•The authors propose Omega-Net: A novel convolutional neural network architecture for the detection, orientation, and segmentation of cardiac MR images.•Three modules comprise the network: a ...coarse-grained segmentation module, an attention module, and a fine-grained segmentation module.•The network is trained end-to-end from scratch using three-fold crossvalidation in 63 subjects (42 with hypertrophic cardiomyopathy, 21 healthy).•Performance of the Omega-Net is substantively improved compared with UNet alone.•In addition, to be comparable with other works, Omega-Net was retrained from scratch using five-fold cross-validation on the publicly available 2017 MICCAI Automated Cardiac Diagnosis Challenge (ACDC) dataset, achieving state-of-the-art performance in two of three segmentation classes.
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Pixelwise segmentation of the left ventricular (LV) myocardium and the four cardiac chambers in 2-D steady state free precession (SSFP) cine sequences is an essential preprocessing step for a wide range of analyses. Variability in contrast, appearance, orientation, and placement of the heart between patients, clinical views, scanners, and protocols makes fully automatic semantic segmentation a notoriously difficult problem. Here, we present Ω-Net (Omega-Net): A novel convolutional neural network (CNN) architecture for simultaneous localization, transformation into a canonical orientation, and semantic segmentation. First, an initial segmentation is performed on the input image; second, the features learned during this initial segmentation are used to predict the parameters needed to transform the input image into a canonical orientation; and third, a final segmentation is performed on the transformed image. In this work, Ω-Nets of varying depths were trained to detect five foreground classes in any of three clinical views (short axis, SA; four-chamber, 4C; two-chamber, 2C), without prior knowledge of the view being segmented. This constitutes a substantially more challenging problem compared with prior work. The architecture was trained using three-fold cross-validation on a cohort of patients with hypertrophic cardiomyopathy (HCM, N=42) and healthy control subjects (N=21). Network performance, as measured by weighted foreground intersection-over-union (IoU), was substantially improved for the best-performing Ω-Net compared with U-Net segmentation without localization or orientation (0.858 vs 0.834). In addition, to be comparable with other works, Ω-Net was retrained from scratch using five-fold cross-validation on the publicly available 2017 MICCAI Automated Cardiac Diagnosis Challenge (ACDC) dataset. The Ω-Net outperformed the state-of-the-art method in segmentation of the LV and RV bloodpools, and performed slightly worse in segmentation of the LV myocardium. We conclude that this architecture represents a substantive advancement over prior approaches, with implications for biomedical image segmentation more generally.
Genetic testing is an important tool in the diagnosis and management of patients and families with hypertrophic cardiomyopathy (HCM). Modern testing can identify causative variants in 30 to >60% of ...patients, with probability of a positive test varying with baseline characteristics such as known family history of HCM. Patients diagnosed with HCM should be offered genetic counseling and genetic testing as appropriate. Standard multigene panels evaluate sarcomeric genes known to cause HCM as well as genetic conditions that can mimic HCM but require different management. Positive genetic testing (finding a pathogenic or likely pathogenic variant) helps to clarify diagnosis and assists in family screening. If there is high confidence that an identified variant is the cause of HCM, at-risk family members can pursue predictive testing to determine if they are truly at risk or if they can be dismissed from serial screening based on whether they inherited the family’s causative variant. Interpreting test results can be complex, and providers should make use of multidisciplinary teams as well as evidence-based resources to obtain the best possible understanding of pathogenicity.
BACKGROUND:A better understanding of the factors that contribute to heterogeneous outcomes and lifetime disease burden in hypertrophic cardiomyopathy (HCM) is critically needed to improve patient ...management and outcomes. The SHaRe registry (Sarcomeric Human Cardiomyopathy Registry) was established to provide the scale of data required to address these issues, aggregating longitudinal data sets curated by 8 international HCM specialty centers.
METHODS:Data on 4591 patients with HCM (2763 genotyped) followed up for a mean of 5.4±6.9 years (24 791 patient-years; median, 2.9 years; interquartile range, 0.3–7.9 years) were analyzed for cardiac arrest, cardiac transplantation, appropriate implantable cardioverter-defibrillator therapy, all-cause death, atrial fibrillation, stroke, New York Heart Association functional class III/IV symptoms (all making up the overall composite end point), and left ventricular ejection fraction <35%. Outcomes were analyzed individually and as composite end points.
RESULTS:Median age at diagnosis was 45.8 (interquartile range, 30.9–58.1) years, and 37% of patients were female. Age at diagnosis and sarcomere mutation status were predictive of outcomes. Patients <40 years old at diagnosis had a 77% (95% CI, 72–80) cumulative incidence of the overall composite outcome by 60 years of age compared with 32% (95% CI, 29–36) by 70 years of age for patients diagnosed at >60 years old. Young patients with HCM (age, 20–29 years) had 4-fold higher mortality than the general US population at a similar age. Patients with pathogenic/likely pathogenic sarcomere mutations had a 2-fold greater risk for adverse outcomes compared with patients without mutations; sarcomere variants of uncertain significance were associated with intermediate risk. Heart failure and atrial fibrillation were the most prevalent adverse events, although typically not emerging for several years after diagnosis. Ventricular arrhythmias occurred in 32% (95% CI, 23–40) of patients <40 years of age at diagnosis but in 1% (95% CI, 1–2) of those >60 years old at diagnosis.
CONCLUSIONS:The cumulative burden of HCM is substantial and dominated by heart failure and atrial fibrillation occurring many years after diagnosis. Young age at diagnosis and the presence of a sarcomere mutation are powerful predictors of adverse outcomes. These findings highlight the need for close surveillance throughout life and the need to develop disease-modifying therapies.
This study shows that myocardial fibrosis is an early characteristic of hypertrophic cardiomyopathy caused by sarcomere mutations. The C-terminal propeptide of procollagen type I was shown to be a ...serum biomarker of early myocardial fibrosis.
Hypertrophic cardiomyopathy is caused by mutations in genes encoding sarcomere proteins.
1
,
2
With a prevalence of approximately 1 case per 500 persons in the general population, hypertrophic cardiomyopathy is the most common monogenic cardiac disorder.
3
The clinical diagnosis depends on the identification of unexplained left ventricular hypertrophy, but this finding is present only in persons with established disease and is typically absent in childhood.
4
In contrast, genetic diagnosis identifies pathogenic sarcomere mutations in persons at any age, including mutation carriers with overt hypertrophic cardiomyopathy and mutation carriers without hypertrophy who are at high risk for the development of disease. Studying . . .
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 <50%. The prognosis of HCM-LVSD has reportedly been poor, but because of its relative rarity, the natural history remains incompletely characterized.
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 <35% (HR, 2.0 95% CI, 1.3–2.8). The incidence of new HCM-LVSD was ≈7.5% over 15 years. Significant predictors of developing incident HCM-LVSD included greater left ventricular cavity size (HR, 1.1 95% CI, 1.0–1.3 and wall thickness (HR, 1.3 95% CI, 1.1–1.4), left ventricular ejection fraction of 50% to 60% (HR, 1.8 95% CI, 1.2, 2.8–2.8 95% CI, 1.8–4.2) at baseline evaluation, the presence of late gadolinium enhancement on cardiac magnetic resonance imaging (HR, 2.3 95% CI, 1.0–4.9), and the presence of a pathogenic/likely pathogenic sarcomeric variant, particularly in thin filament genes (HR, 1.5 95% CI, 1.0–2.1 and 2.5 95% CI, 1.2–5.1, respectively).
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).
Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile ...mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM.
MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM.
The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6.
Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009).
Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy MAVERICK-HCM; NCT03442764).
Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere ...proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted.
A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up.
In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for
(myosin light chain 3) to ≈55% for
(myosin-binding protein C3), ≈60% for
(troponin T2) and
(troponin I3), and ≈65% for
(myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for
and ≈23% for
.
The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM.
Abstract Background Mild hypertrophy but increased arrhythmic risk characterizes the stereotypic phenotype proposed for hypertrophic cardiomyopathy (HCM) caused by thin-filament mutations. However, ...whether such clinical profile is different from more prevalent thick-filament–associated disease is unresolved. Objectives This study aimed to assess clinical features and outcomes in a large cohort of patients with HCM associated with thin-filament mutations compared with thick-filament HCM. Methods Adult HCM patients (age >18 years), 80 with thin-filament and 150 with thick-filament mutations, were followed for an average of 4.5 years. Results Compared with thick-filament HCM, patients with thin-filament mutations showed: 1) milder and atypically distributed left ventricular (LV) hypertrophy (maximal wall thickness 18 ± 5 mm vs. 24 ± 6 mm; p < 0.001) and less prevalent outflow tract obstruction (19% vs. 34%; p = 0.015); 2) higher rate of progression to New York Heart Association functional class III or IV (15% vs. 5%; p = 0.013); 3) higher prevalence of systolic dysfunction or restrictive LV filling at last evaluation (20% vs. 9%; p = 0.038); 4) 2.4-fold increase in prevalence of triphasic LV filling pattern (26% vs. 11%; p = 0.002); and 5) similar rates of malignant ventricular arrhythmias and sudden cardiac death (p = 0.593). Conclusions In adult HCM patients, thin-filament mutations are associated with increased likelihood of advanced LV dysfunction and heart failure compared with thick-filament disease, whereas arrhythmic risk in both subsets is comparable. Triphasic LV filling is particularly common in thin-filament HCM, reflecting profound diastolic dysfunction.
EXPLORER-HCM (Clinical Study to Evaluate Mavacamten MYK-461 in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy) demonstrated that mavacamten, a cardiac myosin inhibitor, improves ...symptoms, exercise capacity, and left ventricular outflow tract (LVOT) obstruction in patients with obstructive hypertrophic cardiomyopathy (oHCM).
The purpose of this study was to evaluate mavacamten's effect on measures of cardiac structure and function and its association with changes in other clinical measures.
Key echocardiographic parameters from serial echocardiograms over 30 weeks from 251 symptomatic oHCM patients (mavacamten n = 123, placebo n = 128) were assessed in a core laboratory.
More patients on mavacamten (80.9%; n = 76 of 94) vs placebo (34.0%; n = 33 of 97) showed complete resolution of mitral valve systolic anterior motion after 30 weeks (difference, 46.8%; P < 0.0001). Mavacamten also improved measures of diastolic function vs placebo, including left atrial volume index (LAVI) (mean ± SD baseline: 40 ± 12 mL/m
vs 41 ± 14 mL/m
; mean change from baseline of -7.5 mL/m
95% CI: -9.0 to -6.1 mL/m
vs -0.09 mL/m
95% CI: -1.6 to 1.5 mL/m
; P < 0.0001) and lateral E/e' (baseline, 15 ± 6 vs 15 ± 8; change of -3.8 95% CI: -4.7 to -2.8 vs 0.04 95% CI: -0.9 to 1.0; P < 0.0001). Among mavacamten-treated patients, improvement in resting, Valsalva, and post-exercise LVOT gradients, LAVI, and lateral E/e' was associated with reduction in N-terminal pro-B-type natriuretic peptide (P ≤ 0.03 for all). Reduction in LAVI was associated with improved peak exercise oxygen consumption (P = 0.04).
Mavacamten significantly improved measures of left ventricular diastolic function and systolic anterior motion. Improvement in LVOT obstruction, LAVI, and E/e' was associated with reduction in a biomarker of myocardial wall stress (N-terminal pro-B-type natriuretic peptide). These findings demonstrate improvement in important markers of the pathophysiology of oHCM with mavacamten. (Clinical Study to Evaluate Mavacamten MYK-461 in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT03470545).
International guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false-positive rate over test ...sensitivity and diagnostic yield. Genetic testing is also more likely informative in individuals with well-characterised variants from extensively studied European-ancestry populations. Inherited cardiomyopathies are relatively common Mendelian diseases that allow empirical calibration and assessment of this framework.
We compared rare variants in large hypertrophic cardiomyopathy (HCM) cohorts (up to 6179 cases) to reference populations to identify variant classes with high prior likelihoods of pathogenicity, as defined by etiological fraction (EF). We analysed the distribution of variants using a bespoke unsupervised clustering algorithm to identify gene regions in which variants are significantly clustered in cases.
Analysis of variant distribution identified regions in which variants are significantly enriched in cases and variant location was a better discriminator of pathogenicity than generic computational functional prediction algorithms. Non-truncating variant classes with an EF ≥ 0.95 were identified in five established HCM genes. Applying this approach leads to an estimated 14-20% increase in cases with actionable HCM variants, i.e. variants classified as pathogenic/likely pathogenic that might be used for predictive testing in probands' relatives.
When found in a patient confirmed to have disease, novel variants in some genes and regions are empirically shown to have a sufficiently high probability of pathogenicity to support a "likely pathogenic" classification, even without additional segregation or functional data. This could increase the yield of high confidence actionable variants, consistent with the framework and recommendations of current guidelines. The techniques outlined offer a consistent and unbiased approach to variant interpretation for Mendelian disease genetic testing. We propose adaptations to ACMG/AMP guidelines to incorporate such evidence in a quantitative and transparent manner.
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