Yield of genetic testing in hypertrophic cardiomyopathy

OBJECTIVE: To determine the clinical parameters of hypertrophic cardiomyopathy (HCM) that correlated significantly with the presence of an identifiable sarcomeric mutation. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Hypertrophic cardiomyopathy: a review of etiology and treatment

Hypertrophic cardiomyopathy (HCM) is a congenital cardiac disease with an estimated prevalence of 1:500 in the population. Individuals with HCM can present with clinical manifestations that include left ventricular outflow obstruction, cardiac dysrhythmias, diastolic heart failure, cardiac angina, and sudden cardiac death. Current treatments include pharmacologic intervention to reduce heart rate and ventricular contractility as well as surgery or septal alcohol ablation to reduce myocardial septal size. Implantable cardiac defibrillators are considered a treatment option in individuals with HCM who are at an increased risk for sudden cardiac death. The identification of persons at risk for complications related to HCM is important for reducing mortality and morbidity in this population. In addition, diagnosis of HCM in an individual allows the healthcare provider caring for these patients to screen, educate, and institute timely preventative measures in other members of the family. The purpose of this review is to provide clinicians caring for cardiac patients with a guide for recognition, diagnosis, prevention, and treatment of HCM.     

Arrhythmias associated with electroconvulsive therapy in hypertrophic cardiomyopathy

Patients with hypertrophic cardiomyopathy (HCM) are inherently prone to arrhythmias. Electroconvulsive therapy (ECT), a well-known treatment in psychiatry, leads to a catecholamine surge and may cause arrhythmias in patients with severe coronary and valvular heart diseases and heart failure. Whether ECT is safe in HCM is unknown. We systematically investigated the effects of ECT on the arrhythmia profile and left ventricular outflow obstruction of a HCM patient by serial ambulatory Holter electrocardiograms and echocardiograms before and after ECT. Our observations provide insight into the evaluation and management of a HCM patient undergoing ECT.     

Current perspectives in hypertrophic cardiomyopathy with the focus on patients in the Finnish population: a review

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, with the prevalence of about 1/500. During the last two decades, the knowledge of the etiology, pathogenesis, risk stratification and prevention of sudden death in HCM has substantially advanced. Most often, HCM is familial and caused by mutations in sarcomere genes, inherited in an autosomal dominant manner. In Finland, genetic background of HCM is unique, with a few founder mutations in cardiac sarcomere genes accounting for a considerable proportion of the disease. Pathogenic mechanisms induced by disease-causing mutations are still poorly understood, although alterations in intracellular calcium handling and inefficient generation of contractile force in myocytes are considered key features in triggering the hypertrophic response. Clinical features of the disease are highly variable from no symptoms to the spectrum of exertional dyspnea, angina, palpitations, syncope and sudden death. In the current patient care, implantable cardioverter defibrillators (ICDs) are successfully used to prevent sudden cardiac death in high risk subjects. Targeted genetic testing is recommended to confirm the diagnosis in patients with HCM and to identify family members with the disease. Future research is needed to elucidate key cellular mechanisms leading to HCM, which may allow specific prevention and treatment of the disease.

• Key messages

• Hypertrophic cardiomyopathy, most often caused by defects in sarcomere genes, is the most common inherited heart disease, and a common cause of sudden cardiac death (SCD) in athletes and young subjects.

• Cardiac imaging, ECG and genetic testing are pivotal in the diagnosis of the disease in patients and first-degree relatives.

• Implantable cardioverter defibrillators in patients with high risk for SCD and tailored pharmacotherapy are efficient tools in patient care, but so far, exact mechanisms leading to cardiac hypertrophy in HCM are only partially understood, and there is no curative treatment for the disease.

     

Isolated left ventricular non-compaction, not hypertrophic cardiomyopathy

Sir, Hypertrophic cardiomyopathy (HCM) is a relatively common cardiacdisease (1:500 in the general population), which both generalphysicians and cardiologists encounter frequently in clinicalpractice. However, there are conditions that may mimic HCM (Table 1).We describe a patient with an initial diagnosis of hypertrophiccardiomyopathy. Further investigations several years later revealedan alternative     

Clinical Utility of Cardiovascular Magnetic Resonance in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is characterized by substantial genetic and phenotypic heterogeneity, leading to considerable diversity in clinical course including the most common cause of sudden death in young people and a determinant of heart failure symptoms in patients of any age. Traditionally, two-dimensional echocardiography has been the most reliable method for establishing a clinical diagnosis of HCM. However, cardiovascular magnetic resonance (CMR), with its high spatial resolution and tomographic imaging capability, has emerged as a technique particularly well suited to characterize the diverse phenotypic expression of this complex disease. For example, CMR is often superior to echocardiography for HCM diagnosis, by identifying areas of segmental hypertrophy (ie., anterolateral wall or apex) not reliably visualized by echocardiography (or underestimated in terms of extent). High-risk HCM patient subgroups identified with CMR include those with thin-walled scarred LV apical aneurysms (which prior to CMR imaging in HCM remained largely undetected), end-stage systolic dysfunction, and massive LV hypertrophy. CMR observations also suggest that the cardiomyopathic process in HCM is more diffuse than previously regarded, extending beyond the LV myocardium to include thickening of the right ventricular wall as well as substantial morphologic diversity with regard to papillary muscles and mitral valve. These findings have implications for management strategies in patients undergoing invasive septal reduction therapy. Among HCM family members, CMR has identified unique phenotypic markers of affected genetic status in the absence of LV hypertrophy including: myocardial crypts, elongated mitral valve leaflets and late gadolinium enhancement. The unique capability of contrast-enhanced CMR with late gadolinium enhancement to identify myocardial fibrosis has raised the expectation that this may represent a novel marker, which may enhance risk stratification. At this time, late gadolinium enhancement appears to be an important determinant of adverse LV remodeling associated with systolic dysfunction. However, the predictive significance of LGE for sudden death is incompletely resolved and ultimately future large prospective studies may provide greater insights into this issue. These observations underscore an important role for CMR in the contemporary assessment of patients with HCM, providing important information impacting diagnosis and clinical management strategies.     

Uncommon cause of a common disease

Myocardial infarction is a common life-threatening condition. Multiple agents can be used to treat acute coronary syndrome (ACS). These therapeutic agents pose potential life-threatening complications when used outside the realm of the acute coronary syndrome. Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disorder, occurring in 1 in 500 individuals, which may mimic ACS. The hypertrophy most typically involves the septum in patients with HCM. As many as 25% of Japanese patients with HCM have predominately apical involvement. Apical hypertrophic cardiomyopathy (AHC) occurs in only 1 to 2% of the non-Japanese population. Despite its low incidence, physicians caring for patients with chest pain need to consider AHC in their differential diagnosis. We present the case of a patient with chest pain and electrocardiographic changes suggestive of ACS who was later found to have AHC.     

Secondary myocardial hypertrophy in newborn infants and infants without congenital heart defect

Secondary hypertrophic cardiomyopathy (HCM) was diagnosed in 55 newborns and infants without heart disease. The 17 newborn infants of diabetic mothers, 23 infants given ACTH treatment for infantile spasms, 9 ventilated premature infants or babies with bronchopulmonary dysplasia and 6 infants with different underlying diseases comprising this group underwent 2-dimensional echocardiography. In almost all cases echocardiographic evidence of HCM resolved after removal of the exogenous or endogenous causative factor. Myocardial effects of several substances are known and their pathophysiological mechanisms are discussed. Since HCM may precede systemic disease or may often be the first pointer to a triggering agent, further diagnostic procedures are always indicated. Hence, the diagnosis of primary HCM should be made by exclusion.     

Hypertrophic cardiomyopathy associated with sleep apnea: serious implications and cogent management strategy

Obstructive sleep apnea (OSA) affects an estimated 20 million adult Americans and is present in a large proportion of patients with hypertension and in those with other cardiovascular disorders, including hypertrophic cardiomyopathy (HCM). This review seeks to highlight concepts and evidence important to understanding the interactions between OSA and HCM, with particular attention to more recent advances in patient-oriented research. Studies of patients with HCM have found the prevalence of sleep-disordered breathing to range from 40 to 80%. Increased sympathetic activity, impaired vagal activity, increased afterload, insulin resistance and endothelial dysfunction have been proposed as potential mechanisms for the association. Specific questions include whether OSA is important in unmasking symptoms in hitherto undiagnosed patients with HCM, whether OSA in patients with established HCM accelerates disease progression and whether treatment of OSA results in clinical improvement, fewer cardiovascular events and reduced mortality. Because obesity, cardiovascular disease, metabolic syndrome, and diabetes are often present in patients with OSA, it can be difficult to attribute abnormalities evident in the sleep apnea patient with HCM to the effects of OSA, the effects of HCM or synergies between these conditions. Although further research is needed to answer these specific questions, recent investigations have clearly shown the coexistence of OSA and HCM, as well as elucidated the contribution of heightened sympathetic nerve activity in OSA to drug-refractory symptoms and worsening left ventricular outflow tract obstruction. This review aims to highlight the current literature available on the association of OSA and HCM, provide directions for future research and summarize the key features related to this association based on the authors’ best understanding and experience.     

The role of imaging in the diagnosis and management of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy, affecting approximately 1:500 people. As the yield of genetic testing is only about 35–60%, the diagnosis of HCM is still clinical and based on the demonstration of unexplained and usually asymmetric left ventricular (LV) hypertrophy by imaging modalities. In the past, echocardiography was the sole imaging modality used for the diagnosis and management of HCM. However, in recent years other imaging modalities such as cardiac magnetic resonance have played a major role in the diagnosis, management and risk stratification of HCM, particularly when the location of left ventricular hypertrophy is atypical (apex, lateral wall) and when the echocardiographic imaging is sub-optimal. However, the most unique contribution of cardiac magnetic resonance is the quantification of myocardial fibrosis. Exercise stress echocardiography is the preferred provocative test for the assessment of LV outflow tract obstruction, which is detected only on provocation in one-third of the patients.     

The diagnosis of hypertrophic cardiomyopathy by cardiovascular magnetic resonance

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the heart. HCM is characterized by a wide range of clinical expression, ranging from asymptomatic mutation carriers to sudden cardiac death as the first manifestation of the disease. Over 1000 mutations have been identified, classically in genes encoding sarcomeric proteins. Noninvasive imaging is central to the diagnosis of HCM and cardiovascular magnetic resonance (CMR) is increasingly used to characterize morphologic, functional and tissue abnormalities associated with HCM. The purpose of this review is to provide an overview of the clinical, pathological and imaging features relevant to understanding the diagnosis of HCM. The early and overt phenotypic expression of disease that may be identified by CMR is reviewed. Diastolic dysfunction may be an early marker of the disease, present in mutation carriers prior to the development of left ventricular hypertrophy (LVH). Late gadolinium enhancement by CMR is present in approximately 60% of HCM patients with LVH and may provide novel information regarding risk stratification in HCM. It is likely that integrating genetic advances with enhanced phenotypic characterization of HCM with novel CMR techniques will importantly improve our understanding of this complex disease.     

Cost Efficacy of α-Galactosidase A Enzyme Screening for Fabry Disease

The prevalence of Fabry disease (FD) in adult patients with suspected hypertrophic cardiomyopathy (HCM) has been reported between 0.3% and 4%. Fabry disease–specific therapy necessitates early diagnosis; however, the optimal screening strategy and cost efficacy of routine α-galactosidase A (α-gal A) vs comprehensive galactosidase alpha gene (GLA) testing remain poorly understood. We identified 1192 patients who underwent routine α-gal A screening between January 1, 2011, and December 31, 2017, for suspected HCM. Cost efficacy was explored using prevalence and cost estimates. Ten patients had reduced α-gal A enzyme activity, and 5 (3 women) were ultimately diagnosed with FD (prevalence estimate, 0.42%). An alternative cardiac diagnosis was made in 3 patients with mildly reduced enzyme activity. Two women with reduced borderline enzyme levels did not undergo confirmatory testing, but FD was not suspected. The number needed to screen to diagnose 1 patient with FD in a similar cohort is estimated at 238 (5 new cases per 1192 at-risk individuals) at a cost of approximately US $24,000 per diagnosis. We identified a 0.42% prevalence of FD using routine α-gal A screening in adult patients referred to a dedicated HCM center in the United States. Compared with more comprehensive genetic testing strategies, we identified a similar prevalence of FD at a lower cost per diagnosis.     

深度学习及影像组学在肥厚型心肌病中的应用进展

肥厚型心肌病(HCM)是最常见的非缺血性心肌病之一。超声心动图(UCG)和心脏MR(CMR)等是诊断HCM的主要影像学方法，但分析HCM图像较为繁琐，且需要进行鉴别诊断，导致诊断难度增加。近年来，深度学习和影像组学在智能化诊断HCM、自动化处理图像、预测基因型及心肌纤维化等方面发挥重要作用。本文对深度学习和影像组学技术在HCM中的应用进展进行综述。     

Athlete’s heart or hypertrophic cardiomyopathy?

Intensive endurance training is able to cause a distinct pattern of functional and structural changes of the cardiovascular system. In an unknown proportion of athletes a so called “athlete’s heart” develops. There is an overlap between this type of physiologic cardiac hypertrophy and mild forms of hypertrophic cardiomyopathy (HCM), the most common genetic disorder of the cardiovascular system with a prevalence of 0.2%. HCM is caused by mutations in 14 genes coding for sarcomere proteins. In the literature up to 50% of cases of sudden cardiac death (SCD) in younger sportsmen were connected to hypertrophic cardiomyopathy. It is therefore the most common cause of SCD in highly trained young athletes. Because of this data a great interest in distinguishing these two diagnoses exists. Apart from clinical examination and some non-specific ECG-changes, Echocardiography is the method of choice. The athlete’s heart shows an eccentric biventricular hypertrophy with wall thicknesses under 15 mm and a moderately dilated left ventricle (LVEDD up to 58 mm). HCM is commonly characterized by asymmetric left ventricular hypertrophy with a reduced LV-diameter. In up to 70% of cases left ventricular outflow tract obstruction is evident during stress echocardiography. Systolic function is normal in highly trained athletes and the majority of HCM patients as well. There are important differences regarding diastolic filling patterns. Physiological hypertrophy is consistent with a normal diastolic function with even increased early diastolic filling. In case of HCM diastolic dysfunction (mostly relaxation disturbances) occurs in the majority of patients and is therefore inconsistent with an athlete’s heart. If the diagnosis could not be stated using echocardiography, methods like cardiac-MRI, metabolic exercise testing, histological studies of endomyocardial biopsies and genetic testing can provide further information. A correct diagnosis may on the one hand prevent some athletes from sudden cardiac death. On the other hand sportsmen with an athlete’s heart are reassured and able to continue as competitors. New insights into electrophysiological changes during physiological hypertrophy could probably change this view.     

MR心肌应变力技术在肥厚型心肌病诊断及鉴别诊断中的应用研究

目的应用心脏磁共振组织追踪(cardiac magnetic resonance tissue tracking,CMR-TT)技术定量评价肥厚型心肌病(hypertrophic cardiomyopathy,HCM)患者与心肌淀粉样变性(cardiac amyloidosis,CA)所致左心室肥厚患者心肌功能,并分析...     

Douleur et sant�� mentale : quels traitements ?

Treating each patient??s pain is an important part of quality care. Although patients in psychiatry have their own characteristics which make each step of the diagnosis, the evaluation and the treatment of their pain not that simple, there is no contraindication to prescribe usual therapies for them. Nevertheless, some specific iatrogenic interactions have to be known to make the best therapeutic choice.     

Characterization of a Phenotype-Based Genetic Test Prediction Score for Unrelated Patients With Hypertrophic Cardiomyopathy

ObjectivesTo determine the prevalence and spectrum of mutations and genotype-phenotype relationships in the largest hypertrophic cardiomyopathy (HCM) cohort to date and to provide an easy, clinically applicable phenotype-derived score that provides a pretest probability for a positive HCM genetic test result.Patients and MethodsBetween April 1, 1997, and February 1, 2007, 1053 unrelated patients with the clinical diagnosis of HCM (60% male; mean ± SD age at diagnosis, 44.4±19 years) had HCM genetic testing for the 9 HCM-associated myofilament genes. Phenotyping was performed by review of electronic medical records.ResultsOverall, 359 patients (34%) were genotype positive for a putative HCM-associated mutation in 1 or more HCM-associated genes. Univariate and multivariate analyses identified the echocardiographic reverse curve morphological subtype, an age at diagnosis younger than 45 years, a maximum left ventricular wall thickness of 20 mm or greater, a family history of HCM, and a family history of sudden cardiac death as positive predictors of positive genetic test results, whereas hypertension was a negative predictor. A score, based on the number of predictors of a positive genetic test result, predicted a positive genetic test result ranging from 6% when only hypertension was present to 80% when all 5 positive predictor markers were present.ConclusionIn this largest HCM cohort published to date, the overall yield of genetic testing was 34%. Although all the patients were diagnosed clinically as having HCM, the presence or absence of 6 simple clinical/echocardiographic markers predicted the likelihood of mutation-positive HCM. Phenotype-guided genetic testing using the Mayo HCM Genotype Predictor score provides an easy tool for an effective genetic counseling session.     

Preexcitation in Hypertrophic Cardiomyopathy: A Case of a Fasciculoventricular Mahaim Fiber

STELLBRINK, C., et al .: Preexcitation in Hypertrophic Cardiomyopathy: A Case of a Fasciculoventricular Mahaim Fiber . A patient with hypertrophic cardiomyopathy (HCM) who presented with preexcitation pattern on the surface ECG suggestive of the Wolff-Parkinson-White (WPW) syndrome is described. Intracardiac electrophysiological study revealed a fixed anomalous QRS complex and a short fixed His-ventricular interval indicating a fasciculoventricular Mahaim fiber. As this specific form of accessory connection does not cause reentrant tachycardias, no treatment was required. It is important to distinguish this entity from atriofascicular or nodoventricular Mahaim fibers or the WPW syndrome in patients with HCM showing a preexcitation pattern in the surface ECG, as these may cause life-threatening arrhythmias in this patient population.     

心脏超声造影在肥厚型心肌病冠状动脉微循环功能评价中的应用及影响因素

目的应用心脏超声造影评价肥厚型心肌病（HCM）患者冠状动脉微循环功能,并探讨其可能的影响因素。 方法选取2013年9月至2019年7月于哈尔滨医科大学附属第一医院就诊的HCM患者82例,所有患者均行二维经胸超声心动图（2D-TTE）及左心声学造影（LVO）检查,评估2种方法对HCM的诊断率。应用心肌声学造影（MCE）评价HCM冠状动脉微循环功能。采用单因素分析及多因素Logistic回归方法分析HCM患者冠状动脉微循环功能异常的独立预测因子。 结果82例HCM患者中,2D-TTE诊断率为76.0%（62/82）;LVO诊断率为91.5%（75/82）,2者差异有统计学意义（P<0.001）。13例心尖肥厚型HCM患者中,2D-TTE诊断率为61.5%（8/13）;LVO诊断率为77.0%（10/13）,2者差异有统计学意义（P=0.035）。82例HCM患者中,MCE检出冠状动脉微循环功能障碍60例,冠状动脉微循环功能异常发生率为73.1%（60/82）。依据MCE结果将82例患者分为冠状动脉微循环功能正常组（22例）与异常组（60例）。多因素Logistic回归分析结果显示,超敏肌钙蛋白I（hs-cTnI）升高为HCM患者冠状动脉微循环功能异常的独立预测因子（OR=1.13,95%CI：1.01~1.34,P=0.03）。 结论LVO可提高HCM患者的诊断率,MCE是评价HCM患者冠状动脉微循环功能障碍的可行和有效方法,hs-cTnI升高对HCM患者冠状动脉微循环功能障碍具有独立预测价值。     

Prognosis of hypertrophic and dilated cardiomyopathy

Hypertrophic and dilated cardiomyopathies are a heterogeneous disease, both clinically and genetically. Hypertrophic cardiomyopathy(HCM) is important causes of sudden cardiac death and death from congestive heart failure, although HCM has a relatively benign prognosis. The prognosis of dilated cardiomyopathy(DCM) has improved due to advances in earlier diagnosis and therapy, however, sudden cardiac death and death from congestive heart failure still occur in DCM. Accordingly, it is of importance to know possible risk factors on risk stratification for a high-risk group in HCM and DCM. Possible risk factors may contribute to the construction of therapeutic strategies for the prevention of sudden cardiac death or death from congestive heart failure in patients with HCM and DCM.