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Background: Septal reduction therapy (SRT) in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy (oHCM) is associated with variable morbidity and mortality. The VALOR-HCM trial (A Study to Evaluate Mavacamten in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) examined the effect of mavacamten on the need for SRT through week 32 in oHCM. Methods: A double-blind randomized placebo-controlled multicenter trial at 19 US sites included patients with oHCM on maximal tolerated medical therapy referred for SRT with left ventricular outflow tract gradient ≥50 mm Hg at rest or provocation (enrollment, July 2020–October 2021). The group initially randomized to mavacamten continued the drug for 32 weeks, and the placebo group crossed over to dose-blinded mavacamten from week 16 to week 32. Dose titrations were based on investigator-blinded echocardiographic assessment of left ventricular outflow tract gradient and left ventricular ejection fraction. The principal end point was the proportion of patients proceeding with SRT or remaining guideline eligible at 32 weeks in both treatment groups. Results: From the 112 randomized patients with oHCM, 108 (mean age, 60.3 years; 50% men; 94% in New York Heart Association class III/IV) qualified for week 32 evaluation (56 in the original mavacamten group and 52 in the placebo cross-over group). After 32 weeks, 6 of 56 patients (10.7%) in the original mavacamten group and 7 of 52 patients (13.5%) in the placebo cross-over group met SRT guideline criteria or elected to undergo SRT. After 32 weeks, a sustained reduction in resting left ventricular outflow tract gradient (−33.0 mm Hg [95% CI, −41.1 to −24.9]) and Valsalva left ventricular outflow tract gradient (−43.0 mm Hg [95% CI, −52.1 to −33.9]) was observed in the original mavacamten group. A similar reduction in resting (−33.7 mm Hg [95% CI, −42.2 to −25.2]) and Valsalva (−52.9 mm Hg [95% CI, −63.2 to −42.6]) gradients was quantified in the cross-over group after 16 weeks of mavacamten. After 32 weeks, improvement by ≥1 New York Heart Association class was observed in 48 of 53 patients (90.6%) in the original mavacamten group and 35 of 50 patients (70%) after 16 weeks in the cross-over group. Conclusions: In severely symptomatic patients with oHCM, 32 weeks of mavacamten treatment showed sustained reduction in the proportion proceeding to SRT or remaining guideline eligible, with similar effects observed in patients who crossed over from placebo after 16 weeks. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04349072.

In the EXPLORER-HCM trial, mavacamten improved exercise capacity and symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM). Mavacamten effects on the primary endpoint, a composite of peak oxygen consumption (VOSubgroup analyses by beta-blocker use were performed in patients with oHCM from the EXPLORER-HCM and mavacamten long-term extension (MAVA-LTE) studies. In EXPLORER-HCM, 189 patients (75.3%) were receiving beta-blockers, and 62 (24.7%) were receiving non-dihydropyridine calcium-channel blockers or no background HCM medication; 170 patients (90.4%) receiving beta-blockers had chronotropic incompetence. Improvements in peak VOMavacamten improved measures of functional capacity, LVOT obstruction, symptom burden and biomarkers in patients with HCM regardless of beta-blocker use. Beta-blocker use was often associated with chronotropic incompetence, affecting peak VO

BACKGROUND: The development of left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM) is rare but serious and associated with poor outcomes in adults. Little is known about the prevalence, predictors, and prognosis of LVSD in patients diagnosed with HCM as children. METHODS: Data from patients with HCM in the international, multicenter SHaRe Registry (Sarcomeric Human Cardiomyopathy) were analyzed. LVSD was defined as left ventricular ejection fraction RESULTS: We studied 1010 patients diagnosed with HCM during childhood ( CONCLUSIONS: Patients with childhood-diagnosed HCM have a significantly higher lifetime risk of developing LVSD, and LVSD emerges earlier than for patients with adult-diagnosed HCM. Regardless of age at diagnosis with HCM or LVSD, the prognosis with LVSD is poor, warranting careful surveillance for LVSD, especially as children with HCM transition to adult care.

Cardiorespiratory fitness (as measured by peak oxygen consumption [VO2peak]) is an independent predictor of cardiovascular disease and all-cause mortality. Limited data exist on VO2peak following repair for an acute type A aortic dissection (ATAAD) or proximal thoracic aortic aneurysm (pTAA). This study prospectively evaluated VO2peak, functional capacity, and health-related quality of life (HR-QOL) following open repair. Participants with a history of an ATAAD (n = 21) or pTAA (n = 43) performed cardiopulmonary exercise testing (CPX), 6-minute walk testing, and HR-QOL at 3 (early) and 15 (late) months following open repair. The median age at time of surgery was 55-years-old and 60-years-old in the ATAAD and pTAA groups, respectively. Body mass index significantly increased between early and late timepoints for both ATAAD (p = 0.0245, 56% obese) and pTAA groups (p = 0.0045, 54% obese). VO2peak modestly increased by 0.8 mLO2·kg−1·min−1 within the ATAAD group (p = 0.2312) while VO2peak significantly increased by 2.2 mLO2·kg−1·min−1 within the pTAA group (p = 0.0003). Anxiety significantly decreased in the ATAAD group whereas functional capacity and HR-QOL metrics (social roles and activities, physical function) significantly improved in the pTAA group (p values 1 year after repair. CPX should be considered post-operatively to evaluate exercise tolerance and blood pressure response to determine whether mild-to-moderate aerobic exercise should be recommended to reduce future risk of morbidity and mortality.

PurposeIn response, the purpose of this paper is to provide theoretical frameworks about the organizational uncertainty behind what and when to adopt blockchain technology and their implications on transaction costs. The immature nature and the absence of standards in blockchain technology lead to uncertainty in government organizations concerning the adoption (“what to adopt”) and the identification of the right time (“when to start”).Design/methodology/approachUsing transaction cost theory and path dependency theory, this paper proposes two frameworks: to assess transaction cost risks and opportunities costs; and to depict four different types of transaction costs outcomes regarding blockchain adoption.FindingsThis paper identifies various theoretical concepts that influence blockchain adoption and combine the two critical constructs of “bounded rationality” and the “lock-in effect” to categorize the multiple transaction costs outcomes for blockchain adoption.Research limitations/implicationsAlthough existing research in blockchain highlights mainly the potential benefits of blockchain applications, only a little attention has been given to frameworks that categorize potential transaction costs outcomes under uncertainty, in particular from organizational theorists.Originality/valueBoth frameworks advance the understanding of the decision-making behind blockchain adoption and synthesize the current literature to offer conceptual clarity regarding the varied implications and outcomes linked to the uncertainty regarding transactions costs stemming from blockchain technology.

Selecting the most resilient supplier is a crucial problem for organizations and managers in the supply chain. However, due to the inherited high degree of uncertainty in real-life projects, developing a decision-making framework in a crisp or fuzzy environment may not present accurate or reliable results for the managers. For this reason, it is better to evaluate the potential suppliers in an Interval Type-2 Fuzzy (IT2F) environment for better dealing with this ambiguity. This study developed an improved combined IT2F Best Worst Method (BWM) and IT2F technique for Order Preference by Similarity to Ideal Solution (TOPSIS) model “Atieh Sazan” Co. as a case study, such that the IT2FBWM was employed for obtaining the weight of criteria. The IT2FTOPSIS was utilized for ranking the potential suppliers based on Hamming distance measure. In both phases, the opinions of experts as IT2F linguistic terms were employed for weighting the criteria and obtaining the relative importance of the alternatives in terms of the evaluative criteria. After obtaining the final results, the proposed model was validated by replacing Analytical Hierarchy Process (AHP) and Simple Additive Weighting (SAW) approaches separately instead of BWM for weighting the criteria. After executing both new models, it was found that the final ranking was similar to the final ranking of the proposed model, representing the reliability and accuracy of the obtained results. Moreover, it was concluded that the resilient criteria of “Reorganization” and “Redundancy” are the most determinant measures for selecting the best supplier rather than measures in the Iranian Construction Industry.

Background: In the randomized phase 3 VALOR-HCM study (A Study to Evaluate Mavacamten in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal Reduction Therapy) of patients with obstructive hypertrophic cardiomyopathy, mavacamten reduced the need for septal reduction therapy. Because mavacamten improves ventricular compliance, this sub-study examined the effects of treatment with this cardiac myosin inhibitor on diastolic function. Methods: Symptomatic obstructive hypertrophic cardiomyopathy patients on maximally tolerated medical therapy referred for septal reduction therapy were randomized 1:1 to mavacamten or placebo. At baseline and week 16, a resting and stress echocardiogram was performed with interpretation by a core laboratory. In this exploratory substudy, the principal end point was the change in parameters used to define the grade of diastolic function in patients treated with mavacamten and placebo. A related objective was to assess the proportion of patients with an improvement in diastolic function grade. A secondary aim was to assess for correlation between diastolic function parameters and the secondary end points from VALOR-HCM: New York Heart Association class, quality of life, and cardiac biomarkers. Results: Diastolic dysfunction grade was evaluable in 98 patients at baseline and week 16. Among patients treated with mavacamten, 29.4% (15 of 51) demonstrated improvement in diastolic function grade compared with 12.8% (6 of 47) patients with placebo ( P =0.05). Average E/e’ ratio decreased significantly in patients treated with mavacamten (−3.4±5.3) compared with placebo (0.57±3.5; P 2 ) also decreased significantly in patients who received mavacamten (−5.2±7.8) compared with placebo (−0.51±8.1; P =0.005). After adjustment for change in left ventricular outflow tract gradient and mitral regurgitation, mavacamten was significantly associated with a decrease in average E/e’ ratio and indexed left atrial volumes. Change in average E/e’ ratio was significantly correlated with the secondary end points from VALOR-HCM. Conclusions: In this exploratory substudy, after 16 weeks of therapy, mavacamten improved diastolic function, and this change correlated with improvement in clinical and biomarker end points. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04349072.

Septal reduction therapy (SRT) in patients with intractable symptoms from obstructive hypertrophic cardiomyopathy (oHCM) is associated with variable morbidity and mortality. The VALOR-HCM trial examined the effect of mavacamten on the need for SRT through Week 32 in oHCM.A double-blind randomized placebo-controlled multicenter trial at 19 US sites included oHCM patients on maximal tolerated medical therapy referred for SRT, with left ventricular outflow tract (LVOT) gradient ≥50 mmHg at rest or provocation (enrollment 7/202010/2021). The group initially randomized to mavacamten continued the drug for 32 weeks and the placebo group crossed over to dose-blinded mavacamten from Week 16 to 32. Dose titrations were based on investigator-blinded echocardiographic assessment of LVOT gradient and LV ejection fraction. The principal endpoint was proportion of patients proceeding with SRT or remaining guideline eligible at 32 weeks in both treatment groups.From the 112 randomized oHCM patients, 108 (mean age 60.3 years, 50% men and 94% in New York Heart Association [NYHA] class III/IV) qualified for Week 32 evaluation (56 in original mavacamten and 52 in placebo crossover group). After 32 weeks, 6/56 (10.7%) patients in original mavacamten and 7/52 (13.5%) in placebo crossover group met SRT guideline criteria or elected to undergo SRT. After 32 weeks, a sustained reduction in resting LVOT gradient (-33.0 mmHg 95% confidence interval [CI] -41.1 to -24.9) and Valsalva LVOT gradient (-43.0 mmHg, 95% CI -52.1 to -33.9) was observed in the original mavacamten group. A similar reduction in resting (-33.7 mmHg, 95% CI -42.2 to -25.2) and Valsalva gradients (-52.9 mmHg, 95% CI -63.2 to -42.6) was quantified in the crossover group after 16 weeks of mavacamten. After 32 weeks, ≥1 NYHA class improvement was observed in 48/53 (90.6%) of original mavacamten and 35/50 (70%) after 16 weeks in the crossover group.In severely symptomatic oHCM patients, 32 weeks of mavacamten treatment showed sustained reduction in the proportion proceeding to SRT or remaining guideline eligible, with similar effects observed in patients crossed over from placebo after 16 weeks.URL: Clinicaltrials.gov Unique Identifier: NCT04349072.

Aims Risk stratification algorithms for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) and regional differences in clinical practice have evolved over time. We sought to compare primary prevention implantable cardioverter defibrillator (ICD) implantation rates and associated clinical outcomes in US vs. non-US tertiary HCM centres within the international Sarcomeric Human Cardiomyopathy Registry. Methods and results We included patients with HCM enrolled from eight US sites (n = 2650) and five non-US (n = 2660) sites and used multivariable Cox-proportional hazards models to compare outcomes between sites. Primary prevention ICD implantation rates in US sites were two-fold higher than non-US sites (hazard ratio (HR) 2.27 [1.89–2.74]), including in individuals deemed at high 5-year SCD risk (≥6%) based on the HCM risk-SCD score (HR 3.27 [1.76–6.05]). US ICD recipients also had fewer traditional SCD risk factors. Among ICD recipients, rates of appropriate ICD therapy were significantly lower in US vs. non-US sites (HR 0.52 [0.28–0.97]). No significant difference was identified in the incidence of SCD/resuscitated cardiac arrest among non-recipients of ICDs in US vs. non-US sites (HR 1.21 [0.74–1.97]). Conclusion Primary prevention ICDs are implanted more frequently in patients with HCM in US vs. non-US sites across the spectrum of SCD risk. There was a lower rate of appropriate ICD therapy in US sites, consistent with a lower-risk population, and no significant difference in SCD in US vs. non-US patients who did not receive an ICD. Further studies are needed to understand what drives malignant arrhythmias, optimize ICD allocation, and examine the impact of different ICD utilization strategies on long-term outcomes in HCM.

Background: Recently, magnetic resonance imaging (MRI) has become a useful tool for the early detection of heart failure. A vital step of this process is a valid measurement of the left ventricle's properties, which seriously depends on the accurate segmentation of the heart in captured images. Although various schemes have been tested for this segmentation so far, the latest proposed methods have used the concept of deep learning to estimate the range of the left ventricle in cardiac MRI images. While deep learning methods can lead to better results than their classical alternatives, but unfortunately, the gradient vanishing and exploding problems may hamper their efficiency for the accurate segmentation of the left ventricle in MRI heart images. Methods: In this article, a new concept called residual learning is utilized to improve the performance of deep learning schemes against gradient vanishing problems. For this purpose, the Residual Network of Residual Network (i.e., Residual of Residual) substructure is utilized inside the main deep learning architecture (e.g., Unet), which provides more significant detection indexes. Results and Conclusion: The proposed method's performances and its alternatives were evaluated on Sunnybrook Cardiac Data as a reliable dataset in the left ventricle segmentation. The results show that the detection parameters are improved at least by 5%, 3.5%, 8.1%, and 11.4% compared to its deep alternatives in terms of Jaccard, Dice, precision, and false-positive rate indexes, respectively. These improvements were made when the recall parameter was reduced to a negligible value (i.e., approximately 1%). Overall, the proposed method can be used as a suitable tool for more accurate detection of the left ventricle in MRI images.

Despite the globally reducing hospitalization rates and the much lower risks of Covid-19 mortality, accurate diagnosis of the infection stage and prediction of outcomes are clinically of interest. Advanced current technology can facilitate automating the process and help identifying those who are at higher risks of developing severe illness. Deep-learning schemes including Visual Transformer and Convolutional Neural Networks (CNNs), in particular, are shown to be powerful tools for predicting clinical outcomes when fed with either CT scan images or clinical data of patients.This paper demonstrates how a novel 3D data fusion approach through concatenating CT scan images with patients’ clinical data can remarkably improve the performance of Visual Transformer and CNN models in predicting Covid-19 infection outcomes. Here, we explore and represent comprehensive research on the efficiency of Video Swin Transformers and a number of CNN models fed with fusion datasets and CT scans only vs a set of conventional classifiers fed with patients’ clinical data only. A relatively large clinical dataset from 380 Covid-19 diagnosed patients was used to train/test the models. Results show that the 3D Video Swin Transformers fed with the fusion datasets of 64 sectional CT scans+67 (or 30 selected) clinical labels outperformed all other approaches for predicting outcomes in Covid-19-infected patients amongst all techniques (i.e., TPR=0.95, FPR=0.40, F0.5 score=0.82, AUC=0.77, Kappa=0.6). Results indicate possibilities of predicting the severity of outcome using patients’ CT images and clinical data collected at the time of admission to hospital.

Aims Childhood-onset hypertrophic cardiomyopathy (HCM) is far less common than adult-onset disease, thus natural history is not well characterized. We aim to describe the characteristics and outcomes of childhood-onset HCM. Methods and results We performed an observational cohort study of 7677 HCM patients from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Hypertrophic cardiomyopathy patients were stratified by age at diagnosis [18 years (adulthood)] and assessed for composite endpoints reflecting heart failure (HF), life-threatening ventricular arrhythmias, atrial fibrillation (AF), and an overall composite that also included stroke and death. Stratifying by age of diagnosis, 184 (2.4%) patients were diagnosed in infancy; 1128 (14.7%) in childhood; and 6365 (82.9%) in adulthood. Childhood-onset HCM patients had an ∼2%/year event rate for the overall composite endpoint, with ventricular arrhythmias representing the most common event in the 1st decade following baseline visit, but HF and AF becoming more common by the end of the 2nd decade. Sarcomeric variants were more common in childhood-onset HCM (63%) and carried a worse prognosis than non-sarcomeric disease, including a greater than two-fold increased risk of HF [HRadj 2.39 (1.36–4.20), P = 0.003] and 67% increased risk of the overall composite outcome [HRadj 1.67 (1.16–2.41), P = 0.006]. When compared with adult-onset HCM, childhood-onset was 36% more likely to develop life-threatening ventricular arrhythmias [HRadj 1.36 (1.03–1.80)] and twice as likely to require transplant or ventricular assist device [HRadj 1.99 (1.23–3.23)]. Conclusion Patients with childhood-onset HCM are more likely to have sarcomeric disease, carry a higher risk of life-threatening ventricular arrythmias, and have greater need for advanced HF therapies. These findings provide insight into the natural history of disease and can help inform clinical risk stratification.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiac condition and highly heterogeneous. Echocardiography and genetic and clinical screening have led to detection in women of childbearing age. Maternal and fetal outcomes among women with HCM are favorable. Genetic counseling is recommended. Prepregnancy clinical evaluation and risk assessment are paramount in ensuring optimal outcomes. Most women carry moderate risk of morbidity, have clinical evaluations and echocardiography each trimester, and deliver vaginally. Those who are symptomatic or have significant left ventricular outflow obstruction or recurrent arrhythmias prior to pregnancy are at higher risk and should be monitored at least monthly.

Background Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering t...

Background: The term “end stage” has been used to describe hypertrophic cardiomyopathy (HCM) with left ventricular systolic dysfunction (LVSD), defined as occurring when left ventricular ejection fraction is Methods: Data from 11 high-volume HCM specialty centers making up the international SHaRe Registry (Sarcomeric Human Cardiomyopathy Registry) were used to describe the natural history of patients with HCM-LVSD. Cox proportional hazards models were used to identify predictors of prognosis and incident development. Results: From a cohort of 6793 patients with HCM, 553 (8%) met the criteria for HCM-LVSD. Overall, 75% of patients with HCM-LVSD experienced clinically relevant events, and 35% met the composite outcome (all-cause death [n=128], cardiac transplantation [n=55], or left ventricular assist device implantation [n=9]). After recognition of HCM-LVSD, the median time to composite outcome was 8.4 years. However, there was substantial individual variation in natural history. Significant predictors of the composite outcome included the presence of multiple pathogenic/likely pathogenic sarcomeric variants (hazard ratio [HR], 5.6 [95% CI, 2.3–13.5]), atrial fibrillation (HR, 2.6 [95% CI, 1.7–3.5]), and left ventricular ejection fraction Conclusions: HCM-LVSD affects ≈8% of patients with HCM. Although the natural history of HCM-LVSD was variable, 75% of patients experienced adverse events, including 35% experiencing a death equivalent an estimated median time of 8.4 years after developing systolic dysfunction. In addition to clinical features, genetic substrate appears to play a role in both prognosis (multiple sarcomeric variants) and the risk for incident development of HCM-LVSD (thin filament variants).

Left ventricular outflow tract (LVOT) obstruction is a major determinant of heart failure symptoms in obstructive hypertrophic cardiomyopathy (oHCM). Aficamten, a next-in-class cardiac myosin inhibitor, may lower gradients and improve symptoms in these patients.This study aims to evaluate the safety and efficacy of aficamten in patients with oHCM.Patients with oHCM and LVOT gradients ≥30 mm Hg at rest or ≥50 mm Hg with Valsalva were randomized 2:1 to receive aficamten (n = 28) or placebo (n = 13) in 2 dose-finding cohorts. Doses were titrated based on gradients and ejection fraction (EF). Safety and changes in gradient, EF, New York Heart Association functional class, and cardiac biomarkers were assessed over a 10-week treatment period and after a 2-week washout.From baseline to 10 weeks, aficamten reduced gradients at rest (mean difference: -40 ± 27 mm Hg, and -43 ± 37 mm Hg in Cohorts 1 and 2, P = 0.0003 and P = 0.0004 vs placebo, respectively) and with Valsalva (-36 ± 27 mm Hg and -53 ± 44 mm Hg, P = 0.001 and 0.0001 vs placebo, respectively). There were modest reductions in EF (-6% ± 7.5% and -12% ± 5.9%, P = 0.007 and P0.0001 vs placebo, respectively). Symptomatic improvement in ≥1 New York Heart Association functional class was observed in 31% on placebo, and 43% and 64% on aficamten in Cohorts 1 and 2, respectively (nonsignificant). With aficamten, N-terminal pro-B-type natriuretic peptide was reduced (62% relative to placebo, P = 0.0002). There were no treatment interruptions and adverse events were similar between treatment arms.Aficamten resulted in substantial reductions in LVOT gradients with most patients experiencing improvement in biomarkers and symptoms. These results highlight the potential of sarcomere-targeted therapy for treatment of oHCM.

Aims Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM). The newly developed HCM Risk-Kids model provides clinicians with individualized estimates of risk. The aim of this study was to externally validate the model in a large independent, multi-centre patient cohort. Methods and results A retrospective, longitudinal cohort of 421 patients diagnosed with HCM aged 1–16 years independent of the HCM Risk-Kids development and internal validation cohort was studied. Data on HCM Risk-Kids predictor variables (unexplained syncope, non-sustained ventricular tachycardia, maximal left ventricular wall thickness, left atrial diameter, and left ventricular outflow tract gradient) were collected from the time of baseline clinical evaluation. The performance of the HCM Risk-Kids model in predicting risk at 5 years was assessed. Twenty-three patients (5.4%) met the SCD end-point within 5 years, with an overall incidence rate of 2.03 per 100 patient-years [95% confidence interval (CI) 1.48–2.78]. Model validation showed a Harrell’s C-index of 0.745 (95% CI 0.52–0.97) and Uno’s C-index 0.714 (95% 0.58–0.85) with a calibration slope of 1.15 (95% 0.51–1.80). A 5-year predicted risk threshold of ≥6% identified 17 (73.9%) SCD events with a corresponding C-statistic of 0.702 (95% CI 0.60–0.81). Conclusions This study reports the first external validation of the HCM Risk-Kids model in a large and geographically diverse patient population. A 5-year predicted risk of ≥6% identified over 70% of events, confirming that HCM Risk-Kids provides a method for individualized risk predictions and shared decision-making in children with HCM.