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Ashraf M, Jan MF, Jahangir A, Kroboth S, Abood Z, Walczak S, Sanders H, Tajik AJ. Genotype-phenotype correlations in hypertrophic cardiomyopathy: Insights from an HCM Center of Excellence. Curr Probl Cardiol 2025; 50:102996. [PMID: 39890042 DOI: 10.1016/j.cpcardiol.2025.102996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2025] [Accepted: 01/28/2025] [Indexed: 02/03/2025]
Abstract
BACKGROUND Owing to the recognition of previously unknown pathogenic gene variants and reclassification of longer-known variants, gene distribution in patients with hypertrophic cardiomyopathy (HCM) is ever-changing. Conflicting data make the role of genotype in risk stratification unclear. METHODS We evaluated genotype distribution and genotype-phenotype correlations in all adult patients with HCM seen at our HCM Center of Excellence from March 31, 2010, to April 30, 2023. We also evaluated a composite outcome, including all-cause mortality, stroke, implantable cardioverter-defibrillator placement, heart failure hospitalization, left ventricular assist device implantation, heart transplantation, septal myectomy, and alcohol septal ablation, based on genotype status. All-cause mortality was separately analyzed. RESULTS Of 827 patients with HCM, genotyping was completed in 754 (91.2 %). We identified 202 (27 %) genotype-positive (Gen-P), 163 (22 %) variant of unknown significance (VUS), and 389 (51 %) genotype-negative (Gen-N) patients. Mean ages were 47, 57, and 58 years, respectively. The most common gene implicated was MYBPC3 (63 %). More patients were on optimal medical treatment after following up with our HCM center. Electrocardiographic, Holter, echocardiographic, and cardiac magnetic resonance imaging characteristics differed based on genotype status. The composite outcome was worse in Gen-P than Gen-N (HR 1.84, p<0.001). Although analysis of all-cause mortality showed survival was different for Gen-P and VUS patients than for Gen-N patients, this difference was not statistically significant. CONCLUSION MYBPC3 was the most common gene implicated. Outcomes were worse in Gen-P patients. Centers of Excellence play an important role in the optimal medical management of patients with HCM.
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Affiliation(s)
- Muddasir Ashraf
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Aurora Health Care, 2801 W. Kinnickinnic River Parkway, Ste. 130, Milwaukee, WI 53215 USA
| | - M Fuad Jan
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Aurora Health Care, 2801 W. Kinnickinnic River Parkway, Ste. 130, Milwaukee, WI 53215 USA; Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health-Milwaukee Clinical Campus, 2900 W. Oklahoma Avenue, Milwaukee, WI 53215 USA
| | - Arshad Jahangir
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Aurora Health Care, 2801 W. Kinnickinnic River Parkway, Ste. 130, Milwaukee, WI 53215 USA; Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health-Milwaukee Clinical Campus, 2900 W. Oklahoma Avenue, Milwaukee, WI 53215 USA
| | - Stacie Kroboth
- Academic Affairs, Cardiovascular Research, Aurora Sinai/Aurora St. Luke's Medical Centers, Aurora Health Care, 1020 N. 12th Street, Milwaukee, WI 53233, USA
| | - Zaid Abood
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Aurora Health Care, 2801 W. Kinnickinnic River Parkway, Ste. 130, Milwaukee, WI 53215 USA
| | - Sara Walczak
- Academic Affairs, Cardiovascular Research, Aurora Sinai/Aurora St. Luke's Medical Centers, Aurora Health Care, 1020 N. 12th Street, Milwaukee, WI 53233, USA
| | - Heather Sanders
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Aurora Health Care, 2801 W. Kinnickinnic River Parkway, Ste. 130, Milwaukee, WI 53215 USA
| | - A Jamil Tajik
- Aurora Cardiovascular and Thoracic Services, Aurora Sinai/Aurora St. Luke's Medical Centers, Aurora Health Care, 2801 W. Kinnickinnic River Parkway, Ste. 130, Milwaukee, WI 53215 USA; Division of Cardiovascular Medicine, University of Wisconsin School of Medicine and Public Health-Milwaukee Clinical Campus, 2900 W. Oklahoma Avenue, Milwaukee, WI 53215 USA.
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Kitai T, Kohsaka S, Kato T, Kato E, Sato K, Teramoto K, Yaku H, Akiyama E, Ando M, Izumi C, Ide T, Iwasaki YK, Ohno Y, Okumura T, Ozasa N, Kaji S, Kashimura T, Kitaoka H, Kinugasa Y, Kinugawa S, Toda K, Nagai T, Nakamura M, Hikoso S, Minamisawa M, Wakasa S, Anchi Y, Oishi S, Okada A, Obokata M, Kagiyama N, Kato NP, Kohno T, Sato T, Shiraishi Y, Tamaki Y, Tamura Y, Nagao K, Nagatomo Y, Nakamura N, Nochioka K, Nomura A, Nomura S, Horiuchi Y, Mizuno A, Murai R, Inomata T, Kuwahara K, Sakata Y, Tsutsui H, Kinugawa K. JCS/JHFS 2025 Guideline on Diagnosis and Treatment of Heart Failure. J Card Fail 2025:S1071-9164(25)00100-9. [PMID: 40155256 DOI: 10.1016/j.cardfail.2025.02.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
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Desai D, Song T, Singh RR, Baby A, McNamara J, Green LC, Nabavizadeh P, Ericksen M, Bazrafshan S, Natesan S, Sadayappan S. MYBPC3 D389V Variant Induces Hypercontractility in Cardiac Organoids. Cells 2024; 13:1913. [PMID: 39594661 PMCID: PMC11592734 DOI: 10.3390/cells13221913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 10/27/2024] [Accepted: 11/05/2024] [Indexed: 11/28/2024] Open
Abstract
MYBPC3, encoding cardiac myosin binding protein-C (cMyBP-C), is the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, since little is known about the underlying etiology, additional in vitro studies are crucial to defining the underlying molecular mechanisms. Accordingly, this study aimed to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with a polymorphic variant (D389V) in MYBPC3 by using isogenic human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs). The hiPSC-derived cardiomyocytes (hiPSC-CMs) and hCOs were generated from human subjects to define the molecular, cellular, functional, and energetic changes caused by the MYBPC3D389V variant, which is associated with increased fractional shortening and highly prevalent in South Asian descendants. Recombinant C0-C2, N' region of cMyBP-C (wild-type and D389V), and myosin S2 proteins were also utilized to perform binding and motility assays in vitro. Confocal and electron microscopic analyses of hCOs generated from noncarriers (NC) and carriers of the MYBPC3D389V variant revealed the presence of highly organized sarcomeres. Furthermore, functional experiments showed hypercontractility, faster calcium cycling, and faster contractile kinetics in hCOs expressing MYBPC3D389V than NC hCOs. Interestingly, significantly increased cMyBP-C phosphorylation in MYBPC3D389V hCOs was observed, but without changes in total protein levels, in addition to higher oxidative stress and lower mitochondrial membrane potential (ΔΨm). Next, spatial mapping revealed the presence of endothelial cells, fibroblasts, macrophages, immune cells, and cardiomyocytes in the hCOs. The hypercontractile function was significantly improved after the treatment of the myosin inhibitor mavacamten (CAMZYOS®) in MYBPC3D389V hCOs. Lastly, various vitro binding assays revealed a significant loss of affinity in the presence of MYBPC3D389V with myosin S2 region as a likely mechanism for hypercontraction. Conceptually, we showed the feasibility of assessing the functional and molecular mechanisms of HCM using highly translatable hCOs through pragmatic experiments that led to determining the MYBPC3D389V hypercontractile phenotype, which was rescued by the administration of a myosin inhibitor.
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Affiliation(s)
- Darshini Desai
- Center for Cardiovascular Research, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (T.S.); (R.R.S.); (A.B.); (J.M.); (P.N.)
| | - Taejeong Song
- Center for Cardiovascular Research, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (T.S.); (R.R.S.); (A.B.); (J.M.); (P.N.)
| | - Rohit R. Singh
- Center for Cardiovascular Research, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (T.S.); (R.R.S.); (A.B.); (J.M.); (P.N.)
| | - Akhil Baby
- Center for Cardiovascular Research, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (T.S.); (R.R.S.); (A.B.); (J.M.); (P.N.)
- Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai 625021, India
| | - James McNamara
- Center for Cardiovascular Research, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (T.S.); (R.R.S.); (A.B.); (J.M.); (P.N.)
| | - Lisa C. Green
- Center for Cardiovascular Research, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (T.S.); (R.R.S.); (A.B.); (J.M.); (P.N.)
| | - Pooneh Nabavizadeh
- Center for Cardiovascular Research, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (T.S.); (R.R.S.); (A.B.); (J.M.); (P.N.)
| | - Mark Ericksen
- Center for Cardiovascular Research, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (T.S.); (R.R.S.); (A.B.); (J.M.); (P.N.)
| | - Sholeh Bazrafshan
- Center for Cardiovascular Research, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (T.S.); (R.R.S.); (A.B.); (J.M.); (P.N.)
| | - Sankar Natesan
- Department of Genetic Engineering, School of Biotechnology, Madurai Kamaraj University, Madurai 625021, India
| | - Sakthivel Sadayappan
- Center for Cardiovascular Research, Division of Cardiovascular Health and Disease, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA; (T.S.); (R.R.S.); (A.B.); (J.M.); (P.N.)
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Shlobin NA, Thijs RD, Benditt DG, Zeppenfeld K, Sander JW. Sudden death in epilepsy: the overlap between cardiac and neurological factors. Brain Commun 2024; 6:fcae309. [PMID: 39355001 PMCID: PMC11443455 DOI: 10.1093/braincomms/fcae309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 06/21/2024] [Accepted: 09/25/2024] [Indexed: 10/03/2024] Open
Abstract
People with epilepsy are at risk of premature death, of which sudden unexpected death in epilepsy (SUDEP), sudden cardiac death (SCD) and sudden arrhythmic death syndrome (SADS) are the primary, partly overlapping, clinical scenarios. We discuss the epidemiologies, risk factors and pathophysiological mechanisms for these sudden death events. We reviewed the existing evidence on sudden death in epilepsy. Classification of sudden death depends on the presence of autopsy and expertise of the clinician determining aetiology. The definitions of SUDEP, SCD and SADS lead to substantial openings for overlap. Seizure-induced arrhythmias constitute a minority of SUDEP cases. Comorbid cardiovascular conditions are the primary determinants of increased SCD risk in chronic epilepsy. Genetic mutations overlap between the states, yet whether these are causative, associated or incidentally present is often unclear. Risk stratification for sudden death in people with epilepsy requires a multidisciplinary approach, including a review of clinical history, toxicological analysis and complete autopsy with histologic and, preferably, genetic examination. We recommend pursuing genetic testing of relatives of people with epilepsy who died suddenly, mainly if a post-mortem genetic test contained a Class IV/V (pathogenic/likely pathogenic) gene variant. Further research may allow more precise differentiation of SUDEP, SCD and SADS and the development of algorithms for risk stratification and preventative strategies.
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Affiliation(s)
- Nathan A Shlobin
- Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Stichting Epilepsie Instellingen Nederland (SEIN), 2103 SW Heemstede, The Netherlands
- Department of Neurology and Clinical Neurophysiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Roland D Thijs
- Stichting Epilepsie Instellingen Nederland (SEIN), 2103 SW Heemstede, The Netherlands
- Department of Neurology and Clinical Neurophysiology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
- UCL Queen Square Institute of Neurology, NIHR University College London Hospitals Biomedical Research Centre, London WC1N 3BG, UK
| | - David G Benditt
- Cardiac Arrhythmia and Syncope Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Katja Zeppenfeld
- Department of Cardiology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
| | - Josemir W Sander
- Stichting Epilepsie Instellingen Nederland (SEIN), 2103 SW Heemstede, The Netherlands
- UCL Queen Square Institute of Neurology, NIHR University College London Hospitals Biomedical Research Centre, London WC1N 3BG, UK
- Chalfont Centre for Epilepsy, Chalfont St Peter SL9 0RJ, UK
- Department of Neurology, West China Hospital, Sichuan University, Chengdu 610041, China
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Desai D, Song T, Singh RR, Baby A, McNamara J, Green L, Nabavizadeh P, Ericksen M, Bazrafshan S, Natesan S, Sadayappan S. MYBPC3 D389V Variant Induces Hypercontractility in Cardiac Organoids. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.29.596463. [PMID: 38853909 PMCID: PMC11160759 DOI: 10.1101/2024.05.29.596463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
BACKGROUND MYBPC3 , encoding cardiac myosin binding protein-C (cMyBP-C), is the most mutated gene known to cause hypertrophic cardiomyopathy (HCM). However, since little is known about the underlying etiology, additional in vitro studies are crucial to defining the underlying molecular mechanisms. Accordingly, this study aimed to investigate the molecular mechanisms underlying the pathogenesis of HCM associated with a polymorphic variant (D389V) in MYBPC3 by using human-induced pluripotent stem cell (hiPSC)-derived cardiac organoids (hCOs). METHODS The hiPSC-derived cardiomyocytes (hiPSC-CMs) and hCOs were generated from human subjects to define the molecular, cellular, and functional changes caused by the MYBPC3 D389V variant. This variant is associated with increased fractional shortening and is highly prevalent in South Asian descendants. Recombinant C0-C2, N'-region of cMyBP-C (wildtype and D389V), and myosin S2 proteins were also utilized to perform binding and motility assays in vitro . RESULTS Confocal and electron microscopic analyses of hCOs generated from noncarriers (NC) and carriers of the MYBPC3 D389V variant revealed the presence of highly organized sarcomeres. Furthermore, functional experiments showed hypercontractility with increased contraction velocity, faster calcium cycling, and faster contractile kinetics in hCOs expressing MYBPC3 D389V than NC hCOs. Interestingly, significantly increased cMyBP-C phosphorylation in MYBPC3 D389V hCOs was observed, but without changes in total protein levels, in addition to higher oxidative stress and lower mitochondrial membrane potential (ΔΨm). Next, spatial mapping revealed the presence of endothelial cells, fibroblasts, macrophages, immune cells, and cardiomyocytes in the hCOs. The hypercontractile function was significantly improved after treatment with the myosin inhibitor mavacamten (CAMZYOS®) in MYBPC3 D389V hCOs. Lastly, various in vitro binding assays revealed a significant loss of affinity in the presence of MYBPC3 D389V with myosin S2 region as a likely mechanism for hypercontraction. CONCLUSIONS Conceptually, we showed the feasibility of assessing the functional and molecular mechanisms of HCM using highly translatable hCOs through pragmatic experiments that led to determining the MYBPC3 D389V hypercontractile phenotype, which was rescued by administration of a myosin inhibitor. Novelty and Significance: What Is Known?: MYBPC3 mutations have been implicated in hypertrophic cardiomyopathy. D389V is a polymorphic variant of MYBPC3 predicted to be present in 53000 US South Asians owing to the founder effect. D389V carriers have shown evidence of hyperdynamic heart, and human-induced pluripotent stem cells (hiPSC)-derived cardiomyocytes with D389V show cellular hypertrophy and irregular calcium transients. The molecular mechanism by which the D389V variant develops pathological cardiac dysfunction remains to be conclusively determined.What New Information Does This Article Contribute ?: The authors leveraged a highly translational cardiac organoid model to explore the role of altered cardiac calcium handling and cardiac contractility as a common pathway leading to pathophysiological phenotypes in patients with early HCM. The MYBPC3 D389V -mediated pathological pathway is first studied here by comparing functional properties using three-dimensional cardiac organoids differentiated from hiPSC and determining the presence of hypercontraction. Our data demonstrate that faster sarcomere kinetics resulting from lower binding affinity between D389V-mutated cMyBP-C protein and myosin S2, as evidenced by in vitro studies, could cause hypercontractility which was rescued by administration of mavacamten (CAMZYOS®), a myosin inhibitor. In addition, hypercontractility causes secondary mitochondrial defects such as higher oxidative stress and lower mitochondrial membrane potential (ΔΨm), highlighting a possible early adaptive response to primary sarcomeric changes. Early treatment of MYBPC3 D389V carriers with mavacamten may prevent or reduce early HCM-related pathology. GRAPHICAL ABSTRACT: A graphical abstract is available for this article.
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Bonaventura J, Rowin EJ, Chan RH, Chin MT, Puchnerova V, Polakova E, Macek M, Votypka P, Batorsky R, Perera G, Koethe B, Veselka J, Maron BJ, Maron MS. Relationship Between Genotype Status and Clinical Outcome in Hypertrophic Cardiomyopathy. J Am Heart Assoc 2024; 13:e033565. [PMID: 38757491 PMCID: PMC11179794 DOI: 10.1161/jaha.123.033565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Accepted: 04/19/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND The genetic basis of hypertrophic cardiomyopathy (HCM) is complex, and the relationship between genotype status and clinical outcome is incompletely resolved. METHODS AND RESULTS We assessed a large international HCM cohort to define in contemporary terms natural history and clinical consequences of genotype. Consecutive patients (n=1468) with established HCM diagnosis underwent genetic testing. Patients with pathogenic (or likely pathogenic) variants were considered genotype positive (G+; n=312; 21%); those without definite disease-causing mutations (n=651; 44%) or variants of uncertain significance (n=505; 35%) were considered genotype negative (G-). Patients were followed up for a median of 7.8 years (interquartile range, 3.5-13.4 years); HCM end points were examined by cumulative event incidence. Over follow-up, 135 (9%) patients died, 33 from a variety of HCM-related causes. After adjusting for age, all-cause and HCM-related mortality did not differ between G- versus G+ patients (hazard ratio [HR], 0.78 [95% CI, 0.46-1.31]; P=0.37; HR, 0.93 [95% CI, 0.38-2.30]; P=0.87, respectively). Adverse event rates, including heart failure progression to class III/IV, heart transplant, or heart failure death, did not differ (G- versus G+) when adjusted for age (HR, 1.20 [95% CI, 0.63-2.26]; P=0.58), nor was genotype independently associated with sudden death event risk (HR, 1.39 [95% CI, 0.88-2.21]; P=0.16). In multivariable analysis, age was the only independent predictor of all-cause and HCM-related mortality, heart failure progression, and sudden death events. CONCLUSIONS In this large consecutive cohort of patients with HCM, genotype (G+ or G-) was not a predictor of clinical course, including all-cause and HCM-related mortality and risk for heart failure progression or sudden death. G+ status should not be used to dictate clinical management or predict outcome in HCM.
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Affiliation(s)
- Jiri Bonaventura
- Department of Cardiology, 2nd Faculty of MedicineCharles University and Motol University HospitalPragueCzech Republic
- Hypertrophic Cardiomyopathy CenterLahey Hospital and Medical CenterBurlingtonMAUSA
| | - Ethan J. Rowin
- Hypertrophic Cardiomyopathy CenterLahey Hospital and Medical CenterBurlingtonMAUSA
| | - Raymond H. Chan
- Division of Cardiology, Peter Munk Cardiac CentreToronto General Hospital, University Health NetworkOntarioCanada
| | - Michael T. Chin
- Molecular Cardiology Research InstituteTufts Medical CenterBostonMAUSA
| | - Veronika Puchnerova
- Department of Cardiology, 2nd Faculty of MedicineCharles University and Motol University HospitalPragueCzech Republic
| | - Eva Polakova
- Department of Cardiology, 2nd Faculty of MedicineCharles University and Motol University HospitalPragueCzech Republic
| | - Milan Macek
- Department of Biology and Medical Genetics, 2nd Faculty of MedicineCharles University and Motol University HospitalPragueCzech Republic
| | - Pavel Votypka
- Department of Biology and Medical Genetics, 2nd Faculty of MedicineCharles University and Motol University HospitalPragueCzech Republic
| | - Rebecca Batorsky
- Molecular Cardiology Research InstituteTufts Medical CenterBostonMAUSA
| | - Gayani Perera
- Molecular Cardiology Research InstituteTufts Medical CenterBostonMAUSA
| | - Benjamin Koethe
- Institute for Clinical Research and Health Policy Studies, Tufts Medical CenterBostonMAUSA
| | - Josef Veselka
- Department of Cardiology, 2nd Faculty of MedicineCharles University and Motol University HospitalPragueCzech Republic
| | - Barry J. Maron
- Hypertrophic Cardiomyopathy CenterLahey Hospital and Medical CenterBurlingtonMAUSA
| | - Martin S. Maron
- Hypertrophic Cardiomyopathy CenterLahey Hospital and Medical CenterBurlingtonMAUSA
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Pidaparti M, Geddes GC, Durbin MD. Clinical Genetic and Genomic Testing in Congenital Heart Disease and Cardiomyopathy. J Clin Med 2024; 13:2544. [PMID: 38731073 PMCID: PMC11084871 DOI: 10.3390/jcm13092544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 04/20/2024] [Accepted: 04/21/2024] [Indexed: 05/13/2024] Open
Abstract
Congenital heart disease (CHD) and cardiomyopathies are the leading cause of morbidity and mortality worldwide. These conditions are often caused by genetic factors, and recent research has shown that genetic and genomic testing can provide valuable information for patient care. By identifying genetic causes, healthcare providers can screen for other related health conditions, offer early interventions, estimate prognosis, select appropriate treatments, and assess the risk for family members. Genetic and genomic testing is now the standard of care in patients with CHD and cardiomyopathy. However, rapid advances in technology and greater availability of testing options have led to changes in recommendations for the most appropriate testing method. Several recent studies have investigated the utility of genetic testing in this changing landscape. This review summarizes the literature surrounding the clinical utility of genetic evaluation in patients with CHD and cardiomyopathy.
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Affiliation(s)
- Mahati Pidaparti
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Gabrielle C. Geddes
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
| | - Matthew D. Durbin
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA;
- Herman B Wells Center for Pediatric Research, 1044 W. Walnut, Indianapolis, IN 46202, USA
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Topriceanu CC, Pereira AC, Moon JC, Captur G, Ho CY. Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy. Circulation 2024; 149:107-123. [PMID: 37929589 PMCID: PMC10775968 DOI: 10.1161/circulationaha.123.065987] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 10/27/2023] [Indexed: 11/07/2023]
Abstract
BACKGROUND Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted. METHODS A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up. RESULTS In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosin-binding protein C3), ≈60% for TNNT2 (troponin T2) and TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for MYBPC3 and ≈23% for MYH7. CONCLUSIONS The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM.
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Affiliation(s)
- Constantin-Cristian Topriceanu
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (C.-C.T., A.C.P., C.Y.H.). UCL Institute of Cardiovascular Science (C.-C.T., J.C.M., G.C.) and UCL MRC Unit for Lifelong Health and Ageing (G.C.), University College London, UK. Cardiac MRI Unit, Barts Heart Centre, West Smithfield, London, UK (C.-C.T., J.C.M.). The Royal Free Hospital, Centre for Inherited Heart Muscle Conditions, Cardiology Department, Hampstead, London, UK (G.C.)
| | - Alexandre C. Pereira
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (C.-C.T., A.C.P., C.Y.H.). UCL Institute of Cardiovascular Science (C.-C.T., J.C.M., G.C.) and UCL MRC Unit for Lifelong Health and Ageing (G.C.), University College London, UK. Cardiac MRI Unit, Barts Heart Centre, West Smithfield, London, UK (C.-C.T., J.C.M.). The Royal Free Hospital, Centre for Inherited Heart Muscle Conditions, Cardiology Department, Hampstead, London, UK (G.C.)
| | - James C. Moon
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (C.-C.T., A.C.P., C.Y.H.). UCL Institute of Cardiovascular Science (C.-C.T., J.C.M., G.C.) and UCL MRC Unit for Lifelong Health and Ageing (G.C.), University College London, UK. Cardiac MRI Unit, Barts Heart Centre, West Smithfield, London, UK (C.-C.T., J.C.M.). The Royal Free Hospital, Centre for Inherited Heart Muscle Conditions, Cardiology Department, Hampstead, London, UK (G.C.)
| | - Gabriella Captur
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (C.-C.T., A.C.P., C.Y.H.). UCL Institute of Cardiovascular Science (C.-C.T., J.C.M., G.C.) and UCL MRC Unit for Lifelong Health and Ageing (G.C.), University College London, UK. Cardiac MRI Unit, Barts Heart Centre, West Smithfield, London, UK (C.-C.T., J.C.M.). The Royal Free Hospital, Centre for Inherited Heart Muscle Conditions, Cardiology Department, Hampstead, London, UK (G.C.)
| | - Carolyn Y. Ho
- Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (C.-C.T., A.C.P., C.Y.H.). UCL Institute of Cardiovascular Science (C.-C.T., J.C.M., G.C.) and UCL MRC Unit for Lifelong Health and Ageing (G.C.), University College London, UK. Cardiac MRI Unit, Barts Heart Centre, West Smithfield, London, UK (C.-C.T., J.C.M.). The Royal Free Hospital, Centre for Inherited Heart Muscle Conditions, Cardiology Department, Hampstead, London, UK (G.C.)
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9
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Ananthamohan K, Stelzer JE, Sadayappan S. Hypertrophic cardiomyopathy in MYBPC3 carriers in aging. THE JOURNAL OF CARDIOVASCULAR AGING 2024; 4:9. [PMID: 38406555 PMCID: PMC10883298 DOI: 10.20517/jca.2023.29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/27/2024]
Abstract
Hypertrophic cardiomyopathy (HCM) is characterized by abnormal thickening of the myocardium, leading to arrhythmias, heart failure, and elevated risk of sudden cardiac death, particularly among the young. This inherited disease is predominantly caused by mutations in sarcomeric genes, among which those in the cardiac myosin binding protein-C3 (MYBPC3) gene are major contributors. HCM associated with MYBPC3 mutations usually presents in the elderly and ranges from asymptomatic to symptomatic forms, affecting numerous cardiac functions and presenting significant health risks with a spectrum of clinical manifestations. Regulation of MYBPC3 expression involves various transcriptional and translational mechanisms, yet the destiny of mutant MYBPC3 mRNA and protein in late-onset HCM remains unclear. Pathogenesis related to MYBPC3 mutations includes nonsense-mediated decay, alternative splicing, and ubiquitin-proteasome system events, leading to allelic imbalance and haploinsufficiency. Aging further exacerbates the severity of HCM in carriers of MYBPC3 mutations. Advancements in high-throughput omics techniques have identified crucial molecular events and regulatory disruptions in cardiomyocytes expressing MYBPC3 variants. This review assesses the pathogenic mechanisms that promote late-onset HCM through the lens of transcriptional, post-transcriptional, and post-translational modulation of MYBPC3, underscoring its significance in HCM across carriers. The review also evaluates the influence of aging on these processes and MYBPC3 levels during HCM pathogenesis in the elderly. While pinpointing targets for novel medical interventions to conserve cardiac function remains challenging, the emergence of personalized omics offers promising avenues for future HCM treatments, particularly for late-onset cases.
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Affiliation(s)
- Kalyani Ananthamohan
- Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Julian E. Stelzer
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 45267, USA
| | - Sakthivel Sadayappan
- Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, OH 45267, USA
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10
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Griffeth EM, Dearani JA, Schaff HV, Johnson JN, Ackerman MJ, Bos JM, Alzate-Aguirre M, Todd A, Cannon BC, Wackel PL, Stephens EH. Septal Myectomy Outcomes in Children and Adolescents With Obstructive Hypertrophic Cardiomyopathy. Ann Thorac Surg 2023; 116:499-507. [PMID: 37116851 PMCID: PMC10524729 DOI: 10.1016/j.athoracsur.2023.04.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 03/15/2023] [Accepted: 04/04/2023] [Indexed: 04/30/2023]
Abstract
BACKGROUND Little data exist regarding characteristics and outcomes of pediatric patients undergoing septal myectomy. We evaluated this in a large referral population. METHODS Septal myectomy was performed in 199 consecutive patients aged ≤18 years with obstructive hypertrophic cardiomyopathy from January 1, 1976, to June 30, 2021. RESULTS Median age was 13 years (interquartile range [IQR], 8-15 years). Left ventricular myectomy approaches included transaortic (163 of 198 [82%]), transapical (16 of 198 [8%]), and combined (19 of 198 [10%]). Right ventricular interventions included myectomy (13 of 199 [7%]) and patch reconstruction of the outflow tract (15 of 199 [8%]). Maximum left ventricular outflow tract gradients decreased after myectomy (prebypass: 50 mm Hg [IQR, 31-73 mm Hg] vs postbypass: 4 mm Hg [IQR, 0-9 mm Hg], P < .001), and this was sustained long-term (5 mm Hg [IQR, 5-10 mm Hg] at 10 years). Iatrogenic aortic and mitral valve injuries occurred in 13 of 199 (7%) and 1 of 199 (1%), respectively; however, all were successfully repaired. Operative mortality was 2 of 199 (1%). The cumulative incidence of redo myectomy was low, at 5.8% at 5 and 8.3% at 10 years. Redo myectomy patients had higher maximum left ventricular outflow tract gradients on echocardiography at predischarge and 1 year and were younger at the index operation (8 years [IQR, 2.5-10 years] vs 13 years [IQR, 9-16 years], P < .001). Overall survival at 10 years was 90%, relative to 47% in a previously reported pediatric nonoperative cohort. CONCLUSIONS Pediatric septal myectomy provides safe, effective, and durable relief of ventricular outflow tract obstruction. Iatrogenic valve injury remains a low but nonnegligible risk. Recurrent obstruction requiring redo myectomy is infrequent and can be identified early. Long-term survival in this pediatric septal myectomy cohort appears to fare better than pediatric hypertrophic cardiomyopathy cohorts managed nonoperatively.
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Affiliation(s)
- Elaine M Griffeth
- Department of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota
| | - Joseph A Dearani
- Department of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota.
| | - Hartzell V Schaff
- Department of Cardiovascular Surgery, Mayo Clinic, Rochester, Minnesota
| | | | - Michael J Ackerman
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota; Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - J Martijn Bos
- Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Mateo Alzate-Aguirre
- Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Austin Todd
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota
| | - Bryan C Cannon
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota
| | - Philip L Wackel
- Division of Pediatric Cardiology, Mayo Clinic, Rochester, Minnesota
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11
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Kitai T, Xanthopoulos A, Nakagawa S, Ishii N, Amano M, Triposkiadis F, Izumi C. Contemporary Diagnosis and Management of Hypertrophic Cardiomyopathy: The Role of Echocardiography and Multimodality Imaging. J Cardiovasc Dev Dis 2022; 9:169. [PMID: 35735798 PMCID: PMC9224724 DOI: 10.3390/jcdd9060169] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/15/2022] [Accepted: 05/16/2022] [Indexed: 01/27/2023] Open
Abstract
Hypertrophic cardiomyopathy (HCM) is an underdiagnosed genetic heart disease with an estimated prevalence of 0.2-0.5%. Although the prognosis of HCM is relatively good, with an annual general mortality of ~0.7%, some patients have an increased risk of sudden death, or of developing severe heart failure requiring heart transplantation or left ventricular (LV) assist device therapy. Therefore, earlier diagnosis and proper identification of high-risk patients may reduce disease-related morbidity/mortality by promoting timely treatment. Echocardiography is the primary imaging modality for patients with suspected HCM; it plays central roles in differential diagnosis from other causes of LV hypertrophy and in evaluating morphology, hemodynamic disturbances, LV function, and associated valvular disease. Echocardiography is also an essential tool for the continuous clinical management of patients with confirmed HCM. Other imaging modalities, such as cardiac computed tomography (CT) and cardiac magnetic resonance imaging (MRI), can supplement echocardiography in identifying high-risk as well as milder HCM phenotypes. The role of such multimodality imaging has been steadily expanding along with recent advancements in surgical techniques and minimally invasive procedures, and the emergence of novel pharmacotherapies directly targeting pathogenic molecules such as myosin inhibitors. Here we review essential knowledge surrounding HCM with a specific focus on structural and functional abnormalities assessed by imaging modalities, leading to treatment strategies.
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Affiliation(s)
- Takeshi Kitai
- National Cerebral and Cardiovascular Center, Department of Cardiovascular Medicine, Suita 564-8565, Japan; (S.N.); (N.I.); (M.A.); (C.I.)
| | - Andrew Xanthopoulos
- Department of Cardiology, University Hospital of Larissa, 41110 Larissa, Greece; (A.X.); (F.T.)
| | - Shoko Nakagawa
- National Cerebral and Cardiovascular Center, Department of Cardiovascular Medicine, Suita 564-8565, Japan; (S.N.); (N.I.); (M.A.); (C.I.)
| | - Natsuko Ishii
- National Cerebral and Cardiovascular Center, Department of Cardiovascular Medicine, Suita 564-8565, Japan; (S.N.); (N.I.); (M.A.); (C.I.)
| | - Masashi Amano
- National Cerebral and Cardiovascular Center, Department of Cardiovascular Medicine, Suita 564-8565, Japan; (S.N.); (N.I.); (M.A.); (C.I.)
| | - Filippos Triposkiadis
- Department of Cardiology, University Hospital of Larissa, 41110 Larissa, Greece; (A.X.); (F.T.)
| | - Chisato Izumi
- National Cerebral and Cardiovascular Center, Department of Cardiovascular Medicine, Suita 564-8565, Japan; (S.N.); (N.I.); (M.A.); (C.I.)
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12
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de la Rosa A, Shah M, Shiota T, Siegel R, Rader F. Comparing echocardiographic characteristics in genotype positive-phenotype positive hypertrophic cardiomyopathy and hypertensive left ventricular hypertrophy. Eur Heart J Cardiovasc Imaging 2022; 23:340-348. [PMID: 34694376 DOI: 10.1093/ehjci/jeab217] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Accepted: 10/05/2021] [Indexed: 12/22/2022] Open
Abstract
AIMS There is little information about hypertrophic cardiomyopathy (HCM) with pathologic genetic mutations and concurrent hypertension (HTN). Hypertensive left ventricular hypertrophy (LVH) does not exclude an underlying genetic aetiology. METHODS AND RESULTS This was a single-centre case-control study of 39 adults with pathologic HCM mutations, confirmed by genetic testing, compared to 39 age- and gender-matched patients with hypertensive LVH. The gene-positive HCM cohort was further stratified by the coexisting presence or absence of HTN. Clinical and echocardiographic characteristics were compared. Of 39 gene-positive HCM, 43.6% (17/39) had concurrent HTN. The gene-positive HCM cohort had larger left atrial (LA) area (22.1 cm2 vs. 18.9 cm2, P = 0.002), more diastolic predominant pulmonary vein flow (38.5% vs. 7.7%, P = 0.001), and more moderate diastolic dysfunction (33.3% vs. 12.8%, P = 0.032) when compared with the hypertensive LVH cohort. Greater left ventricular (LV) mass (277.7 g vs. 207.7 g, P = 0.025), increased frequency of severe LVH (58.8% vs. 27.3%, P = 0.047), and more abnormal global longitudinal strain (GLS) (-14.1% vs. -16.9%, P = 0.049) was observed in the gene-positive HCM cohort with concurrent HTN. CONCLUSION Gene-positive HCM, compared to hypertensive LVH, is characterized by more advanced diastolic dysfunction and larger LA size. Gene-positive HCM patients with concomitant HTN had greater LV mass, more severe LVH, and more abnormal GLS, suggesting HTN may negatively affect the progression of myocardial dysfunction in genetic HCM. LVH out-of-proportion to pressure burden in HTN patients should raise suspicion of underlying genetic HCM.
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Affiliation(s)
- Angelo de la Rosa
- Department of Internal Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 5512, Los Angeles, CA 90048, USA
| | - Maulin Shah
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Boulevard, #A3600, Los Angeles, CA 90048, USA
| | - Takahiro Shiota
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Boulevard, #A3600, Los Angeles, CA 90048, USA
| | - Robert Siegel
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Boulevard, #A3600, Los Angeles, CA 90048, USA
| | - Florian Rader
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S. San Vicente Boulevard, #A3600, Los Angeles, CA 90048, USA
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13
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Vogiatzi G, Lazaros G, Oikonomou E, Lazarou E, Vavuranakis E, Tousoulis D. Role of genetic testing in cardiomyopathies: Α primer for cardiologists. World J Cardiol 2022; 14:29-39. [PMID: 35126870 PMCID: PMC8788175 DOI: 10.4330/wjc.v14.i1.29] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/18/2021] [Accepted: 01/11/2022] [Indexed: 02/06/2023] Open
Abstract
Recent advances in cardiovascular genetics have transformed genetic testing into a valuable part of management of families with inherited cardiomyopathies. As novel mutations have been identified, understanding when to consider genetic testing has emerged as an important consideration in the management of these cases. Specific genetic testing has a paramount importance in the risk stratification of family members, in the prognosis of probands at higher risk of a serious phenotype expression, and finally in the identification of new mutations, all of which are discussed in this review. The indications for each type of cardiomyopathy are described, along with the limitations of genetic testing. Finally, the importance of public sharing of variants in large data sets is emphasized. The ultimate aim of this review is to present key messages about the genetic testing process in order to minimize potential harms and provide suggestions to specialized clinicians who act as a part of a multidisciplinary team in order to offer the best care to families with inherited cardiomyopathies.
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Affiliation(s)
- Georgia Vogiatzi
- The Third Department of Cardiology, Sotiria Hospital, Athens 11527, Greece.
| | - George Lazaros
- The First Department of Cardiology, Hippokration Hospital, Athens 11526, Greece
| | - Evangelos Oikonomou
- The First Department of Cardiology, Hippokration Hospital, Medical School of National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Emilia Lazarou
- The First Department of Cardiology, Hippokration Hospital, Athens 11526, Greece
| | | | - Dimitris Tousoulis
- The First Department of Cardiology, Hippokration Hospital, Athens 11526, Greece
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14
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Finocchiaro G, Sheikh N, Leone O, Westaby J, Mazzarotto F, Pantazis A, Ferrantini C, Sacconi L, Papadakis M, Sharma S, Sheppard MN, Olivotto I. Arrhythmogenic potential of myocardial disarray in hypertrophic cardiomyopathy: genetic basis, functional consequences and relation to sudden cardiac death. Europace 2021; 23:985-995. [PMID: 33447843 DOI: 10.1093/europace/euaa348] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Accepted: 10/28/2020] [Indexed: 12/19/2022] Open
Abstract
Myocardial disarray is defined as disorganized cardiomyocyte spatial distribution, with loss of physiological fibre alignment and orientation. Since the first pathological descriptions of hypertrophic cardiomyopathy (HCM), disarray appeared as a typical feature of this condition and sparked vivid debate regarding its specificity to the disease and clinical significance as a diagnostic marker and a risk factor for sudden death. Although much of the controversy surrounding its diagnostic value in HCM persists, it is increasingly recognized that myocardial disarray may be found in physiological contexts and in cardiac conditions different from HCM, raising the possibility that central focus should be placed on its quantity and distribution, rather than a mere presence. While further studies are needed to establish what amount of disarray should be considered as a hallmark of the disease, novel experimental approaches and emerging imaging techniques for the first time allow ex vivo and in vivo characterization of the myocardium to a molecular level. Such advances hold the promise of filling major gaps in our understanding of the functional consequences of myocardial disarray in HCM and specifically on arrhythmogenic propensity and as a risk factor for sudden death. Ultimately, these studies will clarify whether disarray represents a major determinant of the HCM clinical profile, and a potential therapeutic target, as opposed to an intriguing but largely innocent bystander.
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Affiliation(s)
- Gherardo Finocchiaro
- Cardiothoracic Centre, Guy's and St Thomas' Hospital, London, UK.,King's College London
| | - Nabeel Sheikh
- Cardiothoracic Centre, Guy's and St Thomas' Hospital, London, UK.,King's College London
| | - Ornella Leone
- Cardiovascular and Cardiac Transplant Pathology Unit, Department of Pathology, Sant'Orsola-Malpighi University Hospital, Bologna, Italy
| | - Joe Westaby
- Cardiovascular Pathology Unit and Cardiology Clinical and Academic Group. St George's, University of London, London and St George's University Hospital NHS Foundation Trust, UK
| | - Francesco Mazzarotto
- Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy.,Department of Experimental and Clinical Medicine, University of Florence, Italy.,National Heart and Lung Institute, Imperial College London, UK.,Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
| | - Antonis Pantazis
- Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, UK
| | - Cecilia Ferrantini
- University of Florence, Florence, Italy.,European Laboratory for Non-Linear Spectroscopy, Florence, Italy
| | - Leonardo Sacconi
- European Laboratory for Non-Linear Spectroscopy, Florence, Italy.,Institute for Experimental Cardiovascular Medicine, University of Freiburg, Freiburg, Germany
| | - Michael Papadakis
- Cardiovascular Pathology Unit and Cardiology Clinical and Academic Group. St George's, University of London, London and St George's University Hospital NHS Foundation Trust, UK
| | - Sanjay Sharma
- Cardiovascular Pathology Unit and Cardiology Clinical and Academic Group. St George's, University of London, London and St George's University Hospital NHS Foundation Trust, UK
| | - Mary N Sheppard
- Cardiovascular Pathology Unit and Cardiology Clinical and Academic Group. St George's, University of London, London and St George's University Hospital NHS Foundation Trust, UK
| | - Iacopo Olivotto
- Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy
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15
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Marston NA, Han L, Olivotto I, Day SM, Ashley EA, Michels M, Pereira AC, Ingles J, Semsarian C, Jacoby D, Colan SD, Rossano JW, Wittekind SG, Ware JS, Saberi S, Helms AS, Ho CY. Clinical characteristics and outcomes in childhood-onset hypertrophic cardiomyopathy. Eur Heart J 2021; 42:1988-1996. [PMID: 33769460 PMCID: PMC8139852 DOI: 10.1093/eurheartj/ehab148] [Citation(s) in RCA: 72] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 12/21/2020] [Accepted: 03/02/2021] [Indexed: 02/03/2023] Open
Abstract
AIMS Childhood-onset hypertrophic cardiomyopathy (HCM) is far less common than adult-onset disease, thus natural history is not well characterized. We aim to describe the characteristics and outcomes of childhood-onset HCM. METHODS AND RESULTS We performed an observational cohort study of 7677 HCM patients from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Hypertrophic cardiomyopathy patients were stratified by age at diagnosis [<1 year (infancy), 1-18 years (childhood), >18 years (adulthood)] and assessed for composite endpoints reflecting heart failure (HF), life-threatening ventricular arrhythmias, atrial fibrillation (AF), and an overall composite that also included stroke and death. Stratifying by age of diagnosis, 184 (2.4%) patients were diagnosed in infancy; 1128 (14.7%) in childhood; and 6365 (82.9%) in adulthood. Childhood-onset HCM patients had an ∼2%/year event rate for the overall composite endpoint, with ventricular arrhythmias representing the most common event in the 1st decade following baseline visit, but HF and AF becoming more common by the end of the 2nd decade. Sarcomeric variants were more common in childhood-onset HCM (63%) and carried a worse prognosis than non-sarcomeric disease, including a greater than two-fold increased risk of HF [HRadj 2.39 (1.36-4.20), P = 0.003] and 67% increased risk of the overall composite outcome [HRadj 1.67 (1.16-2.41), P = 0.006]. When compared with adult-onset HCM, childhood-onset was 36% more likely to develop life-threatening ventricular arrhythmias [HRadj 1.36 (1.03-1.80)] and twice as likely to require transplant or ventricular assist device [HRadj 1.99 (1.23-3.23)]. CONCLUSION Patients with childhood-onset HCM are more likely to have sarcomeric disease, carry a higher risk of life-threatening ventricular arrythmias, and have greater need for advanced HF therapies. These findings provide insight into the natural history of disease and can help inform clinical risk stratification.
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Affiliation(s)
- Nicholas A Marston
- Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA.,TIMI Study Group, Boston, MA, USA
| | - Larry Han
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Iacopo Olivotto
- Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy
| | - Sharlene M Day
- Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Euan A Ashley
- Stanford Center for Inherited Heart Disease, Stanford, CA, USA
| | - Michelle Michels
- Department of Cardiology, Thoraxcenter, Erasmus MC Rotterdam, The Netherlands
| | | | - Jodie Ingles
- Department of Cardiology, Royal Prince Alfred Hospital, Agnes Ginges Centre for Molecular Cardiology, at Centenary Institute, The University of Sydney, Australia
| | - Christopher Semsarian
- Department of Cardiology, Royal Prince Alfred Hospital, Agnes Ginges Centre for Molecular Cardiology, at Centenary Institute, The University of Sydney, Australia
| | | | - Steven D Colan
- Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Samuel G Wittekind
- Cincinnati Children's Hospital Medical Center, Heart Institute, Cincinnati, OH, USA
| | - James S Ware
- National Heart & Lung Institute & Royal Brompton Cardiovascular Research Centre, Imperial College London, London, England
| | - Sara Saberi
- Department of Internal Medicine-Cardiology, University of Michigan, Ann Arbor, MI, USA
| | - Adam S Helms
- Department of Internal Medicine-Cardiology, University of Michigan, Ann Arbor, MI, USA
| | - Carolyn Y Ho
- Division of Cardiology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA
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16
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Vullaganti S, Levine J, Raiker N, Syed AA, Collins JD, Carr JC, Bonow RO, Choudhury L. Fibrosis in Hypertrophic Cardiomyopathy Patients With and Without Sarcomere Gene Mutations. Heart Lung Circ 2021; 30:1496-1501. [PMID: 34023176 DOI: 10.1016/j.hlc.2021.04.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 03/14/2021] [Accepted: 04/15/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Patients with hypertrophic cardiomyopathy (HCM) and an identified sarcomere mutation have worse outcomes than those without though the underlying mechanism is incompletely understood. The presence of replacement fibrosis measured by late gadolinium enhancement (LGE) and diffuse fibrosis measured by extracellular volume (ECV) using cardiac magnetic resonance imaging (CMR) are associated with ventricular arrhythmias and cardiac mortality. We aimed to associate these two forms of fibrosis with identified sarcomere mutations. METHODS AND RESULTS Three hundred and thirty-six (336) patients with HCM underwent CMR at a single quaternary referral centre between January 2012 and February 2017. Genetic testing was performed in 73 of these patients, yielding an identified sarcomeric mutation in 29 (G+), no mutation in 39 (G-), and a variant of unknown significance (VUS) in five. LGE was more prevalent in G+ compared to G- patients (86 vs. 56%, OR 4.3, p=0.01) and was more extensive (7.5±5.5% of left ventricular [LV] mass vs. 3.0±3.0%, p<0.001). Global ECV from myocardial segments excluding LGE was similar among both groups (26.9±2.9 vs. 25.6±2.8%, p=0.46). However, in G+ patients ECV was greater in the hypertrophied regions of the basal anteroseptum (30.2±7.0 vs. 26.8±3.6%, p=0.004) and basal inferoseptum (28.1±4.3 vs. 26.2±2.9%, p=0.005). CONCLUSIONS Genotyped HCM patients with an identified sarcomere mutation have greater LGE and greater regional, but not global, ECV than HCM patients without an identified mutation. This difference in fibrosis may contribute to worse outcomes in patients with an identified HCM mutation.
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Affiliation(s)
- Sirish Vullaganti
- Division of Cardiology, Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| | - Jonathan Levine
- Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Nisha Raiker
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Amer Ahmed Syed
- Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | - James C Carr
- Department of Radiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Robert O Bonow
- Division of Cardiology, Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Lubna Choudhury
- Division of Cardiology, Bluhm Cardiovascular Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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17
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Nakashima Y, Kubo T, Sugiura K, Ochi Y, Takahashi A, Baba Y, Hirota T, Yamasaki N, Kimura A, Doi YL, Kitaoka H. Lifelong Clinical Impact of the Presence of Sarcomere Gene Mutation in Japanese Patients With Hypertrophic Cardiomyopathy. Circ J 2020; 84:1846-1853. [PMID: 32830170 DOI: 10.1253/circj.cj-20-0027] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Hypertrophic cardiomyopathy (HCM) is mainly caused by mutations in sarcomere genes. Regarding the clinical implications of genetic information, little is known about the lifelong clinical effect of sarcomere mutations in Japanese HCM patients. METHODS AND RESULTS We studied 211 consecutive Japanese patients with HCM who had agreed to genetic testing between 2003 and 2013. Genetic analyses were performed by direct DNA sequencing in the 6 common sarcomere genes (MYH7,MYBPC3,TNNT2,TNNI3,TPM1,ACTC). Through variant filtering, 21 mutations were identified in 67 patients. After excluding 8 patients whose variants were determined as having uncertain significance, finally 203 patients (130 men, age at study entry: 61.8±14.1 years) were investigated for clinical presentation and course. At the time of study entry, patients with mutations were younger, had more frequent non-sustained ventricular tachycardia, had greater interventricular wall thickness, were more frequently in the dilated phase and less frequently had apical HCM. Through their lifetimes, a total of 98 HCM-related morbid events occurred in 72 patients. Survival analysis revealed that patients with sarcomere gene mutations experienced those morbid events significantly more frequently, and this tendency was more prominent for lethal arrhythmic events. CONCLUSIONS In our HCM cohort, patients with sarcomere gene mutations had poorer lifelong outcome. Genetic information is considered important for better management of HCM.
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Affiliation(s)
- Yasuteru Nakashima
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | - Toru Kubo
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | - Kenta Sugiura
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | - Yuri Ochi
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | - Asa Takahashi
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | - Yuichi Baba
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | - Takayoshi Hirota
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | - Naohito Yamasaki
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | - Akinori Kimura
- Department of Molecular Pathogenesis, Medical Research Institute, Tokyo Medical and Dental University
| | - Yoshinori L Doi
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | - Hiroaki Kitaoka
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
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Reza N, Musunuru K, Owens AT. From Hypertrophy to Heart Failure: What Is New in Genetic Cardiomyopathies. Curr Heart Fail Rep 2020; 16:157-167. [PMID: 31243690 DOI: 10.1007/s11897-019-00435-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE The purpose of this review is to provide an update on the recent advances in the research and clinical care of patients with the major phenotypes of inherited cardiomyopathies-hypertrophic, dilated, and arrhythmogenic. Developments in genetics, risk stratification, therapies, and disease modeling will be discussed. RECENT Diagnostic, prognostic, and therapeutic tools which incorporate genetic and genomic data are being steadily incorporated into the routine clinical care of patients with genetic cardiomyopathies. Human pluripotent stem cells are a breakthrough model system for the study of genetic variation associated with inherited cardiovascular disease. Next-generation sequencing technology and molecular-based diagnostics and therapeutics have emerged as valuable tools to improve the recognition and care of patients with hypertrophic, dilated, and arrhythmogenic cardiomyopathies. Improved adjudication of variant pathogenicity and management of genotype-positive/phenotype-negative individuals are imminent challenges in this realm of precision medicine.
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Affiliation(s)
- Nosheen Reza
- Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Cardiovascular Institute, Philadelphia, PA, 19104, USA.
| | - Kiran Musunuru
- Division of Cardiovascular Medicine, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, 11 South Pavilion, Room 11-134, 3400 Civic Center Boulevard, Philadelphia, PA, 19104, USA
| | - Anjali Tiku Owens
- Division of Cardiovascular Medicine, Department of Medicine, and Department of Genetics, Perelman School of Medicine at the University of Pennsylvania, Cardiovascular Institute, Philadelphia, PA, 19104, USA
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Kitaoka H, Kubo T, Doi YL. Hypertrophic Cardiomyopathy - A Heterogeneous and Lifelong Disease in the Real World. Circ J 2020; 84:1218-1226. [PMID: 32669480 DOI: 10.1253/circj.cj-20-0524] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Hypertrophic cardiomyopathy (HCM) is the most frequent hereditary cardiomyopathy, showing an autosomal-dominant f inheritance. A great deal of attention has been paid to genetics, left ventricular tract obstruction and the prediction and prevention of sudden cardiac death in HCM. Needless to say, these are very important, but we should recognize the heterogeneity in etiology, morphology, clinical course and management of this unique cardiomyopathy. Another important perspective is that HCM causes left ventricular remodeling over time and is a disease that requires lifelong management in the real world.
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Affiliation(s)
- Hiroaki Kitaoka
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
| | - Toru Kubo
- Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University
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20
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Gurka J, Piherova L, Majer F, Chaloupka A, Zakova D, Pelak O, Krebsova A, Peichl P, Krejci J, Freiberger T, Melenovsky V, Kautzner J, Kalina T, Sikora J, Kubanek M. Danon disease is an underdiagnosed cause of advanced heart failure in young female patients: a LAMP2 flow cytometric study. ESC Heart Fail 2020; 7:2534-2543. [PMID: 32657043 PMCID: PMC7524080 DOI: 10.1002/ehf2.12823] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 05/04/2020] [Accepted: 05/20/2020] [Indexed: 01/14/2023] Open
Abstract
Aims Danon disease (DD) is a rare X‐linked disorder caused by mutations in the lysosomal‐associated membrane protein type 2 gene (LAMP2). DD is difficult to distinguish from other causes of dilated or hypertrophic cardiomyopathy (HCM) in female patients. As DD female patients regularly progress into advanced heart failure (AHF) aged 20–40 years, their early identification is critical to improve patient survival and facilitate genetic counselling. In this study, we evaluated the prevalence of DD among female patients with non‐ischemic cardiomyopathy, who reached AHF and were younger than 40 years. Methods and results The study cohort comprised 60 female patients: 47 (78%) heart transplant recipients, 2 (3%) patients treated with ventricular assist device, and 11 (18%) patients undergoing pre‐transplant assessment. Aetiology of the cardiomyopathy was known in 15 patients (including two DD patients). LAMP2 expression in peripheral white blood cells (WBC) was tested by flow cytometry (FC) in the remaining 45 female patients. Whole exome sequencing was used as an alternative independent testing method to FC. Five additional female DD patients (two with different novel LAMP2 mutations) were identified by FC. The total prevalence of DD in this cohort was 12%. HCM phenotype (57% vs. 9%, *P = 0.022) and delta waves identified by electrocardiography (43% vs. 0%, **P = 0.002) were significantly more frequent in DD female patients. Conclusions Danon disease is an underdiagnosed cause of AHF in young female patients. LAMP2 expression testing in peripheral WBCs by FC can be used as an effective screening/diagnostic tool to identify DD in this patient population.
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Affiliation(s)
- Jiri Gurka
- Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Lenka Piherova
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Filip Majer
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Anna Chaloupka
- 1st Internal Cardioangiologic Clinic, Faculty of Medicine, Masaryk University and St. Anne's University Hospital, Brno, Czech Republic
| | - Daniela Zakova
- Centre of Cardiovascular and Transplant Surgery, St. Annes University Hospital, Brno, Czech Republic
| | - Ondrej Pelak
- Department of Paediatric Haematology and Oncology, Childhood Leukaemia Investigation Prague, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Alice Krebsova
- Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Petr Peichl
- Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Jan Krejci
- 1st Internal Cardioangiologic Clinic, Faculty of Medicine, Masaryk University and St. Anne's University Hospital, Brno, Czech Republic
| | - Tomas Freiberger
- Centre of Cardiovascular and Transplant Surgery, St. Annes University Hospital, Brno, Czech Republic
| | - Vojtech Melenovsky
- Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Josef Kautzner
- Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Tomas Kalina
- Department of Paediatric Haematology and Oncology, Childhood Leukaemia Investigation Prague, Second Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Jakub Sikora
- Research Unit for Rare Diseases, Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.,Institute of Pathology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic
| | - Milos Kubanek
- Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
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Risk Stratification in Hypertrophic Cardiomyopathy. Insights from Genetic Analysis and Cardiopulmonary Exercise Testing. J Clin Med 2020; 9:jcm9061636. [PMID: 32481709 PMCID: PMC7356142 DOI: 10.3390/jcm9061636] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/22/2020] [Accepted: 05/26/2020] [Indexed: 01/06/2023] Open
Abstract
The role of genetic testing over the clinical and functional variables, including data from the cardiopulmonary exercise test (CPET), in the hypertrophic cardiomyopathy (HCM) risk stratification remains unclear. A retrospective genotype–phenotype correlation was performed to analyze possible differences between patients with and without likely pathogenic/pathogenic (LP/P) variants. A total of 371 HCM patients were screened at least for the main sarcomeric genes MYBPC3 (myosin binding protein C), MYH7 (β-myosin heavy chain), TNNI3 (cardiac troponin I) and TNNT2 (cardiac troponin T): 203 patients had at least an LP/P variant, 23 patients had a unique variant of uncertain significance (VUS) and 145 did not show any LP/P variant or VUS. During a median 5.4 years follow-up, 51 and 14 patients developed heart failure (HF) and sudden cardiac death (SCD) or SCD-equivalents events, respectively. The LP/P variant was associated with a more aggressive HCM phenotype. However, left atrial diameter (LAd), circulatory power (peak oxygen uptake*peak systolic blood pressure, CP%) and ventilatory efficiency (C-index = 0.839) were the only independent predictors of HF whereas only LAd and CP% were predictors of the SCD end-point (C-index = 0.738). The present study reaffirms the pivotal role of the clinical variables and, particularly of those CPET-derived, in the HCM risk stratification.
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Mazzarotto F, Olivotto I, Boschi B, Girolami F, Poggesi C, Barton PJR, Walsh R. Contemporary Insights Into the Genetics of Hypertrophic Cardiomyopathy: Toward a New Era in Clinical Testing? J Am Heart Assoc 2020; 9:e015473. [PMID: 32306808 PMCID: PMC7428545 DOI: 10.1161/jaha.119.015473] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Genetic testing for hypertrophic cardiomyopathy (HCM) is an established clinical technique, supported by 30 years of research into its genetic etiology. Although pathogenic variants are often detected in patients and used to identify at-risk relatives, the effectiveness of genetic testing has been hampered by ambiguous genetic associations (yielding uncertain and potentially false-positive results), difficulties in classifying variants, and uncertainty about genotype-negative patients. Recent case-control studies on rare variation, improved data sharing, and meta-analysis of case cohorts contributed to new insights into the genetic basis of HCM. In particular, although research into new genes and mechanisms remains essential, reassessment of Mendelian genetic associations in HCM argues that current clinical genetic testing should be limited to a small number of validated disease genes that yield informative and interpretable results. Accurate and consistent variant interpretation has benefited from new standardized variant interpretation guidelines and innovative approaches to improve classification. Most cases lacking a pathogenic variant are now believed to indicate non-Mendelian HCM, with more benign prognosis and minimal risk to relatives. Here, we discuss recent advances in the genetics of HCM and their application to clinical genetic testing together with practical issues regarding implementation. Although this review focuses on HCM, many of the issues discussed are also relevant to other inherited cardiac diseases.
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Affiliation(s)
- Francesco Mazzarotto
- Cardiomyopathy UnitCareggi University HospitalFlorenceItaly
- Cardiovascular Research CenterRoyal Brompton and Harefield NHS Foundation TrustLondonUnited Kingdom
- National Heart and Lung InstituteImperial College LondonUnited Kingdom
- Department of Clinical and Experimental MedicineUniversity of FlorenceItaly
| | - Iacopo Olivotto
- Cardiomyopathy UnitCareggi University HospitalFlorenceItaly
- Department of Clinical and Experimental MedicineUniversity of FlorenceItaly
| | - Beatrice Boschi
- Cardiomyopathy UnitCareggi University HospitalFlorenceItaly
- Genetic UnitCareggi University HospitalFlorenceItaly
| | - Francesca Girolami
- Cardiomyopathy UnitCareggi University HospitalFlorenceItaly
- Department of Paediatric CardiologyMeyer Children's HospitalFlorenceItaly
| | - Corrado Poggesi
- Department of Clinical and Experimental MedicineUniversity of FlorenceItaly
| | - Paul J. R. Barton
- Cardiovascular Research CenterRoyal Brompton and Harefield NHS Foundation TrustLondonUnited Kingdom
- National Heart and Lung InstituteImperial College LondonUnited Kingdom
| | - Roddy Walsh
- Department of Clinical and Experimental CardiologyHeart CenterAcademic Medical CenterAmsterdamthe Netherlands
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The Impact of Emergency Interventions and Patient Characteristics on the Risk of Heart Failure in Patients with Nontraumatic OHCA. Emerg Med Int 2019; 2019:6218389. [PMID: 31934452 PMCID: PMC6942846 DOI: 10.1155/2019/6218389] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/08/2019] [Accepted: 11/18/2019] [Indexed: 12/20/2022] Open
Abstract
Background Since out-of-hospital cardiac arrest- (OHCA-) related dysfunction (ischemic/reperfusion injury and inflammatory response) might result in long-term impairment, we suspect that new-onset heart failure might be common in long-term survivors. However, these relationships had not been well addressed, and we aimed to analyze the impact of emergency interventions and patient characteristics on the risk of new-onset heart failure in patients with nontraumatic OHCA. Methods The Taiwanese government healthcare database contains data for 49,101 nontraumatic OHCA adult patients from 2011-2012, which were analyzed in this study. Nontraumatic OHCA patients who survived to the intensive care unit (ICU) were included as the study group (n = 7,321). Matched patients (n = 21,963) were recruited as a comparison group. Patients with any history of heart failure or cardiac arrest were not included in either group. All patients were followed-up for 6 months for the identification of new-onset heart failure. Adjustments were made for demographics, age, emergency interventions, and comorbidities as potential risk factors. Results In all, 3.84% (n = 281) of OHCA patients suffered new-onset heart failure, while only 1.24% (n = 272) of matched patients in the comparison group suffered new-onset heart failure. Strong risk factors for heart failure were age (60-75 years, HR: 11.4; 95% CI: 9-14.4), medical history (myocardial infarction, HR: 2.47; 95% CI: 2.05-2.98 and cardiomyopathy, HR: 2.94; 95% CI: 1.45-5.94), and comorbidities during hospitalization (ischemic heart disease, HR: 4.5; 95% CI: 3.46-5.86). Only extracorporeal membrane oxygenation (ECMO) decreased the risk of heart failure. Most (53.6%) heart failure events occurred within 60 days after OHCA. Conclusion An age from 61 to 75 years, a history of myocardial infarction or cardiomyopathy, and ischemic heart disease or infection as comorbidities occurring during hospitalization were strong risk factors for new-onset heart failure in OHCA patients. However, ECMO could decrease this risk. More importantly, most heart failure events occurred within 60 days after OHCA.
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Nguyen A, Schaff HV, Nishimura RA, Geske JB, Ackerman MJ, Bos JM, Dearani JA, Ommen SR. Survival After Myectomy for Obstructive Hypertrophic Cardiomyopathy: What Causes Late Mortality? Ann Thorac Surg 2019; 108:723-729. [DOI: 10.1016/j.athoracsur.2019.03.026] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 03/02/2019] [Accepted: 03/04/2019] [Indexed: 12/31/2022]
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Tran Vu MT, Nguyen TV, Huynh NV, Nguyen Thai HT, Pham Nguyen V, Ho Huynh TD. Presence of Hypertrophic Cardiomyopathy Related Gene Mutations and Clinical Manifestations in Vietnamese Patients With Hypertrophic Cardiomyopathy. Circ J 2019; 83:1908-1916. [PMID: 31308319 DOI: 10.1253/circj.cj-19-0190] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Hypertrophic cardiomyopathy (HCM) is associated primarily with pathogenic mutations in sarcomeric genes. The aim of this study was to identify the prevalence and distribution of disease-causing mutations in HCM-associated genes and the genotype-phenotype relationship in Vietnamese patients with HCM. METHODS AND RESULTS Genetic testing was performed by next-generation sequencing in 104 unrelated probands for 23 HCM-related genes and in 57 family members for the mutation(s) detected. Clinical manifestations were recorded for genotype-phenotype correlation analysis. Mutation detection rate was 43.4%. Mutations inMYBPC3accounted for 38.6%, followed byTPM1(20.5%),MYH7(18.2%),TNNT2(9.1%),TNNI3(4.5%) andMYL2(2.3%). A mutation inGLAassociated with Fabry disease was found in 1 patient. A mutation inTPM1(c.842T>C, p.Met281Thr) was identified in 8 unrelated probands (18.2%) and 8 family members from 5 probands. Genotype-positive status related toMYH7,TPM1, andTNNT2mutations was associated with severe clinical manifestations.MYH7-positive patients displayed worse prognosis compared withMYBPC3-positive patients. Interestingly,TPM1c.842T>C mutation was associated with high penetrance and severe HCM phenotype. CONCLUSIONS We report for the first time the prevalence of HCM-related gene variants in Vietnamese patients with HCM.MYH7,TPM1, andTNNT2mutations were associated with unfavorable prognosis.
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Affiliation(s)
| | - Thuy Vy Nguyen
- Research Center for Genetics and Reproductive Health, School of Medicine, Viet Nam National University
- Department of Genetics, Faculty of Biology and Biotechnology, University of Science, VNUHCM
| | | | - Hoang Tam Nguyen Thai
- Department of Genetics, Faculty of Biology and Biotechnology, University of Science, VNUHCM
| | | | - Thuy Duong Ho Huynh
- Research Center for Genetics and Reproductive Health, School of Medicine, Viet Nam National University
- Department of Genetics, Faculty of Biology and Biotechnology, University of Science, VNUHCM
- KTEST Science Company
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Hoedemakers S, Vandenberk B, Liebregts M, Bringmans T, Vriesendorp P, Willems R, Van Cleemput J. Long-term outcome of conservative and invasive treatment in patients with hypertrophic obstructive cardiomyopathy. Acta Cardiol 2019; 74:253-261. [PMID: 30451084 DOI: 10.1080/00015385.2018.1491673] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Background and objective: Treatment for patients with hypertrophic obstructive cardiomyopathy (HOCM) can be either conservative or invasive (alcohol septal ablation (ASA) and myectomy). As there is no clear consensus on the long-term effects of these different strategies, the aim was to compare the long-term outcome in a large tertiary referral university hospital. Methods: We retrospectively included 106 HOCM patients. Twenty-nine (27.4%) patients were treated conservatively, 25 (23.6%) underwent ASA and 52 (49.0%) myectomy. Endpoints were all-cause mortality and sudden cardiac death (SCD)-related events (including SCD, aborted SCD and appropriate ICD shocks). Kaplan-Meier survival analysis and Cox proportional hazard regression models were used. Results: The mean follow-up period was 7.7 ± 4.9 years. Overall, there was no significant difference in survival between the three treatment strategies (p = 0.7). Annual rates of SCD-related events at 5 years and the complete follow-up period were significantly higher (p = 0.034) after conservative treatment (4.9%/year and 2.7%/year, respectively) compared to ASA (0.9%/year, 0.5%/year) and myectomy (1.0%/year, 0.6%/year). Independent predictors of SCD-related events were: conservative treatment (HR 10.66; 1.88-60.55), a known mutation (HR 9.36; 1.43-61.20), left ventricular wall thickness (LVWT) > 30 mm (HR 6.48; 1.05-39.92) and non-sustained VT (HR 16.82; 2.29-123.29). Invasive treatment resulted in a significant higher proportion of patients requiring pacing (p = 0.033). Conclusions: Long-term mortality rates for patients with HOCM are similarly low between treatment groups. However, conservative treatment was associated with SCD-related events, as were known mutations, increased LVWT and non-sustained VT. Invasive treatment was associated with a higher need for implantation of a pacemaker.
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Affiliation(s)
- Sarah Hoedemakers
- Department of Cardiology, University Hospitals Leuven, Leuven, Belgium
| | - Bert Vandenberk
- Department of Cardiology, University Hospitals Leuven, Leuven, Belgium
- Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
| | - Max Liebregts
- Department of Cardiology, St. Antonius Ziekenhuis Nieuwegein, Nieuwegein, The Netherlands
| | - Tijs Bringmans
- Department of Cardiology, University Hospitals Leuven, Leuven, Belgium
| | | | - Rik Willems
- Department of Cardiology, University Hospitals Leuven, Leuven, Belgium
- Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
| | - Johan Van Cleemput
- Department of Cardiology, University Hospitals Leuven, Leuven, Belgium
- Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium
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Abstract
Genetic testing has an increasingly important role in the diagnosis and management of cardiac disorders, where it confirms the diagnosis, aids prognostication and risk stratification and guides treatment. A genetic diagnosis in the proband also enables clarification of the risk for family members by cascade testing. Genetics in cardiac disorders is complex where epigenetic and environmental factors might come into interplay. Incomplete penetrance and variable expressivity is also common. Genetic results in cardiac conditions are mostly probabilistic and should be interpreted with all available clinical information. With this complexity in cardiac genetics, testing is only indicated in patients with a strong suspicion of an inheritable cardiac disorder after a full clinical evaluation. In this review we discuss the genetics underlying the major cardiomyopathies and channelopathies, and the practical aspects of diagnosing these conditions in the laboratory.
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Abstract
Hypertrophic cardiomyopathy is a genetic heart disease with heterogeneous clinical features, including progression to advanced heart failure. The development of these symptoms can be related to outflow obstruction but in some patients reflects an underlying process of fibrosis and progressive ventricular dysfunction. For patients with end-stage disease, traditional heart failure therapies have not proved beneficial. As such, more advanced therapies, such as left ventricular assist device or cardiac transplantation, should be considered for these patients. Although left ventricular assist device support is used infrequently due to the restrictive physiology underlying hypertrophic cardiomyopathy, transplant represents an effective treatment, with encouraging long-term outcome data.
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Affiliation(s)
- Avi Levine
- Advanced Heart Failure and Cardiac Transplantation, Division of Cardiology, Department of Medicine, Westchester Medical Center, New York Medical College, Macy Pavilion, Suite 100, 100 Woods Road, Valhalla, NY 10595, USA.
| | - Chhaya Aggarwal Gupta
- Advanced Heart Failure and Cardiac Transplantation, Division of Cardiology, Department of Medicine, Westchester Medical Center, New York Medical College, Macy Pavilion, Suite 100, 100 Woods Road, Valhalla, NY 10595, USA
| | - Alan Gass
- Heart Transplant and Mechanical Circulatory Support, Division of Cardiology, Department of Medicine, Westchester Medical Center, New York Medical College, Macy Pavilion, Suite 100, 100 Woods Road, Valhalla, NY 10595, USA
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30
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Ho CY, Day SM, Ashley EA, Michels M, Pereira AC, Jacoby D, Cirino AL, Fox JC, Lakdawala NK, Ware JS, Caleshu CA, Helms AS, Colan SD, Girolami F, Cecchi F, Seidman CE, Sajeev G, Signorovitch J, Green EM, Olivotto I. Genotype and Lifetime Burden of Disease in Hypertrophic Cardiomyopathy: Insights from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Circulation 2018; 138:1387-1398. [PMID: 30297972 PMCID: PMC6170149 DOI: 10.1161/circulationaha.117.033200] [Citation(s) in RCA: 544] [Impact Index Per Article: 77.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2017] [Accepted: 06/12/2018] [Indexed: 01/28/2023]
Abstract
Background A better understanding of the factors that contribute to heterogeneous outcomes and lifetime disease burden in hypertrophic cardiomyopathy (HCM) is critically needed to improve patient management and outcomes. The Sarcomeric Human Cardiomyopathy Registry (SHaRe) was established to provide the scale of data required to address these issues, aggregating longitudinal datasets curated by eight international HCM specialty centers. Methods Data on 4591 HCM patients (2763 genotyped), followed for a mean of 5.4±6.9 years (24,791 patient-years; median [interquartile range] 2.9 [0.3-7.9] years) were analyzed regarding cardiac arrest, cardiac transplantation, appropriate implantable cardioverter-defibrillator (ICD) therapy, all-cause death, atrial fibrillation, stroke, New York Heart Association Functional Class III/IV symptoms (all comprising the overall composite endpoint), and left ventricular ejection fraction (LVEF)<35%. Outcomes were analyzed individually and as composite endpoints. Results Median age of diagnosis was 45.8 [30.9-58.1] years and 37% of patients were female. Age of diagnosis and sarcomere mutation status were predictive of outcomes. Patients <40 years old at diagnosis had a 77% [95% confidence interval: 72%, 80%] cumulative incidence of the overall composite outcome by age 60, compared to 32% [29%, 36%] by age 70 for patients diagnosed >60 years. Young HCM patients (20-29 years) had 4-fold higher mortality than the general United States population at a similar age. Patients with pathogenic/likely pathogenic sarcomere mutations had two-fold greater risk for adverse outcomes compared to patients without mutations; sarcomere variants of uncertain significance were associated with intermediate risk. Heart failure and atrial fibrillation were the most prevalent adverse events, although typically not emerging for several years after diagnosis. Ventricular arrhythmias occurred in 32% [23%, 40%] of patients <40 years at diagnosis, but in 1% [1%, 2%] >60 years. Conclusions The cumulative burden of HCM is substantial and dominated by heart failure and atrial fibrillation occurring many years following diagnosis. Young age of diagnosis and the presence of a sarcomere mutation are powerful predictors of adverse outcomes. These findings highlight the need for close surveillance throughout life, and the need to develop disease-modifying therapies.
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Affiliation(s)
- Carolyn Y. Ho
- Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (C.Y.H., A.L.C., N.K.L.)
| | - Sharlene M. Day
- Department of Internal Medicine, University of Michigan, Ann Arbor (S.M.D., A.S.H., C.E.S.)
| | - Euan A. Ashley
- Stanford Center for Inherited Heart Disease, CA (E.A.A., C.A.C.)
| | - Michelle Michels
- Department of Cardiology, Thoraxcenter, Erasmus Medical Center Rotterdam, the Netherlands (M.M.)
| | - Alexandre C. Pereira
- Heart Institute (InCor), University of Sao Paulo Medical School, Brazil (A.C.P.)
| | | | - Allison L. Cirino
- Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (C.Y.H., A.L.C., N.K.L.)
| | | | - Neal K. Lakdawala
- Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (C.Y.H., A.L.C., N.K.L.)
| | - James S. Ware
- National Heart and Lung Institute and National Institute for Health Research Royal Brompton Cardiovascular Biomedical Research Unit, Imperial College London, United Kingdom (J.S.W.)
| | | | - Adam S. Helms
- Department of Internal Medicine, University of Michigan, Ann Arbor (S.M.D., A.S.H., C.E.S.)
| | - Steven D. Colan
- Department of Cardiology, Boston Children’s Hospital, MA (S.D.C.)
| | - Francesca Girolami
- Cardiomyopathy Unit and Genetic Unit, Careggi University Hospital, Florence, Italy (F.G., F.C., I.O.)
| | - Franco Cecchi
- Cardiomyopathy Unit and Genetic Unit, Careggi University Hospital, Florence, Italy (F.G., F.C., I.O.)
| | - Christine E. Seidman
- Department of Internal Medicine, University of Michigan, Ann Arbor (S.M.D., A.S.H., C.E.S.)
- Howard Hughes Medical Institute, Chevy Chase, MD (C.E.S.)
| | | | | | - Eric M. Green
- MyoKardia, Inc, South San Francisco, CA (J.D.F., E.M.G.)
| | - Iacopo Olivotto
- Cardiomyopathy Unit and Genetic Unit, Careggi University Hospital, Florence, Italy (F.G., F.C., I.O.)
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Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM. Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2018; 20:899-909. [PMID: 29904160 DOI: 10.1038/s41436-018-0039-z] [Citation(s) in RCA: 182] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2018] [Accepted: 04/03/2018] [Indexed: 12/24/2022] Open
Abstract
PURPOSE The purpose of this document is to provide updated guidance for the genetic evaluation of cardiomyopathy and for an approach to manage secondary findings from cardiomyopathy genes. The genetic bases of the primary cardiomyopathies (dilated, hypertrophic, arrhythmogenic right ventricular, and restrictive) have been established, and each is medically actionable; in most cases established treatments or interventions are available to improve survival, reduce morbidity, and enhance quality of life. METHODS A writing group of cardiologists and genetics professionals updated guidance, first published in 2009 for the Heart Failure Society of America (HFSA), in a collaboration with the American College of Medical Genetics and Genomics (ACMG). Each recommendation was assigned to teams of individuals by expertise, literature was reviewed, and recommendations were decided by consensus of the writing group. Recommendations for family history, phenotype screening of at-risk family members, referral to expert centers as needed, genetic counseling, and cardiovascular therapies, informed in part by phenotype, are presented in the HFSA document. RESULTS A genetic evaluation of cardiomyopathy is indicated with a cardiomyopathy diagnosis, which includes genetic testing. Guidance is also provided for clinical approaches to secondary findings from cardiomyopathy genes. This is relevant as cardiomyopathy is the phenotype associated with 27% of the genes on the ACMG list for return of secondary findings. Recommendations herein are considered expert opinion per current ACMG policy as no systematic approach to literature review was conducted. CONCLUSION Genetic testing is indicated for cardiomyopathy to assist in patient care and management of at-risk family members.
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Affiliation(s)
- Ray E Hershberger
- Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
| | - Michael M Givertz
- Division of Cardiovascular Medicine, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Carolyn Y Ho
- Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Daniel P Judge
- Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, USA
| | - Paul F Kantor
- Division of Pediatric Cardiology, University of Alberta and Stollery Children's Hospital, Edmonton, Alberta, Canada
| | - Kim L McBride
- Center for Cardiovascular Research, Nationwide Children's Hospital, and Department of Pediatrics, Ohio State University, Columbus, Ohio, USA
| | - Ana Morales
- Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Matthew R G Taylor
- Adult Medical Genetics Program, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Matteo Vatta
- Invitae Corporation, San Francisco, California, USA.,Departments of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Departments of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Stephanie M Ware
- Departments of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.,Departments of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA
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Abstract
PURPOSE OF REVIEW As rapid genetic testing has become increasingly accessible in a timely fashion, more genetic mutations are identified in inherited conditions such as cardiomyopathies. Understanding when to consider genetic testing is an important part of the management of patients whose presentations vary from decompensated heart failure to sudden cardiac death. RECENT FINDINGS We describe the benefits of genetic testing for risk stratification of family members, prognostication of probands, and identification of novel disease-causing mutations and examine the possible role of genetic predisposition in seemingly acquired cardiomyopathies such as peripartum and anthracycline-induced cardiomyopathy. SUMMARY Genetic screening for the recognition of family members who have inherited a cardiomyopathy is important, and testing may identify patients at higher risk of sudden death. However, genetic testing does have its limitations, such as the identification of variants of unknown significance that often complicate the clinical picture.
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Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM. Genetic Evaluation of Cardiomyopathy-A Heart Failure Society of America Practice Guideline. J Card Fail 2018; 24:281-302. [PMID: 29567486 PMCID: PMC9903357 DOI: 10.1016/j.cardfail.2018.03.004] [Citation(s) in RCA: 295] [Impact Index Per Article: 42.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
This guideline describes the approach and expertise needed for the genetic evaluation of cardiomyopathy. First published in 2009 by the Heart Failure Society of America (HFSA), the guideline has now been updated in collaboration with the American College of Medical Genetics and Genomics (ACMG). The writing group, composed of cardiologists and genetics professionals with expertise in adult and pediatric cardiomyopathy, reflects the emergence and increased clinical activity devoted to cardiovascular genetic medicine. The genetic evaluation of cardiomyopathy is a rapidly emerging key clinical priority, because high-throughput sequencing is now feasible for clinical testing and conventional interventions can improve survival, reduce morbidity, and enhance quality of life. Moreover, specific interventions may be guided by genetic analysis. A systematic approach is recommended: always a comprehensive family history; an expert phenotypic evaluation of the proband and at-risk family members to confirm a diagnosis and guide genetic test selection and interpretation; referral to expert centers as needed; genetic testing, with pre- and post-test genetic counseling; and specific guidance as indicated for drug and device therapies. The evaluation of infants and children demands special expertise. The approach to managing secondary and incidental sequence findings as recommended by the ACMG is provided.
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Affiliation(s)
- Ray E Hershberger
- Division of Human Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio; Division of Cardiovascular Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio.
| | - Michael M Givertz
- Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
| | - Carolyn Y Ho
- Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
| | - Daniel P Judge
- Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina
| | - Paul F Kantor
- Division of Pediatric Cardiology, University of Alberta and Stollery Children's Hospital, Edmonton, Canada
| | - Kim L McBride
- Center for Cardiovascular Research, Nationwide Children's Hospital, and Department of Pediatrics, Ohio State University, Columbus Ohio
| | - Ana Morales
- Division of Human Genetics, Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Matthew R G Taylor
- Adult Medical Genetics Program, Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Matteo Vatta
- Invitae Corporation, San Francisco, California; Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Stephanie M Ware
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
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van Velzen HG, Schinkel AFL, Oldenburg RA, van Slegtenhorst MA, Frohn-Mulder IME, van der Velden J, Michels M. Clinical Characteristics and Long-Term Outcome of Hypertrophic Cardiomyopathy in Individuals With a MYBPC3 (Myosin-Binding Protein C) Founder Mutation. ACTA ACUST UNITED AC 2018; 10:CIRCGENETICS.116.001660. [PMID: 28794111 DOI: 10.1161/circgenetics.116.001660] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 05/02/2017] [Indexed: 01/05/2023]
Abstract
BACKGROUND MYBPC3 (Myosin-binding protein C) founder mutations account for 35% of hypertrophic cardiomyopathy (HCM) cases in the Netherlands. We compared clinical characteristics and outcome of MYBPC3 founder mutation (FG+) HCM with nonfounder genotype-positive (G+) and genotype-negative (G-) HCM. METHODS AND RESULTS The study included 680 subjects: 271 FG+ carriers, 132 G+ probands with HCM, and 277 G- probands with HCM. FG+ carriers included 134 FG+ probands with HCM, 54 FG+ relatives diagnosed with HCM after family screening, 74 FG+/phenotype-negative relatives, and 9 with noncompaction or dilated cardiomyopathy. The clinical phenotype of FG+ and G+ probands with HCM was similar. FG+ and G+ probands were younger with less left ventricular outflow tract obstruction than G- probands, however, had more hypertrophy, and nonsustained ventricular tachycardia. FG+ relatives with HCM had less hypertrophy, smaller left atria, and less systolic and diastolic dysfunction than FG+ probands with HCM. After 8±6 years, cardiovascular mortality in FG+ probands with HCM was similar to G+ HCM (22% versus 14%; log-rank P=0.14), but higher than G- HCM (22% versus 6%; log-rank P<0.001) and FG+ relatives with HCM (22% versus 4%; P=0.009). Cardiac events were absent in FG+/phenotype-negative relatives; subtle HCM developed in 11% during 6 years of follow-up. CONCLUSIONS Clinical phenotype and outcome of FG+ HCM was similar to G+ HCM but worse than G- HCM and FG+ HCM diagnosed in the context of family screening. These findings indicate the need for more intensive follow-up of FG+ and G+ HCM versus G- HCM and FG+ HCM in relatives.
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Affiliation(s)
- Hannah G van Velzen
- From the Department of Cardiology, Thoraxcenter (H.G.v.V., A.F.L.S., M.M.), Department of Clinical Genetics (R.A.O., M.A.v.S.), and Department of Pediatrics (I.M.E.F.-M.), Erasmus Medical Center, Rotterdam, The Netherlands; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and Netherlands Heart Institute, Utrecht (J.v.d.V.).
| | - Arend F L Schinkel
- From the Department of Cardiology, Thoraxcenter (H.G.v.V., A.F.L.S., M.M.), Department of Clinical Genetics (R.A.O., M.A.v.S.), and Department of Pediatrics (I.M.E.F.-M.), Erasmus Medical Center, Rotterdam, The Netherlands; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and Netherlands Heart Institute, Utrecht (J.v.d.V.)
| | - Rogier A Oldenburg
- From the Department of Cardiology, Thoraxcenter (H.G.v.V., A.F.L.S., M.M.), Department of Clinical Genetics (R.A.O., M.A.v.S.), and Department of Pediatrics (I.M.E.F.-M.), Erasmus Medical Center, Rotterdam, The Netherlands; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and Netherlands Heart Institute, Utrecht (J.v.d.V.)
| | - Marjon A van Slegtenhorst
- From the Department of Cardiology, Thoraxcenter (H.G.v.V., A.F.L.S., M.M.), Department of Clinical Genetics (R.A.O., M.A.v.S.), and Department of Pediatrics (I.M.E.F.-M.), Erasmus Medical Center, Rotterdam, The Netherlands; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and Netherlands Heart Institute, Utrecht (J.v.d.V.)
| | - Ingrid M E Frohn-Mulder
- From the Department of Cardiology, Thoraxcenter (H.G.v.V., A.F.L.S., M.M.), Department of Clinical Genetics (R.A.O., M.A.v.S.), and Department of Pediatrics (I.M.E.F.-M.), Erasmus Medical Center, Rotterdam, The Netherlands; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and Netherlands Heart Institute, Utrecht (J.v.d.V.)
| | - Jolanda van der Velden
- From the Department of Cardiology, Thoraxcenter (H.G.v.V., A.F.L.S., M.M.), Department of Clinical Genetics (R.A.O., M.A.v.S.), and Department of Pediatrics (I.M.E.F.-M.), Erasmus Medical Center, Rotterdam, The Netherlands; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and Netherlands Heart Institute, Utrecht (J.v.d.V.)
| | - Michelle Michels
- From the Department of Cardiology, Thoraxcenter (H.G.v.V., A.F.L.S., M.M.), Department of Clinical Genetics (R.A.O., M.A.v.S.), and Department of Pediatrics (I.M.E.F.-M.), Erasmus Medical Center, Rotterdam, The Netherlands; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (J.v.d.V.); and Netherlands Heart Institute, Utrecht (J.v.d.V.)
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Mathew J, Zahavich L, Lafreniere-Roula M, Wilson J, George K, Benson L, Bowdin S, Mital S. Utility of genetics for risk stratification in pediatric hypertrophic cardiomyopathy. Clin Genet 2017; 93:310-319. [DOI: 10.1111/cge.13157] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 09/17/2017] [Accepted: 09/27/2017] [Indexed: 12/29/2022]
Affiliation(s)
- J. Mathew
- Cardiology Department; The Royal Children’s Hospital; Melbourne Victoria Australia
| | - L. Zahavich
- Division of Cardiology, Department of Pediatrics; Hospital for Sick Children, University of Toronto; Toronto Ontario Canada
| | - M. Lafreniere-Roula
- Division of Cardiology, Department of Pediatrics; Hospital for Sick Children, University of Toronto; Toronto Ontario Canada
| | - J. Wilson
- Division of Cardiology, Department of Pediatrics; Hospital for Sick Children, University of Toronto; Toronto Ontario Canada
| | - K. George
- Division of Cardiology, Department of Pediatrics; Hospital for Sick Children, University of Toronto; Toronto Ontario Canada
| | - L. Benson
- Division of Cardiology, Department of Pediatrics; Hospital for Sick Children, University of Toronto; Toronto Ontario Canada
| | - S. Bowdin
- Division of Cardiology, Department of Pediatrics; Hospital for Sick Children, University of Toronto; Toronto Ontario Canada
| | - S. Mital
- Division of Cardiology, Department of Pediatrics; Hospital for Sick Children, University of Toronto; Toronto Ontario Canada
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Abstract
Nonischemic dilated cardiomyopathy (DCM) often has a genetic pathogenesis. Because of the large number of genes and alleles attributed to DCM, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at risk or with early stage disease, offering the opportunity for early intervention. This review will address diagnosis and management of DCM, including the role of genetic evaluation. We will also overview distinct genetic pathways linked to DCM and their pathogenetic mechanisms. Historically, cardiac morphology has been used to classify cardiomyopathy subtypes. Determining genetic variants is emerging as an additional adjunct to help further refine subtypes of DCM, especially where arrhythmia risk is increased, and ultimately contribute to clinical management.
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Affiliation(s)
- Elizabeth M McNally
- From the Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago IL (E.M.M.); and Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora (L.M.).
| | - Luisa Mestroni
- From the Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago IL (E.M.M.); and Cardiovascular Institute, University of Colorado Anschutz Medical Campus, Aurora (L.M.).
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Price J, Clarke N, Turer A, Quintana E, Mestres C, Huffman L, Peltz M, Wait M, Ring WS, Jessen M, Bajona P. Hypertrophic obstructive cardiomyopathy: review of surgical treatment. Asian Cardiovasc Thorac Ann 2017; 25:594-607. [PMID: 28901158 DOI: 10.1177/0218492317733111] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Hypertrophic cardiomyopathy ranks among the most common congenital cardiac diseases, affecting up to 1 in 200 of the general population. When it causes left ventricular outflow tract obstruction, treatment is guided to reduce symptoms and the risk of sudden cardiac death. Pharmacologic therapy is the first-line treatment, but when it fails, surgical myectomy or percutaneous ablation of the hypertrophic myocardium are the standard therapies to eliminate subaortic obstruction. Both surgical myectomy and percutaneous ablation are proven safe and effective treatments; however, myectomy is the gold standard with a significantly lower complication rate and more complete and lasting reduction of left ventricular outflow tract obstruction.
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Affiliation(s)
- Jonathan Price
- 1 Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Nicholas Clarke
- 1 Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Aslan Turer
- 2 Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Eduard Quintana
- 3 Hospital Clínic de Barcelona, Cardiovascular Surgery Department, Cardiovascular Institute, University of Barcelona Medical School, Barcelona, Spain
| | - Carlos Mestres
- 4 Department of Cardiovascular Surgery, University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Lynn Huffman
- 1 Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Matthias Peltz
- 1 Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Michael Wait
- 1 Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - W Steves Ring
- 1 Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Michael Jessen
- 1 Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Pietro Bajona
- 1 Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA.,5 Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy
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Thompson AD, Day SM. Founder Mutations in Myosin-Binding Protein C: Maybe Not So Benign After All. CIRCULATION. CARDIOVASCULAR GENETICS 2017; 10:CIRCGENETICS.117.001872. [PMID: 28794114 DOI: 10.1161/circgenetics.117.001872] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Andrea D Thompson
- From the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor
| | - Sharlene M Day
- From the Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor.
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Kumar A, Rani B, Sharma R, Kaur G, Prasad R, Bahl A, Khullar M. ACE2, CALM3 and TNNI3K polymorphisms as potential disease modifiers in hypertrophic and dilated cardiomyopathies. Mol Cell Biochem 2017; 438:167-174. [PMID: 28744816 DOI: 10.1007/s11010-017-3123-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 07/15/2017] [Indexed: 12/18/2022]
Abstract
The marked clinical and genetic heterogeneity seen in hypertrophic (HCM) and dilated cardiomyopathies (DCM) suggests involvement of disease modifiers and environmental factors in the pathophysiology of these diseases. In the current study, we examined association of single nucleotide polymorphisms (SNPs) of three candidate genes, ACE2 (rs6632677), TNNI3K (rs49812611) and CALM3 (rs13477425) with clinical phenotypes of HCM and DCM patients of North Indian ethnicity. Prevalence of ACE2 (7160726 C>G) variant genotypes (CG and GG) was significantly higher in DCM subjects as compared to controls. Prevalence of TNNI3K (3784 C>T) and CALM3 (-34T>A) variant homozygous genotype were significantly higher in HCM and DCM subjects as compared to controls. DCM patients with CT genotype showed significant decrease in LVEF as compared to CC genotype (p < 0.03). There was significant gene-gene interaction between these SNPs and three-way SNP combination of ACE2 C>G, TNN13K C>T, CALM3 A>T gene variants and was associated with high risk of HCM and DCM. Presence of ACE2 (7160726 C>G) and CALM3 (-34T>A) variant genotypes in HCM Patients with mutations (sarcomeric or non sarcomeric genes) was associated with increased mean septal thickness, further suggesting a role of these gene variants in modifying disease phenotype. Our results suggest that ACE2, TNNI3K and CALM3 polymorphisms are associated with increased risk of HCM and DCM and may act as disease modifiers of these diseases.
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Affiliation(s)
- Amit Kumar
- Department of Experimental Medicine and Biotechnology, PGIMER, Lab No 2009, Research Block B, Chandigarh, 160012, India
| | - Bindu Rani
- Department of Experimental Medicine and Biotechnology, PGIMER, Lab No 2009, Research Block B, Chandigarh, 160012, India
| | - Rajni Sharma
- Department of Otolaryngology, PGIMER, Chandigarh, India
| | - Gurjeet Kaur
- Department of Endocrinology, PGIMER, Chandigarh, India
| | - Rishikesh Prasad
- Department of Experimental Medicine and Biotechnology, PGIMER, Lab No 2009, Research Block B, Chandigarh, 160012, India
| | - Ajay Bahl
- Department of Cardiology, PGIMER, Chandigarh, India
| | - Madhu Khullar
- Department of Experimental Medicine and Biotechnology, PGIMER, Lab No 2009, Research Block B, Chandigarh, 160012, India.
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Genetic testing impacts the utility of prospective familial screening in hypertrophic cardiomyopathy through identification of a nonfamilial subgroup. Genet Med 2017. [DOI: 10.1038/gim.2017.79] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Fourey D, Care M, Siminovitch KA, Weissler-Snir A, Hindieh W, Chan RH, Gollob MH, Rakowski H, Adler A. Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy. ACTA ACUST UNITED AC 2017; 10:CIRCGENETICS.116.001685. [DOI: 10.1161/circgenetics.116.001685] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 02/07/2017] [Indexed: 11/16/2022]
Abstract
Background—
Available data suggests that double mutations in patients with hypertrophic cardiomyopathy are not rare and are associated with a more severe phenotype. Most of this data, however, is based on noncontemporary variant classification.
Methods and Results—
Clinical data of all hypertrophic cardiomyopathy patients with 2 rare genetic variants were retrospectively reviewed and compared with a group of patients with a single disease-causing variant. Furthermore, a literature search was performed for all studies with information on prevalence and outcome of patients with double mutations. Classification of genetic variants was reanalyzed according to current guidelines. In our cohort (n=1411), 9% of gene-positive patients had 2 rare variants in sarcomeric genes but only in 1 case (0.4%) were both variants classified as pathogenic. Patients with 2 rare variants had a trend toward younger age at presentation when compared with patients with a single mutation. All other clinical variables were similar. In data pooled from cohort studies in the literature, 8% of gene-positive patients were published to have double mutations. However, after reanalysis of reported variants, this prevalence diminished to 0.4%. All patients with 2 radical mutations in
MYBPC3
in the literature had severe disease with death or heart transplant during the first year of life. Data on other specific genotype–phenotype correlations were scarce.
Conclusions—
Double mutations in patients with hypertrophic cardiomyopathy are much less common than previously estimated. With the exception of double radical
MYBPC3
mutations, there is little data to guide clinical decision making in cases with double mutations.
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Affiliation(s)
- Dana Fourey
- From the Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada (D.F., A.W.-S., W.H., R.H.C., M.H.G., H.R., A.A.); Fred A. Litwin & Family Center in Genetic Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada (M.C., K.A.S.)
| | - Melanie Care
- From the Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada (D.F., A.W.-S., W.H., R.H.C., M.H.G., H.R., A.A.); Fred A. Litwin & Family Center in Genetic Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada (M.C., K.A.S.)
| | - Katherine A. Siminovitch
- From the Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada (D.F., A.W.-S., W.H., R.H.C., M.H.G., H.R., A.A.); Fred A. Litwin & Family Center in Genetic Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada (M.C., K.A.S.)
| | - Adaya Weissler-Snir
- From the Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada (D.F., A.W.-S., W.H., R.H.C., M.H.G., H.R., A.A.); Fred A. Litwin & Family Center in Genetic Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada (M.C., K.A.S.)
| | - Waseem Hindieh
- From the Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada (D.F., A.W.-S., W.H., R.H.C., M.H.G., H.R., A.A.); Fred A. Litwin & Family Center in Genetic Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada (M.C., K.A.S.)
| | - Raymond H. Chan
- From the Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada (D.F., A.W.-S., W.H., R.H.C., M.H.G., H.R., A.A.); Fred A. Litwin & Family Center in Genetic Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada (M.C., K.A.S.)
| | - Michael H. Gollob
- From the Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada (D.F., A.W.-S., W.H., R.H.C., M.H.G., H.R., A.A.); Fred A. Litwin & Family Center in Genetic Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada (M.C., K.A.S.)
| | - Harry Rakowski
- From the Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada (D.F., A.W.-S., W.H., R.H.C., M.H.G., H.R., A.A.); Fred A. Litwin & Family Center in Genetic Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada (M.C., K.A.S.)
| | - Arnon Adler
- From the Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Ontario, Canada (D.F., A.W.-S., W.H., R.H.C., M.H.G., H.R., A.A.); Fred A. Litwin & Family Center in Genetic Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada (M.C., K.A.S.)
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Veselka J, Anavekar NS, Charron P. Hypertrophic obstructive cardiomyopathy. Lancet 2017; 389:1253-1267. [PMID: 27912983 DOI: 10.1016/s0140-6736(16)31321-6] [Citation(s) in RCA: 194] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 07/22/2016] [Accepted: 08/02/2016] [Indexed: 12/23/2022]
Abstract
Hypertrophic obstructive cardiomyopathy is an inherited myocardial disease defined by cardiac hypertrophy (wall thickness ≥15 mm) that is not explained by abnormal loading conditions, and left ventricular obstruction greater than or equal to 30 mm Hg. Typical symptoms include dyspnoea, chest pain, palpitations, and syncope. The diagnosis is usually suspected on clinical examination and confirmed by imaging. Some patients are at increased risk of sudden cardiac death, heart failure, and atrial fibrillation. Patients with an increased risk of sudden cardiac death undergo cardioverter-defibrillator implantation; in patients with severe symptoms related to ventricular obstruction, septal reduction therapy (myectomy or alcohol septal ablation) is recommended. Life-long anticoagulation is indicated after the first episode of atrial fibrillation.
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Affiliation(s)
- Josef Veselka
- Department of Cardiology, 2nd Medical School, Charles University and Motol University Hospital, Prague, Czech Republic.
| | - Nandan S Anavekar
- Departments of Cardiology and Radiology, Mayo Clinic, Rochester, MN, USA
| | - Philippe Charron
- Université Paris Sud, UVSQ, INSERM U1018, CESP, Boulogne-Billancourt, France; APHP, ICAN, Hôpital de la Pitié Salpêtrière, Paris, France
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Michels M, Olivotto I, Asselbergs FW, van der Velden J. Life-long tailoring of management for patients with hypertrophic cardiomyopathy : Awareness and decision-making in changing scenarios. Neth Heart J 2017; 25:186-199. [PMID: 28005231 PMCID: PMC5313451 DOI: 10.1007/s12471-016-0943-2] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hypertrophic cardiomyopathy (HCM) is the most common genetic heart disease, characterised by complex pathophysiology and extensive genetic and clinical heterogeneity. In most patients, HCM is caused by mutations in cardiac sarcomere protein genes and inherited as an autosomal dominant trait. The clinical phenotype ranges from severe presentations at a young age to lack of left ventricular hypertrophy in genotype-positive individuals. No preventative treatment is available as the sequence and causality of the pathomechanisms that initiate and exacerbate HCM are unknown. Sudden cardiac death and end-stage heart failure are devastating expressions of this disease. Contemporary management including surgical myectomy and implantable cardiac defibrillators has shown significant impact on long-term prognosis. However, timely recognition of specific scenarios - including transition to the end-stage phase - may be challenging due to limited awareness of the progression patterns of HCM. This in turn may lead to missed therapeutic opportunities. To illustrate these difficulties, we describe two HCM patients who progressed from the typical hyperdynamic stage of asymmetric septal thickening to end-stage heart failure with severely reduced ejection fraction. We highlight the different stages of this complex inherited cardiomyopathy based on the clinical staging proposed by Olivotto and colleagues. In this way, we aim to provide a practical guide for clinicians and hope to increase awareness for this common form of cardiac disease.
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Affiliation(s)
- M Michels
- Thoraxcenter, Department of Cardiology, Erasmus MC, Rotterdam, The Netherlands
| | - I Olivotto
- Careggi University Hospital, Florence, Italy
| | - F W Asselbergs
- University Medical Center Utrecht, Utrecht, The Netherlands
| | - J van der Velden
- VU University Medical Center, Amsterdam, The Netherlands.
- Netherlands Heart Institute, Utrecht, The Netherlands.
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Alejandra Restrepo-Cordoba M, Campuzano O, Ripoll-Vera T, Cobo-Marcos M, Mademont-Soler I, Gámez JM, Dominguez F, Gonzalez-Lopez E, Padron-Barthe L, Lara-Pezzi E, Alonso-Pulpon L, Brugada R, Garcia-Pavia P. Usefulness of Genetic Testing in Hypertrophic Cardiomyopathy: an Analysis Using Real-World Data. J Cardiovasc Transl Res 2017; 10:35-46. [PMID: 28138913 DOI: 10.1007/s12265-017-9730-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 01/15/2017] [Indexed: 10/20/2022]
Abstract
This study sought to determine the usefulness of genetic testing to predict evolution in hypertrophic cardiomyopathy (HCM) and to assess the role of genetic testing in clinical practice. Genetic results of 100 HCM patients tested for mutations in ≥10 HCM-causing genes were evaluated. Patients were classified as with poor (group A) or favourable (group B) clinical course. Forty-five pathogenic mutations (PM) were identified in 28 patients (56 %) from group A and in 23 (46 %) from group B (p = 0.317). Only 40 patients (40 %) exhibited PM that had been previously reported and only 15 (15 %) had PM reported in ≥10 individuals. PM associated with poor prognosis were identified in just five patients from group A (10 %). Genetic findings are not useful to predict prognosis in most HCM patients. By contrast, real-world data reinforce the usefulness of genetic testing to provide genetic counselling and to enable cascade genetic screening.
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Affiliation(s)
- M Alejandra Restrepo-Cordoba
- Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla 2, Majadahonda, 28222, Madrid, Spain
| | - Oscar Campuzano
- Cardiovascular Genetics Centre, Institut d'Investigació Biomèdica de Girona (IDIBGi), Girona, Spain
- Department of Medical Science, Medical School, Universitat de Girona (UdG), Girona, Spain
- Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Tomás Ripoll-Vera
- Department of Cardiology, Hospital Son Llatzer & IdISPa, Mallorca, Spain
| | - Marta Cobo-Marcos
- Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla 2, Majadahonda, 28222, Madrid, Spain
- Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Irene Mademont-Soler
- Cardiovascular Genetics Centre, Institut d'Investigació Biomèdica de Girona (IDIBGi), Girona, Spain
- Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - José M Gámez
- Department of Cardiology, Hospital Son Llatzer & IdISPa, Mallorca, Spain
| | - Fernando Dominguez
- Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla 2, Majadahonda, 28222, Madrid, Spain
- Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- Myocardial Biology Programme, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Esther Gonzalez-Lopez
- Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla 2, Majadahonda, 28222, Madrid, Spain
- Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- Department of Cardiology, Hospital Son Llatzer & IdISPa, Mallorca, Spain
| | - Laura Padron-Barthe
- Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla 2, Majadahonda, 28222, Madrid, Spain
- Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- Myocardial Biology Programme, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Enrique Lara-Pezzi
- Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- Myocardial Biology Programme, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
| | - Luis Alonso-Pulpon
- Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla 2, Majadahonda, 28222, Madrid, Spain
- Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Ramon Brugada
- Cardiovascular Genetics Centre, Institut d'Investigació Biomèdica de Girona (IDIBGi), Girona, Spain
- Department of Medical Science, Medical School, Universitat de Girona (UdG), Girona, Spain
- Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
- Department of Cardiology, Hospital Josep Trueta, Girona, Spain
| | - Pablo Garcia-Pavia
- Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitario Puerta de Hierro, Manuel de Falla 2, Majadahonda, 28222, Madrid, Spain.
- Centro de Investigacion Biomedica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
- Myocardial Biology Programme, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
- Francisco de Vitoria University, Madrid, Spain.
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45
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Walsh R, Cook SA. Issues and Challenges in Diagnostic Sequencing for Inherited Cardiac Conditions. Clin Chem 2016; 63:116-128. [PMID: 27879323 DOI: 10.1373/clinchem.2016.254698] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 10/24/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND Inherited cardiac conditions are a relatively common group of Mendelian diseases associated with ill health and death, often in the young. Research into the genetic causes of these conditions has enabled confirmatory and predictive diagnostic sequencing to become an integral part of the clinical management of inherited cardiomyopathies, arrhythmias, aortopathies, and dyslipidemias. CONTENT Currently, the principle benefit of clinical genetic testing is the cascade screening of family members of patients with a pathogenic variant, enabling targeted follow up of presymptomatic genotype-positive individuals and discharge of genotype-negative individuals to health. For the affected proband, diagnostic sequencing can also be useful in discriminating inherited disease from alternative diagnoses, directing treatment, and for molecular autopsy in cases of sudden unexplained death. Advances in sequencing technology have expanded testing panels for inherited cardiac conditions and driven down costs, further improving the cost-effectiveness of genetic testing. However, this expanded testing requires great rigor in the identification of pathogenic variants, with domain-specific knowledge required for variant interpretation. SUMMARY Diagnostic sequencing has the potential to become an integral part of the clinical management of patients with inherited cardiac conditions. However, to move beyond just confirmatory and predictive testing, a much greater understanding is needed of the genetic basis of these conditions, the role of the environment, and the underlying disease mechanisms. With this additional information it is likely that genetic testing will increasingly be used for stratified and preventative strategies in the era of genomic medicine.
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Affiliation(s)
- Roddy Walsh
- NIHR Cardiovascular Biomedical Research Unit, Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, UK.,National Heart and Lung Institute, Imperial College London, London, UK
| | - Stuart A Cook
- National Heart and Lung Institute, Imperial College London, London, UK; .,National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore.,MRC Clinical Sciences Centre, Imperial College London, London, UK.,Division of Cardiovascular & Metabolic Disorders, Duke-National University of Singapore, Singapore
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van Velzen HG, Vriesendorp PA, Oldenburg RA, van Slegtenhorst MA, van der Velden J, Schinkel AFL, Michels M. Value of Genetic Testing for the Prediction of Long-Term Outcome in Patients With Hypertrophic Cardiomyopathy. Am J Cardiol 2016; 118:881-887. [PMID: 27476098 DOI: 10.1016/j.amjcard.2016.06.038] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 06/14/2016] [Accepted: 06/14/2016] [Indexed: 01/06/2023]
Abstract
Pathogenic gene mutations are found in about 50% of patients with hypertrophic cardiomyopathy (HC). Previous studies have shown an association between sarcomere mutations and medium-term outcome. The association with long-term outcome has not been described. The aim of this cohort study was to assess the long-term outcomes of patients with genotype positive (G+) and genotype negative (G-) HC. The study population consisted of 626 patients with HC (512 probands and 114 relatives) who underwent phenotyping and genetic testing from 1985 to 2014. End points were all-cause mortality, cardiovascular (CV) mortality, heart failure (HF)-related mortality, and sudden cardiac death/aborted sudden cardiac death (SCD/aborted SCD). Kaplan-Meier and multivariate Cox regression analyses were performed. A pathogenic mutation was detected in 327 patients (52%). G+ probands were younger than G- probands (46 ± 15 vs 55 ± 15 years, p <0.001), had more non sustained ventricular tachycardia (34% vs 13%; p <0.001), more often a history of syncope (14% vs 7%; p = 0.016), and more extreme hypertrophy (maximal wall thickness ≥30 mm, 7% vs 1%; p <0.001). G- probands were more symptomatic (New York Heart Association ≥II, 73% vs 53%, p <0.001) and had higher left ventricular outflow tract gradients (42 ± 39 vs 29 ± 33 mm Hg, p = 0.001). During 12 ± 9 years of follow-up, G+ status was an independent risk factor for all-cause mortality (hazard ratio [HR] 1.90, 95% CI 1.14 to 3.15; p = 0.014), CV mortality (HR 2.82, 95% CI 1.49 to 5.36; p = 0.002), HF-related mortality (HR 6.33, 95% CI 1.79 to 22.41; p = 0.004), and SCD/aborted SCD (HR 2.88, 95% CI 1.23 to 6.71; p = 0.015). In conclusion, during long-term follow-up, patients with G+ HC are at increased risk of all-cause death, CV death, HF-related death, and SCD/aborted SCD.
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Affiliation(s)
- Hannah G van Velzen
- Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands.
| | - Pieter A Vriesendorp
- Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Rogier A Oldenburg
- Department of Clinical Genetics, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | - Jolanda van der Velden
- Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands; Netherlands Heart Institute, Utrecht, The Netherlands
| | - Arend F L Schinkel
- Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Michelle Michels
- Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands
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Nuclear Imaging for Assessment of Myocardial Perfusion, Metabolism, and Innervation in Hypertrophic Cardiomyopathy. CURRENT CARDIOVASCULAR IMAGING REPORTS 2016. [DOI: 10.1007/s12410-016-9379-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Lahrouchi N, Behr ER, Bezzina CR. Next-Generation Sequencing in Post-mortem Genetic Testing of Young Sudden Cardiac Death Cases. Front Cardiovasc Med 2016; 3:13. [PMID: 27303672 PMCID: PMC4885007 DOI: 10.3389/fcvm.2016.00013] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2016] [Accepted: 05/02/2016] [Indexed: 12/19/2022] Open
Abstract
Sudden cardiac death (SCD) in the young (<40 years) occurs in the setting of a variety of rare inherited cardiac disorders and is a disastrous event for family members. Establishing the cause of SCD is important as it permits the pre-symptomatic identification of relatives at risk of SCD. Sudden arrhythmic death syndrome (SADS) is defined as SCD in the setting of negative autopsy findings and toxicological analysis. In such cases, reaching a diagnosis is even more challenging and post-mortem genetic testing can crucially contribute to the identification of the underlying cause of death. In this review, we will discuss the current achievements of “the molecular autopsy” in young SADS cases and provide an overview of key challenges in assessing pathogenicity (i.e., causality) of genetic variants identified through next-generation sequencing.
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Affiliation(s)
- Najim Lahrouchi
- Department of Clinical and Experimental Cardiology, Heart Center, AMC , Amsterdam , Netherlands
| | - Elijah R Behr
- Cardiology Clinical Academic Group, St George's University of London , London , UK
| | - Connie R Bezzina
- Department of Clinical and Experimental Cardiology, Heart Center, AMC , Amsterdam , Netherlands
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Slowing of contractile kinetics by myosin-binding protein C can be explained by its cooperative binding to the thin filament. J Mol Cell Cardiol 2015; 96:2-10. [PMID: 26454159 DOI: 10.1016/j.yjmcc.2015.10.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 10/05/2015] [Accepted: 10/06/2015] [Indexed: 12/30/2022]
Abstract
Cardiac myosin binding protein C (cMyBP-C) is a thick filament-associated protein that participates in the regulation of muscle contraction. Simplified in vitro systems show that cMyBP-C binds not only to myosin, but also to the actin filament. The physiological significance of these separate binding interactions remains unclear, as does the question of whether either interaction is capable of explaining the behavior of intact muscle from which cMyBP-C has been removed. We have used a computational model to explore the characteristic effects of myosin-binding versus actin-binding by cMyBP-C. Simulations suggest that myosin-cMyBP-C interactions reduce peak force and Ca2 + sensitivity of the myofilaments, but have no appreciable effect on the rate of force redevelopment (ktr). In contrast, cMyBP-C binding to actin increases myofilament Ca2 + sensitivity and slows ktrat sub-maximal Ca2 + values. This slowing is due to cooperation between cMyBP-C ‘crossbridges’ and traditional myosin crossbridges as they bind to and activate the actin thin filament. We further observed that an overall recapitulation of skinned myocardial data from wild type and cMyBP-C knockout mice requires the interaction of cMyBP-C with of both of its binding targets in our model. The assumption of significant interactions with both partners was also sufficient to explain published effects of cMyBP-C ablation on twitch kinetics. These modeling results strongly support the view that both binding interactions play critical roles in the physiology of intact muscle. Furthermore, they suggest that the widely observed phenomenon of slowed force development in the presence of cMyBP-C may actually be a manifestation of cooperative binding of this protein to the thin filament.
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50
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Affiliation(s)
- Barry J Maron
- From the Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis (B.J.M.); and Hypertropic Cardiomyopathy Center, Tufts Medical Center, Boston, MA (M.S.M.).
| | - Martin S Maron
- From the Hypertrophic Cardiomyopathy Center, Minneapolis Heart Institute Foundation, Minneapolis (B.J.M.); and Hypertropic Cardiomyopathy Center, Tufts Medical Center, Boston, MA (M.S.M.)
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