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Original Investigation
March 2017

Evaluation of Structural Progression in Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

Author Affiliations
  • 1Division of Cardiology, Department of Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
  • 2Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 3Department of Radiology, University Medical Center Utrecht, Utrecht, the Netherlands
  • 4Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands
  • 5Netherlands Heart Institute, Utrecht, the Netherlands
JAMA Cardiol. 2017;2(3):293-302. doi:10.1001/jamacardio.2016.5034
Key Points

Question  To what extent is arrhythmogenic right ventricular dysplasia/cardiomyopathy a structural progressive disease?

Findings  In this cohort study of 85 patients with 6 years of follow-up, one-third of the patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy showed significant progressive structural dysfunction, with marked interpatient variability in the rate of progression.

Meaning  The results of this study pave the way for designing and launching trials to further study progression in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy.


Importance  Considerable research has described the arrhythmic course of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C). However, objective data characterizing structural progression, such as ventricular enlargement and cardiac dysfunction, in ARVD/C are relatively scarce.

Objectives  To define the extent of structural progression, identify determinants of structural progression, and determine the association between structural progression and electrocardiographic (ECG) changes in patients with ARVD/C.

Design, Setting, and Participants  In this cohort study, first- and last-available echocardiograms of 85 patients with ARVD/C fulfilling 2010 Task Force diagnostic criteria (TFC) from a transatlantic ARVD/C registry were retrospectively compared to assess structural disease progression. Right ventricular (RV) size and systolic function between baseline and last follow-up were compared. The RV size was determined by RV outflow tract dimension, and RV and left ventricular (LV) systolic function were determined by RV fractional area change (RV-FAC) and LV ejection fraction (LVEF), respectively. Multivariable logistic regression was used to study associations between baseline characteristics and the occurrence of structural progression.

Main Outcomes and Measures  The main outcome was the change in variables indicating structural progression. Secondary outcomes were the correlation with electrical progression and identification of the association between baseline characteristics and occurence structural progression.

Results  Among the 85 patients with ARVD/C, mean (SD) age at baseline was 42.8 (14.4) years and 47 (55%) were men. After a mean (SD) follow-up of 6.4 (2.5) years, RV outflow tract dimension increased from 35 mm (interquartile range [IQR], 31 to 39) to 37 mm (IQR, 33 to 41) (P < .001), RV-FAC decreased from 39% (IQR, 33% to 44%) to 34% (IQR, 24% to 42%) (P < .001) (rate −3.3% per 5 years; IQR, −8.9% to 1.2%), indicating large interpatient variability. The LVEF decreased from 55% (IQR, 52% to 60%) to 54% (IQR, 49% to 57%) (P = .001) (rate, −0.2% per 5 years; IQR, −6.5% to 1.7%). Forty examinations were reanalyzed to establish the measurement error. Patients exceeding the measurement error by ±2 SDs were identified with significant progressive disease for RV, with a decrease in RV-FAC greater than 10% (n = 21) and, for LV, a decrease in LVEF greater than 7% (n = 23). Progression of RV disease was associated with depolarization criteria at baseline (odds ratio [OR], 9.0; 95% CI, 1.1-74.2; P = .04), whereas progression of LV disease was associated with phospholamban (PLN) mutation (OR, 8.8; 95% CI, 2.1-37.2; P = .003). There was no association between progressive RV/LV structural disease and newly developed ECG TFC.

Conclusions and Relevance  Structural dysfunction in ARVD/C is progressive with substantial interpatient variability. Significant structural RV progression was associated with prior depolarization abnormalities, whereas LV progression is modified by genetic background. Structural progression was not associated with development of new ECG TFC. The results of this study pave the way for designing and launching trials aimed at reducing structural progression in patients with ARVD/C.