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Concept: Hypertrophic cardiomyopathy


Background For more than a decade, risk stratification for hypertrophic cardiomyopathy has been enhanced by targeted genetic testing. Using sequencing results, clinicians routinely assess the risk of hypertrophic cardiomyopathy in a patient’s relatives and diagnose the condition in patients who have ambiguous clinical presentations. However, the benefits of genetic testing come with the risk that variants may be misclassified. Methods Using publicly accessible exome data, we identified variants that have previously been considered causal in hypertrophic cardiomyopathy and that are overrepresented in the general population. We studied these variants in diverse populations and reevaluated their initial ascertainments in the medical literature. We reviewed patient records at a leading genetic-testing laboratory for occurrences of these variants during the near-decade-long history of the laboratory. Results Multiple patients, all of whom were of African or unspecified ancestry, received positive reports, with variants misclassified as pathogenic on the basis of the understanding at the time of testing. Subsequently, all reported variants were recategorized as benign. The mutations that were most common in the general population were significantly more common among black Americans than among white Americans (P<0.001). Simulations showed that the inclusion of even small numbers of black Americans in control cohorts probably would have prevented these misclassifications. We identified methodologic shortcomings that contributed to these errors in the medical literature. Conclusions The misclassification of benign variants as pathogenic that we found in our study shows the need for sequencing the genomes of diverse populations, both in asymptomatic controls and the tested patient population. These results expand on current guidelines, which recommend the use of ancestry-matched controls to interpret variants. As additional populations of different ancestry backgrounds are sequenced, we expect variant reclassifications to increase, particularly for ancestry groups that have historically been less well studied. (Funded by the National Institutes of Health.).

Concepts: Genetics, United States, Sequence, Hypertrophic cardiomyopathy, White American, African American, European American, English American


BACKGROUND: The presence of myocardial fibrosis is associated with worse clinical outcomes in hypertrophic cardiomyopathy (HCM). Cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) sequences can detect regional, but not diffuse myocardial fibrosis. Post-contrast T1 mapping is an emerging CMR technique that may enable the non-invasive evaluation of diffuse myocardial fibrosis in HCM. The purpose of this study was to non-invasively detect and quantify diffuse myocardial fibrosis in HCM with CMR and examine its relationship to diastolic performance. METHODS: We performed CMR on 76 patients - 51 with asymmetric septal hypertrophy due to HCM and 25 healthy controls. Left ventricular (LV) morphology, function and distribution of regional myocardial fibrosis were evaluated with cine imaging and LGE. A CMR T1 mapping sequence determined the post-contrast myocardial T1 time as an index of diffuse myocardial fibrosis. Diastolic function was assessed by transthoracic echocardiography. RESULTS: Regional myocardial fibrosis was observed in 84% of the HCM group. Post-contrast myocardial T1 time was significantly shorter in patients with HCM compared to controls, consistent with diffuse myocardial fibrosis (498 +/- 80 ms vs. 561 +/- 47 ms, p < 0.001). In HCM patients, post-contrast myocardial T1 time correlated with mean E/e' (r = -0.48, p < 0.001). CONCLUSIONS: Patients with HCM have shorter post-contrast myocardial T1 times, consistent with diffuse myocardial fibrosis, which correlate with estimated LV filling pressure, suggesting a mechanistic link between diffuse myocardial fibrosis and abnormal diastolic function in HCM.

Concepts: Cardiology, Cardiomyopathy, Heart, Echocardiography, Nuclear magnetic resonance, Hypertrophic cardiomyopathy, Diastolic dysfunction, Hypertrophy


BACKGROUND: Percutaneous transluminal septal myocardial ablation using microsphere embolisation is a new interventional technique to treat patients with hypertrophic obstructive cardiomyopathy. METHODS AND RESULTS: In two patients, considered at high risk for myectomy, targeted septal perforators were occluded with microsphere embolisation instead of alcohol ablation to reduce left ventricular outflow gradient. In both cases the left ventricular outflow tract gradient was immediately reduced. No adverse events occurred. CONCLUSION: This is the first clinical experience with Embozene® Microspheres in the Netherlands as an alternative for alcohol septal ablation. In both cases it resulted in immediate improvement in the haemodynamics, without any adverse events.

Concepts: Alcohol, Carbon dioxide, Clinical trial, Cardiomyopathy, Hypertrophic cardiomyopathy, Netherlands, Alcohol septal ablation, Microsphere


In LEOPARD Syndrome (LS) patients, mutations in the protein tyrosine phosphatase Shp2 cause hypertrophic cardiomyopathy (HCM). The pro-hypertrophic effects of mutant Shp2 are mediated downstream by hyperactivation of mammalian target of rapamycin (mTOR). Our goal was to further define the signaling cascade that is essential for the underlying pathomechanism, thus expanding the list of potential future therapeutic targets. Using cultured neonatal rat cardiomyocytes (NRCM) with adenoviral gene delivery and pharmacological inhibitors, we found that hypertrophy induced by a particularly aggressive LS mutation in Shp2 depends on hyperactivation of Akt and focal adhesion kinase (FAK) as well as mTOR. Dissecting domain-specific functions of Shp2 using double and truncation mutants, we determined that the hypertrophic effects of mutant Shp2 depend on the two SH2 domains and on an intact catalytic center. The latter finding prompted us to test the efficacy of a Shp2 inhibitor targeted directly at the catalytic pocket. This compound, PHPS1, effectively prevented mutant Shp2-induced hypertrophy. In summary, we identified three novel targets for pharmacological therapy of LS-associated cardiac hypertrophy. Of particular importance is the finding that intervention directly at the mutant Shp2 protein is effective, since this would facilitate custom-tailored therapeutic approaches for patients carrying LS mutations in Shp2.

Concepts: Signal transduction, Enzyme, Mutant, Tyrosine kinase, Hypertrophic cardiomyopathy, Focal adhesion, PTEN, EC 3.1.3


The Pediatric Cardiac Genomics Consortium (PCGC) designed the Congenital Heart Disease Genetic Network Study to provide phenotype and genotype data for a large congenital heart defects (CHDs) cohort. This article describes the PCGC cohort, overall and by major types of CHDs (e.g., conotruncal defects) and subtypes of conotrucal heart defects (e.g., tetralogy of Fallot) and left ventricular outflow tract obstructions (e.g., hypoplastic left heart syndrome). Cases with CHDs were recruited through ten sites, 2010-2014. Information on cases (N = 9,727) and their parents was collected through interviews and medical record abstraction. Four case characteristics, eleven parental characteristics, and thirteen parent-reported neurodevelopment outcomes were summarized using counts and frequencies and compared across CHD types and subtypes. Eleven percent of cases had a genetic diagnosis. Among cases without a genetic diagnosis, the majority had conotruncal heart defects (40%) or left ventricular outflow tract obstruction (21%). Across CHD types, there were significant differences (p<0.05) in the distribution of all four case characteristics (e.g., sex), four parental characteristics (e.g., maternal pregestational diabetes), and five neurodevelopmental outcomes (e.g., learning disabilities). Several characteristics (e.g., sex) were also significantly different across CHD subtypes. The PCGC cohort is one of the largest CHD cohorts available for the study of genetic determinants of risk and outcomes. The majority of cases do not have a genetic diagnosis. This description of the PCGC cohort, including differences across CHD types and subtypes, provides a reference work for investigators who are interested in collaborating with or using publically available resources from the PCGC.

Concepts: Gene, Heart, Hypertrophic cardiomyopathy, Down syndrome, Congenital heart defect, Congenital heart disease, Tetralogy of Fallot, Hypoplastic left heart syndrome


On autopsy, a patient is found to have hypertrophic cardiomyopathy. The patient’s family pursues genetic testing that shows a “likely pathogenic” variant for the condition on the basis of a study in an original research publication. Given the dominant inheritance of the condition and the risk of sudden cardiac death, other family members are tested for the genetic variant to determine their risk. Several family members test negative and are told that they are not at risk for hypertrophic cardiomyopathy and sudden cardiac death, and those who test positive are told that they need to be regularly monitored for cardiomyopathy . . .

Concepts: DNA, Genetics, Human genome, Death, Biology, Cardiac arrest, Hypertrophic cardiomyopathy, Sudden cardiac death


Hypertrophic cardiomyopathy is a common inherited cardiovascular disease present in one in 500 of the general population. It is caused by more than 1400 mutations in 11 or more genes encoding proteins of the cardiac sarcomere. Although hypertrophic cardiomyopathy is the most frequent cause of sudden death in young people (including trained athletes), and can lead to functional disability from heart failure and stroke, the majority of affected individuals probably remain undiagnosed and many do not experience greatly reduced life expectancy or substantial symptoms. Clinical diagnosis is based on otherwise unexplained left-ventricular hypertrophy identified by echocardiography or cardiovascular MRI. While presenting with a heterogeneous clinical profile and complex pathophysiology, effective treatment strategies are available, including implantable defibrillators to prevent sudden death, drugs and surgical myectomy (or, alternatively, alcohol septal ablation) for relief of outflow obstruction and symptoms of heart failure, and pharmacological strategies (and possibly radiofrequency ablation) to control atrial fibrillation and prevent embolic stroke. A subgroup of patients with genetic mutations but without left-ventricular hypertrophy has emerged, with unresolved natural history. Now, after more than 50 years, hypertrophic cardiomyopathy has been transformed from a rare and largely untreatable disorder to a common genetic disease with management strategies that permit realistic aspirations for restored quality of life and advanced longevity.

Concepts: Genetics, Cancer, Disease, Cardiology, Heart, Stroke, Atrial fibrillation, Hypertrophic cardiomyopathy


The heart either hypertrophies or dilates in response to familial mutations in genes encoding sarcomeric proteins, which are responsible for contraction and pumping. These mutations typically alter calcium-dependent tension generation within the sarcomeres, but how this translates into the spectrum of hypertrophic versus dilated cardiomyopathy is unknown. By generating a series of cardiac-specific mouse models that permit the systematic tuning of sarcomeric tension generation and calcium fluxing, we identify a significant relationship between the magnitude of tension developed over time and heart growth. When formulated into a computational model, the integral of myofilament tension development predicts hypertrophic and dilated cardiomyopathies in mice associated with essentially any sarcomeric gene mutations, but also accurately predicts human cardiac phenotypes from data generated in induced-pluripotent-stem-cell-derived myocytes from familial cardiomyopathy patients. This tension-based model also has the potential to inform pharmacologic treatment options in cardiomyopathy patients.

Concepts: DNA, Gene, Evolution, Cardiomyopathy, Vector space, Hypertrophic cardiomyopathy, Mouse, Dilated cardiomyopathy


The classic Morrow technique for hypertrophic obstructive cardiomyopathy (HOCM) in patients with simultaneous obstruction of left ventricular (LV) midcavity and right ventricular outflow tract (RVOT) combined with extreme left ventricular hypertrophy, is not effective. A new technique for HOCM surgical correction in patients with severe hypertrophy is proposed.

Concepts: Cardiology, Cardiomyopathy, Left-wing politics, Left ventricular hypertrophy, Hypertrophic cardiomyopathy, Political spectrum, Hypertrophy


Asymmetric septal hypertrophic cardiomyopathy (ASH) is the common phenotype of hypertrophic cardiomyopathy (HCM). We sought to classify ASH using magnetic resonance imaging (MRI) and to determine whether the MRI classification of ASH is related to the presence of risk factors for HCM. Ninety-three patients with ASH underwent cine and delayed-enhancement MRI. The ASH was classified morphologically using cine MRI at end-diastole. We evaluated the association between the MRI findings and the presence of risk factors in the ASH. The ASH was classified into three subtypes by MRI: contiguous subtype showing various clinical and MRI features (57%), sigmoid subtype (29%) with fewer risk factors, and reverse-curve subtype (14%) in younger patients with the larger myocardial mass and delayed-enhancement, which were significantly related to the risk factors. MRI was used to classify ASH into three subtypes, which might be related to the presence of risk factors.

Concepts: Nuclear magnetic resonance, Magnetic resonance imaging, Hypertrophic cardiomyopathy