Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study

Abstract

AimsAnecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin.Methods and resultsMurine: the DSP (±) mice underwent electrophysiological, echocardiographic, and immunohistochemical studies. They had normal echocardiograms but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Sodium current density and myocardial histology were normal at 2 months of age. Human: ten patients with heterozygous mutations in DSP without overt structural heart disease (DSP+) and 12 controls with supraventricular tachycardia were studied by high-density electrophysiological mapping of the right ventricle. Using a standard S1–S2 protocol, restitution curves of local conduction and repolarization parameters were constructed. Significantly greater mean increases in delay were identified particularly in the outflow tract vs. controls (P< 0.01) coupled with more uniform wavefront progression. The odds of a segment with a maximal activation–repolarization interval restitution slope >1 was 99% higher (95% CI: 13%; 351%, P= 0.017) in DSP+ vs. controls. Immunostaining revealed Cx43 mislocalization and variable Na channel distribution.ConclusionDesmoplakin disease causes connexin mislocalization in the mouse and man preceding any overt histological abnormalities resulting in significant alterations in conduction–repolarization kinetics prior to morphological changes detectable on conventional cardiac imaging. Haploinsufficiency of desmoplakin is sufficient to cause significant Cx43 mislocalization. Changes in sodium current density and histological abnormalities may contribute to a worsening phenotype or disease but are not necessary to generate an arrhythmogenic substrate. This has important implications for the earlier diagnosis of ARVC and risk stratification.

Correlation of Ventricular Arrhythmias With Genotype in Arrhythmogenic Right Ventricular Cardiomyopathy

“…[5][6][7][8][9][10][11][12] Previous studies have shown that genetic identification is related to different clinical characteristics of ARVC. [13][14][15][16] However, the correlation between genotype and VA features remains unclear.…”

The ventricular ectopic QRS interval (VEQSI): Diagnosis of arrhythmogenic right ventricular cardiomyopathy in patients with incomplete disease expression

“…Electrical changes appear to predate structural changes and VEB are frequent. (7,8) We hypothesized that VEB indices: VEQSI, number of VEB morphologies and VEB fragmentation would provide markers for presence and severity of abnormal ventricular structure and function and a measure of the risk of ventricular arrhythmia. (1) We hypothesized that VEB indices may be useful in early ARVC diagnosis.…”

“…(5,6) In early ARVC, cardiac imaging is frequently normal and electrical changes appear to predate structural changes. (4,7,8 VEQSI measurement only requires presence of VEB making it applicable for a greater number of patients. In our cohorts 30% definite ARVC, 15% incompletely expressed ARVC and 8% RVOT ectopy patients exhibited VT, whereas 100% definite ARVC and RVOT ectopy patients and 90% incompletely expressed ARVC patients demonstrated VEB.…”

Arrhythmogenic Right Ventricular Cardiomyopathy

“…2,30,38 Older patients with a longlasting disease more often experience scar-related, hemodynamically stable VT. 2,3 More recently, gap junction remodeling and ion channel interference preceding the fibro-fatty scar have been postulated as alternative substrates for conduction delay and ventricular arrhythmias in the prephenotypic phase of the disease (Figure 1), as supported by experimental animal models. [62][63][64][65][66] The unpredictability of SCD in a subgroup of patients explains why there has been a trend toward implantable cardioverter-defibrillator (ICD) placement once the disease is diagnosed, without appropriate risk stratification. Prevention of SCD is the most important management strategy of ARVC.…”

“…As far as the pathophysiology of ventricular arrhythmias is concerned, a new perspective is that suggesting that impaired mechanical coupling attributable to desmosomal gene mutations might account for abnormal electrical coupling or ion channel dysfunction, leading to electrical instability even before ventricular structural remodeling. [62][63][64][65][66] If proven, then this revolutionary theory could dramatically change our approach in risk stratification and management of patients affected with ARVC.…”