Ingrid A W van Rijsingen1, Paul A van der Zwaag1, Judith A Groeneweg1, Eline A Nannenberg1, Jan D H Jongbloed1, Aeilko H Zwinderman1, Yigal M Pinto1, Ronald H Lekanne Dit Deprez1, Jan G Post1, Hanno L Tan1, Rudolf A de Boer1, Richard N W Hauer1, Imke Christiaans1, Maarten P van den Berg1, J Peter van Tintelen2, Arthur A M Wilde2. 1. Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands. 2. Departments of Cardiology (I.A.W.v.R., Y.M.P., H.L.T., A.A.M.W.), Genetics (E.A.N., R.H.L.d.D., I.C.), and Epidemiology (A.H.Z.), Academic Medical Center, Amsterdam, The Netherlands; Departments of Genetics (P.A.v.d.Z., J.D.H.J., J.P.v.T.) and Cardiology (R.A.d.B., M.P.v.d.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands (J.A.G., Y.M.P., R.N.W.H., A.A.M.W.); Departments of Cardiology (J.A.G., R.N.W.H.) and Genetics (J.G.P.), University Medical Center Utrecht, Utrecht, The Netherlands. a.a.wilde@amc.uva.nl j.p.van.tintelen@umcg.nl.
Abstract
BACKGROUND: The pathogenic phospholamban R14del mutation causes dilated and arrhythmogenic right ventricular cardiomyopathies and is associated with an increased risk of malignant ventricular arrhythmias and end-stage heart failure. We performed a multicentre study to evaluate mortality, cardiac disease outcome, and risk factors for malignant ventricular arrhythmias in a cohort of phospholamban R14del mutation carriers. METHODS AND RESULTS: Using the family tree mortality ratio method in a cohort of 403 phospholamban R14del mutation carriers, we found a standardized mortality ratio of 1.7 (95% confidence interval, 1.4-2.0) with significant excess mortality starting from the age of 25 years. Cardiological data were available for 295 carriers. In a median follow-up period of 42 months, 55 (19%) individuals had a first episode of malignant ventricular arrhythmias and 33 (11%) had an end-stage heart failure event. The youngest age at which a malignant ventricular arrhythmia occurred was 20 years, whereas for an end-stage heart failure event this was 31 years. Independent risk factors for malignant ventricular arrhythmias were left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia with hazard ratios of 4.0 (95% confidence interval, 1.9-8.1) and 2.6 (95% confidence interval, 1.5-4.5), respectively. CONCLUSIONS: Phospholamban R14del mutation carriers are at high risk for malignant ventricular arrhythmias and end-stage heart failure, with left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia as independent risk factors. High mortality and a poor prognosis are present from late adolescence. Genetic and cardiac screening is, therefore, advised from adolescence onwards.
BACKGROUND: The pathogenic phospholamban R14del mutation causes dilated and arrhythmogenic right ventricular cardiomyopathies and is associated with an increased risk of malignant ventricular arrhythmias and end-stage heart failure. We performed a multicentre study to evaluate mortality, cardiac disease outcome, and risk factors for malignant ventricular arrhythmias in a cohort of phospholamban R14del mutation carriers. METHODS AND RESULTS: Using the family tree mortality ratio method in a cohort of 403 phospholamban R14del mutation carriers, we found a standardized mortality ratio of 1.7 (95% confidence interval, 1.4-2.0) with significant excess mortality starting from the age of 25 years. Cardiological data were available for 295 carriers. In a median follow-up period of 42 months, 55 (19%) individuals had a first episode of malignant ventricular arrhythmias and 33 (11%) had an end-stage heart failure event. The youngest age at which a malignant ventricular arrhythmia occurred was 20 years, whereas for an end-stage heart failure event this was 31 years. Independent risk factors for malignant ventricular arrhythmias were left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia with hazard ratios of 4.0 (95% confidence interval, 1.9-8.1) and 2.6 (95% confidence interval, 1.5-4.5), respectively. CONCLUSIONS: Phospholamban R14del mutation carriers are at high risk for malignant ventricular arrhythmias and end-stage heart failure, with left ventricular ejection fraction <45% and sustained or nonsustained ventricular tachycardia as independent risk factors. High mortality and a poor prognosis are present from late adolescence. Genetic and cardiac screening is, therefore, advised from adolescence onwards.
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Authors: Martin K Stiles; Arthur A M Wilde; Dominic J Abrams; Michael J Ackerman; Christine M Albert; Elijah R Behr; Sumeet S Chugh; Martina C Cornel; Karen Gardner; Jodie Ingles; Cynthia A James; Jyh-Ming Jimmy Juang; Stefan Kääb; Elizabeth S Kaufman; Andrew D Krahn; Steven A Lubitz; Heather MacLeod; Carlos A Morillo; Koonlawee Nademanee; Vincent Probst; Elizabeth V Saarel; Luciana Sacilotto; Christopher Semsarian; Mary N Sheppard; Wataru Shimizu; Jonathan R Skinner; Jacob Tfelt-Hansen; Dao Wu Wang Journal: Heart Rhythm Date: 2020-10-19 Impact factor: 6.343