Early Mechanical Alterations in Phospholamban Mutation Carriers: Identifying Subclinical Disease Before Onset of Symptoms

Karim Taha*, Wouter P. te Rijdt, Tom E. Verstraelen, Maarten J. Cramer, Rudolf A. de Boer, Rianne H.A.C.M. de Bruin-Bon, Berto J. Bouma, Folkert W. Asselbergs, Arthur A.M. Wilde, Maarten P. van den Berg, Arco J. Teske

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)885-896
Number of pages12
JournalJACC: Cardiovascular Imaging
Issue number5
Early online date13 Nov 2020
Publication statusPublished - May 2021


  • deformation imaging
  • early detection
  • echocardiography
  • family screening
  • phospholamban
  • risk stratification


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