Testing For Hypertrophic Cardiomyopathy Research Articles

Perspectives on current recommendations for genetic testing in HCM.

[first paragraph of article]Hypertrophic cardiomyopathy (HCM) is defined as a primary cardiac muscle disease characterized by the presence of myocardial hypertrophy in the absence of apparent causes for the observed degree of hypertrophy. This definition includes both familial and sporadic (apparently non-familial) forms of the disease. HCM is usually considered as a genetically determined condition. Current genotyping technologies allow for the identification of the genetic causes of the disease in 50 to 70% of the patients who fulfill clinical diagnostic criteria. However, the etiology of 30 to 40% of the cases remains elusive. This review is focused on the current role of genetic testing in HCM, and the potential benefits of the identification of the genetic etiology of the disease.

The genetics of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is most commonly transmitted as an autosomal dominant trait, caused by mutations in genes encoding cardiac sarcomere proteins1–3. Other inheritable causes of the disease include mutations in genes coding for proteins important in calcium handling or that form part of the cytoskeleton4–6. At present, the primary clinical role of genetic testing in HCM is to facilitate familial screening to allow the identification of individuals at risk of developing the disease7,8. It is also used to diagnose genocopies, such as lysosomal9–11 and glycogen storage disease which have different treatment strategies, rates of disease progression and prognosis12–14. The role of genetic testing in predicting prognosis is limited at present, but emerging data suggest that knowledge of the genetic basis of disease will assume an important role in disease stratification15–17 and offer potential targets for disease-modifying therapy in the near future18.

The utility of the Mayo Score for predicting the yield of genetic testing in patients with hypertrophic cardiomyopathy.

IntroductionThe yield of genetic testing in hypertrophic cardiomyopathy (HCM) is variable. The Mayo HCM Genotype Predictor score (Mayo Score) provides the pre-test probability of a positive HCM genetic test. In the original cohort of Mayo Score patients, only 9 HCM-associated myofilament genes were evaluated. The aim of this study was to validate the Mayo Score in the national HCM cohort and assess the yield of genetic testing using next generation sequencing (NGS) evaluating up to 229 genes.Material and methodsWe included 336 consecutive unrelated HCM patients (41% women, mean age: 53 ±15 years). We performed NGS-based genomic testing with classification of identified variants according to American College of Medical Genetics and Genomics guidelines. NGS findings were compared with the Mayo Score (ranging from –1 to 5) based on clinical and echocardiographic variables.ResultsWe identified 72 variants classified as pathogenic or likely pathogenic in 70 (21%) HCM patients. One patient with the highest Mayo Score of 5 had a pathogenic mutation (100% yield). Patients with a Mayo Score of 4 had a pathogenic mutation in 71% of cases. Patients with a Mayo Score of 3 or 2 had a pathogenic mutation in 50 and 35% of cases, respectively. The yield of genetic testing in patients with a Mayo Score of –1 to 1 was low (6–21%).ConclusionsThe overall yield of genetic testing using NGS evaluating up to 229 genes was low. The yield of genetic testing was consistently predicted with Mayo Score values.

Two decades of genetic testing in hypertrophic cardiomyopathy in a single center: The additive value of extended next-generation sequencing panels lies in the early diagnosis of metabolic mimics

Two decades of genetic testing in hypertrophic cardiomyopathy in a single center: The additive value of extended next-generation sequencing panels lies in the early diagnosis of metabolic mimics

Genetics of hypertrophic cardiomyopathy: A review of current state.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease. HCM is a highly complex and heterogeneous disease regarding not only the number of associated mutations but also the severity of phenotype, symptom burden, and the risk of complications, such as heart failure and sudden death. The penetrance is incomplete and it is age and gender dependent. It is accepted as a disease of the sarcomere. Sixty percent of HCM cases carry mutations in 1 of 8 sarcomere protein genes, mainly non-sense MYBPC3 and missense MYH7 variants. Young patients with severe phenotype and other clinical features are included in proposed scores for prediction of high positive genetic result. The number of genes reported as disease-causing has increased in the last few years, in some cases without robust evidence. Currently available in silico tools are not always useful for differentiation between benign and deleterious variants. There is enough information on genotype-phenotype correlations to start understanding the mechanisms of the disease. Genetic and environmental modifiers have been explored with some interesting insights from miRNA studies with potential as biomarkers and therapeutic agents. There is an additional value of genetic testing in HCM for prognosis. Knowledge about genetics and functional studies are the basis of near future therapies.

Safety profile and utility of treadmill exercise in patients with high-gradient hypertrophic cardiomyopathy

Exercise echocardiography in the evaluation of hypertrophic cardiomyopathy (HCM) provides valuable information for risk stratification, selection of optimal treatment, and prognostication. However, HCM patients with left ventricular outflow tract gradients ≥30mm Hg are often excluded from exercise testing because of safety considerations. We examined the safety and utility of exercise testing in patients with high-gradient HCM. We evaluated clinical characteristics, hemodynamics, and imaging variables in 499 consecutive patients with HCM who performed 959 exercise tests. Patients were divided based on peak left ventricular outflow tract gradients using a 30-mm Hg threshold into the following: obstructive (n=152), labile-obstructive (n=178), and nonobstructive (n=169) groups. There were no deaths during exercise testing. We noted 20 complications (2.1% of tests) including 3 serious ventricular arrhythmias (0.3% of tests). There was no difference in complication rate between groups. Patients with obstructive HCM had a higher frequency of abnormal blood pressure response (obstructive: 53% vs labile: obstructive: 41% and nonobstructive: 37%; P=.008). Obstructive patients also displayed a lower work capacity (obstructive: 8.4±3.4 vs labile obstructive: 10.9±4.2 and nonobstructive: 10.2±4.0, metabolic equivalent; P<.001). Exercise testing provided incremental information regarding sudden cardiac death risk in 19% of patients with high-gradient HCM, and we found a poor correlation between patient-reported functional class and work capacity. Our results suggest that exercise testing in HCM is safe, and serious adverse events are rare. Although numbers are limited, exercise testing in high-gradient HCM appears to confer no significant additional safety hazard in our selected cohort and could potentially provide valuable information.

Abstract 243: A Novel PRKAG2 Mutation (K475E): Infantile-onset Hypertrophic Cardiomyopathy Phenotype and Impact on mTOR Signaling

Objective: PRKAG2 encodes the 2 subunit isoform of the 5’ AMP-activated protein kinase (AMPK), a heterotrimeric enzyme with major roles in regulation of energy metabolism in response to cellular stress. Mutations in PRKAG2 have been implicated in a unique hypertrophic cardiomyopathy (HCM) characterized by cardiac glycogen overload and hypertrophy. We identified a novel PRKAG2 mutation in a neonate with prenatal onset of HCM noted on a 27-week prenatal ultrasound. Molecular testing for HCM revealed a de novo PRKAG2 mutation (K475E). We aim to investigate the signaling pathway of mutation in PRKAG2 gene. Methods: HEK-293 and H9C2 cells stably expressing wild type (WT) or K475E FLAG-tagged 2 from a tetracycline-inducible promoter were established. Basal AMPK activities were measured at varying AMP concentrations. Phenformin-stimulated AMPK activity and T172-phosphorylation were also measured. Changes in mTOR signaling pathway were accessed by Western blot. Cells were treated with angiotensin II, rapamycin (RAPA) or both followed by staining or flow cytometry to assess cell area/size. Primary fibroblasts from the K475E patient and non-diseased controls were cultured and compared. Finally, transgenic mice with cardiac-specific overexpression of human wild type (Tg WT ) or K475E (TgK 475E ) were established for further study of the PRKAG2 phenotype by histology and echocardiography. Result: HEK-293 cells: K475E mutation induced a markedly increase in the basal AMPK activity and T172-phosphorylation, reduced sensitivity to AMP in allosteric activation and loss of response to phenformin. H9c2 cells: K475E mutation induced increases in the phosphorylation of p-P70S6K, p-4EBP1 and a hypertrophy phenotype which was reversed by RAPA. Transgenic mice: Tg K475E mice had an early onset hypertrophy and were prone to sudden death. Histology revealed large vacuoles and high glycogen content in Tg K475E myocytes throughout the ventricles. Echocardiography confirmed significantly enlarged heart in Tg K475E mice. Conclusions: We identified a novel infantile-onset PRKAG2 mutation with a severe cardiac phenotype. In vitro study revealed involvement of mTOR signaling pathway and reversal of the hypertrophy phenotype by mTOR inhibitor.

Clinical correlates of autonomic response during tilting test in hypertrophic cardiomyopathy.

The aim is to investigate autonomic nervous system imbalance in hypertrophic cardiomyopathy (HCM) by combining echocardiographic morphological and functional parameters with the analysis of the autonomic responses to orthostatic stress. A 10-min tilting test and a transthoracic echocardiogram focused on ventricular septal systolic (S wave) and diastolic function (isovolumic relaxation time) were performed. Low frequency on high frequency ratio (LF/HF) and RR variation (variation of beat to beat intervals) in response to passive orthostatism were used as measures of sympathetic reflex activation [delta LF/HF (D-LF/HF) and delta RR (DRR), respectively]. Brain natriuretic peptide was measured. A total of 50 HCM patients were categorized in two groups: D-LF/HF more than 0 (group 1, sympathetic response) and D-LF/HF 0 or less (group 2, parasympathetic response). Patients in group 2 had higher New York Heart Association class, a more frequent history of atrial fibrillation (38 versus 9% P = 0.04) or syncope (46 versus 12% P = 0.01) and an increased septal isovolumic relaxation time (122 versus 82 ms P = 0.02). The same categorization was made according to lowest quartile DRR (DRR at least 23 ms, group 1: sympathetic response; DRR less than 23 ms, group 2: parasympathetic response). In group 2, patients were older, with advanced New York Heart Association class and higher history of atrial fibrillation. Autonomic response to passive orthostatism in HCM appears correlated with specific functional features of the hypertrophic heart. Altered neural afferent traffic from the localized area of segmental hypertrophy resulted in autonomic changes with a blunted sympathetic response, and an inappropriate vagal activation, especially in patients with history of atrial fibrillation or syncope.

Diagnostic impact of genetic testing in hypertrophic cardiomyopathy: The story of two families

Diagnostic impact of genetic testing in hypertrophic cardiomyopathy: The story of two families

Application of Genetic Testing in Hypertrophic Cardiomyopathy for Preclinical Disease Detection.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular diseases, with a prevalence of at least 1 in 500 in the general population.1,2 HCM is characterized by left ventricular hypertrophy, in the absence of other loading conditions, such as hypertension.3 The hallmark feature of HCM is significant clinical heterogeneity in presentation, ranging from asymptomatic patients to those who have the most serious outcomes of heart failure and sudden cardiac death. Over 1500 mutations in at least 15 sarcomere-encoding genes have been identified.4–7 The significance of cardiac genetic testing in clinical practice is 2-fold. For the proband, identification of the underlying genetic cause in some cases can clarify the cause of hypertrophy, for example, clarifying phenocopies, such as PRKAG2-glycogen storage disease and Fabry disease. The greatest utility, however, is in cascade genetic testing of asymptomatic relatives, with clear benefits either for confirming a borderline clinical diagnosis, or suspicious clinical changes suggestive of early disease, or most importantly ruling out the disease in those who test gene-negative. Identification of a silent gene carrier will guide cascade testing of additional family members, in effect clarifying their risk status. Of most benefit, a negative genetic result can reassure offspring that they are not at risk of HCM. The escalation in our understanding of the genetic basis of HCM has been catalyzed by the implementation of next generation sequencing technologies. In response to faster and more affordable testing, commercial genetic testing for HCM now often comprises vast cardiac gene chips (ie, 50–200 or more genes). This approach, although comprehensive, also draws into sharp focus the limitations of our current knowledge. The challenges of cardiac genetic testing are increasingly documented, such as identification of variants of uncertain significance (VUS), incidental genetic findings,8 reclassification of variants,9 increased need …

Cardiopulmonary Responses and Prognosis in Hypertrophic Cardiomyopathy: A Potential Role for Comprehensive Noninvasive Hemodynamic Assessment

ObjectivesThis study sought to discover the key determinants of exercise capacity, maximal oxygen consumption (oxygen uptake [Vo2]), and ventilatory efficiency (ventilation/carbon dioxide output [VE/Vco2] slope) and assess the prognostic potential of metabolic exercise testing in hypertrophic cardiomyopathy (HCM). BackgroundThe intrinsic mechanisms leading to reduced functional tolerance in HCM are unclear. MethodsThe study sample included 156 HCM patients consecutively enrolled from January 1, 2007 to January 1, 2012 with a complete clinical assessment, including rest and stress echocardiography and cardiopulmonary exercise test (CPET) with impedance cardiography. Patients were also followed for the composite outcome of cardiac-related death, heart transplant, and functional deterioration leading to septal reduction therapy (myectomy or septal alcohol ablation). ResultsAbnormalities in CPET responses were frequent, with 39% (n = 61) of the sample showing a reduced exercise tolerance (Vo2 max <80% of predicted) and 19% (n = 30) characterized by impaired ventilatory efficiency (VE/Vco2 slope >34). The variables most strongly associated with exercise capacity (expressed in metabolic equivalents), were peak cardiac index (r = 0.51, p < 0.001), age (r = –0.25, p < 0.01), male sex (r = 0.24, p = 0.02), and indexed right ventricular end-diastolic area (r = 0.31, p = 0.002), resulting in an R2 of 0.51, p < 0.001. Peak cardiac index was the main predictor of peak Vo2 (r = 0.61, p < 0.001). The variables most strongly related to VE/VCO2 slope were E/E′ (r = 0.23, p = 0.021) and indexed left atrial volume index (LAVI) (r = 0.34, p = 0.005) (model R2 = 0.15). The composite endpoint occurred in 21 (13%) patients. In an exploratory analysis, 3 variables were independently associated with the composite outcome (mean follow-up 27 ± 11 months): peak Vo2 <80% of predicted (hazard ratio: 4.11; 95% confidence interval [CI]: 1.46 to 11.59; p = 0.008), VE/Vco2 slope >34 (hazard ratio: 3.14; 95% CI: 1.26 to 7.87; p = 0.014), and LAVI >40 ml/m2 (hazard ratio: 3.32; 95% CI: 1.08 to 10.16; p = 0.036). ConclusionsIn HCM, peak cardiac index is the main determinant of exercise capacity, but it is not significantly related to ventilatory efficiency. Peak Vo2, ventilatory inefficiency, and LAVI are associated with an increased risk of major events in the short-term follow-up.

Gene database for the development of genetic testing for hypertrophic cardiomyopathy

Background Hypertrophic cardiomyopathy (HCM) is a disease characterised by hypertrophy of the left ventricle of the heart. HCM has a prevalence of ~1 in 500 in the general population and is the leading cause of sudden cardiac death (SCD). Mutations in 30 genes have been found to be associated with HCM and accounting for 50-60% genetic causes [1]; etiologies of a larger percentage of HCM still remain unknown. These observations prompted us to create a gene database on genes implicated in HCM and to predict the function of the mutated genes. The findings of more new genes directly or indirectly implicated in HCM will be more helpful in developing comprehensive genetic tests for HCM.

Clinical predictors of a positive genetic test in hypertrophic cardiomyopathy in the Brazilian population

BackgroundHypertrophic cardiomyopathy is a genetic autosomal dominant disease characterized by left ventricular hypertrophy. The molecular diagnosis is important but still expensive. This work aimed to find clinical predictors of a positive genetic test in a Brazilian tertiary centre cohort of index cases with HCM.MethodsIn the study were included patients with HCM clinical diagnosis. For genotype x phenotype comparison we have evaluated echocardiographic, electrocardiographic, and nuclear magnetic resonance measures. All patients answered a questionnaire about familial history of HCM and/or sudden death. β-myosin heavy chain, myosin binding protein C, and troponin T genes were sequenced for genetic diagnosis.ResultsThe variables related to a higher probability of a positive genetic test were familial history of HCM, higher mean heart frequency, presence of NSVT and lower age. Probabilities of having a positive molecular genetic test were calculated from the final multivariate logistic regression model and were used to identify those with a higher probability of a positive molecular diagnosis.ConclusionsWe developed an easy and fast screening method that takes into account only clinical data that can help to select the patients with a high probability of positive genetic results from molecular sequencing of Brazilian HCM patients.

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

Major advances have been made in our understanding and clinical application of genetic testing in hypertrophic cardiomyopathy. Determining pathogenicity of a single-nucleotide variant remains a major clinical challenge. This study sought to reassess single-nucleotide variant classification in hypertrophic cardiomyopathy probands. Consecutive probands with hypertrophic cardiomyopathy with a reported pathogenic mutation or variation of uncertain significance were included. Family and medical history were obtained. Each single-nucleotide variant was reassessed by a panel of four reviewers for pathogenicity based on established criteria together with updated cosegregation data and current population-based allele frequencies. From 2000 to 2012, a total of 136 unrelated hypertrophic cardiomyopathy probands had genetic testing, of which 63 (46%) carried at least one pathogenic mutation. MYBPC3 (n = 34; 47%) and MYH7 (n = 23; 32%) gene variants together accounted for 79%. Five variants in six probands (10%) were reclassified: two variation of uncertain significance were upgraded to pathogenic, one variation of uncertain significance and one pathogenic variant were downgraded to benign, and one pathogenic variant (found in two families) was downgraded to variation of uncertain significance. None of the reclassifications had any adverse clinical consequences. Given the rapid growth of genetic information available in both disease and normal populations, periodic reassessment of single-nucleotide variant data is essential in hypertrophic cardiomyopathy.

Clinical Implication of Genetic Testing for Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is caused by a dominant mutation of the sarcomere protein gene in approximately 60% of cases. Genetic testing of HCM has several benefits. Diagnosis can be confirmed if the sarcomere protein gene mutation is identified. Genetic testing enables to follow-up blood relatives who are mutationpositive only, and can identify asymptomatic and non-onset patients. Relatives with negative results of genetic testing could be freed from anguish. On the other hand, genetic testing has some disadvantages. Treatment often does not change after testing. Forty percent of cases has unknown causative genes. Relationship between gene mutation and clinical findings or treatment responsiveness is little known, and so on. Many issues need to be resolved to incorporate genetic diagnosis into daily practice for HCM. However, genetic testing for HCM cannot be regarded as unnecessary and expensive debauchery, but rather represents a valuable measure in the medical facilities. Although there still remain questions about genetic diagnosis of HCM, accumulated knowledge to date is fairly enough to establish the genetic testing as a useful tool for individualized management of HCM patients and their families.

Utility of Genetic Testing in Hypertrophic Cardiomyopathy in a Statewide Service

Utility of Genetic Testing in Hypertrophic Cardiomyopathy in a Statewide Service

Clinical relevance of genetic testing in hypertrophic cardiomyopathy

More than two decades have elapsed since the discovery that sarcomere gene defects cause familial hypertrophic cardiomyopathy (HCM). Since then, genetic testing in HCM has developed, and become an important tool in clinical practice for diagnosis and prognosis overall in the Western countries. However its practical benefits are still understimated and clinicians often question about cost-effectiveness of genic testing in HCM patients and their families. This resistance is in contrast with considerable evidence supporting the role of genetics in tailoring management for HCM patients. Several current clinical uses of genetic testing in HCM, ranging from diagnosis in ambiguous situations, identification of disease phenocopies and HCM complex genotypes and confirmation of inherited disease in family members are reviewed. In the near future it is hoped that next generation sequencing will provide further diffusion of genetic testing in HCM and improvement in care.

Letter by Dimitrow and Cheng Regarding Article, “Exercise Testing in Nonatherosclerotic Heart Disease: Hypertrophic Cardiomyopathy, Valvular Heart Disease, and Arrhythmias”

To the Editor: In the review1 on exercise testing in nonatherosclerotic heart disease, the important role of upright position during exercise stress test in hypertrophic cardiomyopathy to provoke left ventricular (LV) outflow tract gradient (LVOTG) was not mentioned. Changing position from supine to standing may provoke LVOTG by reduction of LV preload and may induce the symptom of presyncope. Standing position during exercise, especially in a stress test using the more natural treadmill instead of the less natural supine bicycle, reflects the physiological condition during …

Genetic Testing for Hypertrophic Cardiomyopathy: Ongoing Voyage from Exploration to Clinical Exploitation

More than two decades have elapsed since the discovery that sarcomere gene defects cause familial hypertrophic cardiomyopathy (HCM). Since then, genetic testing in HCM has developed and expanded, and is now widely available as a potential clinical service in the Western countries. In the meantime, however, the cross-talk between geneticists and clinicians has developed slowly, and still remains unstandardized, with modalities of interaction and degree of mutual comprehension that vary wildly in various settings. In addition, clinicians often question the clinical utility of genetic testing in HCM patients and their families. The apparent lack of practical benefit, in the face of considerable costs, has long hindered large-scale diffusion of genetic testing, particularly in developing countries, and still accounts for understandable (but not always justifiable) resistance on the part of the physicians. However, such resistance is in contrast with considerable evidence supporting a role for molecular diagnosis in tailoring management for HCM patients. We here review several sound clinical reasons in favour of systematic genetic testing in HCM, ranging from identification of complex genotypes, heralding severe disease expression and outcome, to the added benefit of multidisciplinary genetic teamwork, enhancing awareness towards inheritable diseases in the cardiology community. We hope to show that to underestimate the clinical potential of genetic testing in HCM, and to defer its implementation until more advanced knowledge becomes available, is to lose an important opportunity for present improvement in care.

Genetics and Clinical Destiny: Improving Care in Hypertrophic Cardiomyopathy

The greatest opportunity afforded by discovering the genetic basis of human heart disease is accurate prediction and prevention of illness. Hypertrophic cardiomyopathy (HCM) provides a paradigm to fulfill this opportunity. Human genetics research has identified many gene mutations that result in cardiac hypertrophy, of which HCM is the most common and well-characterized. Sarcomere gene mutations in HCM result in left ventricular hypertrophy (LVH), myocardial fibrosis and disarray, diastolic dysfunction, and increased risk for arrhythmias, sudden death, and heart failure. Making the clinical diagnosis of HCM currently hinges on identifying unexplained hypertrophy, but LVH is a sign of established disease only. This finding cannot identify at-risk mutation carriers and cannot discriminate HCM from other forms of cardiac hypertrophy, either genetic or acquired. Response by Landstrom on p 2440 In contrast, gene-based diagnosis is not constrained in this manner. Defining the mutation that causes LVH in an individual provides an accurate diagnosis for that patient and, therefore, considerable information about their prognosis. Moreover, unlike clinical diagnosis which only identifies overt disease, genetic diagnosis can also identify patients at risk for developing disease. There are certainly many challenges to realizing the full potential of genetics, but such information provides unprecedented promise. Continued efforts to refine and clinically implement genetic testing in HCM will bring important payoffs in the future, and will serve as a model for other genetic cardiovascular diseases. By identifying at-risk individuals prior to clinical diagnosis, characterizing disease pathogenesis, and fostering development of novel therapies to delay or prevent phenotypic expression, genetic discoveries will improve the lives of our patients with HCM. ### Genetics of HCM The familial, autosomal-dominant nature of HCM has long been recognized, but the precise genetic etiology was discovered through genome-wide linkage studies in the 1980s. This seminal work identified pathogenic mutations in genes encoding contractile proteins and established the paradigm …