Review

Authors: Alan G Japp, Ankur Gulati, Stuart A Cook...

Dilated cardiomyopathy (DCM) is best understood as the final common response of myocardium to diverse genetic and environmental insults. A rigorous work-up can exclude alternative causes of left ventricular (LV) dilation and dysfunction, identify etiologies that may respond to specific treatments, and guide family screening. A significant proportion of DCM cases have an underlying genetic or inflammatory basis. Measurement of LV size and ejection fraction remain central to diagnosis, risk stratification, and treatment, but other aspects of cardiac remodeling inform prognosis and carry therapeutic implications. Assessment of myocardial fibrosis predicts both risk of sudden cardiac death and likelihood of LV functional recovery, and has significant potential to guide patient selection for cardioverter-defibrillator implantation. Detailed mitral valve assessment is likely to assume increasing importance with the emergence of percutaneous interventions for functional mitral regurgitation. Detection of pre-clinical DCM could substantially reduce morbidity and mortality by allowing early instigation of cardioprotective therapy.

Topics: Cardiomyopathy, Dilated; Humans; Phenotype

PubMed: 27339497
DOI: 10.1016/j.jacc.2016.03.590

Review

Authors: Elizabeth M McNally, Luisa Mestroni

Nonischemic dilated cardiomyopathy (DCM) often has a genetic pathogenesis. Because of the large number of genes and alleles attributed to DCM, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at risk or with early stage disease, offering the opportunity for early intervention. This review will address diagnosis and management of DCM, including the role of genetic evaluation. We will also overview distinct genetic pathways linked to DCM and their pathogenetic mechanisms. Historically, cardiac morphology has been used to classify cardiomyopathy subtypes. Determining genetic variants is emerging as an additional adjunct to help further refine subtypes of DCM, especially where arrhythmia risk is increased, and ultimately contribute to clinical management.

Topics: Animals; Biopsy; Cardiac Imaging Techniques; Cardiomyopathy, Dilated; DNA Mutational Analysis; Genetic Markers; Genetic Predisposition to Disease; Humans; Molecular Diagnostic Techniques; Mutation; Myocardium; Phenotype; Predictive Value of Tests; Prognosis; Risk Assessment; Risk Factors; Ventricular Function

PubMed: 28912180
DOI: 10.1161/CIRCRESAHA.116.309396

Review

Authors: Nicoletta Orphanou, Efstathios Papatheodorou, Aris Anastasakis...

Dilated cardiomyopathy (DCM) is an umbrella term entailing a wide variety of genetic and non-genetic etiologies, leading to left ventricular systolic dysfunction and dilatation, not explained by abnormal loading conditions or coronary artery disease. The clinical presentation can vary from asymptomatic to heart failure symptoms or sudden cardiac death (SCD) even in previously asymptomatic individuals. In the last 2 decades, there has been striking progress in the understanding of the complex genetic basis of DCM, with the discovery of additional genes and genotype-phenotype correlation studies. Rigorous clinical work-up of DCM patients, meticulous family screening, and the implementation of advanced imaging techniques pave the way for a more efficient and earlier diagnosis as well as more precise indications for implantable cardioverter defibrillator implantation and prevention of SCD. In the era of precision medicine, genotype-directed therapies have started to emerge. In this review, we focus on updates of the genetic background of DCM, characteristic phenotypes caused by recently described pathogenic variants, specific indications for prevention of SCD in those individuals and genotype-directed treatments under development. Finally, the latest developments in distinguishing athletic heart syndrome from subclinical DCM are described.

Topics: Cardiomyopathy, Dilated; Death, Sudden, Cardiac; Humans; Phenotype; Precision Medicine; Ventricular Dysfunction, Left

PubMed: 34263412
DOI: 10.1007/s10741-021-10139-0

Review

Authors: Daniel Harding, Ming H A Chong, Nishant Lahoti...

Dilated cardiomyopathy (DCM) is typically defined by left ventricular dilation and systolic dysfunction in the absence of a clear precipitant. Idiopathic disease is common; up to 50% of patients with DCM have no cause found despite imaging, genetic and biopsy assessments. Treatment remains focused on managing symptoms, reducing the risk of sudden cardiac death and ameliorating the structural and electrical complications of disease progression. In the absence of aetiology-specific treatments, the condition remains associated with a poor prognosis; mortality is approximately 40% at 10 years. The role of immune-mediated inflammatory injury in the development and progression of DCM was first proposed over 30 years ago. Despite the subsequent failures of three large clinical trials of immunosuppressive treatment (ATTACH, RENEWAL and the Myocarditis Treatment Trial), evidence for an abnormal adaptive immune response in DCM remains significant. In this review, we summarise and discuss available evidence supporting immune dysfunction in DCM, with a specific focus on cellular immunity. We also highlight current clinical and experimental treatments. We propose that the success of future immunosuppressive treatment trials in DCM will be dependent on the deep immunophenotyping of patients, to identify those with active inflammation and/or an abnormal immune response who are most likely to respond to therapy.

Topics: Humans; Cardiomyopathy, Dilated; Myocarditis; Heart; Arrhythmias, Cardiac; Inflammation

PubMed: 36030368
DOI: 10.1111/joim.13556

Review

Authors: Marco Merlo, Antonio Cannatà, Marco Gobbo...

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.

Topics: Cardiomyopathy, Dilated; Disease Management; Early Diagnosis; Heart Failure; Humans; Prognosis

PubMed: 29271570
DOI: 10.1002/ejhf.1103

Review

Authors: J Lukas Laws, Megan C Lancaster, M Ben Shoemaker...

There is increasing evidence regarding the prevalence of genetic cardiomyopathies, for which arrhythmias may be the first presentation. Ventricular and atrial arrhythmias presenting in the absence of known myocardial disease are often labelled as idiopathic, or lone. While ventricular arrhythmias are well-recognized as presentation for arrhythmogenic cardiomyopathy in the right ventricle, the scope of arrhythmogenic cardiomyopathy has broadened to include those with dominant left ventricular involvement, usually with a phenotype of dilated cardiomyopathy. In addition, careful evaluation for genetic cardiomyopathy is also warranted for patients presenting with frequent premature ventricular contractions, conduction system disease, and early onset atrial fibrillation, in which most detected genes are in the cardiomyopathy panels. Sudden death can occur early in the course of these genetic cardiomyopathies, for which risk is not adequately tracked by left ventricular ejection fraction. Only a few of the cardiomyopathy genotypes implicated in early sudden death are recognized in current indications for implantable cardioverter defibrillators which otherwise rely upon a left ventricular ejection fraction ≤0.35 in dilated cardiomyopathy. The genetic diagnoses impact other aspects of clinical management such as exercise prescription and pharmacological therapy of arrhythmias, and new therapies are coming into clinical investigation for specific genetic cardiomyopathies. The expansion of available genetic information and implications raises new challenges for genetic counseling, particularly with the family member who has no evidence of a cardiomyopathy phenotype and may face a potentially negative impact of a genetic diagnosis. Discussions of risk for both probands and relatives need to be tailored to their numeric literacy during shared decision-making. For patients presenting with arrhythmias or cardiomyopathy, extension of genetic testing and its implications will enable cascade screening, intervention to change the trajectory for specific genotype-phenotype profiles, and enable further development and evaluation of emerging targeted therapies.

Topics: Atrial Fibrillation; Cardiomyopathies; Cardiomyopathy, Dilated; Death, Sudden; Death, Sudden, Cardiac; Humans; Stroke Volume; Ventricular Function, Left

PubMed: 35617362
DOI: 10.1161/CIRCRESAHA.122.319835

Review

Authors: D Reichart, C Magnussen, T Zeller...

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.

Topics: Age of Onset; Cardiomyopathy, Dilated; Diagnosis, Differential; Disease Progression; Heart Function Tests; Humans; Incidence; Mutation; Phenotype; Prevalence; Prognosis; Risk Factors

PubMed: 31132311
DOI: 10.1111/joim.12944

Review

Authors: Paulo Soares, Gustavo Rocha, Susana Pissarra...

Cardiomyopathies are rare diseases of the heart muscle, of multiple causes, that manifest with various structural and functional phenotypes but are invariably associated with cardiac dysfunction. Dilated cardiomyopathy is the commonest cardiomyopathy in children, and the majority present before one year of age. Its etiology may be acquired or genetic. Myocarditis is an important cause and is responsible for the majority of acquired cases. Inherited (familial) forms of dilated cardiomyopathy may occur in 25-50% of patients. Echocardiographic and tissue Doppler studies are the basis for diagnosis of dilated cardiomyopathy in most patients. Marked dilatation of the left ventricle with global hypokinesis is the hallmark of the disease. This review will cover the classification, epidemiology and management of newborns with dilated cardiomyopathy. In particular, a comprehensive and up-to-date review of the genetic study of dilated cardiomyopathy and of detailed echocardiographic assessment of these patients will be presented.

Topics: Cardiomyopathy, Dilated; Humans; Infant, Newborn

PubMed: 28256370
DOI: 10.1016/j.repc.2016.10.007

Review

Authors: Marta Gigli, Davide Stolfo, Marco Merlo...

Dilated cardiomyopathy (DCM) is a complex disease with multiple causes and various pathogenic mechanisms. Despite improvements in the prognosis of patients with DCM in the past decade, this condition remains a leading cause of heart failure and premature death. Conventional treatment for DCM is based on the foundational therapies for heart failure with reduced ejection fraction. However, increasingly, attention is being directed towards individualized treatments and precision medicine. The ability to confirm genetic causality is gradually being complemented by an increased understanding of genotype-phenotype correlations. Non-genetic factors also influence the onset of DCM, and growing evidence links genetic background with concomitant non-genetic triggers or precipitating factors, increasing the extreme complexity of the pathophysiology of DCM. This Review covers the spectrum of pathophysiological mechanisms in DCM, from monogenic causes to the coexistence of genetic abnormalities and triggering environmental factors (the 'two-hit' hypothesis). The roles of common genetic variants in the general population and of gene modifiers in disease onset and progression are also discussed. Finally, areas for future research are highlighted, particularly novel therapies, such as small molecules, RNA and gene therapy, and measures for the prevention of arrhythmic death.

Topics: Humans; Cardiomyopathy, Dilated; Precision Medicine; Genetic Predisposition to Disease; Phenotype; Risk Factors

PubMed: 39394525
DOI: 10.1038/s41569-024-01074-2

Authors: Hong Lian, Shen Song, Wenzheng Chen...

BACKGROUND

Dilated cardiomyopathy (DCM) is one of the most frequent causes of heart failure and heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx remains to be further studied. This study aimed to characterize the genetic basis of DCM HTx in the Chinese population.

METHODS

In total, 208 unrelated DCM patients who underwent HTx at Fuwai Hospital between June 2004 and June 2017 were included in this study. Whole-exome sequencing (WES) was performed for all patients. Gene burden analysis, variant classification, and genotype-phenotype correlation analysis were subsequently performed.

RESULTS

After completing the bioinformatics analysis, gene burden analysis suggested that titin (TTN), filamin C (FLNC) and lamin A/C (LMNA) were significantly enriched with rare protein-altering variants. The frequencies of TTN and FLNC truncating variants in our cohort were 18.8% and 8.7%, respectively. Among the 165 rare variants in high evidence DCM-related genes, 27 (16.4%) and 59 (35.8%) were interpreted as pathogenic (P) and likely pathogenic (LP), respectively. In addition, 41 (47.7%) and 16 (18.6%) of these 86 P/LP variants are located in TTN and FLNC, respectively. The FLNC group contained more patients with NYHA class IV than the P/LP-negative group (FLNC, 16/18 vs. P/LP-negative, 81/123, P = 0.049).

CONCLUSIONS

Based on WES, we provided a primary genetic spectrum of DCM patients undergoing HTx in the Chinese population. TTN and FLNC harbour the most P/LP variants. FLNC truncation may lead to severe clinical symptoms in DCM patients.

Topics: Humans; Cardiomyopathy, Dilated; East Asian People; Exome Sequencing; Genetic Association Studies; Heart Transplantation; Mutation

PubMed: 37461109
DOI: 10.1186/s12967-023-04282-5