per z-unit 2.633 (95% CI 2.156-3.216), p < 0.0001), while the STS prom score failed to reach statistical significance ( p = 0.226). Conclusions : The newly developed ABC-AS score is an improved risk stratification tool to predict cardiovascular outcomes for patients undergoing aortic valve intervention.

Quantitative 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid ([ 99m Tc]Tc-DPD) SPECT may be used for risk-stratifying patients with amyloid transthyretin-related cardiomyopathy (ATTR-CM). We aimed to analyze the predictive value of quantitative [ 99m Tc]Tc-DPD SPECT/CT in suspected and confirmed ATTR-CM according to different disease stages. Methods: The study enrolled consecutive patients with suspected ATTR-CM who were referred to a single tertiary center and underwent quantitative [ 99m Tc]Tc-DPD SPECT/CT allowing SUV max and SUV peak analysis. Patients were divided into 2 groups according to left ventricular ejection fraction (LVEF) at baseline (i.e., ≥50% and <50%). Clinical, laboratory, and echocardiographic parameters and major adverse cardiac events (i.e., all-cause death, sustained ventricular tachyarrhythmia, hospitalization for heart failure, implantation of a cardioverter defibrillator) were investigated for any correlation with quantitative uptake values. Results: In total, 144 patients with suspected ATTR-CM were included in the study (98 with LVEF ≥ 50% and 46 with LVEF < 50%), of whom 99 were diagnosed with ATTR-CM (68.8%; 69 with LVEF ≥ 50% and 30 with LVEF < 50%). A myocardial SUV max of at least 7 was predictive of major adverse cardiac events at 21.9 ± 13.0 mo of follow-up (hazard ratio, 2.875; 95% CI, 1.23-6.71; P = 0.015) in patients with suspected or confirmed ATTR-CM (global χ 2 = 6.892, P = 0.02) and an LVEF of at least 50%. SUV max was not predictive in patients with an LVEF of less than 50% and suspected or confirmed ATTR-CM. Conclusion: In patients with suspected or confirmed ATTR-CM and preserved LVEF, representing an early disease stage, quantitative [ 99m Tc]Tc-DPD SPECT should be considered to improve early-stage risk stratification., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) often coexists with severe aortic stenosis (AS). Although strain analysis from cardiac MRI and echocardiography was demonstrated to predict coexisting ATTR-CM, comparable data from four-dimensional (4D) cardiac CT are lacking despite wide availability. Purpose To evaluate the diagnostic performance of 4D cardiac CT-derived parameters in identifying ATTR-CM in older adults considered for transcatheter aortic valve implantation (TAVI). Materials and Methods This prospective single-center screening study for ATTR-CM included consecutive patients with severe AS considered for TAVI who underwent 4D cardiac CT between August 2019 and August 2021 approximately 1 day before technetium 99m ( 99m Tc) 3,3-diphosphono-1,2-propanodicarboxylic-acid (DPD) scintigraphy. The diagnostic performance of CT-based left ventricular (LV), right ventricular, and left atrial dimensions, ejection fraction (EF), and myocardial strain were evaluated against 99m Tc-DPD scintigraphy as the reference standard to identify ATTR-CM. Predictors and an unweighted cardiac CT score were validated with internal bootstrapping. The assignment of variables to the score was based on cutoff values achieving the highest Youden index J . Results Among 263 participants (mean age, 83 years ± 4.6 [SD]; 149 male and 114 female participants), 99m Tc-DPD scintigraphy (Perugini grade 2 or 3) confirmed coexisting ATTR-CM in 27 (10.3%). CT-derived LV mass index, LV and LA global longitudinal strain (GLS), and relative apical longitudinal strain each predicted the presence of ATTR-CM with an area under the curve (AUC) of at least 0.70. Implementing these parameters with cutoff values of 81 g/m 2 or higher, -14.9% or higher, less than 11.5%, and 1.7 or higher in the CT score, respectively, yielded high diagnostic performance (AUC = 0.89; 95% CI: 0.81, 0.94; P < .001) robust to internal bootstrapping validation (AUC = 0.88; 95% CI: 0.82, 0.94). If two criteria were fulfilled, the sensitivity and specificity in the detection of ATTR-CM were 96.3% (95% CI: 81.0, 99.9) and 58.9% (95% CI: 52.3, 65.2), respectively. Conclusion When compared against 99m Tc-DPD scintigraphy as the reference standard, routine 4D cardiac CT in older adults considered for TAVI provided high diagnostic performance in the detection of concomitant ATTR-CM by assessing LV and left atrial GLS, relative apical longitudinal strain, and LV mass index. ClinicalTrials.gov registration no.: NCT04061213 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Tavakoli and Onder in this issue.

Introduction: Previous analyses have reported the outcomes of transcatheter aortic valve replacement (TAVR) for patients with low-flow, low-gradient (LFLG) aortic stenosis (AS), without stratifying according to the route of access. Differences in mortality rates among access routes have been established for high-gradient (HG) patients and hypothesized to be even more pronounced in LFLG AS patients. This study aims to compare the outcomes of patients with LFLG or HG AS following transfemoral (TF) or transapical (TA) TAVR., Methods: A total of 910 patients, who underwent either TF or TA TAVR with a median follow-up of 2.22 (IQR: 1.22-4.03) years, were included in this multicenter cohort study. In total, 146 patients (16.04%) suffered from LFLG AS. The patients with HG and LFLG AS were stratified according to the route of access and compared statistically., Results: The operative mortality rates of patients with HG and LFLG were found to be comparable following TF access. The operative mortality rate was significantly increased for patients who underwent TA access [odds ratio (OR): 2.91 (1.54-5.48), p  = 0.001] and patients with LFLG AS [OR: 2.27 (1.13-4.56), p  = 0.02], which could be corroborated in a propensity score-matched subanalysis. The observed increase in the risk of operative mortality demonstrated an additive effect [OR for TA LFLG: 5.45 (2.35-12.62), p  < 0.001]. LFLG patients who underwent TA access had significantly higher operative mortality rates (17.78%) compared with TF LFLG (3.96%, p  = 0.016) and TA HG patients (6.36%, p  = 0.024)., Conclusions: HG patients experienced a twofold increase in operative mortality rates following TA compared with TF access, while LFLG patients had a fivefold increase in operative mortality rates. TA TAVR appears suboptimal for patients with LFLG AS. Prospective studies should be conducted to evaluate alternative options in cases where TF is not possible., Competing Interests: The 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., (© 2023 Maier, Lambert, Senoner, Dobner, Hoppe, Fellner, Pfeifer, Feuchtner, Friedrich, Semsroth, Bonaros, Holfeld, Müller, Reinthaler, Steinwender and Barbieri.)

Despite being considered druggable and attractive therapeutic targets, most of the solute carrier (SLC) membrane transporters remain pharmacologically underexploited. One of the reasons for this is a lack of reliable chemical screening assays, made difficult by functional redundancies among SLCs. In this study we leveraged synthetic lethality between the lactate transporters SLC16A1 and SLC16A3 in a screening strategy that we call paralog-dependent isogenic cell assay (PARADISO). The system involves five isogenic cell lines, each dependent on various paralog genes for survival/fitness, arranged in a screening cascade tuned for the identification of SLC16A3 inhibitors. We screened a diversity-oriented library of ∼90,000 compounds and further developed our hits into slCeMM1, a paralog-selective and potent SLC16A3 inhibitor. By implementing chemoproteomics, we showed that slCeMM1 is selective also at the proteome-wide level, thus fulfilling an important criterion for chemical probes. This study represents a framework for the development of specific cell-based drug discovery assays., Competing Interests: Declaration of interests V.D., A.C., and G.S.-F. are co-authors of patent applications related to presented study. S.K., G.E.W., and G.S.-F. are co-founders of company related to SLCs. G.S.-F. is the Academic Project Coordinator of the IMI RESOLUTE/Resolution consortium in partnership with Pfizer, Novartis, Bayer, Sanofi, Boehringer Ingelheim and Vifor Pharma. G.S.-F., G.E.W., and S.K. laboratories receive funds from Pfizer., (Copyright © 2023 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences GmbH. Published by Elsevier Ltd.. All rights reserved.)

Background The prevalence of calcific aortic stenosis and amyloid transthyretin cardiomyopathy (ATTR-CM) increase with age, and they often coexist. The objective was to determine the prevalence of ATTR-CM in patients with severe aortic stenosis and evaluate differences in presentations and outcomes of patients with concomitant ATTR-CM undergoing transcatheter aortic valve implantation. Methods and Results Prospective screening for ATTR-CM with Technetium 99 -3,3-diphosphono-1,2-propanodicarboxylic acid bone scintigraphy was performed in 315 patients referred with severe aortic stenosis between August 2019 and August 2021. Myocardial Technetium 99 -3,3-diphosphono-1,2-propanodicarboxylic acid tracer uptake was detected in 34 patients (10.8%), leading to a diagnosis of ATTR-CM in 30 patients (Perugini ≥2: 9.5%). Age (85.7±4.9 versus 82.8±4.5; P =0.001), male sex (82.4% versus 57.7%; P =0.005), and prior carpal tunnel surgery (17.6% versus 4.3%; P =0.007) were associated with coexisting ATTR-CM, as were ECG (discordant QRS voltage to left ventricular wall thickness [42% versus 12%; P <0.001]), echocardiographic (left ventricular ejection fraction 48.8±12.8 versus 58.4±10.8; P <0.001; left ventricular mass index, 144.4±45.8 versus 117.2±34.4g/m 2 ; P <0.001), and hemodynamic parameters (mean aortic valve gradient, 23.4±12.6 versus 35.5±16.6; P <0.001; mean pulmonary artery pressure, 29.5±9.7 versus 25.8±9.5; P =0.037). Periprocedural (cardiovascular death: hazard ratio [HR], 0.71 [95% CI, 0.04-12.53]; stroke: HR, 0.46 [95% CI, 0.03-7.77]; pacemaker implantation: HR, 1.54 [95% CI, 0.69-3.43]) and 1-year clinical outcomes (cardiovascular death: HR, 1.04 [95% CI, 0.37-2.96]; stroke: HR, 0.34 [95% CI, 0.02-5.63]; pacemaker implantation: HR, 1.50 [95% CI, 0.67-3.34]) were similar between groups. Conclusions Coexisting ATTR-CM was observed in every 10th elderly patient with severe aortic stenosis referred for therapy. While patients with coexisting pathologies differ in clinical presentation and echocardiographic and hemodynamic parameters, peri-interventional risk and early clinical outcomes were comparable up to 1 year after transcatheter aortic valve implantation. REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT04061213.

Aims: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in heart failure patients with reduced and preserved left ventricular ejection fraction (LVEF), but have not yet been investigated in transthyretin amyloid cardiomyopathy (ATTR-CM). This study aimed to evaluate tolerability, clinical outcomes, and changes in NT-proBNP levels and glomerular filtration rate (GFR) in ATTR-CM patients treated with dapagliflozin., Methods and Results: Patients with stable, tafamidis-treated ATTR-CM were retrospectively evaluated at the initiation of dapagliflozin and 3 months thereafter. Tafamidis-treated ATTR-CM patients without SGLT2i served as a reference cohort. Overall, SLGT2i therapy was initiated in 34 patients. Seventeen patients with stable disease on tafamidis, who were subsequently started on dapagliflozin, were included in the analysis. Patients selected for SGLT2i presented with signs of advanced disease, evidenced by higher Gillmore disease stage (stage ≥2: 53% vs. 27.5%; P = 0.041), baseline median NT-proBNP [median (IQR) 2668 pg/mL (1314-3451) vs. 1424 (810-2059); P = 0.038] and loop diuretic demand (76.5% vs. 45% of patients; P = 0.044), and lower LVEF (46.6 ± 12.9 vs. 53.7 ± 8.7%; P = 0.019) and GFR (51.8 ± 16.5 vs. 68.5 ± 18.6 mL/min; P = 0.037) compared with the reference cohort. At 3-month follow-up, a numerical decrease in NT-proBNP levels was observed in 13/17 (76.5%) patients in the dapagliflozin (-190 pg/mL, IQR: -1,028-71, P = 0.557) and 27/40 (67.5%) of patients in the control cohort (-115 pg/mL, IQR: -357-105, P = 0.551). Other disease parameters remained stable and no adverse events occurred., Conclusions: In tafamidis-treated ATTR-CM patients, initiation of dapagliflozin was well tolerated. The efficacy of SGLT2i therapy in patients with ATTR-CM needs to be studied in randomized controlled trials., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

We observed a lesion pattern in a series of 4 cases of RANBP2 -mutation-linked acute necrotizing encephalopathy, which appears to be specific for this condition. The setting of synchronous bilateral mammillary, amygdaloid, and lateral geniculate lesions, along with claustro-parahippocampal lesions, can serve as a diagnostic tool in this condition. We add several further details to the MR imaging features of the typical brain lesions encountered in this disease., (© 2021 by American Journal of Neuroradiology.)

Transthyretin amyloidosis (ATTR amyloidosis) is a disease caused by deposition of transthyretin fibrils in organs and tissues, which causes their dysfunction. The clinical heterogeneity of ATTR amyloidosis and the variable presentation of symptoms at early disease stages, historically meant treatment delays. Diagnostic tools and therapy options of ATTR amyloidosis have markedly improved in recent years. The first Swiss Amyloidosis Network (SAN) meeting (Zurich, Switzerland, January 2020) aimed to define a consensus statement regarding the diagnostic work-up and treatment for systemic amyloidosis, tailored to the Swiss healthcare system. A consortium of 45 clinicians and researchers from all Swiss regions and universities was selected by the SAN committee to represent all sub-specialty groups involved in care of patients with amyloidosis. A steering committee conducted the literature search and analysis, wrote the critical synthesis and elaborated a list of statements that were evaluated by all the participants. These recommendations will improve outcomes and quality of life for patients with ATTR amyloidosis. A global review of these guidelines is planned every 3 years with a formal meeting of all the involved experts.

Sex-related differences in prevalence, clinical presentation, and outcome of cardiac channelopathies are increasingly recognized, despite their autosomal transmission and hence equal genetic predisposition among sexes. In congenital long-QT syndrome, adult women carry a greater risk for Torsades de pointes and sudden cardiac death than do men. In contrast, Brugada syndrome is observed predominantly in adult men, with a considerably higher risk of arrhythmic sudden cardiac death in adult men than in women. In both conditions, the risk for arrhythmias varies with age. Sex-associated differences appear less evident in other cardiac channelopathies, likely a reflection of their rare(r) occurrence and our limited knowledge. In several cardiac channelopathies, sex-specific predictors of outcome have been identified. Together with genetic and environmental factors, sex hormones contribute to the sex-related disparities in cardiac channelopathies through modulation of the expression and function of cardiac ion channels. Despite these insights, essential knowledge gaps exist in the mechanistic understanding of these differences, warranting further investigation. Precise application of the available knowledge may improve the individualized care of patients with cardiac channelopathies. Promoting the reporting of sex-related phenotype and outcome parameters in clinical and experimental studies and advancing research on cardiac channelopathy animal models should translate into improved patient outcomes. This review provides a critical digest of the current evidence for sex-related differences in cardiac channelopathies and emphasizes their clinical implications and remaining gaps requiring further research.

Hereby, the supplemental data of the research article "Long-Term Prognostic Value of High-Sensitivity Troponin T added to N-Terminal Pro Brain Natriuretic Peptide Plasma Levels before Valve Replacement for Severe Aortic Stenosis" are presented [1]. It offers enhanced input on the predictive value of these biomarkers considering the influence of the presence of concomitant coronary artery disease (CAD) in various severities as well as an additional cox proportional hazard model on cardiovascular mortality. Furthermore, the receiver operating characteristic (ROC) curves are shown as figures. The material described increases therefore the understanding of the predictive value of these already routinely available biomarkers and reduces the risk of potential bias due to possible confounding factors. It also underlines the urge for a multi-factorial approach in diagnostics to detect the optimal point for referral to valve replacement other than just symptomatic status, an observed reduction in left ventricular ejection fraction or the presence of CAD with the necessity for coronary artery bypass grafting (CABG) [2]. The data of the 3595 patients were gathered retrospectively at a consortium of four university hospital centers in Austria and combined with prospectively collected data on cardiovascular and all-cause mortality., (© 2020 The Authors.)

We present the experimental realization of transverse mode conversion in an optical fiber via an optically induced long-period grating. The transient gratings are generated by femtosecond laser pulses, exploiting the Kerr effect to translate intensity patterns emerging from multimode interference into a spatial refractive index modulation. Since these modulations exist only while the pump beam is present, they can be used for optical switching of transverse modes. As only a localized part of the grating was written at a time and the probe beam was co-propagating with the pump beam the required pulse energies could be reduced to 120 nJ which is about a factor of 600 lower than in previous quasi-continuous-wave experiments. Accompanying numerical simulations allow a better understanding of the involved effects and show excellent agreement to the experimental results.

We present the hyperspectral imaging capabilities of in-line interferometric femtosecond stimulated Raman scattering. The beneficial features of this method, namely, the improved signal-to-background ratio compared to other applicable broadband stimulated Raman scattering methods and the simple experimental implementation, allow for a rather fast acquisition of three-dimensional raster-scanned hyperspectral data-sets, which is shown for PMMA beads and a lipid droplet in water as a demonstration. A subsequent application of a principle component analysis displays the chemical selectivity of the method.

We present in-line interferometric femtosecond stimulated Raman scattering (II-FSRS), a new method to measure the spectral Raman intensity and phase over a broad spectral range, potentially in a single shot. An analytic model is developed, that excellently reproduces the measured spectra. Additionally, the performance of II-FSRS is directly compared in experiments to two established techniques, namely femtosecond stimulated Raman scattering and femtosecond Raman induced Kerr-effect spectroscopy.

Biomaterials are increasingly being investigated as a means of reducing stress within the ventricular wall of infarcted hearts and thus attenuating pathological remodelling and loss of function. In this context, we have examined the influence of timing of delivery on the efficacy of a polyethylene glycol hydrogel polymerised with an enzymatically degradable peptide sequence. Delivery of the hydrogel immediately after infarct induction resulted in no observable improvements, but a delay of one week in delivery resulted in significant increases in scar thickness and fractional shortening, as well as reduction in end-systolic diameter against saline controls and immediately injected hydrogel at both 2 and 4 weeks post-infarction (p < 0.05). Hydrogels injected at one week were degraded significantly slower than those injected immediately and this may have played a role in the differing outcomes. The hydrogel assumed markedly different morphologies at the two time points having either a fibrillar or bulky appearance after injection immediately or one week post-infarction respectively. We argue that the different morphologies result from infarction induced changes in the cardiac structure and influence the degradability of the injectates. The results indicate that timing of delivery is important and that very early time points may not be beneficial., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Interleukin 33 (IL-33), a member of the Interleukin 1 cytokine family, is implicated in numerous human inflammatory diseases such as asthma, atherosclerosis, and rheumatoid arthritis. Despite its pathophysiologic importance, fundamental questions regarding the basic biology of IL-33 remain. Nuclear localization and lack of an export signal sequence are consistent with the view of IL-33 as a nuclear factor with the ability to repress RNA transcription. However, signaling via the transmembrane receptor ST2 and documented caspase-dependent inactivation have suggested IL-33 is liberated during cellular necrosis to effect paracrine signaling. We determined the subcellular localization of IL-33 and tracked its intracellular mobility and extracellular release. In contrast to published data, IL-33 localized simultaneously to nuclear euchromatin and membrane-bound cytoplasmic vesicles. Fluorescent pulse-chase fate-tracking documented dynamic nucleo-cytoplasmic flux, which was dependent on nuclear pore complex function. In murine fibroblasts in vitro and in vivo, mechanical strain induced IL-33 secretion in the absence of cellular necrosis. These data document IL-33 dynamic inter-organelle trafficking and release during biomechanical overload. As such we recharacterize IL-33 as both an inflammatory as well as mechanically responsive cytokine secreted by living cells.

External mesh constriction of vein grafts was shown to mitigate intimal hyperplasia by lowering circumferential wall stress and increasing fluid shear stress. As under-constriction leaves vein segments unsupported and thus prone to neointimal proliferation while over-constriction may cause wall folding optimal mesh sizing holds a key to clinical success. Diameter fluctuations and the occurrence of wall folding as a consequence of external constriction with knitted Nitinol meshes were assessed in saphenous vein grafts from 100 consecutive coronary artery bypass (CABG) patients. Subsequently, mesh dimensions were identified that resulted in the lowest number of mesh sizes for all patients either guaranteeing tight continual mesh contact along the entire graft length (stipulation A) or preventing wall folding (stipulation B). A mathematical data classification analysis and a statistical single-stage partitioning approach were independently applied alternatively prioritizing stipulation A or B. Although the risk of folding linearly increased when constriction exceeded 24.6% (Chi squared test p = 0.0004) the actual incidence of folding (8.6% of veins) as well as the degree of lumenal encroachment (6.2 ± 2.1%) were low. Folds were always single, narrow longitudinal formations (height: 23.3 ± 4.0% of inner diameter/base: 16.6 ± 18.1% of luminal circumference). Both analytical methods provided an optimum number of 4 mesh sizes beyond which no further advantage was seen. While the size ranges recommended by both methods assured continual tight mesh contact with the vein the narrower range suggested by the mathematical data classification analysis (3.0-3.7 mm) put 20.6 ± 12.5% of length in 69% of veins at risk of folding as opposed to 21.3 ± 25.9% being at risk in the wider size range (3.0-4.2 mm) suggested by the statistical partitioning approach. Four mesh sizes would provide uninterrupted mesh contact in 98% of vein grafts in CABG procedures with only 26% of their length being at risk of relatively mild wall folding., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Growth factors are often used in tissue regeneration to stimulate vascularisation of polymeric scaffolds, with vascular endothelial growth factor (VEGF) having been extensively studied for short-term vessel ingrowth. We have therefore evaluated the effect of different concentrations of VEGF on the vascularisation of a porous scaffold in the short-, intermediate- and long-term, by delivering 15, 150 and 1500ng VEGF/day to polyurethane scaffolds by osmotic pumps for up to 6 weeks. An increased vascularisation months after termination of VEGF delivery was only achieved with 150ng/day (46%, p<0.05). This dosage consistently showed elevated levels of vascularisation (144, 125, 160 and 60% above PBS controls at 10, 20, 30 and 42 days, respectively, p<0.05), whilst the vessels induced by the highest dosage, though initially maximally elevated (265 and 270% at 10 and 20 days, p<0.05) tended to regress after 20 days of VEGF delivery. Pericyte coverage was decreased at 20 days for the highest dosage (30%, p<0.05). Lectin perfusion demonstrated that vessels within the scaffold were connected to the host vasculature at all time points and perfusion was substantially raised by VEGF delivery at day 20. These results suggest concentration of VEGF plays a critical role in the nature and persistence of vasculature formed in a tissue regenerative scaffold.