Biophysical Modeling to Determine the Optimization of Left Ventricular Pacing Site and AV/VV Delays in the Acute and Chronic Phase of Cardiac Resynchronization Therapy.

BACKGROUND: Cardiac anatomy and function adapt in response to chronic cardiac resynchronization therapy (CRT). The effects of these changes on the optimal left ventricle (LV) lead location and timing delay settings have yet to be fully explored. OBJECTIVE: To predict the effects of chronic CRT on the optimal LV lead location and device timing settings over time. METHODS: Biophysical computational cardiac models were generated for 3 patients, immediately post-implant (ACUTE) and after at least 6 months of CRT (CHRONIC). Optimal LV pacing area and device settings were predicted by pacing the ACUTE and CHRONIC models across the LV epicardium (49 sites each) with a range of 9 pacing settings and simulating the acute hemodynamic response (AHR) of the heart. RESULTS: There were statistically significant differences between the distribution of the AHR in the ACUTE and CHRONIC models (P < 0.0005 in all cases). The site delivering the maximal AHR shifted location between the ACUTE and CHRONIC models but provided a negligible improvement (<2%). The majority of the acute optimal LV pacing regions (76-100%) and device settings (76-91%) remained optimal chronically. CONCLUSION: Optimization of the LV pacing location and device settings were important at the time of implant, with a reduced benefit over time, where the majority of the acute optimal LV pacing region and device settings remained optimal with chronic CRT.

Factors determining the magnitude of the pre-ejection leftward septal motion in left bundle branch block.

AIMS: An abnormal large leftward septal motion prior to ejection is frequently observed in left bundle branch block (LBBB) patients. This motion has been proposed as a predictor of response to cardiac resynchronization therapy (CRT). Our goal was to investigate factors that influence its magnitude. METHODS AND RESULTS: Left (LVP) and right ventricular (RVP) pressures and left ventricular (LV) volume were measured in eight canines. After induction of LBBB, LVP and, hence, the transmural septal pressure (PLV-RV = LVP-RVP) increased more slowly (P < 0.01) during the phase when septum moved leftwards. A biventricular finite-element LBBB simulation model confirmed that the magnitude of septal leftward motion depended on reduced rise of PLV-RV. The model showed that leftward septal motion was decreased with shorter activation delay, reduced global or right ventricular (RV) contractility, septal infarction, or when the septum was already displaced into the LV at end diastole by RV volume overload. Both experiments and simulations showed that pre-ejection septal hypercontraction occurs, in part, because the septum performs more of the work pushing blood towards the mitral valve leaflets to close them as the normal lateral wall contribution to this push is lost. CONCLUSIONS: Left bundle branch block lowers afterload against pre-ejection septal contraction, expressed as slowed rise of PLV-RV, which is a main cause and determinant of the magnitude of leftward septal motion. The motion may be small or absent due to septal infarct, impaired global or RV contractility or RV volume overload, which should be kept in mind if this motion is to be used in evaluation of CRT response.

Improvement of Right Ventricular Hemodynamics with Left Ventricular Endocardial Pacing during Cardiac Resynchronization Therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) with biventricular epicardial (BV-CS) or endocardial left ventricular (LV) stimulation (BV-EN) improves LV hemodynamics. The effect of CRT on right ventricular function is less clear, particularly for BV-EN. Our objective was to compare the simultaneous acute hemodynamic response (AHR) of the right and left ventricles (RV and LV) with BV-CS and BV-EN in order to determine the optimal mode of CRT delivery. METHODS: Nine patients with previously implanted CRT devices successfully underwent a temporary pacing study. Pressure wires measured the simultaneous AHR in both ventricles during different pacing protocols. Conventional epicardial CRT was delivered in LV-only (LV-CS) and BV-CS configurations and compared with BV-EN pacing in multiple locations using a roving decapolar catheter. RESULTS: Best BV-EN (optimal AHR of all LV endocardial pacing sites) produced a significantly greater RV AHR compared with LV-CS and BV-CS pacing (P < 0.05). RV AHR had a significantly increased standard deviation compared to LV AHR (P < 0.05) with a weak correlation between RV and LV AHR (Spearman rs = -0.06). Compromised biventricular optimization, whereby RV AHR was increased at the expense of a smaller decrease in LV AHR, was achieved in 56% of cases, all with BV-EN pacing. CONCLUSIONS: BV-EN pacing produces significant increases in both LV and RV AHR, above that achievable with conventional epicardial pacing. RV AHR cannot be used as a surrogate for optimizing LV AHR; however, compromised biventricular optimization is possible. The beneficial effect of endocardial LV pacing on RV function may have important clinical benefits beyond conventional CRT.

Surgeon Knowledge of the Pulmonary Arterial System and Surgical Plan Confidence Is Improved by Interactive Virtual 3D-CT Models of Lung Cancer Patient Anatomies.

Objective: Interactive three-dimensional virtual models of pulmonary structures (3D-CT) may improve the safety and accuracy of robotic-assisted thoracic surgery (RATS). The aim of this study was to evaluate the impact of 3D-CT models as an imaging adjunct on surgical confidence and anatomical assessment for lobectomy planning. Methods: We retrospectively analyzed the response of 10 specialist thoracic surgeons who each reviewed 10 pre-operative images of patients undergoing robotic-assisted lobectomy lung cancer cases from June to November 2018 in our institute, resulting in 100 data points. The number of arteries, veins, and bronchi entering the resected lobes were determined from the operation video recording by the operating surgeon. 3D-CT models were generated for each case and made available for online visualization and manipulation. Thoracic surgeons were invited to participate in the survey which consisted of evaluation of CT (control) and 3D-CT (intervention) models. A questionnaire regarding anatomical structures, surgical approach, and confidence was administered. Results: Ten participants were recruited. 3D-CT models led to a significant (p < 0.003) increase in the surgeons' ability to correctly identifying pulmonary arteries entering the resection lobes in 35% (CT) and 57% (3D-CT) of cases. A significant (p < 1e-13) improvement in anatomy assessment and surgical plan confidence was observed for the 3D-CT arm, with median Likert scale scores of "2-Slightly easy" (CT) and "4-Very easy" (3D-CT). Conclusion: The use of 3D-CT models for thoracic surgery planning increases the surgeon confidence in recognizing anatomical structures, largely by enhanced appreciation of anatomical variations in the segmental pulmonary arterial system. Further studies are needed to investigate if 3D-CT models can be used in providing precise information about segmental artery distribution and therefore surgical planning of sub-lobar resections.

Robotic-assisted Laparoscopic Partial Nephrectomy in a Horseshoe Kidney. A Case Report and Review of the Literature.

Horseshoe kidney is a rare renal fusion anomaly, and because of limited mobilization of the kidney and its multiple arterial blood supplies, minimally invasive surgery for renal tumors can be challenging. We describe a case of a right-side oncocytoma in a horseshoe kidney managed robotically and review the literature of robotic-assisted laparoscopic surgical resection of kidney tumors in renal fusion anomalies. Robotic-assisted laparoscopic partial nephrectomy in a horseshoe kidney is feasible. Fusion-related limited mobility during the procedure, as well as an extremely variable blood supply, require meticulous planning. Multi-phase computed tomography and interactive 3D anatomical models are helpful tools to prepare for surgery.

Measurement and modeling of coronary blood flow.

Ischemic heart disease that comprises both coronary artery disease and microvascular disease is the single greatest cause of death globally. In this context, enhancing our understanding of the interaction of coronary structure and function is not only fundamental for advancing basic physiology but also crucial for identifying new targets for treating these diseases. A central challenge for understanding coronary blood flow is that coronary structure and function exhibit different behaviors across a range of spatial and temporal scales. While experimental studies have sought to understand this feature by isolating specific mechanisms, in tandem, computational modeling is increasingly also providing a unique framework to integrate mechanistic behaviors across different scales. In addition, clinical methods for assessing coronary disease severity are continuously being informed and updated by findings in basic physiology. Coupling these technologies, computational modeling of the coronary circulation is emerging as a bridge between the experimental and clinical domains, providing a framework to integrate imaging and measurements from multiple sources with mathematical descriptions of governing physical laws. State-of-the-art computational modeling is being used to combine mechanistic models with data to provide new insight into coronary physiology, optimization of medical technologies, and new applications to guide clinical practice.

The impact of beat-to-beat variability in optimising the acute hemodynamic response in cardiac resynchronisation therapy.

BACKGROUND: Acute indicators of response to cardiac resynchronisation therapy (CRT) are critical for developing lead optimisation algorithms and evaluating novel multi-polar, multi-lead and endocardial pacing protocols. Accounting for beat-to-beat variability in measures of acute haemodynamic response (AHR) may help clinicians understand the link between acute measurements of cardiac function and long term clinical outcome. METHODS AND RESULTS: A retrospective study of invasive pressure tracings from 38 patients receiving an acute pacing and electrophysiological study was performed. 602 pacing protocols for left ventricle (LV) (n = 38), atria-ventricle (AV) (n = 9), ventricle-ventricle (VV) (n = 12) and endocardial (ENDO) (n = 8) optimisation were performed. AHR was measured as the maximal rate of LV pressure development (dP/dtMx) for each beat. The range of the 95% confidence interval (CI) of mean AHR was ~ 7% across all optimisation protocols compared with the reported CRT response cut off value of 10%. A single clear optimal protocol was identifiable in 61%, 22%, 25% and 50% for LV, AV, VV and ENDO optimisation cases, respectively. A level of service (LOS) optimisation that aimed to maximise the expected AHR 5th percentile, minimising variability and maximising AHR, led to distinct optimal protocols from conventional mean AHR optimisation in 34%, 78%, 67% and 12.5% of LV, AV, VV and ENDO optimisation cases, respectively. CONCLUSION: The beat-to-beat variation in AHR is significant in the context of CRT cut off values. A LOS optimisation offers a novel index to identify the optimal pacing site that accounts for both the mean and variation of the baseline measurement and pacing protocol.

Beneficial Effect on Cardiac Resynchronization From Left Ventricular Endocardial Pacing Is Mediated by Early Access to High Conduction Velocity Tissue: Electrophysiological Simulation Study.

BACKGROUND: Cardiac resynchronization therapy (CRT) delivered via left ventricular (LV) endocardial pacing (ENDO-CRT) is associated with improved acute hemodynamic response compared with LV epicardial pacing (EPI-CRT). The role of cardiac anatomy and physiology in this improved response remains controversial. We used computational electrophysiological models to quantify the role of cardiac geometry, tissue anisotropy, and the presence of fast endocardial conduction on myocardial activation during ENDO-CRT and EPI-CRT. METHODS AND RESULTS: Cardiac activation was simulated using the monodomain tissue excitation model in 2-dimensional (2D) canine and human and 3D canine biventricular models. The latest activation times (LATs) for LV endocardial and biventricular epicardial tissue were calculated (LVLAT and TLAT), as well the percentage decrease in LATs for endocardial (en) versus epicardial (ep) LV pacing (defined as %dLV=100×(LVLATep-LVLATen)/LVLATep and %dT=100×(TLATep-TLATen)/TLATep, respectively). Normal canine cardiac anatomy is responsible for %dLV and %dT values of 7.4% and 5.5%, respectively. Concentric and eccentric remodeled anatomies resulted in %dT values of 15.6% and 1.3%, respectively. The 3D biventricular-paced canine model resulted in %dLV and %dT values of -7.1% and 1.5%, in contrast to the experimental observations of 16% and 11%, respectively. Adding fast endocardial conduction to this model altered %dLV and %dT to 13.1% and 10.1%, respectively. CONCLUSIONS: Our results provide a physiological explanation for improved response to ENDO-CRT. We predict that patients with viable fast-conducting endocardial tissue or distal Purkinje network or both, as well as concentric remodeling, are more likely to benefit from reduced ATs and increased synchrony arising from endocardial pacing.

Multi-scale parameterisation of a myocardial perfusion model using whole-organ arterial networks.

A method to extract myocardial coronary permeabilities appropriate to parameterise a continuum porous perfusion model using the underlying anatomical vascular network is developed. Canine and porcine whole-heart discrete arterial models were extracted from high-resolution cryomicrotome vessel image stacks. Five parameterisation methods were considered that are primarily distinguished by the level of anatomical data used in the definition of the permeability and pressure-coupling fields. Continuum multi-compartment porous perfusion model pressure results derived using these parameterisation methods were compared quantitatively via a root-mean-square metric to the Poiseuille pressure solved on the discrete arterial vasculature. The use of anatomical detail to parameterise the porous medium significantly improved the continuum pressure results. The majority of this improvement was attributed to the use of anatomically-derived pressure-coupling fields. It was found that the best results were most reliably obtained by using porosity-scaled isotropic permeabilities and anatomically-derived pressure-coupling fields. This paper presents the first continuum perfusion model where all parameters were derived from the underlying anatomical vascular network.

Parameterisation of multi-scale continuum perfusion models from discrete vascular networks.

Experimental data and advanced imaging techniques are increasingly enabling the extraction of detailed vascular anatomy from biological tissues. Incorporation of anatomical data within perfusion models is non-trivial, due to heterogeneous vessel density and disparate radii scales. Furthermore, previous idealised networks have assumed a spatially repeating motif or periodic canonical cell, thereby allowing for a flow solution via homogenisation. However, such periodicity is not observed throughout anatomical networks. In this study, we apply various spatial averaging methods to discrete vascular geometries in order to parameterise a continuum model of perfusion. Specifically, a multi-compartment Darcy model was used to provide vascular scale separation for the fluid flow. Permeability tensor fields were derived from both synthetic and anatomically realistic networks using (1) porosity-scaled isotropic, (2) Huyghe and Van Campen, and (3) projected-PCA methods. The Darcy pressure fields were compared via a root-mean-square error metric to an averaged Poiseuille pressure solution over the same domain. The method of Huyghe and Van Campen performed better than the other two methods in all simulations, even for relatively coarse networks. Furthermore, inter-compartment volumetric flux fields, determined using the spatially averaged discrete flux per unit pressure difference, were shown to be accurate across a range of pressure boundary conditions. This work justifies the application of continuum flow models to characterise perfusion resulting from flow in an underlying vascular network.

Myocardial perfusion distribution and coronary arterial pressure and flow signals: clinical relevance in relation to multiscale modeling, a review.

Coronary artery disease, CAD, is associated with both narrowing of the epicardial coronary arteries and microvascular disease, thereby limiting coronary flow and myocardial perfusion. CAD accounts for almost 2 million deaths within the European Union on an annual basis. In this paper, we review the physiological and pathophysiological processes underlying clinical decision making in coronary disease as well as the models for interpretation of the underlying physiological mechanisms. Presently, clinical decision making is based on non-invasive magnetic resonance imaging, MRI, of myocardial perfusion and invasive coronary hemodynamic measurements of coronary pressure and Doppler flow velocity signals obtained during catheterization. Within the euHeart project, several innovations have been developed and applied to improve diagnosis-based understanding of the underlying biophysical processes. Specifically, MRI perfusion data interpretation has been advanced by the gradientogram, a novel graphical representation of the spatiotemporal myocardial perfusion gradient. For hemodynamic data, functional indices of coronary stenosis severity that do not depend on maximal vasodilation are proposed and the Valsalva maneuver for indicating the extravascular resistance component of the coronary circulation has been introduced. Complementary to these advances, model innovation has been directed to the porous elastic model coupled to a one-dimensional model of the epicardial arteries. The importance of model development is related to the integration of information from different modalities, which in isolation often result in conflicting treatment recommendations.