An Efficient Assisted Bidirectional Glenn Design With Lowered Superior Vena Cava Pressure for Stage-One Single Ventricle Patients.

Recently, the assisted bidirectional Glenn (ABG) procedure has been proposed as an alternative to the modified Blalock-Taussig shunt (mBTS) operation for neonates with single-ventricle physiology. Despite success in reducing heart workload and maintaining sufficient pulmonary flow, the ABG also raised the superior vena cava (SVC) pressure to a level that may not be tolerated by infants. To lower the SVC pressure, we propose a modified version of the ABG (mABG), in which a shunt with a slit-shaped nozzle exit is inserted at the junction of the right and left brachiocephalic veins. The proposed operation is compared against the ABG, the mBTS, and the bidirectional Glenn (BDG) operations using closed-loop multiscale simulations. Both normal (2.3 Wood units-m2) and high (7 Wood units-m2) pulmonary vascular resistance (PVR) values are simulated. The mABG provides the highest oxygen saturation, oxygen delivery, and pulmonary flow rate in comparison to the BDG and the ABG. At normal PVR, the SVC pressure is significantly reduced below that of the ABG and the BDG (mABG: 4; ABG: 8; BDG: 6; mBTS: 3 mmHg). However, the SVC pressure remains high at high PVR (mABG: 15; ABG: 16; BDG: 12; mBTS: 3 mmHg), motivating an optimization study to improve the ABG hemodynamics efficiency for a broader range of conditions in the future. Overall, the mABG preserves all advantages of the original ABG procedure while reducing the SVC pressure at normal PVR.

Long-term surveillance biopsy: Is it necessary after pediatric heart transplant?

Due to limited and conflicting data in pediatric patients, long-term routine surveillance endomyocardial biopsy (RSB) in pediatric heart transplant (HT) remains controversial. We sought to characterize the rate of positive RSB and determine factors associated with RSB-detected rejection. Records of patients transplanted at a single institution from 1995 to 2015 with >2 year of post-HT biopsy data were reviewed for RSB-detected rejections occurring >2 year post-HT. We illustrated the trajectory of significant rejections (ISHLT Grade ≥3A/2R) among total RSB performed over time and used multivariable logistic regression to model the association between time and risk of rejection. We estimated Kaplan-Meier freedom from rejection rates by patient characteristics and used the log-rank test to assess differences in rejection probabilities. We identified the best-fitting Cox proportional hazards regression model. In 140 patients, 86% did not have any episodes of significant RSB-detected rejection >2 year post-HT. The overall empirical rate of RSB-detected rejection >2 year post-HT was 2.9/100 patient-years. The percentage of rejection among 815 RSB was 2.6% and remained stable over time. Years since transplant remained unassociated with rejection risk after adjusting for patient characteristics (OR = 0.98; 95% CI 0.78-1.23; P = 0.86). Older age at HT was the only factor that remained significantly associated with risk of RSB-detected rejection under multivariable Cox analysis (P = 0.008). Most pediatric patients did not have RSB-detected rejection beyond 2 years post-HT, and the majority of those who did were older at time of HT. Indiscriminate long-term RSB in pediatric heart transplant should be reconsidered given the low rate of detected rejection.

Ventricular mechanics in adolescent and adult patients with a Fontan circulation: Relation to geometry and wall stress.

BACKGROUND: Patients with single ventricle physiology and Fontan circulation are at increased risk for late complications and reduced survival. The aim of the study was to investigate the correlation between ventricular geometry and systolic regional function in different underlying anatomic conditions in adolescent and adult Fontan-palliated patients. METHOD: In a retrospective cross-sectional study, we measured 2D strain, ventricular diameters, ventricular volumes, ejection fraction (EF), global and segmental wall stress, and sphericity index. The same analyses were performed in 99 age- and gender-matched healthy individuals. RESULTS: One hundred and one patients were included at a mean age of 21 (range 14-59) years. In comparison with healthy subjects, patients with Fontan circulation displayed larger ventricular volumes (153 ± 78 mL vs 116 ± 38 mL P < 0.05), reduced EF (43% ± 15% vs 55% ± 8% P < 0.05), reduced longitudinal (-13% ± 6% vs -21% ± 4% P < 0.05) and circumferential strain values (-15% ± 7% vs -22% ± 4% P < 0.05). Functionally single ventricles were more spherical (ratio of longitudinal to short-axis diameters 1.3 ± 0.3 vs 1.7 ± 0.2 P < 0.05). Circumferential strain correlated well with global wall stress and the degree of sphericity (R2  = 0.320), while segmental strain did not correlate with segmental wall stress. The percentage of segments with akinesia was relatively high (16 ± 16% vs 0 ± 0% P < 0.05) indicating reduced segmental contractile function. CONCLUSION: Functionally single ventricles after Fontan palliation have significantly reduced systolic regional and global function with a high intersegmental inhomogeneity. The underlying pathological mechanisms might be multifactorial, including ventricular geometry, sphericity, and regional contractile properties. Future studies are needed to investigate the role of ventricular geometry for clinical performance and outcome.

Performance characterization of a rotary centrifugal left ventricular assist device with magnetic suspension.

The MiTiHeart (MiTiHeart Corporation, Gaithersburg, MD, USA) left ventricular assist device (LVAD), a third-generation blood pump, is being developed for destination therapy for adult heart failure patients of small to medium frame that are not being served by present pulsatile devices. The pump design is based on a novel, patented, hybrid passive/active magnetic bearing system with backup hydrodynamic thrust bearing and exhibits low power loss, low vibration, and low hemolysis. Performance of the titanium alloy prototype was evaluated in a series of in vitro tests with blood analogue to map out the performance envelop of the pump. The LVAD prototype was implanted in a calf animal model, and the in vivo pump performance was evaluated. The animal's native heart imparted a strong pulsatility to the flow rate. These tests confirmed the efficacy of the MiTiHeart LVAD design and confirmed that the pulsatility does not adversely affect the pump performance.

Classic-Pattern Dyssynchrony in Adolescents and Adults With a Fontan Circulation.

BACKGROUND: Previous studies have suggested the presence of dyssynchrony in the functionally single ventricle. The aim of this study was to investigate the presence of classic-pattern dyssynchrony (CPD), characterized by typical early and late deformation of opposite walls, and its relation to QRS duration and myocardial function in patients with single-ventricle physiology after Fontan palliation. METHODS: In a retrospective cross-sectional study, 101 adolescent and adult patients with single-ventricle physiology after the Fontan procedure were investigated. Strain curves were visually assessed for the presence of CPD. Systolic and diastolic function were assessed using echocardiography. RESULTS: One hundred one patients were included, with varying anatomic morphology: two sizable ventricular components (n = 21), right dominant (n = 21), left dominant (n = 49), and undefined anatomy (n = 10). Fifteen of 101 Fontan patients had CPD. Forty-three percent of patients with two sizable ventricular masses displayed CPD, mostly with prolonged QRS, while the number of patients with CPD with right-dominant (9%) and left-dominant (6%) morphology was significantly lower (P = .016). Those with CPD displayed significantly (P < .05) larger QRS widths (142 ± 22 vs 112 ± 24 msec), lower ejection fractions (31 ± 14% vs 45 ± 14%), lower global early diastolic strain rates (0.7 ± 0.5 vs 1.2 ± 0.8 sec-1), and global systolic circumferential (-10 ± 5% vs -16 ± 7%) and longitudinal (-9 ± 5% vs -14 ± 5%) strain, respectively. CONCLUSIONS: CPD is present in a proportion of adolescent and adult patients after Fontan palliation. The presence of CPD is associated with reduced systolic and diastolic function compared with Fontan patients without CPD. Because the presence of CPD appears to be a promising predictor for response to cardiac resynchronization therapy in patients with biventricular circulation, these findings may have important potential for prospective evaluation of cardiac resynchronization therapy in patients with univentricular circulation.

Microtextured materials for circulatory support devices: preliminary studies.

Thromboembolic events (TE) associated with circulatory support devices are a major source of mortality and morbidity. Clinically, the lowest TE rates are claimed with devices that incorporate textured blood-contacting materials. The textured materials currently used in circulatory assist devices are composed of small, attached fibers that form the boundaries of connected cavities. These cavities entrap blood components to form a "neointimal" layer, which is believed to minimize thromboembolic events. We believe that the three-dimensional surface topography of blood-contacting materials is a major controlling factor in the formation of a stable neointimal layer upon the material. Particle-cast cavities were used to form geometric features in segmented polyurethane. This microtextured material was incorporated as part of a flexible blood-contacting surface in a blood pump that was implanted as a left ventricular assist device in calves. The structure, thickness, stability, and development of the neointimal layer were then evaluated. These preliminary studies have shown that a stable neointimal layer can be formed upon the particle-cast surfaces. The results also indicate that the cavity size on the particle-cast surfaces has a significant effect on neointimal adhesion. The methods employed can be used in the design of future circulatory support devices.

Bone formation in carotid plaques: a clinicopathological study.

BACKGROUND AND PURPOSE: Bone formation and dystrophic calcification are present in carotid endarterectomy plaques. The clinical significance of these findings is unknown. The purpose of this study was to determine whether bone formation and extensive dystrophic calcification are associated with stable plaques and protective against ischemic vascular events. METHODS: Carotid endarterectomy plaques were collected from 142 patients (94 men) with carotid stenosis. The specimens were evaluated for lamellar bone formation, dystrophic calcifications, inflammatory infiltrates, neovascularization, and histological type or grade of plaque according to a standard AHA grading system. Immunohistochemical staining was performed to identify vascular endothelial cells in neovascularization (factor VIII) and lymphocytes. Clinical data, including history of cerebrovascular and cardiovascular events, were recorded at the time of surgery. RESULTS: Patients with calcification of carotid plaques had fewer symptoms of stroke and transient ischemic attack (P=0.042) than those without calcification. Stroke and transient ischemic attack occurred less frequently in patients with plaques with large calcific granules (P=0.021). Of the patients, 13% had lamellar bone formation, which directly correlated with the presence of sheetlike calcifications (P=0.0001) and inversely correlated with ulcerated lesions (P=0.048). The presence of bone also correlated with diabetes (P<0.01) and coronary artery disease (P<0.01). Of the 20 patients with bone, 6 had a history of stoke and transient ischemic attack (P=0.5). CONCLUSIONS: The results indicate that bone formation tends to occur in heavily calcified carotid lesions devoid of ulceration and hemorrhage. Patients with extensive calcification of the carotid plaques are less likely to have symptomatic disease.

Platelet factor 4 localization in carotid atherosclerotic plaques: correlation with clinical parameters.

Emerging evidence supports a role for platelets in the progression of atherosclerosis in addition to an involvement in thrombotic vascular occlusion. Platelet Factor 4 (PF4), a chemokine released by activated platelets, stimulates several pro-atherogenic processes. Therefore, we examined the localization of PF4 and the homologous protein, Neutrophil Activating Protein-2 (NAP-2) in lesions representing the evolution of human atherosclerotic plaques. Carotid plaques from 132 patients with critical carotid stenosis and 6 autopsy specimens were studied. Clinical, histologic and immunohistochemical data were analyzed using a chi(2)-test. PF4 was detected in the cytoplasm of luminal and neovascular endothelium, in macrophages and in regions of plaque calcification. The presence of PF4 in macrophages and neovascular endothelium correlated with lesion grade (p = 0.004; p = 0.044). Staining of macrophages for PF4 correlated with the presence of symptomatic atherosclerotic disease (p = 0.028). In early lesions, PF4 was commonly found in macrophages of early lesions (Grade I/II), whereas NAP-2 was rarely present. In conclusion, correlation between PF4 deposition, lesion severity and symptomatic atherosclerosis suggests that persistent platelet activation may contribute to the evolution of atherosclerotic vascular lesions. These studies support the rationale for the chronic use of anti-platelet therapy in patients at risk for developing symptomatic atherosclerosis.

Anatomic fit assessment for the Penn State pediatric ventricular assist device.

This investigation determined the ages and weights of children that could be supported with 12 and 25 ml Penn State pediatric ventricular assist devices (PVADs) using 6, 8, and 10 mm outlet cannulas and grafts. Future patients will be matched to devices based on cardiac output (CO) and ascending aortic diameter (AA). These were calculated for children 0-10 years with regression formulas given as clinical standards [<5 kg, CO = 0.2171(kg) + 0.0703], [>5 kg, CO = 3.06 (m2) + 0.37], [AA = -0.0427 + 14.54 (m2)1/2]. The 12 ml PVAD will be useful for patients from approximately birth to 3-8 months, weighing 2-7 kg, and having 0.5-1.4 L/min CO; the 25 ml PVAD will be for children 2-6 months to 5-9 years old, weighing 6-23 kg, and having 1.3-3.0 L/min of CO. The 6 mm outlet graft will fit children from 0 to 12 months, weighing 2-8 kg; the 8 mm graft from 0 to 47 months, weighing 4-14 kg; and the 10 mm graft for children 4 months to 8 years, weighing 8-21 kg.

Anticoagulation of juvenile sheep and goats with heparin, warfarin, and clopidogrel.

Little data exist on anticoagulation of young sheep and goats. We tested the effect of heparin, warfarin, and clopidogrel in two sheep and two goats weighing 17-35 kg. Each animal received heparin boluses of 80, 100, and 200 units/kg; goats also received 300, 350, and 400 units/kg. All animals received continuous heparin 40, 60, and 80 units/kg/hour; oral warfarin 0.3, 0.6, and 0.9 mg/kg/day; and oral clopidogrel 75 and 150 mg/day (2.8-3.4 and 5.6-6.9 mg/kg/day). Results were in the form of complete blood counts, activated clotting times (ACT), partial thromboplastin times, prothrombin times, thromboelastograms, and whole-blood lumiaggregometry. After heparin boluses of 200 units/kg, sheep and goats reached mean peak ACTs over 400 seconds. After continuous infusions of 40, 60 and 80 units/kg/hour, sheep and goats exceeded our therapeutic range for ACTs (195-215 seconds for sheep, 155-175 seconds for goats). For warfarin therapy, both sheep and goats required treatment with >0.6 mg/kg/day to achieve INRs over 2.5. Clopidogrel treatment, after 14-17 days of 75-150 mg/day, inhibited sheep platelets by 25-36% and goat platelets by 35-46%. We conclude that young sheep and goats can be safely and effectively anticoagulated with heparin and warfarin, and can also show a modest antiplatelet response to clopidogrel. Doses for each drug were generally higher than those used for humans, and warfarin therapy in sheep may be unpredictable. These results should be useful for developing anticoagulation protocols to test pediatric mechanical circulatory support devices.

The effect of left ventricular function and drive pressures on the filling and ejection of a pulsatile pediatric ventricular assist device in an acute animal model.

Penn State is currently developing a 12-mL, pulsatile, pneumatically driven pediatric ventricular assist device intended to be used in infants. After extensive in vitro testing of the pump in a passive-filling, mock circulatory loop, an acute animal study was performed to obtain data with a contracting ventricle. The objectives were to determine the range of pneumatic pressures and time required to completely fill and empty the pediatric ventricular assist device under various physiologic conditions, simulate reductions in ventricular contractility and blood volume, and provide data for validation of the mock circulatory loop. A 15-kg goat was used. The cannulation was achieved via left thoracotomy from the left ventricle to the descending aorta. The pump rate and systolic duration were controlled manually to maintain complete filling and ejection. The mean ejection time ranged from 280 ms to 382 ms when the systolic pressure ranged from 350 mm Hg to 200 mm Hg. The mean filling time ranged from 352 ms to 490 ms, for the diastolic pressure range of -60 mm Hg to 0 mm Hg. Esmolol produced a decrease in left ventricular pressure, required longer pump filling time, and reduced LVAD flow.

Comparison of hollow-fiber membrane oxygenators with different perfusion modes during normothermic and hypothermic CPB in a simulated neonatal model.

PURPOSE: The objectives of this investigation were (1) to compare two hollow-fiber membrane oxygenators (Capiox Baby RX versus Lilliput 1-D901) in terms of pressure drops and surplus hemodynamic energy (SHE) during normothermic and hypothermic cardiopulmonary bypass (CPB) in a simulated neonatal model; and (2) to evaluate pulsatile and non-pulsatile perfusion modes for each oxygenator in terms of SHE levels. METHODS: In a simulated patient, CPB was initiated at a constant pump flow rate of 500 mL/min. The circuit was primed with fresh bovine blood. After 5 min of normothermic CPB, the pseudo-patient was cooled down to 25 degrees C for 10 min followed by 30 min of hypothermic CPB. The pseudo-patient then underwent 10 min of rewarming and 5 min of normothermic CPB. At each experimental site (pre- and post-oxygenator and pre-aortic cannula), SHE was calculated using the following formula {SHE (ergs/cm3) = 1332 [((integralfpdt)/(integralfdt)) - mean arterial pressure]} (f = pump flow and p = pressure). A linear mixed-effects model that accounts for the correlation among repeated measurements was fit to the data to assess differences in SHE between oxygenators, pumps, and sites. Tukey's multiple comparison procedure was used to adjust p-values for post-hoc pairwise comparisons. RESULTS: The pressure drops in the Capiox group compared to the Lilliput group were significantly lower during hypothermic non-pulsatile (21.3 +/- 0.5 versus 50.7 +/- 0.9 mmHg, p < 0.001) and pulsatile (22 +/- 0.0 versus 53.3 +/- 0.5 mmHg, p < 0.001) perfusion, respectively. Surplus hemodynamic energy levels were significantly higher in the pulsatile group compared to the non-pulsatile group, with Capiox (1655 +/- 92 versus 10008 +/- 1370 ergs/cm3, p < 0.001) or Lilliput (1506 +/- 112 versus 7531 +/- 483 ergs/cm3, p < 0.001) oxygenators. During normothermic CPB, both oxygenators had patterns similar to those observed under hypothermic conditions. CONCLUSIONS: The Capiox oxygenator had a significantly lower pressure drop in both pulsatile and non-pulsatile perfusion modes. For each oxygenator, the SHE levels were significantly higher in the pulsatile mode.