Arrhythmogenic Noncompaction Cardiomyopathy: Is There an Echocardiographic Phenotypic Overlap of Two Distinct Cardiomyopathies?
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ABSTRACT:
SUBMITTER: Aras D
PROVIDER: S-EPMC4595707 | biostudies-other | 2015 Sep
REPOSITORIES: biostudies-other
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Arrhythmogenic Noncompaction Cardiomyopathy: Is There an Echocardiographic Phenotypic Overlap of Two Distinct Cardiomyopathies?
Aras Dursun D Ozeke Ozcan O Cay Serkan S Ozcan Firat F Baser Kazım K Dogan Umuttan U Unlu Murat M Demirkan Burcu B Tufekcioglu Omac O Topaloglu Serkan S
Journal of cardiovascular ultrasound 20150924 3
The clinical diagnosis of right ventricular (RV) cardiomyopathies is often challenging. It is difficult to differentiate the isolated left ventricular (LV) noncompaction cardiomyopathy (NC) from biventricular NC or from coexisting arrhythmogenic ventricular cardiomyopathy (AC). There are currently few established morphologic criteria for the diagnosis other than RV dilation and presence of excessive regional trabeculation. The gross and microscopic changes suggest pathological similarities betwe ...[more]
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Project description:BackgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited genetic myocardial disease characterized by fibrofatty replacement of the myocardium and a predisposition to cardiac arrhythmias and sudden death. We evaluated the cardiomyopathy gene titin (TTN) as a candidate ARVC gene because of its proximity to an ARVC locus at position 2q32 and the connection of the titin protein to the transitional junction at intercalated disks.Methods and resultsAll 312 titin exons known to be expressed in human cardiac titin and the complete 3' untranslated region were sequenced in 38 ARVC families. Eight unique TTN variants were detected in 7 families, including a prominent Thr2896Ile mutation that showed complete segregation with the ARVC phenotype in 1 large family. The Thr2896IIe mutation maps within a highly conserved immunoglobulin-like fold (Ig10 domain) located in the spring region of titin. Native gel electrophoresis, nuclear magnetic resonance, intrinsic fluorescence, and proteolysis assays of wild-type and mutant Ig10 domains revealed that the Thr2896IIe exchange reduces the structural stability and increases the propensity for degradation of the Ig10 domain. The phenotype of TTN variant carriers was characterized by a history of sudden death (5 of 7 families), progressive myocardial dysfunction causing death or heart transplantation (8 of 14 cases), frequent conduction disease (11 of 14), and incomplete penetrance (86%).ConclusionsOur data provide evidence that titin mutations can cause ARVC, a finding that further expands the origin of the disease beyond desmosomal proteins. Structural impairment of the titin spring is a likely cause of ARVC and constitutes a novel mechanism underlying myocardial remodeling and sudden cardiac death.
| S-EPMC3167235 | biostudies-literature
Project description:BACKGROUND:Arrhythmogenic cardiomyopathy (ACM) is a variably penetrant disease increasingly identified in young patients. OBJECTIVES:This study sought to describe the diverse phenotype, genotype, and outcomes in pediatric and adolescent patients. METHODS:Records from 1999 to 2016 were reviewed for individuals age <21 years with a consistent personal or family history. Patients were categorized by right ventricular (RV), left dominant (LD), or biventricular subtypes using 2010 Task Force Criteria or proposed features of LD disease, encompassing electrocardiographic, structural, histological, and arrhythmic characteristics. Genetic variants classified as pathogenic and/or likely pathogenic by 2015 American College of Medical Genetics and Genomics criteria in recognized disease-associated genes were included. RESULTS:Manifest disease was evident in 32 patients (age 15.1 ± 3.8 years), of whom 22 were probands, including 16 RV, 7 LD, and 9 biventricular ACM. Nondiagnostic features were seen in 5 of 15 family members. RV disease was associated with cardiac arrest and ventricular tachycardia (p = 0.02) and prevalence of PKP2 variants (p < 0.01), whereas biventricular disease was associated with a younger age of onset (p = 0.02). LD ACM was associated with variants in DSP and LMNA, and biventricular ACM with more a diverse etiology in desmosomal genes. Cardiac arrest was observed in 5 probands (age 15.3 ± 1.9 years) and ventricular tachycardia in 10 (age 16.6 ± 2.7 years), 6 probands, and 4 family members. Features suggestive of myocardial inflammation were seen in 6 patients, with ventricular tachycardia and/or cardiac arrest in 3 patients. Cardiac transplantation was performed in 10 patients. There were no deaths. In RV and biventricular disease, electrocardiographic preceded imaging features, whereas the reverse was seen in LD disease. CONCLUSIONS:ACM in the young has highly varied phenotypic expression incorporating life-threatening arrhythmia, heart failure, and myocardial inflammation. Increased awareness of early onset, aggressive disease has important implications for patient management and familial screening.
| S-EPMC7261020 | biostudies-literature
Project description:This review focuses on the genetic cardiomyopathies: principally dilated cardiomyopathy, with salient features of hypertrophic cardiomyopathy and arrhythmogenic right ventricular dysplasia/cardiomyopathy, regarding genetic etiology, genetic testing, and genetic counseling. Enormous progress has recently been made in identifying genetic causes for each cardiomyopathy, and key phenotype and genotype information is reviewed. Clinical genetic testing is rapidly emerging with a principal rationale of identifying at-risk asymptomatic or disease-free relatives. Knowledge of a disease-causing mutation can guide clinical surveillance for disease onset, thereby enhancing preventive and treatment interventions. Genetic counseling is also indicated for patients and their family members regarding the symptoms of their cardiomyopathy, its inheritance pattern, family screening recommendations, and genetic testing options and possible results.
| S-EPMC2927103 | biostudies-literature
Project description:Arrhythmogenic cardiomyopathy (AC) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias and pathologically by an acquired and progressive dystrophy of the ventricular myocardium with fibro-fatty replacement. Due to an estimated prevalence of 1:2000-1:5000, AC is listed among rare diseases. A familial background consistent with an autosomal-dominant trait of inheritance is present in most of AC patients; recessive variants have also been reported, either or not associated with palmoplantar keratoderma and woolly hair. AC-causing genes mostly encode major components of the cardiac desmosome and up to 50% of AC probands harbor mutations in one of them. Mutations in non-desmosomal genes have been also described in a minority of AC patients, predisposing to the same or an overlapping disease phenotype. Compound/digenic heterozygosity was identified in up to 25% of AC-causing desmosomal gene mutation carriers, in part explaining the phenotypic variability. Abnormal trafficking of intercellular proteins to the intercalated discs of cardiomyocytes and Wnt/beta catenin and Hippo signaling pathways have been implicated in disease pathogenesis.AC is a major cause of sudden death in the young and in athletes. The clinical picture may include a sub-clinical phase; an overt electrical disorder; and right ventricular or biventricular pump failure. Ventricular fibrillation can occur at any stage. Genotype-phenotype correlation studies led to identify biventricular and dominant left ventricular variants, thus supporting the use of the broader term AC.Since there is no "gold standard" to reach the diagnosis of AC, multiple categories of diagnostic information have been combined and the criteria recently updated, to improve diagnostic sensitivity while maintaining specificity. Among diagnostic tools, contrast enhanced cardiac magnetic resonance is playing a major role in detecting left dominant forms of AC, even preceding morpho-functional abnormalities. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, sarcoidosis, dilated cardiomyopathy, right ventricular infarction, congenital heart diseases with right ventricular overload and athlete heart. A positive genetic test in the affected AC proband allows early identification of asymptomatic carriers by cascade genetic screening of family members. Risk stratification remains a major clinical challenge and antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator are the currently available therapeutic tools. Sport disqualification is life-saving, since effort is a major trigger not only of electrical instability but also of disease onset and progression. We review the current knowledge of this rare cardiomyopathy, suggesting a flowchart for primary care clinicians and geneticists.
| S-EPMC4818879 | biostudies-literature
Project description:BackgroundMutations in desmoplakin (DSP), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of DSP cardiomyopathy have been limited to small case series.MethodsClinical and genetic data were collected on 107 patients with pathogenic DSP mutations and 81 patients with pathogenic plakophilin 2 (PKP2) mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed.ResultsDSP and PKP2 cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients with DSP (55% versus 0% for PKP2, P<0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with DSP versus 40% for PKP2 (P<0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for DSP cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with DSP (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with DSP. Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with DSP and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4 DSP cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction <55% was strongly associated with severe ventricular arrhythmias for DSP cases (P<0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for PKP2 cases (P<0.001) but was poorly associated for DSP cases (P=0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both DSP (80%) and PKP2 (91%) groups (P=non-significant).ConclusionsDSP cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used.
| S-EPMC7286080 | biostudies-literature
Project description:Practical relevanceHypertrophic cardiomyopathy (HCM) is the most common form of feline cardiomyopathy observed clinically and may affect up to approximately 15% of the domestic cat population, primarily as a subclinical disease. Fortunately, severe HCM, leading to heart failure or arterial thromboembolism (ATE), only occurs in a small proportion of these cats.Patient groupDomestic cats of any age from 3 months upward, of either sex and of any breed, can be affected. A higher prevalence in male and domestic shorthair cats has been reported.DiagnosticsSubclinical feline HCM may or may not produce a heart murmur or gallop sound. Substantial left atrial enlargement can often be identified radiographically in cats with severe HCM. Biomarkers should not be relied on solely to diagnose the disease. While severe feline HCM can usually be diagnosed via echocardiography alone, feline HCM with mild to moderate left ventricular (LV) wall thickening is a diagnosis of exclusion, which means there is no definitive test for HCM in these cats and so other disorders that can cause mild to moderate LV wall thickening (eg, hyperthyroidism, systemic hypertension, acromegaly, dehydration) need to be ruled out.Key findingsWhile a genetic cause of HCM has been identified in two breeds and is suspected in another, for most cats the cause is unknown. Systolic anterior motion of the mitral valve (SAM) is the most common cause of dynamic left ventricular outflow tract obstruction (DLVOTO) and, in turn, the most common cause of a heart murmur with feline HCM. While severe DLVOTO is probably clinically significant and so should be treated, lesser degrees probably are not. Furthermore, since SAM can likely be induced in most cats with HCM, the distinction between HCM without obstruction and HCM with obstruction (HOCM) is of limited importance in cats. Diastolic dysfunction, and its consequences of abnormally increased atrial pressure leading to signs of heart failure, and sluggish atrial blood flow leading to ATE, is the primary abnormality that causes clinical signs and death in affected cats. Treatment (eg, loop diuretics) is aimed at controlling heart failure. Preventive treatment (eg, antithrombotic drugs) is aimed at reducing the risk of complications (eg, ATE).ConclusionsMost cats with HCM show no overt clinical signs and live a normal or near-normal life despite this disease. However, a substantial minority of cats develop overt clinical signs referable to heart failure or ATE that require treatment. For most cats with clinical signs caused by HCM, the long-term prognosis is poor to grave despite therapy.Areas of uncertaintyGenetic mutations (variants) that cause HCM have been identified in a few breeds, but, despite valiant efforts, the cause of HCM in the vast majority of cats remains unknown. No treatment currently exists that reverses or even slows the cardiomyopathic process in HCM, again despite valiant efforts. The search goes on.
| S-EPMC8642168 | biostudies-literature
Project description:Arrhythmogenic cardiomyopathy (AC) is a rare heart muscle disease with a genetic background and autosomal dominant mode of transmission. The clinical manifestation is characterized by ventricular arrhythmias (VA), heart failure (HF) and the risk of sudden cardiac death (SCD). Pregnancy in young female patients with AC represents a challenging condition for the life and family planning of young affected women. In addition to genetic mechanisms that influence the complex pathophysiology of AC, experimental and clinical data have confirmed the pathogenetic role of strenuous exercise and competitive sports in the early onset and rapid progression of AC symptoms and complications. Pregnancy and exercise share a number of physiological aspects of adaptation. In AC, both result in ventricular volume overload and myocardial stretch. Therefore, pregnancy has been postulated as a potential risk factor for HF, VA, SCD, and pregnancy-related obstetric complications in patients with AC. However, the available evidence on pregnancy in AC does not confirm this hypothesis. In most women with AC, pregnancies are well tolerated, uneventful, and follow a benign course. Pregnancy-related symptoms (VA, syncope, HF) and mortality, as well as obstetric complications, are uncommon in AC patients and range in the order of background populations and cohorts with AC and no pregnancy. The number of completed pregnancies is not associated with an acceleration of AC pathology or an increased risk of VA or HF during pregnancy and follow-up. Accordingly, there is no medical indication to advise against pregnancy in patients with AC. Preconditions include stability of rhythm and hemodynamics at baseline, as well as clinical follow-ups and the availability of multidisciplinary expert consultation during pregnancy and postpartum. Genetic counseling is recommended prior to pregnancy for all couples and their families affected by AC.
| S-EPMC8166670 | biostudies-literature
Project description:Arrhythmogenic cardiomyopathy (ACM) is a genetic-based cardiac disease accompanied by severe ventricular arrhythmias and a progressive substitution of the myocardium with fibro-fatty tissue. ACM is often associated with sudden cardiac death. Due to the reduced penetrance and variable expressivity, the presence of a genetic defect is not conclusive, thus complicating the diagnosis of ACM. Recent studies on human induced pluripotent stem cells-derived cardiomyocytes (hiPSC-CMs) obtained from ACM individuals showed a dysregulated metabolic status, leading to the hypothesis that ACM pathology is characterized by an impairment in the energy metabolism. However, despite efforts having been made for the identification of ACM specific biomarkers, there is still a substantial lack of information regarding the whole metabolomic profile of ACM patients. The aim of the present study was to investigate the metabolic profiles of ACM patients compared to healthy controls (CTRLs). The targeted Biocrates AbsoluteIDQ® p180 assay was used on plasma samples. Our analysis showed that ACM patients have a different metabolome compared to CTRLs, and that the pathways mainly affected include tryptophan metabolism, arginine and proline metabolism and beta oxidation of fatty acids. Altogether, our data indicated that the plasma metabolomes of arrhythmogenic cardiomyopathy patients show signs of endothelium damage and impaired nitric oxide (NO), fat, and energy metabolism.
| S-EPMC8064316 | biostudies-literature
Project description:Summary backgroundArrhythmogenic right ventricular cardiomyopathy (ARVC) is a heritable cardiomyopathy, characterized by fibrofatty replacement of myocytes in the right ventricular, left ventricular or both ventricles. It is caused by pathogenic variants of genes encoding desmosomal (JUP, DSP, PKP2, DSG2, DSC2) and non-desmosomal proteins, and is one of the most common causes of sudden cardiac death in young athletes. Therefore, early identification, correct prevention and treatment can prevent adverse outcomes.Case reportOur case presents a 65-years-old man with recurrent ventricular tachycardia. The ischemic cause was the first to rule out. Echocardiography revealed right ventricular structural and functional abnormalities. After suspicion of ARVC, magnetic resonance imaging was performed showing reduced right ventricular ejection fraction with local aneurysms, structural changes ir the right and left myocardium. Subsequently performed genetic testing identified a novel ARVC likely pathogenic variant in DSC2 gene and variant of uncertain significance in RYR2 gene.ConclusionsDiagnostic evaluation of ARVC is challenging and requires multidisciplinary team collaboration. Further functional tests for elucidation of the clinical significance of the two novel variants of ARVC-associated genes could be suggested.
| S-EPMC8311837 | biostudies-literature
Project description:To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM).We screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 %) ARVC patients and in 39 (15 %) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 % of R14del carriers. Compared with R14del- DCM patients, R14del+ DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 % vs. 10 % , P < 0.001), cardiac transplantation (18 % vs. 2 % , P < 0.001), and a family history for sudden cardiac death (SCD) at < 50 years (36 % vs. 16 % , P = 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 %) R14del+ ARVC samples, but in only one of nine (11 %) R14del+ DCM samples (P = 0.03).The PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del+ patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of 'arrhythmogenic cardiomyopathy'.
| S-EPMC3475434 | biostudies-literature