The Long Wait for a New Drug for Human African Trypanosomiasis.

Human African trypanosomiasis (HAT) is responsible for around 3000 reported cases each year. Treatments for HAT are expensive and problematic to administer, and available drugs are old and less than ideal, some with high levels of toxicity that result in debilitating and, in some cases, fatal side effects. Treatment options are limited, with only one drug, eflornithine, introduced in the last 28 years. Here we examine the limitations of current chemotherapeutic approaches to manage HAT, the constraints to new drug development exploring drug failures and new drugs on the horizon, and consider the epidemiological, political, social, and economic factors influencing drug development.

A Lumped Parameter Model to Study Atrioventricular Valve Regurgitation in Stage 1 and Changes Across Stage 2 Surgery in Single Ventricle Patients.

GOAL: This manuscript evaluates atrioventric-ular valve regurgitation (AVVR) in babies born with an already very challenging heart condition, i.e., with single ventricle physiology. Although the second surgery that single ventricle patients undergo is thought to decrease AVVR, there is much controversy in the clinical literature about AVVR treatment. METHODS: The effect of AVVR on Stage 1 haemodynamics and resulting acute changes from conversion to Stage 2 circulation in single ventricle patients are analyzed through lumped parameter models. Several degrees of AVVR severity are analyzed, for two types of valve regurgitation: incomplete leaflet closure and valve prolapse. RESULTS: The models show that increasing AVVR in Stage 1 induces the following effects: first, higher stroke volume and associated decrease in ventricular end-systolic volume; second, increase in atrial volumes with V-loop enlargement in pressure-volume curves; third, pulmonary venous hypertension. The Stage 2 surgery results in volume unloading of the ventricle, thereby, driving a decrease in AVVR. However, this effect is offset by an increase in ventricular pressures resulting in a net increase in regurgitation fraction (RF) of approximately 0.1 (for example, in severe AVVR, the preoperative RF increases from 60% to 70% postoperatively). Moreover, despite some improvements to sarcomere function early after Stage 2 surgery, it may deteriorate in cases of severe AVVR. CONCLUSION: In patients with moderate to severe AVVR, restoration of atrioventricular valve competence prior to, or at the time of, Stage 2 surgery would likely lead to improved haemodynamics and clinical outcome as the models suggest that uncorrected AVVR can worsen across Stage 2 surgery. This was found to be independent of the AVVR degree and mechanisms.

Statistical Shape Modeling for Cavopulmonary Assist Device Development: Variability of Vascular Graft Geometry and Implications for Hemodynamics.

Patients born with a single functional ventricle typically undergo three-staged surgical palliation in the first years of life, with the last stage realizing a cross-like total cavopulmonary connection (TCPC) of superior and inferior vena cavas (SVC and IVC) with both left and right pulmonary arteries, allowing all deoxygenated blood to flow passively back to the lungs (Fontan circulation). Even though within the past decades more patients survive into adulthood, the connection comes at the prize of deficiencies such as chronic systemic venous hypertension and low cardiac output, which ultimately may lead to Fontan failure. Many studies have suggested that the TCPC's inherent insufficiencies might be addressed by adding a cavopulmonary assist device (CPAD) to provide the necessary pressure boost. While many device concepts are being explored, few take into account the complex cardiac anatomy typically associated with TCPCs. In this study, we focus on the extra cardiac conduit vascular graft connecting IVC and pulmonary arteries as one possible landing zone for a CPAD and describe its geometric variability in a cohort of 18 patients that had their TCPC realized with a 20mm vascular graft. We report traditional morphometric parameters and apply statistical shape modeling to determine the main contributors of graft shape variability. Such information may prove useful when designing CPADs that are adapted to the challenging anatomical boundaries in Fontan patients. We further compute the anatomical mean 3D graft shape (template graft) as a representative of key shape features of our cohort and prove this template graft to be a significantly better approximation of population and individual patient's hemodynamics than a commonly used simplified tube geometry. We therefore conclude that statistical shape modeling results can provide better models of geometric and hemodynamic boundary conditions associated with complex cardiac anatomy, which in turn may impact on improved cardiac device development.

Inverse problems in reduced order models of cardiovascular haemodynamics: aspects of data assimilation and heart rate variability.

Inverse problems in cardiovascular modelling have become increasingly important to assess each patient individually. These problems entail estimation of patient-specific model parameters from uncertain measurements acquired in the clinic. In recent years, the method of data assimilation, especially the unscented Kalman filter, has gained popularity to address computational efficiency and uncertainty consideration in such problems. This work highlights and presents solutions to several challenges of this method pertinent to models of cardiovascular haemodynamics. These include methods to (i) avoid ill-conditioning of the covariance matrix, (ii) handle a variety of measurement types, (iii) include a variety of prior knowledge in the method, and (iv) incorporate measurements acquired at different heart rates, a common situation in the clinic where the patient state differs according to the clinical situation. Results are presented for two patient-specific cases of congenital heart disease. To illustrate and validate data assimilation with measurements at different heart rates, the results are presented on a synthetic dataset and on a patient-specific case with heart valve regurgitation. It is shown that the new method significantly improves the agreement between model predictions and measurements. The developed methods can be readily applied to other pathophysiologies and extended to dynamical systems which exhibit different responses under different sets of known parameters or different sets of inputs (such as forcing/excitation frequencies).

Data assimilation and modelling of patient-specific single-ventricle physiology with and without valve regurgitation.

A closed-loop lumped parameter model of blood circulation is considered for single-ventricle shunt physiology. Its parameters are estimated by an inverse problem based on patient-specific haemodynamics measurements. As opposed to a black-box approach, maximizing the number of parameters that are related to physically measurable quantities motivates the present model. Heart chambers are described by a single-fibre mechanics model, and valve function is modelled with smooth opening and closure. A model for valve prolapse leading to valve regurgitation is proposed. The method of data assimilation, in particular the unscented Kalman filter, is used to estimate the model parameters from time-varying clinical measurements. This method takes into account both the uncertainty in prior knowledge related to the parameters and the uncertainty associated with the clinical measurements. Two patient-specific cases - one without regurgitation and one with atrioventricular valve regurgitation - are presented. Pulmonary and systemic circulation parameters are successfully estimated, without assumptions on their relationships. Parameters governing the behaviour of heart chambers and valves are either fixed based on biomechanics, or estimated. Results of the inverse problem are validated qualitatively through clinical measurements or clinical estimates that were not included in the parameter estimation procedure. The model and the estimation method are shown to successfully capture patient-specific clinical observations, even with regurgitation, such as the double peaked nature of valvular flows and anomalies in electrocardiogram readings. Lastly, biomechanical implications of the results are discussed.

Pulmonary Hemodynamics Simulations Before Stage 2 Single Ventricle Surgery: Patient-Specific Parameter Identification and Clinical Data Assessment.

Single ventricle heart defects involve pathologies in which the heart has only one functional pumping chamber. In these conditions, treatment consists of three staged procedures. At stage 1 pulmonary flow is provided through an artificial shunt from the systemic circulation. Representative hemodynamics models able to explore different virtual surgical options can be built based on pre-operative imaging and patient data. In this context, the specification of boundary conditions is necessary to compute pressure and flow in the entire domain. However, these boundary conditions are rarely the measured variables. Moreover, to take into account the rest of the circulation outside of the three-dimensional modeled domain, a number of reduced order models exist. A simplified method is presented to iteratively, but automatically, tune reduced model parameters from hemodynamic data clinically measured before stage 2 surgery. Patient-specific local hemodynamics around the distal systemic-to-pulmonary shunt anastomosis and the connected pulmonary arteries are also analyzed. Multi-scale models of pre-stage 2 single ventricle patients are developed, including a 3D model of shunt-pulmonary connection and a number of pulmonary arteries. For each pulmonary outlet a total downstream resistance is identified, consistent with measured flow split and pressures. Target pressures such as minimum, maximum or average over one or both lungs are considered, depending on the clinical measurement. When possible, both steady and pulsatile identifications are performed. The methodology is demonstrated with six patient-specific models: the clinical target data are well-matched, except for one case where clinical data were subsequently found inconsistent. Inhomogeneous pressure, swirling blood flow patterns and very high wall shear stress 3D maps highlight similarities and differences among patients. Steady and pulsatile tuning results are similar. This work demonstrates (1) how to use routine clinical data to define boundary conditions for patient-specific 3D models in pre-stage 2 single ventricle circulations and (2) how simulations can help to check the coherence of clinical data, or provide insights to clinicians that are otherwise difficult to measure, such as in the presence of kinks. Finally, the choice of steady vs. pulsatile tuning, limitations and possible extensions of this work are discussed.

Hemodynamic effects of left pulmonary artery stenosis after superior cavopulmonary connection: a patient-specific multiscale modeling study.

OBJECTIVE: Currently, no quantitative guidelines have been established for treatment of left pulmonary artery (LPA) stenosis. This study aims to quantify the effects of LPA stenosis on postoperative hemodynamics for single-ventricle patients undergoing stage II superior cavopulmonary connection (SCPC) surgery, using a multiscale computational approach. METHODS: Image data from 6 patients were segmented to produce 3-dimensional models of the pulmonary arteries before stage II surgery. Pressure and flow measurements were used to tune a 0-dimensional model of the entire circulation. Postoperative geometries were generated through stage II virtual surgery; varying degrees of LPA stenosis were applied using mesh morphing and hemodynamics assessed through coupled 0-3-dimensional simulations. To relate metrics of stenosis to clinical classifications, pediatric cardiologists and surgeons ranked the degrees of stenosis in the models. The effects of LPA stenosis were assessed based on left-to-right pulmonary artery flow split ratios, mean pressure drop across the stenosis, cardiac pressure-volume loops, and other clinically relevant parameters. RESULTS: Stenosis of >65% of the vessel diameter was required to produce a right pulmonary artery:LPA flow split <30%, and/or a mean pressure drop of >3.0 mm Hg, defined as clinically significant changes. CONCLUSIONS: The effects of <65% stenosis on SCPC hemodynamics and physiology were minor and may not justify the increased complexity of adding LPA arterioplasty to the SCPC operation. However, in the longer term, pulmonary augmentation may affect outcomes of the Fontan completion surgery, as pulmonary artery distortion is a risk factor that may influence stage III physiology.

Integration of clinical data collected at different times for virtual surgery in single ventricle patients: a case study.

Newborns with single ventricle physiology are usually palliated with a multi-staged procedure. When cardiovascular complications e.g., collateral vessel formation occur during the inter-stage periods, further treatments are required. An 8-month-old patient, who underwent second stage (i.e., bi-directional Glenn, BDG) surgery at 4 months, was diagnosed with a major veno-venous collateral vessel (VVC) which was endovascularly occluded to improve blood oxygen saturations. Few clinical data were collected at 8 months, whereas at 4 months a more detailed data set was available. The aim of this study is threefold: (i) to show how to build a patient-specific model describing the hemodynamics in the presence of VVC, using patient-specific clinical data collected at different times; (ii) to use this model to perform virtual VVC occlusion for quantitative hemodynamics prediction; and (iii) to compare predicted hemodynamics with post-operative measurements. The three-dimensional BDG geometry, resulting from the virtual surgery on the first stage model, was coupled with a lumped parameter model (LPM) of the 8-month patient's circulation. The latter was developed by scaling the 4-month LPM to account for changes in vascular impedances due to growth and adaptation. After virtual VVC closure, the model confirmed the 2 mmHg BDG pressure increase, as clinically observed, suggesting the importance of modeling vascular adaptation following the BDG procedure.

An integrated approach to patient-specific predictive modeling for single ventricle heart palliation.

In patients with congenital heart disease and a single ventricle (SV), ventricular support of the circulation is inadequate, and staged palliative surgery (usually 3 stages) is needed for treatment. In the various palliative surgical stages individual differences in the circulation are important and patient-specific surgical planning is ideal. In this study, an integrated approach between clinicians and engineers has been developed, based on patient-specific multi-scale models, and is here applied to predict stage 2 surgical outcomes. This approach involves four distinct steps: (1) collection of pre-operative clinical data from a patient presenting for SV palliation, (2) construction of the pre-operative model, (3) creation of feasible virtual surgical options which couple a three-dimensional model of the surgical anatomy with a lumped parameter model (LPM) of the remainder of the circulation and (4) performance of post-operative simulations to aid clinical decision making. The pre-operative model is described, agreeing well with clinical flow tracings and mean pressures. Two surgical options (bi-directional Glenn and hemi-Fontan operations) are virtually performed and coupled to the pre-operative LPM, with the hemodynamics of both options reported. Results are validated against postoperative clinical data. Ultimately, this work represents the first patient-specific predictive modeling of stage 2 palliation using virtual surgery and closed-loop multi-scale modeling.

Effects of pulmonary artery banding and retrograde aortic arch obstruction on the hybrid palliation of hypoplastic left heart syndrome.

OBJECTIVES: The hybrid approach achieves stage 1 palliation of hypoplastic left heart syndrome with flow and physiologic characteristics that are different from those of the surgical Norwood circulations. In addition to having branch pulmonary arterial banding regulating the balance between pulmonary and systemic blood flows, coronary and cerebral perfusion are dependent on retrograde flow through the native aortic arch when aortic atresia is present. Accordingly, we used computational modeling to assess the effects of pulmonary artery banding diameter and retrograde aortic arch hypoplasia or obstruction on the hybrid stage 1 circulation, including the influence on systemic and cerebral oxygen deliveries. METHODS: A computational modeling technique was used to couple a 3-dimensional geometry of the hybrid palliation with a hydraulic network of the entire circulation based on pre-stage 2 hemodynamics. This validated multiscale approach predicts clinically relevant outcomes, such as flow, pressure, ejection fraction, and oxygen delivery. Simulations with pulmonary artery banding varying between 1.5 and 3.5 mm were performed. To examine the effects of retrograde aortic arch hypoplasia and obstruction, models of differing aortic arch diameter (2-5 mm) and isthmus coarctation (2.5-5 mm) were studied. RESULTS: Banding the branch pulmonary arteries to 2 mm led to pulmonary and systemic blood flows closest to 1:1 and produced the highest mixed venous saturation and systemic oxygen delivery. Both cerebral and coronary perfusion decreased markedly when the retrograde aortic arch or the coarctation was less than 3 mm in diameter. Moreover, flow reversal in the carotid arteries was observed during diastole in all models. CONCLUSIONS: These computational simulations of the stage 1 hybrid palliation for hypoplastic left heart syndrome with aortic atresia suggest that small differences in the degree of branch pulmonary arterial banding can result in significant changes in the overall performance of the hybrid palliation. Furthermore, retrograde aortic arch hypoplasia or obstruction can lead to suboptimal cerebral and coronary perfusion. Precise pulmonary artery banding may be important to optimize interstage physiology in patients undergoing the hybrid approach, and pre-interventional imaging of the aortic arch and isthmus should be performed to rule out potential for post-procedural suboptimal cerebral and coronary perfusion.

Predictive modeling of the virtual Hemi-Fontan operation for second stage single ventricle palliation: two patient-specific cases.

Single ventricle hearts are congenital cardiovascular defects in which the heart has only one functional pumping chamber. The treatment for these conditions typically requires a three-staged operative process where Stage 1 is typically achieved by a shunt between the systemic and pulmonary arteries, and Stage 2 by connecting the superior venous return to the pulmonary circulation. Surgically, the Stage 2 circulation can be achieved through a procedure called the Hemi-Fontan, which reconstructs the right atrium and pulmonary artery to allow for an enlarged confluence with the superior vena cava. Based on pre-operative data obtained from two patients prior to Stage 2 surgery, we developed two patient-specific multi-scale computational models, each including the 3D geometrical model of the surgical junction constructed from magnetic resonance imaging, and a closed-loop systemic lumped-parameter network derived from clinical measurements. "Virtual" Hemi-Fontan surgery was performed on the 3D model with guidance from clinical surgeons, and a corresponding multi-scale simulation predicts the patient's post-operative hemodynamic and physiologic conditions. For each patient, a post-operative active scenario with an increase in the heart rate (HR) and a decrease in the pulmonary and systemic vascular resistance (PVR and SVR) was also performed. Results between the baseline and this "active" state were compared to evaluate the hemodynamic and physiologic implications of changing conditions. Simulation results revealed a characteristic swirling vortex in the Hemi-Fontan in both patients, with flow hugging the wall along the SVC to Hemi-Fontan confluence. One patient model had higher levels of swirling, recirculation, and flow stagnation. However, in both models, the power loss within the surgical junction was less than 13% of the total power loss in the pulmonary circulation, and less than 2% of the total ventricular power. This implies little impact of the surgical junction geometry on the SVC pressure, cardiac output, and other systemic parameters. In contrast, varying HR, PVR, and SVR led to significant changes in theses clinically relevant global parameters. Adopting a work-flow of customized virtual planning of the Hemi-Fontan procedure with patient-specific data, this study demonstrates the ability of multi-scale modeling to reproduce patient specific flow conditions under differing physiological states. Results demonstrate that the same operation performed in two different patients can lead to different hemodynamic characteristics, and that modeling can be used to uncover physiologic changes associated with different clinical conditions.

Implementing the Sano modification in an experimental model of first-stage palliation of hypoplastic left heart syndrome.

This study describes the implementation of an experimental model of the "Sano" variant (right-ventricle to pulmonary-artery shunt) of the Norwood operation used to treat hypoplastic left-heart syndrome (HLHS). The Sano operation is an alternative to the modified Blalock-Taussig shunt (innominate to pulmonary artery shunt). In the experimental setup, the single ventricle is simulated using a Berlin Heart Excor ventricular assist device and the Sano shunt is constructed by attaching a Tygon tube (6 mm internal diameter, 40 mm long) to the perforated de-airing valve of the Berlin Heart at one end, and to a pulmonary compliance chamber at the other end. The feasibility of the setup was verified by testing two rapid-prototyped patient-specific anatomical models (one without and one with aortic coarctation) under pulsatile flow conditions typical of Norwood patients. Results showed physiological and repeatable pressure and flow signals, as well as physiological values for pulmonary and aortic flow. Shunt flow was regulated by shunt size, and diastolic runoff through the shunt was also observed, both being features of Sano physiology. This system allows for comparing variations of first stage palliation of HLHS in vitro, and it also represents a source of data for validation of computational models.

Reduced ascending aorta distensibility relates to adverse ventricular mechanics in patients with hypoplastic left heart syndrome: noninvasive study using wave intensity analysis.

OBJECTIVE: To evaluate the aortic arch elastic properties and ventriculoarterial coupling efficiency in patients with single ventricle physiology, with and without a surgically reconstructed arch. METHODS: We studied 21 children with single ventricle physiology after bidirectional superior cavopulmonary surgery: 10 with hypoplastic left heart syndrome, who underwent surgical arch reconstruction, and 11 with other types of single ventricle physiology but without arch reconstruction. All children underwent pre-Fontan magnetic resonance imaging. No patient exhibited aortic recoarctation. Data on aortic wave speed, aortic distensibility and wave intensity profiles were all extracted from the magnetic resonance imaging studies using an in-house-written plug-in for the Digital Imaging and Communications in Medicine viewer OsiriX. RESULTS: Children with hypoplastic left heart syndrome had significantly greater wave speed (P = .002), and both stiffer (P = .004) and larger (P < .0001) ascending aortas than the patients with a nonreconstructed arch. Aortic distensibility was not influenced by ventricular stroke volume but depended on a combination of increased aortic diameter and abnormal wall mechanical properties. Those with hypoplastic left heart syndrome had a lower peak wave intensity and reduced energy carried by the forward compression and the forward expansion waves, even after correction for stroke volume, suggesting an abnormal systolic and diastolic function. Lower wave energy was associated with an increased aortic diameter. CONCLUSIONS: Using a novel, noninvasive technique based on image analysis, we have demonstrated that aortic arch reconstruction in children with hypoplastic left heart syndrome is associated with reduced aortic distensibility and unfavorable ventricular-vascular coupling compared with those with single ventricle physiology without aortic arch reconstruction.

A non-invasive clinical application of wave intensity analysis based on ultrahigh temporal resolution phase-contrast cardiovascular magnetic resonance.

BACKGROUND: Wave intensity analysis, traditionally derived from pressure and velocity data, can be formulated using velocity and area. Flow-velocity and area can both be derived from high-resolution phase-contrast cardiovascular magnetic resonance (PC-CMR). In this study, very high temporal resolution PC-CMR data is processed using an integrated and semi-automatic technique to derive wave intensity. METHODS: Wave intensity was derived in terms of area and velocity changes. These data were directly derived from PC-CMR using a breath-hold spiral sequence accelerated with sensitivity encoding (SENSE). Image processing was integrated in a plug-in for the DICOM viewer OsiriX, including calculations of wave speed and wave intensity. Ascending and descending aortic data from 15 healthy volunteers (30 ± 6 years) data were used to test the method for feasibility, and intra- and inter-observer variability. Ascending aortic data were also compared with results from 15 patients with coronary heart disease (61 ± 13 years) to assess the clinical usefulness of the method. RESULTS: Rapid image acquisition (11 s breath-hold) and image processing was feasible in all volunteers. Wave speed was physiological (5.8 ± 1.3 m/s ascending aorta, 5.0 ± 0.7 m/s descending aorta) and the wave intensity pattern was consistent with traditionally formulated wave intensity. Wave speed, peak forward compression wave in early systole and peak forward expansion wave in late systole at both locations exhibited overall good intra- and inter-observer variability. Patients with coronary heart disease had higher wave speed (p <0.0001), and lower forward compression wave (p <0.0001) and forward expansion wave (p <0.0005) peaks. This difference is likely related to the older age of the patients' cohort, indicating stiffer aortas, as well as compromised ventricular function due to their underlying condition. CONCLUSION: A non-invasive, semi-automated and reproducible method for performing wave intensity analysis is presented. Its application is facilitated by the use of a very high temporal resolution spiral sequence. A formulation of wave intensity based on area change has also been proposed, involving no assumptions about the cross-sectional shape of the vessel.

In vitro study of the Norwood palliation: a patient-specific mock circulatory system.

The aim of this study was to build a mock circulatory system replicating in vitro the hemodynamics following the Norwood procedure and testing patient-specific anatomies focusing on the effect of aortic coarctation. Three anatomies were reconstructed from magnetic resonance images and rapid prototyped with transparent rigid resin. The models presented varying degrees of coarctation (none, moderate, and severe). A Blalock-Taussing (BT) shunt was modeled in all phantoms, which were inserted into a mock circulation. The single ventricle was simulated using a Berlin Heart driven with a PC-controlled piston. Resistive and compliant elements were implemented, creating a lumped parameter network. Pressure was measured at three locations: the transverse aortic arch, just after the aortic isthmus, and further downstream in the thoracic aorta. Volume distribution was derived from the instantaneous flow measurements at three outlets: upper body, lower body, and BT shunt. The combination of three-dimensional (3D) detailed anatomy and lumped parameter network effectively renders the circuit a multiscale in vitro model that successfully reproduces physiologic pressure signals. The pressure results highlight the larger pressure drop caused by coarctation and show the effect of pressure recovery. Results also suggest a reduction of flow to the lower body with increasing severity of coarctation, to the advantage of upper body and pulmonary circulation.