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Ventricular Arrhythmia Research – From Translational Models to Novel Therapeutic Strategies (Group leader: PD Dr. med. Ardan M. Saguner)

The research of the Saguner lab aims to improve the diagnosis and therapy of ventricular arrhythmias in rare electrical and structural heart diseases. Rapid advances in genetics and epigenetics of cardiovascular disease within the last years have led to a better understanding of the etiology of hereditary channelopathies and cardiomyopathies leading to ventricular arrhythmias and sudden cardiac death, and have improved deep phenotyping and personalized approaches for diagnosis, risk stratification and therapies of these complex entities.

Recent studies have stressed the importance of the combination of genetic, epigenetic and environmental factors to develop channelopathies and cardiomyopathies and to predict outcome. Therefore, our research focuses on the identification of novel pathogenic causative genetic variants and environmental factors that lead to disease manifestation, progression, arrhythmogenicity, variable disease penetrance and adverse outcome, as well as diagnostic tools such as disease-specific biomarkers (figure). Moreover, our work aims at improving the risk stratification process in these diseases. With regard to this, we work on the identification of clinical parameters that help to refine the prediction of potentially life-threatening ventricular arrhythmias and sudden cardiac death in these diseases, which often affect the young population. Lastly, we study novel therapeutic strategies such as stereotactic arrhythmia radioablation (STAR) and different exercise modalities in order to improve the disease course and reduce ventricular arrhythmia burden in structural heart disease.

Figure. A). Serum binding intensity to desmoglein-2 oligopeptides is presented as colour grades onto a Protter (http://wlab.ethz.ch/protter) plot of the desmoglein-2 protein (red, strong binding; orange, moderate biding; yellow, weak binding; green, faint binding). Strongest binding is in regions of the fourth extracellular cadherin and extracellular anchor domains. EC=extracellular region, IC=cytoplasmic region. B). Pearson correlation coefficient (R) = 0.188 (p = 0.039) for PET inflammatory activity (SUV) vs. anti-DSG2 antibody (Ab) intensity assessed by pixel count of the western blot bands; C). Western blot bands of serum: anti-desmoglein-2 antibodies (anti-DSG2 Abs) were identified in 6 sarcoidosis patients (all showing cardiac involvement), whereas it was negative or below cut-off level (indicating unspecific binding) in the remaining 19/25 sarcoidosis patients; D). Central Illustration: Anti-DSG2 Abs in Arrhythmogenic Cardiomyopathy (ACM) and cardiac sarcoidosis (CS). In ACM (due to desmosomal instability) and in CS (due to granulomatous inflammation) the cadherin DSG2 epitopes are unmasked and exposed to the acquired immune system, inducing an autoimmune response to DSG2. This further promotes failure in cell crosslinking and enhances fibrosis, seen in both entities at later stages.

Ongoing research lines

  • Assessing the consequences of PKP2 mutations on SCN5A function using high throughput automated planar patch clamp
  • Identification of a proteomics signature to improve early diagnosis and risk stratification in arrhythmogenic cardiomyopathy
  • Presence of anti-desmoglein2 autoantibodies in cardiac sarcoidosis and correlation with cardiac 18F-FDG positron-emission-tomography activity
  • Characterization of arrhythmogenic activity during and after physical exercise in patients with arrhythmogenic cardiomyopathy
  • Combined positron emission tomography – computed tomography immediately following ventricular tachyarrhythmia or electrical storm in patients with non-ischemic heart disease
  • STOPSTORM: a prospective European validation cohort for stereotactic therapy of reentrant tachycardia
  • Population-wide screens of the immune repertoire: a reverse personalized-medicine approach

Research Team

  • Boldizsar Kovacs, MD
  • Gonca Suna, MD PhD
  • Valentina Rossi, MD
  • Denny Lunk, MD
  • Nicole R. Bonetti, MD
  • Valon Gllareva
  • Kai Thaler

Funding

  • Schweizerische Herzstiftung/Swiss Heart Foundation
  • Horizon 2020 European Commission
  • Swiss Personalized Health Initiative