Parameter subset reduction for imaging-based digital twin generation of patients with left ventricular mechanical discoordination.

BACKGROUND: Integration of a patient's non-invasive imaging data in a digital twin (DT) of the heart can provide valuable insight into the myocardial disease substrates underlying left ventricular (LV) mechanical discoordination. However, when generating a DT, model parameters should be identifiable to obtain robust parameter estimations. In this study, we used the CircAdapt model of the human heart and circulation to find a subset of parameters which were identifiable from LV cavity volume and regional strain measurements of patients with different substrates of left bundle branch block (LBBB) and myocardial infarction (MI). To this end, we included seven patients with heart failure with reduced ejection fraction (HFrEF) and LBBB (study ID: 2018-0863, registration date: 2019-10-07), of which four were non-ischemic (LBBB-only) and three had previous MI (LBBB-MI), and six narrow QRS patients with MI (MI-only) (study ID: NL45241.041.13, registration date: 2013-11-12). Morris screening method (MSM) was applied first to find parameters which were important for LV volume, regional strain, and strain rate indices. Second, this parameter subset was iteratively reduced based on parameter identifiability and reproducibility. Parameter identifiability was based on the diaphony calculated from quasi-Monte Carlo simulations and reproducibility was based on the intraclass correlation coefficient ( ICC ) obtained from repeated parameter estimation using dynamic multi-swarm particle swarm optimization. Goodness-of-fit was defined as the mean squared error ( χ 2 ) of LV myocardial strain, strain rate, and cavity volume. RESULTS: A subset of 270 parameters remained after MSM which produced high-quality DTs of all patients ( χ 2 < 1.6), but minimum parameter reproducibility was poor ( ICC min = 0.01). Iterative reduction yielded a reproducible ( ICC min = 0.83) subset of 75 parameters, including cardiac output, global LV activation duration, regional mechanical activation delay, and regional LV myocardial constitutive properties. This reduced subset produced patient-resembling DTs ( χ 2 < 2.2), while septal-to-lateral wall workload imbalance was higher for the LBBB-only DTs than for the MI-only DTs (p < 0.05). CONCLUSIONS: By applying sensitivity and identifiability analysis, we successfully determined a parameter subset of the CircAdapt model which can be used to generate imaging-based DTs of patients with LV mechanical discoordination. Parameters were reproducibly estimated using particle swarm optimization, and derived LV myocardial work distribution was representative for the patient's underlying disease substrate. This DT technology enables patient-specific substrate characterization and can potentially be used to support clinical decision making.

Impact of Estimated Left Atrial Pressure on Cardiac Resynchronization Therapy Outcome.

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.

Comparison of novel ventricular pacing strategies using an electro-mechanical simulation platform.

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.

Clinical and Experimental Evidence for a Strain-Based Classification of Left Bundle Branch Block-Induced Cardiac Remodeling.

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.

Acute redistribution of regional left ventricular work by cardiac resynchronization therapy determines long-term remodelling.

AIMS: Investigating the acute impact of cardiac resynchronization therapy (CRT) on regional myocardial work distribution in the left ventricle (LV) and to which extent it is related to long-term reverse remodelling. METHODS AND RESULTS: One hundred and thirty heart failure patients, referred for CRT implantation, were recruited in our prospective multicentre study. Regional myocardial work was calculated from non-invasive segmental stress-strain loop area before and immediately after CRT. The magnitude of volumetric reverse remodelling was determined from the change in LV end-systolic volume, 11 ± 2 months after implantation. CRT caused acute redistribution of myocardial work across the LV, with an increase in septal work, and decrease in LV lateral wall work (all P < 0.05). Amongst all LV walls, the acute change in work in the septum and lateral wall of the four-chamber view correlated best and significantly with volumetric reverse remodelling (r = 0.62, P < 0.0001), with largest change seen in patients with most volumetric reverse remodelling. In multivariate linear regression analysis, including conventional parameters, such as pre-implant QRS morphology and duration, LV ejection fraction, ischaemic origin of cardiomyopathy, and the redistribution of work across the septal and lateral walls, the latter appeared as the strongest determinant of volumetric reverse remodelling after CRT (model R2 = 0.414, P < 0.0001). CONCLUSION: The acute redistribution of regional myocardial work between the septal and lateral wall of the LV is an important determinant of reverse remodelling after CRT implantation. Our data suggest that the treatment of the loading imbalance should, therefore, be the main aim of CRT.

Mechanism of Abnormal Septal Motion in Left Bundle Branch Block: Role of Left Ventricular Wall Interactions and Myocardial Scar.

OBJECTIVES: This study sought to investigate how regional left ventricular (LV) function modifies septal motion in left bundle branch block (LBBB). BACKGROUND: In LBBB, the interventricular septum often has marked pre-ejection shortening, followed by immediate relengthening (rebound stretch). This motion, often referred to as septal flash, is associated with positive response to cardiac resynchronization therapy (CRT). METHODS: In 10 anesthetized dogs, we induced LBBB by radiofrequency ablation and occluded the circumflex (CX) (n = 10) and left anterior descending (LAD) (n = 6) coronary arteries, respectively. Myocardial dimensions were measured by sonomicrometry and myocardial work by pressure-segment length analysis. In 40 heart failure patients with LBBB, including 20 with post-infarct scar and 20 with nonischemic cardiomyopathy, myocardial strain was measured by speckle-tracking echocardiography and myocardial work by pressure-strain analysis. Scar was assessed by cardiac magnetic resonance imaging with late gadolinium enhancement. RESULTS: During LBBB, each animal showed typical septal flash with pre-ejection shortening and rebound stretch, followed by reduced septal systolic shortening (p < 0.01). CX occlusion caused LV lateral wall dysfunction and abolished septal flash due to loss of rebound stretch (p < 0.0001). Furthermore, CX occlusion restored septal systolic shortening to a similar level as before induction of LBBB and substantially improved septal work (p < 0.001). LAD occlusion, however, accentuated septal flash by increasing rebound stretch (p < 0.05). Consistent with the experimental findings, septal flash was absent in patients with LV lateral wall scar due to lack of rebound stretch (p < 0.001), and septal systolic shortening and septal work far exceeded values in nonischemic cardiomyopathy (p < 0.0001). Septal flash was present in most patients with anteroseptal scar. CONCLUSIONS: LV lateral wall dysfunction and scar abolished septal flash and markedly improved septal function in LBBB. Therefore, function and scar in the LV lateral wall should be taken into account when septal motion is used to evaluate dyssynchrony.

Sex-specific difference in outcome after cardiac resynchronization therapy.

AIMS: Observation of better outcome in women after cardiac resynchronization therapy (CRT) has led to controversies about a potential sex-specific response. In this study, we investigated to which extent this sex-specific difference in CRT outcome could be explained by differences in baseline characteristics between both sexes. METHODS AND RESULTS: We retrospectively analysed data from a multicentre registry of 1058 patients who received CRT. Patients were examined by echocardiography before and 12 ± 6 months after implantation. Response was defined as ≥15% reduction of left ventricular end-systolic volume at follow-up. Patient's characteristics at baseline, including New York Heart Association class, ejection fraction, QRS width and morphology, ischaemic aetiology of cardiomyopathy (ICM), number of scarred segments, age at implantation, atrial fibrillation, and mechanical dyssynchrony (Dyss) were analysed. Patients were followed for a median duration of 59 months. Primary end point was all-cause mortality. Women (24% of the population) had less ICM (23% vs. 49%, P < 0.0001), less scarred segments (0.4 ± 1.3 vs. 1.0 ± 2.1, P < 0.0001), more left bundle branch block (LBBB; 87% vs. 80%, P = 0.01), and more Dyss at baseline (78% vs. 57%, P < 0.0001). Without matching baseline differences, women showed better survival (log rank P < 0.0001). After matching, survival was similar (log rank P = 0.58). In multivariable analysis, female sex was no independent predictor of neither volumetric response (P = 0.06) nor survival (P = 0.31). CONCLUSION: Our data suggest that the repeatedly observed better outcome in women after CRT is mainly due to the lower rate ICM and smaller scars. When comparing patients with similar baseline characteristics, the response of both sexes to CRT is similar.

Papillary muscles contribute significantly more to left ventricular work in dilated hearts.

Aims: Left ventricular (LV) dilatation results in increased sphericity and affects position and orientation of papillary muscles (PMs), which may influence their performed work. The aim of this study was to assess the contribution of PM to LV function and its changes with dilatation. Methods and results: Fifteen sheep were investigated. Ten animals were subjected to 8 weeks of rapid (180 bpm) pacing, inducing LV dilatation. Five animals served as controls. High-resolution gated computed tomography was performed to assess LV volumes, left ventricular ejection fraction (LVEF), global longitudinal strain (GLS), sphericity index, and PM angle, width and fractional shortening. 18F-fluorodeoxyglucose positron emission tomography (PET) was used to measure glucose metabolism as surrogate of regional myocardial work. Spatial resolution of PET images was maximized by electrocardiogram- and respiratory-gating. 18F-fluorodeoxyglucose uptake was measured in PM and compared with remaining left ventricular myocardium (MYO) to obtain a PM/MYO ratio. Animals with dilated heart had a more spherical left ventricle, with reduced LVEF (P < 0.0001) and GLS (P < 0.0001). In dilated hearts, PET analysis revealed a higher contribution of both PM to LV myocardial work (P < 0.0001); and PM angle towards LV wall correlated with PM work, together with PM width and the LV sphericity index. Sphericity index and posterior PM angle were strongest determinants of posterior PM/MYO ratio (R2 = 0.754; P < 0.0001), while anterior PM/MYO was mostly determined by sphericity index and the PM width (R2 = 0.805; P < 0.0001). Conclusion: In dilated hearts, PM contribute relatively more to LV myocardial work. We hypothesize that this is caused by the more cross-sectional orientation of the subvalvular apparatus, which leads to a higher stress on the PM compared with the spherical LV walls. The reduced cross-sectional area of the PM may further explain their increased stress.

Assessment of mechanical dyssynchrony can improve the prognostic value of guideline-based patient selection for cardiac resynchronization therapy.

Aim: To determine if incorporation of assessment of mechanical dyssynchrony could improve the prognostic value of patient selection based on current guidelines. Methods and results: Echocardiography was performed in 1060 patients before and 12 ± 6 months after cardiac resynchronization therapy (CRT) implantation. Mechanical dyssynchrony, defined as the presence of apical rocking or septal flash was visually assessed at the baseline examination. Response was defined as ≥15% reduction in left ventricular end-systolic volume at follow-up. Patients were followed for a median of 59 months (interquartile range 37-86 months) for the occurrence of death of any cause. Applying the latest European guidelines retrospectively, 63.4% of the patients had been implanted with a Class I recommendation, 18.2% with Class IIa, 9.4% with Class IIb, and in 9% no clear therapy recommendation was present. Response rates were 65% in Class I, 50% in IIa, 38% in IIb patients, and 40% in patients without a clear guideline-based recommendation. Assessment of mechanical dyssynchrony improved response rates to 77% in Class I, 75% in IIa, 62% in IIb, and 69% in patients without a guideline-based recommendation. Non-significant difference in survival among guideline recommendation classes was found (Log-rank P = 0.2). Presence of mechanical dyssynchrony predicted long-term outcome better than guideline Classes I, IIa, IIb (Log-rank P < 0.0001, 0.006, 0.004, respectively) and in patients with no guideline recommendation (P = 0.02). Comparable results were observed using the latest American Guidelines. Conclusion: Our data suggest that current guideline criteria for CRT candidate selection could be improved by incorporating assessment of mechanical asynchrony.