Guidelines for the diagnosis and management of familial dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a myocardial disorder that is a major cause of heart failure and death. Recent data indicate that genetic factors are important in the pathogenesis of DCM and may account for at least one-third of cases of "idiopathic" DCM. Apart from a positive family history, there are no specific clinical manifestations that reliably distinguish familial from non-familial DCM, and phenotypic features may vary between families and within members of a single family. Clinical screening with ECG and echocardiography of all first-degree relatives of index cases with "idiopathic" DCM is strongly recommended to identify familial disease and to determine the number of affected individuals within families. Molecular genetics studies have shown that familial DCM is a genetically-heterogeneous disorder with nearly 40 chromosomal loci and disease genes identified to date. Mutations in the known disease genes occur relatively infrequently however. Although commercial genetic testing for selected disease genes is available, the cost and low yield have limited its widespread use. The development of next-generation sequencing technologies promises to expedite the discovery of new DCM disease genes and help to take genetic testing from the research laboratory into routine clinical practice. Affected individuals should receive standard pharmacological therapy according to the severity of symptoms and signs of heart failure. Asymptomatic family members should undergo periodic echocardiographic screening to detect early signs of disease. The optimal management of asymptomatic individuals with suspected early disease is not yet established.     

Non-ischaemic dilated cardiomyopathy: recognising the genetic links

The landscape of genetically related cardiac disease continues to evolve. Heritable genetic variants can be a primary cause of familial or sporadic dilated cardiomyopathy (DCM). There is also increasing recognition that genetic variation is an important determinant of susceptibility to acquired causes of DCM. Genetic forms of DCM can show a wide variety of phenotypic manifestations. Identifying patients who are most likely to benefit from genetic testing is paramount. The objective of this review is to highlight the importance of recognising genetic DCM, key genotype–phenotype correlations and the value of genetic testing in clinical management for both the individual and their family. This is likely to become more relevant as management strategies continue to be refined with genotype-specific recommendations and disease-modifying therapies.     

扩张型心肌病的分期及其临床意义

目的 :探讨扩张型心肌病 (DCM)的临床分期 ,评价 DCM不同阶段干预治疗的效果。方法 :将来自国内16所医院的 DCM患者 2 2 1例 ,按 NYHA心功能分级标准进行临床分期 :无心力衰竭 (心衰 )期 ,心衰期和心衰晚期。采用随机单盲安慰剂对照试验 ,在心衰治疗基础上 ,加用地尔硫 6 0 m g/ d或安慰剂 ,借助心肌病分期方案 ,评价地尔硫对 DCM的干预试验。结果 :单纯治疗心衰对于 DCM无心衰期患者的心功能参数没有显著性影响 ,心衰期患者心功能参数均明显减退 ,心衰晚期患者心功能参数无明显变化。加用地尔硫治疗 DCM,能够显著改善无心衰期和心衰期患者的心功能参数 ,而心衰晚期患者心功能参数无明显改善。预后分析发现安慰剂组需要反复住院治疗人数和病死率均显著高于地尔硫组。结论 :对 DCM进行临床分期 ,有助于疾病的早期诊断和全面评价干预试验 ,具有临床实用价值。应用地尔硫对 DCM早期干预 ,将改变 DCM自然进程 ,提高患者生活质量和生存率。     

Dilated cardiomyopathies and non-compaction cardiomyopathy

Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy and one of the most common causes of heart failure. It is characterized by left or biventricular dilation and a reduced systolic function. The causes are manifold and range from myocarditis to alcohol and other toxins, to rheumatological, endocrinological, and metabolic diseases. Peripartum cardiomyopathy is a special form that occurs at the end of or shortly after pregnancy. Genetic mutations can be detected in approximately 30–50% of DCM patients. Owing to the growing possibilities of genetic diagnostics, increasingly more triggering variants and hereditary mechanisms emerge. This is particularly important with regard to risk stratification for patients with variants with an increased risk of arrhythmias. Patient prognosis is determined by the occurrence of heart failure and arrhythmias. In addition to the treatment of the underlying disease or the elimination of triggering harmful toxins, therapy consists in guideline-directed heart failure treatment including drug and device therapy.     

抗心律失常药在心力衰竭中的临床应用

医疗水平提升使心脏病患者的生存期延长,心力衰竭患病率亦呈上升趋势。心力衰竭患者常见并发心律失常,且发生心脏性猝死(SCD)的风险极高。如何防治心力衰竭,尤其是射血分数降低的心力衰竭(HFrEF)患者的心律失常及SCD,是临床面临的棘手问题。抗心律失常药的不良反应极大地限制了其在心力衰竭并心律失常中的临床应用,且药物防治SCD的作用极为有限。本文从临床角度,简述了近年来有关心力衰竭与心律失常的关联、抗心律失常药在心力衰竭临床应用的最新观点,为临床医师提供参考。     

Dilated cardiomyopathy: from epidemiologic to genetic phenotypes

Dilated cardiomyopathy (DCM) is characterized by left ventricular dilatation and, consecutively, contractile dysfunction. The causes of DCM are heterogeneous. DCM often results from myocarditis, exposure to alcohol, drugs or other toxins and metabolic or endocrine disturbances. In about 35% of patients, genetic mutations can be identified that usually involve genes responsible for cytoskeletal, sarcomere and nuclear envelope proteins. Due to its heterogeneity, a detailed diagnostic work‐up is necessary to identify the specific underlying cause and exclude other conditions with phenotype overlap. Patients with DCM show typical systolic heart failure symptoms, but, with progress of the disease, diastolic dysfunction is present as well. Depending on the underlying pathology, DCM patients also become apparent through arrhythmias, thromboembolic events or cardiogenic shock. Disease progression and prognosis are mostly driven by disease severity and reverse remodelling within the heart. The worst prognosis is seen in patients with lowest ejection fractions or severe diastolic dysfunction, leading to terminal heart failure with subsequent need for left ventricular assist device implantation or heart transplantation. Guideline‐based heart failure medication and device therapy reduces the frequency of heart failure hospitalizations and improves survival.     

Genetic cardiomyopathies

Dilated cardiomyopathy (DCM) is a multifactorial disease of the heart muscle and a leading cause of congestive heart failure. Human genetic studies and the establishment of suitable animal models such as mice and zebrafish have already revealed parts of its genetic etiology. With the next generation of genomic sequencing technologies (NGS) on the rise, the comprehensive genetic dissection of DCM patients will reveal clinically relevant information, novel causes, and modifiers of this complex disorder. The recent exploration of the epigenome as another mechanism of cardiac gene regulation will further elucidate unexplained variations observed in the correlation between the patient's genotype and phenotype. Some of these intriguing advances being made in basic genetic research will soon find their way into clinical practice for more individualized treatment of cardiomyopathy patients.     

Pharmacogenomics of angiotensin receptor/neprilysin inhibitor and its long‐term side effects

The development of the promising agent sacubitril/valsartan, known as an angiotensin receptor blocker‐neprilysin inhibitor (ARNI), to improve heart failure (HF) management, may benefit morbidity, mortality, and readmission rates in patients with HF. The PARADIGM‐HF trial demonstrated that the ARNI can reduce morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), while ongoing PARAMOUNT and PARAGON‐HF trials determined whether the ARNI has morbidity and mortality benefits in patients with heart failure with preserved ejection fraction (HFpEF). However, the risk of long‐term side effects of the ARNI such as cognitive dysfunction or Alzheimer's disease (AD) remains unknown. In fact, neprilysin (NEP), encoded by NEP or MME gene, is a principal peptidase involved in the degradation of β‐amyloid (Aβ) protein. Several studies have demonstrated that polymorphisms of the NEP gene may be associated with AD and cerebral amyloid angiopathy (CAA). Pharmacogenomics, the study of variability in drug response due to genetic polymorphisms, can potentially explain the variability in the effect of the ARNI and their side effects. Therefore, we have attempted to highlight pharmacogenomic factors and potential long‐term side effects of the ARNI. Physicians should carefully monitor elderly patients with genetic risk factors for AD and CAA. In the future, genetic testing and genomic testing for NEP polymorphisms may play an important role in monitoring long‐term side effects in ARNI‐treated HF patients.     

Genomics,heart failure and sudden cardiac death

Sudden cardiac death (SCD) is among the most common causes of death in developed countries throughout the world. Despite decreased overall cardiac mortality, SCD rates appear to be increasing in concert with escalating global prevalence of coronary disease and heart failure, the two major conditions predisposing to SCD. This unfavorable trend is a consequence of our inability to identify those who will die suddenly from lethal ventricular arrhythmias and to develop effective therapies for all populations at risk. The known risk factors for SCD lack the predictive power needed to generate preventive strategies for the large number of fatal arrhythmic events that occur among lower-risk subsets of the population. Even among recognized high-risk subsets, prediction of SCD remains challenging. With the exception of the implantable cardioverter defibrillator (ICD) there are few effective strategies for the prevention and treatment of SCD. This article discusses the prospect of genomic science as an approach to the identification of patients at high-risk for SCD. While the final common pathway for SCD is malignant ventricular arrhythmias, there are many potential contributors, pathways, and mechanisms by which common genetic variants (polymorphisms) could affect initiation and propagation of life-threatening cardiac arrhythmias. Recent advances in genomic medicine now provide us with novel approaches to both identify candidate genes/pathways and relatively common polymorphisms which may predispose patients to increased risk for SCD. Improved understanding of the relationship between common polymorphisms and SCD will not only improve risk stratification such that ICDs can be targeted to those patients most likely to benefit from them but also provide new insight into the pathophysiology of SCD.     

Approaching Biomarker Discovery through Genomics

The promise of genomic medicine lies in the ability to identify those factors that modify risk of disease at the individual level and, once identified, to be able to provide a personalized treatment or intervention to ablate the disease process. This concept is based upon a number of assumptions and current limitations that genomic science has yet to address. Critical to the development of personalized medicine is the determination of the genetic and epidemiologic cause of complex human disease, such as coronary heart disease, diabetes, asthma, and stroke. The risk factors that predispose an individual to any one of these disorders may not be unique, and the genomic profiles may be similar. Increasing the complexity of understanding the pathogenesis of these disorders is the growing recognition that the genetic risk factors likely interact not only with each other but also with poorly understood environmental factors. Ultimately, the prediction of an individual’s risk for any disorder will be determined by their genotype and their environmental exposures; however, in the absence of a defined genomic fingerprint, a subset of confirmed genetic risk factors can be used to help define biomarkers of disease. Clinically validated biomarkers can then serve as surrogates for the combined effects of genotype and environment and provide insights into disease pathogenesis.     

Cardiomyopathy in Africa: heredity versus environment

Unlike other parts of the world in which cardiomyopathy is rare, heart muscle disease is endemic in Africa. The major forms of cardiomyopathy in Africa are dilated cardiomyopathy (DCM) and endomyocardial fibrosis (EMF). Whereas DCM is a major cause of heart failure throughout the continent, EMF is restricted to the tropical regions of East, Central, and West Africa. Although epidemiological studies are lacking, hypertrophic cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy seem to have characteristics similar to those of other populations elsewhere in the world. Recent advances in the genetic analysis of DCM in other parts of the world indicate that it is a genetically heterogeneous disorder in which some cases have a Mendelian cause and others have a non-genetic or multifactorial cause. This heterogeneous pattern of inheritance has been confirmed in small studies that have been conducted so far in Africa. The advent of human immunodeficiency virus infection and its association with cardiomyopathy has emphasised the role of inflammatory agents in the pathogenesis of DCM. By contrast with DCM in which some cases have major genetic contributions, there is scanty evidence for the role of genetic factors in the aetiology of EMF. Although the pathogenesis of EMF is not fully understood, it appears that the conditioning factor may be geography (in its widest sense, to include climate and socio-economic status), the triggering factor may be an as yet unidentified infective agent, and the perpetuating factor may be eosinophilia. There is a need for renewed effort to identify genetic and non-genetic factors in EMF and other forms of heart muscle disease that are prevalent on the continent of Africa.     

Biomarkers in atrial fibrillation, ventricular arrhythmias, and sudden cardiac death

Cardiac arrhythmias including atrial fibrillation, ventricular tachycardia, and ventricular fibrillation are important causes of cardiovascular morbidity and mortality. Although they usually occur in the setting of structural heart disease, these arrhythmias can be the primary manifestation of subclinical cardiovascular disease and have deleterious consequences including stroke, heart failure, and death. Investigational efforts have focused on developing risk stratification algorithms and diagnostic methods to identify patients who are most likely to sustain cardiac arrhythmias and benefit from early pharmacologic and interventional therapies. This review highlights important clinical and translational studies that identify potential biological markers to predict the onset of cardiac arrhythmias and their complications. Particular focus is placed on mechanisms involving the neurohormonal system, inflammation, the renin-angiotensin-aldosterone system, and metabolic pathways.     

Structural pathways and prevention of heart failure and sudden death

We review the macroscopic and microscopic anatomy of myocardial disease associated with heart failure (HF) and sudden cardiac death (SCD) and focus on the prevention of SCD in light of its structural pathways. Compared to patients without SCD, patients with SCD exhibit 5- to 6-fold increases in the risks of ventricular arrhythmias and SCD. Epidemiologically, left ventricular hypertrophy by ECG or echocardiography acts as a potent dose-dependent SCD predictor. Dyslipidemia, a coronary disease risk factor, independently predicts echocardiographic hypertrophy. In adult SCD autopsy studies, increases in heart weight and severe coronary disease are constant findings, whereas rates of acute coronary thrombi vary remarkably. The microscopic myocardial anatomy of SCD is incompletely defined but may include prevalent changes of advanced myocardial disease, including cardiomyocyte hypertrophy, cardiomyocyte apoptosis, fibroblast hyperplasia, diffuse and focal matrix protein accumulation, and recruitment of inflammatory cells. Hypertrophied cardiomyocytes express "fetospecific" genetic programs that can account for acquired long QT physiology with risk for polymorphic ventricular arrhythmias. Structural heart disease associated with HF and high SCD risk is causally related to an up-regulation of the adrenergic renin-angiotensin-aldosterone pathway. In outcome trials, suppression of this pathway with combinations of beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, and mineralocorticoid receptor blockers have achieved substantial total mortality and SCD reductions. Contrarily, trials with ion channel-active agents that are not known to reduce structural heart disease have failed to reduce these risks. Device therapy effectively prevents SCD, but whether biventricular pacing-induced remodeling decreases left ventricular mass remains uncertain.     

Sudden cardiac death: an update

Sudden cardiac death (SCD) is a devastating and all too common result of both acquired and genetic heart diseases. The profound sadness endured by families is compounded by the risk many of these deaths confer upon surviving relatives. For those with known cardiac disease, disease‐specific therapy and risk stratification are key to reducing sudden death. For families of a SCD victim, uncovering a definitive cause of death can help relieve the agonising uncertainty and is a vital first step in screening surviving relatives and instituting therapy to reduce SCD risk. Increasing knowledge about the molecular mechanisms and genetic drivers of malignant arrhythmias in the diverse clinical entities that can cause SCD is vital if we are to optimise risk stratification and personalise patient care. Advances in diagnostic tools, disease‐specific therapy and defibrillator technology are improving outcomes for patients and their families but there is still much progress to be made.     

Evolving concepts in dilated cardiomyopathy

Dilated cardiomyopathy (DCM) represents a particular aetiology of systolic heart failure that frequently has a genetic background and usually affects young patients with few co‐morbidities. The prognosis of DCM has improved substantially during the last decades due to more accurate aetiological characterization, the red‐flag integrated approach to the disease, early diagnosis through systematic familial screening, and the concept of DCM as a dynamic disease requiring constant optimization of medical and non‐pharmacological evidence‐based treatments. However, some important issues in clinical management remain unresolved, including the role of cardiac magnetic resonance for diagnosis and risk categorization and the interaction between genotype and clinical phenotype, and arrhythmic risk stratification. This review offers a comprehensive survey of these and other emerging issues in the clinical management of DCM, providing where possible practical recommendations.     

Epidemiology and risk stratification in acute heart failure

Heart failure (HF) is a significant cause of morbidity and mortality worldwide. Acute HF is the leading medical cause of hospitalization among people aged > or = 65 years in the United States, European countries, Australia, and New Zealand. Patients hospitalized with HF are at particularly high risk for early mortality and rehospitalization. Outcomes during and after an HF hospitalization are, however, highly variable. The inhospital mortality rates reported for patients hospitalized with HF has varied greatly, ranging from 2% to 20%. Mortality rates in the first 30 days and 1 year after hospitalization, although high, also significantly vary. A large number of individual variables predictive of prognosis in patients hospitalized with acute HF exist. More recent studies have developed and validated models to allow clinicians to more reliably identify patients with HF at lower, intermediate, and higher risk for mortality based on patient characteristics, vital signs, and laboratories at the time of admission. Identification of individual prognostic variables and use of clinical risk prediction tools may be helpful in triaging patients with acute HF and guiding medical decision making. This article will discuss the epidemiology, mortality predictors, and risk stratification models for patients hospitalized with acute HF and provide a perspective on the value of integrating these tools in clinical practice.     

The electrocardiogram in the diagnosis and management of patients with dilated cardiomyopathy

The term dilated cardiomyopathy (DCM) defines a heterogeneous group of cardiac disorders, which are characterized by left ventricular or biventricular dilatation and systolic dysfunction in the absence of abnormal loading conditions or coronary artery disease sufficient to cause global systolic impairment. In approximately one third of cases, DCM is familial with a genetic pathogenesis and various patterns of inheritance. Although the electrocardiogram (ECG) has been considered traditionally non‐specific in DCM, the recently acquired knowledge of the genotype–phenotype correlations provides novel opportunities to identify patterns and abnormalities that may point toward specific DCM subtypes. A learned ECG interpretation in combination with an appropriate use of other ECG‐based techniques including ambulatory ECG monitoring, exercise tolerance test and imaging modalities, such as echocardiography and cardiovascular magnetic resonance, may allow the early identification of specific genetic or acquired forms of DCM. Furthermore, ECG abnormalities may reflect the severity of the disease and provide a useful tool in risk stratification and management. In the present review, we discuss the current role of the ECG in the diagnosis and management of DCM. We describe various clinical settings where the appropriate use and interpretation of the ECG can provide invaluable clues, contributing to the important role of this basic tool as cardiovascular medicine evolves.     

Dilatative Kardiomyopathie

Dilated cardiomyopathy (DCM) has a familial accumulation in 20?C50% of cases and, therefore, frequently has a genetic cause. Currently, numerous mutations are known in more than 40?genes, which account for around 20% of familial cases. The structured evaluation of family history with recording of a family tree is an obligatory part of the initial diagnosis of DCM. By evaluation of family members other persons at risk can be identified. With the exception of the lamin A/C gene (LMNA), genetic testing does not allow risk stratification. DCM caused by LMNA mutations is associated with a high risk of sudden cardiac death. In cases of familial conduction disease, sudden cardiac death and a concomitant muscle disease LMNA mutation should be excluded. Implantation of an ICD is indicated if the LVEF is chronically less than 35% independent from etiology. This applies with some restrictions for asymptomatic patients in NYHA class?I. Patients should receive optimal drug therapy for 3?C12?months before ICD implantation.