Eric D Smith1, Neal K Lakdawala2, Nikolaos Papoutsidakis3, Gregory Aubert4, Andrea Mazzanti5, Anthony C McCanta6, Prachi P Agarwal7, Patricia Arscott1, Lisa M Dellefave-Castillo8, Esther E Vorovich9, Kavitha Nutakki2, Lisa D Wilsbacher8, Silvia G Priori5, Daniel L Jacoby3, Elizabeth M McNally8, Adam S Helms1. 1. Department of Internal Medicine, Division of Cardiovascular Medicine (E.D.S., P.A., A.S.H.), University of Michigan, Ann Arbor. 2. Cardiovascular Genetics Program, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (N.K.L., K.N.). 3. Inherited Cardiomyopathy Program, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT (N.P., D.L.J.). 4. Center for Genetic Medicine (G.A.), Feinberg School of Medicine, Northwestern University, Chicago, IL. 5. Department of Molecular Cardiology, Istituto di Ricovero e Cura a Carattere Scientifico Instituti Clinici Scientifici Maugeri, Pavia, Italy (A.M., S.G.P.). 6. Department of Pediatric Cardiology, University of California-Irvine and Children's Hospital of Orange County, Orange (A.C.M.). 7. Division of Cardiothoracic Radiology, Department of Radiology (P.P.A.), University of Michigan, Ann Arbor. 8. Feinberg Cardiovascular Research Institute (L.M.D.-C., L.D.W., E.M.M.), Feinberg School of Medicine, Northwestern University, Chicago, IL. 9. Division of Cardiology (E.E.V.), Feinberg School of Medicine, Northwestern University, Chicago, IL.
Abstract
BACKGROUND: Mutations in desmoplakin (DSP), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of DSP cardiomyopathy have been limited to small case series. METHODS: Clinical and genetic data were collected on 107 patients with pathogenic DSP mutations and 81 patients with pathogenic plakophilin 2 (PKP2) mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed. RESULTS: DSP and PKP2 cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients with DSP (55% versus 0% for PKP2, P<0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with DSP versus 40% for PKP2 (P<0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for DSP cardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with DSP (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with DSP. Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with DSP and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4 DSP cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction <55% was strongly associated with severe ventricular arrhythmias for DSP cases (P<0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for PKP2 cases (P<0.001) but was poorly associated for DSP cases (P=0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both DSP (80%) and PKP2 (91%) groups (P=non-significant). CONCLUSIONS: DSP cardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used.
BACKGROUND: Mutations in desmoplakin (DSP), the primary force transducer between cardiac desmosomes and intermediate filaments, cause an arrhythmogenic form of cardiomyopathy that has been variably associated with arrhythmogenic right ventricular cardiomyopathy. Clinical correlates of DSPcardiomyopathy have been limited to small case series. METHODS: Clinical and genetic data were collected on 107 patients with pathogenic DSP mutations and 81 patients with pathogenic plakophilin 2 (PKP2) mutations as a comparison cohort. A composite outcome of severe ventricular arrhythmia was assessed. RESULTS:DSP and PKP2 cohorts included similar proportions of probands (41% versus 42%) and patients with truncating mutations (98% versus 100%). Left ventricular (LV) predominant cardiomyopathy was exclusively present among patients with DSP (55% versus 0% for PKP2, P<0.001), whereas right ventricular cardiomyopathy was present in only 14% of patients with DSP versus 40% for PKP2 (P<0.001). Arrhythmogenic right ventricular cardiomyopathy diagnostic criteria had poor sensitivity for DSPcardiomyopathy. LV late gadolinium enhancement was present in a primarily subepicardial distribution in 40% of patients with DSP (23/57 with magnetic resonance images). LV late gadolinium enhancement occurred with normal LV systolic function in 35% (8/23) of patients with DSP. Episodes of acute myocardial injury (chest pain with troponin elevation and normal coronary angiography) occurred in 15% of patients with DSP and were strongly associated with LV late gadolinium enhancement (90%), even in cases of acute myocardial injury with normal ventricular function (4/5, 80% with late gadolinium enhancement). In 4 DSP cases with 18F-fluorodeoxyglucose positron emission tomography scans, acute LV myocardial injury was associated with myocardial inflammation misdiagnosed initially as cardiac sarcoidosis or myocarditis. Left ventricle ejection fraction <55% was strongly associated with severe ventricular arrhythmias for DSP cases (P<0.001, sensitivity 85%, specificity 53%). Right ventricular ejection fraction <45% was associated with severe arrhythmias for PKP2 cases (P<0.001) but was poorly associated for DSP cases (P=0.8). Frequent premature ventricular contractions were common among patients with severe arrhythmias for both DSP (80%) and PKP2 (91%) groups (P=non-significant). CONCLUSIONS:DSPcardiomyopathy is a distinct form of arrhythmogenic cardiomyopathy characterized by episodic myocardial injury, left ventricular fibrosis that precedes systolic dysfunction, and a high incidence of ventricular arrhythmias. A genotype-specific approach for diagnosis and risk stratification should be used.
Entities:
Keywords:
arrhythmogenic right ventricular cardiomyopathy; cardiomyopathy; desmoplakin; desmosome
Authors: W James Kent; Charles W Sugnet; Terrence S Furey; Krishna M Roskin; Tom H Pringle; Alan M Zahler; David Haussler Journal: Genome Res Date: 2002-06 Impact factor: 9.043
Authors: Frank I Marcus; William J McKenna; Duane Sherrill; Cristina Basso; Barbara Bauce; David A Bluemke; Hugh Calkins; Domenico Corrado; Moniek G P J Cox; James P Daubert; Guy Fontaine; Kathleen Gear; Richard Hauer; Andrea Nava; Michael H Picard; Nikos Protonotarios; Jeffrey E Saffitz; Danita M Yoerger Sanborn; Jonathan S Steinberg; Harikrishna Tandri; Gaetano Thiene; Jeffrey A Towbin; Adalena Tsatsopoulou; Thomas Wichter; Wojciech Zareba Journal: Circulation Date: 2010-02-19 Impact factor: 29.690
Authors: Alexandros Protonotarios; Eleanor Wicks; Michael Ashworth; Edward Stephenson; Oliver Guttmann; Kostas Savvatis; Neha Sekhri; Saidi A Mohiddin; Petros Syrris; Leon Menezes; Perry Elliott Journal: Int J Cardiol Date: 2018-10-26 Impact factor: 4.164
Authors: Saurabh Kumar; Samuel H Baldinger; Estelle Gandjbakhch; Philippe Maury; Jean-Marc Sellal; Alexander F A Androulakis; Xavier Waintraub; Philippe Charron; Anne Rollin; Pascale Richard; William G Stevenson; Ciorsti J Macintyre; Carolyn Y Ho; Tina Thompson; Jitendra K Vohra; Jonathan M Kalman; Katja Zeppenfeld; Frederic Sacher; Usha B Tedrow; Neal K Lakdawala Journal: J Am Coll Cardiol Date: 2016-11-29 Impact factor: 24.094
Authors: Aditya Bhonsale; Judith A Groeneweg; Cynthia A James; Dennis Dooijes; Crystal Tichnell; Jan D H Jongbloed; Brittney Murray; Anneline S J M te Riele; Maarten P van den Berg; Hennie Bikker; Douwe E Atsma; Natasja M de Groot; Arjan C Houweling; Jeroen F van der Heijden; Stuart D Russell; Pieter A Doevendans; Toon A van Veen; Harikrishna Tandri; Arthur A Wilde; Daniel P Judge; J Peter van Tintelen; Hugh Calkins; Richard N Hauer Journal: Eur Heart J Date: 2015-01-23 Impact factor: 29.983
Authors: T Maruthappu; A Posafalvi; S Castelletti; P J Delaney; P Syrris; E A O'Toole; K J Green; P M Elliott; P D Lambiase; A Tinker; W J McKenna; D P Kelsell Journal: Br J Dermatol Date: 2019-01-02 Impact factor: 9.302
Authors: Kristopher W Cummings; Sanjeev Bhalla; Cylen Javidan-Nejad; Andrew J Bierhals; Fernando R Gutierrez; Pamela K Woodard Journal: Radiographics Date: 2009 Jan-Feb Impact factor: 5.333
Authors: Nadine Kawel-Boehm; Alicia Maceira; Emanuela R Valsangiacomo-Buechel; Jens Vogel-Claussen; Evrim B Turkbey; Rupert Williams; Sven Plein; Michael Tee; John Eng; David A Bluemke Journal: J Cardiovasc Magn Reson Date: 2015-04-18 Impact factor: 5.364
Authors: Ankur Gulati; Andrew Jabbour; Tevfik F Ismail; Kaushik Guha; Jahanzaib Khwaja; Sadaf Raza; Kishen Morarji; Tristan D H Brown; Nizar A Ismail; Marc R Dweck; Elisa Di Pietro; Michael Roughton; Ricardo Wage; Yousef Daryani; Rory O'Hanlon; Mary N Sheppard; Francisco Alpendurada; Alexander R Lyon; Stuart A Cook; Martin R Cowie; Ravi G Assomull; Dudley J Pennell; Sanjay K Prasad Journal: JAMA Date: 2013-03-06 Impact factor: 56.272
Authors: Alberto Cipriani; Giulia Mattesi; Riccardo Bariani; Annagrazia Cecere; Nicolò Martini; Laura De Michieli; Stefano Da Pozzo; Simone Corradin; Giorgio De Conti; Alessandro Zorzi; Raffaella Motta; Manuel De Lazzari; Barbara Bauce; Sabino Iliceto; Cristina Basso; Domenico Corrado; Martina Perazzolo Marra Journal: Eur Radiol Date: 2022-07-05 Impact factor: 5.315
Authors: Rahul Goli; Jian Li; Jeff Brandimarto; Lisa D Levine; Valerie Riis; Quentin McAfee; Steven DePalma; Alireza Haghighi; J G Seidman; Christine E Seidman; Daniel Jacoby; George Macones; Daniel P Judge; Sarosh Rana; Kenneth B Margulies; Thomas P Cappola; Rami Alharethi; Julie Damp; Eileen Hsich; Uri Elkayam; Richard Sheppard; Jeffrey D Alexis; John Boehmer; Chizuko Kamiya; Finn Gustafsson; Peter Damm; Anne S Ersbøll; Sorel Goland; Denise Hilfiker-Kleiner; Dennis M McNamara; Zolt Arany Journal: Circulation Date: 2021-04-20 Impact factor: 29.690
Authors: Nisha A Gilotra; Jan M Griffin; Noelle Pavlovic; Brian A Houston; Jessica Chasler; Colleen Goetz; Jonathan Chrispin; Michelle Sharp; Edward K Kasper; Edward S Chen; Ron Blankstein; Leslie T Cooper; Emer Joyce; Farooq H Sheikh Journal: J Card Fail Date: 2021-07-11 Impact factor: 5.712
Authors: Eric D Carruth; Dominik Beer; Amro Alsaid; Marci L B Schwartz; Megan McMinn; Melissa A Kelly; Adam H Buchanan; Christopher D Nevius; Hugh Calkins; Cynthia A James; Brittney Murray; Crystal Tichnell; Martin E Matsumura; H Lester Kirchner; Brandon K Fornwalt; Amy C Sturm; Christopher M Haggerty Journal: Circ Genom Precis Med Date: 2021-03-08