Intra-ventricular resynchronization for optimal left ventricular function during pacing in experimental left bundle branch block.

OBJECTIVES: We sought to investigate to what extent intra-ventricular asynchrony (intraVA) and inter-ventricular asynchrony (interVA) determine left ventricular (LV) function in canine hearts with left bundle branch block (LBBB) during ventricular pacing. BACKGROUND: Pacing therapy improves LV pump function in patients with heart failure and abnormal ventricular conduction supposedly due to resynchronization. However, the relationship between LV pump function and measures of asynchrony is not well established. METHODS: In 15 experiments, LV (various sites) and biventricular (BiV) pacing was performed at atrioventricular (AV) delays of 20 to 140 ms. Measured were the maximum rate of increase (dP/dt(max)) of LV pressure and LV stroke work (SW) (conductance catheter), interVA (time delay between the upslope of LV and RV pressures), and intraVA (from endocardial electrical activation maps). RESULTS: Induction of LBBB increased interVA (-6.4 +/- 8.6 to -28.4 +/- 8.5 ms [RV earlier]) and intraVA (4.9 +/- 2.4 to 18.0 +/- 3.3 ms), whereas LV dP/dt(max) and SW decreased (-13 +/- 18% and -39 +/- 24%, respectively). During LBBB, LV and BiV pacing increased LV dP/dt(max) and SW (mean increases 14% to 21% and 11% to 15%, respectively) without changing diastolic function or preload. Optimal improvement in LV function was obtained consistently when intraVA returned to pre-LBBB values, while interVA remained elevated. Normalization of intraVA required AV delays shorter than the baseline PQ time during LV apex and BiV pacing, thus excluding endogenous LV activation, but AV delays virtually equal to the baseline PQ time (difference 4 +/- 9 ms, p = NS) during pacing at (mid)lateral LV sites to obtain fusion between pacing-induced and endogenous activation. CONCLUSIONS: In LBBB hearts, optimal restoration of LV systolic function by pacing requires intra-ventricular resynchronization. The optimal AV delay to achieve this depends on both the site of pacing and baseline PQ time.

Left ventricular septal and apex pacing for optimal pump function in canine hearts.

OBJECTIVES: The goal of this study was to test the hypothesis that left ventricular (LV) pump function is optimal when pacing is performed at the LV near the sites where the impulses exit the Purkinje system. BACKGROUND: Pacing at the conventional site, the right ventricular (RV) apex, adversely affects hemodynamics. During normal sinus rhythm (SR), electrical activation of the working myocardium starts at the LV septal endocardium and spreads from apex to base. METHODS: Experiments were conducted in anesthetized open-chest dogs with normal ventricular conduction to investigate hemodynamic effects of pacing at various epicardial LV sites, the RV apex, and combinations of these sites (n = 11) and of RV and LV septal pacing (n = 8). The LV septal endocardium was reached via the RV by puncturing through the septum with a barbed electrode. Left ventricular systolic (LVdP/dtpos and stroke work) and diastolic (LVdP/dtneg and Tau) function were assessed using pressure-volume relations (conductance catheter technique). RESULTS: Left ventricular systolic and diastolic function were highly dependent on the site of pacing, but not on QRS duration. Left ventricular function was maintained at SR level during LV septal, LV apex, and multisite pacing, was moderately depressed during pacing at epicardial LV free wall sites, and was most severely depressed during RV apex pacing. On average, RV septal pacing did not improve LV function, compared with RV apex pacing, but in each experiment one (variable) RV pacing site was found, which only moderately reduced LV function. CONCLUSIONS: During ventricular pacing, LV pump function is maintained best (i.e., at SR level) when pacing at the LV septum or LV apex, potentially because pacing from these sites creates a physiological propagation of electrical conduction.

Absence of reverse electrical remodeling during regression of volume overload hypertrophy in canine ventricles.

OBJECTIVE: Ventricular hypertrophy predisposes for cardiac arrhythmias, presumably due to prolongation of repolarization (electrical remodeling). The temporal relation between the development of hypertrophy and electrical remodeling, as well as their reversibility upon restoration of normal load, however, are poorly understood. This was investigated in the present study using volume overload hypertrophy induced by atrio-ventricular (AV) block and normalization of load by pacing. METHODS: Dogs were subjected to either 16 weeks of AV-block (CAVB group, n=9) or 8 weeks of AV-block followed by 8 weeks of right ventricular (RV) pacing at physiological heart rate (CAVB+PACE group, n=9). RESULTS: Left ventricular (LV) mass (2D-echocardiography) increased after 8 weeks of AV-block to approximately 30% above baseline and returned to 10+/-14% after 8 weeks of pacing. QT-time (surface ECG) also increased after AV-block. However, 8 weeks of pacing did not decrease QT and QTc-time (c=corrected for heart rate), neither during physiological pacing nor during temporary pacing at 100 beats/min. Lack of reverse electrical remodeling was confirmed by the absence of changes in LV and RV action potential duration (monophasic action potentials) at week 8 and 16. CONCLUSIONS: In volume overload hypertrophy due to AV-block, structural and electrical remodeling develop in parallel but restoration of physiological heart rate causes dissociation between reverse structural remodeling and reverse electrical remodeling.

Efficient and specific cardiac IK1 inhibition by a new pentamidine analogue.

AIMS: In excitable cells, KIR2.x ion-channel-carried inward rectifier current (IK1) is thought to set the negative and stable resting membrane potential, and contributes to action potential repolarization. Loss- or gain-of-function mutations correlate with cardiac arrhythmias and pathological remodelling affects normal KIR2.x protein levels. No specific IK1 inhibitor is currently available for in vivo use, which severely hampers studies on the precise role of IK1 in normal cardiac physiology and pathophysiology. The diamine antiprotozoal drug pentamidine (P) acutely inhibits IK1 by plugging the cytoplasmic pore region of the channel. We aim to develop more efficient and specific IK1 inhibitors based on the P structure. METHODS AND RESULTS: We analysed seven pentamidine analogues (PA-1 to PA-7) for IK1 blocking potency at 200 nM using inside-out patches from KIR2.1 expressing HEK-293 cells. PA-6 showed the highest potency and was tested further. PA-6 blocked KIR2.x currents of human and mouse with low IC50 values (12-15 nM). Modelling indicated that PA-6 had less electrostatic but more lipophilic interactions with the cytoplasmic channel pore than P, resulting in a higher channel affinity for PA-6 (ΔG -44.1 kJ/Mol) than for P (ΔG -31.7 kJ/Mol). The involvement of acidic amino acid residues E224 and E299 in drug-channel interaction was confirmed experimentally. PA-6 did not affect INav1.5, ICa-L, IKv4.3, IKv11.1, and IKv7.1/minK currents at 200 nM. PA-6 inhibited the inward (50 nM 40%; 100 nM 59%; 200 nM 77%) and outward (50 nM 40%; 100 nM 76%; 200 nM 100%) components of IK1 in isolated canine adult-ventricular cardiomyocytes (CMs). PA-6 prolonged action potential duration of CMs by 8 (n = 9), 26 (n = 5), and 34% (n = 11) at 50, 100, and 200 nM, respectively. Unlike P, PA-6 had no effect on KIR2.1 channel expression at concentrations from 0.1 to 3 µM. However, PA-6 at 10 µM increased KIR2.1 expression levels. Also, PA-6 did not affect the maturation of hERG, except when applied at 10 µM. CONCLUSION: PA-6 has higher efficiency and specificity to KIR2.x-mediated current than P, lengthens action potential duration, and does not affect channel trafficking at concentrations relevant for complete IK1 block.

Left bundle branch block induces ventricular remodelling and functional septal hypoperfusion.

AIMS: Left ventricular (LV) dilatation, hypertrophy, and septal perfusion defects are frequently observed in patients with left bundle branch block (LBBB). We investigated whether isolated LBBB causes these abnormalities. METHODS AND RESULTS: In eight dogs, LBBB was induced by radio frequency ablation. Two-dimensional echocardiography showed that 16 weeks of LBBB decreased LV ejection fraction (by 23+/-14%) and increased LV cavity volume (by 25+/-19%) and wall mass (by 17+/-16%). The LV septal-to-lateral wall mass ratio decreased by 6+/-9%, indicating asymmetric hypertrophy. After onset of LBBB, myocardial blood flow (MBF, fluorescent microspheres) and systolic circumferential shortening [CS(sys), magnetic resonance (MR) tagging] decreased in the septum to 83+/-16% and -11+/-20% of baseline, respectively, and increased in LV lateral wall to 118+/-12% and 180+/-90% of baseline, respectively. MBF and CS(sys) values did not change over 16 weeks of LBBB. Changes in external mechanical work paralleled those in CS(sys). Glycogen content was not significantly different between septum and LV lateral wall of LBBB hearts (16 weeks) and control samples, indicating absence of hibernation. CONCLUSIONS: The asynchronous ventricular activation during LBBB leads to redistribution of circumferential shortening and myocardial blood flow and, in the long run, LV remodelling. Septal hypoperfusion during LBBB appears to be primarily determined by reduced septal workload.

Relation between the pacing induced sequence of activation and left ventricular pump function in animals.

The main goal of this article was to review animal experimental work on the effect of asynchronous activation on ventricular pump function. During normal sinus rhythm and atrial pacing, the Purkinje system contributes significantly to the rapid electrical activation of the ventricles. In contrast, during ventricular pacing the impulse is almost exclusively conducted through the normal myocardium. As a consequence, electrical activation of the ventricles becomes asynchronous and has an abnormal sequence. The abnormal impulse conduction causes considerable disturbances to occur in regional systolic fiber shortening, mechanical work, blood flow, and oxygen consumption; low values occurring in early activated regions and values above normal being present in late activated regions. Many animal studies have now shown that the abnormal electrical activation, induced by ventricular pacing, leads to a depression of systolic and diastolic LV function. Pacing at the right ventricular apex (the conventional pacing site) reduces LV function more than pacing at the high ventricular septum or at LV sites. In canine hearts with experimental LBBB, LV pacing significantly improves LV pump function. Differences in LV pump function between (combinations of) pacing sites are poorly correlated with QRS duration. Therefore, the cause of the depression of LV function during abnormal electrical activation appears to be a combination of the asynchrony and the sequence of activation. These experimental findings justify continuing attention for optimizing the site(s) of ventricular pacing in patients with normal and abnormal ventricular impulse conduction.

Relation between abnormal ventricular impulse conduction and heart failure.

Ventricular pacing and left bundle branch block (LBBB) are two of the most common causes of asynchronous electrical activation of the ventricles. The sequence of activation is an important determinant of cardiac pump function. The sequence of activation during LBBB and during pacing at the conventional pacing site, the RV apex, is similar. In this article the literature on the effect of RV pacing and LBBB on regional and global LV pump function, on long-term adaptations (remodeling) and on their possible contribution to the development of heart failure is discussed. Evidence is increasing that asynchronous electrical activation contributes significantly to the development of heart failure.

Quantification of interventricular asynchrony during LBBB and ventricular pacing.

The quantification of mechanical interventricular asynchrony (IVA) was investigated. In 12 dogs left bundle branch block (LBBB) was induced by radio frequency ablation. Left ventricular (LV) and right ventricular (RV) pressures were recorded before and after induction of LBBB and during LBBB + LV apex pacing at different atrioventricular (AV) delays. Four IVA measures were validated using computer simulations on experimentally obtained pressure signals. The most robust measure for IVA was the time delay between the upslope of the LV and RV pressure signals (DeltaT(up)), estimated by cross correlation. The induction of experimental LBBB decreased DeltaT(up) from -6.9 +/- 7.0 ms (RV before LV) to -33.9 +/- 7.6 ms (P < 0.05) in combination with a significant decrease of LV maximal first derivative of pressure development over time (dP/dt(max)). During LV apex pacing, DeltaT(up) increased with decreasing AV delay up to +20.9 +/- 14.6 ms (P < 0.05). Interventricular resynchronization (DeltaT(up) = 0 ms) significantly improved LV dP/dt(max) by 15.1 +/- 5.9%. QRS duration increased significantly after induction of LBBB but did not change during LV apex pacing. In conclusion, DeltaT(up) is a reliable measure of mechanical IVA, which adds valuable information concerning the nature of asynchronous activation of the ventricles.