Harilaos Bogossian

Vernakalant in an experimental model of pacing-induced heart failure: lack of proarrhythmia despite prolongation of repolarization.

BACKGROUND The present ESC guidelines on atrial fibrillation have introduced vernakalant (VER) for pharmacologic cardioversion of atrial fibrillation. The aim of the present study was to investigate possible proarrhythmic effects of vernakalant in an experimental model of heart failure (HF). METHODS AND RESULTS In 12 female rabbits, HF was induced with the use of 4 weeks of rapid ventricular pacing. Twelve rabbits were sham operated. Isolated hearts demonstrated a significant prolongation of myocardial repolarization after induction of HF. Vernakalant caused a concentration-dependent (10 μmol/L and 30 μmol/L) increase of action potential duration (APD90) and QT interval without affecting spatial and temporal dispersion of repolarization. The increase in APD90 was accompanied by a greater increase in refractory period resulting in a significant increase in post-repolarization refractoriness. In control conditions, programmed ventricular stimulation and burst pacing led to ventricular fibrillation (VF) in 2 of the 12 sham (4 episodes) and in 3 of the 12 HF (24 episodes) subjects. In the presence of 30 μmol/L vernakalant, VF was no longer inducible in both groups (0 episodes). In the presence of low K+ concentration, neither sham nor HF vernakalant-treated subjects developed early after-depolarizations or ventricular tachyarrhythmias. CONCLUSION In the present study, application of vernakalant led to a significant prolongation of myocardial repolarization and increased post-repolarization refractoriness but did not induce early after-depolarization and therefore did not cause proarrhythmia in failing hearts.

A randomized comparison of 5 versus 12 hours per day of cardiac contractility modulation treatment for heart failure patients: A preliminary report.

BACKGROUND Cardiac contractility modulation (CCM) signals are non-excitatory electrical signals delivered during the absolute refractory period intended to improve contraction and cardiac function. Clinical trials have shown that CCM treatment significantly improves exercise tolerance and quality of life in symptomatic heart failure patients. Studies with CCM therapy typically include CCM delivery for 3, 5 or 7 h per day, although other configurations are also commonly used. Each has been associated with improved outcomes in heart failure, but it is not clear whether different application durations are associated with the various degrees of benefit. The purpose of the current pilot evaluation study was to evaluate the quality of life, exercise tolerance, and cardiac function, over a 6-month period when CCM was delivered for 5 h/day vs. 12 h/day. Increasing the daily CCM therapy duration is safe and as good as the standard CCM periods of application per day. METHODS This single center pilot evaluation study involved 19 medically refractory symptomatic patients with heart failure and reduced left ventricular function who underwent implantation of an Optimizer™ system (Impulse Dynamics, Orangeburg, NY, USA). Patients were randomized into one of two treatment groups; 5 h/day CCM treatment or 12 h/day CCM treatment. Subjects and evaluating physicians were blinded to the study group. Subjects returned to the hospital after 12 and 24 weeks. Efficacy evaluations included changes from baseline to 24 weeks in Minnesota Living With Heart Failure Questionnaire score (MLWHFQ), maximal oxygen consumption in the cardio-pulmonary stress test (peak VO2), New York Heart Association classification (NYHA), 6-min walk distance (6MWD), and ejection fraction (EF). RESULTS At the end of 24 weeks, clinical improvement was observed in the entire cohort in all efficacy measures (mean change from baseline of -17.1 in MLWHFQ, -0.86 in NYHA, and improvement trend of 1.48 mL O2/kg/min in peak VO2, 31.3 m in 6MWD, and 2.25% in EF). There were no significant differences, either clinically or statistically, between the groups receiving CCM for 5 h/day vs. 12 h/day. Three subjects were voluntarily withdrawn before completing the study. One subject died from pneumonia after 125 days, and 6 serious adverse events were reported, none of which was classified as related to either the device or the procedure. CONCLUSIONS Together with previously reported experience with CCM, delivery of CCM therapy is equally safe and appears similarly effective over the range of shorter (5 h) to longer (12 h) daily periods of application. Given the small sample size, further studies are warranted.

Evaluation of the prognostic value of electrocardiography parameters and heart rhythm in patients with pulmonary hypertension

BACKGROUND Several studies have analyzed arrhythmias in patients with pulmonary hypertension (PH) and increased P-wave duration was identified as a risk factor for development of atrial fibrillation (AF). METHODS We retrospectively analyzed the incidence of arrhythmias in patients with an initial diagnosis of PH during long-term follow-up and assessed the prognostic value of electrocardiography (ECG) data. Data from 167 patients were analyzed (Dana Point Classification: Group 1: 59 patients, Group 2: 28 patients, Group 3: 39 patients, Group 4: 41 patients). Clinical, 6-min-ute walk distance test, echocardiography and right heart catheterization data were collected, and baseline/follow-up ECGs were analyzed. RESULTS Baseline ECGs revealed sinus rhythm in 137 patients. Thirteen patients had newly onset AF during follow-up. In 30 patients, baseline ECG showed AF. Patients with baseline AF showed higher atrial diameters and higher right atrial pressure. Patients with P-wave du-ration > 0.11 s had shorter survival. Other ECG parameters (PQ-interval, QRS-width, QT-/ /QTc-interval) were not associated with survival. Mean survival times were 79.4 ± 5.4 months (sinus rhythm), 64.4 ± 12.9 months (baseline AF) and 58.8 ± 8.9 months (newly onset AF during follow-up) (p = 0.565). CONCLUSIONS Atrial fibrillation predict adverse prognosis in patients with PH and a longer P-wave (> 0.11 s) is associated with shorter survival time.

Catheter ablation of atrial fibrillation and atrial flutter in patients with diabetes mellitus: Who benefits and who does not? Data from the German ablation registry.

BACKGROUND Diabetes mellitus (DM) is an independent risk factor for cardiovascular disease and arrhythmias. Procedural data and complication rates in patients with DM undergoing catheter ablation for atrial arrhythmias are unknown. METHODS The German Ablation Registry has been designed as a multi-center prospective registry. Between January 2007 and January 2010 data from ablation of right atrial flutter (AFlut) and atrial fibrillation (AF) were collected from 51 German centres. Patients with DM and without DM were compared. RESULTS We included 8175 patients who underwent catheter ablation of AFlut or AF. Patients with DM (n=944) were older and presented significantly more severe comorbidities. Major periprocedural complications did not significantly differ between patients with and without DM for both ablation of AFlut and AF. Kaplan-Meier survival analysis for 366days of follow-up, showed a significant increase of MACCE for DM patients as compared to controls after AFlut [6.1% vs. 3.4%(p=0.002)], but not after AF ablation [1.2% vs. 0.9%(p=0.59)]. Ablation of AFlut led to a comparable reduction of palpitations and NYHA class in both patient groups. AF ablation reduced palpitations and NYHA class in patients without DM, while patients with DM reported no improvement of NYHA class despite a reduction of palpitations. CONCLUSION As compared to non-DM, patients with DM show no increased periprocedural risk and no increased arrhythmia recurrence after ablation of AFlut or AF. As expected patients with DM exhibit more comorbidities and an increased ongoing mortality after atrial flutter ablation presumably caused by the higher age of this group as compared to controls.

Applicability of a Novel Formula (Bogossian formula ) for Evaluation of the QT-Interval in Heart Failure and Left Bundle Branch Block Due to Right Ventricular Pacing: QT-INTERVAL IN PATIENTS WITH BUNDLE BRANCH BLOCK AND HEART FAILURE

The presence of left bundle branch block (LBBB) due to right ventricular pacing represents a particular challenge in properly measuring the QTc interval. In 2014, a new formula for the evaluation of QT interval in patients with LBBB was reported.

Antiarrhythmic effect of vernakalant in an experimental model of Long-QT-syndrome

Aims The antiarrhythmic drug vernakalant exerts antiarrhythmic effects in atrial fibrillation. Recent experimental data suggest interactions with the late sodium current and antiarrhythmic effects in ventricular arrhythmias. We aimed at investigating whether treatment with vernakalant reduces polymorphic ventricular tachycardia (VT) in an experimental model of Long-QT-syndrome (LQTS). Methods and results Twenty-nine isolated rabbit hearts were assigned to two groups and treated with erythromycin (300 µM, n = 15) or veratridine (0.5 µM, n = 14) after obtaining baseline data. Thereafter, vernakalant (10 µM) was additionally infused. Infusion of erythromycin or veratridine significantly increased action potential duration (APD90) and QT interval. Erythromycin and veratridine also significantly augmented spatial dispersion of repolarization (erythromycin: +43 ms; veratridine: +55 ms, P < 0.01, respectively) and temporal dispersion of repolarization. After lowering extracellular [K+] in bradycardic hearts, 11 of 15 erythromycin-treated hearts and 4 of 14 veratridine-treated hearts showed early afterdepolarizations and subsequent polymorphic VT. Additional treatment with vernakalant resulted in a significant reduction of spatial dispersion of spatial dispersion in both groups (erythromycin: -32 ms; veratridine: -35 ms, P < 0.05 each) and a stabilization of temporal dispersion. After additional treatment with vernakalant, only 5 of 15 erythromycin-treated hearts (P = 0.07) and 1 of 14 veratridine-treated hearts (P = 0.32) presented polymorphic VT. Conclusion Vernakalant has antiarrhythmic effects in this experimental model of acquired LQTS. A reduction of spatial dispersion of repolarization and a stabilization of temporal dispersion in hearts showing polymorphic VT represent the major underlying electrophysiological mechanisms.

Low proarrhythmic potential of citalopram and escitalopram in contrast to haloperidol in an experimental whole-heart model.

In several case reports proarrhythmic effects of citalopram and escitalopram have been reported. Systematic analyses on prorarrhythmic effects of these drugs are not yet available. The aim of the present study was to investigate if application of citalopram, escitalopram or haloperidol provokes polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In isolated rabbit hearts monophasic action potentials and ECG showed a significant QT-prolongation after application of citalopram (2µM: +47ms, 4µM: +56ms, P<0.05) accompanied by an increase of action potential duration (APD) but not dispersion of repolarization. Reduced potassium concentration in bradycardic AV-blocked hearts provoked early afterdepolarizations (EAD) in 2 of 12 hearts but no polymorphic ventricular tachycardia (pVT). Application of escitalopram also increased QT-interval (2µM: +3ms, 4µM: +30ms, P<0.05) and APD without effects on dispersion. 3 of 10 hearts showed EAD and pVT in 2 of 10 hearts (32 episodes). The results were compared to 12 rabbits treated with haloperidol which led to an increase in QT-interval (1µM:+62ms; 2µM:+96ms; P<0.01), APD and dispersion (1µM:+15ms, 2µM:+40ms; P<0.01) and induced EAD in all 12 and pVT in 10 of 12 hearts (152 episodes). Citalopram and escitalopram demonstrated a rather safe electrophysiologic profile despite significant QT prolongation. In contrast, haloperidol led to significant increase of dispersion of repolarization while this parameter remained stable under the influence of citalopram or escitalopram. These results imply that application of citalopram or escitalopram is not as proarrhythmic as some case reports might suggest while haloperidol is torsadogenic.

Divergent electrophysiologic profile of fluconazole and voriconazole in an experimental whole-heart model of proarrhythmia.

In several case reports a prolongation of the QT-interval and even proarrhythmic effects of fluconazole and voriconazole were reported. The aim of the present study was to investigate if application of fluconazole or voriconazole has the potential to provoke polymorphic ventricular tachycardia in a sensitive model of proarrhythmia. In female rabbits, fluconazole (10, 30 and 50 µM, n=6) and voriconazole (10, 30 and 50 µM, n=6) were infused after obtaining baseline data. Eight endocardial and epicardial monophasic action potentials and a simultaneously recorded 12-lead ECG showed a significant QT prolongation after application of fluconazole as compared with baseline (10 µM:+12 ms, 30 µM:+22 ms, 50 µM:+37 ms; P<0.05) accompanied by an increase of action potential duration (APD90). Administration of voriconazole also induced QT prolongation (30 µM:+10 ms, 50 µM:+20 ms, P<0.05). Spatial dispersion of repolarization remained stable in voriconazole-treated hearts while fluconazole induced a significant increase (30 µM:+15 ms, 50 µM:+16 ms; P<0.05). Lowering of potassium concentration in bradycardic AV-blocked hearts did not provoke any early afterdepolarizations (EADs) or polymorphic ventricular tachycardia in voriconazole-treated hearts. Application of fluconazole led to the reproducible induction of EADs in 4 of 6 hearts and polymorphic ventricular tachycardia in 3 of 6 hearts (36 episodes). In the present study, voriconazole demonstrated a safe electrophysiologic profile despite significant QT prolongation. In contrast, fluconazole led to a more marked prolongation of myocardial repolarization combined with a more marked increase of dispersion of repolarization. These results imply that application of fluconazole might be torsadogenic and the QT-interval should be closely monitored.

Prognostic Relevance of Nonsustained Ventricular Tachycardia in Patients with Pulmonary Hypertension

Background. Increased pulmonary vascular resistance in patients with pulmonary hypertension (PH) leads to an increased afterload of right heart and cardiac remodeling which could provide the substrate or trigger for arrhythmias. Supraventricular arrhythmias were associated with clinical deterioration but were not associated with sudden cardiac death (SCD). SCD has been reported to account for approximately 30% of deaths in patients with pulmonary arterial hypertension (PAH). Objective. The role of nonsustained ventricular tachycardia (nsVT) and its prognostic relevance in patients with PH remains unclear. This study evaluated the prognostic relevance of nsVT in patients with PAH and chronic thromboembolic pulmonary hypertension (CTEPH). Methods. Retrospectively, patients with PAH and CTEPH who underwent Holter ECG monitoring and available data of survival were investigated. Results. Seventy-eight (PAH: 55, CTEPH: 23) patients were evaluated. Holter ECG revealed nsVT in 12 patients. Twenty-one patients died during follow-up. In patients with nsVT, tricuspid annular plane systolic excursion was lower (p = 0.001), and systolic pulmonary arterial pressure was higher (p = 0.163). Mean survival of patients without/with nsVT was 155.2 ± 8.5/146.4 ± 21.4 months (p = 0.690). The association between arrhythmias and survival was not confounded by age (p = 0.681), gender (p = 0.752), 6-MW distance (p = 0.196), or arterial hypertension (p = 0.238). Conclusions. In patients with PH, nsVT occurs more often than previously reported, and patients with PH group 1 seem to be more at risk.

Right atrial tachycardia despite silent right atrium: a case report and review of the literature.

Atrial standstill (AS) is a rare condition defined by a lack of active atrial contraction caused by an inability of the atrial myocardium to create or perpetuate electrical activity. Drugs (e.g. quinidine or digitalis), electrolyte disorder as well as structural heart diseases (hypertensive heart disease, dilated cardiomyopathy, valvular heart disease and myocarditis) and genetic predispositions may contribute to this condition [1–6]. Obstructive sleep apnea with consecutively increased right atrial pressure, underlying hypertension and paroxysms of atrial fibrillation might be further synergistically interacting contributing factors. According to the reports of Nakazato and Zipes AS seems to be a progressive disease which initially involves the high right atrium (RA) and then progresses towards the lower RA. Just the vicinity of the tricuspid valve, the lower interatrial septum and the region of the ostium of the coronary sinus remain excitable [5, 7]. As the main right atrium is not excitable, patients with AS and symptomatic bradycardia were often treated by implantation of a VVI pacemaker [5]. We present the case of a patient suffering from severe palpitations despite AS. We saw a 62-year-old male DDDR pacemaker (PM) patient, implanted due to intermittent AV-Block III in another hospital. Currently the patient suffered from severe palpitations during his atrial driven tachycardia with a heart rate of 105 bpm with 1:1 ventricular stimulation (cycle length 575 ms) for 8 weeks (Fig. 1a). Coronary heart disease had already been ruled out previously via coronary angiogram. Echocardiographic examination showed an only slightly reduced systolic left ventricular function (EF 48 %) without any major valvular dysfunction. Cardiac risk factors were hypertension, hyperlipidemia and diabetes mellitus. Additionally, the patient suffered from obstructive sleep apnea and paroxysmal atrial fibrillation. To better study tachycardia during the EP Study, PM was programmed from DDDR to VVI 30/min followed by a drop in ventricular rate to 53 bpm due to 2:1 atrioventricular block (Fig. 1c). Figure 2a depicts the catheter positioning with an electrical silent right atrium (RA) along the 20 polar halo catheter which could neither sense nor evoke electrical signals even under high output stimulation (Fig. 2a). Exclusively in the coronary sinus (CS) and directly adjacent areas a remnant strand of vital right atrial myocardium displayed rapid centrifugal activity (Fig. 2b). We performed entrainment stimulation along the coronary sinus electrodes where we achieved similar post-pacing intervals (PPI) at the most proximal pair of electrodes and consecutively longer PPIs while stimulating more distally. Atrial ectopy from the pulmonary veins was excluded after transseptal puncture with a 20-polar Lasso Catheter. A CS anomaly or a CS diverticle was ruled out by CS phlebography. 3-D electroanatomical mapping was employed after pacing manoeuvres including entrainment and post-pacing H. Bogossian (&) B. Lemke M. Zarse Department of Cardiology and Angiology, Klinikum Ludenscheid, Markische Kliniken GmbH, Paulmannshoherstr. 14, 58515 Ludenscheid, Germany e-mail: bogossian@t-online.de; Harilaos.bogossian@klinikumluedenscheid.de