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The application of artificial intelligence (AI) for automated diagnosis of electrocardiograms (ECGs) can improve care in remote settings but is limited by the reliance on infrequently available signal-based data. We report the development of a multilabel automated diagnosis model for electrocardiographic images, more suitable for broader use. A total of 2,228,236 12-lead ECGs signals from 811 municipalities in Brazil are transformed to ECG images in varying lead conformations to train a convolutional neural network (CNN) identifying 6 physician-defined clinical labels spanning rhythm and conduction disorders, and a hidden label for gender. The image-based model performs well on a distinct test set validated by at least two cardiologists (average AUROC 0.99, AUPRC 0.86), an external validation set of 21,785 ECGs from Germany (average AUROC 0.97, AUPRC 0.73), and printed ECGs, with performance superior to signal-based models, and learning clinically relevant cues based on Grad-CAM. The model allows the application of AI to ECGs across broad settings. The application of artificial intelligence for automated diagnosis of electrocardiograms can improve care in remote settings but is limited by the reliance on infrequently available signal-based data. Here, the authors report the development of a multi-label automated diagnosis model for electrocardiographic images.

Key Points Although the ACC Foundation (ACCF)/AHA and ESC guidelines show widespread concordance, the ESC definition of hypertrophic cardiomyopathy (HCM) includes nonsarcomeric disease states associated with load-independent left ventricular hypertrophy (LVH) Relatives of patients with HCM should be offered screening; autosomal dominant inheritance is typical, and a range of electrocardiographic and imaging features are recognized to precede the development of LVH Prognostic assessment at baseline and follow-up is recommended for all patients with HCM; despite recognizing many of the same predictors of sudden death, the ACCF/AHA and ESC adopt distinct approaches to risk profiling Specialist HCM centres promote implementation of best-practice guidelines by offering facilities and skills for investigations such as exercise stress echocardiography, cardiovascular magnetic resonance (CMR), and genetic analysis, in addition to high-volume programmes for invasive septal reduction Patients referred to specialist HCM centres also benefit from multidisciplinary support systems and clinical experience in interpreting equivocal clinical findings, adjudicating borderline risk profiles, and managing complex cases Advances in the evaluation of HCM include CMR-based T1 mapping for demonstrating diffuse and interstitial fibrosis; in the therapeutic arena, several putative substrate-modulating agents are progressing from preclinical to clinical trials Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease. In this Review, Sen-Chowdhry et al . discuss the guideline recommendations for the evaluation and management of HCM, and provide a summary of the important advances in genetics, imaging, and molecular research on HCM. Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting 1 in 500 individuals worldwide. Existing epidemiological studies might have underestimated the prevalence of HCM, however, owing to limited inclusion of individuals with early, incomplete phenotypic expression. Clinical manifestations of HCM include diastolic dysfunction, left ventricular outflow tract obstruction, ischaemia, atrial fibrillation, abnormal vascular responses and, in 5% of patients, progression to a 'burnt-out' phase characterized by systolic impairment. Disease-related mortality is most often attributable to sudden cardiac death, heart failure, and embolic stroke. The majority of individuals with HCM, however, have normal or near-normal life expectancy, owing in part to contemporary management strategies including family screening, risk stratification, thromboembolic prophylaxis, and implantation of cardioverter–defibrillators. The clinical guidelines for HCM issued by the ACC Foundation/AHA and the ESC facilitate evaluation and management of the disease. In this Review, we aim to assist clinicians in navigating the guidelines by highlighting important updates, current gaps in knowledge, differences in the recommendations, and challenges in implementing them, including aids and pitfalls in clinical and pathological evaluation. We also discuss the advances in genetics, imaging, and molecular research that will underpin future developments in diagnosis and therapy for HCM.

Objective This longitudinal study aimed to measure precarious employment in the US using a multidimensional indicator. Methods We used data from the National Longitudinal Survey of Youth (1988-2016) and the Occupational Information Network database to create a longitudinal precarious employment score (PES) among 7568 employed individuals over 18 waves (N=101 290 observations). We identified 13 survey indicators to operationalize 7 dimensions of precarious employment, which we included in our PES (range: 0-7, with 7 indicating the most precarious): material rewards, working-time arrangements, stability, workers' rights, collective organization, interpersonal relations, and training. Using generalized estimating equations, we estimated the mean PES and changes over time in the PES overall and by race/ethnicity, gender, education, income, and region. Results On average, the PES was 3.17 [standard deviation (SD) 1.19], and was higher among women (3.34, SD 1.20), people of color (Hispanics: 3.24, SD 1.23; non-Hispanic Blacks: 3.31, SD 1.23), those with less education (primary: 3.99, SD 1.07; high school: 3.43, SD 1.19), and with lower-incomes (3.84, SD 1.08), and those residing in the South (3.23, SD 1.17). From 1988 to 2016, the PES increased by 9% on average [0.29 points; 95% confidence interval (CI) 0.26-0.31]. While precarious employment increased over time across all subgroups, the increase was largest among males (0.35 points; 95% CI 0.33-0.39), higher-income (0.39 points; 95% CI 0.36-0.42) and college-educated (0.37 points; 95% CI 0.33-0.41) individuals. Conclusions Long-term decreases in employment quality are widespread in the US. Women and those from racialized and less-educated populations remain disproportionately precariously employed; however, we observed the largest increases among men, college graduates and higher-income individuals.

Reliance upon part-time instructors within U. S. post-secondary institutions has received a great deal of attention, particularly as the percentage of such faculty has become the largest single category of faculty in academia. Understanding how part-time markets operate may allow better policy. Most current studies on the subject examine national markets, and emphasize demand factors motivating expansion of the part-time workforce. Although the subject of supply was once critical to discussions it has received less attention of late in part due to a faulty understanding of how part-time markets operate. Cross sectional regression analysis is performed to explore potential correlations between the number of graduating masters and doctoral students and reliance upon part-time faculty at neighboring institutions of higher education. Where previous researchers have found that institutions in more urbanized settings exhibit greater reliance upon part-time faculty, this analysis indicates that local availability of recently minted masters and PhD degrees within commuting distances of the hiring institution more closely fits staffing data. Policy actors may be able to use these results to better coordinate regional or local demand to supply, which has implications for unions and other policy actors attempting to limit reliance upon part-time faculty.

Beta-blockers have been the initial treatment for symptomatic obstructive hypertrophic cardiomyopathy (HCM) despite limited evidence of their efficacy. Aficamten is a cardiac myosin inhibitor that reduces left ventricular outflow tract gradients, improves exercise capacity, and decreases HCM symptoms when added to standard medications. Whether aficamten as monotherapy provides greater clinical benefit than beta-blockers as monotherapy remains unknown. We conducted an international, double-blind, double-dummy trial in which adults with symptomatic obstructive HCM were randomly assigned in a 1:1 ratio to receive aficamten (at a daily dose of 5 mg to 20 mg) plus placebo or metoprolol (at a daily dose of 50 mg to 200 mg) plus placebo. The primary end point was the change in peak oxygen uptake at week 24; secondary end points were improvement at week 24 in New York Heart Association (NYHA) functional class and changes at week 24 in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), left ventricular outflow tract gradient after the Valsalva maneuver, N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, left atrial volume index, and left ventricular mass index. A total of 88 patients were assigned to the aficamten group and 87 to the metoprolol group. The mean age of the patients was 58 years, 58.3% were men, and the mean left ventricular outflow tract gradient was 47 mm Hg at rest and 74 mm Hg after the Valsalva maneuver. At 24 weeks, the change in the peak oxygen uptake was 1.1 ml per kilogram of body weight per minute (95% confidence interval [CI], 0.5 to 1.7) in the aficamten group and -1.2 ml per kilogram per minute (95% CI, -1.7 to -0.8) in the metoprolol group (least-squares mean between-group difference, 2.3 ml per kilogram per minute; 95% CI, 1.5 to 3.1; P<0.001). Patients who received aficamten had significantly greater improvements in NYHA class, KCCQ-CSS, left ventricular outflow tract gradient, NT-proBNP level, and left atrial volume index than patients who received metoprolol. No significant difference in left ventricular mass index was observed. Adverse events appeared to be similar in the two treatment groups. Among patients with symptomatic obstructive HCM, aficamten monotherapy was superior to metoprolol monotherapy in improving peak oxygen uptake and hemodynamics and decreasing symptoms. (Funded by Cytokinetics; MAPLE-HCM ClinicalTrials.gov number, NCT05767346.).

Psychological stress is common in patients with heart failure, due in part to the complexities of effective disease self-management and progressively worsening functional limitations, including frequent symptom exacerbations and hospitalizations. Emerging evidence suggests that heart failure patients who experience higher levels of stress may have a more burdensome disease course, with diminished quality of life and increased risk for adverse events, and that multiple behavioral and pathophysiological pathways are involved. Furthermore, the reduced quality of life associated with heart failure can serve as a life stressor for many patients. The purpose of this review is to summarize the current state of the science concerning psychological stress in patients with heart failure and to discuss potential pathways responsible for the observed effects. Key knowledge gaps are also outlined, including the need to understand patterns of exposure to various heart failure-related and daily life stressors and their associated effects on heart failure symptoms and pathophysiology, to identify patient subgroups at increased risk for stress exposure and disease-related consequences, and the effect of stress specifically for patients who have heart failure with preserved ejection fraction. Stress is a potentially modifiable factor, and addressing these gaps and advancing the science of stress in heart failure is likely to yield important insights about actionable pathways for improving patient quality of life and outcomes.

We have developed an engineered heart tissue (EHT) system that uses laser-cut sheets of decellularized myocardium as scaffolds. This material enables formation of thin muscle strips whose biomechanical characteristics are easily measured and manipulated. To create EHTs, sections of porcine myocardium were laser-cut into ribbon-like shapes, decellularized and mounted in specialized clips for seeding and culture. Scaffolds were first tested by seeding with neonatal rat ventricular myocytes. EHTs beat synchronously by day five and exhibited robust length-dependent activation by day 21. Fiber orientation within the scaffold affected peak twitch stress, demonstrating its ability to guide cells toward physiologic contractile anisotropy. Scaffold anisotropy also made it possible to probe cellular responses to stretch as a function of fiber angle. Stretch that was aligned with the fiber direction increased expression of brain natriuretic peptide, but off-axis stretches (causing fiber shear) did not. The method also produced robust EHTs from cardiomyocytes derived from human embryonic stem cells and induced pluripotent stem cells (hiPSC). hiPSC-EHTs achieved maximum peak stress of 6.5 mN/mm 2 and twitch kinetics approaching reported values from adult human trabeculae. We conclude that laser-cut EHTs are a viable platform for novel mechanotransduction experiments and characterizing the biomechanical function of patient-derived cardiomyoctyes.

In the phase 3 study SEQUOIA‐HCM (NCT05186818), aficamten, a next‐in‐class cardiac myosin inhibitor, was safe and efficacious in participants with obstructive hypertrophic cardiomyopathy (oHCM). Using pharmacokinetics/pharmacodynamics (PKPD) modeling, we quantified the relationship between aficamten exposure and cardiodynamic measures of safety (left ventricular ejection fraction [LVEF]) and efficacy (post‐Valsalva left ventricular outflow tract gradient [LVOT‐G]), and used Clinical Trial Simulations (CTS) to predict cardiodynamics for a flexible dose regimen in a post‐approval setting. PKPD relationships between aficamten average concentration over 24 h (Cavg,24) and LVEF or LVOT‐G were well quantified. Within‐subject variability for LVEF was low (CV = 7.6%), indicating that prior LVEF readings are highly predictive of future readings during stable therapy. A 2% decrease in LVEF is expected per 100 ng/mL increase in Cavg,24. LVOT‐G slope was 10‐fold steeper vs. LVEF, suggesting a relatively large therapeutic window. The commercial regimen allows for individualized flexible echocardiography‐based dose titration (every 2–8 weeks) from 5 to 20 mg once daily and flexible maintenance dose monitoring. CTS demonstrated minimal differences in population progression of LVOT‐G < 30 mmHg and LVEF < 50% between evaluated dose‐titration frequencies (every 2, 4, 6, or 8 weeks) over the first 6 months of treatment, supporting a 2–8 week window for dose titration. With maintenance doses, the probability of maintaining LVOT‐G < 30 mmHg ( 60%) was high and the probability of occurrences of LVEF < 50% ( 3%) was low. Therefore, this regimen should maintain safe and efficacious cardiodynamics while increasing convenience and access for patients with oHCM. Study Highlights What is the current knowledge on the topic? ○A phase 3 study demonstrated aficamten, a next‐in‐class CMI, to be highly safe and efficacious in participants with oHCM. What question did this study address? ○This study quantitatively addresses key questions about aficamten treatment: What are the relationships between exposure and cardiodynamic measures of safety and efficacy? Does the phase 3 PKPD data support safe and efficacious use when administered as a flexible titration and maintenance regimen in a post‐approval setting? What does this study add to our knowledge? ○Modeling revealed consistent and reliable relationships between aficamten exposure and cardiodynamic safety (LVEF) and efficacy (LVOT‐G). These relationships translate to the ability to maintain high LVOT‐G response with minimal chance for low LVEF events when administered via a highly flexible titration (every 2–8 weeks) and maintenance (up to every 6 months) schedule. How might this change drug discovery, development, and/or therapeutics? ○These results establish that the FDA approved aficamten commercial regimen is likely to maintain safe and efficacious cardiodynamic results observed in phase 3, with increased convenience and access for patients with oHCM.

Aficamten is a next‐in‐class, cardiac myosin inhibitor in development as a potential chronic oral treatment for patients with hypertrophic cardiomyopathy (HCM). A population pharmacokinetic (PK) model was developed using data from nine clinical studies to characterize aficamten PK and identify covariates that may alter aficamten exposure. Aficamten PK was best described by a 2‐compartment model with linear elimination and first‐order absorption following a time lag (Tlag). Population parameter estimates for a typical male participant with obstructive HCM (oHCM) and weighing 80 kg were: apparent clearance (CL/F), 2.62 L/h; apparent volume of the central compartment (Vc/F), 18.1 L; apparent intercompartmental clearance (Q/F), 57.6 L/h; and apparent volume of the peripheral compartment (Vp/F), 295 L. Estimated interindividual variability on CL/F and overall residual error (includes within‐subject variability) was low; the coefficient of variation was 28.7% and 20.3%, respectively. Body weight on volume and clearance, population and sex on CL/F and Vp/F were identified as statistically significant covariates. A male patient with a baseline body weight of 56 kg (5th percentile of the population) exhibited a 23% higher AUCtau compared with a male patient with a typical body weight of 80 kg. Female patients demonstrated a 14.7% higher AUCtau than male patients of the same body weight. Healthy participants had a 23% lower AUCtau compared with participants with oHCM. This population PK analysis demonstrated that aficamten has a linear and predictable PK profile, with a favorable half‐life and time‐to‐steady state, and low interindividual variability on CL/F and overall residual error (includes within‐subject variability).