Aims: Focus of pacemaker therapy is shifting from right ventricular (RV) apex pacing (RVAP) and biventricular pacing (BiVP) to conduction system pacing. Direct comparison between the different pacing modalities and their consequences to cardiac pump function is difficult, due to the practical implications and confounding variables. Computational modelling and simulation provide the opportunity to compare electrical, mechanical, and haemodynamic consequences in the same virtual heart.Methods and results: Using the same single cardiac geometry, electrical activation maps following the different pacing strategies were calculated using an Eikonal model on a three-dimensional geometry, which were then used as input for a lumped mechanical and haemodynamic model (CircAdapt). We then compared simulated strain, regional myocardial work, and haemodynamic function for each pacing strategy. Selective His-bundle pacing (HBP) best replicated physiological electrical activation and led to the most homogeneous mechanical behaviour. Selective left bundle branch (LBB) pacing led to good left ventricular (LV) function but significantly increased RV load. RV activation times were reduced in non-selective LBB pacing (nsLBBP), reducing RV load but increasing heterogeneity in LV contraction. LV septal pacing led to a slower LV and more heterogeneous LV activation than nsLBBP, while RV activation was similar. BiVP led to a synchronous LV–RV, but resulted in a heterogeneous contraction. RVAP led to the slowest and most heterogeneous contraction. Haemodynamic differences were small compared to differences in local wall behaviour.Conclusion: Using a computational modelling framework, we investigated the mechanical and haemodynamic outcome of the prevailing pacing strategies in hearts with normal electrical and mechanical function. For this class of patients, nsLBBP was the best compromise between LV and RV function if HBP is not possible.

Background: Septal strain patterns measured by echocardiography reflect the severity of left bundle branch block (LBBB)-induced left ventricular (LV) dysfunction. We investigated whether these LBBB strain stages predicted the response to cardiac resynchronization therapy in an observational study and developed a sheep model of LBBB-induced cardiomyopathy. Methods: The clinical study enrolled cardiac resynchronization therapy patients who underwent echocardiographic examination with speckle-tracking strain analysis before cardiac resynchronization therapy implant. In an experimental sheep model with pacing-induced dyssynchrony, LV remodeling and strain were assessed at baseline, at 8 and 16 weeks. Septal strain curves were classified into 5 patterns (LBBB-0 to LBBB-4). Results: The clinical study involved 250 patients (age 65 [58; 72] years; 79% men; 89% LBBB) with a median LV ejection fraction of 25 [21; 30]%. Across the stages, cardiac resynchronization therapy resulted in a gradual volumetric response, ranging from no response in LBBB-0 patients (ΔLV end-systolic volume 0 [−12; 15]%) to super-response in LBBB-4 patients (ΔLV end-systolic volume −44 [−64; −18]%) ( P< 0.001). LBBB-0 patients had a less favorable long-term outcome compared with those in stage LBBB≥1 (log-rank P =0.003). In 13 sheep, acute right ventricular pacing resulted in LBBB-1 (23%) and LBBB-2 (77%) patterns. Over the course of 8−16 weeks, continued pacing resulted in progressive LBBB-induced dysfunction, coincident with a transition to advanced strain patterns (92% LBBB-2 and 8% LBBB-3 at week 8; 75% LBBB-3 and 25% LBBB-4 at week 16) ( P =0.023). Conclusions: The strain-based LBBB classification reflects a pathophysiological continuum of LBBB-induced remodeling over time and is associated with the extent of reverse remodeling in observational cardiac resynchronization therapy-eligible patients.

In the latest version of the European Society of Cardiology (ESC) guidelines on cardiac pacing and cardiac resynchronization therapy (CRT), a new and stricter definition of left bundle branch block (LBBB) was introduced (ESC-2021).¹ In the current work, we investigate the impact of applying the ESC-2021 vs. the ESC-2013 definitions of LBBB on the relation between LBBB at baseline and (i) LV reverse remodelling after CRT and (ii) baseline mechanical dyssynchrony, both assessed by echocardiography.²

Background: We investigated the impact of baseline left atrial (LA) strain data and estimated left atrial pressure (LAP) by applying the 2016 American Society of Echocardiography and the European Association of Cardiovascular Imaging (ASE/EACVI) guidelines on cardiac resynchronization therapy (CRT) outcomes. Methods: Datasets of 219 CRT patients were retrospectively analysed. All patients had full echocardiographic diastolic function assessment before CRT and were classified based on the guideline algorithm into normal LAP (nLAP = 40%), elevated LAP (eLAP = 49%) and indeterminate LAP (iLAP = 11%). All relevant baseline characteristics were analysed. CRT-induced left ventricular (LV) reverse remodeling was measured as the relative change of LV end-systolic volume (LVESV) at 12 ± 6 months after CRT compared to baseline. Patients were followed up for all-cause mortality for a mean of 4.8 years [interquartile range (IQR): 2.7–6.0 years]. Results: At follow-up, CRT resulted in more pronounced reduction of LVESV in patients with nLAP than in patients with eLAP. In univariate analysis, nLAP was associated with LV reverse remodelling (p < 0.001), as well as long-term survival after CRT (p < 0.01). However, multivariable analysis showed that only the association between nLAP and LV reverse remodelling after CRT is independent (p < 0.01). Adding LA strain analysis to the guideline algorithm improved the feasibility of LAP estimation without affecting the association between estimated LAP and CRT outcome. Conclusion: Normal LAP before CRT, estimated using the 2016 ASE/EACVI guideline algorithm, is associated with LV reverse remodelling and long-term survival after CRT. Albeit non-independent, it can serve as a non-invasive imaging-based predictor of effective therapy. Furthermore, the inclusion of LA reservoir strain in the guideline algorithm can enhance the feasibility of LAP estimation without affecting the association between LAP and CRT outcome.

Aims: Previous studies have not examined the role of non-electrical myocardial disease substrates in determining the optimal atrio-ventricular delay (AVD) settings. We conducted virtual patient simulations to evaluate whether myocardial disease substrates influence the acute response to AVD optimization at rest and during exercise. Methods and results: The CircAdapt cardiovascular model was used to simulate various left ventricular (LV) remodelling found in cardiac resynchronization therapy candidates. We simulated electrical dyssynchrony, LV dilatation with preserved and reduced contractility, and increased LV passive stiffness. We simulated cardiac resynchronization following biventricular (BiVP) and non-selective LBB pacing (nsLBBP). The paced-AVD ranged from 220 to 40 ms. Cardiac output and heart rate were increased to simulate different levels of exercise. The optimal AVD was the one leading to the highest stroke volume (SV) and the lowest mean left atrial pressure (mLAP). At rest, in simulations with healthy myocardium the gain in SV by AVD optimization was larger compared to those with reduced contractility and stiff myocardium. However, mLAP was comparably decreased by AVD optimization in both healthy and diseased myocardium. During exercise, the optimal AVD shifted to shorter values, and mLAP was more sensitive to AVD, particularly in the presence of hypo-contractile and stiff myocardium. Conclusion: Simulations show that hypocontractility and stiffness reduce the effect of AVD optimization on SV but enhance its benefit in lowering mLAP. Notably, virtual patients with stiff ventricles experience greater benefits from AVD optimization during exercise compared to resting conditions. Furthermore, nsLBBP provides more favourable improvements in mLAP than BiVP.

Aims: Both left ventricular (LV) mechanical dyssynchrony and filling pressure have been shown to be associated with outcome in heart failure patient treated with cardiac resynchronisation therapy (CRT). To investigate the mechanistic link between mechanical dyssynchrony and filling pressure and to assess their combined prognostic value in CRT candidates. Methods and results: Left atrial pressure (LAP) estimation and quantification of mechanical dyssynchrony were retrospectively performed in 219 CRT patients using echocardiography. LAP was elevated (eLAP) in 49% of the population, normal (nLAP) in 40%, and indeterminate in 11%. CRT response was defined as per cent-decrease in LV end-systolic volume after 12 ± 6 months CRT. Clinical endpoint was all-cause mortality during 4.8 years (interquartile range: 2.7–6.0 years). To investigate the mechanistic link between mechanical dyssynchrony and filling pressure, the CircAdapt computer model was used to simulate cardiac mechanics and haemodynamics in virtual hearts with left bundle branch block (LBBB) and various causes of increased filling pressure. Patients with nLAP had more significant mechanical dyssynchrony than those with eLAP. The combined assessment of both parameters before CRT was significantly associated with reverse LV remodelling and post-CRT survival. Simulations revealed that mechanical dyssynchrony is attenuated by increased LV operational chamber stiffness, regardless of whether it is caused by passive or active factors, explaining the link between mechanical dyssynchrony and filling pressure. Conclusion: Our combined clinical-computational data demonstrate that in patients with LBBB, the presence of mechanical dyssynchrony indicates relatively normal LV compliance and low filling pressure, which may explain their strong association with positive outcomes after CRT.