A Case of Inappropriate Therapies for Atrial Flutter From a Subcutaneous ICD

Hypertrophic cardiomyopathy’s (HCM) association with sudden cardiac death is well recognised. The risk of sudden cardiac death is known to increase when there is a history of unexplained syncope, abnormal blood pressure response during exercise, severe left ventricular hypertrophy or a family history of unexplained death.Implantable Cardioverter Defibrillator (ICD) implantation has been widely used for primary and secondary prevention of sudden cardiac death (SCD) in people with HCM. Subcutaneous ICD (S-ICD) therapy has been developed to overcome some of the problems associated with the transvenous leads used in conventional ICDs.In this article, we report the use of S-ICD in a patient with HCM and multiple risk factors for sudden cardiac death, this device had to be extracted due to recurrent inappropriate shocks caused by over sensing of atrial flutter and failure to treat a VT episode. We are not aware of any reports of inappropriate shocks caused by atrial flutter in people with a S-ICD.     

Preventing sudden death and the use of prophylactic implanted defibrillators

Implanted defibrillators have become mainstream therapy for the prevention of sudden cardiac death from ventricular tachyarrhythmias. A decade of studies has confirmed the superiority of ICDs over antiarrhythmic drug therapy in prolonging the life of patients with a prior history of sustained VT or VF. More recent studies have compared ICD therapy to drugs or no antiarrhythmic therapy as 'primary prophylaxis' in patients considered at high risk for sudden death or with prior MIs. In selected patients, ICDs lead to important relative and absolute reductions in mortality in patients with no prior history of sustained VT or VF. Clinicians need to carefully consider these studies in their management of patients with CAD and severe LV dysfunction.     

Hypertrophic cardiomyopathy in daily practice: an introduction on diagnosis,prognosis and treatment

Hypertrophic cardiomyopathy (HCM) is a complex, inherited cardiac disease that has been subject to intense investigation since it was first described in 1957. Over the past 40 years, understanding has evolved regarding the diagnosis, prognosis and treatment of HCM. Analyses of HCM populations from nonreferral centres have refined the insights into the natural history and the occurrence of sudden cardiac death, which is the most devastating component of its natural history. Therapeutic strategies are diverse and may vary during the course of the disease. Optimal therapy depends on symptoms, haemodynamic findings and the presence of risk factors for sudden cardiac death. At present, invasive therapy for patients with obstructive HCM and drug-refractory symptoms includes surgery or percutaneous transluminal septal myocardial ablation.This report summarises the diagnostic criteria, clinical course and therapeutic management of HCM. Attention is also paid to certain issues of special interest in this disease.     

Beyond the cardiac myofilament: hypertrophic cardiomyopathy- associated mutations in genes that encode calcium-handling proteins

Traditionally regarded as a genetic disease of the cardiac sarcomere, hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease and a significant cause of sudden cardiac death. While the most common etiologies of this phenotypically diverse disease lie in a handful of genes encoding critical contractile myofilament proteins, approximately 50% of patients diagnosed with HCM worldwide do not host sarcomeric gene mutations. Recently, mutations in genes encoding calcium-sensitive and calcium-handling proteins have been implicated in the pathogenesis of HCM. Among these are mutations in TNNC1- encoded cardiac troponin C, PLN-encoded phospholamban, and JPH2-encoded junctophilin 2 which have each been associated with HCM in multiple studies. In addition, mutations in RYR2-encoded ryanodine receptor 2, CASQ2-encoded calsequestrin 2, CALR3-encoded calreticulin 3, and SRI-encoded sorcin have been associated with HCM, although more studies are required to validate initial findings. While a relatively uncommon cause of HCM, mutations in genes that encode calcium-handling proteins represent an emerging genetic subset of HCM. Furthermore, these naturally occurring disease-associated mutations have provided useful molecular tools for uncovering novel mechanisms of disease pathogenesis, increasing our understanding of basic cardiac physiology, and dissecting important structure-function relationships within these proteins.     

Termination of Ventricular Tachycardia with Antitachycardia Pacing after Ineffective Shock Therapy in an ICD Recipient with Hypertrophic Cardiomyopathy

Implantable Cardioverter Defibrillator (ICD) implantation is the only established therapy for primary or secondary prevention of sudden cardiac death in patients with Hypertrophic Cardiomyopathy (HCM). Ineffectiveness of shock therapy for the termination of potentially fatal ventricular arrhythmias in ICD recipients is rare in the presence of appropriate arrhythmia detection by the device. We report the case of a 48-year-old woman with HCM and a single chamber ICD, who received five inefficient high-energy (35 Joules) shocks for the termination of an appropriately detected episode of Ventricular Tachycardia (VT). The episode was safely terminated with a subsequent application of Antitachycardia Pacing (ATP) by the device. At the following ICD control, an acceptable defibrillation threshold was detected.     

Mutation-specific pathology and treatment of hypertrophic cardiomyopathy in patients,mouse models and human engineered heart tissue

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and is characterized by asymmetric left ventricular hypertrophy and diastolic dysfunction, and a frequent cause of sudden cardiac death at young age. Pharmacological treatment to prevent or reverse HCM is lacking. This may be partly explained by the variety of underlying disease causes. Over 1500 mutations have been associated with HCM, of which the majority reside in genes encoding sarcomere proteins, the cardiac contractile building blocks. Several mutation-mediated disease mechanisms have been identified, with proof for gene- and mutation-specific cellular perturbations. In line with mutation-specific changes in cellular pathology, the response to treatment may depend on the underlying sarcomere gene mutation. In this review, we will discuss evidence for mutation-specific pathology and treatment responses in HCM patients, mouse models and engineered heart tissue. The pros and cons of these experimental models for studying mutation-specific HCM pathology and therapies will be outlined.     

Familial screening and genetic counselling in hypertrophic cardiomyopathy: the Rotterdam experience

Hypertrophic cardiomyopathy (HCM) is a disease characterised by unexplained left ventricular hypertrophy (LVH) (i.e. LVH in the absence of another cardiac or systemic disease that could produce a similar degree of hypertrophy), electrical instability and sudden death (SD). Germline mutations in genes encoding for sarcomere proteins are found in more than half of the cases of unexplained LVH. The autosomal dominant inherited forms of HCM are characterised by incomplete penetrance and variability in clinical and echocardiographic features, prognosis and therapeutic modalities. The identification of the genetic defect in one of the HCM genes allows accurate presymptomatic detection of mutation carriers in a family. Cardiac evaluation of at-risk relatives enables early diagnosis and identification of those patients at high risk for SD, which can be the first manifestation of the disease in asymptomatic persons. In this article we present our experience with genetic testing and cardiac screening in our HCM population and give an overview of the current literature available on this subject. (Neth Heart J 2007;15:184-9.)     

Primary prevention by implantable cardioverter defibrillators: shock proof?

In the last two decades, the focus of implantable cardioverter defibrillator {ICD} trials has mainly been on prophylactic implantation of ICDs in high-risk populations for the prevention of sudden cardiac death. In particular, prophylactic ICDs in high-risk post-MI patients with a depressed left ventricular ejection fraction has resulted in significantly improved survival. These benefits are in addition to those of optimal pharmacological therapy and ICD therapy should be considered the standard of care in these patients.     

Dutch outcome in implantable cardioverter-defibrillator therapy (DO-IT): registry design and baseline characteristics of a prospective observational cohort study to predict appropriate indication for implantable cardioverter-defibrillator

Background

Implantable cardioverter-defibrillators (ICDs) are widely used for the prevention of sudden cardiac death. At present, both clinical benefit and cost-effectiveness of ICD therapy in primary prevention patients are topics of discussion, as only a minority of these patients will eventually receive appropriate ICD therapy.

Methods/design

The DO-IT Registry is a nationwide prospective cohort with a target enrolment of 1,500 primary prevention ICD patients with reduced left ventricular function in a setting of structural heart disease. The primary outcome measures are death and appropriate ICD therapy for ventricular tachyarrhythmias. Secondary outcome measures are inappropriate ICD therapy, death of any cause, hospitalisation for ICD related complications and for cardiovascular reasons. As of December 2016, data on demographic, clinical, and ICD characteristics of 1,468 patients have been collected. Follow-up will continue up to 24 months after inclusion of the last patient. During follow-up, clinical and ICD data are collected based on the normal follow-up of these patients, assuming ICD interrogations take place every six months and clinical follow-up is once a year. At baseline, the mean age was 66 (standard deviation [SD] 10) years and 27% were women.

Conclusion

The DO-IT Registry represents a real-world nationwide cohort of patients receiving ICDs for primary prevention of sudden cardiac death with reduced left ventricular function in a setting of structural heart disease. The registry investigates the efficacy of the current practice and aims to develop prediction rules to identify subgroups who will not (sufficiently) benefit from ICD implantation and to provide results regarding costs and budget impact of targeted supply of primary preventions ICDs.

     

Hypertrophic cardiomyopathy：from gene defect to clinical disease

Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions.Hypertrophic cardiomyopathy(HCM)was the first cardiac disorder in which a genetic basis was identified and as such,has acted as a paradigm for the study of an inherited cardiac disorder.HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death.HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes.At least ten genes have now been identified,defects in which cause HCM.All of these genes encode proteins which comprise the basic contractile unit of the heart,i.e.the sarcomere.While much is now known about which genes cause disease and the various clinical presentations,very little is known about how these gene defects cause disease,and what factors modify the expression of the mutant genes.Studies in both cell culture and animal models of HCM are now beginning to shed light on the signalling pathways involved in HCM,and the role of both environmental and genetic modifying factors.Understanding these mechanisms will ultimately improve our knowledge of the basic biology of heart muscle function,and will therefore provide new avenues for treating cardiovascular disease in man.     

Hypertrophic cardiornyopathy: from gene defect to clinical disease

Major advances have been made over the last decade in our understanding of the molecular basis of several cardiac conditions. Hypertrophic cardiomyopathy (HCM) was the first cardiac disorder in which a genetic basis was identified and as such, has acted as a paradigm for the study of an inherited cardiac disorder. HCM can result in clinical symptoms ranging from no symptoms to severe heart failure and premature sudden death. HCM is the commonest cause of sudden death in those aged less than 35 years, including competitive athletes. At least ten genes have now been identified, defects in which cause HCM. All of these genes encode proteins which comprise the basic contractile unit of the heart, i.e. the sarcomere. While much is now known about which genes cause disease and the various clinical presentations, very little is known about how these gene defects cause disease, and what factors modify the expression of the mutant genes. Studies in both cell culture and animal models of HCM are now beginning to     

Clinical implementation of guidelines for cardioverter defibrillator implantation: lost in translation?

Purpose: Guidelines for implantation of cardioverter defibrillators (ICD) are increasingly including indications for primary prevention of sudden cardiac death in high-risk groups, where ICDs were traditionally implanted for secondary prevention. We performed a single-centre audit to evaluate adherence to the recent Dutch guidelines. Methods: All 1886 patients visiting a large regional Dutch teaching hospital (attending 1.8 to 2.0% of the Dutch population) in November 2005 were screened using the recently updated Dutch guidelines. Patients fulfilling these criteria were categorised as having an ICD indication for primary or secondary prevention. Results: 135 patients had an indication for ICD, 19 of whom had one or received one. Of the remaining 116 patients, 14 were ‘new’ to the department of cardiology. The 102 ‘known’ patients had 466 doctor-patient contacts in the previous year, which averages 4.57 cardiology contacts per patient per year. Patients were more likely to receive an ICD for the secondary prevention of SCD (10/11, 91%) than for primary prevention (9/124, 7%). Conclusion: In a large regional teaching hospital in the Netherlands, only a small proportion of patients eligible for ICD implantation actually receive one. Cardiologists tend to implant ICDs for secondary prevention of SCD. The low ICD implantation rate for primary prevention of SCD may relate to logistics (e.g. permission to implant ICDs, the presence of an electrophysiology lab) or the perceived low cost-benefit ratio. Our results indicate that once the substantial backlog (13,500 ICDs) has been addressed, the annual implantation of new ICDs should rise from the current 125 to at least 510 per million inhabitants per year in the Netherlands. (Neth Heart J 2007;15:129-32.)     

Mice expressing mutant myosin heavy chains are a model for familial hypertrophic cardiomyopathy.

BACKGROUND: Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by ventricular hypertrophy, myocellular disarray, arrhythmias, and sudden death. Mutations in several contractile proteins, including cardiac myosin heavy chains, have been described in families with this disease, leading to the hypothesis that HCM is a disease of the sarcomere. MATERIALS AND METHODS: A mutation in the myosin heavy chain (Myh) predicted to interfere strongly with myosin's binding to actin was designed and used to create an animal model for HCM. Five independent lines of transgenic mice were produced with cardiac-specific expression of the mutant Myh. RESULTS: Although the mutant Myh represents a small proportion (1-12%) of the heart's myosin, the mice exhibit the cardiac histopathology seen in HCM patients. Histopathology is absent from the atria and primarily restricted to the left ventricle. The line exhibiting the highest level of mutant Myh expression demonstrates ventricular hypertrophy by 12 weeks of age, but the further course of the disease is strongly affected by the sex of the animal. Hypertrophy increases with age in female animals while the hearts of male show severe dilation by 8 months of age, in the absence of increased mass. CONCLUSIONS: The low levels of the transgene protein in the presence of the phenotypic features of HCM suggest that the mutant protein acts as a dominant negative. In addition, the distinct phenotypes developed by aging male or female transgenic mice suggest that extragenic factors strongly influence the development of the disease phenotype.     

Ventricular tachycardia prediction in patients with implantable cardioverter-defibrillators for primary prevention of sudden cardiac death

Clinical data analysis of 83 patients with implantable cardioverter-defibrillators (ICDs) for sudden cardiac death (SCD) primary prevention has been done. We revealed 5 parameters associated with the detection of life-threatening ventricular arrhythmias. These parameters formed the basis for constructing a logistic regression model. The model makes it possible to obtain the probability of occurrence of a specific event depending on the severity of the predictive parameters and the degree of its influence (risk of true ventricular arrhythmias detection). Estimating the potential risk of the life-threatening arrhythmias, individual programming options are required in implantable cardioverter-defibrillators (ICDs) to reduce the amount of unnecessary electrotherapy, as well as more accurate monitoring of the patient's drug therapy.     

Risk stratification for sudden cardiac death in hypertrophic cardiomyopathy: Dutch cardiologists and the care of mutation carriers

Background. Patients with hypertrophic cardiomyopathy (HCM) and HCM mutation carriers are at risk of sudden cardiac death (SCD). Both groups should therefore be subject to regular cardiological testing – including risk stratification for SCD – according to international guidelines. We evaluated Dutch cardiologists' knowledge of and adherence to international guidelines on risk stratification and prevention of SCD in mutation carriers with and without manifest HCM. Methods. A questionnaire was sent to 1109 Dutch cardiologists (in training) containing case-based questions. Results. The response rate was 21%. Own general knowledge on HCM care was rated as insufficient by 63% of cardiologists. The percentage of correct answers (i.e. in agreement with international guidelines), on the case-based questions ranged from 37 to 96%, being lowest in cases with an unknown number of risk factors for SCD. A substantial portion of correct answers was based on the correct answer ‘ask an expert opinion’. Significantly more correct answers were provided in cases with manifest HCM. There was little difference between the answers of cardiologists with different self-reported levels of knowledge, with different numbers of HCM patients in their practice or with different numbers of carriers without manifest HCM. Conclusion. Knowledge on risk stratification and preventive therapy was mediocre, and knowledge gaps exist, especially on HCM mutation carriers without manifest disease. Fortunately, experts are frequently asked for their opinion which might bring patient care to an adequate level. Hopefully, our results will stimulate cardiologists to follow developments in this field, thereby increasing quality of care for HCM patients and mutation carriers. (Neth Heart J 2009:17:464–9.).     

A Mutation in TNNC1-encoded Cardiac Troponin C, TNNC1-A31S, Predisposes to Hypertrophic Cardiomyopathy and Ventricular Fibrillation

Defined as clinically unexplained hypertrophy of the left ventricle, hypertrophic cardiomyopathy (HCM) is traditionally understood as a disease of the cardiac sarcomere. Mutations in TNNC1-encoded cardiac troponin C (cTnC) are a relatively rare cause of HCM. Here, we report clinical and functional characterization of a novel TNNC1 mutation, A31S, identified in a pediatric HCM proband with multiple episodes of ventricular fibrillation and aborted sudden cardiac death. Diagnosed at age 5, the proband is family history-negative for HCM or sudden cardiac death, suggesting a de novo mutation. TnC-extracted cardiac skinned fibers were reconstituted with the cTnC-A31S mutant, which increased Ca(2+) sensitivity with no effect on the maximal contractile force generation. Reconstituted actomyosin ATPase assays with 50% cTnC-A31S:50% cTnC-WT demonstrated Ca(2+) sensitivity that was intermediate between 100% cTnC-A31S and 100% cTnC-WT, whereas the mutant increased the activation of the actomyosin ATPase without affecting the inhibitory qualities of the ATPase. The secondary structure of the cTnC mutant was evaluated by circular dichroism, which did not indicate global changes in structure. Fluorescence studies demonstrated increased Ca(2+) affinity in isolated cTnC, the troponin complex, thin filament, and to a lesser degree, thin filament with myosin subfragment 1. These results suggest that this mutation has a direct effect on the Ca(2+) sensitivity of the myofilament, which may alter Ca(2+) handling and contribute to the arrhythmogenesis observed in the proband. In summary, we report a novel mutation in the TNNC1 gene that is associated with HCM pathogenesis and may predispose to the pathogenesis of a fatal arrhythmogenic subtype of HCM.     

Blocking cardiac growth in hypertrophic cardiomyopathy induces cardiac dysfunction and decreased survival only in males

Mutations in myosin heavy chain (MyHC) can cause hypertrophic cardiomyopathy (HCM) that is characterized by hypertrophy, histopathology, contractile dysfunction, and sudden death. The signaling pathways involved in the pathology of HCM have not been elucidated, and an unresolved question is whether blocking hypertrophic growth in HCM may be maladaptive or beneficial. To address these questions, a mouse model of HCM was crossed with an antihypertrophic mouse model of constitutive activated glycogen synthase kinase-3beta (caGSK-3beta). Active GSK-3beta blocked cardiac hypertrophy in both male and female HCM mice. However, doubly transgenic males (HCM/GSK-3beta) demonstrated depressed contractile function, reduced sarcoplasmic (endo) reticulum Ca(2+)-ATPase (SERCA) expression, elevated atrial natriuretic factor (ANF) expression, and premature death. In contrast, female HCM/GSK-3beta double transgenic mice exhibited similar cardiac histology, function, and survival to their female HCM littermates. Remarkably, dietary modification from a soy-based diet to a casein-based diet significantly improved survival in HCM/GSK-3beta males. These findings indicate that activation of GSK-3beta is sufficient to limit cardiac growth in this HCM model and the consequence of caGSK-3beta was sexually dimorphic. Furthermore, these results show that blocking hypertrophy by active GSK-3beta in this HCM model is not therapeutic.     

Surgery for hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a genetically determined cardiac disease characterised by otherwise unexplained myocardial hypertrophy of the left ventricle, and may result in left ventricular outflow tract obstruction. It is the most common cause of sudden cardiac death in young adults due to arrhythmias. Septal myectomy is a surgical treatment for HCM with moderate to severe outflow tract obstruction, and is indicated for patients with severe symptoms refractory to medical therapy. The surgical approach involves obtaining access to the interventricular septum via transaortic, transapical or transmitral approaches, and excising a portion of the hypertrophied myocardium to relieve the outflow tract obstruction. Large, contemporary series from centres experienced in septal myectomy patients have demonstrated a low early mortality of <2 %, excellent long-term survival that matches the general population, and durable relief of symptoms.     

肥厚型心肌病的致病分子机制研究进展

肥厚型心肌病(Hypertrophic cardiomyopathy,HCM)是以左心室及室间隔不对称肥厚为基本特征的原发性心肌病,其发病率约为0.2%,是青少年和运动员心源性猝死的最常见原因。HCM的发病年龄、发病程度和猝死风险等临床表型具有多样性,通常呈常染色体显性遗传。目前已报道的HCM相关突变超过900种,主要定位在β肌球蛋白重链基因、肌球蛋白结合蛋白C基因、心脏肌钙蛋白T基因等13个心脏肌节蛋白基因;另一方面,越来越多的研究显示线粒体基因突变与HCM发生相关。文章在简单介绍HCM形态学特征及临床表型的基础上,着重综述了HCM的致病分子机制及其最新研究进展。     

36 例心源性猝死尸检的临床病理学研究*

目的:分析心源性猝死的临床病理学特征,为心源性猝死的诊断和预防提供理论依据。方法:收集36例心源性猝死病例的尸检解剖资料,进行病理组织学检查。结果:36例心源性猝死者中,冠心病21例,占心源性猝死者总数的58.33%;心律失常性右心室心肌病猝死者3例,占心源性猝死者总数的8.33%。结论:科学系统的尸检可以明确猝死原因,为医疗纠纷鉴定提供可靠依据,同时,对提高医疗质量,早期诊断、治疗心血管系统疾病和减少猝死发生起有重要作用。