Animal Models of Dyssynchrony

Cardiac resynchronization therapy (CRT) is an important therapy for patients with heart failure and conduction pathology, but the benefits are heterogeneous between patients and approximately a third of patients do not show signs of clinical or echocardiographic response. This calls for a better understanding of the underlying conduction disease and resynchronization. In this review, we discuss to what extent established and novel animal models can help to better understand the pathophysiology of dyssynchrony and the benefits of CRT

Body dysmorphia in common skin diseases: Results of an observational, cross-sectional multi-centre study among dermatological out-patients in 17 European countries

Background Body dysmorphic disorder (BDD) is a common psychiatric disorder associated with high costs for healthcare systems as patients may repeatedly ask for different, often not effective interventions. BDD symptoms are more prevalent in patients with dermatological conditions than the general population, but there are no large sample studies comparing the prevalence of BDD symptoms between patients with dermatological conditions and healthy skin controls. Objectives To compare the prevalence of BDD symptoms between patients with different dermatological conditions and healthy skin controls and to describe sociodemographic, physical and psychological factors associated with BDD symptoms to identify patients who may have a particularly high chance of having this condition. Methods This observational cross-sectional, comparative multi-centre study included 8295 participants: 5487 consecutive patients with different skin diseases (56% female) recruited among dermatological out-patients at 22 clinics in 17 European countries and 2808 healthy skin controls (66% female). All patients were examined by a dermatologist. BDD symptoms were assessed by the Dysmorphic Concern Questionnaire (DCQ). Sociodemographic data, information on psychological factors and physical conditions were collected. Each patient was given a dermatological diagnosis according to ICD-10 by a dermatologist. Results The participation rate of invited dermatological patients was 82.4% on average across all centres. BDD symptoms were five times more prevalent in patients with dermatological conditions than in healthy skin controls (10.5% vs. 2.1%). Patients with hyperhidrosis, alopecia and vitiligo had a more than eleven-fold increased chance (adjusted Odds Ratio (OR) > 11) of having BDD symptoms compared to healthy skin controls, and patients with atopic dermatitis, psoriasis, acne, hidradenitis suppurativa, prurigo and bullous diseases had a more than six-fold increased chance (adjusted OR > 6) of having BDD symptoms. Using a logistic regression model, BDD symptoms were significantly related to lower age, female sex, higher psychological stress and feelings of stigmatisation. Conclusions This study reveals that clinical BDD symptoms are significantly associated with common dermatological diseases. As such symptoms are associated with higher levels of psychological distress and multiple unhelpful consultations, general practitioners and dermatologists should consider BDD and refer patients when identified to an appropriate service for BDD screening and management

Transseptal conduction as an important determinant for cardiac resynchronization therapy, as revealed by extensive electrical mapping in the dyssynchronous canine heart

BACKGROUND: Simple conceptual ideas about cardiac resynchronization therapy assume that biventricular (BiV) pacing results in collision of right and left ventricular (LV) pacing-derived wavefronts. However, this concept is contradicted by the minor reduction in QRS duration usually observed. We investigated the electric mechanisms of cardiac resynchronization therapy by performing detailed electric mapping during extensive pacing protocols in dyssynchronous canine hearts. METHODS AND RESULTS: Studies were performed in anesthetized dogs with acute left bundle-branch block (LBBB, n=10) and chronic LBBB with tachypacing-induced heart failure (LBBB+HF, n=6). Activation times (AT) were measured using LV endocardial contact and noncontact mapping and epicardial contact mapping. BiV pacing reduced QRS duration by 21±10% in LBBB but only by 5±12% in LBBB+HF hearts. Transseptal impulse conduction was significantly slower in LBBB+HF than in LBBB hearts (67±9 versus 44±16 ms, respectively), and in both groups significantly slower than transmural LV conduction (≈30 ms). In both groups QRS duration and vector and the epicardial AT vector amplitude and angle were significantly different between LV and BiV pacing, whereas the endocardial AT vector was similar. During variation of atrioventricular delay while LV pacing, and ventriculo-ventricular delay while BiV pacing, the optimal hemodynamic effect was achieved when epicardial AT and QRS vectors were minimal and endocardial AT vector indicated LV preexcitation. CONCLUSIONS: Due to slow transseptal conduction, the LV electric activation sequence is similar in LV and BiV pacing, especially in failing hearts. Optimal hemodynamic cardiac resynchronization therapy response coincides with minimal epicardial asynchrony and QRS vector and LV preexcitation

Transseptal Conduction as an Important Determinant for Cardiac Resynchronization Therapy, as Revealed by Extensive Electrical Mapping in the Dyssynchronous Canine Heart

BACKGROUND: Simple conceptual ideas about cardiac resynchronization therapy assume that biventricular (BiV) pacing results in collision of right and left ventricular (LV) pacing-derived wavefronts. However, this concept is contradicted by the minor reduction in QRS duration usually observed. We investigated the electric mechanisms of cardiac resynchronization therapy by performing detailed electric mapping during extensive pacing protocols in dyssynchronous canine hearts. METHODS AND RESULTS: Studies were performed in anesthetized dogs with acute left bundle-branch block (LBBB, n=10) and chronic LBBB with tachypacing-induced heart failure (LBBB+HF, n=6). Activation times (AT) were measured using LV endocardial contact and noncontact mapping and epicardial contact mapping. BiV pacing reduced QRS duration by 21±10% in LBBB but only by 5±12% in LBBB+HF hearts. Transseptal impulse conduction was significantly slower in LBBB+HF than in LBBB hearts (67±9 versus 44±16 ms, respectively), and in both groups significantly slower than transmural LV conduction (≈30 ms). In both groups QRS duration and vector and the epicardial AT vector amplitude and angle were significantly different between LV and BiV pacing, whereas the endocardial AT vector was similar. During variation of atrioventricular delay while LV pacing, and ventriculo-ventricular delay while BiV pacing, the optimal hemodynamic effect was achieved when epicardial AT and QRS vectors were minimal and endocardial AT vector indicated LV preexcitation. CONCLUSIONS: Due to slow transseptal conduction, the LV electric activation sequence is similar in LV and BiV pacing, especially in failing hearts. Optimal hemodynamic cardiac resynchronization therapy response coincides with minimal epicardial asynchrony and QRS vector and LV preexcitation

Interplay of electrical wavefronts as determinant of the response to cardiac resynchronization therapy in dyssynchronous canine hearts

BACKGROUND: The relative contribution of electromechanical synchronization and ventricular filling to the optimal hemodynamic effect in cardiac resynchronization therapy (CRT) during adjustment of stimulation-timings is incompletely understood. We investigated whether optimal hemodynamic effect in CRT requires collision of pacing-induced and intrinsic activation waves and optimal filling of the left ventricle (LV). METHODS AND RESULTS: CRT was performed in dogs with chronic left bundle-branch block (n=8) or atrioventricular (AV) block (n=6) through atrial (A), right ventricular (RV) apex, and LV-basolateral pacing. A 100 randomized combinations of A-LV/A-RV intervals were tested. Total activation time (TAT) was calculated from >100 contact mapping electrodes. Mechanical interventricular dyssynchrony was determined as the time delay between upslopes of LV and RV pressure curves. Settings providing an increase in LVdP/dtmax (maximal rate of rise of left ventricular pressure) of ≥90% of the maximum LVdP/dtmax value were defined as optimal (CRTopt). Filling was assessed by changes in LV end-diastolic volume (EDV; conductance catheter technique). In all hearts, CRTopt was observed during multiple settings, providing an average LVdP/dtmax increase of ≈15%. In AV-block hearts, CRTopt exclusively depended on interventricular-interval and not on AV-interval. In left bundle-branch block hearts, CRTopt occurred at A-LV intervals that allowed fusion of LV-pacing-derived activation with right bundle-derived activation. In all animals, CRTopt occurred at settings resulting in the largest decrease in TAT and mechanical interventricular dyssynchrony, whereas LV EDV hardly changed. CONCLUSIONS: In left bundle-branch block and AV-block hearts, optimal hemodynamic effect of CRT depends on optimal interplay between pacing-induced and intrinsic activation waves and the corresponding mechanical resynchronization rather than filling

Electrophysiological and Hemodynamic Effects of Vernakalant and Flecainide During Cardiac Resynchronization in Dyssynchronous Canine Hearts

INTRODUCTION: Patients with heart failure and left bundle branch block (LBBB) are frequently treated with biventricular pacing (BiVP). Approximately one-third of them suffer from atrial fibrillation. Pharmacological conversion of atrial fibrillation is performed with drugs that slow ventricular conduction, but the effects of these drugs on the benefit of BiVP are poorly understood. METHODS: Experiments were performed in dogs with chronic LBBB, investigating the effects of Vernakalant and Flecainide (n = 6 each) on hemodynamics and electrophysiology during epicardial (EPI) and endocardial BiVP. The degree of dyssynchrony and conduction slowing was quantified using QRS width and EPI electrical mapping. RESULTS: Compared with LBBB, EPI and endocardial BiVP reduced QRS duration by 7% ± 9% (P < 0.05 compared with LBBB) and 20% ± 13% (P < 0.05 compared with LBBB, P < 0.05 between modes), respectively. During BiVP, the administration of Vernakalant and Flecainide increased QRS duration by 20% ± 14% (P < 0.05 compared with predrug BiVP) and 34% ± 10% (P < 0.05 compared with predrug BiVP, P < 0.05 between drugs). left ventricular (LV) dP/dtmax decreased by 16% ± 8% (P < 0.05 compared with predrug BiVP) during Vernakalant and by 14% ± 15% (P < 0.05 compared with predrug BiVP) during Flecainide. The drugs did not affect the relative changes in QRS width and LV dP/dtmax induced by BiVP. CONCLUSIONS: Vernakalant and Flecainide decrease contractility, slow myocardial conduction velocity, and increase activation time. The electrical and hemodynamic benefits of BiVP are not altered by the drugs

Electrophysiological and haemodynamic effects of vernakalant and flecainide in dyssynchronous canine hearts

AIMS About one-third of patients with mild dyssynchronous heart failure suffer from atrial fibrillation (AF). Drugs that convert AF to sinus rhythm may further slowdown ventricular conduction. We aimed to investigate the electrophysiological and haemodynamic effects of vernakalant and flecainide in a canine model of chronic left bundle branch block (LBBB). METHODS AND RESULTS Left bundle branch block was induced in 12 canines. Four months later, vernakalant or flecainide was administered using a regime, designed to achieve clinically used plasma concentrations of the drugs, n = 6 for each drug. Epicardial electrical contact mapping showed that both drugs uniformly prolonged myocardial conduction time. Vernakalant increased QRS width significantly less than flecainide (17 ± 13 vs. 34 ± 15%, respectively). Nevertheless, both drugs equally decreased LVdP/dtmax by ∼15%, LVdP/dtmin by ∼10%, and left ventricular systolic blood pressure by ∼5% (P = n.s. between drugs). CONCLUSIONS Vernakalant prolongs ventricular conduction less than flecainide, but both drugs had a similar, moderate negative effect on ventricular contractility and relaxation. Part of these reductions seems to be related to the increase in dyssynchrony

ECHOCARDIOGRAPHIC ASSESSMENT OF LEFT BUNDLE BRANCH-RELATED STRAIN DYSSYNCHRONY:A COMPARISON WITH TAGGED MRI

Recent studies have shown the efficacy of myocardial strain estimated using speckle tracking echocardiography (STE) in predicting response to cardiac resynchronisation therapy. This study focuses on circumferential strain patterns, comparing STE-acquired strains to tagged-magnetic resonance imaging (MRI-T). Second, the effect of regularisation was examined. Two-dimensional parasternal ultrasound (US) and MRI-T data were acquired in the left ventricular short-axis view of canines before (n = 8) and after (n = 9) left bunch branch block (LBBB) induction. US-based strain analysis was performed on Digital Imaging and Communications in Medicine data at the mid-level using three overall methods ("Commercial software," "Basic block-matching," "regularised block-matching"). Moreover, three regularisation approaches were implemented and compared. MRI-T analysis was performed using SinMod. Normalised regional circumferential strain curves, based on standard six or septal/lateral segments, were analysed and cross-correlated with MRI-T data. Systolic strain (SS) and septal rebound stretch (SRS) were calculated and compared. Overall agreement of normalised circumferential strain was good between all methods on a global and regional level. All STE methods showed a bias (>= 4% strain) toward higher SS estimates. Pre-LBBB, septal and lateral segment correlation was excellent between the Basic (mean rho = 0.96) and regularised (mean rho = 0.97) methods and MRI-T. The Commercial method showed a significant discrepancy between the two walls (septal rho = 0.94, lateral rho = 0.68). Correlation with MRI-T reduced between pre- and post-LBBB (Commercial rho = 0.79, Basic rho = 0.82, mean regularised rho = 0.86). Septal strain patterns and SRS varied with the STE software and type of regularisation, with all STE methods estimating nonzero SRS values pre-LBBB. Absolute values showed moderate agreement, with a bias for higher strain from STE. SRS varied with the type of software and extra regularisation applied. Open efforts are needed to understand the underlying causes of differences between STE methods before standardisation can be achieved. This is particularly important given the apparent clinical value of strain-based parameters such as SRS. (C) 2019 The Author(s). Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology