Karim Taha1, Wouter P Te Rijdt2, Tom E Verstraelen3, Maarten J Cramer4, Rudolf A de Boer5, Rianne H A C M de Bruin-Bon3, Berto J Bouma3, Folkert W Asselbergs6, Arthur A M Wilde3, Maarten P van den Berg5, Arco J Teske4. 1. Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands; Netherlands Heart Institute, Utrecht, the Netherlands. Electronic address: k.taha-2@umcutrecht.nl. 2. Netherlands Heart Institute, Utrecht, the Netherlands; Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 3. Heart Center, Department of Cardiology, Amsterdam University Medical Center, Location Academic Medical Center, Amsterdam, the Netherlands. 4. Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands. 5. Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. 6. Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands; Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom; Health Data Research United Kingdom and Institute of Health Informatics, University College London, London, United Kingdom.
Abstract
OBJECTIVES: This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms. BACKGROUND: Carriers of the genetic PLN p.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent. METHODS: PLN p.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of <500/24 h, and a left ventricular (LV) ejection fraction of ≥45%. In addition, we included 70 control subjects with similar age and sex distribution as the pre-symptomatic mutation carriers. Comprehensive echocardiographic analysis (including deformation imaging) was performed. RESULTS: The final study population consisted of 281 PLN p.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p < 0.001). In addition, post-systolic shortening (PSS) in the LV apex was observed in 43 pre-symptomatic mutation carriers (31%) and in none of the control subjects. During a median follow-up of 3.2 years (interquartile range: 2.1 to 5.6 years) in 104 pre-symptomatic mutation carriers, nonsustained VA occurred in 13 (13%). Presence of apical PSS was the strongest echocardiographic predictor of VA (multivariable hazards ratio: 5.11; 95% confidence interval [CI]: 1.37 to 19.08; p = 0.015), which resulted in a negative predictive value of 96% (95% CI: 89% to 98%) and a positive predictive value of 29% (95% CI: 21% to 40%). CONCLUSIONS: Global and regional LV mechanical alterations in PLN p.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk.
OBJECTIVES: This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms. BACKGROUND: Carriers of the genetic PLNp.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent. METHODS:PLNp.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of <500/24 h, and a left ventricular (LV) ejection fraction of ≥45%. In addition, we included 70 control subjects with similar age and sex distribution as the pre-symptomatic mutation carriers. Comprehensive echocardiographic analysis (including deformation imaging) was performed. RESULTS: The final study population consisted of 281 PLNp.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p < 0.001). In addition, post-systolic shortening (PSS) in the LV apex was observed in 43 pre-symptomatic mutation carriers (31%) and in none of the control subjects. During a median follow-up of 3.2 years (interquartile range: 2.1 to 5.6 years) in 104 pre-symptomatic mutation carriers, nonsustained VA occurred in 13 (13%). Presence of apical PSS was the strongest echocardiographic predictor of VA (multivariable hazards ratio: 5.11; 95% confidence interval [CI]: 1.37 to 19.08; p = 0.015), which resulted in a negative predictive value of 96% (95% CI: 89% to 98%) and a positive predictive value of 29% (95% CI: 21% to 40%). CONCLUSIONS: Global and regional LV mechanical alterations in PLNp.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk.
Authors: S M Kamel; C J M van Opbergen; C D Koopman; A O Verkerk; B J D Boukens; B de Jonge; Y L Onderwater; E van Alebeek; S Chocron; C Polidoro Pontalti; W J Weuring; M A Vos; T P de Boer; T A B van Veen; J Bakkers Journal: Nat Commun Date: 2021-12-09 Impact factor: 14.919