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Severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HC) may benefit from surgical myectomy. In patients with enlarged mitral leaflets and mitral regurgitation, myectomy can be combined with anterior mitral leaflet extension (AMLE) to stiffen the midsegment of the leaflet. The aim of this study was to evaluate the long-term results of myectomy combined with AMLE in patients with obstructive HC. This prospective, observational, single-center cohort study included 98 patients (49 ± 14 years, 37% female) who underwent myectomy combined with AMLE from 1991 to 2012. End points included all-cause mortality and change in clinical and echocardiographic characteristics. Mortality was compared with age- and gender-matched patients with nonobstructive HC and subjects from the general population. Long-term follow-up was 8.3 ± 6.1 years. There was no operative mortality, and New York Heart Association class was reduced from 2.8 ± 0.5 to 1.3 ± 0.5 (p <0.001), left ventricular outflow tract gradient from 93 ± 25 to 9 ± 8 mm Hg (p <0.001), mitral valve regurgitation from grade 2.0 ± 0.9 to 0.5 ± 0.8 (p <0.001), and systolic anterior motion of the mitral valve from grade 2.4 ± 0.9 to 0.1 ± 0.3 (p <0.001). The 1-, 5-, 10-, and 15-year cumulative survival rates were 98%, 92%, 86%, and 83%, respectively, and did not differ from the general population (99%, 97%, 92%, and 85%, respectively, p = 0.3) or patients with nonobstructive HC (98%, 97%, 88%, and 83%, respectively, p = 0.8). In conclusion, in selected patients with obstructive HC, myectomy combined with AMLE is a low-risk surgical procedure. It results in long-term symptom relief and survival similar to the general population.

Background 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. Methods 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. Results 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. Conclusions 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.

Hypertrophic cardiomyopathy (HCM) is the most frequent genetic cardiac disease with a prevalence of 1:500 to 1:200. While most patients show obstructive HCM and a relatively stable clinical phenotype (stage II), a small group of patients progresses to end-stage HCM (stage IV) within a relatively brief period. Previous research has shown sex-differences in stage II HCM with more diastolic dysfunction in female than in male patients. Moreover, female patients more often show progression to heart failure. Here we investigated if differences in functional and structural properties of the heart may underlie sex-differences in disease progression from stage II to stage IV HCM. Cardiac tissue from stage II and IV patients was obtained during myectomy (n = 54) and heart transplantation (n = 10), respectively. Isometric force was measured in membrane-permeabilized cardiomyocytes to define active and passive myofilament force development. Titin isoform composition was assessed using gel electrophoresis, and the amount of fibrosis and capillary density were determined with histology. In accordance with disease stage-dependent adverse cardiac remodeling end-stage patients showed a thinner interventricular septal wall and larger left ventricular and atrial diameters compared to stage II patients. Cardiomyocyte contractile properties and fibrosis were comparable between stage II and IV, while capillary density was significantly lower in stage IV compared to stage II. Women showed more adverse cellular remodeling compared to men at stage II, evident from more compliant titin, more fibrosis and lower capillary density. However, the disease stage-dependent reduction in capillary density was largest in men. In conclusion, the more severe cellular remodeling in female compared to male stage II patients suggests a more advanced disease stage at the time of myectomy in women. Changes in cardiomyocyte contractile properties do not explain the progression of stage II to stage IV, while reduced capillary density may underlie disease progression to end-stage heart failure.

Sudden cardiac death (SCD) is the most devastating complication of hypertrophic cardiomyopathy (HCM), but this can be prevented by an implantable cardioverter-defibrillator (ICD). The aim of this study is to evaluate HCM patients with ICDs for primary or secondary prevention of SCD. The study population consisted of all HCM patients with an ICD in 2 tertiary referral clinics. End points during follow-up were total and cardiac mortality, appropriate and inappropriate ICD intervention, and device-related complications. Cox-regression analysis was performed to identify predictors of outcome. ICDs were implanted in 134 patients with HCM (mean age 44 ± 17 years, 34% women, 4.2 ± 4.8 years follow-up). Annualized cardiac mortality rate was 3.4% per year and associated with New York Heart Association class III or IV (HR 5.2 [2.0-14, P = .002]) and cardiac resynchronization therapy (HR 6.3 [2.1-20, P = .02]). Appropriate ICD interventions occurred in 38 patients (6.8%/year) and was associated with implantation for secondary prevention of SCD (HR 4.0 [1.8-9.1], P = .001) and male gender (HR 3.3 [1.2-9.0], P = .02). Inappropriate ICD intervention occurred in 21 patients (3.7%/year) and in 20 patients device related complications were documented (3.6%/year). ICDs successfully abort life-threatening arrhythmias in HCM patients at increased risk of SCD with an annualized intervention rate of 6.8% per year. End-stage heart failure is the main cause of mortality in these patients. The annualized rate of inappropriate ICD intervention was 3.7% per year, whereas device-related complications occurred 3.6% per year.

Atrial fibrillation (AF) is a common complication of hypertrophic cardiomyopathy (HC) and associated with adverse clinical outcomes, such as thromboembolisms. Cardiac implantable electronic devices (CIEDs) enable early detection of AF. The aim of this study was to assess the incidence of device-detected AF and the impact on long-term outcomes in patients with HC. The cohort consisted of 132 patients (63% men, mean age 52 ± 16 years) with a diagnosis of HC and a CIED. Follow-up started at the date of CIED implantation to assess the incidence of device-detected AF. Patients with persistent AF at the time of implantation were excluded from the analysis of the incidence of AF. End points were all-cause and cardiac mortality, device-detected AF, and thromboembolism (stroke, transient ischemic attack, or peripheral arterial embolism). In total, 114 patients were in sinus rhythm at time of CIED implantation. During the median 2.8 (interquartile range 1.2 to 5.4) years of follow-up, device-detected AF occurred in 29 patients (25%), resulting in an annual incidence of 7.0%/year. Device-detected AF led to a change in the clinical management in 22 patients (76%). Anticoagulation therapy was started in 13 (45%), antiarrhythmic medication in 9 (31%), and electrical cardioversion in 8 (28%) patients. Six patients (5%) suffered a thromboembolic complication. All-cause mortality was 27 (20%), and cardiac mortality was 21 (16%). A history of AF at time of implantation was an independent predictor of cardiac death (hazard ratio 4.7, p = 0.003). In conclusion, the incidence of device-detected AF in patients with HC was 7.0%/year, leading to a change in clinical management in the majority (76%) of cases to reduce the risk of thromboembolic complications. These findings stress the importance of AF detection in HC and advocate vigilant interrogation of the device.

Diastolic dysfunction is general to all idiopathic dilated (IDCM) and hypertrophic cardiomyopathy (HCM) patients. Relaxation deficits may result from increased actin–myosin formation during diastole due to altered tropomyosin position, which blocks myosin binding to actin in the absence of Ca²⁺. We investigated whether ADP-stimulated force development (without Ca²⁺) can be used to reveal changes in actin–myosin blockade in human cardiomyopathy cardiomyocytes. Cardiac samples from HCM patients, harboring thick-filament (MYH7 mut,MYBPC3 mut) and thin-filament (TNNT2 mut,TNNI3 mut) mutations, and IDCM were compared with sarcomere mutation-negative HCM (HCMsmn) and nonfailing donors. Myofilament ADP sensitivity was higher in IDCM and HCM compared with donors, whereas it was lower forMYBPC3. Increased ADP sensitivity in IDCM, HCMsmn, andMYH7 mutwas caused by low phosphorylation of myofilament proteins, as it was normalized to donors by protein kinase A (PKA) treatment. Troponin exchange experiments in aTNNT2 mutsample corrected the abnormal actin–myosin blockade. InMYBPC3 truncsamples, ADP sensitivity highly correlated with cardiac myosin-binding protein-C (cMyBP-C) protein level. Incubation of cardiomyocytes with cMyBP-C antibody against the actin-binding N-terminal region reduced ADP sensitivity, indicative of cMyBP-C’s role in actin–myosin regulation. In the presence of Ca²⁺, ADP increased myofilament force development and sarcomere stiffness. Enhanced sarcomere stiffness in sarcomere mutation-positive HCM samples was irrespective of the phosphorylation background. In conclusion, ADP-stimulated contraction can be used as a tool to study how protein phosphorylation and mutant proteins alter accessibility of myosin binding on actin. In the presence of Ca²⁺, pathologic [ADP] and low PKA-phosphorylation, high actin–myosin formation could contribute to the impaired myocardial relaxation observed in cardiomyopathies.

Evidence is accumulating that mindfulness training has favorable effects on psychological outcomes, but studies on physiological outcomes are limited. Patients with heart disease have a high incidence of physiological and psychological problems and may benefit from mindfulness training. Our aim was to determine the beneficial physiological and psychological effects of online mindfulness training in patients with heart disease. The study was a pragmatic randomized controlled single-blind trial. Between June 2012 and April 2014 we randomized 324 patients (mean age 43.2 years, 53.7% male) with heart disease in a 2:1 ratio (n = 215 versus n = 109) to a 12-week online mindfulness training in addition to usual care (UC) compared to UC alone. The primary outcome was exercise capacity measured with the 6 minute walk test (6MWT). Secondary outcomes were other physiological parameters (heart rate, blood pressure, respiratory rate, and NT-proBNP), subjective health status (SF-36), perceived stress (PSS), psychological well-being (HADS), social support (PSSS12) and a composite endpoint (all-cause mortality, heart failure, symptomatic arrhythmia, cardiac surgery, and percutaneous cardiac intervention). Linear mixed models were used to evaluate differences between groups on the repeated outcome measures. Compared to UC, mindfulness showed a borderline significant improved 6MWT (effect size, meters: 13.2, 95%CI: -0.02; 26.4, p = 0.050). There was also a significant lower heart rate in favor of the mindfulness group (effect size, beats per minute: -2.8, 95%CI: -5.4;-0.2, p = 0.033). No significant differences were seen on other outcomes. Mindfulness training showed positive effects on the physiological parameters exercise capacity and heart rate and it might therefore be a useful adjunct to current clinical therapy in patients with heart disease. Dutch Trial Register 3453.

Pathogenic gene mutations are found in about 50% of patients with hypertrophic cardiomyopathy (HC). Previous studies have shown an association between sarcomere mutations and medium-term outcome. The association with long-term outcome has not been described. The aim of this cohort study was to assess the long-term outcomes of patients with genotype positive (G+) and genotype negative (G−) HC. The study population consisted of 626 patients with HC (512 probands and 114 relatives) who underwent phenotyping and genetic testing from 1985 to 2014. End points were all-cause mortality, cardiovascular (CV) mortality, heart failure (HF)–related mortality, and sudden cardiac death/aborted sudden cardiac death (SCD/aborted SCD). Kaplan–Meier and multivariate Cox regression analyses were performed. A pathogenic mutation was detected in 327 patients (52%). G+ probands were younger than G− probands (46 ± 15 vs 55 ± 15 years, p <0.001), had more non sustained ventricular tachycardia (34% vs 13%; p <0.001), more often a history of syncope (14% vs 7%; p = 0.016), and more extreme hypertrophy (maximal wall thickness ≥30 mm, 7% vs 1%; p <0.001). G− probands were more symptomatic (New York Heart Association ≥II, 73% vs 53%, p <0.001) and had higher left ventricular outflow tract gradients (42 ± 39 vs 29 ± 33 mm Hg, p = 0.001). During 12 ± 9 years of follow-up, G+ status was an independent risk factor for all-cause mortality (hazard ratio [HR] 1.90, 95% CI 1.14 to 3.15; p = 0.014), CV mortality (HR 2.82, 95% CI 1.49 to 5.36; p = 0.002), HF-related mortality (HR 6.33, 95% CI 1.79 to 22.41; p = 0.004), and SCD/aborted SCD (HR 2.88, 95% CI 1.23 to 6.71; p = 0.015). In conclusion, during long-term follow-up, patients with G+ HC are at increased risk of all-cause death, CV death, HF-related death, and SCD/aborted SCD.

There is increasing evidence that mindfulness can reduce stress, and thereby affect other psychological and physiological outcomes as well. Earlier, we reported the direct 3-month results of an online modified mindfulness-based stress reduction training in patients with heart disease, and now we evaluate the effect at 12-month follow-up. 324 patients (mean age 43.2 years, 53.7% male) were randomized in a 2:1 ratio to additional 3-month online mindfulness training or to usual care alone. The primary outcome was exercise capacity measured with the 6 minute walk test (6MWT). Secondary outcomes were blood pressure, heart rate, respiratory rate, NT-proBNP, cortisol levels (scalp hair sample), mental and physical functioning (SF-36), anxiety and depression (HADS), perceived stress (PSS), and social support (PSSS12). Differences between groups on the repeated outcome measures were analyzed with linear mixed models. At 12-months follow-up, participants showed a trend significant improvement exercise capacity (6MWT: 17.9 meters, p = 0.055) compared to UC. Cohen's D showed significant but small improvement on exercise capacity (d = 0.22; 95%CI 0.05 to 0.39), systolic blood pressure (d = 0.19; 95%CI 0.03 to 0.36), mental functioning (d = 0.22; 95%CI 0.05 to 0.38) and depressive symptomatology (d = 0.18; 95%CI 0.02 to 0.35). All other outcome measures did not change statistically significantly. In the as-treated analysis, systolic blood pressure decreased significantly with 5.5 mmHg (p = 0.045; d = 0.23 (95%CI 0.05-0.41)). Online mindfulness training shows favorable albeit small long-term effects on exercise capacity, systolic blood pressure, mental functioning, and depressive symptomatology in patients with heart disease and might therefore be a beneficial addition to current clinical care. www.trialregister.nl NTR3453.

Background Shear waves are generated by the closure of the heart valves. Significant differences in shear wave velocity have been found recently between normal myocardium and disease models of diffusely increased muscle stiffness. In this study we correlate in vivo myocardial shear wave imaging (SWI) with presence of scarred tissue, as model for local increase of stiffness. Stiffness variation is hypothesized to appear as velocity variation. Methods Ten healthy volunteers (group 1), 10 hypertrophic cardiomyopathy (HCM) patients without any cardiac intervention (group 2), and 10 HCM patients with prior septal reduction therapy (group 3) underwent high frame rate tissue Doppler echocardiography. The SW in the interventricular septum after aortic valve closure was mapped along two M-mode lines, in the inner and outer layer. Results We compared SWI to 3D echocardiography and strain imaging. In groups 1 and 2, no change in velocity was detected. In group 3, 8/10 patients showed a variation in SW velocity. All three patients having transmural scar showed a simultaneous velocity variation in both layers. Out of six patients with endocardial scar, five showed variations in the inner layer. Conclusion Local variations in stiffness, with myocardial remodeling post septal reduction therapy as model, can be detected by a local variation in the propagation velocity of naturally occurring shear waves.