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In silico clinical trials (ISCTs) are an emerging method in modeling and simulation where medical interventions are evaluated using computational models of patients. ISCTs have the potential to provide cost-effective, time-efficient, and ethically favorable alternatives for evaluating the safety and effectiveness of medical devices. However, ensuring the credibility of ISCT results is a significant challenge. This paper aims to identify unique considerations for assessing the credibility of ISCTs and proposes an ISCT credibility assessment workflow based on recently published model assessment frameworks. First, we review various ISCTs described in the literature, carefully selected to showcase the range of methodological options available. These studies cover a wide variety of devices, reasons for conducting ISCTs, patient model generation approaches including subject-specific versus 'synthetic' virtual patients, complexity levels of devices and patient models, incorporation of clinician or clinical outcome models, and methods for integrating ISCT results with real-world clinical trials. We next discuss how verification, validation, and uncertainty quantification apply to ISCTs, considering the range of ISCT approaches identified. Based on our analysis, we then present a hierarchical workflow for assessing ISCT credibility, using a general credibility assessment framework recently published by the FDA's Center for Devices and Radiological Health. Overall, this work aims to promote standardization in ISCTs and contribute to the wider adoption and acceptance of ISCTs as a reliable tool for evaluating medical devices.

Background Embolic stroke of unknown source (ESUS) accounts for 1 in 6 ischemic strokes. Current guidelines do not recommend routine cardiac magnetic resonance (CMR) imaging in ESUS, and beyond the identification of cardioembolic sources, there are no data assessing new clinical findings from CMR in ESUS. This study aimed to assess the prevalence of new cardiac and noncardiac findings and to determine their impact on clinical care in patients with ESUS. Methods and Results In this prospective, multicenter, observational study, CMR imaging was performed within 3 months of ESUS. All scans were reported according to standard clinical practice. A new clinical finding was defined as one not previously identified through prior clinical evaluation. A clinically significant finding was defined as one resulting in further investigation, follow‐up, or treatment. A change in patient care was defined as initiation of medical, interventional, surgical, or palliative care. From 102 patients recruited, 96 underwent CMR imaging. One or more new clinical findings were observed in 59 patients (61%). New findings were clinically significant in 48 (81%) of these patients. Of 40 patients with a new clinically significant cardiac finding, 21 (53%) experienced a change in care (medical therapy, n=15; interventional/surgical procedure, n=6). In 12 patients with a new clinically significant extracardiac finding, 6 (50%) experienced a change in care (medical therapy, n=4; palliative care, n=2). Conclusions CMR imaging identifies new clinically significant cardiac and noncardiac findings in half of patients with recent ESUS. Advanced cardiovascular screening should be considered in patients with ESUS. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04555538.

Leadless pacing is a rapidly growing field. Initially designed to provide right ventricular pacing for those who were contraindicated for conventional devices, the technology is growing to explore the potential benefit of avoiding long-term transvenous leads in any patient who requires pacing. In this review, we first examine the safety and performance of leadless pacing devices. We then review the evidence for their use in special populations, such as patients with high risk of device infection, patients on haemodialysis, and patients with vasovagal syncope who represent a younger population who may wish to avoid transvenous pacing. We also summarise the evidence for leadless cardiac resynchronisation therapy and conduction system pacing and discuss the challenges of managing issues, such as system revisions, end of battery life and extractions. Finally, we discuss future directions in the field, such as completely leadless cardiac resynchronisation therapy-defibrillator devices and whether leadless pacing has the potential to become a first-line therapy in the near future.

Patients with atrial fibrillation (AF) were largely excluded from the major clinical trials of cardiac resynchronization therapy (CRT), despite the presence of AF in up to 40% of patients receiving CRT in clinical practice. AF appears to attenuate the response to CRT, by the combination of a reduction in biventricular pacing and the loss of atrioventricular synchrony. In addition, remodeling secondary to CRT may influence the progression of AF. Management options for patients with AF and CRT include rate control, with drugs or atrioventricular node ablation, or rhythm control, with electrical cardioversion and antiarrhythmic therapy, or AF catheter ablation. The evidence for these therapies in patients with CRT is largely limited to observational studies or inferred from randomized studies in the general heart failure population. In this review, we explore the complex interaction between AF, heart failure, and CRT and discuss the evidence for the treatment options in this difficult patient cohort.

Reliable and robust simulation of individual patients using patient-specific models (PSMs) is one of the next frontiers for modeling and simulation (M&S) in healthcare. PSMs, which form the basis of digital twins, can be employed as clinical tools to, for example, assess disease state, predict response to therapy, or optimize therapy. They may also be used to construct virtual cohorts of patients, for in silico evaluation of medical product safety and/or performance. Methods and frameworks have recently been proposed for evaluating the credibility of M&S in healthcare applications. However, such efforts have generally been motivated by models of medical devices or generic patient models; how best to evaluate the credibility of PSMs has largely been unexplored. The aim of this paper is to understand and demonstrate the credibility assessment process for PSMs using patient-specific cardiac electrophysiological (EP) modeling as an exemplar. We first review approaches used to generate cardiac PSMs and consider how verification, validation, and uncertainty quantification (VVUQ) apply to cardiac PSMs. Next, we execute two simulation studies using a publicly available virtual cohort of 24 patient-specific ventricular models, the first a multi-patient verification study, the second investigating the impact of uncertainty in personalized and non-personalized inputs in a virtual cohort. We then use the findings from our analyses to identify how important characteristics of PSMs can be considered when assessing credibility with the approach of the ASME V&V40 Standard, accounting for PSM concepts such as inter- and intra-user variability, multi-patient and “every-patient” error estimation, uncertainty quantification in personalized vs non-personalized inputs, clinical validation, and others. The results of this paper will be useful to developers of cardiac and other medical image based PSMs, when assessing PSM credibility. Author summary Patient-specific models are computational models that have been personalized using data from a patient. After decades of research, recent computational, data science and healthcare advances have opened the door to the fulfilment of the enormous potential of such models, from truly personalized medicine to efficient and cost-effective testing of new medical products. However, reliability (credibility) of patient-specific models is key to their success, and there are currently no general guidelines for evaluating credibility of patient-specific models. Here, we consider how frameworks and model evaluation activities that have been developed for generic (not patient-specific) computational models, can be extended to patient specific models. We achieve this through a detailed analysis of the activities required to evaluate cardiac electrophysiological models, chosen as an exemplar field due to its maturity and the complexity of such models. This is the first paper on the topic of reliability of patient-specific models and will help pave the way to reliable and trusted patient-specific modeling across healthcare applications.

Cardiac stereotactic body radiation therapy (cSBRT) is a non-invasive treatment modality that has been recently reported as an effective treatment for ventricular arrhythmias refractory to medical therapy and catheter ablation. The approach leverages tools developed and refined in radiation oncology, where experience has been accumulated in the treatment of a wide variety of malignant conditions. However, important differences exist between rapidly dividing malignant tumor cells and fully differentiated myocytes in pathologically remodeled ventricular myocardium, which represent the respective radiation targets. Despite its initial success, little is known about the radiobiology of the anti-arrhythmic effect cSBRT. Pre-clinical data indicates a late fibrotic effect of that appears between 3 and 4 months following cSBRT, which may result in conduction slowing and block. However, there is clear clinical evidence of an anti-arrhythmic effect of cSBRT that precedes the appearance of radiation induced fibrosis for which the mechanism is unclear. In addition, the data to date suggests that even the late anti-arrhythmic effect of cSBRT is not fully attributable to radiation.-induced fibrosis. Pre-clinical data has identified upregulation of proteins expected to result in both increased cell-to-cell coupling and excitability in the early post cSBRT period and demonstrated an associated increase in myocardial conduction velocity. These observations indicate a complex response to radiotherapy and highlight the lack of clarity regarding the different stages of the anti-arrhythmic mechanism of cSBRT. It may be speculated that in the future cSBRT therapy could be planned to deliver both early and late radiation effects titrated to optimize the combined anti-arrhythmic efficacy of the treatment. In addition to these outstanding mechanistic questions, the optimal patient selection, radiation modality, radiation dose and treatment planning strategy are currently being investigated. In this review, we consider the structural and functional effect of radiation on myocardium and the possible anti-arrhythmic mechanisms of cSBRT. Review of the published data highlights the exciting prospects for the development of knowledge and understanding in this area in which so many outstanding questions exist.

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.

Conduction System Pacing (CSP) delivered by His Bundle Pacing (HBP) or Left Bundle Pacing (LBP) are exciting novel interventions in the field of Cardiac Resynchronization Therapy (CRT). As the evidence base for CSP grows, the volume of implants worldwide is projected to rise significantly in the coming years. As such, physicians will be confronted with increasingly prevalent and vital issues arising in long-term follow up, including the management of infected, malfunctioning, or redundant CSP leads. Transvenous lead extraction (TLE) is the first-line option for removal of pacing leads when indicated in these circumstances. The evidence base for TLE in the context of CSP is still in its infancy. In this article, we first provide a brief overview of TLE. We then examine the data on the long-term performance of HBP leads. Next, we describe the features of the Medtronic Select Secure 3,830 lead, and how experience of TLE of this lead in the paediatric population has informed our practice. Finally, we review the current evidence for TLE in HBP and LBP, and discuss how future studies can address gaps in our current knowledge.

Leadless left bundle branch area pacing (LBBAP) represents the merger of two rapidly progressing areas in the field of cardiac resynchronisation therapy (CRT). It combines the attractive concepts of pacing the native conduction system to allow more physiological activation of the myocardium than conventional biventricular pacing, with the potential added benefits of avoiding long-term complications associated with transvenous leads via leadless left ventricular endocardial pacing. This perspective article will first review the evidence for the efficacy of leadless pacing in CRT. We then summarise the procedural steps and pilot data for leadless LBBAP, followed by a discussion of the safety and efficacy of this novel technique. Finally, we will examine how further mechanistic evidence may shed light to which patients may benefit most from leadless LBBAP, and how improvements in current experience and technology could promote widespread uptake and expand current clinical indications.

Background: No periprocedural metric has demonstrated improved cardiac resynchronization therapy (CRT) outcomes in a multicenter setting. Objective: We sought to determine if left ventricular (LV) lead placement targeted to the coronary sinus (CS) branch generating the best acute hemodynamic response (AHR) results in improved outcomes at 6 months. Methods: In this multicenter randomized controlled trial, patients were randomized to guided CRT or conventional CRT. Patients in the guided arm had LV dP/dtmax measured during biventricular (BIV) pacing. Target CS branches were identified and the final LV lead position was the branch with the best AHR and acceptable threshold values. The primary endpoint was the proportion of patients with a reduction in LV end-systolic volume (LVESV) of ≥15% at 6 months. Results: A total of 281 patients were recruited across 12 centers. Mean age was 70.8 ± 10.9 years and 54% had ischemic etiology. Seventy-three percent of patients in the guided arm demonstrated a reduction in LVESV of ≥15% at 6 months vs 60% in the conventional arm (P = .02). Patients with AHR ≥ 10% were more likely to demonstrate a reduction of ESV ≥ 15% (84% of patients with an AHR ≥10% vs 28% with an AHR

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.

BackgroundDelayed enhancement CT (CT-DE) has been evaluated as a tool for the detection of myocardial scar and compares well to the gold standard of MRI with late gadolinium enhancement (MRI-LGE). Prior work has established that high performance can be achieved with manual reading; however, few studies have looked at quantitative measures to differentiate scar and healthy myocardium on CT-DE or automated analysis.MethodsEighteen patients with clinically indicated MRI-LGE were recruited for CT-DE at multiple 80 and 100 kV post contrast imaging. Left ventricle segmentation was performed on both imaging modalities, along with scar segmentation on MRI-LGE. Segmentations were registered together and scar regions were estimated on CT-DE. 93 radiomic features were calculated and analysed for their ability to differentiate between scarred and non-scarred myocardium regions. Machine learning (ML) classifiers were trained using the strongest set of radiomic features to classify segments containing scar on CT-DE. Features and classifiers were compared across both tube voltages and combined-energy images.ResultsThere were 59 and 51 statistically significant features in the 80 and 100 kV images respectively. Combined-energy imaging increased this to 63 with more features having area under the curve (AUC) above 0.9. The 10 highest AUC features for each image were used in the ML classifiers. The 100 kV images produced the best ML classifier, a support vector machine with an AUC of 0.88 (95% CI 0.87–0.90). Comparable performance was achieved with both the 80 kV and combined-energy images.ConclusionsCT-DE can be quantitatively analyzed using radiomic feature calculations. These features may be suitable for ML classification techniques to prospectively identify AHA segments with performance comparable to previously reported manual reading. Future work on larger CT-DE datasets is warranted to establish optimum imaging parameters and features.

Background: The majority of data regarding tissue substrate for post myocardial infarction (MI) VT has been collected during hemodynamically tolerated VT, which may be distinct from the substrate responsible for VT with hemodynamic compromise (VT-HC). This study aimed to characterize tissue at diastolic locations of VT-HC in a porcine model.Methods: Late Gadolinium Enhancement (LGE) cardiovascular magnetic resonance (CMR) imaging was performed in eight pigs with healed antero-septal infarcts. Seven pigs underwent electrophysiology study with venous arterial-extra corporeal membrane oxygenation (VA-ECMO) support. Tissue thickness, scar and heterogeneous tissue (HT) transmurality were calculated at the location of the diastolic electrograms of mapped VT-HC.Results: Diastolic locations had median scar transmurality of 33.1% and a median HT transmurality 7.6%. Diastolic activation was found within areas of non-transmural scar in 80.1% of cases. Tissue activated during the diastolic component of VT circuits was thinner than healthy tissue (median thickness: 5.5 mm vs. 8.2 mm healthy tissue, p < 0.0001) and closer to HT (median distance diastolic tissue: 2.8 mm vs. 11.4 mm healthy tissue, p < 0.0001). Non-scarred regions with diastolic activation were closer to steep gradients in thickness than non-scarred locations with normal EGMs (diastolic locations distance = 1.19 mm vs. 9.67 mm for non-diastolic locations, p < 0.0001). Sites activated late in diastole were closest to steep gradients in tissue thickness.Conclusions: Non-transmural scar, mildly decreased tissue thickness, and steep gradients in tissue thickness represent the structural characteristics of the diastolic component of reentrant circuits in VT-HC in this porcine model and could form the basis for imaging criteria to define ablation targets in future trials.

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 Background Ex-vivo cardiovascular magnetic resonance (CMR) imaging has played an important role in the validation of in-vivo CMR characterization of pathological processes. However, comparison between in-vivo and ex-vivo imaging remains challenging due to shape changes occurring between the two states, which may be non-uniform across the diseased heart. A novel two-step process to facilitate registration between ex-vivo and in-vivo CMR was developed and evaluated in a porcine model of chronic myocardial infarction (MI). Methods Seven weeks after ischemia-reperfusion MI, 12 swine underwent in-vivo CMR imaging with late gadolinium enhancement followed by ex-vivo CMR 1 week later. Five animals comprised the control group, in which ex-vivo imaging was undertaken without any support in the LV cavity, 7 animals comprised the experimental group, in which a two-step registration optimization process was undertaken. The first step involved a heart specific flexible 3D printed scaffold generated from in-vivo CMR, which was used to maintain left ventricular (LV) shape during ex-vivo imaging. In the second step, a non-rigid co-registration algorithm was applied to align in-vivo and ex-vivo data. Tissue dimension changes between in-vivo and ex-vivo imaging were compared between the experimental and control group. In the experimental group, tissue compartment volumes and thickness were compared between in-vivo and ex-vivo data before and after non-rigid registration. The effectiveness of the alignment was assessed quantitatively using the DICE similarity coefficient. Results LV cavity volume changed more in the control group (ratio of cavity volume between ex-vivo and in-vivo imaging in control and experimental group 0.14 vs 0.56, p

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.

Aims: Left atrial (LA) remodelling is a common feature of many cardiovascular pathologies and is a sensitive marker of adverse cardiovascular outcomes. The aim of this study was to establish normal ranges for LA parameters derived from coronary computed tomographic angiography (CCTA) imaging using a standardised image processing pipeline to establish normal ranges in a previously described cohort. Methods: CCTA imaging from 193 subjects recruited to the Budapest GLOBAL twin study was analysed. Indexed LA cavity volume (LACVi), LA surface area (LASAi), wall thickness and LA tissue volume (LATVi) were calculated. Wall thickness maps were combined into an atlas. Indexed LA parameters were compared with clinical variables to identify early markers of pathological remodelling. Results: LACVi is similar between sexes (31 ml/m2 v 30 ml/m2) and increased in hypertension (33 ml/m2 v 29 ml/m2, p = 0.009). LASAi is greater in females than males (47.8 ml/m2 v 45.8 ml/m2 male, p = 0.031). Median LAWT was 1.45 mm. LAWT was lowest at the inferior portion of the posterior LA wall (1.14 mm) and greatest in the septum (median = 2.0 mm) (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.

The potential for acute shortages of ventilators at the peak of the COVID-19 pandemic has raised the possibility of needing to support two patients from a single ventilator. To provide a system for understanding and prototyping designs, we have developed a mathematical model of two patients supported by a mechanical ventilator. We propose a standard set-up where we simulate the introduction of T-splitters to supply air to two patients and a modified set-up where we introduce a variable resistance in each inhalation pathway and one-way valves in each exhalation pathway. Using the standard set-up, we demonstrate that ventilating two patients with mismatched lung compliances from a single ventilator will lead to clinically significant reductions in tidal volume in the patient with the lowest respiratory compliance. Using the modified set-up, we demonstrate that it could be possible to achieve the same tidal volumes in two patients with mismatched lung compliances, and we show that the tidal volume of one patient can be manipulated independently of the other. The results indicate that, with appropriate modifications, two patients could be supported from a single ventilator with independent control of tidal volumes.

BackgroundRe-entrant ventricular tachycardia may be non-inducible or haemodynamically compromising, requiring assessment of the electrophysiological properties of the myocardium during sinus rhythm (i.e., substrate mapping). Areas of heart tissue with slow conduction can act as a critical isthmus for re-entrant electrical excitation and are a potential target for ablation therapy.AimTo develop and validate a novel metric of local conduction delay in the heart, the amplitude-normalized electrogram area (norm_EA).MethodsA computational model of a propagating mouse action potential was used to establish the impact of altering sodium channel conductance, intracellular conductivity, fibrosis density, and electrode size/orientation on bipolar electrogram morphology. Findings were then validated in experimental studies in mouse and guinea pig hearts instrumented for the recording of bipolar electrograms from a multipolar linear mapping catheter. norm_EA was calculated by integrating the absolute area of a bipolar electrogram divided by the electrogram amplitude. Electrogram metrics were correlated with the local conduction delay during sodium channel block, gap junction inhibition, and acute ischemia.ResultsIn computational simulations, reducing sodium channel conductance and intracellular conductivity resulted in a decrease in signal amplitude and increase in norm_EA (reflecting a broadening of electrogram morphology). For larger electrodes (3 mm diameter/7.1 mm2 area), the change in norm_EA was essentially linear with the change in local conduction delay. Experimental studies supported this finding, showing that the magnitude of change in norm_EA induced by flecainide (1–4 μM), carbenoxolone (10–50 μM), and low-flow ischemia (25% of initial flow rate) was linearly correlated with the local conduction delay in each condition (r2 = 0.92). Qualitatively similar effects were observed in guinea pig hearts perfused with flecainide. Increasing fibrosis density in the computational model also resulted in a decrease in signal amplitude and increase in norm_EA. However, this remains to be validated using experimental/clinical data of chronic infarct.Conclusionnorm_EA is a quantitative measure of local conduction delay between the electrode pair that generates a bipolar electrogram, which may have utility in electrophysiological substrate mapping of non-inducible or haemodynamically compromising tachyarrhythmia.

Background: Biventricular pacing has been shown to increase both cardiac contractility and coronary flow acutely but the causal relationship is unclear. We hypothesised that changes in coronary flow are secondary to changes in cardiac contractility. We sought to examine this relationship by modulating coronary flow and cardiac contractility. Methods: Contractility and lusitropy were altered by varying the location of pacing in 8 patients. Coronary autoregulation was transiently disabled with intracoronary adenosine. Simultaneous coronary flow velocity, coronary pressure and left ventricular pressure data were measured in the different pacing settings with and without hyperaemia and wave intensity analysis performed. Results: Multisite pacing was effective at altering left ventricular contractility and lusitropy (pos. dp/dtmax −13% to +10% and neg. dp/dtmax −15% to +17% compared to baseline). Intracoronary adenosine decreased microvascular resistance (362.5 mm Hg/s/m to 156.7 mm Hg/s/m, p

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

The clinical use of the anthracycline doxorubicin is limited by its cardiotoxicity which is associated with mitochondrial dysfunction. Redox cycling, mitochondrial DNA damage and electron transport chain inhibition have been identified as potential mechanisms of toxicity. However, the relative roles of each of these proposed mechanisms are still not fully understood. The purpose of this study is to identify which of these pathways independently or in combination are responsible for doxorubicin toxicity. A state of the art mathematical model of the mitochondria including the citric acid cycle, electron transport chain and ROS production and scavenging systems was extended by incorporating a novel representation for mitochondrial DNA damage and repair. In silico experiments were performed to quantify the contributions of each of the toxicity mechanisms to mitochondrial dysfunction during the acute and chronic stages of toxicity. Simulations predict that redox cycling has a minor role in doxorubicin cardiotoxicity. Electron transport chain inhibition is the main pathway for acute toxicity for supratherapeutic doses, being lethal at mitochondrial concentrations higher than 200μM. Direct mitochondrial DNA damage is the principal pathway of chronic cardiotoxicity for therapeutic doses, leading to a progressive and irreversible long term mitochondrial dysfunction.

The myocardial ischemic border zone is associated with the initiation and sustenance of arrhythmias. The profile of ionic concentrations across the border zone play a significant role in determining cellular electrophysiology and conductivity, yet their spatial-temporal evolution and regulation are not well understood. To investigate the changes in ion concentrations that regulate cellular electrophysiology, a mathematical model of ion movement in the intra and extracellular space in the presence of ionic, potential and material property heterogeneities was developed. The model simulates the spatial and temporal evolution of concentrations of potassium, sodium, chloride, calcium, hydrogen and bicarbonate ions and carbon dioxide across an ischemic border zone. Ischemia was simulated by sodium-potassium pump inhibition, potassium channel activation and respiratory and metabolic acidosis. The model predicted significant disparities in the width of the border zone for each ionic species, with intracellular sodium and extracellular potassium having discordant gradients, facilitating multiple gradients in cellular properties across the border zone. Extracellular potassium was found to have the largest border zone and this was attributed to the voltage dependence of the potassium channels. The model also predicted the efflux of [Formula: see text] from the ischemic region due to electrogenic drift and diffusion within the intra and extracellular space, respectively, which contributed to [Formula: see text] depletion in the ischemic region.