Testing For Hypertrophic Cardiomyopathy Research Articles

A New Era in Clinical Genetic Testing for Hypertrophic Cardiomyopathy

Building on seminal studies of the last 20 years, genetic testing for hypertrophic cardiomyopathy (HCM) has become a clinical reality in the form of targeted exonic sequencing of known disease-causing genes. This has been driven primarily by the decreasing cost of sequencing, but the high profile of genome-wide association studies, the launch of direct-to-consumer genetic testing, and new legislative protection have also played important roles. In the clinical management of hypertrophic cardiomyopathy, genetic testing is primarily used for family screening. An increasing role is recognized, however, in diagnostic settings: in the differential diagnosis of HCM; in the differentiation of HCM from hypertensive or athlete's heart; and more rarely in preimplantation genetic diagnosis. Aside from diagnostic clarification and family screening, use of the genetic test for guiding therapy remains controversial, with data currently too limited to derive a reliable mutation risk prediction from within the phenotypic noise of different modifying genomes. Meanwhile, the power of genetic testing derives from the confidence with which a mutation can be called present or absent in a given individual. This confidence contrasts with our more limited ability to judge the significance of mutations for which co-segregation has not been demonstrated. These variants of "unknown" significance represent the greatest challenge to the wider adoption of genetic testing in HCM. Looking forward, next-generation sequencing technologies promise to revolutionize the current approach as whole genome sequencing will soon be available for the cost of today's targeted panel. In summary, our future will be characterized not by lack of genetic information but by our ability to effectively parse it.

Exercise in Hypertrophic Cardiomyopathy

The risk of sudden cardiac death (SCD) associated with vigorous athletic competition in individuals with hypertrophic cardiomyopathy (HCM) is well documented, and is the basis for recommended exclusion from competitive sports independent of other risk factors. Although SCD risk with recreational exercise is less well defined, published guidelines for participation in recreational sports, based on a consensus of expert opinion, offer a valuable framework for counseling patients. Exercise stress testing is an important diagnostic and prognostic tool in the evaluation of HCM patients, providing an objective measure of functional capacity, physiologic hemodynamic responses to stress, presence of ischemia, and provocable left ventricular outflow tract obstruction. The value of cardiopulmonary exercise testing in HCM is less well studied than in the heart failure population, but can be used to set a safe target for exercise intensity as part of an individualized exercise prescription. The long-term effects of exercise on HCM pathophysiology are largely theoretical at this stage. Potential harmful effects of fatiguing exercise include prolonged contractile dysfunction resulting from microvascular ischemia and energetic compromise. Conversely, several animal studies have shown that voluntary exercise prevents or reverses many pathologic features of HCM, including those related to apoptosis and energetics. Substantial evidence for health-promoting benefits of exercise in the general population, in addition to promising safety and efficacy data in patients with chronic heart failure, emphasizes the need to attain a reasonable balance between potential risks and benefits of aerobic fitness in individuals with HCM.

A Good Idea: A Physician’s Perspective on Genetic Counseling for Hypertrophic Cardiomyopathy

In this special issue of the Journal of Cardiovascular Translational Research, two articles provide a pediatric and an adult perspective on genetic counseling for evaluation of patients with hypertrophic cardiomyopathy. The articles by Demo et al. (“Genetic counseling and testing for hypertrophic cardiomyopathy: the pediatric perspective”) and Skrzynia (“Genetic counseling and testing for hypertrophic cardiomyopathy: an adult perspective”) provide important viewpoints on genetic counseling with specific examples of this application in patients and families suspected of having or definitively having genetic forms of hypertrophic cardiomyopathy. These articles provide thoughtful overviews of many positive contributions of genetic counseling to clinical care of cardiac patients, while also outlining some of the present limitations to widespread implementation of cardiac genetic counseling. I would like to highlight several key issues from a physician’s perspective for genetic counseling in this circumstance.

Genetic Counseling and Testing for Hypertrophic Cardiomyopathy: An Adult Perspective

Hypertrophic cardiomyopathy (HCM) is considered to be a genetic disease. As such, multidisciplinary approach is needed to evaluate and treat this condition. We present several patient vignettes to illustrate the complementary skills of cardiologists and genetic counselors in providing comprehensive care. Translational application of research will continue to expand as more genetic causes of HCM will be recognized and more genetic tests will become available. Now is the opportunity to build a strong collaboration between the two disciplines to be prepared for the era of personalized medicine.

Genetic Counseling and Testing for Hypertrophic Cardiomyopathy: the Pediatric Perspective

Hypertrophic cardiomyopathy (HCM) is a common cardiac disease that is now being identified in the pediatric population. The etiology of this disease is largely genetic, and as a result, genetics professionals are becoming more involved in the management of these patients. We present multiple case scenarios that highlight the complex nature of this disease and how genetic counselors and cardiologists can interact to identify the genetic etiology of HCM and provide comprehensive care for these patients. Additionally, we describe knowledge gaps in this field and how research endeavors can assist in more effectively managing this patient cohort.

Uptake of genetic counselling and predictive DNA testing in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is a common autosomal dominant disease, associated with heart failure and arrhythmias predisposing to sudden cardiac death. After the detection of the causal mutation in the proband predictive DNA testing of relatives is possible (cascade screening). Prevention of sudden cardiac death in patients with a high risk by means of an implantable cardioverter defibrillator is effective. In 97 hypertrophic cardiomyopathy families with a sarcomere gene mutation we retrospectively determined uptake of genetic counselling and predictive DNA testing in relatives within 1 year after the detection of the causal mutation in the proband. Uptake of genetic counselling was 39% and did not differ significantly by proband's or relative's gender, nor by young age of the relative (< 18 years) or a family history positive for sudden cardiac death. In second-degree relatives, eligible for predictive DNA testing when the first-degree relative had died, uptake was 27.5% (P = 0.047). Uptake of predictive genetic testing was 39%; conditional uptake of predictive genetic testing was 99%. Uptake of genetic counselling in hypertrophic cardiomyopathy is comparable to uptake in oncogenetics. Conditional uptake of predictive DNA testing, however, is much higher. Because sudden cardiac death can be prevented uptake of genetic counselling in hypertrophic cardiomyopathy should be as high as possible. To achieve this research into the determinants of uptake is needed.

Array-Based Resequencing Assay for Mutations Causing Hypertrophic Cardiomyopathy

Background: Dissecting the complex genetic basis of hypertrophic cardiomyopathy (HCM) may be key to both better understanding and optimally managing this most prevalent genetic cardiovascular disease. An array-based resequencing (ABR) assay was developed to facilitate genetic testing in HCM.Methods: An Affymetrix resequencing array and a single long-range PCR protocol were developed to cover the 3 most commonly affected genes in HCM, MYH7 (myosin, heavy chain 7, cardiac muscle, beta), MYBPC3 (myosin binding protein C, cardiac), and TNNT2 [troponin T type 2 (cardiac)].Results: The assay detected the underlying point mutation in 23 of 24 reference samples and provided pointers toward identifying a G insertion and a 3-bp deletion. The comparability of array-based assay results to conventional capillary sequencing was ≥99.9%. Both techniques detected 1 heterozygous variant that was missed by the other method.Conclusions: The data provide evidence that ABR can substantially reduce the high workload previously associated with a genetic test for HCM. Therefore, the HCM array could facilitate large-scale studies aimed at broadening the understanding of the genetic and phenotypic diversity of HCM and related cardiomyopathies.

Genetic testing in cardiac disease: from bench to bedside

Although genetic testing for hypertrophic cardiomyopathy and long QT syndrome is now clinically available, are we ready to reap the practical benefits of these molecular discoveries? How can genetic testing for heritable cardiovascular disorders improve the care of our patients now and in the future? As Allison Cirino and Carolyn Ho outline in this month's Viewpoint, the best is yet to come for genetic testing in cardiac disease.

The value of changes in QRS width and in ST-T segment during exercise test in hypertrophic cardiomyopathy for identification of associated coronary artery disease

Objectives Non-invasive methods cannot reliably predict the presence of coronary artery disease (CAD) in hypertrophic cardiomyopathy (HCM). This study aims to define the accuracy of QRS width changes versus standard ST-T criteria for recognition of associated ischemic CAD in patients with HCM undergoing exercise testing (ET). Methods A retrospective study including patients with HCM. HCM was defined by left ventricular hypertrophy (LVH) of unknown etiology of at least 15 mm. Coronary angiography was performed as a gold standard for definition of CAD (≥ 70% obstruction in at least one major artery). QRS width duration was measured at peak ET by a computerized method employing an optical scanner. No changes in QRS width or shortening during ET were considered normal; QRS width prolongation of more than 3 ms was defined as abnormal. Results 68 patients (56/12 M/F) aged 60 ± 12 y were studied. During ET, abnormal QRS response was found in 40 (58.8%) and Ischemic ST-T changes in 52 (76.5%) patients. CAD in at least one artery was diagnosed in 31 patients (45.5%). The sensitivity of QRS width versus ST-T changes during ET for associated CAD was 82% and 28%, respectively. Specificity was 75% and 48%, respectively. Positive and negative predictive values were 88%; 68% for QRS width and 67%; 59% for ST-T changes respectively. Conclusions In patients with HCM undergoing ET, the association with CAD was more accurately predicted by an increase in QRS complex width than by standard criteria of ST-T segment changes. Thus, its use should be encouraged, especially in patients with HCM.

Yield of Genetic Testing in Hypertrophic Cardiomyopathy

Yield of Genetic Testing in Hypertrophic Cardiomyopathy

Yield of Genetic Testing in Hypertrophic Cardiomyopathy

To determine the clinical parameters of hypertrophic cardiomyopathy (HCM) that correlated significantly with the presence of an identifiable sarcomeric mutation. Previous comprehensive mutational analyses of all protein-coding exons of 8 sarcomeric genes revealed pathogenic mutations in 147 (38%) of 389 unrelated patients seen at the HCM outpatient clinic at the Mayo Clinic in Rochester, Minn, between April 1997 and December 2001. Clinical data, extracted from patient records and blinded to patient genotype, were maintained in a custom database. In 389 unrelated patients, younger age at diagnosis, family history of HCM, and Increasing left ventricular wall thickness were all associated with Increased likelihood of identifying an HCM-associated sarcomeric mutation. In contrast, family history of sudden cardiac death, myectomy status, and anatomical subtype did not correlate significantly with genotype-positive status. With use of a simple scoring system based on age at diagnosis, left ventricular wall thickness, and family history of HCM, the likelihood of a sarcomeric mutation could be estimated. Clinical predictors of positive genotype, such as the presence of an implantable cardioverter-defibrillator, age at diagnosis, degree of left ventricular wall hypertrophy, and family history of HCM, may aid in patient selection for genetic testing and increase the yield of cardiac sarcomere gene screening.

Genetics and cardiomyopathy: where are we now?

Many cases of cardiomyopathy have a genetic component: 90% of cases of hypertrophic cardiomyopathy are familial, and genetic factors may be responsible for 30% to 50% of cases of dilated cardiomyopathy. Clinical genetic testing for hypertrophic cardiomyopathy is becoming available, with significant implications for the clinician. This article gives an overview of how these genetic discoveries were made and how these new insights from genetics will affect clinical practice.

Der plötzliche Herztod bei familiärer hypertropher Kardiomyopathie

Hypertrophic cardiomyopathy (HCM) is a relatively frequent, genetically determined primary cardiomyopathy, characterized by most often asymmetric hypertrophy of the ventricular septum with or without systolic obstruction of the left ventricular outflow tract. HCM is a genetically heterogeneous disease, with 12 different disease-causing genes beeing indentified to date. Histologically the disease is characterized by hypertophy and disarray of myofibrils as well as by an increase in myocardial fibrosis. Clinically, these changes may lead to palpitations, dyspnoe on exertion, and/or angina pectoris. However, they also lead to an increased propensity to the development of severe ventricular tachyarrhythmias and sudden cardiac death. The incidence of sudden death is significantly increased in HCM, particularly in affected young subjects. Risk stratification in HCM should include a complete clinical-cardiological evaluation that should also consider new diagnostic features, e. g. MR imaging. Major risk factors for sudden cardiac death include a survived cardiac arrest (ventricular fibrillation), non-sustained and sustained ventricular tachycardia, a history of premature familial sudden death, unexplained syncope, an abnormal blood pressure response on exercise, and left ventricular thickness greater than or equal to 3 cm. Ideally, risk stratification should also include genetic testing, since some gene mutations seem to be associated with a higher risk for sudden cardiac death than others. However, genetic testing in HCM in not yet available on a routine basis. The implantation of a cardioverter/defibrillator is first-line therapy in patients with documented ventricular tachycardia/fibrillation or patients who have survived sudden cardiac death. These devices also play an important role in the primary prevention of sudden cardiac death in HCM. Algorithms and scores are available to estimate the risk of sudden death, however, the decision to implant a cardioverter/defibrillator remains an individual decision in every single patient.

Plasma N-Terminal Pro-Brain Natriuretic Peptide is a sensitive marker of functional severity in hypertrophic cardiomyopathy

Objectives: This study sought to determine the diagnostic utility of measurement of plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with hypertrophic cardiomyopathy (HCM), and the capacity of the method to assess the severity of left ventricular (LV) dysfunction. Background: Plasma BNP is useful in heart failure and HCM. Plasma NT-proBNP has been increasingly used in cardiac diseases but there is no report of NT-proBNP measurement in HCM. Methods: We studied 70 ambulatory patients (mean age 32.6±11.4 years) with HCM (septal thickness >15mm, a non-dilated LV with normal ejection fraction). 15 (21.4%) patients had a resting outflow gradient >30mmHg (obstructive) and 55 did not have (non- obstructive). A control group of 20 normal volunteers age and sex matched were enrolled. The pts were examined by Doppler echocardiography and a blood sample was drawn for NT-proBNP measurement (electrochemiluminescence immunoassay Roche). Comparisons were made between HCM and normals, and between subgroups of HCM. Correlations were verified between levels of NT-proBNP and echocardiographic variables. Results: In the HCM group, the mean plasma NT-proBNP was 1312±1364 pg/ml, versus 41.2±28.3 pg/ml in the control group (p<0.0001). The levels of the peptide were correlated with LA diameter (r=0.39; p=0.001), septal thickness (r=0.24; p=0.04). There was no linear correlation with obstruction but there were differences in the concentrations of NT-proBNP between obstructive (2116±1812 pg/ml) and non-obstructive (1103±1176 pg/ml) HCM groups (p=0.02). Patients with Doppler derived signs of LV filling pressure elevation presented higher levels of NT-proBNP than the others. Conclusions: Measurement of plasma NT-proBNP in HCM pts is a sensitive method for diagnosis and functional evaluation. Further studies are necessary to verify the prognostic value of the test in HCM.

Metabolic exercise testing in hypertrophic cardiomyopathy: relation of submaximal parameters to clinical features

Metabolic exercise testing in hypertrophic cardiomyopathy: relation of submaximal parameters to clinical features

An Ethical Debate: Testing may be unhelpful

Once a mutation associated with hypertrophic cardiomyopathy has been identified in a family testing children at risk becomes relatively simple. Ryan and colleagues are aware that such presymptomatic testing is regarded by some as ethically contentious but argue that there are sufficient benefits to justify it. We disagree with this position, but are not opposed to all such testing. We carry out predictive genetic testing programmes in children for some conditions. The case for genetic testing for hypertrophic cardiomyopathy in neonates has not, however, been made. Firstly, there is a potential confusion concerning the word “screening.” We believe that the term genetic screening should be restricted to mass testing of populations or specific groups when the benefits are known and should not be applied to family based testing. The ethical approval for the project will have been granted for a research study aiming at identifying genetic defects giving rise to hypertrophic cardiomyopathy. Did this approval extend to the use of genetic testing of children at risk in a carrier family? Such testing, where there is no clear benefit to the child, should be regarded as a research procedure …

Exercise testing in hypertrophic cardiomyopathy

Exercise testing in hypertrophic cardiomyopathy

Genetic Testing for Hypertrophic Cardiomyopathy

Genetic Testing for Hypertrophic Cardiomyopathy

Treadmill stress test in hypertrophic cardiomyopathy

Treadmill stress test in hypertrophic cardiomyopathy

QRS alterations immediately following production of left ventricular free-wall ischemia in dogs.

QRS alterations immediately following production of left ventricular free-wall ischemia in dogs.