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Papageorgiou VE, Zegkos T, Efthimiadis G, Tsaklidis G. Analysis of digitalized ECG signals based on artificial intelligence and spectral analysis methods specialized in ARVC. INTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN BIOMEDICAL ENGINEERING 2022; 38:e3644. [PMID: 36053812 DOI: 10.1002/cnm.3644] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 04/13/2022] [Accepted: 08/17/2022] [Indexed: 06/15/2023]
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease that appears between the second and forth decade of a patient's life, being responsible for 20% of sudden cardiac deaths before the age of 35. The effective and punctual diagnosis of this disease based on electrocardiograms (ECGs) could have a vital role in reducing premature cardiovascular mortality. In our analysis, we first outline the digitalization process of paper-based ECG signals enhanced by a spatial filter aiming to eliminate dark regions in the dataset's images that do not correspond to ECG waveform, producing undesirable noise. Next, we propose the utilization of a low-complexity convolutional neural network for the detection of an arrhythmogenic heart disease, that has not been studied through the usage of deep learning methodology to date, achieving high classification accuracy, namely 99.98% training and 98.6% testing accuracy, on a disease the major identification criterion of which are infinitesimal millivolt variations in the ECG's morphology, in contrast with other arrhythmogenic abnormalities. Finally, by performing spectral analysis we investigate significant differentiations in the field of frequencies between normal ECGs and ECGs corresponding to patients suffering from ARVC. In 16 out of the 18 frequencies where we encounter statistically significant differentiations, the normal ECGs are characterized by greater normalized amplitudes compared to the abnormal ones. The overall research carried out in this article highlights the importance of integrating mathematical methods into the examination and effective diagnosis of various diseases, aiming to a substantial contribution to their successful treatment.
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Affiliation(s)
| | - Thomas Zegkos
- 1st Cardiology Department, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Georgios Efthimiadis
- 1st Cardiology Department, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - George Tsaklidis
- Department of Mathematics, Aristotle University of Thessaloniki, Thessaloniki, Greece
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2
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Sharma A, Bosman LP, Tichnell C, Nanavati J, Murray B, Nonyane BA, Tandri H, Calkins H, James CA. Arrhythmogenic Right Ventricular Cardiomyopathy Prevalence and Arrhythmic Outcomes in At-Risk Family Members: A Systematic Review and Meta-Analysis. Circ Genom Precis Med 2022; 15:e003530. [DOI: 10.1161/circgen.121.003530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background:
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a complex cardiomyopathy with autosomal dominant inheritance and age-related incomplete penetrance, characterized by a high risk of sudden cardiac death. Recent professional consensus guidelines recommend clinical cardiac lifelong serial screening for at-risk family members refined only by age, but family genotype might influence necessary screening. Although numerous studies report prevalence of disease and arrhythmia in family members and explore predictors of penetrance and arrhythmic risk, a systematic review consolidating this evidence is lacking.
Methods:
We searched Medline (PubMed), Embase, The Cochrane Library, and Web of Science for studies that reported prevalence of (1) diagnosis of ARVC per 2010 Task Force Criteria and/or (2) sustained ventricular arrhythmias (VA) in at least 10 family members of definite patients with ARVC.
Results:
We identified 41 studies, including 36 that reported diagnosis by Task Force Criteria and 22 VA. Meta-analysis of 1359 family members, from 13 unique cohorts showed an average prevalence estimate of 25% for diagnosis as per Task Force Criteria (95% CI, 0.15–0.35, I
2
=
96.44%). Overall prevalence of VA among gene-positive family members was 18% (95% CI, 0.13–0.23, I
2
=33.25%) in 7 independent studies (n=597). Family genotype was a significant risk factor for diagnosis of both ARVC (odds ratio, 6.91 [95% CI, 1.27–37.70];
P
=0.0005) and VA (odds ratio, 13.62 [95% CI, 0.91–204.13];
P
=0.06). Male gender was not associated with disease prevalence (odds ratio, 1.18 [95% CI, 0.72–1.95];
P
=0.42) or VA (odds ratio, 0.81 [95% CI, 0.51–1.29];
P
=0.91).
Conclusions:
The prevalence of ARVC and VA in at-risk family members differs significantly based on family genotype. Although recent recommendations provide a guideline based only on age, we propose screening every 1 to 2 years for gene-positive family members and every 3 to 5 years for first-degree relatives of gene-elusive cases, as long as they are asymptomatic and not athletes.
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Affiliation(s)
- Apurva Sharma
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (A.S., C.T., B.M., H.T., H.C., C.A.J.)
| | - Laurens P. Bosman
- Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, Utrecht University, the Netherlands (L.P.B.)
| | - Crystal Tichnell
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (A.S., C.T., B.M., H.T., H.C., C.A.J.)
| | - Julie Nanavati
- Welch Medical Library, Johns Hopkins School of Medicine (J.N.)
| | - Brittney Murray
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (A.S., C.T., B.M., H.T., H.C., C.A.J.)
| | - Bareng A.S. Nonyane
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (B.A.S.N.)
| | - Harikrishna Tandri
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (A.S., C.T., B.M., H.T., H.C., C.A.J.)
| | - Hugh Calkins
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (A.S., C.T., B.M., H.T., H.C., C.A.J.)
| | - Cynthia A. James
- Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (A.S., C.T., B.M., H.T., H.C., C.A.J.)
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3
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The value of genetic testing in the diagnosis and risk stratification of arrhythmogenic right ventricular cardiomyopathy. Heart Rhythm 2022; 19:1659-1665. [DOI: 10.1016/j.hrthm.2022.05.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/13/2022] [Accepted: 05/20/2022] [Indexed: 11/18/2022]
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4
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Svensson A, Platonov PG, Haugaa KH, Zareba W, Jensen HK, Bundgaard H, Gilljam T, Madsen T, Hansen J, Dejgaard LA, Karlsson LO, Gréen A, Polonsky B, Edvardsen T, Svendsen JH, Gunnarsson C. Genetic Variant Score and Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Plakophilin-2 Mutation Carriers. Cardiology 2021; 146:763-771. [PMID: 34469894 DOI: 10.1159/000519231] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 06/14/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Whether detailed genetic information contributes to risk stratification of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) remains uncertain. Pathogenic genetic variants in some genes seem to carry a higher risk for arrhythmia and earlier disease onset than others, but comparisons between variants in the same gene have not been done. Combined Annotation Dependent Depletion (CADD) score is a bioinformatics tool that measures the pathogenicity of each genetic variant. We hypothesized that a higher CADD score is associated with arrhythmic events and earlier age at ARVC manifestations in individuals carrying pathogenic or likely pathogenic genetic variants in plakophilin-2 (PKP2). METHODS CADD scores were calculated using the data from pooled Scandinavian and North American ARVC cohorts, and their association with cardiac events defined as ventricular tachycardia/ventricular fibrillation (VT/VF) or syncope and age at definite ARVC diagnosis were assessed. RESULTS In total, 33 unique genetic variants were reported in 179 patients (90 males, 71 probands, 96 with definite ARVC diagnosis at a median age of 35 years). Cardiac events were reported in 76 individuals (43%), of whom 53 had sustained VT/VF (35%). The CADD score was neither associated with age at cardiac events (HR 1.002, 95% CI: 0.953-1.054, p = 0.933) nor with age at definite ARVC diagnosis (HR 0.992, 95% CI: 0.947-1.039, p = 0.731). CONCLUSION No correlation was found between CADD scores and clinical manifestations of ARVC, indicating that the score has no additional risk stratification value among carriers of pathogenic or likely pathogenic PKP2 genetic variants.
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Affiliation(s)
- Anneli Svensson
- Department of Cardiology and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Pyotr G Platonov
- Department of Cardiology, Clinical Sciences, Lund University and Arrhythmia Clinic, Skåne University Hospital, Lund, Sweden
| | - Kristina H Haugaa
- Department of Cardiology, Centre for Cardiological Innovation, Oslo University Hospital, Oslo, Norway and University of Oslo, Oslo, Norway
| | - Wojciech Zareba
- University of Rochester Medical Center, Rochester, New York, USA
| | - Henrik Kjærulf Jensen
- Department of Cardiology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Henning Bundgaard
- Unit for Inherited Cardiac Diseases, The Heart Center, The National University Hospital, Copenhagen, Denmark
| | - Thomas Gilljam
- Department of Cardiology, Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Trine Madsen
- Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
| | - Jim Hansen
- Department of Cardiology, Herlev-Gentofte Hospital, University of Copenhagen, Hellerup, Denmark
| | - Lars A Dejgaard
- Department of Cardiology, Centre for Cardiological Innovation, Oslo University Hospital, Oslo, Norway and University of Oslo, Oslo, Norway
| | - Lars O Karlsson
- Department of Cardiology and Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Anna Gréen
- Department of Clinical Genetics, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | | | - Thor Edvardsen
- Department of Cardiology, Centre for Cardiological Innovation, Oslo University Hospital, Oslo, Norway and University of Oslo, Oslo, Norway
| | - Jesper Hastrup Svendsen
- Department of Cardiology, The Heart Centre, Rigshospitalet, University of Copenhagen, and Danish National Research Foundation Centre for Cardiac Arrhythmia (DARC), Copenhagen, Denmark and Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Cecilia Gunnarsson
- Department of Clinical Genetics, and Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.,Centre for Rare Diseases in Southeast Region of Sweden, Linköping University, Linköping, Sweden
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5
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Bosman LP, Cadrin-Tourigny J, Bourfiss M, Aliyari Ghasabeh M, Sharma A, Tichnell C, Roudijk RW, Murray B, Tandri H, Khairy P, Kamel IR, Zimmerman SL, Reitsma JB, Asselbergs FW, van Tintelen JP, van der Heijden JF, Hauer RNW, Calkins H, James CA, Te Riele ASJM. Diagnosing arrhythmogenic right ventricular cardiomyopathy by 2010 Task Force Criteria: clinical performance and simplified practical implementation. Europace 2021; 22:787-796. [PMID: 32294163 PMCID: PMC7203633 DOI: 10.1093/europace/euaa039] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 02/03/2020] [Indexed: 12/03/2022] Open
Abstract
Aims Arrhythmogenic right ventricular cardiomyopathy (ARVC) is diagnosed by a complex set of clinical tests as per 2010 Task Force Criteria (TFC). Avoiding misdiagnosis is crucial to prevent sudden cardiac death as well as unnecessary implantable cardioverter-defibrillator implantations. This study aims to validate the overall performance of the TFC in a real-world cohort of patients referred for ARVC evaluation. Methods and results We included patients consecutively referred to our centres for ARVC evaluation. Patients were diagnosed by consensus of three independent clinical experts. Using this as a reference standard, diagnostic performance was measured for each individual criterion as well as the overall TFC classification. Of 407 evaluated patients (age 38 ± 17 years, 51% male), the expert panel diagnosed 66 (16%) with ARVC. The clinically observed TFC was false negative in 7/66 (11%) patients and false positive in 10/69 (14%) patients. Idiopathic outflow tract ventricular tachycardia was the most common alternative diagnosis. While the TFC performed well overall (sensitivity and specificity 92%), signal-averaged electrocardiogram (SAECG, P = 0.43), and several family history criteria (P ≥ 0.17) failed to discriminate. Eliminating these criteria reduced false positives without increasing false negatives (net reclassification improvement 4.3%, P = 0.019). Furthermore, all ARVC patients met at least one electrocardiogram (ECG) or arrhythmia criterion (sensitivity 100%). Conclusion The TFC perform well but are complex and can lead to misdiagnosis. Simplification by eliminating SAECG and several family history criteria improves diagnostic accuracy. Arrhythmogenic right ventricular cardiomyopathy can be ruled out using ECG and arrhythmia criteria alone, hence these tests may serve as a first-line screening strategy among at-risk individuals.
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Affiliation(s)
- Laurens P Bosman
- Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, the Netherlands.,Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Julia Cadrin-Tourigny
- Department of Medicine, Montreal Heart Institute, University of Montreal, Montreal, Canada
| | - Mimount Bourfiss
- Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Mounes Aliyari Ghasabeh
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Apurva Sharma
- Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Crystal Tichnell
- Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Rob W Roudijk
- Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, the Netherlands.,Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Brittney Murray
- Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Harikrishna Tandri
- Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Paul Khairy
- Department of Medicine, Montreal Heart Institute, University of Montreal, Montreal, Canada
| | - Ihab R Kamel
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Stefan L Zimmerman
- Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Johannes B Reitsma
- Department of Epidemiology, Julius Center, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Folkert W Asselbergs
- Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, the Netherlands.,Division of 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.,Health Data Research UK and Institute of Health Informatics, University College London, London, UK
| | - J Peter van Tintelen
- Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, the Netherlands.,Department of Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Jeroen F van der Heijden
- Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Richard N W Hauer
- Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, the Netherlands.,Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
| | - Hugh Calkins
- Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Cynthia A James
- Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Anneline S J M Te Riele
- Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, the Netherlands.,Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands
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6
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Abstract
PURPOSE OF REVIEW Aim of the paper was to address all strengths and weakness of cardiac magnetic resonance (CMR) in arrhythmogenic cardiomyopathy, trying to highlight areas where further research and investigations should be carried out to fill current gaps in scientific knowledge. RECENT FINDINGS Arrhythmogenic cardiomyopathy represents a multifaceted clinical entity associated with arrhythmias and sudden death. Even though different diagnostic tools are available for appropriate identification and risk stratification, over the last few years cardiac magnetic resonance (CMR) has surfaced as an unmatched non-invasive imaging tool. CMR is mandatory in the evaluation of arrhythmogenic cardiomyopathy. It is the only imaging technique providing the identification of myocardial fibrosis, particularly for left ventricular myocardium, as recent evidences demonstrated that left ventricular involvement in arrhythmogenic cardiomyopathy is associated with greater risk of sudden death than lone right ventricular involvement.
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7
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Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, Daubert JP, de Chillou C, DePasquale EC, Desai MY, Estes NAM, Hua W, Indik JH, Ingles J, James CA, John RM, Judge DP, Keegan R, Krahn AD, Link MS, Marcus FI, McLeod CJ, Mestroni L, Priori SG, Saffitz JE, Sanatani S, Shimizu W, van Tintelen JP, Wilde AAM, Zareba W. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy: Executive summary. Heart Rhythm 2020; 16:e373-e407. [PMID: 31676023 DOI: 10.1016/j.hrthm.2019.09.019] [Citation(s) in RCA: 129] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Indexed: 01/14/2023]
Abstract
Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia.
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Affiliation(s)
- Jeffrey A Towbin
- Le Bonheur Children's Hospital, Memphis, Tennessee; University of Tennessee Health Science Center, Memphis, Tennessee
| | - William J McKenna
- University College London, Institute of Cardiovascular Science, London, United Kingdom
| | | | | | | | | | | | | | | | | | - N A Mark Estes
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Wei Hua
- Fu Wai Hospital, Beijing, China
| | - Julia H Indik
- University of Arizona, Sarver Heart Center, Tucson, Arizona
| | - Jodie Ingles
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia
| | | | - Roy M John
- Vanderbilt University Medical Center, Nashville, Tennessee
| | - Daniel P Judge
- Medical University of South Carolina, Charleston, South Carolina
| | - Roberto Keegan
- Hospital Privado Del Sur, Buenos Aires, Argentina; Hospital Español, Bahia Blanca, Argentina
| | | | - Mark S Link
- UT Southwestern Medical Center, Dallas, Texas
| | - Frank I Marcus
- University of Arizona, Sarver Heart Center, Tucson, Arizona
| | | | - Luisa Mestroni
- University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Silvia G Priori
- University of Pavia, Pavia, Italy; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart); ICS Maugeri, IRCCS, Pavia, Italy
| | | | | | - Wataru Shimizu
- Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan
| | - J Peter van Tintelen
- University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands; Utrecht University Medical Center Utrecht, University of Utrecht, Department of Genetics, Utrecht, the Netherlands
| | - Arthur A M Wilde
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart); University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands; Department of Medicine, Columbia University Irving Medical Center, New York, New York
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8
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Funny waves in repolarisation and tachycardia in a patient suspected for Brugada syndrome. Neth Heart J 2019; 27:451-452. [PMID: 31115760 PMCID: PMC6712179 DOI: 10.1007/s12471-019-1291-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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9
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Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, Daubert JP, de Chillou C, DePasquale EC, Desai MY, Estes NAM, Hua W, Indik JH, Ingles J, James CA, John RM, Judge DP, Keegan R, Krahn AD, Link MS, Marcus FI, McLeod CJ, Mestroni L, Priori SG, Saffitz JE, Sanatani S, Shimizu W, van Tintelen JP, Wilde AAM, Zareba W. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm 2019; 16:e301-e372. [PMID: 31078652 DOI: 10.1016/j.hrthm.2019.05.007] [Citation(s) in RCA: 505] [Impact Index Per Article: 84.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Indexed: 02/08/2023]
Abstract
Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia.
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Affiliation(s)
- Jeffrey A Towbin
- Le Bonheur Children's Hospital, Memphis, Tennessee; University of Tennessee Health Science Center, Memphis, Tennessee
| | - William J McKenna
- University College London, Institute of Cardiovascular Science, London, United Kingdom
| | | | | | | | | | | | | | | | | | - N A Mark Estes
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Wei Hua
- Fu Wai Hospital, Beijing, China
| | - Julia H Indik
- University of Arizona, Sarver Heart Center, Tucson, Arizona
| | - Jodie Ingles
- Agnes Ginges Centre for Molecular Cardiology at Centenary Institute, The University of Sydney, Sydney, Australia
| | | | - Roy M John
- Vanderbilt University Medical Center, Nashville, Tennessee
| | - Daniel P Judge
- Medical University of South Carolina, Charleston, South Carolina
| | - Roberto Keegan
- Hospital Privado Del Sur, Buenos Aires, Argentina; Hospital Español, Bahia Blanca, Argentina
| | | | - Mark S Link
- UT Southwestern Medical Center, Dallas, Texas
| | - Frank I Marcus
- University of Arizona, Sarver Heart Center, Tucson, Arizona
| | | | - Luisa Mestroni
- University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Silvia G Priori
- University of Pavia, Pavia, Italy; European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart); ICS Maugeri, IRCCS, Pavia, Italy
| | | | | | - Wataru Shimizu
- Department of Cardiovascular Medicine, Nippon Medical School, Tokyo, Japan
| | - J Peter van Tintelen
- University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands; Utrecht University Medical Center Utrecht, University of Utrecht, Department of Genetics, Utrecht, the Netherlands
| | - Arthur A M Wilde
- European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart (ERN GUARD-Heart); University of Amsterdam, Academic Medical Center, Amsterdam, the Netherlands; Department of Medicine, Columbia University Irving Medical Center, New York, New York
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10
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Mansour MJ, Hamoui O, Asmar J, Chammas E, Ayoub W, Daher J, AlJaroudi WA. Patients with Isolated Focal Right Ventricular Dyskinetic Segments: Toward a Better Understanding of This Cohort. J Cardiovasc Imaging 2019; 27:93-101. [PMID: 30993943 PMCID: PMC6470069 DOI: 10.4250/jcvi.2019.27.e16] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 01/17/2019] [Accepted: 02/06/2019] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND The 2010 revised Task Force criteria for the diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC) provided guidance for the classification of patients as definitive, borderline or possible ARVC. However, many patients with clinical suspicion for ARVC have isolated RV dyskinetic segments only and partly meet cardiac magnetic resonance (CMR) imaging criteria. This subgroup of patients and the implication of this imaging finding remain not well defined. METHODS There were 65 consecutive patients with clinical suspicion for ARVC who were referred for CMR between 2015 and 2017. The presence of fatty infiltration and fibrosis were assessed using T2 imaging and myocardial delayed enhancement sequences, respectively. RV wall motions, volumes and ejection fraction (EF) of all patients were re-analysed and quantified. Available data on family history, Holter findings, and electrocardiograms were also reviewed. RESULTS There were 5 patients (7.7%) that fulfilled major CMR criteria for ARVC: 4 were classified as having definitive ARVC; and 1/5 as borderline. There were 33 patients with no RV dyskinetic segments: none were classified as having definitive or borderline ARVC; 4/33 were classified as possible ARVC, leaving 29/33 as normal or no ARVC. Finally, there were 27 remaining patients (41.5%) with isolated RV dyskinetic segments: 1/27 was classified as definitive ARVC; 4/27 as borderline; 8/27 as possible; leaving 15/27 as indeterminate. Compared to control, those with isolated RV dyskinesia (including the subgroup labelled as indeterminate 15/27) had more abnormal RVEF, larger RV end-diastolic volume index (82 ± 12 mL/m2 vs. 72 ± 12 mL/m2, p-value 0.0127), and a trend for higher odds of dilated RV (odds ratio 3.0 [0.81–11], p-value 0.09). CONCLUSIONS Among patients with a clinical suspicion for ARVC, almost 40% had isolated focal RV dyskinetic segments with the majority remaining unclassified. This cohort had more RV dilation and abnormal EF compared to control.
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Affiliation(s)
- Mohamad Jihad Mansour
- Division of Cardiology, Faculty of Medical Sciences, Lebanese University, Hadath, Lebanon
- Division of Cardiovascular Medicine, Clemenceau Medical Center, Beirut, Lebanon
| | - Omar Hamoui
- Division of Cardiovascular Medicine, Clemenceau Medical Center, Beirut, Lebanon
| | - Joseph Asmar
- Division of Cardiology, Faculty of Medical Sciences, Lebanese University, Hadath, Lebanon
| | - Elie Chammas
- Division of Cardiology, Faculty of Medical Sciences, Lebanese University, Hadath, Lebanon
- Division of Cardiovascular Medicine, Clemenceau Medical Center, Beirut, Lebanon
| | - Wadih Ayoub
- Division of Cardiovascular Medicine, Clemenceau Medical Center, Beirut, Lebanon
| | - Jihad Daher
- Department of Radiology, Clemenceau Medical Center, Beirut, Lebanon
| | - Wael A. AlJaroudi
- Division of Cardiovascular Medicine, Clemenceau Medical Center, Beirut, Lebanon
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Wang W, James CA, Calkins H. Diagnostic and therapeutic strategies for arrhythmogenic right ventricular dysplasia/cardiomyopathy patient. Europace 2019; 21:9-21. [PMID: 29688316 PMCID: PMC6321962 DOI: 10.1093/europace/euy063] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 03/16/2018] [Indexed: 12/21/2022] Open
Abstract
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a rare inherited heart muscle disease characterized by ventricular tachyarrhythmia, predominant right ventricular dysfunction, and sudden cardiac death. Its pathophysiology involves close interaction between genetic mutations and exposure to physical activity. Mutations in genes encoding desmosomal protein are the most common genetic basis. Genetic testing plays important roles in diagnosis and screening of family members. Syncope, palpitation, and lightheadedness are the most common symptoms. The 2010 Task Force Criteria is the standard for diagnosis today. Implantation of a defibrillator in high-risk patients is the only therapy that provides adequate protection against sudden death. Selection of patients who are best candidates for defibrillator implantation is challenging. Exercise restriction is critical in affected individuals and at-risk family members. Antiarrhythmic drugs and ventricular tachycardia ablation are valuable but palliative components of the management. This review focuses on the current diagnostic and therapeutic strategies in ARVD/C and outlines the future area of development in this field.
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Affiliation(s)
- Weijia Wang
- Division of Cardiology, Department of Medicine, Johns Hopkins University, 600 N. Wolfe Street, Sheikh Zayed Tower 7125R, Baltimore, MD, USA
| | - Cynthia A James
- Division of Cardiology, Department of Medicine, Johns Hopkins University, 600 N. Wolfe Street, Sheikh Zayed Tower 7125R, Baltimore, MD, USA
| | - Hugh Calkins
- Division of Cardiology, Department of Medicine, Johns Hopkins University, 600 N. Wolfe Street, Sheikh Zayed Tower 7125R, Baltimore, MD, USA
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12
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Quality of life metrics in arrhythmogenic right ventricular cardiomyopathy patients: The impact of age, shock and sex. Int J Cardiol 2017; 248:216-220. [DOI: 10.1016/j.ijcard.2017.08.026] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 07/18/2017] [Accepted: 08/09/2017] [Indexed: 11/24/2022]
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13
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Femia G, Sy RW, Puranik R. Systematic review: Impact of the new task force criteria in the diagnosis of arrhythmogenic right ventricular cardiomyopathy. Int J Cardiol 2017; 241:311-317. [DOI: 10.1016/j.ijcard.2017.03.069] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Accepted: 03/13/2017] [Indexed: 11/26/2022]
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Current Concepts on Diagnosis and Prognosis of Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia. J Thorac Imaging 2016; 31:324-335. [DOI: 10.1097/rti.0000000000000171] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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15
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te Riele AS, James CA, Groeneweg JA, Sawant AC, Kammers K, Murray B, Tichnell C, van der Heijden JF, Judge DP, Dooijes D, van Tintelen JP, Hauer RN, Calkins H, Tandri H. Approach to family screening in arrhythmogenic right ventricular dysplasia/cardiomyopathy. Eur Heart J 2015; 37:755-63. [DOI: 10.1093/eurheartj/ehv387] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2015] [Accepted: 07/21/2015] [Indexed: 12/21/2022] Open
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16
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Rastegar N, Burt JR, Corona-Villalobos CP, Te Riele AS, James CA, Murray B, Calkins H, Tandri H, Bluemke DA, Zimmerman SL, Kamel IR. Cardiac MR findings and potential diagnostic pitfalls in patients evaluated for arrhythmogenic right ventricular cardiomyopathy. Radiographics 2015; 34:1553-70. [PMID: 25310417 DOI: 10.1148/rg.346140194] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiomyopathy characterized by fibrofatty replacement of the myocardium, ventricular tachycardia, and ventricular dysfunction that affects primarily the right ventricle (RV). This disease is not common but can be seen more frequently in young adults, and clinical manifestations range from no symptoms to lethal arrhythmia and sudden death. The diagnosis of ARVC is challenging and is based on the recently revised international task force criteria. Given the strengths of cardiac magnetic resonance (MR) imaging for depicting the RV, this modality plays an important role in the diagnosis of ARVC. Functional and structural abnormalities of the RV depicted with cardiac MR imaging constitute major and minor criteria in the revised task force criteria. Since the ARVC program was established at our center in 1998, there has been an increased awareness of a number of normal variants that are commonly misinterpreted as showing evidence for ARVC. On the basis of our clinical experience, the overdiagnosis of ARVC appears to reflect two fundamental problems: (a) a lack of awareness of diagnostic criteria that identify major and minor variables to be used for the diagnosis of ARVC, and (b) a lack of familiarity with the normal variants and mimics that may be misinterpreted as showing evidence of ARVC. The purpose of this article is to review the typical patterns of ventricular involvement in ARVC at cardiac MR imaging and to compare those with the patterns of normal variants and other diseases that can mimic ARVC. Online supplemental material is available for this article.
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Affiliation(s)
- Neda Rastegar
- From the Russell H. Morgan Department of Radiology and Radiological Sciences (N.R., J.R.B., C.P.C., S.L.Z., I.R.K.) and Division of Cardiology (C.A.J., B.M., H.C., H.T.), Johns Hopkins University School of Medicine, 600 N Wolfe St, MRI 143, Baltimore, MD 21287; Division of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands (A.S.t.R.); and Department of Radiology and Imaging Sciences, National Institutes of Health Clinical Center, Bethesda, Md (D.A.B.)
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Affiliation(s)
- Kyla E. Dunn
- From the Center for Inherited Cardiovascular Disease, Departments of Medicine and Genetics, Stanford University School of Medicine, Stanford, CA (K.E.D., E.A.A.), and Pediatric Heart Center, Lucile Packard Children's Hospital, Stanford Children's Health, Palo Alto, CA (K.E.D.)
| | - Euan A. Ashley
- From the Center for Inherited Cardiovascular Disease, Departments of Medicine and Genetics, Stanford University School of Medicine, Stanford, CA (K.E.D., E.A.A.), and Pediatric Heart Center, Lucile Packard Children's Hospital, Stanford Children's Health, Palo Alto, CA (K.E.D.)
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Jeudy J, Burke AP, White CS, Kramer GBG, Frazier AA. Cardiac Sarcoidosis: The Challenge of Radiologic-Pathologic Correlation:From the Radiologic Pathology Archives. Radiographics 2015; 35:657-79. [DOI: 10.1148/rg.2015140247] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Perazzolo Marra M, Rizzo S, Bauce B, De Lazzari M, Pilichou K, Corrado D, Thiene G, Iliceto S, Basso C. Arrhythmogenic right ventricular cardiomyopathy. Herz 2015; 40:600-6. [DOI: 10.1007/s00059-015-4228-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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21
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Te Riele ASJM, Hauer RN. Arrhythmogenic right ventricular dysplasia/cardiomyopathy: clinical challenges in a changing disease spectrum. Trends Cardiovasc Med 2015; 25:191-8. [PMID: 25601034 DOI: 10.1016/j.tcm.2014.11.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2014] [Revised: 11/03/2014] [Accepted: 11/06/2014] [Indexed: 01/09/2023]
Abstract
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy characterized by fibro-fatty replacement of predominantly the right ventricle (RV), which predisposes patients to life-threatening ventricular arrhythmias and usually slowly progressive ventricular dysfunction. The disease is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. Increased appreciation of ARVD/C as a "disease of the desmosome" has fueled research into possible disease mechanisms, and insights into ARVD/C pathogenesis are rapidly advancing. Although ARVD/C is known to preferentially affect the RV, early and/or predominant left ventricular involvement is increasingly recognized. Diagnosis is made by combining multiple sources of diagnostic information as prescribed by the consensus-based Task Force criteria. Affected individuals typically present in the third to fifth decade of life with palpitations, lightheadedness, or syncope due to frequent ventricular ectopy or arrhythmias originating from the RV. However, disease expression is highly variable, even among subjects from the same family or those carrying the same mutation. Since sudden cardiac death can be the first manifestation of the disease, optimizing the approach to early detection and risk stratification of ARVD/C is of utmost importance. This review will discuss the changing spectrum of ARVD/C based on recent advances in diagnosis, genetics, and improved understanding of disease pathophysiology.
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Affiliation(s)
- Anneline S J M Te Riele
- Division of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands; Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
| | - Richard N Hauer
- Division of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
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Pinamonti B, Brun F, Mestroni L, Sinagra G. Arrhythmogenic right ventricular cardiomyopathy: From genetics to diagnostic and therapeutic challenges. World J Cardiol 2014; 6:1234-44. [PMID: 25548613 PMCID: PMC4278158 DOI: 10.4330/wjc.v6.i12.1234] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 09/03/2014] [Accepted: 10/31/2014] [Indexed: 02/06/2023] Open
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disease characterized by myocyte loss and fibro-fatty tissue replacement. Diagnosis of ARVC remains a clinical challenge mainly at its early stages and in patients with minimal echocardiographic right ventricular (RV) abnormalities. ARVC shares some common features with other cardiac diseases, such as RV outflow ventricular tachycardia, Brugada syndrome, and myocarditis, due to arrhythmic expressivity and biventricular involvement. The identification of ARVC can be often challenging, because of the heterogeneous clinical presentation, highly variable intra- and inter-family expressivity and incomplete penetrance. This genotype-phenotype "plasticity" is largely unexplained. A familial history of ARVC is present in 30% to 50% of cases, and the disease is considered a genetic cardiomyopathy, usually inherited in an autosomal dominant pattern with variable penetrance and expressivity; in addition, autosomal recessive forms have been reported (Naxos disease and Carvajal syndrome). Diagnosis of ARVC relays on a scoring system, with major or minor criteria on the Revised Task Force Criteria. Implantable cardioverter defibrillators (ICDs) are increasingly utilized in patients with ARVC who have survived sudden death (SD) (secondary prevention). However, there are few data available to help identifying ARVC patients in whom the prophylactic implantation of an ICD is truly warranted. Prevention of SD is the primary goal of management. Pharmacologic treatment of arrhythmias, catheter ablation of ventricular tachycardia, and ICD are the mainstay of treatment of ARVC.
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Affiliation(s)
- Bruno Pinamonti
- Bruno Pinamonti, Francesca Brun, Gianfranco Sinagra, Cardiovascular Department, Ospedali Riuniti of Trieste, 34100 Trieste, Italy
| | - Francesca Brun
- Bruno Pinamonti, Francesca Brun, Gianfranco Sinagra, Cardiovascular Department, Ospedali Riuniti of Trieste, 34100 Trieste, Italy
| | - Luisa Mestroni
- Bruno Pinamonti, Francesca Brun, Gianfranco Sinagra, Cardiovascular Department, Ospedali Riuniti of Trieste, 34100 Trieste, Italy
| | - Gianfranco Sinagra
- Bruno Pinamonti, Francesca Brun, Gianfranco Sinagra, Cardiovascular Department, Ospedali Riuniti of Trieste, 34100 Trieste, Italy
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te Riele ASJM, Tandri H, Bluemke DA. Arrhythmogenic right ventricular cardiomyopathy (ARVC): cardiovascular magnetic resonance update. J Cardiovasc Magn Reson 2014; 16:50. [PMID: 25191878 PMCID: PMC4222825 DOI: 10.1186/s12968-014-0050-8] [Citation(s) in RCA: 100] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2014] [Accepted: 06/24/2014] [Indexed: 12/23/2022] Open
Abstract
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is one of the most arrhythmogenic forms of inherited cardiomyopathy and a frequent cause of sudden death in the young. Affected individuals typically present between the second and fourth decade of life with arrhythmias coming from the right ventricle. Pathogenic mutations in genes encoding the cardiac desmosome can be found in approximately 60% of index patients, leading to our current perception of ARVC as a desmosomal disease. Although ARVC is known to preferentially affect the right ventricle, early and/or predominant left ventricular involvement is increasingly recognized. Diagnosis is made by combining multiple sources of diagnostic information as prescribed by the "Task Force" criteria. Recent research suggests that electrical abnormalities precede structural changes in ARVC. Cardiovascular Magnetic Resonance (CMR) is an ideal technique in ARVC workup, as it provides comprehensive information on cardiac morphology, function, and tissue characterization in a single investigation. Prevention of sudden cardiac death using implantable cardioverter-defibrillators is the most important management consideration. This purpose of this paper is to provide an updated review of our understanding of the genetics, diagnosis, current state-of-the-art CMR acquisition and analysis, and management of patients with ARVC.
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Affiliation(s)
- Anneline SJM te Riele
- Department of Medicine, Division of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands
- Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Harikrishna Tandri
- Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - David A Bluemke
- Department of Radiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Radiology and Imaging Sciences, National Institutes of Health Clinical Center, 10 Center Drive, Bethesda 20892, MD, USA
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Groeneweg JA, van der Heijden JF, Dooijes D, van Veen TAB, van Tintelen JP, Hauer RN. Arrhythmogenic cardiomyopathy: diagnosis, genetic background, and risk management. Neth Heart J 2014; 22:316-25. [PMID: 24817548 PMCID: PMC4099433 DOI: 10.1007/s12471-014-0563-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Arrhythmogenic cardiomyopathy (AC), also known as arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), is a hereditary disease characterised by ventricular arrhythmias, right ventricular and/or left ventricular dysfunction, and fibrofatty replacement of cardiomyocytes. Patients with AC typically present between the second and the fourth decade of life with ventricular tachycardias. However, sudden cardiac death (SCD) may be the first manifestation, often at young age in the concealed stage of disease. AC is diagnosed by a set of clinically applicable criteria defined by an international Task Force. The current Task Force Criteria are the essential standard for a correct diagnosis in individuals suspected of AC. The genetic substrate for AC is predominantly identified in genes encoding desmosomal proteins. In a minority of patients a non-desmosomal mutation predisposes to the phenotype. Risk stratification in AC is imperfect at present. Genotype-phenotype correlation analysis may provide more insight into risk profiles of index patients and family members. In addition to symptomatic treatment, prevention of SCD is the most important therapeutic goal in AC. Therapeutic options in symptomatic patients include antiarrhythmic drugs, catheter ablation, and ICD implantation. Furthermore, patients with AC and also all pathogenic mutation carriers should be advised against practising competitive and endurance sports.
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Affiliation(s)
- J A Groeneweg
- Department of Cardiology, University Medical Center Utrecht, HP Q05.2.314, Heidelberglaan 100, PO Box 85500, 3508 GA, Utrecht, the Netherlands,
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25
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Making the Decision to Participate in Predictive Genetic Testing for Arrhythmogenic Right Ventricular Cardiomyopathy. J Genet Couns 2014; 23:1045-55. [DOI: 10.1007/s10897-014-9733-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Accepted: 05/28/2014] [Indexed: 10/25/2022]
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Vakil K, Minami E, Fishbein DP. Right ventricular sarcoidosis: is it time for updated diagnostic criteria? Tex Heart Inst J 2014; 41:203-7. [PMID: 24808785 DOI: 10.14503/thij-12-3086] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
A 55-year-old woman with a history of complete heart block, atrial flutter, and progressive right ventricular failure was referred to our tertiary care center to be evaluated for cardiac transplantation. The patient's clinical course included worsening right ventricular dysfunction for 3 years before the current evaluation. Our clinical findings raised concerns about arrhythmogenic right ventricular cardiomyopathy. Noninvasive imaging, including a positron emission tomographic scan, did not reveal obvious myocardial pathologic conditions. Given the end-stage nature of the patient's right ventricular failure and her dependence on inotropic agents, she underwent urgent listing and subsequent heart transplantation. Pathologic examination of the explanted heart revealed isolated right ventricular sarcoidosis with replacement fibrosis. Biopsy samples of the cardiac allograft 6 months after transplantation showed no recurrence of sarcoidosis. This atypical presentation of isolated cardiac sarcoidosis posed a considerable diagnostic challenge. In addition to discussing the patient's case, we review the relevant medical literature and discuss the need for updated differential diagnostic criteria for end-stage right ventricular failure that mimics arrhythmogenic right ventricular cardiomyopathy.
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Affiliation(s)
- Kairav Vakil
- Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington 98195
| | - Elina Minami
- Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington 98195
| | - Daniel P Fishbein
- Division of Cardiology, Department of Medicine, University of Washington, Seattle, Washington 98195
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Femia G, Hsu C, Singarayar S, Sy RW, Kilborn M, Parker G, McGuire M, Semsarian C, Puranik R. Impact of new task force criteria in the diagnosis of arrhythmogenic right ventricular cardiomyopathy. Int J Cardiol 2014; 171:179-83. [DOI: 10.1016/j.ijcard.2013.11.092] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2013] [Accepted: 11/28/2013] [Indexed: 10/25/2022]
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Shaheen F, Iqbal K, Hafeez I, Choh NA, Tramboo NA, Lone A, Iqbal S, Ahmed W, Gupta A. Clinico-radiological profile of arrhythmogenic right ventricular dysplasia at a tertiary care center: Two year experience. J Saudi Heart Assoc 2013; 25:79-84. [PMID: 24174851 DOI: 10.1016/j.jsha.2013.03.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Revised: 03/06/2013] [Accepted: 03/07/2013] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Arrythmogenic right ventricular dysplasia (ARVD/C) refers to fibro fatty infiltration replacement of ventricular myocardium especially that of right ventricle. The clinical presentation varies from asymptomatic state to ventricular tachycardia, heart failure and even sudden death. Diagnosis is established using modified ARVD/C taskforce criteria. Among all the various modalities of diagnosis, magnetic resonance imaging (MRI) gives most comprehensive evaluation of both morphological and functional abnormalities in this disease. MRI may not only obviate need for myocardial biopsy but also give insights into the nature of disease like presence of left ventricular myocardial involvement. We present our 2 years experience of ARVD/C patents who were admitted in our center and in whom diagnosis of ARVD/C was supported by excellent MR imaging. MATERIALS AND METHODS This study was conducted by Department of Radiology and Cardiology SKIMS, a tertiary care center for a period of 2 years. Patients with suspected ARVD/C based on clinical, electrophysiological and echocardiographic findings were subjected to MR imaging. Patients were excluded if they had history metallic implants, claustrophobia or were uncooperative. In this study stress was laid on diagnostic role of MRI in ARVD/C. RESULTS The median age at presentation was 31 years (range 21-43 years). 80% of patients were males. Most common clinical presentation was palpatations (40%). Syncope was present in 27% and heart failure in 13%. EKG suggestive of ARVD was seen in 87%. Echocardiographic features suggestive of ARVD/C was seen in all 15 patients. Family history of premature sudden death less than 35 years old was present in one patient only. MRI evidence classical for ARVD/C was seen in 80%. CONCLUSION Demographic features and mode of presentation of our patients is consistent with what has been rest of the world. We performed MRI in all patients to increase the specificity of our diagnosis. MR imaging allows a three-dimensional evaluation of the right ventricle and provides the most important anatomic, functional, and morphologic criteria for diagnosis of ARVD/C within one single study. MR imaging appears to be the optimal imaging technique for detection and follow-up of clinically suspected ARVD/C.
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Affiliation(s)
- Feroze Shaheen
- Department of Radiology, Shere-Kashmir-Institute of Medical Sciences (SKIMS), Soura, Srinagar, J&K 190 011
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Groeneweg JA, van der Zwaag PA, Olde Nordkamp LRA, Bikker H, Jongbloed JDH, Jongbloed R, Wiesfeld ACP, Cox MGPJ, van der Heijden JF, Atsma DE, de Boer K, Doevendans PA, Vink A, van Veen TAB, Dooijes D, van den Berg MP, Wilde AAM, van Tintelen JP, Hauer RN. Arrhythmogenic right ventricular dysplasia/cardiomyopathy according to revised 2010 task force criteria with inclusion of non-desmosomal phospholamban mutation carriers. Am J Cardiol 2013; 112:1197-206. [PMID: 23871674 DOI: 10.1016/j.amjcard.2013.06.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 06/06/2013] [Accepted: 06/06/2013] [Indexed: 01/15/2023]
Abstract
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is frequently associated with desmosomal mutations. However, nondesmosomal mutations may be involved. The aim of this study was to assess the contribution of a phospholamban (PLN) gene mutation to ARVD/C diagnosis according to the revised 2010 task force criteria (TFC). In 142 Dutch patients (106 men, mean age 51 ± 13 years) with proven ARVD/C (fulfillment of 2010 TFC for diagnosis), 5 known desmosomal genes (PKP2, DSP, DSC2, DSG2, and JUP) and the nondesmosomal PLN gene were screened. After genetic analysis, phenotypic characteristics of desmosomal versus PLN mutation carriers were compared. In 59 of 142 patients with ARVD/C (42%), no desmosomal mutation was found. In 19 of 142 patients (13%), the PLN founder mutation c.40_42delAGA (p.Arg14del) was identified. PLN mutation carriers more often had low-voltage electrocardiograms (p = 0.004), inverted T waves in leads V4 to V6 (p <0.001), and additional structural (p = 0.007) or functional (p = 0.017) left ventricular impairment, whereas desmosomal mutation carriers had more solitary right ventricular abnormalities. The revised TFC included 21 of 142 patients with proven ARVD/C who did not meet the 1994 TFC, including 7 PLN mutation carriers. In conclusion, there is a substantial contribution of PLN mutation to ARVD/C diagnosis by the 2010 TFC. In 32% of patients (19 of 59) with genetically unexplained proven ARVD/C, this nondesmosomal mutation was found. PLN mutation carriers have ARVD/C characteristics, including important right ventricular involvement, and additionally more often low-voltage electrocardiograms, inverted T waves in the left precordial leads, and left ventricular involvement.
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Affiliation(s)
- Judith A Groeneweg
- Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands.
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Te Riele ASJM, James CA, Philips B, Rastegar N, Bhonsale A, Groeneweg JA, Murray B, Tichnell C, Judge DP, Van Der Heijden JF, Cramer MJM, Velthuis BK, Bluemke DA, Zimmerman SL, Kamel IR, Hauer RNW, Calkins H, Tandri H. Mutation-positive arrhythmogenic right ventricular dysplasia/cardiomyopathy: the triangle of dysplasia displaced. J Cardiovasc Electrophysiol 2013; 24:1311-20. [PMID: 23889974 DOI: 10.1111/jce.12222] [Citation(s) in RCA: 140] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2013] [Accepted: 06/12/2013] [Indexed: 12/25/2022]
Abstract
INTRODUCTION The traditional description of the Triangle of Dysplasia in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) predates genetic testing and excludes biventricular phenotypes. METHODS AND RESULTS We analyzed Cardiac Magnetic Resonance (CMR) studies of 74 mutation-positive ARVD/C patients for regional abnormalities on a 5-segment RV and 17-segment LV model. The location of electroanatomic endo- and epicardial scar and site of successful VT ablation was recorded in 11 ARVD/C subjects. Among 54/74 (73%) subjects with abnormal CMR, the RV was abnormal in almost all (96%), and 52% had biventricular involvement. Isolated LV abnormalities were uncommon (4%). Dyskinetic basal inferior wall (94%) was the most prevalent RV abnormality, followed by basal anterior wall (87%) dyskinesis. Subepicardial fat infiltration in the posterolateral LV (80%) was the most frequent LV abnormality. Similar to CMR data, voltage maps revealed scar (<0.5 mV) in the RV basal inferior wall (100%), followed by the RV basal anterior wall (64%) and LV posterolateral wall (45%). All 16 RV VTs originated from the basal inferior wall (50%) or basal anterior wall (50%). Of 3 LV VTs, 2 localized to the posterolateral wall. In both modalities, RV apical involvement never occurred in isolation. CONCLUSION Mutation-positive ARVD/C exhibits a previously unrecognized characteristic pattern of disease involving the basal inferior and anterior RV, and the posterolateral LV. The RV apex is only involved in advanced ARVD/C, typically as a part of global RV involvement. These results displace the RV apex from the Triangle of Dysplasia, and provide insights into the pathophysiology of ARVD/C.
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Affiliation(s)
- Anneline S J M Te Riele
- Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Malignant arrhythmogenic right ventricular dysplasia/cardiomyopathy with a normal 12-lead electrocardiogram: a rare but underrecognized clinical entity. Heart Rhythm 2013; 10:1484-91. [PMID: 23816439 DOI: 10.1016/j.hrthm.2013.06.022] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Indexed: 12/25/2022]
Abstract
BACKGROUND In Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C), a normal electrocardiogram (ECG) is considered reassuring. However, some patients with ARVD/C experiencing ventricular arrhythmias have a normal ECG. OBJECTIVES To estimate how often patients with ARVD/C experiencing ventricular arrhythmias have a normal ECG during sinus rhythm, and to provide a clinical profile of these patients. METHODS We included 145 patients with ARVD/C experiencing a documented sustained ventricular arrhythmia. Conventional 12-lead sinus rhythm ECGs within 6 months of the event were reviewed for diagnostic Task Force Criteria (TFC). ECGs were classified as abnormal (≥1 TFC), nonspecific (abnormal, no TFC), or normal. Cardiologic investigations within 6 months of the event were evaluated as per TFC in those with a nonspecific or normal ECG. RESULTS The ECG was nonspecific or normal in 17 of 145 (12%) subjects. Mean age of these patients was 41.3 ± 12.4 years and 14 (82%) were men, comparable to those with an abnormal ECG. Most patients with a nonspecific or normal ECG showed ≥1 TFC on Holter monitoring (n = 9 of 10) and signal-averaged ECG (n = 4 of 5), and all had nonsustained ventricular tachycardia recorded. Among 15 patients who underwent structural evaluation, 11 (73%) showed structural TFC (9 major and 2 minor). CONCLUSIONS Although most patients with ARVD/C experiencing arrhythmias have an abnormal ECG, a nonspecific or normal ECG does not preclude ARVD/C diagnosis. All patients with a nonspecific or normal ECG had alternative evidence of disease expression. These results alert the physician not to rely exclusively on ECG in ARVD/C, but to assess arrhythmic risk by comprehensive clinical evaluation.
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Noorman M, Hakim S, Asimaki A, Vreeker A, van Rijen HVM, van der Heyden MAG, de Jonge N, de Weger RA, Hauer RNW, Saffitz JE, van Veen TAB. Reduced plakoglobin immunoreactivity in arrhythmogenic cardiomyopathy: methodological considerations. Cardiovasc Pathol 2013; 22:314-8. [PMID: 23688911 DOI: 10.1016/j.carpath.2013.04.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Revised: 04/03/2013] [Accepted: 04/06/2013] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Arrhythmogenic cardiomyopathy (AC) primarily is considered to be a desmosomal disease with a predominant right ventricular phenotype. Reduced signal intensity for junctional plakoglobin (JUP) at the intercalated disks has been proposed as a marker that contributes to diagnosis of the disease. In this technical study, we investigated how methodology-related differences caused by tissue preservation and antibody dilutions affect an appropriate diagnosis. METHODS Autopsy and biopsy material was available from a total of 7 control and 25 AC patients that fulfilled the diagnostic Task Force Criteria as proposed in 2010. Immunohistochemical analysis was performed on cryosections and formalin-fixed material using antibodies against JUP and N-Cadherin. RESULTS Immunohistochemistry (1:1000 antibody dilution) on formalin-fixed material showed a reduced signal for JUP in 7/10 AC patients in a bidirectional, double-blinded exchange experiment in which 77% of individuals were correctly classified. Unmasking this disturbed JUP pattern was highly dependent on tissue preservation and antibody dilution since on cryosections the disturbed pattern in patients could only be unmasked at a very strong antibody dilution of 1:100000. CONCLUSIONS Reduced immunoreactive signal of JUP at the intercalated disks can be observed in a majority of AC patients. These changes can comparably be detected on both cryo- (74%) and formalin-fixed material (70%) but demand a different, highly defined, and uniformly used approach.
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Affiliation(s)
- Maartje Noorman
- Department of Medical Physiology, University Medical Center Utrecht, 3584CM Utrecht, The Netherlands; Interuniversity Cardiology Institute, The Netherlands
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Paul M, Wichter T, Fabritz L, Waltenberger J, Schulze-Bahr E, Kirchhof P. Arrhythmogenic right ventricular cardiomyopathy: an update on pathophysiology, genetics, diagnosis, and risk stratification. Herzschrittmacherther Elektrophysiol 2012; 23:186-95. [PMID: 23011601 DOI: 10.1007/s00399-012-0233-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2012] [Accepted: 07/20/2012] [Indexed: 12/17/2022]
Abstract
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy accounting for life-threatening ventricular tachyarrhythmias and sudden death in young individuals and athletes. Over the past years, mutations in desmosomal genes have been identified as disease-causative. However, genetic heterogeneity and variable phenotypic expression alongside with diverse disease progression still render the evaluation of its prognostic implication difficult. ARVC was initially entered into the canon of cardiomyopathies of the World Health Organization in 1995, and international efforts have resulted in the 2010 modified diagnostic criteria for ARVC. Despite all additional insights into pathophysiology, clinical management, and modern risk stratification, under-/misdiagnosing of ARVC remains a problem and hampers reliable statements on the incidence, prevalence, and natural course of the disease.This review provides a comprehensive overview of the current literature on the pathogenesis, diagnosis, treatment, and prognosis of ARVC and sheds some light on potential new developments in these areas.
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Affiliation(s)
- M Paul
- Division of Cardiology, Department of Cardiovascular Medicine, University Hospital Münster, Albert-Schweitzer-Campus 1 (Gebäude A1), 48149, Münster, Germany.
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Teske AJ, Cox MGPJ, Te Riele ASJM, De Boeck BW, Doevendans PA, Hauer RNW, Cramer MJM. Early detection of regional functional abnormalities in asymptomatic ARVD/C gene carriers. J Am Soc Echocardiogr 2012; 25:997-1006. [PMID: 22727198 DOI: 10.1016/j.echo.2012.05.008] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2011] [Indexed: 02/07/2023]
Abstract
BACKGROUND The overt stage of arrhythmogenic right ventricular (RV) dysplasia/cardiomyopathy (ARVD/C) is preceded by a concealed stage with minor or no signs of disease. However, sudden death may occur in this early phase. Deformation imaging may contribute to early diagnosis. The aims of this study were to compare the diagnostic accuracy of the conventional (1994) versus the recently published (2010) new echocardiographic criteria for ARVD/C and to evaluate the additional value of echocardiographic tissue deformation imaging to detect subclinical RV functional abnormalities in asymptomatic carriers of pathogenic ARVD/C mutations. METHODS Fourteen asymptomatic first-degree relatives of ARVD/C probands (the ARVD/C-r group; mean age, 38.0 ± 13.2 years) with a pathogenic plakophilin-2 mutation and a group of age-matched controls (n = 56; mean age, 38.2 ± 12.7 years) were included at a 1:4 ratio. A complete echocardiographic evaluation (dimensions, global systolic parameters, and visual assessment and deformation imaging of the RV free wall including Doppler tissue imaging and two-dimensional strain echocardiography) was obtained. Peak systolic strain less negative than -18% and/or postsystolic shortening (postsystolic index > 15%) in any RV segment was considered abnormal. RESULTS RV dimensions in the ARVD/C-r group were similar to those in controls (RV outflow tract, 15.4 ± 2.9 vs 14.4 ± 1.9 mm/m(2), P = NS; RV inflow tract, 18.6 ± 2.6 vs 19.1 ± 2.6 mm/m(2), P = NS), and global systolic parameters were moderately reduced (tricuspid annular plane systolic excursion, 20.0 ± 3.2 vs 23.9 ± 2.8 mm, P = .001; RV fractional area change, 40.3 ± 8.4 vs 40.6 ± 7.1, P = NS). According to task force criteria, 57% of the ARVD/C-r group and 29% of controls were classified as abnormal when applying the 1994 criteria and 29% and 4% when applying the 2010 criteria, respectively. Doppler tissue imaging and two-dimensional strain deformation (and strain rate) values were reduced in the ARVD/C-r group in the basal and mid RV segments compared with controls (P < .001). In the ARVD/C-r group, peak systolic strain less negative than -18% was seen in six patients (43%), postsystolic strain in nine (64%), and either abnormality in 10 (71%), almost exclusively in the basal segment; these findings were observed in none of the controls. CONCLUSIONS The 2010 criteria for ARVD/C improve specificity, whereas sensitivity is significantly reduced in this asymptomatic population. In contrast, echocardiographic deformation imaging detects functional abnormalities in the subtricuspid region in 71% of asymptomatic carriers of a pathogenic plakophilin-2 mutation, while regional deformation was normal in all control subjects, indicating superiority of both sensitivity and specificity with these new modalities.
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Affiliation(s)
- Arco J Teske
- Department of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands.
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35
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Rickelt S. Plakophilin-2: a cell-cell adhesion plaque molecule of selective and fundamental importance in cardiac functions and tumor cell growth. Cell Tissue Res 2012; 348:281-94. [PMID: 22281687 PMCID: PMC3349858 DOI: 10.1007/s00441-011-1314-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2011] [Accepted: 12/16/2011] [Indexed: 01/23/2023]
Abstract
Within the characteristic ensemble of desmosomal plaque proteins, the armadillo protein plakophilin-2 (Pkp2) is known as a particularly important regulatory component in the cytoplasmic plaques of various other cell-cell junctions, such as the composite junctions (areae compositae) of the myocardiac intercalated disks and in the variously-sized and -shaped complex junctions of permanent cell culture lines derived therefrom. In addition, Pkp2 has been detected in certain protein complexes in the nucleoplasm of diverse kinds of cells. Using a novel set of highly sensitive and specific antibodies, both kinds of Pkp2, the junctional plaque-bound and the nuclear ones, can also be localized to the cytoplasmic plaques of diverse non-desmosomal cell-cell junction structures. These are not only the puncta adhaerentia and the fasciae adhaerentes connecting various types of highly proliferative non-epithelial cells growing in culture but also some very proliferative states of cardiac interstitial cells and cardiac myxomata, including tumors growing in situ as well as fetal stages of heart development and cultures of valvular interstitial cells. Possible functions and assembly mechanisms of such Pkp2-positive cell-cell junctions as well as medical consequences are discussed.
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Affiliation(s)
- Steffen Rickelt
- Helmholtz Group for Cell Biology, German Cancer Research Center, Heidelberg, Germany.
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Rickelt S, Pieperhoff S. Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases. Cell Tissue Res 2012; 348:325-33. [PMID: 22450909 PMCID: PMC3349860 DOI: 10.1007/s00441-012-1365-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2012] [Accepted: 02/03/2012] [Indexed: 01/30/2023]
Abstract
In the past decade, an avalanche of findings and reports has correlated arrhythmogenic ventricular cardiomyopathies (ARVC) and Naxos and Carvajal diseases with certain mutations in protein constituents of the special junctions connecting the polar regions (intercalated disks) of mature mammalian cardiomyocytes. These molecules, apparently together with some specific cytoskeletal proteins, are components of (or interact with) composite junctions. Composite junctions contain the amalgamated fusion products of the molecules that, in other cell types and tissues, occur in distinct separate junctions, i.e. desmosomes and adherens junctions. As the pertinent literature is still in an expanding phase and is obviously becoming important for various groups of researchers in basic cell and molecular biology, developmental biology, histology, physiology, cardiology, pathology and genetics, the relevant references so far recognized have been collected and are presented here in the following order: desmocollin-2 (Dsc2, DSC2), desmoglein-2 (Dsg2, DSG2), desmoplakin (DP, DSP), plakoglobin (PG, JUP), plakophilin-2 (Pkp2, PKP2) and some non-desmosomal proteins such as transmembrane protein 43 (TMEM43), ryanodine receptor 2 (RYR2), desmin, lamins A and C, striatin, titin and transforming growth factor-β3 (TGFβ3), followed by a collection of animal models and of reviews, commentaries, collections and comparative studies.
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Affiliation(s)
- Steffen Rickelt
- Helmholtz Group for Cell Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Building TP4, 69120 Heidelberg, Germany
- Progen Biotechnik, Heidelberg, Germany
| | - Sebastian Pieperhoff
- BHF Centre for Cardiovascular Science, The Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, EH164TJ Edinburgh, Scotland UK
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Impact of the revision of arrhythmogenic right ventricular cardiomyopathy/dysplasia task force criteria on its prevalence by CMR criteria. JACC Cardiovasc Imaging 2012; 4:282-7. [PMID: 21414577 DOI: 10.1016/j.jcmg.2011.01.005] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2010] [Revised: 01/20/2011] [Accepted: 01/20/2011] [Indexed: 12/15/2022]
Abstract
OBJECTIVES The purpose of our study was to assess the impact of revised versus original criteria on the prevalence of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) criteria in cardiac magnetic resonance (CMR) studies. BACKGROUND Recently, the ARVC/D task force criteria have been revised, aiming for a better diagnostic sensitivity. The implications of this revision on clinical decision making are unknown. METHODS We retrospectively evaluated the CMR scans of 294 patients referred for ARVC/D between 2005 and 2010, and determined the presence or absence of major and minor CMR criteria using the original and the revised task force criteria. Previously, major and minor abnormalities were identified by the presence of right ventricle dilation (global or segmental), right ventricle microaneurysm, or regional hypokinesis. The revised criteria require the combination of severe regional wall motion abnormalities (akinesis or dyskinesis or dyssynchrony) with global right ventricle dilation or dysfunction (quantitative assessment). RESULTS Applying the original criteria, 69 patients (23.5%) had major original criteria, versus 19 patients (6.5%) with the revised criteria. Forty-three patients (62.3%) with major original criteria did not meet any of the revised criteria. Using the original criteria, 172 patients (58.5%) had at least 1 minor criterion versus 12 patients (4%) with the revised task force criteria; 167 patients (97%) with minor original criteria did not meet any of the revised criteria. In the subgroup of 134 patients with complete diagnostic work-up of ARVC, 10 patients met the diagnosis of proven ARVC/D without counting imaging criteria. Only 4 of 10 met major criteria according to the revised CMR criteria; none met minor criteria. However, 112 of 124 patients without ARVC/D were correctly classified as negative by major and minor criteria (specificity 94% and 96%, respectively). CONCLUSIONS In our experience, the revision of the ARVC/D task force imaging criteria significantly reduced the overall prevalence of major and minor criteria. The revision, although maintaining a high specificity, may not have improved the sensitivity for identifying patients with ARVC/D. Larger studies including follow-up are required.
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The Editors. Circulation: Arrhythmia and Electrophysiology
Editors' Picks. Circ Arrhythm Electrophysiol 2011. [DOI: 10.1161/circep.111.968941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The following articles are being highlighted as part of
Circulation: Arrhythmia and Electrophysiology's
Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in
Circulation: Arrhythmia and Electrophysiology
and the rest of the
Circulation
portfolio. The studies included in this article represent the most read manuscripts published on the topic of atrial fibrillation in 2009 and 2010.
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39
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Cardiovascular genetics provides new insights for early onset arrhythmogenic right ventricular dysplasia/cardiomyopathy. Heart Rhythm 2011; 8:1696-7. [DOI: 10.1016/j.hrthm.2011.07.024] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2011] [Indexed: 11/22/2022]
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Affiliation(s)
- Jeffrey E. Saffitz
- From the Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA
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Aro AL, Anttonen O, Tikkanen JT, Junttila MJ, Kerola T, Rissanen HA, Reunanen A, Huikuri HV. Intraventricular Conduction Delay in a Standard 12-Lead Electrocardiogram as a Predictor of Mortality in the General Population. Circ Arrhythm Electrophysiol 2011; 4:704-10. [DOI: 10.1161/circep.111.963561] [Citation(s) in RCA: 131] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Background—
Prolonged duration of QRS complex in a 12-lead ECG is associated with adverse prognosis in patients with cardiac disease, but its significance is not well established in the general population. In particular, there is a paucity of data on the prognostic significance of nonspecific intraventricular conduction delay in apparently healthy subjects.
Methods and Results—
We evaluated the 12-lead ECGs of 10 899 Finnish middle-aged subjects from the general population (52% of whom were men; mean age 44±8.5 years) between 1966 and 1972 and followed them for 30±11 years. Primary end points were all-cause mortality, cardiac mortality, and arrhythmic death. Prolonged QRS duration was defined as QRS ≥110 ms and intraventricular conduction delay as QRS ≥110 ms, without the criteria of complete or incomplete bundle-branch block. QRS duration ≥110 ms was present in 1.3% (n=147) and intraventricular conduction delay in 0.6% (n=67) of the subjects. Prolonged QRS duration predicted all-cause mortality (multivariate-adjusted relative risk [RR] 1.48; 95% confidence interval [CI] 1.22–1.81;
P
<0.001), cardiac mortality (RR 1.94; CI 1.44–2.63;
P
<0.001), and sudden arrhythmic death (RR 2.14; CI 1.38–3.33;
P
=0.002). Subjects with intraventricular conduction delay had increased all-cause mortality (RR 2.01; CI 1.52–2.66;
P
<0.001), increased cardiac mortality (RR 2.53; CI 1.64–3.90;
P
<0.001), and an elevated risk of arrhythmic death (RR 3.11; CI 1.74–5.54;
P
=0.001). Left bundle-branch block also weakly predicted arrhythmic death (
P
=0.04), but right bundle-branch block was not associated with increased mortality.
Conclusions—
Prolonged QRS duration in a standard 12-lead ECG is associated with increased mortality in a general population, with intraventricular conduction delay being most strongly associated with an increased risk of arrhythmic death.
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Affiliation(s)
- Aapo L. Aro
- From the Division of Cardiology (A.L.A.), Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Department of Internal Medicine (A.L.A., O.A., T.K.), Päijät-Häme Central Hospital, Lahti, Finland; Institute of Clinical Medicine (J.T.T., M.J.J., H.V.H.), Department of Internal Medicine, University of Oulu, Oulu, Finland; and National Institute for Health & Welfare (H.A.R., A.R.), Helsinki, Finland
| | - Olli Anttonen
- From the Division of Cardiology (A.L.A.), Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Department of Internal Medicine (A.L.A., O.A., T.K.), Päijät-Häme Central Hospital, Lahti, Finland; Institute of Clinical Medicine (J.T.T., M.J.J., H.V.H.), Department of Internal Medicine, University of Oulu, Oulu, Finland; and National Institute for Health & Welfare (H.A.R., A.R.), Helsinki, Finland
| | - Jani T. Tikkanen
- From the Division of Cardiology (A.L.A.), Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Department of Internal Medicine (A.L.A., O.A., T.K.), Päijät-Häme Central Hospital, Lahti, Finland; Institute of Clinical Medicine (J.T.T., M.J.J., H.V.H.), Department of Internal Medicine, University of Oulu, Oulu, Finland; and National Institute for Health & Welfare (H.A.R., A.R.), Helsinki, Finland
| | - M. Juhani Junttila
- From the Division of Cardiology (A.L.A.), Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Department of Internal Medicine (A.L.A., O.A., T.K.), Päijät-Häme Central Hospital, Lahti, Finland; Institute of Clinical Medicine (J.T.T., M.J.J., H.V.H.), Department of Internal Medicine, University of Oulu, Oulu, Finland; and National Institute for Health & Welfare (H.A.R., A.R.), Helsinki, Finland
| | - Tuomas Kerola
- From the Division of Cardiology (A.L.A.), Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Department of Internal Medicine (A.L.A., O.A., T.K.), Päijät-Häme Central Hospital, Lahti, Finland; Institute of Clinical Medicine (J.T.T., M.J.J., H.V.H.), Department of Internal Medicine, University of Oulu, Oulu, Finland; and National Institute for Health & Welfare (H.A.R., A.R.), Helsinki, Finland
| | - Harri A. Rissanen
- From the Division of Cardiology (A.L.A.), Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Department of Internal Medicine (A.L.A., O.A., T.K.), Päijät-Häme Central Hospital, Lahti, Finland; Institute of Clinical Medicine (J.T.T., M.J.J., H.V.H.), Department of Internal Medicine, University of Oulu, Oulu, Finland; and National Institute for Health & Welfare (H.A.R., A.R.), Helsinki, Finland
| | - Antti Reunanen
- From the Division of Cardiology (A.L.A.), Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Department of Internal Medicine (A.L.A., O.A., T.K.), Päijät-Häme Central Hospital, Lahti, Finland; Institute of Clinical Medicine (J.T.T., M.J.J., H.V.H.), Department of Internal Medicine, University of Oulu, Oulu, Finland; and National Institute for Health & Welfare (H.A.R., A.R.), Helsinki, Finland
| | - Heikki V. Huikuri
- From the Division of Cardiology (A.L.A.), Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland; Department of Internal Medicine (A.L.A., O.A., T.K.), Päijät-Häme Central Hospital, Lahti, Finland; Institute of Clinical Medicine (J.T.T., M.J.J., H.V.H.), Department of Internal Medicine, University of Oulu, Oulu, Finland; and National Institute for Health & Welfare (H.A.R., A.R.), Helsinki, Finland
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Abstract
The following articles are being highlighted as part of
Circulation's
Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in
Circulation
and the
Circulation
subspecialty journals. The studies included in this article represent the most read manuscripts published on the topic of arrhythmia and electrophysiology in 2009 and 2010.
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Kapplinger JD, Landstrom AP, Salisbury BA, Callis TE, Pollevick GD, Tester DJ, Cox MGPJ, Bhuiyan Z, Bikker H, Wiesfeld ACP, Hauer RNW, van Tintelen JP, Jongbloed JDH, Calkins H, Judge DP, Wilde AAM, Ackerman MJ. Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise. J Am Coll Cardiol 2011; 57:2317-27. [PMID: 21636032 DOI: 10.1016/j.jacc.2010.12.036] [Citation(s) in RCA: 235] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2010] [Revised: 11/18/2010] [Accepted: 12/01/2010] [Indexed: 02/08/2023]
Abstract
OBJECTIVES The aims of this study were to determine the spectrum and prevalence of "background genetic noise" in the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) genetic test and to determine genetic associations that can guide the interpretation of a positive test result. BACKGROUND ARVC is a potentially lethal genetic cardiovascular disorder characterized by myocyte loss and fibrofatty tissue replacement of the right ventricle. Genetic variation among the ARVC susceptibility genes has not been systematically examined, and little is known about the background noise associated with the ARVC genetic test. METHODS Using direct deoxyribonucleic acid sequencing, the coding exons/splice junctions of PKP2, DSP, DSG2, DSC2, and TMEM43 were genotyped for 93 probands diagnosed with ARVC from the Netherlands and 427 ostensibly healthy controls of various ethnicities. Eighty-two additional ARVC cases were obtained from published reports, and additional mutations were included from the ARVD/C Genetic Variants Database. RESULTS The overall yield of mutations among ARVC cases was 58% versus 16% in controls. Radical mutations were hosted by 0.5% of control individuals versus 43% of ARVC cases, while 16% of controls hosted missense mutations versus a similar 21% of ARVC cases. Relative to controls, mutations in cases occurred more frequently in non-Caucasians, localized to the N-terminal regions of DSP and DSG2, and localized to highly conserved residues within PKP2 and DSG2. CONCLUSIONS This study is the first to comprehensively evaluate genetic variation in healthy controls for the ARVC susceptibility genes. Radical mutations are high-probability ARVC-associated mutations, whereas rare missense mutations should be interpreted in the context of race and ethnicity, mutation location, and sequence conservation.
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Affiliation(s)
- Jamie D Kapplinger
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
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Yamashina Y, Yagi T, Namekawa A, Ishida A, Sato H, Nakagawa T, Sakuramoto M, Sato E, Yambe T. Prevalence and characteristics of idiopathic right ventricular outflow tract arrhythmias associated with J-waves. Europace 2011; 13:1774-80. [PMID: 21846644 DOI: 10.1093/europace/eur256] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
AIM The arrhythmogenic relationship between the presence of J-waves during sinus rhythm and idiopathic ventricular tachycardia (VT) or pre-mature ventricular contractions (PVCs) originating from the right ventricular outflow tract (RVOT) has not been reported. The aim of this study was to investigate the prevalence and characteristics of idiopathic RVOT-VT/PVCs associated with J-waves. METHODS AND RESULTS The study enrolled 138 consecutive idiopathic RVOT-VT/PVC patients undergoing radiofrequency catheter ablation (RFCA) and 276 age- and gender-matched control subjects. The prevalence of J-waves was assessed in each cohort, and the clinical and electrophysiological data were compared between the RVOT-VT/PVC patients with J-waves (J-RVOT-VT/PVC group) and those without (non-J-RVOT-VT/PVC group). J-waves were more common among patients with idiopathic RVOT-VT/PVCs than among the matched control subjects (40 vs. 16% P < 0.001). The J-RVOT-VT/PVC group had a higher incidence of sustained VT (25 vs. 5%, P < 0.01), shorter VT cycle length (302 ± 57 vs. 351 ± 58 ms, P < 0.001), and more episodes of syncope (25 vs. 2%, P < 0.001) than did the non-J-RVOT-VT/PVC group. However, no patients demonstrated any ventricular fibrillation (VF) or cardiac sudden death in either group. CONCLUSIONS There was a high prevalence of J-waves in the idiopathic RVOT-VT/PVC patients referred for RFCA. Although patients with idiopathic RVOT arrhythmias associated with J-waves might have a more enhanced arrhythmogenicity than those without J-waves, the significance of those J-waves was limited in terms of the prognosis and VF.
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Navarro-Manchón J, Fernández E, Igual B, Asimaki A, Syrris P, Osca J, Salvador A, Zorio E. Miocardiopatía arritmogénica con afectación predominante del ventrículo izquierdo por una mutación nueva «sin sentido» en desmoplaquina. Rev Esp Cardiol 2011; 64:530-4. [DOI: 10.1016/j.recesp.2010.10.020] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2010] [Accepted: 10/12/2010] [Indexed: 01/20/2023]
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Abnormal atrial activation is common in patients with arrhythmogenic right ventricular cardiomyopathy. J Electrocardiol 2011; 44:237-41. [DOI: 10.1016/j.jelectrocard.2010.08.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2010] [Indexed: 11/21/2022]
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Azaouagh A, Churzidse S, Konorza T, Erbel R. Arrhythmogenic right ventricular cardiomyopathy/dysplasia: a review and update. Clin Res Cardiol 2011; 100:383-94. [PMID: 21360243 DOI: 10.1007/s00392-011-0295-2] [Citation(s) in RCA: 78] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2010] [Accepted: 01/26/2011] [Indexed: 12/23/2022]
Abstract
Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a predominantly genetically determined and heritable form of cardiomyopathy that is characterized pathologically by the replacement of myocytes by adipose and fibrous tissue and leads to right ventricular failure, arrhythmias, and sudden cardiac death. The estimated prevalence of ARVC/D in the general population ranges from 1 in 2,000 to 1 in 5,000, men are more frequently affected than women, with an approximate ratio of 3:1. ARVC/D can be inherited as an autosomal dominant disease with reduced penetrance and variable expression, autosomal recessive inheritance is also described. There have been 12 genes identified which are linked to ARVC/D, encoding several components of the cardiac desmosome. Dysfunctional desmosomes resulting in defective cell adhesion proteins, such as plakoglobin (JUP), desmoplakin (DSP), plakophilin-2 (PKP-2), and desmoglein-2 (DSG-2) consequently cause loss of electrical coupling between cardiac myocytes, leading to myocyte cell death, fibrofatty replacement and arrhythmias. Diagnosis is based on the finding a combination of characteristic abnormalities in family history, electrocardiography, cardiac imaging as well as endomyocardial biopsy (original task force criteria). Therapeutic options remain limited because of the progressive nature of ARVC/D. Competitive athletics should be avoided. Patients with ARVC/D with a history of having been resuscitated from sudden cardiac death, patients with syncope, very young patients, and those who have marked right ventricular involvement are at the highest risk for arrhythmic death and also, the presence of left ventricular involvement is a risk factor. Several authors concluded that patients who meet the Task Force criteria for ARVC/D are at high risk for sudden cardiac death and should undergo ICD placement for primary and secondary prevention, regardless of electrophysiologic testing results. The role of electrophysiologic study and VT catheter ablation in ARVC/D remains poorly defined, and is frequently used as a palliative measure for patients with refractory VT. The progressive nature of ARVC/D suggests that catheter ablation would not be a long-term curative procedure. Sotalol proved to be highly effective in patients with ARVC/D and inducible as well as non-inducible ventricular tachycardia; if it is ineffective in inducible ventricular tachycardia response to other antiarrhythmic drugs is unlikely and therefore non-pharmacological therapy without further drug testing should be considered. Orthotopic heart transplantation is considered in patients with progressive heart failure and intractable recurrent ventricular arrhythmias.
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Affiliation(s)
- A Azaouagh
- Department of Medicine, Westgerman Cancer Center, University Hospital Essen, Hufelandstraße 55, 45147, Essen, Germany.
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Recent progress in the genetics of cardiomyopathy and its role in the clinical evaluation of patients with cardiomyopathy. Curr Opin Cardiol 2011; 26:155-64. [DOI: 10.1097/hco.0b013e3283439797] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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