Apostolos-Ilias Vouliotis

Mechanistic insights into arrhythmogenic right ventricular cardiomyopathy caused by desmocollin-2 mutations

Aims Recent immunohistochemical studies observed the loss of plakoglobin (PG) from the intercalated disc (ID) as a hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), suggesting a final common pathway for this disease. However, the underlying molecular processes are poorly understood. Methods and results We have identified novel mutations in the desmosomal cadherin desmocollin 2 (DSC2 R203C, L229X, T275M, and G371fsX378). The two missense mutations (DSC2 R203C and T275M) have been functionally characterized, together with a previously reported frameshift variant (DSC2 A897fsX900), to examine their pathogenic potential towards PGs functions at the ID. The three mutant proteins were transiently expressed in various cellular systems and assayed for expression, processing, localization, and binding to other desmosomal components in comparison to wild-type DSC2a protein. The two missense mutations showed defects in proteolytic cleavage, a process which is required for the functional activation of mature cadherins. In both cases, this is thought to cause a reduction of functional DSC2 at the desmosomes in cardiac cells. In contrast, the frameshift variant was incorporated into cardiac desmosomes; however, it showed reduced binding to PG. Conclusion Despite different modes of action, for all three variants, the reduced ability to provide a ligand for PG at the desmosomes was observed. This is in agreement with the reduced intensity of PG at these structures observed in ARVC patients.

Primary prevention of sudden cardiac death in a nonischemic dilated cardiomyopathy population: reappraisal of the role of programmed ventricular stimulation.

Background— We considered the role of programmed ventricular stimulation in primary prevention of sudden cardiac death in an idiopathic dilated cardiomyopathy population. Methods and Results— One hundred fifty-eight patients with idiopathic dilated cardiomyopathy underwent programmed ventricular stimulation. Ventricular tachycardia/ventricular fibrillation was triggered in 44 patients (group I, 27.8%) versus 114 patients (group II), where ventricular tachycardia/ventricular fibrillation was not induced. Sixty-nine patients with idiopathic dilated cardiomyopathy underwent implantable cardioverter-defibrillator (ICD) implantation: 41/44 in group I and 28/114 in group II. The major end points of the study were overall mortality and appropriate ICD activation. Overall mortality during the 46.9 months of mean follow-up was not significantly different between the 2 groups. Patients with left ventricular ejection fraction ≤35% (n=119) demonstrated a higher overall mortality rate compared with the patients with left ventricular ejection fraction >35% (n=39; 16.8% versus 10.3%, log-rank P =0.025). Advanced New York Heart Association class (III and IV versus I and II) was the single independent and strongest prognostic factor of overall mortality (hazard ratio, 11.909; P <0.001; confidence interval, 3.106–45.65), as well as of cardiac mortality (hazard ratio, 14.787; P =0.001; confidence interval, 2.958–73.922). Among ICD recipients, ICD activation rate was significantly higher in group I compared with group II (30 of 41 patients–73.2% versus 5 of 28 patients–17.9%; log-rank P =0.001), either in the form of antitachycardia pacing (68.3% versus 17.9%; log-rank P =0.001) or in the shock delivery form (51.2% versus 17.9%; log-rank P =0.05). Induction of ventricular tachycardia/ventricular fibrillation during programmed ventricular stimulation in contrast to left ventricular ejection fraction was the single independent prognostic factor for future ICD activation (hazard ratio, 4.195; P =0.007; confidence interval, 1.467–11.994). Conclusions— Inducibility of ventricular tachycardia/ventricular fibrillation was associated with an increased likelihood of subsequent ICD activation and sudden cardiac death surrogate.Background—We considered the role of programmed ventricular stimulation in primary prevention of sudden cardiac death in an idiopathic dilated cardiomyopathy population. Methods and Results—One hundred fifty-eight patients with idiopathic dilated cardiomyopathy underwent programmed ventricular stimulation. Ventricular tachycardia/ventricular fibrillation was triggered in 44 patients (group I, 27.8%) versus 114 patients (group II), where ventricular tachycardia/ventricular fibrillation was not induced. Sixty-nine patients with idiopathic dilated cardiomyopathy underwent implantable cardioverter-defibrillator (ICD) implantation: 41/44 in group I and 28/114 in group II. The major end points of the study were overall mortality and appropriate ICD activation. Overall mortality during the 46.9 months of mean follow-up was not significantly different between the 2 groups. Patients with left ventricular ejection fraction ⩽35% (n=119) demonstrated a higher overall mortality rate compared with the patients with left ventricular ejection fraction >35% (n=39; 16.8% versus 10.3%, log-rank P=0.025). Advanced New York Heart Association class (III and IV versus I and II) was the single independent and strongest prognostic factor of overall mortality (hazard ratio, 11.909; P<0.001; confidence interval, 3.106–45.65), as well as of cardiac mortality (hazard ratio, 14.787; P=0.001; confidence interval, 2.958–73.922). Among ICD recipients, ICD activation rate was significantly higher in group I compared with group II (30 of 41 patients–73.2% versus 5 of 28 patients–17.9%; log-rank P=0.001), either in the form of antitachycardia pacing (68.3% versus 17.9%; log-rank P=0.001) or in the shock delivery form (51.2% versus 17.9%; log-rank P=0.05). Induction of ventricular tachycardia/ventricular fibrillation during programmed ventricular stimulation in contrast to left ventricular ejection fraction was the single independent prognostic factor for future ICD activation (hazard ratio, 4.195; P=0.007; confidence interval, 1.467–11.994). Conclusions—Inducibility of ventricular tachycardia/ventricular fibrillation was associated with an increased likelihood of subsequent ICD activation and sudden cardiac death surrogate.

Specific electrocardiographic features associated with Cushing's disease

Objective  Hypercortisolaemia is associated with an increased risk of cardiovascular disease (CVD), either through a direct action on the myocardium or by increased traditional cardiovascular risk factors. The aim of this study was to investigate whether the alterations in the ECG in Cushing’s disease (CD) are predictable from risk factor analysis alone.

Arrhythmogenic right ventricular cardiomyopathy: the challenge of genetic interpretation in clinically suspected cases.

This is the case of a 43-year-old Caucasian man with frequent episodes of paroxysmal atrial fibrillation (AF) and normal resting electrocardiogram (ECG), who fulfilled two minor diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy (ARVC): late potentials by signal-averaged ECG and regional right ventricular outflow tract (RVOT) dyskinesia with mildly dilated RVOT end-diastolic diameter. Genetic test results revealed a disease-associated missense mutation in DSC2 (p.E102K), adding a major diagnostic criterion according to recently published modified Task Force Criteria. However, 2 years after successful ablative therapy for AF, the patient remains completely asymptomatic, without any clinical signs of ARVC. Both ventricular and supraventricular arrhythmias had vanished after AF ablation. Our patient mainly suffered AF without significant ventricular arrhythmias, a very uncommon clinical presentation of ARVC.

Primary Prevention of Sudden Cardiac Death in a Nonischemic Dilated Cardiomyopathy PopulationClinical Perspective: Reappraisal of the Role of Programmed Ventricular Stimulation

Background— We considered the role of programmed ventricular stimulation in primary prevention of sudden cardiac death in an idiopathic dilated cardiomyopathy population. Methods and Results— One hundred fifty-eight patients with idiopathic dilated cardiomyopathy underwent programmed ventricular stimulation. Ventricular tachycardia/ventricular fibrillation was triggered in 44 patients (group I, 27.8%) versus 114 patients (group II), where ventricular tachycardia/ventricular fibrillation was not induced. Sixty-nine patients with idiopathic dilated cardiomyopathy underwent implantable cardioverter-defibrillator (ICD) implantation: 41/44 in group I and 28/114 in group II. The major end points of the study were overall mortality and appropriate ICD activation. Overall mortality during the 46.9 months of mean follow-up was not significantly different between the 2 groups. Patients with left ventricular ejection fraction ≤35% (n=119) demonstrated a higher overall mortality rate compared with the patients with left ventricular ejection fraction >35% (n=39; 16.8% versus 10.3%, log-rank P =0.025). Advanced New York Heart Association class (III and IV versus I and II) was the single independent and strongest prognostic factor of overall mortality (hazard ratio, 11.909; P <0.001; confidence interval, 3.106–45.65), as well as of cardiac mortality (hazard ratio, 14.787; P =0.001; confidence interval, 2.958–73.922). Among ICD recipients, ICD activation rate was significantly higher in group I compared with group II (30 of 41 patients–73.2% versus 5 of 28 patients–17.9%; log-rank P =0.001), either in the form of antitachycardia pacing (68.3% versus 17.9%; log-rank P =0.001) or in the shock delivery form (51.2% versus 17.9%; log-rank P =0.05). Induction of ventricular tachycardia/ventricular fibrillation during programmed ventricular stimulation in contrast to left ventricular ejection fraction was the single independent prognostic factor for future ICD activation (hazard ratio, 4.195; P =0.007; confidence interval, 1.467–11.994). Conclusions— Inducibility of ventricular tachycardia/ventricular fibrillation was associated with an increased likelihood of subsequent ICD activation and sudden cardiac death surrogate.Background—We considered the role of programmed ventricular stimulation in primary prevention of sudden cardiac death in an idiopathic dilated cardiomyopathy population. Methods and Results—One hundred fifty-eight patients with idiopathic dilated cardiomyopathy underwent programmed ventricular stimulation. Ventricular tachycardia/ventricular fibrillation was triggered in 44 patients (group I, 27.8%) versus 114 patients (group II), where ventricular tachycardia/ventricular fibrillation was not induced. Sixty-nine patients with idiopathic dilated cardiomyopathy underwent implantable cardioverter-defibrillator (ICD) implantation: 41/44 in group I and 28/114 in group II. The major end points of the study were overall mortality and appropriate ICD activation. Overall mortality during the 46.9 months of mean follow-up was not significantly different between the 2 groups. Patients with left ventricular ejection fraction ⩽35% (n=119) demonstrated a higher overall mortality rate compared with the patients with left ventricular ejection fraction >35% (n=39; 16.8% versus 10.3%, log-rank P=0.025). Advanced New York Heart Association class (III and IV versus I and II) was the single independent and strongest prognostic factor of overall mortality (hazard ratio, 11.909; P<0.001; confidence interval, 3.106–45.65), as well as of cardiac mortality (hazard ratio, 14.787; P=0.001; confidence interval, 2.958–73.922). Among ICD recipients, ICD activation rate was significantly higher in group I compared with group II (30 of 41 patients–73.2% versus 5 of 28 patients–17.9%; log-rank P=0.001), either in the form of antitachycardia pacing (68.3% versus 17.9%; log-rank P=0.001) or in the shock delivery form (51.2% versus 17.9%; log-rank P=0.05). Induction of ventricular tachycardia/ventricular fibrillation during programmed ventricular stimulation in contrast to left ventricular ejection fraction was the single independent prognostic factor for future ICD activation (hazard ratio, 4.195; P=0.007; confidence interval, 1.467–11.994). Conclusions—Inducibility of ventricular tachycardia/ventricular fibrillation was associated with an increased likelihood of subsequent ICD activation and sudden cardiac death surrogate.

Primary Prevention of Sudden Cardiac Death in a Nonischemic Dilated Cardiomyopathy PopulationClinical Perspective

Background— We considered the role of programmed ventricular stimulation in primary prevention of sudden cardiac death in an idiopathic dilated cardiomyopathy population. Methods and Results— One hundred fifty-eight patients with idiopathic dilated cardiomyopathy underwent programmed ventricular stimulation. Ventricular tachycardia/ventricular fibrillation was triggered in 44 patients (group I, 27.8%) versus 114 patients (group II), where ventricular tachycardia/ventricular fibrillation was not induced. Sixty-nine patients with idiopathic dilated cardiomyopathy underwent implantable cardioverter-defibrillator (ICD) implantation: 41/44 in group I and 28/114 in group II. The major end points of the study were overall mortality and appropriate ICD activation. Overall mortality during the 46.9 months of mean follow-up was not significantly different between the 2 groups. Patients with left ventricular ejection fraction ≤35% (n=119) demonstrated a higher overall mortality rate compared with the patients with left ventricular ejection fraction >35% (n=39; 16.8% versus 10.3%, log-rank P =0.025). Advanced New York Heart Association class (III and IV versus I and II) was the single independent and strongest prognostic factor of overall mortality (hazard ratio, 11.909; P <0.001; confidence interval, 3.106–45.65), as well as of cardiac mortality (hazard ratio, 14.787; P =0.001; confidence interval, 2.958–73.922). Among ICD recipients, ICD activation rate was significantly higher in group I compared with group II (30 of 41 patients–73.2% versus 5 of 28 patients–17.9%; log-rank P =0.001), either in the form of antitachycardia pacing (68.3% versus 17.9%; log-rank P =0.001) or in the shock delivery form (51.2% versus 17.9%; log-rank P =0.05). Induction of ventricular tachycardia/ventricular fibrillation during programmed ventricular stimulation in contrast to left ventricular ejection fraction was the single independent prognostic factor for future ICD activation (hazard ratio, 4.195; P =0.007; confidence interval, 1.467–11.994). Conclusions— Inducibility of ventricular tachycardia/ventricular fibrillation was associated with an increased likelihood of subsequent ICD activation and sudden cardiac death surrogate.Background—We considered the role of programmed ventricular stimulation in primary prevention of sudden cardiac death in an idiopathic dilated cardiomyopathy population. Methods and Results—One hundred fifty-eight patients with idiopathic dilated cardiomyopathy underwent programmed ventricular stimulation. Ventricular tachycardia/ventricular fibrillation was triggered in 44 patients (group I, 27.8%) versus 114 patients (group II), where ventricular tachycardia/ventricular fibrillation was not induced. Sixty-nine patients with idiopathic dilated cardiomyopathy underwent implantable cardioverter-defibrillator (ICD) implantation: 41/44 in group I and 28/114 in group II. The major end points of the study were overall mortality and appropriate ICD activation. Overall mortality during the 46.9 months of mean follow-up was not significantly different between the 2 groups. Patients with left ventricular ejection fraction ⩽35% (n=119) demonstrated a higher overall mortality rate compared with the patients with left ventricular ejection fraction >35% (n=39; 16.8% versus 10.3%, log-rank P=0.025). Advanced New York Heart Association class (III and IV versus I and II) was the single independent and strongest prognostic factor of overall mortality (hazard ratio, 11.909; P<0.001; confidence interval, 3.106–45.65), as well as of cardiac mortality (hazard ratio, 14.787; P=0.001; confidence interval, 2.958–73.922). Among ICD recipients, ICD activation rate was significantly higher in group I compared with group II (30 of 41 patients–73.2% versus 5 of 28 patients–17.9%; log-rank P=0.001), either in the form of antitachycardia pacing (68.3% versus 17.9%; log-rank P=0.001) or in the shock delivery form (51.2% versus 17.9%; log-rank P=0.05). Induction of ventricular tachycardia/ventricular fibrillation during programmed ventricular stimulation in contrast to left ventricular ejection fraction was the single independent prognostic factor for future ICD activation (hazard ratio, 4.195; P=0.007; confidence interval, 1.467–11.994). Conclusions—Inducibility of ventricular tachycardia/ventricular fibrillation was associated with an increased likelihood of subsequent ICD activation and sudden cardiac death surrogate.