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Background: Patients who improve following cardiac resynchronization therapy (CRT) have left ventricular (LV) remodeling and improved cardiac output (CO). Effects on the systemic circulation are unknown. Objective: To explore the effects of CRT on aortic and pulmonary blood flow and systemic afterload. Methods: At CRT implant patients underwent a noninvasive assessment of central hemodynamics, including wave intensity analysis (n = 28). This was repeated at 6 months after CRT. A subsample (n = 11) underwent an invasive electrophysiological and hemodynamic assessment immediately following CRT. CRT response was defined as reduction in LV end-systolic volume ≥15% at 6 months. Results: In CRT responders (75% of those in the noninvasive arm), there was a significant increase in CO (from 3 ± 2 L/min to 4 ± 2 L/min, P = .002) and LV dP/dtmax (from 846 ± 162 mm Hg/s to 958 ± 194 mm Hg/s, P = .001), immediately after CRT in those in the invasive arm. They demonstrated a significant increase in aortic forward compression wave (FCW) both acutely and at follow-up. The relative change in LV dP/dtmax strongly correlated with changes in the aortic FCW (Rs 0.733, P = .025). CRT responders displayed a significant reduction in afterload, and a decrease in systemic vascular resistance and pulse wave velocity acutely; there was a significant decrease in acute pulmonary afterload measured by the pulmonary FCW and forward expansion wave. Conclusion: Improved cardiac function following CRT is attributable to a combination of changes in the cardiac and cardiovascular system. The relative importance of these 2 mechanisms may then be important for optimizing CRT.

Abstract Recent dose reduction techniques have made retrospective computed tomography (CT) scans more applicable and extracting myocardial function from cardiac computed tomography (CCT) images feasible. However, hyperparameters of generic image intensity-based registration techniques, which are used for tracking motion, have not been systematically optimised for this modality. There is limited work on their validation for measuring regional strains from retrospective gated CCT images and open-source software for motion analysis is not widely available. We calculated strain using our open-source platform by applying an image registration warping field to a triangulated mesh of the left ventricular endocardium. We optimised hyperparameters of two registration methods to track the wall motion. Both methods required a single semi-automated segmentation of the left ventricle cavity at end-diastolic phase. The motion was characterised by the circumferential and longitudinal strains, as well as local area change throughout the cardiac cycle from a dataset of 24 patients. The derived motion was validated against manually annotated anatomical landmarks and the calculation of strains were verified using idealised problems. Optimising hyperparameters of registration methods allowed tracking of anatomical measurements with a mean error of 6.63% across frames, landmarks, and patients, comparable to an intra-observer error of 7.98%. Both registration methods differentiated between normal and dyssynchronous contraction patterns based on circumferential strain ( $$p_1=0.0065$$ p 1 = 0.0065 , $$p_2=0.0011$$ p 2 = 0.0011 ). To test whether a typical 10 temporal frames sampling of retrospective gated CCT datasets affects measuring cardiac mechanics, we compared motion tracking results from 10 and 20 frames datasets and found a maximum error of $$8.51\pm 0.8\%$$ 8.51 ± 0.8 % . Our findings show that intensity-based registration techniques with optimal hyperparameters are able to accurately measure regional strains from CCT in a very short amount of time. Furthermore, sufficient sensitivity can be achieved to identify heart failure patients and left ventricle mechanics can be quantified with 10 reconstructed temporal frames. Our open-source platform will support increased use of CCT for quantifying cardiac mechanics.

Background: Cardiac resynchronization therapy (CRT) produces acute changes in electric resynchronization that can be measured noninvasively with electrocardiographic body surface mapping (ECGi). The relation between baseline acute electrophysiology metrics and their manipulation with CRT and reverse remodeling is unclear. Objective: To test (ECGi) derived parameters of electrical activation as predictors of volumetric response to CRT. Methods: ECGi was performed in 21 patients directly following CRT implant. Activation parameters (left ventricular total activation time [LVtat], global biventricular total activation time [VVtat], global left/right ventricular electrical synchrony [VVsync], and global left ventricular dispersion of activation times [LVdisp]) were measured at baseline and following echocardiographically optimized CRT. Remodeling response (>15% reduction left ventricular end-systolic volume) was assessed 6 months post CRT. Results: Patients were aged 68.9 ± 12.1 years, 81% were male, and 57% were ischemic. Baseline measures of dyssynchrony were more pronounced in left bundle branch block (LBBB) vs non-LBBB. ECGi demonstrated a trend of greater interventricular dyssynchrony between responders and nonresponders that did not reach statistical significance (VVsync: -45.7 ± 22.4 ms vs -25.1 ± 29.3 ms, P = .227). Remaining activation parameters were similar between responders and nonresponders (VVtat 101 ± 22.0 ms vs 98.9 ± 23.4 ms, P = .838; LVtat 86.4 ± 17.1 ms vs 85.1 ± 27.7 ms, P = .904; LVdisp 28.2 ± 6.3 ms vs 27.0 ± 8.7 ms, P = .726). In volumetric responders activation parameters were significantly improved with CRT compared to nonresponders: VV sync (-45.67 ± 22.41 ms vs 2.33±18.87 ms, P = .001), VVtat (101 ± 22.04 ms vs 71 ± 14.01 ms, P = .002), LVtat (86.44 ± 17.15 ms vs 67.67 ± 11.31 ms, P = .006), and LVdisp (28.22 ± 6.3 ms vs 21.56 ± 4.45 ms, P = .008). Conclusion: Baseline ECGi activation times did not predict CRT volumetric response. Volumetric responders exhibited significant improvements in ECGi-derived metrics with CRT. ECGi does not select CRT candidates but may be a useful adjunct to guide left ventricle lead implants and to perform postimplant CRT optimization.

Objectives: The aim of this study is to develop a scar detection method for routine computed tomography angiography (CTA) imaging using deep convolutional neural networks (CNN), which relies solely on anatomical information as input and is compatible with existing clinical workflows.Background: Identifying cardiac patients with scar tissue is important for assisting diagnosis and guiding interventions. Late gadolinium enhancement (LGE) magnetic resonance imaging (MRI) is the gold standard for scar imaging; however, there are common instances where it is contraindicated. CTA is an alternative imaging modality that has fewer contraindications and is faster than Cardiovascular magnetic resonance imaging but is unable to reliably image scar.Methods: A dataset of LGE MRI (200 patients, 83 with scar) was used to train and validate a CNN to detect ischemic scar slices using segmentation masks as input to the network. MRIs were segmented to produce 3D left ventricle meshes, which were sampled at points along the short axis to extract anatomical masks, with scar labels from LGE as ground truth. The trained CNN was tested with an independent CTA dataset (25 patients, with ground truth established with paired LGE MRI). Automated segmentation was performed to provide the same input format of anatomical masks for the network. The CNN was compared against manual reading of the CTA dataset by 3 experts.Results: Note that 84.7% cross-validated accuracy (AUC: 0.896) for detecting scar slices in the left ventricle on the MRI data was achieved. The trained network was tested against the CTA-derived data, with no further training, where it achieved an 88.3% accuracy (AUC: 0.901). The automated pipeline outperformed the manual reading by clinicians.Conclusion: Automatic ischemic scar detection can be performed from a routine cardiac CTA, without any scar-specific imaging or contrast agents. This requires only a single acquisition in the cardiac cycle. In a clinical setting, with near zero additional cost, scar presence could be detected to triage images, reduce reading times, and guide clinical decision-making.

Background: Pre-procedural assessment of patients undergoing cardiac resynchronization therapy (CRT) is heterogenous and patients implanted with unfavorable characteristics may account for non-response. A dedicated CRT pre-assessment clinic (CRT PAC) was developed to standardize the review process and undertake structured pre-procedural evaluation. The aim of this analysis was to determine the effectiveness on patient selection and outcomes. Methods: A prospective database of consecutive patients attending the CRT PAC between 2013 and 2018 was analyzed. Pre-operative assessment included cardiac magnetic resonance (CMR) and cardiopulmonary exercise testing (CPET). Patients were considered CRT responders based on improvement in clinical composite score (CCS) and/or reduction in left ventricular end-systolic volume (LVESV) ≥ 15% at 6-months follow-up. Results: Of 252 patients reviewed in the CRT PAC during the analysis period, 192 fulfilled consensus guidelines for implantation. Of the patients receiving CRT, 82% showed improvement in their CCS and 57% had a reduction in LVESV ≥ 15%. The presence of subendocardial scar on CMR and a peak VO2 ≤ 12 ml/kg/min on CPET predicted CRT non-response. Two patients were unsuitable for CRT as they had end-stage heart failure and died during follow-up. The majority of patients initially deemed unsuitable for CRT did not suffer from unexpected hospitalization for decompensated heart failure or died from cardiovascular disease; only 8 patients (13%) received CRT devices during follow-up because of symptomatic left ventricular systolic impairment. Conclusion: A dedicated CRT PAC is able to appropriately select patients for CRT. Pre-procedural investigation/imaging can identify patients unlikely to respond to, or may not yet be suitable for CRT.

Abstract Despite medical advancements, the prognosis of patients with heart failure remains poor. While echocardiography and cardiac magnetic resonance imaging remain at the forefront of diagnosing and monitoring patients with heart failure, cardiac computed tomography (CT) has largely been considered to have a limited role. With the advancements in scanner design, technology, and computer processing power, cardiac CT is now emerging as a valuable adjunct to clinicians managing patients with heart failure. In the current manuscript, we review the current applications of cardiac CT to patients with heart failure and also the emerging areas of research where its clinical utility is likely to extend into the realm of treatment, procedural planning, and advanced heart failure therapy implementation.

Abstract We shall discuss a patient who underwent a tricuspid valve‐in‐valve implantation for a failing bioprosthetic valve replacement. The procedure was complicated by detachment of the valve deployment apparatus which was removed in its entirety, using percutaneous extraction techniques. We believe this was the first ever case to report such a complication.

Abstract Aim Quadripolar lead technology and multi‐point pacing (MPP) are important clinical adjuncts in cardiac resynchronization therapy (CRT) pacing aimed at reducing the rate of non‐response to therapy. Mixed results have been achieved using MPP and it is critical to identify which patients require this approach and how to configure their MPP stimulation, in order to achieve optimal electrical resynchronization. Methods & Results We sought to investigate whether electrocardiographic imaging (ECGi), using the CARDIOINSIGHT™ inverse ECG mapping system, could identify alterations in electrical resynchronization during different methods of device optimization. In no patient did a single form of programming optimization provide the best electrical response. The effects of utilizing MPP were idiosyncratic and highly patient specific. ECGi activation maps were clearly able to discern changes in bulk LV activation during differing MPP programming. In two of the five subjects, MPP resulted in more rapid activation of the left ventricle compared to standard CRT; however, in the remaining three patients, the use of MPP did not appear to acutely improve electrical resynchronization. Crucially, this cohort showed evidence of extensive LV scarring which was well visualized using both CMR and ECGi voltage mapping. Conclusions Our work suggests a potential role for ECGi in the optimization of non‐responders to CRT, as it allows the fusion of activation maps and scar analysis above and beyond interrogation of the 12 lead ECG.

Background: The new category of heart failure (HF), Heart Failure with mid range Ejection Fraction (HFmrEF) has recently been proposed with recent publications reporting that HFmrEF represents a transitional phase. The aim of this study was to determine the prevalence and clinical characteristics of patients with HFmrEF and to establish what proportion of patients transitioned to other types of HF, and how this affected clinical outcomes. Methods and results: Patients were diagnosed with HF according to the 2016 ESC guidelines. Clinical outcomes and variables were recorded for all consecutive in-patients referred to the heart failure service. In total, 677 patients with new HF were identified; 25.6% with HFpEF, 21% with HFmrEF and 53.5% with HFrEF. While clinical characteristics and prognostic factors of HFmrEF were intermediate between HFrEF and HFpEF, HFmrEF patients had the best outcome, with higher mortality in the HFrEF population (p 0.02) and higher HF rehospitalisation rates in the HFpEF population (p

Introduction Patient evaluation before cardiac resynchronisation therapy (CRT) remains heterogeneous across centres and it is suspected a proportion of patients with unfavourable characteristics proceed to implantation. We developed a unique CRT preassessment clinic (CRT PAC) to act as a final review for patients already considered for CRT. We hypothesised that this clinic would identify some patients unsuitable for CRT through updated investigations and review. The purpose of this analysis was to determine whether the CRT PAC led to savings for the National Health Service (NHS).Methods A decision tree model was made to evaluate two clinical pathways; (1) standard of care where all patients initially seen in an outpatient cardiology clinic proceeded directly to CRT and (2) management of patients in CRT PAC.Results 244 patients were reviewed in the CRT PAC; 184 patients were eligible to proceed directly for implantation and 48 patients did not meet consensus guidelines for CRT so were not implanted. Following CRT, 82.4% of patients had improvement in their clinical composite score and 57.7% had reduction in left ventricular end-systolic volume ≥15%. Using the decision tree model, by reviewing patients in the CRT PAC, the total savings for the NHS was £966 880. Taking into consideration the additional cost of the clinic and by applying this model structure throughout the NHS, the potential savings could be as much as £39 million.Conclusions CRT PAC appropriately selects patients and leads to substantial savings for the NHS. Adopting this clinic across the NHS has the potential to save £39 million.

Computational models of the heart are increasingly being used in the development of devices, patient diagnosis and therapy guidance. While software techniques have been developed for simulating single hearts, there remain significant challenges in simulating cohorts of virtual hearts from multiple patients. To facilitate the development of new simulation and model analysis techniques by groups without direct access to medical data, image analysis techniques and meshing tools, we have created the first publicly available virtual cohort of twenty-four four-chamber hearts. Our cohort was built from heart failure patients, age 67±14 years. We segmented four-chamber heart geometries from end-diastolic (ED) CT images and generated linear tetrahedral meshes with an average edge length of 1.1±0.2mm. Ventricular fibres were added in the ventricles with a rule-based method with an orientation of -60° and 80° at the epicardium and endocardium, respectively. We additionally refined the meshes to an average edge length of 0.39±0.10mm to show that all given meshes can be resampled to achieve an arbitrary desired resolution. We ran simulations for ventricular electrical activation and free mechanical contraction on all 1.1mm-resolution meshes to ensure that our meshes are suitable for electro-mechanical simulations. Simulations for electrical activation resulted in a total activation time of 149±16ms. Free mechanical contractions gave an average left ventricular (LV) and right ventricular (RV) ejection fraction (EF) of 35±1% and 30±2%, respectively, and a LV and RV stroke volume (SV) of 95±28mL and 65±11mL, respectively. By making the cohort publicly available, we hope to facilitate large cohort computational studies and to promote the development of cardiac computational electro-mechanics for clinical applications.

BackgroundRecent clinical, experimental and modeling studies link oscillations of ventricular repolarization in the low frequency (LF) (approx. 0.1 Hz) to arrhythmogenesis. Sympathetic provocation has been shown to enhance both LF oscillations of action potential duration (APD) and beat-to-beat variability (BVR) in humans. We hypothesized that beta-adrenergic blockade would reduce LF oscillations of APD and BVR of APD in humans and that the two processes might be linked.Methods and ResultsTwelve patients with normal ventricles were studied during routine electrophysiological procedures. Activation-recovery intervals (ARI) as a conventional surrogate for APD were recorded from 10 left and 10 right ventricular endocardial sites before and after acute beta-adrenergic adrenergic blockade. Cycle length was maintained constant with right ventricular pacing. Oscillatory behavior of ARI was quantified by spectral analysis and BVR as the short-term variability. Beta-adrenergic blockade reduced LF ARI oscillations (8.6 ± 4.5 ms2 vs. 5.5 ± 3.5 ms2, p = 0.027). A significant correlation was present between the initial control values and reduction seen following beta-adrenergic blockade in LF ARI (rs = 0.62, p = 0.037) such that when initial values are high the effect is greater. A similar relationship was also seen in the beat-to beat variability of ARI (rs = 0.74, p = 0.008). There was a significant correlation between the beta-adrenergic blockade induced reduction in LF power of ARI and the witnessed reduction of beat-to-beat variability of ARI (rs = 0.74, p = 0.01). These clinical results accord with recent computational modeling studies which provide mechanistic insight into the interactions of LF oscillations and beat-to-beat variability of APD at the cellular level.ConclusionBeta-adrenergic blockade reduces LF oscillatory behavior of APD (ARI) in humans in vivo. Our results support the importance of LF oscillations in modulating the response of BVR to beta-adrenergic blockers, suggesting that LF oscillations may play role in modulating beta-adrenergic mechanisms underlying BVR.

Study hypothesis. We sought to investigate the association between echocardiographic optimisation and ventricular activation time in cardiac resynchronisation therapy (CRT) patients, obtained through the use of electrocardiographic mapping (ECM). We hypothesised that echocardiographic optimisation of the pacing delay between the atrial and ventricular leads—atrioventricular delay (AVD)—and the delay between ventricular leads—interventricular pacing interval (VVD)—would correlate with reductions in ventricular activation time. Background. Optimisation of AVD and VVD may improve CRT patient outcome. Optimal delays are currently set based on echocardiographic indices; however, acute studies have found that reductions in bulk ventricular activation time correlate with improvements in acute haemodynamic performance. Materials and methods. Twenty-one patients with established CRT criteria were recruited. After implantation, patients underwent echo-guided optimisation of the AVD and VVD. During this procedure, the participants also underwent noninvasive ECM. ECM maps were constructed for each AVD and VVD. ECM maps were analysed offline. Total ventricular activation time (TVaT) and a ventricular activation time index (VaT10-90) were calculated to identify the optimal AVD and VVD timings that gave the minimal TVaT and VaT10-90 values. We correlated cardiac output with these electrical timings. Results. Echocardiographic programming optimisation was not associated with the greatest reductions in biventricular activation time (VaT10-90 and TVaT). Instead, bulk activation times were reduced by a further 20% when optimised with ECM. A significant inverse correlation was identified between reductions in bulk ventricular activation time and improvements in LVOT VTI (p

Background: The temporal pattern of ventricular repolarization is of critical importance in arrhythmogenesis. Enhanced beat-to-beat variability (BBV) of ventricular action potential duration (APD) is pro-arrhythmic and is increased during sympathetic provocation. Since sympathetic nerve activity characteristically exhibits burst patterning in the low frequency range, we hypothesized that physiologically enhanced sympathetic activity may not only increase BBV of left ventricular APD but also impose a low frequency oscillation which further increases repolarization instability in humans.Methods and Results: Heart failure patients with cardiac resynchronization therapy defibrillator devices (n = 11) had activation recovery intervals (ARI, surrogate for APD) recorded from left ventricular epicardial electrodes alongside simultaneous non-invasive blood pressure and respiratory recordings. Fixed cycle length was achieved by right ventricular pacing. Recordings took place during resting conditions and following an autonomic stimulus (Valsalva). The variability of ARI and the normalized variability of ARI showed significant increases post Valsalva when compared to control (p = 0.019 and p = 0.032, respectively). The oscillatory behavior was quantified by spectral analysis. Significant increases in low frequency (LF) power (p = 0.002) and normalized LF power (p = 0.019) of ARI were seen following Valsalva. The Valsalva did not induce changes in conduction variability nor the LF oscillatory behavior of conduction. However, increases in the LF power of ARI were accompanied by increases in the LF power of systolic blood pressure (SBP) and the rate of systolic pressure increase (dP/dtmax). Positive correlations were found between LF-SBP and LF-dP/dtmax (rs = 0.933, p < 0.001), LF-ARI and LF-SBP (rs = 0.681, p = 0.001) and between LF-ARI and LF-dP/dtmax (rs = 0.623, p = 0.004). There was a strong positive correlation between the variability of ARI and LF power of ARI (rs = 0.679, p < 0.001).Conclusions: In heart failure patients, physiological sympathetic provocation induced low frequency oscillation (~0.1 Hz) of left ventricular APD with a strong positive correlation between the LF power of APD and the BBV of APD. These findings may be of importance in mechanisms underlying stability/instability of repolarization and arrhythmogenesis in humans.

Background: Exaggerated beat-to-beat variability of ventricular action potential duration (APD) is linked to arrhythmogenesis. Sympathetic stimulation has been shown to increase QT interval variability, but its effect on ventricular APD in humans has not been determined.Methods and Results: Eleven heart failure patients with implanted bi-ventricular pacing devices had activation–recovery intervals (ARI, surrogate for APD) recorded from LV epicardial electrodes under constant RV pacing. Sympathetic activity was increased using a standard autonomic challenge (Valsalva) and baroreceptor indices were applied to determine changes in sympathetic stimulation. Two Valsalvas were performed for each study and were repeated, both off and on bisoprolol. In addition sympathetic nerve activity (SNA) was measured from skin electrodes on the thorax using a novel validated method. Autonomic modulation significantly increased mean short-term variability in ARI; off bisoprolol mean STV increased from 3.73 ± 1.3 to 5.27 ± 1.04 ms (p = 0.01), on bisoprolol mean STV of ARI increased from 4.15 ± 1.14 to 4.62 ± 1 ms (p = 0.14). Adrenergic indices of the Valsalva demonstrated significantly reduced beta-adrenergic function when on bisoprolol (Δ pressure recovery time, p = 0.04; Δ systolic overshoot in Phase IV, p = 0.05). Corresponding increases in SNA from rest both off (1.4 uV, p < 0.01) and on (0.7 uV, p < 0.01) bisoprolol were also seen.Conclusions: Beat-to-beat variability of ventricular APD increases during brief periods of increased sympathetic activity in patients with heart failure. Bisoprolol reduces, but does not eliminate, these effects. This may be important in the genesis of ventricular arrhythmias in heart failure patients.