On a sparse pressure-flow rate condensation of rigid circulation models.

Cardiovascular simulation has shown potential value in clinical decision-making, providing a framework to assess changes in hemodynamics produced by physiological and surgical alterations. State-of-the-art predictions are provided by deterministic multiscale numerical approaches coupling 3D finite element Navier Stokes simulations to lumped parameter circulation models governed by ODEs. Development of next-generation stochastic multiscale models whose parameters can be learned from available clinical data under uncertainty constitutes a research challenge made more difficult by the high computational cost typically associated with the solution of these models. We present a methodology for constructing reduced representations that condense the behavior of 3D anatomical models using outlet pressure-flow polynomial surrogates, based on multiscale model solutions spanning several heart cycles. Relevance vector machine regression is compared with maximum likelihood estimation, showing that sparse pressure/flow rate approximations offer superior performance in producing working surrogate models to be included in lumped circulation networks. Sensitivities of outlets flow rates are also quantified through a Sobol׳ decomposition of their total variance encoded in the orthogonal polynomial expansion. Finally, we show that augmented lumped parameter models including the proposed surrogates accurately reproduce the response of multiscale models they were derived from. In particular, results are presented for models of the coronary circulation with closed loop boundary conditions and the abdominal aorta with open loop boundary conditions.

Uncertainty quantification in virtual surgery hemodynamics predictions for single ventricle palliation.

The adoption of simulation tools to predict surgical outcomes is increasingly leading to questions about the variability of these predictions in the presence of uncertainty associated with the input clinical data. In the present study, we propose a methodology for full propagation of uncertainty from clinical data to model results that, unlike deterministic simulation, enables estimation of the confidence associated with model predictions. We illustrate this problem in a virtual stage II single ventricle palliation surgery example. First, probability density functions (PDFs) of right pulmonary artery (PA) flow split ratio and average pulmonary pressure are determined from clinical measurements, complemented by literature data. Starting from a zero-dimensional semi-empirical approximation, Bayesian parameter estimation is used to find the distributions of boundary conditions that produce the expected PA flow split and average pressure PDFs as pre-operative model results. To reduce computational cost, this inverse problem is solved using a Kriging approximant. Second, uncertainties in the boundary conditions are propagated to simulation predictions. Sparse grid stochastic collocation is employed to statistically characterize model predictions of post-operative hemodynamics in models with and without PA stenosis. The results quantify the statistical variability in virtual surgery predictions, allowing for placement of confidence intervals on simulation outputs.

A multiscale model for the study of cardiac biomechanics in single-ventricle surgeries: a clinical case.

Complex congenital heart disease characterized by the underdevelopment of one ventricular chamber (single ventricle (SV) circulation) is normally treated with a three-stage surgical repair. This study aims at developing a multiscale computational framework able to couple a patient-specific three-dimensional finite-element model of the SV to a patient-specific lumped parameter (LP) model of the whole circulation, in a closed-loop fashion. A sequential approach was carried out: (i) cardiocirculatory parameters were estimated by using a fully LP model; (ii) ventricular material parameters and unloaded geometry were identified by means of the stand-alone, three-dimensional model of the SV; and (iii) the three-dimensional model of SV was coupled to the LP model of the circulation, thus closing the loop and creating a multiscale model. Once the patient-specific multiscale model was set using pre-operative clinical data, the virtual surgery was performed, and the post-operative conditions were simulated. This approach allows the analysis of local information on ventricular function as well as global parameters of the cardiovascular system. This methodology is generally applicable to patients suffering from SV disease for surgical planning at different stages of treatment. As an example, a clinical case from stage 1 to stage 2 is considered here.

Haemodynamic consequences of targeted single- and dual-site right ventricular pacing in adults with congenital heart disease undergoing surgical pulmonary valve replacement.

AIMS: The purpose of this study was to create an epicardial electroanatomic map of the right ventricle (RV) and then apply post-operative-targeted single- and dual-site RV temporary pacing with measurement of haemodynamic parameters. Cardiac resynchronization therapy is an established treatment for symptomatic left ventricular (LV) dysfunction. In congenital heart disease, RV dysfunction is a common cause of morbidity-little is known regarding the potential benefits of CRT in this setting. METHODS AND RESULTS: Sixteen adults (age = 32 ± 8 years; 6 M, 10 F) with right bundle branch block (RBBB) and repaired tetralogy of Fallot (n = 8) or corrected congenital pulmonary stenosis (n = 8) undergoing surgical pulmonary valve replacement (PVR) for pulmonary regurgitation underwent epicardial RV mapping and haemodynamic assessment of random pacing configurations including the site of latest RV activation. The pre-operative pulmonary regurgitant fraction was 49 ± 10%; mean LV end-diastolic volume (EDV) 85 ± 19 mL/min/m(2) and RVEDV 183 ± 89 mL/min/m(2) on cardiac magnetic resonance imaging. The mean pre-operative QRS duration is 136 ± 26 ms. The commonest site of latest activation was the RV free wall and DDD pacing here alone or combined with RV apical pacing resulted in significant increases in cardiac output (CO) vs. AAI pacing (P < 0.01 all measures). DDDRV alternative site pacing significantly improved CO by 16% vs. AAI (P = 0.018), and 8.5% vs. DDDRV apical pacing (P = 0.02). CONCLUSION: Single-site RV pacing targeted to the region of latest activation in patients with RBBB undergoing PVR induces acute improvements in haemodynamics and supports the concept of 'RV CRT'. Targeted pacing in such patients has therapeutic potential both post-operatively and in the long term.

Successful mechanical circulatory support for 251 days in a child with intermittent severe neutropenia due to Barth syndrome.

Barth syndrome is an X-linked recessive disorder that is characterized by cardiomyopathy, variable neutropenia, skeletal myopathy, growth delay, and organic aciduria. The cardiac involvement typically results in a high risk of severe heart failure in infancy or early childhood. While Berlin Heart EXCOR is widely accepted as ventricular assistance in pediatric patients with end-stage cardiac failure, infections remain a frequent and potentially severe complication. Therefore, the extended use of the device in the setting of intermittent or severe neutropenia is challenging. We present the case of a three-yr child with Barth syndrome who was bridged successfully to transplant with a Berlin Heart EXCOR assist device for eight months (251 days) without major infectious complication, despite several episodes of severe neutropenia. This case demonstrates that prolonged mechanical circulatory support for a patient with neutropenia is feasible without important morbidity, with careful monitoring and a multidisciplinary approach. G-CSF provides an excellent support in managing neutropenia.

Incompatible ABO-plasma exchange and its impact on patient selection in paediatric cardiac transplantation.

OBJECTIVES: A decade ago, the first series of ABO-incompatible heart transplants was published, with surprising and extremely promising results; drastically reduced waiting list mortalities of infants listed for heart transplantation. Essential to the procedure was the process of plasma exchange transfusion, required to reduce isohaemagglutinin titres and facilitate the crossing of ABO blood group boundaries. Since then, Great Ormond Street Hospital, London has offered ABO-incompatible heart transplants to infants who potentially would die waiting for a suitable organ. We report the results of a decade of evolving plasma exchange experience and its impact upon patient selection. METHODS: A retrospective analysis was undertaken of all elective ABO-incompatible heart transplants at Great Ormond Street Children's Hospital from January 2001 until January 2011. Data were sought on underlying conditions and demographics of the patients, the isohaemagglutinin titre before and after plasma exchange and survival figures to date. RESULTS: Twenty-one patients underwent ABO-incompatible heart transplantation, ranging from 3 to 44 months, with preoperative isohaemagglutinin titres ranging from 0 to 1:32. All patients underwent a "3 times" plasma exchange before transplantation, requiring exchange volumes of up to 3209 mL. Postoperative isohaemagglutinin titres ranged from 0 to 1:16. One patient died of causes unrelated to organ rejection. CONCLUSIONS: Our data showed that eight patients (38.1%) were older than the previously suggested 12-month cut-off age. Using a combination of adult reservoir/paediatric oxygenator and extracorporeal circuit, ABO-incompatible plasma exchange transfusions can be undertaken safely using a simplified '3 times' method, reducing the circulating levels of isohaemagglutinins whilst providing minimal circuit size. This allows ABO-incompatible heart transplantation in a broader patient population than previously reported.

Virtual surgeries in patients with congenital heart disease: a multi-scale modelling test case.

The objective of this work is to perform a virtual planning of surgical repairs in patients with congenital heart diseases--to test the predictive capability of a closed-loop multi-scale model. As a first step, we reproduced the pre-operative state of a specific patient with a univentricular circulation and a bidirectional cavopulmonary anastomosis (BCPA), starting from the patient's clinical data. Namely, by adopting a closed-loop multi-scale approach, the boundary conditions at the inlet and outlet sections of the three-dimensional model were automatically calculated by a lumped parameter network. Successively, we simulated three alternative surgical designs of the total cavopulmonary connection (TCPC). In particular, a T-junction of the venae cavae to the pulmonary arteries (T-TCPC), a design with an offset between the venae cavae (O-TCPC) and a Y-graft design (Y-TCPC) were compared. A multi-scale closed-loop model consisting of a lumped parameter network representing the whole circulation and a patient-specific three-dimensional finite volume model of the BCPA with detailed pulmonary anatomy was built. The three TCPC alternatives were investigated in terms of energetics and haemodynamics. Effects of exercise were also investigated. Results showed that the pre-operative caval flows should not be used as boundary conditions in post-operative simulations owing to changes in the flow waveforms post-operatively. The multi-scale approach is a possible solution to overcome this incongruence. Power losses of the Y-TCPC were lower than all other TCPC models both at rest and under exercise conditions and it distributed the inferior vena cava flow evenly to both lungs. Further work is needed to correlate results from these simulations with clinical outcomes.

Miniaturized implantable pressure and oxygen sensors based on polydimethylsiloxane thin films.

We demonstrate the application of polydimethylsiloxane (PDMS) thin films in highly sensitive pressure and oxygen sensors, designed for pressure and oxygen content measurements within the heart and blood vessels. PDMS thin film displacement as a result of pressure changes was transduced by a capacitive detection technique to produce quantitative measurement of absolute pressures. Oxygen measurements were obtained by transducing the current change between a Pt and an Ag/AgCl electrode on a glass substrate, with KCl soaked filter paper as the electrolytic media that is separated from the oxygen carrying fluid by a thin PDMS membrane. The best sensitivity for the pressure sensor was ~0.1 nA/KPa, with a noise limited resolution of ~0.09 KPa. For the oxygen sensor, the best sensitivity was ~2.75 µA for 1% change in oxygen content of the surrounding media, with a noise limited resolution of ~6.18 ppm oxygen. These experimental results agree with theoretical modeling predictions, and suggest that the semi-permeable and biocompatible PDMS can be successfully adopted as the contacting membrane in an integrated sensor design to quantify pressure and oxygen content in blood.

Effect of fenestration on the sub-diaphragmatic venous hemodynamics in the total-cavopulmonary connection.

OBJECTIVE: To understand differences in the sub-diaphragmatic venous physiology between patients with fenestrated and non-fenestrated total-cavopulmonary connections (TCPC). METHODS: We studied the effects of respiration, retrograde flow, and gravity on the sub-diaphragmatic venous flows in 20 normal healthy volunteers (control), 25 Fontan patients with non-fenestrated TCPC, and 21 with fenestrated TCPC. Subhepatic inferior vena cava (IVC), hepatic vein (HV), and portal vein (PV) flow rates were measured with Doppler ultrasonography during inspiration and expiration in both supine and upright positions. The supine inspiratory-to-expiratory flow rate ratio was calculated to reflect the effect of respiration, the supine-to-upright flow rate ratio was calculated to assess the effect of gravity, and the magnitude of retrograde flow was evaluated with respect to total antegrade flow. Mean IVC, HV, and wedged hepatic venous (WHV) pressures were measured during cardiac catheterization in four TCPC patients before and after fenestration closure. The transhepatic venous pressure gradient (TVPG) was calculated as the difference between the HV and WHV pressure. RESULTS: Compared with control, HV flow in TCPC was heavily dependent on respiration; this inspiratory capacity was greater in fenestrated than non-fenestrated subjects (inspiratory-to-expiratory flow ratio 1.7, 4.4, and 3.0, respectively P<0.001). Normal retrograde HV flow was diminished in TCPC patients, furthermore, fenestrated subjects had less flow reversal than non-fenestrated (retrograde as percent of antegrade flow 43, 19, and 30%, respectively P<0.001). Gravity decreased IVC and HV flows more in TCPC subjects than control, but this effect was not different between the two TCPC groups. Closure of the fenestration resulted in higher IVC and HV pressures (pre-closure versus post-closure pressures [mmHg]: 11.2 +/- 4.0 vs. 12.3 +/- 3.9, and 11.5 +/- 3.8 vs. 12.4 +/- 3.8, respectively P< or =0.001). The normal TVPG was reduced in fenestrated TCPC, and worsened after fenestration closure (0.9 +/- 0.3 and 0.7 +/- 0.4, respectively P < 0.04). CONCLUSIONS: Fenestration of the inferior venous connection has important influences on sub-diaphragmatic venous return in TCPC patients. Although fenestration lowers venous pressures and partially restores TVPG, its beneficial effects on flow in TCPC patients are mediated primarily by an increase in inspiration-derived forward HV flow and reduced flow reversal. These observations suggest fenestration results in a more efficient and less congested splanchnic circulation in TCPC patients, and may have important implications in the early and late management of Fontan patients.

Modeling of the Norwood circulation: effects of shunt size, vascular resistances, and heart rate.

Hypoplastic left heart syndrome is the most common lethal cardiac malformation of the newborn. Its treatment, apart from heart transplantation, is the Norwood operation. The initial procedure for this staged repair consists of reconstructing a circulation where a single outlet from the heart provides systemic perfusion and an interpositioning shunt contributes blood flow to the lungs. To better understand this unique physiology, a computational model of the Norwood circulation was constructed on the basis of compartmental analysis. Influences of shunt diameter, systemic and pulmonary vascular resistance, and heart rate on the cardiovascular dynamics and oxygenation were studied. Simulations showed that 1) larger shunts diverted an increased proportion of cardiac output to the lungs, away from systemic perfusion, resulting in poorer O2 delivery, 2) systemic vascular resistance exerted more effect on hemodynamics than pulmonary vascular resistance, 3) systemic arterial oxygenation was minimally influenced by heart rate changes, 4) there was a better correlation between venous O2 saturation and O2 delivery than between arterial O2 saturation and O2 delivery, and 5) a pulmonary-to-systemic blood flow ratio of 1 resulted in optimal O2 delivery in all physiological states and shunt sizes.

Subdiaphragmatic venous hemodynamics in the Fontan circulation.

OBJECTIVE: We investigated the subdiaphragmatic venous physiology in patients subjected to the Fontan operation to understand some of the early and late problems of this circulation. METHODS: Flows were evaluated by Doppler ultrasonography in the subhepatic inferior vena cava, hepatic vein, and portal vein during respiratory monitoring and with a tilt table. Twenty control subjects (group A) and 56 patients who had the Fontan operation, 27 in functional class I (group B) and 29 in class III or IV (group C), were studied. Inspiratory/expiratory flow ratio was calculated to reflect respiratory effects, and upright/supine flow ratio was calculated to assess gravity effects. Inferior vena caval, hepatic venous, and wedged hepatic venous pressures were measured during catheterization in 21 control subjects and 25 Fontan patients. The difference between wedged and hepatic venous pressures represents the transhepatic venous pressure gradient. RESULTS: Fontan hepatic venous flow depended more on inspiration than control, but without difference between groups B and C (inspiratory/expiratory flow ratios: 1.7, 2.9, and 2.9, respectively; P <.02). Normal portal venous flow was higher in expiration; this effect was lost in group B and reversed in group C (inspiratory/expiratory flow ratios: 0.8, 1.0, and 1.3; P <.0005). Gravity reduced portal venous flow in groups A and B, but progression to functional class III or IV (group C) exacerbated this effect (upright/supine flow ratios: 0.8, 0.7, and 0.5; P <.01). Inferior vena caval, hepatic venous, and wedged hepatic venous pressures (in millimeters of mercury) in the Fontan groups were all elevated compared with the control group (inferior vena cava, 14.4 +/- 4.4 vs 5.9 +/- 2.3; hepatic vein, 14.7 +/- 4.5 vs 5.9 +/- 1.9; wedged hepatic vein, 14.7 +/- 4.0 vs 8.3 +/- 2.6; P <.0001). However, transhepatic venous pressure gradient in the Fontan group was lower than in the control group (0.5 +/- 0.5 vs 2.4 +/- 2.0; P <.001). Univariate analysis of inferior vena caval pressure and transhepatic venous pressure gradient showed significant inverse correlation (r = 0.6, P <.002). CONCLUSIONS: In patients who are in functionally poorer condition after the Fontan operation, portal venous flow loses normal expiratory augmentation and adverse gravity influence is enhanced. These suboptimal flow dynamics, coupled with higher splanchnic venous pressures and lower transhepatic venous pressure gradients, suggest that hepatic sinusoids are congested, acting as "open tubes." Transhepatic gradient loss is incrementally worse with higher caval pressures. These observations may be responsible for late gastrointestinal problems in patients who have had the Fontan operation.

Effects of respiration and gravity on infradiaphragmatic venous flow in normal and Fontan patients.

BACKGROUND: In the Fontan circulation, pulmonary and systemic vascular resistances are in series. The implications of this unique arrangement on infradiaphragmatic venous physiology are poorly understood. METHODS AND RESULTS: We studied the effects of respiration and gravity on infradiaphragmatic venous flows in 20 normal healthy volunteers (control) and 48 Fontan patients (atriopulmonary connection [APC] n=15, total cavopulmonary connection [TCPC] n=30). Hepatic venous (HV), subhepatic inferior vena caval (IVC), and portal venous (PV) flow rates were measured with Doppler ultrasonography during inspiration and expiration in both the supine and upright positions. The inspiratory-to-expiratory flow rate ratio was calculated to reflect the effect of respiration, and the supine-to-upright flow rate ratio was calculated to assess the effect of gravity. HV flow depended heavily on inspiration in TCPC compared with both control and APC subjects (inspiratory-to-expiratory flow rate ratio 3.4, 1.7, and 1.6, respectively; P:<0.0001). Normal PV flow was higher in expiration, but this effect was lost in TCPC and APC patients (inspiratory-to-expiratory flow rate ratio 0.8, 1.0, and 1.1, respectively; P:=0.01). The respiratory influence on IVC flow was the same in all groups. Gravity decreased HV flow more in APC than in TCPC patients (supine-to-upright flow rate ratio 3.2 versus 2.1, respectively; P:<0.04) but reduced PV flow equally in all groups. CONCLUSIONS: Gravity and respiration have important influences on infradiaphragmatic venous return in Fontan patients. Although gravity exerts a significant detrimental effect on lower body venous return, which is more marked in APC than in TCPC patients, the beneficial effects of respiration in TCPC patients are mediated primarily by an increase in HV flow. These effects may have important short- and long-term implications for the hemodynamics of the Fontan circulation.

Computational model of the fluid dynamics in systemic-to-pulmonary shunts.

A systemic-to-pulmonary shunt is a connection created between the systemic and pulmonary arterial circulations in order to improve pulmonary perfusion in children with congenital heart diseases. Knowledge of the relationship between pressure and flow in this new, surgically created, cardiovascular district may be helpful in the clinical management of these patients, whose survival is critically dependent on the blood flow distribution between the pulmonary and systemic circulations. In this study a group of three-dimensional computational models of the shunt have been investigated under steady-state and pulsatile conditions by means of a finite element analysis. The model is used to quantify the effects of shunt diameter (D), curvature, angle, and pulsatility on the pressure-flow (DeltaP-Q) relationship of the shunt. Size of the shunt is the main regulator of pressure-flow relationship. Innominate arterial diameter and angles of insertion have less influence. Curvature of the shunt results in lower pressure drops. Inertial effects can be neglected. The following simplified formulae are derived: DeltaP=(0. 097Q+0.521Q(2))/D(4) and DeltaP=(0.096Q+0.393Q(2))/D(4) for the different shunt geometries investigated (straight and curved shunts, respectively).

Intracoronary arterial occlusion: a novel technique potentially useful for ablation of cardiac arrhythmias.

To develop a new technique for ablating arrhythmias by interrupting coronary perfusion of the myocardium, we studied six mongrel dogs, weighing 20-35 kg. Under angiographic guidance a microcatheter (1.0 mm diameter) was introduced into a branch of the left anterior descending or posterior descending coronary artery. A detachable platinum coil (0.0254 cm diameter, 3 cm length) soldered onto a stainless-steel delivery wire (Guglielmi) was inserted through the microcatheter and advanced to occlude the arterial branch. A 0.5-mA electric current applied to the proximal end of the delivery wire resulted in intravascular thrombosis due to attraction of the negatively charged blood cells, platelets, and fibrinogen to the positively charged platinum coil. In approximately 4.5 minutes, as the thrombus was formed, electric current dissolved the soldering and detached the platinum coil from the delivery wire. Electrocardiograms showed focal ST-T changes but no ventricular tachyarrhythmias. Pathologic studies revealed thrombosis around the platinum coil and well-demarcated focal ischemia/infarction that was correlated with elevation of cardiac enzymes. We conclude that intracoronary arterial embolization and electrothrombosis using an electrolytic platinum coil can be selectively performed in a very small coronary arterial branch, resulting in a limited area of myocardial damage. This technique is potentially useful for ablating arrhythmias and may be safer and more controllable than intracoronary alcohol infusion.

The effect of pregnancy on rat urinary tract dynamics.

We investigated the urodynamics of the renal pelvis and bladder during spontaneous bladder filling and emptying in 13 pregnant and 19 nonpregnant Sprague-Dawley rats to examine the characteristics of the dilated urinary tract in pregnancy. For each group renal pelvic and bladder pressures were measured continuously and simultaneously during various urinary flows, while the bladder was filled and emptied. In pregnant rats the ureter was wider and the renal pelvis was longer and wider than in nonpregnant rats. At urinary flows of 10 to 30 ml/kg. per hour pregnant rats had significantly lower renal pelvic pressures than nonpregnant rats during bladder filling. In addition, pregnant rats had higher bladder compliance and capacity than nonpregnant rats (compliance 0.09 +/- 0.12 ml./cm. water versus 0.05 +/- 0.05 ml./cm. water, p < 0.01 and bladder capacity 0.669 +/- 0.61 ml. versus 0.490 +/- 0.38 ml., p < 0.05). These findings imply that much of the hydroureteronephrosis during pregnancy may relate to increased urinary tract compliance rather than obstruction.