Lars B. van Middendorp

Acute electrical and hemodynamic effects of multisite left ventricular pacing for cardiac resynchronization therapy in the dyssynchronous canine heart

BACKGROUND Multisite left ventricular (multi-LV) epicardial pacing has been proposed as an alternative to conventional single-site LV (single-LV) pacing to increase the efficacy of cardiac resynchronization therapy. OBJECTIVE To compare the effects of multi-LV versus single-LV pacing in dogs with left bundle branch block (LBBB). METHODS Studies were performed in 9 anaesthetized dogs with chronic LBBB using 7 LV epicardial electrodes. Each electrode was tested alone and in combination with 1, 2, 3, and 6 other electrodes, the sequence of which was chosen on the basis of practical real-time electrical mapping to determine the site of the latest activation. LV total activation time (LVTAT) and dispersion of repolarization (DRep) were measured by using approximately 100 electrodes around the ventricles. LV contractility was assessed as the maximum derivative of left ventricular pressure (LVdP/dtmax ). RESULTS Single-LV pacing provided, on average, a -4.0% ± 9.3% change in LVTAT and 0.2% ± 13.7% change in DRep. Multi-LV pacing markedly decreased both LVTAT and DRep in a stepwise fashion to reach -41.3% ± 5% (P < .001 for overall comparison) and -14.2% ± 19.5% (P < .02 for overall comparison) in the septuple-LV pacing configuration, respectively. Single-LV pacing provided a mean increase of 10.7% ± 7.7% in LVdP/dtmax. LVdP/dtmax incrementally increased by the addition of pacing electrodes to 16.4% ± 8.7% (P < .001 for overall comparison). High response to single-LV pacing could not be improved further during multi-LV pacing. CONCLUSIONS Compared with single-LV pacing, multi-LV pacing can considerably reduce both LVTAT and DRep in dogs with LBBB, but the improvement in contractility is limited to conditions where single-LV pacing provides suboptimal improvement. Further studies are warranted to determine whether these acute effects translate in antiarrhythmic properties and better long-term outcomes.

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.

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.

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.

The Interplay of Electrical Wave Fronts 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 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.

Local microRNA-133a downregulation is associated with hypertrophy in the dyssynchronous heart

Left bundle branch block (LBBB) creates considerable regional differences in mechanical load within the left ventricle (LV). We investigated expression of selected microRNAs (miRs) in relation to regional hypertrophy and fibrosis in LBBB hearts and their reversibility upon cardiac resynchronization therapy (CRT).

Prediction of optimal cardiac resynchronization by vectors extracted from electrograms in dyssynchronous canine hearts

Proper optimization of atrioventricular (AV) and interventricular (VV) intervals can improve the response to cardiac resynchronization therapy (CRT). It has been demonstrated that the area of the QRS complex (QRSarea) extracted from the vectorcardiogram can be used as a predictor of optimal CRT‐device settings. We explored the possibility of extracting vectors from the electrograms (EGMs) obtained from pacing electrodes and of using these EGM‐based vectors (EGMVs) to individually optimize acute hemodynamic CRT response.

Ex Vivo and in Vivo Administration of Fluorescent CNA35 Specifically Marks Cardiac Fibrosis

Cardiac fibrosis is a major hallmark of cardiac diseases. For evaluation of cardiac fibrosis, the development of highly specific and preferably noninvasive methods is desired. Our aim was to evaluate CNA35, a protein known to specifically bind to collagen, as a specific marker of cardiac fibrosis. Fluorescently labeled CNA35 was applied ex vivo on tissue sections of fibrotic rat, mouse, and canine myocardium. After quantification of CNA35, sections were examined with picrosirius red (PSR) and compared to CNA35. Furthermore, fluorescently labeled CNA35 was administered in vivo in mice. Hearts were isolated, and CNA35 labeling was examined in tissue sections. Serial sections were histologically examined with PSR. Ex vivo application of CNA35 showed specific binding to collagen and a high correlation with PSR (Pearson r  =  .86 for mice/rats and r  =  .98 for canine; both p < .001). After in vivo administration, CNA35 labeling was observed around individual cardiomyocytes, indicating its ability to penetrate cardiac endothelium. High correlation was observed between CNA35 and PSR (r  =  .91, p < .001). CNA35 specifically binds to cardiac collagen and can cross the endothelial barrier. Therefore, labeled CNA35 is useful to specifically detect collagen both ex vivo and in vivo and potentially can be converted to a noninvasive method to detect cardiac fibrosis.Cardiac fibrosis is a major hallmark of cardiac diseases. For evaluation of cardiac fibrosis, the development of highly specific and preferably noninvasive methods is desired. Our aim was to evaluate CNA35, a protein known to specifically bind to collagen, as a specific marker of cardiac fibrosis. Fluorescently labeled CNA35 was applied ex vivo on tissue sections of fibrotic rat, mouse, and canine myocardium. After quantification of CNA35, sections were examined with picrosirius red (PSR) and compared to CNA35. Furthermore, fluorescently labeled CNA35 was administered in vivo in mice. Hearts were isolated, and CNA35 labeling was examined in tissue sections. Serial sections were histologically examined with PSR. Ex vivo application of CNA35 showed specific binding to collagen and a high correlation with PSR (Pearson r = .86 for mice/rats and r = .98 for canine; both p < .001). After in vivo administration, CNA35 labeling was observed around individual cardiomyocytes, indicating its ability to penetrate cardiac endothelium. High correlation was observed between CNA35 and PSR (r = .91, p < .001). CNA35 specifically binds to cardiac collagen and can cross the endothelial barrier. Therefore, labeled CNA35 is useful to specifically detect collagen both ex vivo and in vivo and potentially can be converted to a noninvasive method to detect cardiac fibrosis.

Assessment of left ventricular mechanical dyssynchrony in left bundle branch block canine model: Comparison between cine and tagged MRI.

To compare cine and tagged magnetic resonance imaging (MRI) for left ventricular dyssynchrony assessment in left bundle branch block (LBBB), using the time‐to‐peak contraction timing, and a novel approach based on cross‐correlation.