Considering discrepancy when calibrating a mechanistic electrophysiology model.

Uncertainty quantification (UQ) is a vital step in using mathematical models and simulations to take decisions. The field of cardiac simulation has begun to explore and adopt UQ methods to characterize uncertainty in model inputs and how that propagates through to outputs or predictions; examples of this can be seen in the papers of this issue. In this review and perspective piece, we draw attention to an important and under-addressed source of uncertainty in our predictions-that of uncertainty in the model structure or the equations themselves. The difference between imperfect models and reality is termed model discrepancy, and we are often uncertain as to the size and consequences of this discrepancy. Here, we provide two examples of the consequences of discrepancy when calibrating models at the ion channel and action potential scales. Furthermore, we attempt to account for this discrepancy when calibrating and validating an ion channel model using different methods, based on modelling the discrepancy using Gaussian processes and autoregressive-moving-average models, then highlight the advantages and shortcomings of each approach. Finally, suggestions and lines of enquiry for future work are provided. This article is part of the theme issue 'Uncertainty quantification in cardiac and cardiovascular modelling and simulation'.

Mechanical Properties and Processing Techniques of Bulk Metal-Organic Framework Glasses.

Melt quenched metal-organic framework (MOF) glasses define a new category of glass, distinct from metallic, organic, and inorganic glasses, owing to the dominant role of metal-ligand coordination bonding. The mechanical properties of glasses in general are important given their application in protective coatings and display technologies, though little is known about MOF glasses in this respect. The experimental elucidation of key properties such as their scratch resistance has been limited by the lack of processing methodologies capable of producing bulk glass samples. Here, nanoindentation was used to investigate the Young's modulus and hardness of four melt-quenched glasses formed from zeolitic imidazolate frameworks (ZIF): agZIF-4, agZIF-62, agZIF-76, and agZIF-76-mbIm. The creep resistance of the melt-quenched glasses was studied via strain-rate jump (SRJ) tests and through constant load and hold (CLH) indentation creep experiments. Values for the strain-rate sensitivity were found to be close to those for other glassy polymers and Se-rich GeSe chalcogenide glasses. Vacuum hot-pressing of agZIF-62 resulted in an inhomogeneous bulk sample containing the glass and amorphous non-melt-quenched aZIF-62. Remelting and annealing, however, resulted in the fabrication of a transparent, bubble-free bulk specimen, which allowed the first scratch testing experiments to be performed on an MOF glass.

Uniqueness of local myocardial strain patterns with respect to activation time and contractility of the failing heart: a computational study.

BACKGROUND: Myocardial deformation measured by strain is used to detect electro-mechanical abnormalities in cardiac tissue. Estimation of myocardial properties from regional strain patterns when multiple pathologies are present is therefore a promising application of computer modelling. However, if different tissue properties lead to indistinguishable strain patterns ('degeneracy'), the applicability of any such method will be limited. We investigated whether estimation of local activation time (AT) and contractility from myocardial strain patterns is theoretically possible. METHODS: For four different global cardiac pathologies local myocardial strain patterns for 1025 combinations of AT and contractility were simulated with a computational model (CircAdapt). For each strain pattern, a cohort of similar patterns was found within estimated measurement error using the sum of least-squared differences. Cohort members came from (1) the same pathology only, and (2) all four pathologies. Uncertainty was calculated as accuracy and precision of cohort members in parameter space. Connectedness within the cohorts was also studied. RESULTS: We found that cohorts drawn from one pathology had parameters with adjacent values although their distribution was neither constant nor symmetrical. In comparison cohorts drawn from four pathologies had disconnected components with drastically different parameter values and accuracy and precision values up to three times higher. CONCLUSIONS: Global pathology must be known when extracting AT and contractility from strain patterns, otherwise degeneracy occurs causing unacceptable uncertainty in derived parameters.

Evaluation of Reoxidation Thresholds for γ-Al2O3-Supported Cobalt Catalysts under Fischer-Tropsch Synthesis Conditions.

Size-dependent phenomena at the nanoscale influence many applications, notably in the science of heterogeneous catalysis. In cobalt-based Fischer-Tropsch synthesis (FTS), the size of Co nanoparticles (NPs) dictates to a high degree catalyst's performance in terms of activity, selectivity, and stability. Here, a highly dispersed Re/Co/γ-Al2O3 catalyst with high Co surface area per gram of catalyst was exposed to industrially relevant FTS conditions and monitored in situ by synchrotron X-ray radiation. X-ray absorption near-edge structure spectra were obtained on the cobalt K edge and Re L3 edge of the working catalyst. The experimental results demonstrate development of tetrahedrally coordinated Co2+ forming at the expense of metallic Co(0). The structure of the oxide resembles CoAl2O4 and appears at the onset (first 5-10 h) of the reaction. Reoxidation of Co(0) is more pronounced close to the outlet of the reactor, where higher pH2O is anticipated. The state of the Re promoter does not change during the FT process. We propose that reoxidation of small Co NPs is followed by spreading of Co oxide that leads to the formation of CoxAlyOz phases. Hence, in order to avoid an irreversible loss of the active phase during process start-up, catalyst design should be restricted to Co NPs larger than 5.3 nm.

Why septal motion is a marker of right ventricular failure in pulmonary arterial hypertension: mechanistic analysis using a computer model.

Rapid leftward septal motion (RLSM) during early left ventricular (LV) diastole is observed in patients with pulmonary arterial hypertension (PAH). RLSM exacerbates right ventricular (RV) systolic dysfunction and impairs LV filling. Increased RV wall tension caused by increased RV afterload has been suggested to cause interventricular relaxation dyssynchrony and RLSM in PAH. Simulations using the CircAdapt computational model were used to unravel the mechanism underlying RLSM by mechanistically linking myocardial tissue and pump function. Simulations of healthy circulation and mild, moderate, and severe PAH were performed. We also assessed the effects on RLSM when PAH coexists with RV or LV contractile dysfunction. Our results showed prolonged RV shortening in PAH causing interventricular relaxation dyssynchrony and RLSM. RLSM was observed in both moderate and severe PAH. A negative transseptal pressure gradient only occurred in severe PAH, demonstrating that negative pressure gradient does not entirely explain septal motion abnormalities. PAH coexisting with RV contractile dysfunction exacerbated both interventricular relaxation dyssynchrony and RLSM. LV contractile dysfunction reduced both interventricular relaxation dyssynchrony and RLSM. In conclusion, dyssynchrony in ventricular relaxation causes RLSM in PAH. Onset of RLSM in patients with PAH appears to indicate a worsening in RV function and hence can be used as a sign of RV failure. However, altered RLSM does not necessarily imply an altered RV afterload, but it can also indicate altered interplay of RV and LV contractile function. Reduction of RLSM can result from either improved RV function or a deterioration of LV function.NEW & NOTEWORTHY A novel approach describes the mechanism underlying abnormal septal dynamics in pulmonary arterial hypertension. Change in motion is not uniquely induced by altered right ventricular afterload, but also by altered ventricular relaxation dyssynchrony. Extension or change in motion is a marker reflecting interplay between right and left ventricular contractility.

Septal flash and septal rebound stretch have different underlying mechanisms.

Abnormal left-right motion of the interventricular septum in early systole, known as septal flash (SF), is frequently observed in patients with left bundle branch block (LBBB). Transseptal pressure gradient and early active septal contraction have been proposed as explanations for SF. Similarities in timing (early systole) and location (septum) suggest that SF may be related to septal systolic rebound stretch (SRSsept). We aimed to clarify the mechanisms generating SF and SRSsept. The CircAdapt computer model was used to isolate the effects of timing of activation of the left ventricular free wall (LVFW), right ventricular free wall (RVFW), and septum on SF and SRSsept. LVFW and septal activation times were varied by ±80 ms relative to RVFW activation time. M-mode-derived wall motions and septal strains were computed and used to quantify SF and SRSsept, respectively. SF depended on early activation of the RVFW relative to the LVFW. SF and SRSsept occurred in LBBB-like simulations and against a rising transseptal pressure gradient. When the septum was activated before both LVFW and RVFW, no SF occurred despite the presence of SRSsept. Computer simulations therefore indicate that SF and SRSsept have different underlying mechanisms, even though both can occur in LBBB. The mechanism of leftward motion during SF is early RVFW contraction pulling on and straightening the septum when unopposed by the LVFW. SRSsept is caused by late LVFW contraction following early contraction of the septum. Changes in transseptal pressure gradient are not the main cause of SF in LBBB.

Fast Simulation of Mechanical Heterogeneity in the Electrically Asynchronous Heart Using the MultiPatch Module.

Cardiac electrical asynchrony occurs as a result of cardiac pacing or conduction disorders such as left bundle-branch block (LBBB). Electrically asynchronous activation causes myocardial contraction heterogeneity that can be detrimental for cardiac function. Computational models provide a tool for understanding pathological consequences of dyssynchronous contraction. Simulations of mechanical dyssynchrony within the heart are typically performed using the finite element method, whose computational intensity may present an obstacle to clinical deployment of patient-specific models. We present an alternative based on the CircAdapt lumped-parameter model of the heart and circulatory system, called the MultiPatch module. Cardiac walls are subdivided into an arbitrary number of patches of homogeneous tissue. Tissue properties and activation time can differ between patches. All patches within a wall share a common wall tension and curvature. Consequently, spatial location within the wall is not required to calculate deformation in a patch. We test the hypothesis that activation time is more important than tissue location for determining mechanical deformation in asynchronous hearts. We perform simulations representing an experimental study of myocardial deformation induced by ventricular pacing, and a patient with LBBB and heart failure using endocardial recordings of electrical activation, wall volumes, and end-diastolic volumes. Direct comparison between simulated and experimental strain patterns shows both qualitative and quantitative agreement between model fibre strain and experimental circumferential strain in terms of shortening and rebound stretch during ejection. Local myofibre strain in the patient simulation shows qualitative agreement with circumferential strain patterns observed in the patient using tagged MRI. We conclude that the MultiPatch module produces realistic regional deformation patterns in the asynchronous heart and that activation time is more important than tissue location within a wall for determining myocardial deformation. The CircAdapt model is therefore capable of fast and realistic simulations of dyssynchronous myocardial deformation embedded within the closed-loop cardiovascular system.

Application of stochastic phenomenological modelling to cell-to-cell and beat-to-beat electrophysiological variability in cardiac tissue.

Variability in the action potential of isolated myocytes and tissue samples is observed in experimental studies. Variability is manifested as both differences in the action potential (AP) morphology between cells (extrinsic variability), and also 'intrinsic' or beat-to-beat variability of repolarization (BVR) in the AP duration of each cell. We studied the relative contributions of experimentally recorded intrinsic and extrinsic variability to dispersion of repolarization in tissue. We developed four cell-specific parameterizations of a phenomenological stochastic differential equation AP model exhibiting intrinsic variability using APs recorded from isolated guinea pig ventricular myocytes exhibiting BVR. We performed simulations in tissue using the four different model parameterizations in the presence and the absence of both intrinsic and extrinsic variability. We altered the coupling of the tissue to determine how inter-cellular coupling affected the dispersion of the AP duration in tissue. Both intrinsic and extrinsic variability were gradually revealed by reduction of tissue coupling. However, the recorded extrinsic variability between individual myocytes produced a greater degree of dispersion in repolarization in tissue than the intrinsic variability of each myocyte.

Influence of left ventricular lead position relative to scar location on response to cardiac resynchronization therapy: a model study.

AIMS: It is unclear how the position of the left ventricular (LV) lead relative to a scar affects the haemodynamic response in patients with dyssynchronous heart failure receiving cardiac resynchronization therapy. We investigated this complex interaction using a computational model. METHODS AND RESULTS: The CircAdapt computational cardiovascular system model was used to simulate heart failure with left bundle branch block (LBBB). Myocardial scar was induced in four different regions of the LV free wall (LVFW). We then simulated biventricular pacing (BVP) in each heart, in which LV lead position was varied. The LV lead position leading to maximal acute change in LV stroke volume (SV) was defined as optimal lead position. In LBBB without scar, SV increase was maximal when pacing the LVFW region most distant from the septum. With a scar adjacent to the septum, maximal response was achieved when pacing remote from both the septum and the scar. When the scar was located further from the septum, the BVP-induced increase of SV was small. For all hearts, pacing from the optimal LV lead position resulted in the most homogeneous distribution of local ventricular myofibre work and the largest increase in summed left and right ventricular pump work. CONCLUSIONS: These computer simulations suggest that, in hearts with LBBB and scar, the optimal LV lead position is a compromise between a position distant from the scar and from the septum. In infarcted hearts, the best haemodynamic effect is achieved when electromechanical resynchronization of the remaining viable myocardium is most effective.

The nucleosynthetic fingerprint of the outermost protoplanetary disk and early Solar System dynamics.

Knowledge of the nucleosynthetic isotope composition of the outermost protoplanetary disk is critical to understand the formation and early dynamical evolution of the Solar System. We report the discovery of outer disk material preserved in a pristine meteorite based on its chemical composition, organic-rich petrology, and 15N-rich, deuterium-rich, and 16O-poor isotope signatures. We infer that this outer disk material originated in the comet-forming region. The nucleosynthetic Fe, Mg, Si, and Cr compositions of this material reveal that, contrary to current belief, the isotope signature of the comet-forming region is ubiquitous among outer Solar System bodies, possibly reflecting an important planetary building block in the outer Solar System. This nucleosynthetic component represents fresh material added to the outer disk by late accretion streamers connected to the ambient molecular cloud. Our results show that most Solar System carbonaceous asteroids accreted material from the comet-forming region, a signature lacking in the terrestrial planet region.

Identifying the need for a UK colorectal cancer screening programme for patients with cystic fibrosis (CF): 10-year retrospective review of colonoscopy and colorectal cancer outcomes at a single CF centre.

OBJECTIVE: Patients with cystic fibrosis (pwCF) have a high incidence of early colorectal cancer (CRC). In the absence of a UK CRC screening programme for pwCF, we evaluated the utility and outcomes of colonoscopy and CRC at a large UK CF centre. DESIGN: In a retrospective study of colonoscopy and CRC outcomes between 2010 and 2020 in pwCF aged≥30 years at a large CF centre, data were collected on colonoscopy indications and findings, polyp detection rates, bowel preparation regimens and outcomes, colonoscopy completion rates, and patient outcomes. RESULTS: We identified 361 pwCF aged ≥30 years, of whom 135 were ≥40 years old. In the absence of a UK CRC screening guideline only 33 (9%)/361 pwCF aged ≥30 years (mean age: 44.8±11.0 years) had a colonoscopy between 2010 and 2020. Colonoscopy completion rate was 94.9%, with a 33% polyp detection rate, 93.8% of the polyps retrieved were premalignant. During the study period no patients developed postcolonoscopy CRC. However, of the patients aged ≥40 years who did not have a colonoscopy (111/135, 82.2%), four (3.6%) patients developed CRC and three pwCF died from complications of CRC. CONCLUSION: In this 10-year experience from a large CF centre, colonoscopy uptake for symptomatic indications was low, yet of high yield for premalignant lesions in pwCF >40 years. These data highlight the risk of potentially preventable, early CRC, and therefore support the need for prospective, large-scale nationwide studies which may inform the need for UK CRC screening guidelines for pwCF.

Smart Drain for Post-Cardiac Surgery Left Ventricular Volumes Evaluated in Large Animal Models.

BACKGROUND: Open heart surgeries for coronary arterial bypass graft and valve replacements are performed on 400,000 Americans each year. Unexplained hypotension during recovery causes morbidity and mortality through cerebral, kidney, and coronary hypoperfusion. An early detection method that distinguishes between hypovolemia and decreased myocardial function before onset of hypotension is desirable. We hypothesized that admittance measured from a modified pericardial drain can detect changes in left ventricular end-systolic, end-diastolic, and stroke volumes. METHODS: Admittance was measured from 2 modified pericardial drains placed in 7 adult female dogs using an open chest preparation, each with 8 electrodes. The resistive and capacitive components of the measured admittance signal were used to distinguish blood and muscle components. Admittance measurements were taken from 12 electrode configurations in each experiment. Left ventricular preload was reduced by inferior vena cava occlusion. Physiologic response to vena cava occlusion was measured by aortic pressure, aortic flow, left ventricle diameter, left ventricular wall thickness, and electrocardiogram. RESULTS: Admittance successfully detected a drop in left ventricular end-diastolic volume (P < .001), end-systolic volume (P < .001), and stroke volume (P < .001). Measured left ventricular muscle resistance correlated with crystal-derived left ventricular wall thickness (R2 = 0.96), validating the method's ability to distinguish blood from muscle components. CONCLUSIONS: Admittance measured from chest tubes can detect changes in left ventricular end-systolic, end-diastolic, and stroke volumes and may therefore have diagnostic value for unexplained hypotension.

The impact of myocardial compressibility on organ-level simulations of the normal and infarcted heart.

Myocardial infarction (MI) rapidly impairs cardiac contractile function and instigates maladaptive remodeling leading to heart failure. Patient-specific models are a maturing technology for developing and determining therapeutic modalities for MI that require accurate descriptions of myocardial mechanics. While substantial tissue volume reductions of 15-20% during systole have been reported, myocardium is commonly modeled as incompressible. We developed a myocardial model to simulate experimentally-observed systolic volume reductions in an ovine model of MI. Sheep-specific simulations of the cardiac cycle were performed using both incompressible and compressible tissue material models, and with synchronous or measurement-guided contraction. The compressible tissue model with measurement-guided contraction gave best agreement with experimentally measured reductions in tissue volume at peak systole, ventricular kinematics, and wall thickness changes. The incompressible model predicted myofiber peak contractile stresses approximately double the compressible model (182.8 kPa, 107.4 kPa respectively). Compensatory changes in remaining normal myocardium with MI present required less increase of contractile stress in the compressible model than the incompressible model (32.1%, 53.5%, respectively). The compressible model therefore provided more accurate representation of ventricular kinematics and potentially more realistic computed active contraction levels in the simulated infarcted heart. Our findings suggest that myocardial compressibility should be incorporated into future cardiac models for improved accuracy.

An in vitro biomechanical comparison of a locking compression plate fixation and kerf cut cylinder fixation for ventral arthrodesis of the fourth and the fifth equine cervical vertebrae.

OBJECTIVES: To (1) define mechanical properties in flexion, extension, and left lateral bending of cadaveric equine 4th and 5th cervical (C4-C5) articulations, (2) compare biomechanical properties of C4-C5 when stabilized with a kerf cut cylinder (KCC) compared with a ventrally placed 4.5 mm locking compression plate (LCP). STUDY DESIGN: In vitro biomechanical investigation. SAMPLE POPULATION: Cadaveric adult equine cervical vertebral columns (n=54). METHODS: Cervical vertebrae aged by horse dentition and size measured from radiographs were divided into 3 age groups then randomly allocated to 3 groups. The C4-C5 articulation was treated differently in each of the groups: KCC group; KCC-implanted LCP group; 8-hole 4.5 mm LCP implanted and intact group; no implant. Specimens were randomly subdivided into 1 of 3 loading conditions, before testing to failure under 4-point bending. Stiffness, yield bending moment, failure bending moment, and failure mode were recorded. General linear models were performed to analyze associations between biomechanical properties and test variables. RESULTS: All specimens failed at the C4-C5 intervertebral articulation. The cervical vertebrae with the LCP construct had significantly higher stiffness, yield bending moment, and failure bending moment than the KCC-implanted cervical vertebrae. Failure modes differed between groups and varied with loading direction: KCC group, fractures of C5 associated with the KCC were common; LCP group, screw pull out or fractures (of C4 and C5 bodies, during extension and the caudal aspect of C4 during left lateral bending) were common; and intact group, subluxations were most common. CONCLUSIONS: In this model, LCP constructs had superior biomechanical properties compared with KCC constructs. Further research investigating the effect of repetitive loading is indicated.

Impact of abrupt versus gradual correction of mitral and tricuspid regurgitation: a modelling study.

AIMS: Correction of mitral and/or tricuspid regurgitation (MR, TR) frequently leads to poor outcomes in the days following intervention. We sought to understand how abrupt correction of MR and TR affects ventricular load and to investigate if gradual correction is beneficial. METHODS AND RESULTS: MR and TR were simulated using the CircAdapt cardiovascular system model with effective regurgitant orifice (ERO) areas of 0.5 cm2 and 0.7 cm2. Ventricular and atrial contractility reductions to 40% of normal and pulmonary hypertension were simulated. Abrupt and gradual ERO closure were simulated with homeostatic regulation of blood pressure and volume. Abrupt correction of MR increased left and right ventricular fibre stress by 40% and 15%, respectively, whereas TR correction increased left and right ventricular fibre stress by 26% and 19%, respectively. This spike was followed by a rapid drop in fibre stress. Myocardial dysfunction prolonged the spike but reduced its amplitude. Right ventricular fibre stress increased more with pulmonary hypertension and TR. Gradual correction demonstrated no spike in tissue load. CONCLUSIONS: Simulations demonstrated that abrupt ERO closure creates a transient increase in ventricular load that is prolonged by worsened myocardial condition and exacerbated by pulmonary hypertension. Gradual closure of the ERO abolishes this spike and merits clinical investigation.

Systolic Stretch Characterizes the Electromechanical Substrate Responsive to Cardiac Resynchronization Therapy.

OBJECTIVES: In this study, the authors tested the hypotheses that the systolic stretch index (SSI) developed by computer modeling and applied using echocardiographic strain imaging may characterize the electromechanical substrate predictive of outcome following cardiac resynchronization therapy (CRT). They included patients with QRS width 120 to 149 ms or non-left bundle branch block (LBBB), where clinical uncertainty for CRT exists. They further tested the hypothesis that global longitudinal strain (GLS) has additional prognostic value. BACKGROUND: Response to CRT is variable. Guidelines favor patient selection by electrocardiographic LBBB with QRS width ≥150 ms. METHODS: The authors studied 442 patients enrolled in the Adaptive CRT 94-site randomized trial with New York Heart Association functional class III-IV heart failure, ejection fraction ≤35%, and QRS ≥120 ms. A novel computer program semiautomatically calculated the SSI from strain curves as the sum of posterolateral prestretch percent before aortic valve opening and the septal rebound stretch percent during ejection. The primary endpoint was hospitalization for heart failure (HF) or death, and the secondary endpoint was death over 2 years after CRT. RESULTS: In all patients, high longitudinal SSI (≥ group median of 3.1%) was significantly associated with freedom from the primary endpoint of HF hospitalization or death (hazard ratio [HR] for low SSI: 2.17; 95% confidence interval [CI]: 1.45 to 3.24, p < 0.001) and secondary endpoint of death (HR for low SSI: 4.06; 95% CI: 1.95 to 8.45, p < 0.001). Among the 203 patients with QRS 120 to 149 ms or non-LBBB, those with high longitudinal SSI (≥ group median of 2.6%) had significantly fewer HF hospitalizations or deaths (HR for low SSI: 2.08; 95% CI: 1.27 to 3.41, p = 0.004) and longer survival (HR for low SSI: 5.08; 95% CI: 1.94 to 13.31, p < 0.001), similar to patients with LBBB ≥150 ms. SSI by circumferential strain had similar associations with clinical outcomes, and GLS was additive to SSI in predicting clinical events (p = 0.001). CONCLUSIONS: Systolic stretch by strain imaging characterized the myocardial substrate associated with favorable CRT response, including in the important patient subgroup with QRS width 120 to 149 ms or non-LBBB. GLS had additive prognostic value.

Relative Impact of Right Ventricular Electromechanical Dyssynchrony Versus Pulmonary Regurgitation on Right Ventricular Dysfunction and Exercise Intolerance in Patients After Repair of Tetralogy of Fallot.

Background The relative impact of right ventricular ( RV ) electromechanical dyssynchrony versus pulmonary regurgitation ( PR ) on exercise capacity and RV function after tetralogy of Fallot repair is unknown. We aimed to delineate the relative effects of these factors on RV function and exercise capacity. Methods and Results We retrospectively analyzed 81 children with tetralogy of Fallot repair using multivariable regression. Predictor parameters were electrocardiographic QRS duration reflecting electromechanical dyssynchrony and PR severity by cardiac magnetic resonance. The outcome parameters were exercise capacity (percentage predicted peak oxygen consumption) and cardiac magnetic resonance ejection fraction (RV ejection fraction). To understand the relative effects of RV dyssynchrony versus PR on exercise capacity and RV function, virtual patient simulations were performed using a closed-loop cardiovascular system model (CircAdapt), covering a wide spectrum of disease severity. Eighty-one patients with tetralogy of Fallot repair (median [interquartile range { IQR} ] age, 14.48 [11.55-15.91] years) were analyzed. All had prolonged QRS duration (median [IQR], 144 [123-152] ms), at least moderate PR (median [IQR], 40% [29%-48%]), reduced exercise capacity (median [IQR], 79% [68%-92%] predicted peak oxygen consumption), and reduced RV ejection fraction (median [IQR], 48% [44%-52%]). Longer QRS duration, more than PR , was associated with lower oxygen consumption and lower RV ejection fraction. In a multivariable regression analysis, oxygen consumption decreased with both increasing QRS duration and PR severity. CircAdapt modeling showed that RV dyssynchrony exerts a stronger limiting effect on exercise capacity and on RV ejection fraction than does PR , regardless of contractile function. Conclusions In both patient data and computer simulations, RV dyssynchrony, more than PR , appears to be associated with reduced exercise capacity and RV systolic dysfunction in patients after TOF repair.

The Left and Right Ventricles Respond Differently to Variation of Pacing Delays in Cardiac Resynchronization Therapy: A Combined Experimental- Computational Approach.

Introduction: Timing of atrial, right (RV), and left ventricular (LV) stimulation in cardiac resynchronization therapy (CRT) is known to affect electrical activation and pump function of the LV. In this study, we used computer simulations, with input from animal experiments, to investigate the effect of varying pacing delays on both LV and RV electrical dyssynchrony and contractile function. Methods: A pacing protocol was performed in dogs with atrioventricular block (N = 6), using 100 different combinations of atrial (A)-LV and A-RV pacing delays. Regional LV and RV electrical activation times were measured using 112 electrodes and LV and RV pressures were measured with catheter-tip micromanometers. Contractile response to a pacing delay was defined as relative change of the maximum rate of LV and RV pressure rise (dP/dtmax) compared to RV pacing with an A-RV delay of 125 ms. The pacing protocol was simulated in the CircAdapt model of cardiovascular system dynamics, using the experimentally acquired electrical mapping data as input. Results: Ventricular electrical activation changed with changes in the amount of LV or RV pre-excitation. The resulting changes in dP/dtmax differed markedly between the LV and RV. Pacing the LV 10-50 ms before the RV led to the largest increases in LV dP/dtmax. In contrast, RV dP/dtmax was highest with RV pre-excitation and decreased up to 33% with LV pre-excitation. These opposite patterns of changes in RV and LV dP/dtmax were reproduced by the simulations. The simulations extended these observations by showing that changes in steady-state biventricular cardiac output differed from changes in both LV and RV dP/dtmax. The model allowed to explain the discrepant changes in dP/dtmax and cardiac output by coupling between atria and ventricles as well as between the ventricles. Conclusion: The LV and the RV respond in a opposite manner to variation in the amount of LV or RV pre-excitation. Computer simulations capture LV and RV behavior during pacing delay variation and may be used in the design of new CRT optimization studies.

Toward three-dimensional nanoengineering of heterogeneous catalysts.

Cobalt-based Fischer-Tropsch systems are widely used to convert synthesis gas to clean hydrocarbon fuel. However, surprisingly little is known about the morphology of the catalysts on the nanoscale. Here we show that scanning transmission electron tomography reveals their true 3-D morphology and provides direct evidence that the support controls the final morphology of the catalyst. Such direct local three-dimensional measurements provide unprecedented insight into catalysis, and can henceforth transform our understanding of these complex materials.