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Dolkar T, Nway N, Hamad AM, Jain H, Dufresne A. Arrhythmogenic Right Ventricular Cardiomyopathy. Cureus 2022; 14:e31446. [DOI: 10.7759/cureus.31446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/12/2022] [Indexed: 11/15/2022] Open
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Ezekian JE, Rehder C, Kishnani PS, Landstrom AP. Interpretation of Incidental Genetic Findings Localizing to Genes Associated With Cardiac Channelopathies and Cardiomyopathies. CIRCULATION-GENOMIC AND PRECISION MEDICINE 2021; 14:e003200. [PMID: 34384235 DOI: 10.1161/circgen.120.003200] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Recent advances in next-genetic sequencing technology have facilitated an expansion in the use of exome and genome sequencing in the research and clinical settings. While this has aided in the genetic diagnosis of individuals with atypical clinical presentations, there has been a marked increase in the number of incidentally identified variants of uncertain diagnostic significance in genes identified as clinically actionable by the American College of Medical Genetics guidelines. Approximately 20 of these genes are associated with cardiac diseases, which carry a significant risk of sudden cardiac death. While identification of at-risk individuals is paramount, increased discovery of incidental variants of uncertain diagnostic significance has placed a burden on the clinician tasked with determining the diagnostic significance of these findings. Herein, we describe the scope of this emerging problem using cardiovascular genetics to illustrate the challenges associated with variants of uncertain diagnostic significance interpretation. We review the evidence for diagnostic weight of these variants, discuss the role of clinical genetics providers in patient care, and put forward general recommendations about the interpretation of incidentally identified variants found with clinical genetic testing.
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Affiliation(s)
- Jordan E Ezekian
- Division of Cardiology, Department of Pediatrics (J.E.E., A.P.L.), Duke University School of Medicine, Durham, NC
| | - Catherine Rehder
- Department of Pathology (C.R.), Duke University School of Medicine, Durham, NC
| | - Priya S Kishnani
- Division of Medical Genetics, Department of Pediatrics (P.S.K.), Duke University School of Medicine, Durham, NC
| | - Andrew P Landstrom
- Division of Cardiology, Department of Pediatrics (J.E.E., A.P.L.), Duke University School of Medicine, Durham, NC.,Department of Cell Biology (A.P.L.), Duke University School of Medicine, Durham, NC
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Kim KH, Pereira NL. Genetics of Cardiomyopathy: Clinical and Mechanistic Implications for Heart Failure. Korean Circ J 2021; 51:797-836. [PMID: 34327881 PMCID: PMC8484993 DOI: 10.4070/kcj.2021.0154] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 06/14/2021] [Indexed: 11/11/2022] Open
Abstract
Genetic cardiomyopathies are an important cause of sudden cardiac death across all age groups. Genetic testing in heart failure clinics is useful for family screening and providing individual prognostic insight. Obtaining a family history of at least three generations, including the creation of a pedigree, is recommended for all patients with primary cardiomyopathy. Additionally, when appropriate, consultation with a genetic counsellor can aid in the success of a genetic evaluation. Clinical screening should be performed on all first-degree relatives of patients with genetic cardiomyopathy. Genetics has played an important role in the understanding of different cardiomyopathies, and the field of heart failure (HF) genetics is progressing rapidly. Much research has also focused on distinguishing markers of risk in patients with cardiomyopathy using genetic testing. While these efforts currently remain incomplete, new genomic technologies and analytical strategies provide promising opportunities to further explore the genetic architecture of cardiomyopathies, afford insight into the early manifestations of cardiomyopathy, and help define the molecular pathophysiological basis for cardiac remodeling. Cardiovascular physicians should be fully aware of the utility and potential pitfalls of incorporating genetic test results into pre-emptive treatment strategies for patients in the preliminary stages of HF. Future work will need to be directed towards elucidating the biological mechanisms of both rare and common gene variants and environmental determinants of plasticity in the genotype-phenotype relationship. This future research should aim to further our ability to identify, diagnose, and treat disorders that cause HF and sudden cardiac death in young patients, as well as prioritize improving our ability to stratify the risk for these patients prior to the onset of the more severe consequences of their disease.
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Affiliation(s)
- Kyung Hee Kim
- Division of Cardiology, Incheon Sejong General Hospital, Incheon, Korea.
| | - Naveen L Pereira
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.,Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
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Lutokhina YA, Blagova OV, Nedostup AV, Alexandrova SA, Evseeva EV, Shestak AG, Zaklyazminskaya EV. Contribution of concomitant myocarditis to the development of various clinical types of arrhythmogenic right ventricular cardiomyopathy. КАРДИОВАСКУЛЯРНАЯ ТЕРАПИЯ И ПРОФИЛАКТИКА 2021. [DOI: 10.15829/1728-8800-2021-2781] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Aim. To assess the contribution of genetic and inflammatory factors to the development of arrhythmogenic right ventricular cardiomyopathy (ARVC).Material and methods. The study involved 54 patients with ARVC (age, 38,7±14,1 years; men, 42,6%; mean follow-up period, 21 [6; 60] months). All patients underwent electrocardiography (ECG), 24-hour ECG monitoring, echocardiography, determination of anticardiac antibodies and DNA of cardiotropic viruses in the blood, molecular genetic ARVC testing, as well as cardiac magnetic resonance imaging (n=49), high-resolution ECG (n=18), right ventricular endomyocardial biopsy (n=2), and autopsy (n=2).Results. Following four clinical types of ARVC were identified: I. Latent arrhythmic form: characterized by frequent premature ventricular contractions and/or nonsustained ventricular tachycardia (VT). II. Manifested arrhythmic form (n=11) — SVT/ventricular fibrillation (VF). III. ARVC with progressive heart failure (HF, n=8). IV. Combination of ARVC with left ventricular noncompaction (LVNC, n=8). Superimposed myocarditis was identified in 74%, 36%, 87,5% and 85,7% of patients in forms I-IV, respectively. Mutations were detected in 11%, 46%, 50%, and 38% of patients in forms I-IV, respectively. Clinical forms were stable: there was no transition from one clinical form to another during follow-up period.Conclusion. The contribution of genetic and inflammatory mechanisms to the clinical picture is different: in the latent arrhythmic form, the leading role belongs to inflammation; in the manifested arrhythmic form, the contribution of pathogenic mutations prevails, and in ARVC with progressive HF and in combination with LVNC, the contribution of genetic and inflammatory factors is equally important.
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Affiliation(s)
| | | | | | - S. A. Alexandrova
- A.N. Bakulev National Medical Research Center of Cardiovascular Surgery
| | | | - A. G Shestak
- B.V. Petrovsky Russian Research Center of Surgery
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Pendela VS, Kudaravalli P, Feitell S, Parikh V. Cardiac sarcoidosis masquerading as arrhythmogenic right ventricular cardiomyopathy: a case report. EUROPEAN HEART JOURNAL-CASE REPORTS 2021; 5:ytab072. [PMID: 34113762 PMCID: PMC8186921 DOI: 10.1093/ehjcr/ytab072] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Revised: 05/20/2021] [Accepted: 01/09/2021] [Indexed: 12/30/2022]
Abstract
Background Cardiac sarcoidosis (CS) and arrhythmogenic right ventricular cardiomyopathy (ARVC) are rare causes of ventricular arrhythmias and are associated with sudden cardiac death. Differentiation between both is important for proper management. Case summary We present a 56-year-old man with sudden cardiac arrest and was diagnosed to have ARVC based on cardiac magnetic resonance imaging (MRI). He developed gradually worsening shortness of breath over the next 1 year. CS was unmasked after a cardiac positron emission tomography (PET). Patient was treated with methotrexate. A repeat cardiac PET scan showed improvement. Discussion The distinction between ARVC and CS is challenging. Both these entities have a patchy involvement and can have similar presentations. ARVC has a predominant right heart involvement. It is diagnosed with the help of an MRI, which shows regional right ventricular wall motion abnormality. These findings can have an overlap with CS. It is important to note that, even though sarcoidosis is a pathologic diagnosis, cardiac biopsy is rarely done owing to its patchy involvement. Cardiac PET scan has a high sensitivity and specificity to diagnose this entity. Once diagnosis is made, patients should be treated with immunosuppressants and should be closely followed. Repeat imaging should be considered at intervals to monitor disease progression. This case highlights the importance of multimodality imaging and tissue diagnosis to unmask the diagnosis of CS, a treatable infiltrative disorder which shares features with a potentially untreatable ARVC.
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Affiliation(s)
- Venkata Satish Pendela
- Department of Internal Medicine, Rochester General Hospital, 1425 Portland Avenue, Rochester, NY 14621, USA
| | - Pujitha Kudaravalli
- Department of Internal Medicine, SUNY Upstate Medical University, 750 E Adams St, Syracuse, NY 13210, USA
| | - Scott Feitell
- Department of Advanced Heart Failure, Sands-Constellation Heart Institute, Rochester Regional Health, 1425 Portland Avenue, Rochester, NY 14621, USA
| | - Vishal Parikh
- Department of Advanced Heart Failure, Sands-Constellation Heart Institute, Rochester Regional Health, 1425 Portland Avenue, Rochester, NY 14621, USA
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Lutokhina Y, Blagova O, Nedostup A, Alexandrova S, Shestak A, Zaklyazminskaya E. Clinical Classification of Arrhythmogenic Right Ventricular Cardiomyopathy. Pulse (Basel) 2020; 8:21-30. [PMID: 32999875 DOI: 10.1159/000505652] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Accepted: 12/25/2019] [Indexed: 02/04/2023] Open
Abstract
Introduction Commonly accepted clinical classification of arrhythmogenic right ventricular cardiomyopathy (ARVC) is still not developed. Objective To study the clinical forms of ARVC. Methods Fifty-four patients (38.7 ± 14.1 years, 42.6% men) with ARVC. Follow-up period: 21 (6-60) months. All patients underwent electrocardiography, 24 h-Holter monitoring, echocardiography, and DNA diagnostic. Magnetic resonance imaging was performed in 49 patients. Results According to the features of clinical course of ARVC, 4 clinical forms were identified. (I) Latent arrhythmic form (n = 27) - frequent premature ventricular contractions and/or nonsustained ventricular tachycardia (VT) in the absence of sustained VT and syncope; characterized by absence of fatal arrhythmic events. (II) Manifested arrhythmic form (n = 11) - sustained VT/ventricular fibrillation; the high incidence of appropriate implantation of cardioverter-defibrillator (ICD) interventions (75%) registered. (III) ARVC with progressive chronic heart failure (CHF, n = 8) as the main manifestation of the disease; incidence of appropriate ICD interventions was 50%, mortality rate due to CHF was 25%. (IV) Combination of ARVC with left ventricular noncompaction (n = 8); characterized by mutations in desmosomal or sarcomere genes, aggressive ventricular arrhythmias, appropriate ICD interventions in 100% patients. Described 4 clinical forms are stable in time, do not transform into each other, and they are genetically determined. Conclusions The described clinical forms of ARVC are determined by a combination of genetic and environmental factors and do not transform into each other. The proposed classification could be used in clinical practice to determine the range of diagnostic and therapeutic measures and to assess the prognosis of the disease in a particular patient.
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Affiliation(s)
- Yulia Lutokhina
- Department of Cardiology of the V.N. Vinogradov Faculty Therapeutic Clinic, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Olga Blagova
- Department of Cardiology of the V.N. Vinogradov Faculty Therapeutic Clinic, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Alexander Nedostup
- Department of Cardiology of the V.N. Vinogradov Faculty Therapeutic Clinic, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russian Federation
| | - Svetlana Alexandrova
- Department of Computer and Magnetic Resonance Tomography, A.N. Bakoulev Center for Cardiovascular Surgery RAMS, Moscow, Russian Federation
| | - Anna Shestak
- Laboratory of Medical Genetics, B.V. Petrovsky Russian Research Center of Surgery, Moscow, Russian Federation
| | - Elena Zaklyazminskaya
- Laboratory of Medical Genetics, B.V. Petrovsky Russian Research Center of Surgery, Moscow, Russian Federation
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Chu YQ, Wang C, Li XM, Wang H. Propafenone-Induced QRS Widening in a Child With Arrhythmogenic Right Ventricular Cardiomyopathy: A Case Report and Literatures Review. Front Pediatr 2020; 8:481330. [PMID: 33194879 PMCID: PMC7661465 DOI: 10.3389/fped.2020.481330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Accepted: 10/05/2020] [Indexed: 12/04/2022] Open
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a rare cardiac disease in children, and can lead to sudden cardiac death (SCD). Propafenone is classIC antiarrhythmic medication, and its side effects include cardiovascular compromise in the form of hypotension, bradycardia, ventricular dysrhythmias, QRS widening, and heart block. Propafenone has been reported causing QRS widening, but rarely in children. In this article, we presented a boy diagnosed with ARVC who meets diagnosis criteria based on typical symptoms, electrocardiograph (ECG), echocardiography (Echo), cardiac magnetic resonance imaging (CMRI), sudden death of first family member, and genetic mutation in desmosomal DSG2 gene. Antiarrhythmic drugs have been used for treating patients with ARVC, by eliminating or decreasing the occurring frequency of arrhythmias. As his ECG showed frequent premature ventricular contractions (PVC), he was prescribed with oral propafenone. One day after the drug treatment, he presented dizziness accompanied with significant QRS widening in ECG. His dizziness was improved when Propafenone dose was reduced, and resolved after sotalol replacement, with ECG recovered to nearly normal state of QRS. Propafenone may lead to QRS widening and increase the risk of ventricular tachycardia, and it may not reduce ARVC associated mortality. This report may serve as a precaution for clinicians when providing cares for ARVC patients.
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Affiliation(s)
- Yan-Qiu Chu
- Department of Pediatrics, Shengjing Hospital, China Medical University, Shenyang, China
| | - Ce Wang
- Department of Pediatrics, Shengjing Hospital, China Medical University, Shenyang, China
| | - Xue-Mei Li
- Department of Pediatrics, Shengjing Hospital, China Medical University, Shenyang, China
| | - Hong Wang
- Department of Pediatrics, Shengjing Hospital, China Medical University, Shenyang, China
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Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting. Am J Hum Genet 2019; 105:526-533. [PMID: 31422818 DOI: 10.1016/j.ajhg.2019.07.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 07/18/2019] [Indexed: 12/15/2022] Open
Abstract
As clinical testing for Mendelian causes of colorectal cancer (CRC) is largely driven by recognition of family history and early age of onset, the rates of such findings among individuals with prevalent CRC not recognized to have these features is largely unknown. We evaluated actionable genomic findings in community-based participants ascertained by three phenotypes: (1) CRC, (2) one or more adenomatous colon polyps, and (3) control participants over age 59 years without CRC or colon polyps. These participants underwent sequencing for a panel of genes that included colorectal cancer/polyp (CRC/P)-associated and actionable incidental findings genes. Those with CRC had a 3.8% rate of positive results (pathogenic or likely pathogenic) for a CRC-associated gene variant, despite generally being older at CRC onset (mean 72 years). Those ascertained for polyps had a 0.8% positive rate and those with no CRC/P had a positive rate of 0.2%. Though incidental finding rates unrelated to colon cancer were similar for all groups, our positive rate for cardiovascular findings exceeds disease prevalence, suggesting that variant interpretation challenges or low penetrance in these genes. The rate of HFE c.845G>A (p.Cys282Tyr) homozygotes in the CRC group reinforces a previously reported, but relatively unexplored, association between hemochromatosis and CRC. These results in a general clinical population suggest that current testing strategies could be improved in order to better detect Mendelian CRC-associated conditions. These data also underscore the need for additional functional and familial evidence to clarify the pathogenicity and penetrance of variants deemed pathogenic or likely pathogenic, particularly among the actionable genes associated with cardiovascular disease.
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Chen DQ, Shen XB, Zhang SH, Ye GY, Xu SH. Malignant Arrhythmia with Variants of Desmocollin-2 and Desmoplakin Genes. Int Heart J 2019; 60:1196-1200. [PMID: 31484862 DOI: 10.1536/ihj.18-681] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Malignant arrhythmia is a fast cardiac arrhythmia that can lead to a hemodynamic abnormality within a short time, most of which is ventricular tachycardia or ventricular fibrillation (VF), which should be managed in time. Both organic and nonorganic cardiac diseases have the potential to cause malignant arrhythmia. We report a noteworthy case of malignant arrhythmia in a teenager during exercise. Transthoracic echocardiography, cardiac magnetic resonance (CMR), electrophysiological study, magnetic resonance imaging of the brain, electroencephalography, chest X-ray, and blood tests were all normal. Twelve-lead electrocardiography showed incomplete right bundle branch block (IRBBB). Two heterozygous missense variants of the desmocollin-2 gene (DSC2, c.G2446A/p.V816M) and desmoplakin gene (DSP, c.G3620A/p.R1207K) were detected in the peripheral blood of this teenager and his father by genetic testing, which encoded a desmosomal protein that was related to arrhythmogenic right ventricular cardiomyopathy (ARVC). In these two rare variants, DSC2 V816M has been reported but uncertain significance, whereas DSP R1207K is never reported. Therefore, the two site variants in DSC2 and DSP genes are likely to become a new research focus for diagnosis and treatment of ARVC in the future. Meanwhile, this report emphasizes that, in addition to a standard set of laboratory tests and examinations, genetic testing may be useful for analyzing the causes of malignant arrhythmia.
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Affiliation(s)
- Da-Qiu Chen
- Department of Cardiology, Affiliated Nanping First Hospital, Fujian Medical University
| | - Xue-Bin Shen
- Department of Cardiology, Affiliated Nanping First Hospital, Fujian Medical University
| | - Shao-Hong Zhang
- Department of Medical Laboratory Medicine, Affiliated Nanping First Hospital, Fujian Medical University
| | - Gui-Yun Ye
- Department of Medical Laboratory Medicine, Affiliated Nanping First Hospital, Fujian Medical University
| | - Shang-Hua Xu
- Department of Cardiology, Affiliated Nanping First Hospital, Fujian Medical University
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van Mil A, Balk GM, Neef K, Buikema JW, Asselbergs FW, Wu SM, Doevendans PA, Sluijter JPG. Modelling inherited cardiac disease using human induced pluripotent stem cell-derived cardiomyocytes: progress, pitfalls, and potential. Cardiovasc Res 2018; 114:1828-1842. [PMID: 30169602 PMCID: PMC6887927 DOI: 10.1093/cvr/cvy208] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 06/06/2018] [Accepted: 08/28/2018] [Indexed: 12/17/2022] Open
Abstract
In the past few years, the use of specific cell types derived from induced pluripotent stem cells (iPSCs) has developed into a powerful approach to investigate the cellular pathophysiology of numerous diseases. Despite advances in therapy, heart disease continues to be one of the leading causes of death in the developed world. A major difficulty in unravelling the underlying cellular processes of heart disease is the extremely limited availability of viable human cardiac cells reflecting the pathological phenotype of the disease at various stages. Thus, the development of methods for directed differentiation of iPSCs to cardiomyocytes (iPSC-CMs) has provided an intriguing option for the generation of patient-specific cardiac cells. In this review, a comprehensive overview of the currently published iPSC-CM models for hereditary heart disease is compiled and analysed. Besides the major findings of individual studies, detailed methodological information on iPSC generation, iPSC-CM differentiation, characterization, and maturation is included. Both, current advances in the field and challenges yet to overcome emphasize the potential of using patient-derived cell models to mimic genetic cardiac diseases.
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Affiliation(s)
- Alain van Mil
- Division Heart and Lungs, Department of Cardiology, Experimental Cardiology Laboratory, Regenerative Medicine Center, University Medical Center Utrecht, Internal Mail No G03.550, GA Utrecht, the Netherlands
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Geerthe Margriet Balk
- Division Heart and Lungs, Department of Cardiology, Experimental Cardiology Laboratory, Regenerative Medicine Center, University Medical Center Utrecht, Internal Mail No G03.550, GA Utrecht, the Netherlands
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Klaus Neef
- Division Heart and Lungs, Department of Cardiology, Experimental Cardiology Laboratory, Regenerative Medicine Center, University Medical Center Utrecht, Internal Mail No G03.550, GA Utrecht, the Netherlands
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Jan Willem Buikema
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Folkert W Asselbergs
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
- Faculty of Population Health Sciences, Institute of Cardiovascular Science, University College London, London, UK
- Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, the Netherlands
- Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, UK
| | - Sean M Wu
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA
- Institute of Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA
| | - Pieter A Doevendans
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Joost P G Sluijter
- Division Heart and Lungs, Department of Cardiology, Experimental Cardiology Laboratory, Regenerative Medicine Center, University Medical Center Utrecht, Internal Mail No G03.550, GA Utrecht, the Netherlands
- Division Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
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Tikkanen JT, Kenttä T, Porthan K, Huikuri HV, Junttila MJ. Electrocardiographic T Wave Abnormalities and the Risk of Sudden Cardiac Death: The Finnish Perspective. Ann Noninvasive Electrocardiol 2015; 20:526-33. [PMID: 26391699 DOI: 10.1111/anec.12310] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 07/13/2015] [Indexed: 02/06/2023] Open
Abstract
The identification of patients at risk for sudden cardiac death (SCD) is still a significant challenge to clinicians and scientists. Noninvasive identification of high-risk patients has been of great interest, and several ventricular depolarization and repolarization abnormalities in the standard 12-lead electrocardiogram (ECG) have been associated with increased vulnerability to lethal ventricular arrhythmias. Several benign and pathological conditions can induce changes in repolarization detected as alteration of the ST segment or T wave. Changes in the ST segment and T waves can be early markers of an underlying cardiovascular disease, and even minor ST-T abnormalities have predicted reduced survival and increased risk of SCD in the adult population. In this review, we will discuss the current knowledge of the SCD risk with standard 12-lead ECG T wave abnormalities in the general population, and possible T wave changes in various cardiac conditions predisposing to SCD.
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Affiliation(s)
- Jani T Tikkanen
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.,Emergency Unit, Haartman Hospital, Helsinki, Finland
| | - Tuomas Kenttä
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Kimmo Porthan
- Division of Cardiology, Department of Medicine, Helsinki University Central Hospital, Finland
| | - Heikki V Huikuri
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - M Juhani Junttila
- Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland
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Que D, Yang P, Song X, Liu L. Traditional vs. genetic pathogenesis of arrhythmogenic right ventricular cardiomyopathy. Europace 2015; 17:1770-6. [DOI: 10.1093/europace/euv042] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 02/08/2015] [Indexed: 12/22/2022] Open
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Said SAM, Bloo R, Nooijer RD, Slootweg A. Cardiac and non-cardiac causes of T-wave inversion in the precordial leads in adult subjects: A Dutch case series and review of the literature. World J Cardiol 2015; 7:86-100. [PMID: 25717356 PMCID: PMC4325305 DOI: 10.4330/wjc.v7.i2.86] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 12/14/2014] [Accepted: 01/12/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To describe the electrocardiographic (ECG) phenomena characterized by T-wave inversion in the precordial leads in adults and to highlight its differential diagnosis.
METHODS: A retrospective chart review of 8 adult patients who were admitted with ECG T-wave inversion in the anterior chest leads with or without prolongation of corrected QT (QTc) interval. They had different clinical conditions. Each patient underwent appropriate clinical assessment including investigation for myocardial involvement. Single and multimodality non-invasive, semi-invasive and invasive diagnostic approach were used to ascertain the diagnosis. The diagnostic assessment included biochemical investigation, cardiac and abdominal ultrasound, cerebral and chest computed tomography, nuclear medicine and coronary angiography.
RESULTS: Eight adult subjects (5 females) with a mean age of 66 years (range 51 to 82) are analyzed. The etiology of T-wave inversion in the precordial leads were diverse. On admission, all patients had normal blood pressure and the ECG showed sinus rhythm. Five patients showed marked prolongation of the QTc interval. The longest QTc interval (639 ms) was found in the patient with pheochromocytoma. Giant T-wave inversion (≥ 10 mm) was found in pheochromocytoma followed by electroconvulsive therapy and finally ischemic heart disease. The deepest T-wave was measured in lead V3 (5 ×). In 3 patients presented with mild T-wave inversion (patients 1, 5 and 4 mm), the QTc interval was not prolonged (432, 409 and 424 msec), respectively.
CONCLUSION: T-wave inversion associated with or without QTc prolongation requires meticulous history taking, physical examination and tailored diagnostic modalities to reach rapid and correct diagnosis to establish appropriate therapeutic intervention.
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Gréen A, Gréen H, Rehnberg M, Svensson A, Gunnarsson C, Jonasson J. Assessment of HaloPlex amplification for sequence capture and massively parallel sequencing of arrhythmogenic right ventricular cardiomyopathy-associated genes. J Mol Diagn 2014; 17:31-42. [PMID: 25445213 DOI: 10.1016/j.jmoldx.2014.09.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Revised: 08/12/2014] [Accepted: 09/03/2014] [Indexed: 12/30/2022] Open
Abstract
The genetic basis of arrhythmogenic right ventricular cardiomyopathy (ARVC) is complex. Mutations in genes encoding components of the cardiac desmosomes have been implicated as being causally related to ARVC. Next-generation sequencing allows parallel sequencing and duplication/deletion analysis of many genes simultaneously, which is appropriate for screening of mutations in disorders with heterogeneous genetic backgrounds. We designed and validated a next-generation sequencing test panel for ARVC using HaloPlex. We used SureDesign to prepare a HaloPlex enrichment system for sequencing of DES, DSC2, DSG2, DSP, JUP, PKP2, RYR2, TGFB3, TMEM43, and TTN from patients with ARVC using a MiSeq instrument. Performance characteristics were determined by comparison with Sanger, as the gold standard, and TruSeq Custom Amplicon sequencing of DSC2, DSG2, DSP, JUP, and PKP2. All the samples were successfully sequenced after HaloPlex capture, with >99% of targeted nucleotides covered by >20×. The sequences were of high quality, although one problematic area due to a presumptive context-specific sequencing error-causing motif located in exon 1 of the DSP gene was detected. The mutations found by Sanger sequencing were also found using the HaloPlex technique. Depending on the bioinformatics pipeline, sensitivity varied from 99.3% to 100%, and specificity varied from 99.9% to 100%. Three variant positions found by Sanger and HaloPlex sequencing were missed by TruSeq Custom Amplicon owing to loss of coverage.
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Affiliation(s)
- Anna Gréen
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Clinical Genetics, County Council of Östergötland, Linköping, Sweden.
| | - Henrik Gréen
- Department of Forensic Genetics and Forensic Toxicology, National Board of Forensic Medicine, Linköping, Sweden; Division of Drug Research, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden; Science for Life Laboratory, School of Biotechnology, Division of Gene Technology, Royal Institute of Technology, Stockholm, Sweden
| | - Malin Rehnberg
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Clinical Genetics, County Council of Östergötland, Linköping, Sweden
| | - Anneli Svensson
- Department of Medicine and Health Science, Linköping University, Linköping, Sweden; Department of Cardiology, County Council of Östergötland, Linköping, Sweden
| | - Cecilia Gunnarsson
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Clinical Genetics, County Council of Östergötland, Linköping, Sweden
| | - Jon Jonasson
- Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Department of Clinical Genetics, County Council of Östergötland, Linköping, Sweden
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15
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Hariharan V, Asimaki A, Michaelson JE, Plovie E, MacRae CA, Saffitz JE, Huang H. Arrhythmogenic right ventricular cardiomyopathy mutations alter shear response without changes in cell-cell adhesion. Cardiovasc Res 2014; 104:280-9. [PMID: 25253076 DOI: 10.1093/cvr/cvu212] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
AIMS The majority of patients diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) have mutations in genes encoding desmosomal proteins, raising the possibility that abnormal intercellular adhesion plays an important role in disease pathogenesis. We characterize cell mechanical properties and molecular responses to oscillatory shear stress in cardiac myocytes expressing mutant forms of the desmosomal proteins, plakoglobin and plakophilin, which are linked to ARVC in patients. METHODS AND RESULTS Cells expressing mutant plakoglobin or plakophilin showed no differences in cell-cell adhesion relative to controls, while knocking down these proteins weakened cell-cell adhesion. However, cells expressing mutant plakoglobin failed to increase the amount of immunoreactive signal for plakoglobin or N-cadherin at cell-cell junctions in response to shear stress, as seen in control cells. Cells expressing mutant plakophilin exhibited a similar attenuation in the shear-induced increase in junctional plakoglobin immunoreactive signal in response to shear stress, suggesting that the phenotype is independent of the type of mutant protein being expressed. Cells expressing mutant plakoglobin also showed greater myocyte apoptosis compared with controls. Apoptosis rates increased greatly in response to shear stress in cells expressing mutant plakoglobin, but not in controls. Abnormal responses to shear stress in cells expressing either mutant plakoglobin or plakophilin could be reversed by SB216763, a GSK3β inhibitor. CONCLUSIONS Desmosomal mutations linked to ARVC do not significantly affect cell mechanical properties, but cause myocytes to respond abnormally to mechanical stress through a mechanism involving GSK3β. These results may help explain why patients with ARVC experience disease exacerbations following strenuous exercise.
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Affiliation(s)
- Venkatesh Hariharan
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 500 W 120th Street, MC 8904, New York, NY 10027, USA
| | - Angeliki Asimaki
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Jarett E Michaelson
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 500 W 120th Street, MC 8904, New York, NY 10027, USA
| | - Eva Plovie
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Calum A MacRae
- Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Jeffrey E Saffitz
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA Department of Pathology, Harvard Medical School, Boston, MA, USA
| | - Hayden Huang
- Department of Biomedical Engineering, Columbia University, 351 Engineering Terrace, 500 W 120th Street, MC 8904, New York, NY 10027, USA
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16
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Rao U, Agarwal S, Gilbert TJ. Arrhythmogenic right ventricular cardiomyopathy (ARVC): case report and review of literature. HEART ASIA 2014; 6:145-9. [PMID: 27326192 DOI: 10.1136/heartasia-2014-010569] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Accepted: 09/14/2014] [Indexed: 11/03/2022]
Abstract
Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited condition characterised by fibrofatty replacement of the right ventricle. It causes sudden death in 30% of young adults and in 5% of those less than 65 years of age. As the presentation is non-specific, ARVD can be a diagnostic challenge leading to delayed treatment. We report a case along with the review of literature, of a 63-year-old man who presented (atypical) with a history of palpitations, dizziness and raised cardiac enzymes associated with ECG changes in the inferior and anterior leads. Further investigation helped in confirming this rare and potentially fatal cardiac condition.
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Affiliation(s)
- Usha Rao
- Department of Cardiology , University Hospital of Norfolk & Norwich , Norwich , UK
| | - S Agarwal
- Department of Cardiology , Papworth Hospital , Cambridge , UK
| | - T J Gilbert
- Department of Cardiology , University Hospital of Norfolk & Norwich , Norwich , UK
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17
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Junttila MJ, Castellanos A, Huikuri HV, Myerburg RJ. Risk markers of sudden cardiac death in standard 12-lead electrocardiograms. Ann Med 2012; 44:717-32. [PMID: 21745092 DOI: 10.3109/07853890.2011.594807] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The annual incidence of sudden cardiac death (SCD) is estimated at 1 per 1,000 for adults over the age of 35 years, and 1 per 100,000 for adolescents and young adults. Although the overall incidence of unexpected SCD among previously healthy persons is small, the emotional impact of these events is devastating. The 12-lead electrocardiogram (ECG) has been used as a risk assessment tool from healthy occupational applicants and athletes to patients with cardiovascular disorders. The ECG is also routinely recorded in the majority of patients hospitalized for non-cardiovascular causes. Thus, it is a widely used tool intended for identification of unsuspected heart disease generally, as well as for diagnosing specific disorders predisposing to fatal arrhythmias in subjects who have not experienced such events but who are at increased risk. Recognition of specific ECG features is of importance for prevention of SCD in asymptomatic persons. The purpose of this review is to catalog the disorders associated with SCD that may be reflected in 12-lead ECGs seen in office or hospital practices and to discuss their prevalence and the magnitude of risks. The focus is on ECG findings suggesting increased SCD risk among the asymptomatic subjects without previously diagnosed cardiac disease.
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Affiliation(s)
- M Juhani Junttila
- Division of Cardiology, University of Miami Miller School of Medicine, Miami, FL, USA.
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18
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Pamuru PR, Maithili DVN, Mohiuddin K, Calambur N, Nallari P. Novel mutations in arrhythmogenic right ventricular cardiomyopathy from Indian population. INDIAN JOURNAL OF HUMAN GENETICS 2011; 17:70-6. [PMID: 22090716 PMCID: PMC3214321 DOI: 10.4103/0971-6866.86182] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive condition with right ventricular myocardium being replaced by fibro-fatty tissue. The spectrum of the expression may range from benign palpitations to the most malignant sudden death. Most of the mutations identified for the condition are localized in desmosomal proteins although three other nondesmosomal genes (cardiac ryanodine receptor-2, TGF-β3, and TMEM43) have also been implicated in ARVC. Both desmosomal and nondesmosomal genes were screened in a set of patients from local population. MATERIALS AND METHODS: A set of 34 patients from local population were included in this study. Diagnosis was based on the criteria proposed by task force of European Society of Cardiology/International Society and Federation of Cardiology. Polymerase chain reaction-based single-strand conformation polymorphism analysis was carried out, and samples with abnormal band pattern were commercially sequenced. RESULTS: Screening of cardiac ryanodine receptor revealed an insertion of a base in the intronic region of exon-28 in a patient, leading to a creation of a cryptic splice site. Screening of plakohilin-2 for mutations revealed an abnormal band pattern in three patients. Two of them had similar abnormal band pattern for exon-3.1. Sequencing revealed a novel 2 base pair deletion (433_434 delCT), which would lead to premature truncation of the protein (L145EfsX8). Another patient showed abnormal band pattern for exon-3.2 and sequencing revealed a missense mutation C792T leading to amino acid change P244L, in N-terminal, and this substitution may cause disturbances in the various protein–protein interactions. CONCLUSION: This study reports novel cardiac ryanodine receptor (RyR-2) mutations and Pkp-2 for the first time from Indian population.
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Affiliation(s)
- Pranathi Rao Pamuru
- Department of Genetics, Osmania University, Hyderabad, Andhra Pradesh, India
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19
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Hall C, Li S, Li H, Creason V, Wahl JK. Arrhythmogenic right ventricular cardiomyopathy plakophilin-2 mutations disrupt desmosome assembly and stability. ACTA ACUST UNITED AC 2011; 16:15-27. [PMID: 19533476 DOI: 10.1080/15419060903009329] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by life-threatening ventricular arrhythmias and fibrofatty replacement of the cardiac tissue. Desmosomes are prominent cell-cell junctions found in a variety of tissues that resist mechanical stress, including the heart, and recruit the intermediate filament cytoskeleton to sites of cell-cell contact. Mutations in several desmosomal components including plakophilin-2 have been identified in ARVC patients; however, the molecular interactions disrupted by plakophilin-2 mutations are currently unknown. To understand the pathological basis of ARVC, the authors analyzed desmosome assembly and stability in epithelial cell lines expressing mutants of plakophilin-2 found in ARVC patients. Mutant plakophilin-2 proteins were unable to disrupt established desmosomes when expressed in an E-cadherin-expressing epithelial cell model; however, they were unable to initiate de novo assembly of desmosomes in an N-cadherin-expressing epithelial cell model. These studies expand our understanding of desmosome assembly and dynamics.
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Affiliation(s)
- Chad Hall
- Department of Oral Biology, University of Nebraska Medical Center College of Dentistry, Lincoln, Nebraska 68583, USA
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20
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Klauke B, Kossmann S, Gaertner A, Brand K, Stork I, Brodehl A, Dieding M, Walhorn V, Anselmetti D, Gerdes D, Bohms B, Schulz U, Zu Knyphausen E, Vorgerd M, Gummert J, Milting H. De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. Hum Mol Genet 2010; 19:4595-607. [PMID: 20829228 DOI: 10.1093/hmg/ddq387] [Citation(s) in RCA: 141] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease, frequently accompanied by sudden cardiac death and terminal heart failure. Genotyping of ARVC patients might be used for palliative treatment of the affected family. We genotyped a cohort of 22 ARVC patients referred to molecular genetic screening in our heart center for mutations in the desmosomal candidate genes JUP, DSG2, DSC2, DSP and PKP2 known to be associated with ARVC. In 43% of the cohort, we found disease-associated sequence variants. In addition, we screened for desmin mutations and found a novel desmin-mutation p.N116S in a patient with ARVC and terminal heart failure, which is located in segment 1A of the desmin rod domain. The mutation leads to the aggresome formation in cardiac and skeletal muscle without signs of an overt clinical myopathy. Cardiac aggresomes appear to be prominent, especially in the right ventricle of the heart. Viscosimetry and atomic force microscopy of the desmin wild-type and N116S mutant isolated from recombinant Escherichia coli revealed severe impairment of the filament formation, which was supported by transfections in SW13 cells. Thus, the gene coding for desmin appears to be a novel ARVC gene, which should be included in molecular genetic screening of ARVC patients.
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Affiliation(s)
- Baerbel Klauke
- Herz- & Diabeteszentrum NRW, Klinik f. Thorax- und Kardiovaskularchirurgie, Erich und Hanna Klessmann-Institutfür Kardiovaskulaere Forschung und Entwicklung/Klinik fuer angeborene Herzfehler, Georgstrasse 11, Bad Oeynhausen, Germany
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21
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Sinagra G, Di Lenarda A, Moretti M, Mestroni L, Pinamonti B, Perkan A, Salvi A, Pyxaras S, Bussani R, Silvestri F, Camerini F. The challenge of cardiomyopathies in 2007. J Cardiovasc Med (Hagerstown) 2008; 9:545-54. [DOI: 10.2459/jcm.0b013e3282f2c9f9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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Thiene G, Corrado D, Basso C. Arrhythmogenic right ventricular cardiomyopathy/dysplasia. Orphanet J Rare Dis 2007; 2:45. [PMID: 18001465 PMCID: PMC2222049 DOI: 10.1186/1750-1172-2-45] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2007] [Accepted: 11/14/2007] [Indexed: 11/29/2022] Open
Abstract
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a heart muscle disease clinically characterized by life-threatening ventricular arrhythmias. Its prevalence has been estimated to vary from 1:2,500 to 1:5,000. ARVC/D is a major cause of sudden death in the young and athletes. The pathology consists of a genetically determined dystrophy of the right ventricular myocardium with fibro-fatty replacement to such an extent that it leads to right ventricular aneurysms. The clinical picture may include: a subclinical phase without symptoms and with ventricular fibrillation being the first presentation; an electrical disorder with palpitations and syncope, due to tachyarrhythmias of right ventricular origin; right ventricular or biventricular pump failure, so severe as to require transplantation. The causative genes encode proteins of mechanical cell junctions (plakoglobin, plakophilin, desmoglein, desmocollin, desmoplakin) and account for intercalated disk remodeling. Familiar occurrence with an autosomal dominant pattern of inheritance and variable penetrance has been proven. Recessive variants associated with palmoplantar keratoderma and woolly hair have been also reported. Clinical diagnosis may be achieved by demonstrating functional and structural alterations of the right ventricle, depolarization and repolarization abnormalities, arrhythmias with the left bundle branch block morphology and fibro-fatty replacement through endomyocardial biopsy. Two dimensional echo, angiography and magnetic resonance are the imaging tools for visualizing structural-functional abnormalities. Electroanatomic mapping is able to detect areas of low voltage corresponding to myocardial atrophy with fibro-fatty replacement. The main differential diagnoses are idiopathic right ventricular outflow tract tachycardia, myocarditis, dialted cardiomyopathy and sarcoidosis. Only palliative therapy is available and consists of antiarrhythmic drugs, catheter ablation and implantable cardioverter defibrillator. Young age, family history of juvenile sudden death, QRS dispersion ≥ 40 ms, T-wave inversion, left ventricular involvement, ventricular tachycardia, syncope and previous cardiac arrest are the major risk factors for adverse prognosis. Preparticipation screening for sport eligibility has been proven to be effective in detecting asymptomatic patients and sport disqualification has been life-saving, substantially declining sudden death in young athletes.
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Affiliation(s)
- Gaetano Thiene
- Pathological Anatomy, Department of Medical-Diagnostic Sciences and Special Therapies, University of Padua Medical School, Padua, Italy.
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23
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Kaartinen M, Heliö T, Lehtonen A, Lahtinen AM, Kärkkäinen S, Keto P, Kontula K, Toivonen L. Characterization of familial and sporadic arrhythmogenic right ventricular cardiomyopathy in Finland. Ann Med 2007; 39:312-8. [PMID: 17558603 DOI: 10.1080/07853890701282003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
BACKGROUND Autosomal dominant inheritance is reported in arrhythmogenic right ventricular cardiomyopathy (ARVC) but the prevalence of the familial and sporadic forms in the general population is unknown. AIM To evaluate the familial occurrence and clinical features of ARVC in the genetically homogenous Finnish population. METHODS The study included 29 Finnish ARVC index patients and 135 relatives from 21 families evaluated. They underwent echocardiography, 24-hour electrocardiographic monitoring, signal-averaged electrocardiography, and exercise stress test. RESULTS Twenty-two index patients had ventricular arrhythmias as first manifestation, and three developed arrhythmias later. The right ventricle (RV) was mildly affected in 22 and strongly dilated in 7 index patients. Patients with dilated RV manifested first symptoms at younger age (mean 28 years) than those without RV dilatation (mean 38 years). Of the 135 relatives, ARVC was present in 12 (9%) patients belonging to 5 of the 21 families studied, resulting in 24% familial involvement. In addition, 46 relatives (34%) had subtle cardiac abnormalities, suggesting subclinical presentation. CONCLUSIONS The ARVC in Finland presents with distinct arrhythmic and RV dilative subtypes. The sporadic disease is similar to the familial one which may reflect low penetration in relatives. The proportion of familial manifestation of ARVC in Finland seems comparable to that elsewhere in Europe.
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Affiliation(s)
- Maija Kaartinen
- Department of Cardiology, Helsinki University Central Hospital, Helsinki, Finland.
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Schenk S, Löscher S, Mickley F, Hartmann A. Female patient with proximal myotonic myopathy and ventricular tachycardia. ACTA ACUST UNITED AC 2005; 94:754-60. [PMID: 16258778 DOI: 10.1007/s00392-005-0281-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2005] [Accepted: 05/23/2005] [Indexed: 01/18/2023]
Abstract
A 68-year-old woman with known proximal myotonic myopathy was transferred to our hospital for further diagnostic and therapeutic evaluation after successful termination of an episode of sustained ventricular tachycardia. In 2001, the myopathy was diagnosed after symptomatic weakness of the hip flexors. A cardiomyopathy with slight reduction of systolic left ventricular function was found in 2002. Coronary angiography excluded relevant coronary artery disease. The electrophysiologic examination could provoke atrial flutter, but neither a ventricular tachycardia nor a delay in the AV conduction was found. ECG and Holter ECG did not reveal any abnormalities. A reduction of the left ventricular systolic function (EF 45%) with normal size of cardiac chambers was demonstrated by echocardiography. It is known that in the patient group with myotonic dystrophies cardiac involvement manifests itself as cardiomyopathy, conduction disturbance or arrhythmia. However, only a small percentage of all patients with myotonic myopathy actually suffer from cardiac involvement. Among the different types of cardiac involvement, conduction disturbances requiring pacemaker implantation are most frequent. Only some patients develop ventricular tachycardias, and even cases of sudden cardiac death have been described. As a result of the case reports in the literature and the findings in our patient an ICD system was implanted on March 4, 2004.
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Affiliation(s)
- S Schenk
- Städtisches Klinikum St. Georg, Delitzscher Str. 141, 04129 Leipzig, Germany
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25
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Francés RJ. Arrhythmogenic right ventricular dysplasia/cardiomyopathy. A review and update. Int J Cardiol 2005; 110:279-87. [PMID: 16099519 DOI: 10.1016/j.ijcard.2005.07.004] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2005] [Revised: 05/19/2005] [Accepted: 07/04/2005] [Indexed: 12/16/2022]
Abstract
The arrhythmogenic right ventricular dysplasia/cardiomyopathy is an important cause of sudden arrhythmic death, often exertional, in young individuals and athletes. Although the aetiology remains partially unknown, genetic abnormalities have been demonstrated. Reported prevalence is 1 in 5000 individuals but it is considered there are many non-diagnosed cases. The characteristic pathologic finding is the progressive fibro-fatty replacement of the right ventricular myocardium. The clinical manifestations vary from asymptomatic patients with an episode of sudden cardiac death as first symptom to chronically symptomatic patients with recurrent palpitations and/or right or biventricular failure. Approximately a third of the patients show the characteristic Epsilon wave in the 12-lead ECG which is a useful screening test. Signal-averaged ECG frequently demonstrates late potentials. The two-dimensional echocardiography, magnetic resonance imaging, computerized tomography and right ventricular cineangiography show morphologic abnormalities in the right ventricle. Therapy is directed to prevent and/or treat malignant ventricular tachyarrhythmias with medications, implantable cardioverter defibrillator and radiofrequency ablation in selected cases.
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Affiliation(s)
- Raúl J Francés
- Section of Cardiac Electrophysiology and Pacing, Sanatorio Centro, Rosario, Argentina.
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26
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Yoerger DM, Marcus F, Sherrill D, Calkins H, Towbin JA, Zareba W, Picard MH. Echocardiographic findings in patients meeting task force criteria for arrhythmogenic right ventricular dysplasia: new insights from the multidisciplinary study of right ventricular dysplasia. J Am Coll Cardiol 2005; 45:860-5. [PMID: 15766820 DOI: 10.1016/j.jacc.2004.10.070] [Citation(s) in RCA: 151] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2004] [Revised: 10/12/2004] [Accepted: 10/18/2004] [Indexed: 11/27/2022]
Abstract
OBJECTIVES The purpose of this study was to quantify the echocardiographic abnormalities in probands who were newly diagnosed with arrhythmogenic right ventricular dysplasia (ARVD). BACKGROUND The diagnosis of ARVD remains challenging. The Multidisciplinary Study of Right Ventricular Dysplasia was initiated to characterize the cardiac structural, clinical, and genetic aspects of ARVD. METHODS Detailed echocardiograms were performed in 29 probands and compared with echoes from 29 normal control patients matched for age, gender, body size, and year of echo. Right atrial (RA) and right ventricular (RV) chamber dimensions, RV regional function, and the presence of morphologic abnormalities (hyper-reflective moderator band, trabecular derangement, and sacculations) were assessed. The RV systolic function was calculated as RV fractional area change (FAC). RESULTS The RV dimensions were significantly increased, and RV FAC was significantly decreased in probands versus control patients (27.2 +/- 16 mm vs. 41.0 +/- 7.1 mm, p = 0.0003). The right ventricular outflow tract (RVOT) was the most commonly enlarged dimension in ARVD probands (37.9 +/- 6.6 mm) versus control patients (26.2 +/- 4.9 mm, p < 0.00001). A RVOT long-axis diastolic dimension >30 mm occurred in 89% of probands and 14% of controls. The RV morphologic abnormalities were present in many probands (trabecular derangement in 54%, hyper-reflective moderator band in 34% and sacculations in 17%) but not in controls. CONCLUSIONS Probands with ARVD have significant RA and RV enlargement and decreased RV function, which can be easily assessed on standard echocardiographic imaging. These parameters should be measured when ARVD is suspected and compared with normal values.
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Affiliation(s)
- Danita M Yoerger
- Cardiac Ultrasound Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
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de la Grandmaison GL, Durigon M. Sudden adult death: a medico-legal series of 77 cases between 1995 and 2000. MEDICINE, SCIENCE, AND THE LAW 2002; 42:225-232. [PMID: 12201067 DOI: 10.1177/002580240204200306] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Among all the autopsies performed between 1995 and 2000 in our Department, 77 adult cases of sudden death were selected. Sex, age, place of death, circumstances of death, causes of death and heart weight were reported from these 77 post-mortem records. A complete forensic autopsy was performed in every case. Sudden death occurred more frequently in males at rest. Strenuous activity was rarely involved in sudden death and 72.7% of the cases died from cardiovascular disease, mainly coronary atherosclerosis. Non-cardiac causes were dominated by pulmonary and neurological diseases. Cardiomegaly was a frequent finding in cases who died from cardiac pathology. This study underlines the importance of complete medico-legal investigations in case of sudden death. Multiple heart samples are required in order to detect focal microscopic lesions, such as myocarditis and some forms of cardiomyopathy with minimal gross abnormalities. The post-mortem diagnosis of such cardiomyopathies is very important because the family of the deceased may undergo a possible screening. Toxicology is useful in the diagnosis of epileptic seizure and in identifying drugs like metamphetamine as a risk factor for some lethal cardiovascular pathologies such as aortic dissection. Molecular biology can also be helpful when limits of morphological diagnosis have been reached.
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Affiliation(s)
- G Lorin de la Grandmaison
- Department of Pathology and Forensic Medicine, Raymond Poincaré Hospital, Paris-Ouest University, 104 Boulevard Raymond Poincaré, 92380 Garches, France.
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Abstract
Arrhythmogenic right ventricular (RV) cardiomyopathy (ARVC) is a cardiomyopathy characterized pathologically by fibrofatty replacement primarily of the RV and clinically by life-threatening ventricular arrhythmias in apparently healthy young people. The prevalence of the disease has been estimated at 1 in 5,000 individuals, although this estimate will likely increase as awareness of the condition increases among physicians. Arrhythmogenic RV cardiomyopathy is recognized as a cause of sudden death during athletic activity because of its association with ventricular arrhythmias that are provoked by exercise-induced catecholamine discharge. Diagnosis may be difficult because many of the electrocardiographic abnormalities mimic patterns seen in normal children, and the disease often involves only patchy areas of the RV. For this reason, international diagnostic criteria for ARVC were proposed by an expert consensus panel in 1996. Treatment is directed to preventing life-threatening cardiac arrhythmias with medications and the use of implantable defibrillators. This article will present in detail the etiology, clinical presentation, diagnosis and management of this condition.
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Affiliation(s)
- C Gemayel
- Hartford Hospital, Division of Cardiology, Hartford, Connecticut, USA
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