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Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Norwegian South East Health Authorities Introduction Identification of disease modification prior to implantation of Cardiac Resynchronization Therapy may help select the right patients, increase responder-rates and promote the utilization of CRT. We tested the hypothesis that shortening of time-to-peak left ventricular pressure rise (Td) with CRT is useful to predict long-term volumetric response (End-systolic volume (ESV) decrease >15%) to CRT. Methods Forty-five heart failure patients admitted for CRT implantation with a class I/IIa indication according to current ESC/AHA guidelines were included in the study. Td was measured from onset QRS at baseline and from onset of pacing with CRT. Results Baseline characteristics were mean age 63 ± 10 years , 71% males, NYHA class 2.5, 87% LBBB, QRS duration 173 ± 15ms, EF biplane 31 ± 1%, ESV 144 ± 12mL and end-diastolic volume 2044 ± 14mL. At 6-months follow-up six patients increased ESV by 5 ± 8%, while 37 responders (85%) had a mean ESV decrease of 40 ± 2%. Responders presented with a higher Td at baseline compared to non-responders (163 ± 4ms vs 119 ± 9ms, p Conclusions Td at baseline and the shortening of Td with CRT accurately identifies responders to CRT, with incremental value on top of current guidelines, in a population with already high response rates. Td carries the potential to become the marker for prediction of long-term volumetric response in CRT candidates. Abstract Figure.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Norwegian South East Health Authorities Introduction Resynchronization therapy effectively restores myocardial function. No measures exist that specifically quantifies resynchronization. A parameter that quantifies resynchronization should be able to detect effective resynchronization and should not respond to changes in contractility caused by heterometric regulation. Left ventricular pacing (LVP) is associated with dyssynchronous contraction patterns, while biventricular pacing (BIVP) promotes resynchronization dependent on the pacing position of the LV electrode. Purpose We compared the acute differences between BIVP and LVP with regards to the preload dependent maximum rate of the LV pressure rise (dP/dtmax), and time to peak dP/dt (Td) to determine which better reflect dyssynchrony and resynchronization. Methods Twenty nine patients in heart failure with LBBB underwent CRT implantation with continuous LV pressure registration. The LV lead was first placed in either apical or anterior position followed by a permanent placement in a lateral position. Sequential LVP and BIVP pacing were performed for one minute, at a rate 10% above intrinsic heart rate, before dP/dtmax measurements were recorded. For LVP, BIVP and RVP a patient specific AV delay was used to avoid fusion with intrinsic conduction. Td was defined as the time from pacemaker stimuli to peak dP/dt. Mixed linear models were used for statistics, numbers are estimated marginal means ± SEM and are only reported when with significance set at p Results We found no differences in dP/dtmax between BIVP (899 ± 37mmHg/s) and LVP (910 ± 37mmHg/s), while RVP (799 ± 37mmHg/s) was lower. Td was lower with BIVP (165 ± 4ms) than LVP (178 ± 4ms) and RVP (184 ± 4ms). We found no differences in dP/dtmax between lateral (890 ± 35mmHg/s) and anterior (874 ± 38mmHg/s) while apical (824 ± 38mmHg/s) was lower. Td was lower in lateral (171 ± 4ms) than in anterior (179 ± 4ms) and apical (182 ± 4ms) positions. BIVP in lateral position (158 ± 4ms) was lower than any other pacingmode*position, with BIVP*anterior at 173 ± 4ms) and LVP*lateral at 170 ± 2ms. No difference was seen in dP/dtmax between (BIVP + LVP)*(lateral + anterior) that was higher than all other pacingmode*positions. Conclusion Td shortens with BIVP and lateral position, and even more so with BIVP in lateral position and thus reflects resynchronization compared to all other combinations tested. DP/dtmax did not reflect resynchronization as BIVP/LVP and lateral/anterior performs equally good. There are no differences between dP/dtmax with any combination of pacing mode (BIVP + LVP) with position (anterior + lateral). This suggests that Td reflects resynchronization while dP/dtmax does not. Resynchronization with biventricular pacing in lateral position translates into a shorter Td and hence links electrical and mechanical events. Td could be the missing link between electrical and mechanical dyssynchrony and may serve as a biomarker for cardiac resynchronization therapy.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Norwegian South East heath Authorities Background We investigated the homeometric autoregulation utilizing a stepwise change in heart rate on dP/dtmax and time to peak dP/dt (Td) with biventricular pacing (BIVP) and the LV lead positioned in the apical, anterior and lateral positions. Pacing at low HR (LHR) and high heart rates (HHR) changes contractility through homeometric autoregulation (Bowditch effect) without changing the resynchronization itself. Purpose To determine the effect of a change in contractility through homeometric autoregulation on two different effect measures of resynchronization therapy. Methods Twenty-nine patients in heart failure with LBBB underwent CRT implantation with continuous LV pressure registration. The LV lead was first placed in either apical or anterior position followed by a permanent placement in a lateral position. Sequential BIVP pacing was performed for one minute, at a rate 10% above intrinsic heart rate (LHR = 75 ± 9bpm), before dP/dtmax measurements were recorded, and the sequence was repeated with pacing rate increased by 30% (HHR = 98 ± 11bpm). Td was defined as the time from pacemaker stimuli to peak dP/dt. Mixed linear models were used for statistics, numbers are estimated marginal means ± SEM. Significance was set at p Results DP/dtmax was higher with HHR in lateral position (1036 ± 41mmHg/s) than with LHR (933mmHg/s). The same was observed for all other lead positions. However, there was no difference between lateral position with LHR and apical position with HHR (930 ± 44mmHg/s). There were no differences in Td between LHR and HHR, but Td was shorter with BIVP in lateral position at pacing LHR (158 ± 4ms) and HHR (155 ± 4ms) than in all other positions. Overall dP/dtmax increased by 10% from LHR to HHR (888 ± 41mmHg/s vs. 980 ± 41 mmHg/s), while overall Td decreased by 2.4% from 168 ± 4ms to 164 ± 4ms. We found a linear relationship between Td and dP/dtmax (R = 0.7) with β=-0.07 that would indicate a 6ms reduction in Td going from LHR to HHR. The overall change in Td from LHR to HHR could therefore be attributed to the change in dP/dtmax. Conclusion Homeometric regulation does not influence Td, but Td is sensitive to changes in resynchronization and pacing lead position. Td is shorter with BIVP in lateral position at both high and low HR as would be expected from a biomarker of resynchronization. HR influences dP/dtmax so distinction between optimal and non-optimal positions using dP/dtmax may be difficult without knowledge of homeometric state.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Norwegian South-East Health Authorities Background We have investigated the timing of the peak left ventricular pressure rise, time to peak dP/dt (Td) as marker of resynchronization to be measured during implantation for detection of effective resynchronization. Td links the time domain (dyssynchrony) to the mechanical domain (pressure) as the dyssynergic muscular contractions resulting from electrical dyssynchrony delays pressure development and hence the timing of peak dP/dt, Td. Td shortens with resynchronization. Purpose In this study we investigated the acute changes in Td by comparing pacing the left ventricle (LV) with fusion of intrinsic right ventricular (RV) conduction (Adaptive, A) with pacing RV and LV (Non-Adaptive, NA), with and without multipoint pacing (MPP) and with different degrees of intraventricular pacing delays (RV-LV). Methods 19 patients with sinus rhythm and LBBB undergoing CRT implantation were studied. We measured pressures with an indwelling LV pressure catheter. Td was calculated as the time from onset of pacing to peak dP/dt, and averaged in 10 subsequent beats at each stage of pacing. We used quadripolar LV pacing leads positioned in what was considered an optimal mid/basal posterolateral/ lateral branch of the coronary sinus and sequential pacing (DDD) was performed; Adaptive and Non-Adaptive pacing was performed at LV distal [LVdist], proximal electrode [LVprox] and at both electrodes as multipoint pacing [MPP]. VV-timing: LV pacing was performed relative to QRS onset (either as a result of intrinsic activation or RV pace, mean ± SD): 1. LV only -76 ± 21ms before QRS activation with minimal fusion with RV activation (LVonly); 2. -28 ± 14ms before QRS activation (Pre); 3. 12 ± 15ms after (Post) QRS activation. Linear mixed models were used for statistics of the pooled data. Results are estimated marginal means ±SEM, and only significant P Results Average Td (data pooled) with RVP was 173 ± 2ms, MPP 144 ± 0.4ms and BIVP 150 ± 0.4ms. When analyzing the interaction between pacingmode (A,NA), VV-timing (LVonly,Pre,Post) and electrode(LVdist,LVprox,MPP) in all interventions we found that Td was shorter (p Conclusion Td shortens the most with LV MPP timed to near simultaneous intrinsic RV activation, indicating a beneficial mechanical effect from Adaptive MPP compared to standard biventricular pacing.

We introduce an S‐transform amplitude ridge tracking (START) algorithm for estimation of 2nd heart sound (S2) splitting and investigated the relationship between S2 splitting and time difference in contraction between right and left ventricle in a porcine model. START was accurate in estimating S2 splitting interval in chirp‐model‐generated heart sounds. S2 splitting correlated well in pacing‐induced time differences in contraction of the ventricles in an animal model., Second heart sound (S2) splitting results from nonsimultaneous closures between aortic (A2) and pulmonic valves (P2) and may be used to detect timing differences (dyssynchrony) in relaxation between right (RV) and left ventricle (LV). However, overlap of A2 and P2 and the change in heart sound morphologies have complicated detection of the S2 splitting interval. This study introduces a novel S‐transform amplitude ridge tracking (START) algorithm for estimating S2 splitting interval and investigates the relationship between S2 splitting and interventricular relaxation dyssynchrony (IRD). First, the START algorithm was validated in a simulated model of heart sound. It showed small errors (

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NWO-ZonMw Background The relative impact of left ventricular (LV) diastolic dysfunction (LVDD) and impaired left atrial (LA) function on cardiac exercise performance (CEP) in heart failure with preserved ejection fraction (HFpEF) remains largely unknown Purpose To elucidate the relative effects of LVDD and impaired LA function on hemodynamics at rest and on cardiac performance during exercise by performing virtual HFpEF patient simulations. Methods Using a well-validated cardiovascular system model (CircAdapt), impaired LV relaxation was simulated by increasing the rate of myocardial relaxation (tau) from 35 to 65 ms. To study the effect of moderate and sever LV myocardial stiffness increase, LV end-diastolic elastance was increased from 0.15 mmHg/ml to 0.60 mmHg/ml and 2.00 mmHg/ml, respectively. In each simulation, LV diastolic function at rest (cardiac output (CO) and heart rate (HR) of 5.1 l/min and 70 bpm, respectively) was assessed using LV ejection fraction (LVEF), mitral E/A ratio, maximum LA volume (LAV), and mean left atrial (LA) pressure (mLAP). To investigate the relative effect of these cardiac abnormalities on exercise capacity, CO and HR were gradually increased using a fixed CO-HR relationship until mLAP exceeded a threshold pressure of 35 mmHg, which was assumed to be a physiological limit of exercise intensity. Results Simulations showed that regardless of the modelled LV and LA function, LVEF was preserved (>50%). Impaired LV relaxation function was associated with decreased E/A-ratio and a small increase in mLAP at rest, regardless of LA function. Increased LV passive stiffness resulted in increased E/A-ratio, LA dilation and markedly elevated mLAP at rest, regardless of LA function (Figure: top-left). Impaired LA function resulted in reduced A-peak velocity, and increased E/A–ratio, LAV and mLAP at rest regardless of LV function (Figure: top-right) Exercise simulations showed that increased LV passive stiffness exerts a stronger exercise-limiting effect than impaired LV relaxation function, in particular when LA function is impaired (Figure: bottom). Conclusions Through simple and well-controlled variations in LV and LA function, we were able to simulate virtual HFpEF patients with a wide range of LVDD severities at rest, preserved LVEF, and reduced cardiac exercise performance. In general, our simulations suggest that increased LV passive stiffness, rather than impaired LV relaxation function, reduces exercise tolerance, especially in the presence of LA dysfunction. Abstract Figure. Simulating rest & exercise hemodynamics

Aims A difficult cardiac resynchronization therapy (CRT) implantation scenario emerges when no lateral pacing option exists. The aim of this study was to explore the effect of biventricular pacing (BIVP) on vectorcardiographic parameters in patients with a non-lateral left ventricular (LV) lead position. We hypothesized that perimeter and area reduction for both the QRS complex and T-wave would predict acute CRT response. Methods and results Twenty-six patients (14 ischaemic) with a mean age of 63 ± 10 years and standard CRT indication underwent device implantation with continuous LV pressure registration. The LV lead was placed in either an anterior or apical position. Biventricular pacing was performed at a rate 10% above intrinsic rhythm with acute CRT response defined as LV ΔdP/dtmax >10%. Using this criterion 12 patients were identified as acute CRT responders (responders: 16.7 ± 4.8% vs. non-responders: 1.9 ± 5.3%, P

Providing therapies tailored to each patient is the vision of precision medicine, enabled by the increasing ability to capture extensive data about individual patients. In this position paper, we argue that the second enabling pillar towards this vision is the increasing power of computers and algorithms to learn, reason, and build the 'digital twin' of a patient. Computational models are boosting the capacity to draw diagnosis and prognosis, and future treatments will be tailored not only to current health status and data, but also to an accurate projection of the pathways to restore health by model predictions. The early steps of the digital twin in the area of cardiovascular medicine are reviewed in this article, together with a discussion of the challenges and opportunities ahead. We emphasize the synergies between mechanistic and statistical models in accelerating cardiovascular research and enabling the vision of precision medicine. ispartof: EUROPEAN HEART JOURNAL vol:41 issue:48 pages:4556-+ ispartof: location:England status: published

BACKGROUND Cardiac resynchronization therapy (CRT) is usually performed by biventricular (BiV) pacing. Previously, feasibility of transvenous implantation of a lead at the left ventricular (LV) endocardial side of the interventricular septum, referred to as LV septal (LVs) pacing, was demonstrated.OBJECTIVES The authors sought to compare the acute electrophysiological and hemodynamic effects of LVs with BiV and His bundle (HB) pacing in CRT patients.METHODS Temporary LVs pacing (transaortic approach) alone or in combination with right ventricular (RV) (LVs+RV), BiV, and HB pacing was performed in 27 patients undergoing CRT implantation. Electrophysiological changes were assessed using electrocardiography (QRS duration), vectorcardiography (QRS area), and multielectrode body surface mapping (standard deviation of activation times [SDAT]). Hemodynamic changes were assessed as the first derivative of LV pressure (LVdP/dtmax).RESULTS As compared with baseline, LVs pacing resulted in a larger reduction in QRS area (to 73 +/- 22 mu Vs) and SDAT (to 26 +/- 7 ms) than BiV (to 93 +/- 26 mVs and 31 +/- 7 ms; both p CONCLUSIONS LVs pacing provides short-term hemodynamic improvement and electrical resynchronization that is at least as good as during BiV and possibly HB pacing. These results indicate that LVs pacing may serve as a valuable alternative for CRT. (C) 2020 by the American College of Cardiology Foundation.

Aims: Correction of mitral and/or tricuspid regurgitation (MR, TR) frequently leads to poor outcomes in the days following intervention. We sought to understand how abrupt correction of MR and TR affects ventricular load and to investigate if gradual correction is beneficial.Methods and results: MR and TR were simulated using the CircAdapt cardiovascular system model with effective regurgitant orifice (ERO) areas of 0.5 cm(2) and 0.7 cm(2). Ventricular and atrial contractility reductions to 40% of normal and pulmonary hypertension were simulated. Abrupt and gradual ERO closure were simulated with homeostatic regulation of blood pressure and volume. Abrupt correction of MR increased left and right ventricular fibre stress by 40% and 15%, respectively, whereas TR correction increased left and right ventricular fibre stress by 26% and 19%, respectively. This spike was followed by a rapid drop in fibre stress. Myocardial dysfunction prolonged the spike but reduced its amplitude. Right ventricular fibre stress increased more with pulmonary hypertension and TR. Gradual correction demonstrated no spike in tissue load.Conclusions: Simulations demonstrated that abrupt ERO closure creates a transient increase in ventricular load that is prolonged by worsened myocardial condition and exacerbated by pulmonary hypertension. Gradual closure of the ERO abolishes this spike and merits clinical investigation.

Background Cardiac resynchronization therapy (CRT) is usually performed with a right (RV) and left ventricular (LV) lead. In a previous patient study, pacing the interventricular septum permanently on the LV endocardial side (LV septum) proved feasible in patients with sinus node dysfunction. Objective To investigate the effects of LV septal pacing as compared to conventional biventricular (BiV) pacing with respect to acute hemodynamic and electrophysiological effects in CRT indicated heart failure patients. Methods Temporary LV septal pacing (transarterial approach) and pacing in the conventional BiV mode using the implanted leads was performed in 26 patients (QRS duration 163±17 ms, 23 left bundle branch block patients) undergoing CRT implantation. Acute hemodynamic response (relative to baseline AAI pacing) was assessed by LVdP/dtmax. Multi-electrode body-surface mapping, what has been used previously to characterize electrical dyssynchrony in CRT patients, was evaluated using the standard deviation of activation times (SDAT) (figure, right panel). Results LV septal pacing resulted in a significant LV dP/dtmax increase, that was comparable to conventional BiV pacing (figure, left panel). Combined RV and LV septal pacing did not provide an additional increase. LV septal pacing resulted in a significantly larger reduction in SDAT than RV plus LV septal pacing and conventional BiV pacing (figure, middle panel). Conclusions LV septal pacing results in acute hemodynamic improvement and electrical resynchronization that is at least as good as conventional BiV pacing. These results suggest that LV septal pacing with a single ventricular lead may serve as an alternative to conventional BiV pacing for cardiac resynchronization. Acknowledgement/Funding Medtronic is a subsidising party.

Background Cardiac resynchronization therapy (CRT) is usually performed with a right (RV) and left ventricular (LV) lead. Previous observational studies showed promising results with His bundle pacing (HBP) in patients with left bundle branch block (LBBB) by capturing and recruiting the native His-Purkinje system as an alternative to provide ventricular resynchronization. Objective To investigate the effects of HBP as compared to conventional biventricular (BiV) pacing with respect to acute hemodynamic and electrophysiological effects in heart failure patients with LBBB. Methods RV apical and BiV pacing, using the implanted leads, and temporary HBP, using an electrophysiology catheter, was performed in 13 patients (QRS duration 168±16 ms) undergoing CRT implantation. Hemodynamic response (relative to baseline AAI pacing) was assessed as change in LVdP/dtmax. Multi-electrode body-surface mapping, what has been used previously to characterize electrical dyssynchrony in CRT patients, was evaluated using the standard deviation of activation times (SDAT) (figure, right panel). Results HBP resulted in a significant LV dP/dtmax increase, that was comparable to the increase during BiV pacing and significantly larger than RV pacing (figure, left panel). HBP resulted in a more homogenized electrical activation and larger reduction in SDAT than both conventional BiV pacing and RV pacing (figure, middle panel). Conclusions Acute HBP results in hemodynamic improvement and electrical resynchronization that is as good as conventional BiV pacing. These results suggest that HBP may serve as an alternative for conventional BiV pacing in LBBB patients, however prospective studies are needed to prove chronic clinical outcomes. Acknowledgement/Funding Medtronic is a subsidising party.

Introduction: Vectorcardiographic (VCG) QRS area of left bundle branch block (LBBB) predicts acute hemodynamic response in cardiac resynchronization therapy (CRT) patients. We hypothesized that changes in QRS area occurring with biventricular pacing (BV) might predict acute hemodynamic CRT response (AHR). Methods and Results: VCGs of 624 BV paced electrocardiograms (25 LBBB patients with 35 different pacing configurations) were calculated according to Frank's orthogonal lead system. Maximum QRS vector amplitudes (X-Ampl, Y-Ampl, Z(Ampl), and 3D(Amp)) and QRS areas (X-Area, Y-Area, Z(Area), and 3D(Area)) in the orthogonal leads (X, Y, and Z) and in 3-dimensional projection were measured. Volume of the 3D vector loop and global QRS duration (QRSD) on the surface electrocardiogram were assessed. Differences (Delta) in VCG parameters between BV paced and LBBB QRS complexes were calculated. An increase of 10% in dP/dt max was considered as AHR. LBBB conduction is characterized by a large Z(Area) (109 mu Vs, interquartile range [ IQR]: 75; 135), significantly larger than X-Area (22 mu Vs, IQR: 10; 57) and Y-Area (44 mu Vs, IQR: 32; 62, P< 0.001). Overall, QRS duration, amplitudes, and areas decrease significantly with BV pacing (P

Background: We sought to determine whether presence, amount and distribution of scar impacts the degree of acute hemodynamic response (AHR) with multisite pacing.Multi-vein pacing (MVP) or multipolar pacing (MPP) with a multi-electrode left ventricular (LV) lead may offer benefits over conventional biventricular pacing in patients with myocardial scar. Methods: In this multi-center study left bundle branch block patients underwent an hemodynamic pacing study measuring LV dP/dtmax. Patients had cardiac magnetic resonance scar imaging to assess the effect of scar presence, amount and distribution on AHR. Results: 24 patients (QRS 171 ± 20 ms) completed the study (83% male). An ischemic etiology was present in 58% and the mean scar volume was 6.0 ± 7.0%. Overall discounting scar, MPP and MVP showed no significant AHR increase compared to an optimized “best BiV” (BestBiV) site. In a minority of patients (6/24) receiver-operator characteristic analysis of scar volume (cut off 8.48%) predicted a small AHR improvement with MPP (sensitivity 83%, specificity 94%) but not MVP. Patients with scar volume > 8.48% had a MPP-BestBiV of 3 ± 6.3% vs. −6.4 ± 7.7% for those below the cutoff. There was a significant correlation between the difference in AHR and scar volume for MPP-BestBiV (R = 0.49, p = 0.02) but not MVP-BestBiV(R = 0.111, p = 0.62). The multielectrode lead positioned in scar predicted MPP AHR improvement (p = 0.04). Conclusions: Multisite pacing with MPP and MVP shows no AHR benefit in all-comers compared to optimized BestBiV pacing. There was a minority of patients with significant scar volume in relation to the LV site that exhibited a small AHR improvement with MPP.(Study identifier NCT01883141) Keywords: Cardiac resynchronization therapy, Multisite pacing, Acute hemodynamic response, Left ventricular scar

The cardiovascular system can be influenced by electrically stimulating the vagal nerve. Selectivity for specific cardiac fibers may be limited when stimulating at the cervical level. Our objective was to increase effectiveness and selectivity for cardiovascular effects of vagal nerve stimulation by using local bipolar stimulation in one nerve cross section using a multi-contact cuff instead of less localized stimulation using a tripolar ring electrode. Both types of cuff electrodes were compared with respect to their relative effects on R-R interval (RRI), P-Q interval (PQI), left ventricular contractility (LVC), and left ventricular pressure (P(LV)) in seven pigs. Stimulation using the optimal bipolar configuration on the multi-contact cuff significantly affected RRI, PQI, LVC, and P(LV), whereas stimulation with the ring electrode only significantly affected RRI and PQI. The cardiovascular parameters that could be significantly influenced varied between the bipolar configurations. These novel findings may be relevant for optimizing electrode configurations for clinical cardiac applications of vagal nerve stimulation.

Vectorcardiographic (VCG) QRS area of left bundle branch block (LBBB) predicts acute hemodynamic response in cardiac resynchronization therapy (CRT) patients. We hypothesized that changes in QRS area occurring with biventricular pacing (BV) might predict acute hemodynamic CRT response (AHR).VCGs of 624 BV paced electrocardiograms (25 LBBB patients with 35 different pacing configurations) were calculated according to Frank's orthogonal lead system. Maximum QRS vector amplitudes (XOf all VCG parameters, reduction in QRS area, calculated in Frank's Z lead, predicts acute hemodynamic response best. This method might be an easy, noninvasive tool to guide CRT implantation and optimization.

Stimulation of the intra-cardiac vagal nerves innervating the AV-node (AVNS) is a promising approach to slow down ventricular rate (VR) during atrial fibrillation (AF). Our purpose was to demonstrate that effects on R-R-interval during stable AF can be maintained for several months once optimized and that AVNS affects specifically the nerves innervating the AV-node. Our study included both an acute and chronic phase. Fifteen goats were implanted with a pacemaker connected to an atrial and ventricular lead and a neurostimulator connected to an atrial lead placed at a certain septal site, to induce an AV prolongation. In the chronic experiments (n = 9), after assessment of optimal AVNS parameters, the effect of continuous AVNS on VR was studied during stable AF for up to 3 months. The mechanism of AVNS was studied using atropine and esmolol. Next, the effects of AVNS during the atrial refractory period on electrophysiological and hemodynamic parameters were investigated acutely (n = 7). The maximal effect was found at a stimulation frequency of 40 Hz, and increased with increasing pulse width (at lower voltages) and increasing voltage. After 0, 1, and 3 months of AVNS during stable AF, AVNS decreased average VR, respectively, 55% (n = 9), 48% (n = 8), and 28% (n = 6). The AVNS effect appeared to be dominantly parasympathetic. AVNS did not influence (1) the sinus node, (2) the refractory period of the atrial, ventricular tissue, and His and (3) hemodynamic parameters. AVNS is efficient in reducing ventricular rate for at least 3 months using optimized parameters and specifically affects the parasympathetic nerves innervating the AV-node.

In this review, we report on electrical modalities, which do not fit the definition of pacemaker, but increase cardiac performance either by direct application to the heart (e. g., post-extrasystolic potentiation or non-excitatory stimulation) or indirectly through activation of the nervous system (e. g., vagal or sympathetic activation). The physiological background of the possible mechanisms of these electrical modalities and their potential application to treat heart failure are discussed.

BackgroundPatient-specific left ventricular (LV) lead optimisation strategies with immediate feedback on cardiac resynchronisation therapy (CRT) effectiveness are needed. The purpose of this study was to compare contractility surrogates derived from biventricular lead motion analysis to the peak positive time derivative of LV pressure (dP/dtmax) in patients undergoing CRT implantation.MethodsTwenty-seven patients underwent CRT implantation with continuous haemodynamic monitoring. The right ventricular (RV) lead was placed in apex and a quadripolar LV lead was placed laterally. Biplane fluoroscopy cine films facilitated construction of three-dimensional RV–LV interlead distance waveforms at baseline and under biventricular pacing (BIVP) from which the following contractility surrogates were derived; fractional shortening (FS), time to peak systolic contraction and peak shortening of the interlead distance (negative slope). Acute haemodynamic CRT response was defined as LV ∆dP/dtmax ≥ 10 %.ResultsWe observed a mean increase in dP/dtmax under BIVP (899±205 mm Hg/s vs 777±180 mm Hg/s, pmax, 18 patients were classified as acute CRT responders and nine as non-responders (23.3%±10.6% vs 1.9±5.3%, pConclusionThe baseline RV–LV interlead distance was associated with echocardiographic LV dimensions. In CRT recipients, contractility surrogates derived from the RV–LV interlead distance waveform could not discriminate between acute haemodynamic responders and non-responders.

Aims We investigated the accuracy and feasibility of a non-invasive arterial pulse contour technique for continuous measurement of stroke volume (SV) in optimization of atrioventricular (AV) delay in cardiac resynchronization therapy (CRT), by comparing SV changes assessed by Nexfin CO-Trek(R) (Nexfin) and echo Doppler aortic velocity-time integral (VTIao). Furthermore, we investigated whether AV-delay optimization increases the effect of CRT when compared with a default AV delay (120 ms). Methods and results In 23 CRT patients, biventricular pacing (BiVP) was applied at various AV delays, while recording 10 beats preceding BiVP (baseline) and the first 10 BiVP beats, for both methods in parallel. Agreement between Nexfin and VTIao measurements was evaluated (Bland-Altman) on beat-to-beat changes in SV, as well as on effects of BiVP (averaged over 8 beats) at various AV delays. Individual optimal AV delays, for Nexfin (AVopt-n) and VTIao (AVopt-ao), were derived from the second-order polynomial fitted to the effect measurements of 20 patients. In 252 episodes assessed, the difference between measurements (=Nexfin - VTIao) was -0.6 +/- 8.1% for beat-to-beat SV changes and -1.3 +/- 7.3% for effects of BiVP. Optimal AV delays for Nexfin were well related to AVopt-ao (R(2) = 0.69). The effect (%) of BiVP at the optimal AV delay was significantly larger than at the default AV delay: median difference (range) being +6.3% (0.1-14.4%; P

Differentiation of foetal cardiomyocytes is accompanied by sequential actin isoform expression, i.e. down-regulation of the 'embryonic' alpha smooth muscle actin, followed by an up-regulation of alpha skeletal actin (alphaSKA) and a final predominant expression of alpha cardiac actin (alphaCA). Our objective was to detect whether re-expression of alphaSKA occurred during cardiomyocyte dedifferentiation, a phenomenon that has been observed in different pathologies characterized by myocardial dysfunction. Immunohistochemistry of alphaCA, alphaSKA and cardiotin was performed on left ventricle biopsies from human patients after coronary bypass surgery. Furthermore, actin isoform expression was investigated in left ventricle samples of rabbit hearts suffering from pressure- and volume-overload and in adult rabbit ventricular cardiomyocytes during dedifferentiation in vitro. Atrial goat samples up to 16 weeks of sustained atrial fibrillation (AF) were studied ultrastructurally and were immunostained for alphaCA and alphaSKA. Up-regulation of alphaSKA was observed in human ventricular cardiomyocytes showing down-regulation of alphaCA and cardiotin. A patchy re-expression pattern of alphaSKA was observed in rabbit left ventricular tissue subjected to pressure- and volume-overload. Dedifferentiating cardiomyocytes in vitro revealed a degradation of the contractile apparatus and local re-expression of alphaSKA. Comparable alphaSKA staining patterns were found in several areas of atrial goat tissue during 16 weeks of AF together with a progressive glycogen accumulation at the same time intervals. The expression of alphaSKA in adult dedifferentiating cardiomyocytes, in combination with PAS-positive glycogen and decreased cardiotin expression, offers an additional tool in the evaluation of myocardial dysfunction and indicates major changes in the contractile properties of these cells.

Myocardial blood flow and oxygen consumption are heterogeneously distributed. Perfusion and myocardial oxygen consumption are closely correlated in the normal heart. It is unknown how this metabolism–perfusion relation is influenced by sympathetic denervation. We investigated this question in seven chloralose-anaesthetized dogs, 3–4 weeks after regional sympathetic denervation of the left circumflex coronary artery area of supply of the left ventricle. Measurements were made of local myocardial blood flow (MBF, in ml min−1 (g dry wt)−1), measured with microspheres, and myocardial oxygen consumption (, in μmol min−1 (g dry wt)−1) in the same location, calculated from the 13C spectrum of tissue extracts after intracoronary infusion of 3–13C-lactate. Since both innervated and denervated regions are subject to the same arterial pressure, lower blood flow indicates higher resistance. Mean MBF was 5.56 ml min−1 (g dry wt)−1 (heterogeneity of 3.47 ml min−1 (g dry wt)−1) innervated, 7.48 ml min−1 (g dry wt)−1 (heterogeneity of 3.62 ml min−1 (g dry wt)−1) denervated (n.s.). Significant linear relations were found between MBF and of individual samples within the innervated and denervated regions. The slopes of these relations were not significantly different, but the adjusted mean was significantly higher in the denervated regions (+1.92 ml min−1 (g dry wt)−1, an increase of 38% of the mean MBF at the pooled mean , P= 0.028, ANCOVA). The ratio (in ml μmol−1) was significantly higher, being 0.296 ± 0.167 ml μmol−1 in the denervated region compared with the innervated region, 0.216 ± 0.126 ml μmol−1, P= 0.0182, Mann–Whitney U test. These results indicate that sympathetic tone under chloralose anaesthesia imposes a moderate vasoconstrictive effect in the myocardium that is not detected by comparison of the mean blood flow or resistance.

Cardiac resynchronization therapy (CRT) reduces mortality and hospitalization in heart failure patients with left bundle branch block. Studies have shown that left ventricular (LV) lead placement is important to the acute response to CRT. The aim of this study was to evaluate if LV lead placement

Long lasting alterations in loading conditions lead to adaptations in structural remodeling (hypertrophy, changes in the size of the cardiac muscle and the cavity and its connective tissue content), mechanical remodeling (abnormal contraction and relaxation of the heart) and electrical remodeling (increased sensitivity to arrhythmias). In canine hearts with atrioventricular (AV)-block (bradycardia-induced volume overload) the three kinds of remodeling follow different time courses, emphasizing the complexity of myocardial adaptation processes. This is further emphasized by the lack of reversibility of electrical remodeling when normalizing volume load by pacing at physiological heart rate. Evidence is increasing that long lasting asynchronous activation (ventricular pacing, left bundle branch block) leads to eccentric hypertrophy with regional differences in structural, electrical and mechanical remodeling.

The heat shock proteins (HSPs) are an important family of endogenous, protective proteins that are found in all tissues. In the heart, HSP72, the inducible form of HSP70, has been the most intensely studied. It is well established that HSP72 is induced with ischemia and is cardioprotective. Overexpression of other HSPs also is protective against cardiac injury. Recently, we observed that 17β-estradiol increases levels of HSPs in male rat cardiac myocytes. We hypothesized that there were gender differences in HSP72 expression in the heart secondary to estrogen. To test this hypothesis, we examined cardiac levels of HSP72 by ELISA in male and female Sprague-Dawley rats. In addition, three other HSPs were assessed by Western blot (HSP27, HSP60, and HSP90). To determine whether estrogen status affected HSP72 expression in other muscles or tissues, two other muscle tissues, slow twitch muscle (soleus muscle) and fast twitch muscle (gastrocnemius muscle), were studied as well as two other organs, the kidney and liver. Because HSP72 is cardioprotective, and females are known to have less cardiovascular disease premenopause, the effects of ovariectomy were examined. We report that female Sprague-Dawley rat hearts have twice as much HSP72 as male hearts. Ovariectomy reduced the level of HSP72 in female hearts, and this could be prevented by estrogen replacement therapy. These data show that the expression of cardiac HSP72 is greater in female rats than in male rats, due to upregulation by estrogen.

ObjectivesWe 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.BackgroundPacing 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.MethodsIn 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/dtmax) 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).ResultsInduction 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/dtmaxand SW decreased (−13 ± 18% and −39 ± 24%, respectively). During LBBB, LV and BiV pacing increased LV dP/dtmaxand 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.ConclusionsIn 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.

Vagal nerve stimulation (VNS) started prior to, or during, ischemia has been shown to reduce infarct size. Here, we investigated the effect of VNS when started just prior to, and continued during early, reperfusion on infarct size and no-reflow and studied the underlying mechanisms. For this purpose, swine (13 VNS, 10 sham) underwent 45 min mid-LAD occlusion followed by 120 min of reperfusion. VNS was started 5 min prior to reperfusion and continued until 15 min of reperfusion. Area at risk, area of no-reflow (% of infarct area) and infarct size (% of area at risk), circulating cytokines, and regional myocardial leukocyte influx were assessed after 120 min of reperfusion. VNS significantly reduced infarct size from 67 ± 2 % in sham to 54 ± 5 % and area of no-reflow from 54 ± 6 % in sham to 32 ± 6 %. These effects were accompanied by reductions in neutrophil (~40 %) and macrophage (~60 %) infiltration in the infarct area (all p

HSP70 is known to protect cells against stressful events. In the present study, the hypothesis was investigated that elevated HSP70 levels protect RNA polymerase I during stress, leading to decreased inhibition of ribosomal RNA (rRNA) synthesis and accelerated recovery of protein translation after stress. To this end, transcriptional and translational activity was studied in H9c2 cells during recovery after a severe heat treatment (SHT, 1 h 45 degrees C) in the presence of elevated HSP70 levels. The latter was achieved by heat pretreatment or by adenovirus-mediated hsp70 gene transfer. Rates of transcription and translation were determined by measuring cellular 3H-labelled uridine and leucine incorporation, respectively. The two types of pretreatment did not affect basal rates of transcription and translation, immediately before SHT. During SHT, both transcriptional and translational rates dropped to less than 10% of basal levels in pretreated as well as non-pretreated cells. Two and four h after SHT, both transcriptional and translational rates were significantly higher in HSP70-overexpressing cells compared to non-pretreated cells. However, immediately after SHT, transcription rates were similarly depressed in non-pretreated and pretreated cells, showing that increased levels of HSP70 did not protect RNA polymerase I activity during SHT. Thus, the HSP70-mediated acceleration of translational recovery is not preceded in time by an enhanced recovery of rRNA synthesis. Therefore, the HSP70-mediated early recovery of protein synthesis after heat stress is independent of rRNA synthesis.

We investigated whether the cardioprotection induced by heat stress (HS) pretreatment is associated with mitigation of phospholipid degradation during the ischemic and/or postischemic period. The hearts, isolated from control rats and from heat-pretreated rats (42°C for 15 min) either 30 min (HS0.5-h) or 24 h (HS24-h) earlier, were subjected to 45 min of no-flow ischemia, followed by 45 min of reperfusion. Unesterified arachidonic acid (AA) accumulation was taken as a measure for phospholipid degradation. Significantly improved postischemic ventricular functional recovery was only found in the HS24-h group. During ischemia, AA accumulated comparably in control and both HS groups. During reperfusion in control and HS0.5-h hearts, AA further accumulated (control hearts from 82 ± 33 to 109 ± 51 nmol/g dry wt, not significant; HS-0.5h hearts from 52 ± 22 to 120 ± 53 nmol/g dry wt; P < 0.05). In contrast, AA was lower at the end of the reperfusion phase in HS24-h hearts than at the end of the preceding ischemic period (74 ± 18 vs. 46 ± 23 nmol/g dry wt; P < 0.05). Thus accelerated reperfusion-induced degradation of phospholipids in control hearts is completely absent in HS24-h hearts. Furthermore, the lack of functional improvement in HS0.5-h hearts is also associated with a lack of beneficial effect on lipid homeostasis. Therefore, it is proposed that enhanced membrane stability during reperfusion is a key mediator in the heat-induced cardioprotection.

Improvement of post-ischemic cardiac function 24 h after heat stress has been attributed to the increased cardiac tissue content of the inducible heat stress protein hsp70. Previous studies indicated that hsp70 is already significantly upregulated a few hours after heat stress. To delineate the relationship between hsp70 tissue content and heat stress-induced cardioprotection in the early time frame after heat stress, if any, post-ischemic functional recovery of isolated, ejecting rat hearts and the actual cardiac hsp70 content were investigated 0.5, 3, 6 and 24 h after heat stress (42 degrees C for 15 min). Recovery (% of pre-ischemic value) of cardiac output, left ventricular developed pressure, and positive and negative left ventricular dP/dtmax was studied during reperfusion after 45 min of global ischemia. Anesthetized non heat-stressed rats served as controls. The recovery of all hemodynamic variables was significantly worse in hearts isolated 30 min after heat stress than in control hearts. When the time interval between heat treatment and the ischemic episode was prolonged, a gradual improvement of post-ischemic functional recovery was observed. Only 24 h after heat treatment functional recovery was significantly better in the heat-stressed than in the control group. Compared to control hearts (0.27+/-0.10 mg/g total protein) cardiac hsp70 content was already significantly increased 0.5 h after heat stress (0.51+/-0.03 mg/g total protein). The cardiac hsp70 content further increased to 0. 70+/-0.11, 0.89+/-0.35 and 1.01+/-0.25 mg/g total protein, at 3, 6 and 24 h after heat stress, respectively. The present findings clearly show that heat stress is associated with a fast rise in the myocardial hsp70 content which, however, is not uniquely correlated with improved ischemia tolerance of the treated hearts, which only occurs 24 h later.

Heat stress pretreatment of the heart is known to protect this organ against an ischemic/reperfusion insult 24 h later. Degradation of membrane phospholipids resulting in tissue accumulation of polyunsaturated fatty acids, such as arachidonic acid, is thought to play an important role in the multifactorial process of ischemia/reperfusion-induced damage.

To explore the effects of heat stress (HS) in aged hypertrophied and nonhypertrophied rat hearts, postischemic recovery was investigated 15 mo after aortic constriction (AoB) or sham operation (Sham). Twenty-four hours after HS (42 degrees C; 15 min) or control treatment (normothermia), global ischemia was induced for 20 min in isolated AoB hearts and for 20 or 30 min in Sham hearts. After HS, postischemic recovery after 20-min ischemia in AoB hearts and 30-min ischemia in Sham hearts, respectively, was significantly better than in corresponding controls. In AoB hearts, cardiac output (CO), left ventricular developed pressure (LVDP), and the positive maximal first derivative of left ventricular pressure (+dP/dtmax) recovered to 33 +/- 26 (means +/- SD), 87 +/- 5, and 72 +/- 12%, respectively, after HS and to 5 +/- 8, 22 +/- 39, and 17 +/- 29% of preischemic values, respectively, in controls. Postischemic arrhythmias were significantly reduced in HS hypertrophied hearts, but creatine kinase (CK) loss was not reduced. In Sham hearts subjected to 30 min ischemia, CO, LVDP, and +dP/dtmax recovered to 20 +/- 20, 75 +/- 8, and 59 +/- 15%, respectively, after HS and to 3 +/- 8, 21 +/- 32, and 16 +/- 32% of preischemic values, respectively, in controls. Duration of arrhythmias and CK loss were not reduced in the heated hearts. When Sham hearts were subjected to only 20-min ischemia, functional recovery was not different in HS and control hearts, indicating that HS pretreatment extends the ischemic interval before irreversible injury occurs in the heart. In all HS Sham hearts, the myocardial 72-kDa HS protein (HSP 70) content was significantly increased. However, in HS AoB hearts, HSP 70 levels were not significantly different from the values in the control hearts. These results indicate that HS pretreatment induces cardioprotection in aged hypertrophied and nonhypertrophied rat hearts, which, however, cannot be unequivocally related to increased HSP 70 tissue contents.

The aim of the present study was to investigate whether the pre-ischemic and post-ischemic hemodynamic function of the heat-shocked rat heart is affected by changes in afterload and extracellular calcium concentrations ( [Ca 2 + ] e ). Experiments were performed on isolated, ejecting Lewis rat hearts 24 h after in vivo heat shock (Lew HS ) or anesthesia alone (Lew C ). In vitro hearts were subjected to 60 min normoxic perfusion, 45 min global ischemia, and 60 min of reperfusion. Pre-ischemic and post-ischemic left ventricular performance was evaluated at [Ca 2 + ] e ranging between 0.65 and 3.0 m m at afterloads of 8.0 kPa and 16.0 kPa. At 8.0 kPa, pre-ischemic function was comparable in Lew HS and Lew C at [Ca 2 + ] e equal to or above 2.25 m m . At lower [Ca 2 + ] e , i.e., 0.65 and 1.25 m m , cardiac output (CO) was significantly lower in Lew HS than in Lew C hearts. At 16.0 kPa, significantly lower CO values were found in Lew HS than Lew C hearts at all [Ca 2 + ] e levels. During post-ischemic reperfusion under basal conditions (8.0 kPa; [Ca 2 + ] e =2.25 m m ) a significantly better recovery was observed in Lew HS than Lew C hearts, persisting at [Ca 2 + ] e equal to 1.25 m m . However, either by lowering [Ca 2 + ] e to 0.65 m m or increasing afterload to 16.0 kPa (at all [Ca 2 + ] e ), heat shock-associated improvement of post-ischemic performance disappeared. In conclusion, pre-ischemic left ventricular performance of the isolated heat-shocked heart is depressed when it performs at low [Ca 2 + ] e or against a relatively high afterload. The heat shock-mediated improvement of post-ischemic function is only present at relatively low afterload levels in combination with normal extracellular calcium concentrations.

Background— Normal coronary blood flow is principally determined by a backward-traveling decompression (suction) wave in diastole. Dyssynchronous chronic heart failure may attenuate suction, because regional relaxation and contraction overlap in timing. We hypothesized that biventricular pacing, by restoring left ventricular (LV) synchronization and improving LV relaxation, might increase this suction wave, improving coronary flow. Method and Results— Ten patients with chronic heart failure (9 males; age 65±12; ejection fraction 26±7%) with left bundle-branch block (LBBB; QRS duration 174±18 ms) were atriobiventricularly paced at 100 bpm. LV pressure was measured and wave intensity calculated from invasive coronary flow velocity and pressure, with native conduction (LBBB) and during biventricular pacing at atrioventricular (AV) delays of 40 ms, 120 ms, and separately preidentified hemodynamically optimal AV delay. In comparison with LBBB, biventricular pacing at separately preidentified hemodynamically optimal AV delay (BiV-Opt) enhanced coronary flow velocity time integral by 15% (7%–25%) ( P =0.007), LV dP/dt max by 15% (10%–21%) ( P =0.005), and neg dP/dt max by 17% (9%–22%) ( P =0.005). The cumulative intensity of the diastolic backward decompression (suction) wave increased by 26% (18%–54%) ( P =0.005). The majority of the increase in coronary flow velocity time integral occurred in diastole (69% [41%–84% ]; P =0.047). The systolic compression waves also increased: forward by 36% (6%–49%) ( P =0.022) and backward by 38% (20%–55%) ( P =0.022). Biventricular pacing at AV delays of 120 ms generated a smaller LV dP/dt max (by 12% [5%–23% ], P =0.013) and neg dP/dt max (by 15% [8%–40% ]; P =0.009) increase than BiV-Opt, against LBBB as reference; BiV-Opt and biventricular pacing at AV delays of 120 ms were not significantly different in coronary flow velocity time integral or waves. Biventricular pacing at AV delays of 40 ms was no different from LBBB. Conclusions— When biventricular pacing improves LV contraction and relaxation, it increases coronary blood flow velocity, predominantly by increasing the dominant diastolic backward decompression (suction) wave.