Characterizing pharmacological ligands to study the long-chain fatty acid receptors GPR40/FFA1 and GPR120/FFA4.

The free fatty acid receptors (FFA) 1 (previously designated GPR40) and FFA4 (previously GPR120) are two GPCRs activated by saturated and unsaturated longer-chain free fatty acids. With expression patterns and functions anticipated to directly or indirectly promote insulin secretion, provide homeostatic control of blood glucose and improve tissue insulin sensitivity, both receptors are being studied as potential therapeutic targets for the control of type 2 diabetes. Furthermore, genetic and systems biology studies in both humans and mouse models link FFA4 receptors to diabetes and obesity. Although activated by the same group of free fatty acids, FFA1 and FFA4 receptors are not closely related and, while the basis of recognition of fatty acids by FFA1 receptors is similar to that of the short-chain fatty acid receptors FFA2 and FFA3, the amino acid residues involved in endogenous ligand recognition by FFA4 receptors are more akin to those of the sphingosine 1 phosphate receptor S1P1 . Screening and subsequent medicinal chemistry programmes have developed a number of FFA1 receptor selective agonists that are effective in promoting insulin secretion in a glucose concentration-dependent manner, and in lowering blood glucose levels. However, the recent termination of Phase III clinical trials employing TAK-875/fasiglifam has caused a setback and raises important questions over the exact nature and mechanistic causes of the problems. Progress in the identification and development of highly FFA4 receptor-selective pharmacological tools has been less rapid and several issues remain to be clarified to fully validate this receptor as a therapeutic target. Despite this, the ongoing development of a range of novel ligands offers great opportunities to further unravel the contributions of these receptors.

Hardware-in-the-loop-simulation of the cardiovascular system, with assist device testing application.

This paper presents a technique for evaluating the performance of biomedical devices by combining physical (mechanical) testing with a numerical, computerised model of a biological system. This technique is developed for evaluation of a cardiac assist device prior to in vivo trials. This device will wrap around a failing heart and provide physical beating assistance (dynamic cardiac compression). In vitro, the device to be tested is placed around a simulator comprising a mechanical simulation of the beating ventricles. This hardware model interfaces with a computerised (software) model of the cardiovascular system. In real time the software model calculates the effect of the assistance on the cardiovascular system and controls the beating motion of the hardware heart simulator appropriately. The software model of the cardiovascular system can represent ventricles in various stages of heart failure, and/or hardened or congested blood vessels as required. The software displays physiological traces showing the cardiac output, depending on the natural function of the modelled heart together with the physical assist power provided. This system was used to evaluate the effectiveness of control techniques applied to the assist device. Experimental results are presented showing the efficacy of prototype assist on healthy and weakened hearts, and the effect of asynchronous assist.

Outcome after extended arch repair for aortic coarctation.

OBJECTIVES: To assess survival and long term arch patency rates in a consecutive group of children after extended arch repair for coarctation of the aorta. METHODS: Review of 191 consecutive children (154 (81%) under 1 year of age) operated on between 1990 and 2002 by a single surgeon using extended arch reconstructive techniques. For assessment of survival patients were divided into three groups: 1, coarctation alone, n = 104; 2, coarctation and ventricular septal defect, n = 38; and 3, coarctation in association with complex intracardiac anomalies, n = 49. A prospective and systematic clinical and echocardiographic evaluation of the aortic arch was undertaken. RESULTS: Median time to follow up was 4.2 years (range 1-10.6 years). Overall actuarial survival was 92%, 88%, and 88% at two, five, and 10 years. Mortality was significantly higher in those patients with complex intracardiac anatomy. Arch obstruction recurred in seven of 165 (4.2%) patients: four of 139 (2.9%) term and three of 10 (30%) premature infants (p < 0.001). CONCLUSIONS: Survival after extended arch reconstruction for coarctation is excellent. At long follow up recurrent arch obstruction is rare, with prematurity the only risk factor.

Surgical and transcatheter (Amplatzer) closure of atrial septal defects: a prospective comparison of results and cost.

OBJECTIVE: To compare effectiveness, complications, and cost of Amplatzer with surgical atrial septal defect (ASD) closure. DESIGN: Prospective study. SETTING: Tertiary cardiac referral centre. PATIENTS: 43 consecutive patients (excluding non-UK residents) aged between 2.1 and 56.8 years (median 7) undergoing ASD closure. MAIN OUTCOME MEASURES: Procedural success, complications, regression of right ventricular dilatation (up to one year postprocedure), cost, inpatient stay, and home convalescent time. RESULTS: Amplatzer ASD closure was successful in 24 of 27 (89%) patients. Surgical closure was successful in all 19 cases. Cardiac complications affecting management occurred in three (11%) of the Amplatzer group (two procedural failures, one device embolisation) and 4 of 19 (21%) surgical patients (one pericardial pain, one global pericardial effusion requiring drainage, and one patient with anaemia requiring haematinics in addition to an incidental pericardial effusion and one further incidental pericardial effusion) (p = NS). There were complications that did not affect management in a further 5 of 19 surgical patients. There was no significant difference in regression of right ventricular dilatation by six months postprocedure (median right ventricular end diastolic diameter decrease: Amplatzer group 17.5%, surgical group 15.1%; median cardiothoracic ratio decrease: Amplatzer 7.9%, surgical 7.5%). Both hospital stay and home convalescent times were significantly shorter after Amplatzer closure (median hospital stay: Amplatzer one day, surgery six days; median convalescent time: Amplatzer two weeks, surgery 5.5 weeks). Median cost was similar for both groups (Amplatzer pound5375, surgical pound5412). CONCLUSIONS: Amplatzer ASD closure has a lower chance of success with a single procedure than surgery. Overall, there were more complications in the surgical group but the majority of these were minor and did not require any change in management. Resolution of right ventricular dilatation over the study period was similar for both techniques. Time spent in hospital and away from work or school was shorter for the Amplatzer group. The cost of both techniques was similar.

Assessment of mortality rates for congenital heart defects and surgeons' performance.

BACKGROUND: In the absence of reliable national data, we have collected results of all operations for congenital heart defects from five departments to assess mortality rates and compare them among surgeons and departments. METHODS: Data relating to all operations (2,718) carried out at the five centers during a period from April 1, 1997 through March 31, 1999. Clearly defined criteria were agreed for the classification of patients into various subgroups. RESULTS: The overall hospital mortality was 4.4% (95% confidence intervals 3.7%-5.3%). Mortality for open-operations was 12.6% in neonates, 5.1% in infants, and 3.5% in children. Mortality rates were 1.1% for coarctation, 0.4% ventricular septal defect, 4.1% atrioventricular septal defect, 2.9% Fallot, 0.9% switch, and 15.6% truncus arteriosus. Although individual surgeons' mortality rates ranged from 1.8% to 7.5%, none of the 12 surgeons' data were above 95% confidence intervals. For individual surgeons, the change in mortality rates between the 2 years ranged between -3.3% and +3.8%. CONCLUSIONS: With 2 years' data available, estimates of mortality rates are more precise as reflected by tighter confidence intervals. There were relatively small data sets for individual hospitals and surgeons, which made statistical evaluation difficult. For setting standards, data from more departments for a longer period will be required. Statistical methods alone cannot be used as a sole arbiter of what is considered acceptable performance.

The influence of ventricular input impedance on the hydrodynamic performance of bioprosthetic aortic roots in vitro.

BACKGROUND AND AIM OF THE STUDY: Hydrodynamic function testing using pulsatile flow simulators provides a valuable means of comparative assessment of heart valves in vitro. The majority of pulsatile flow simulators consist of modular rigid chambers and a positive displacement pump with an infinite input impedance, in which the inertia of the test fluid results in pressure oscillations when the valves under test are opening and closing. For mechanical and stented bioprosthetic valves these pressure oscillations decay quickly. However, due to the highly compliant nature of tissue roots, the resulting pressure and flow oscillations are extreme and extend throughout systole. With increasing interest in the use of free-sewn roots and valves it is most desirable to improve this hydrodynamic model. The aim of this study was to investigate the influence in changes in ventricular input impedance on the hydrodynamic characteristics of free-sewn aortic roots and stented valves. METHODS: The Leeds pulsatile flow simulator was modified to incorporate additional compliance chambers in the form of a viscoelastic impedance adaptor (VIA) at the pump/ventricular interface. Six 23 mm bioprosthetic aortic roots fixed with 0.5% buffered glutaraldehyde at zero pressure, and a size 23 mm stented porcine aortic bioprosthesis were tested in this modified simulator, at the conditions of maximum and minimum input compliance. RESULTS: The pressure and flow waveforms for the fixed aortic roots showed considerable differences at the conditions of maximum and minimum input compliance. Indeed, the extreme pressure oscillations observed at minimum compliance (infinite input impedance) were not present at maximum compliance, and the forward flow waveform was much smoother. In contrast, for the stented valve, the differences in the pressure and flow waveforms between maximum and minimum input compliance were minimal, but this was expected due to the lack of compliance in the stented valve itself. In addition, the flow and pressure waveforms at maximum compliance in the VIA were comparable for the fixed aortic roots and the stented bioprosthesis, thus allowing direct comparison of the characteristics of these two different devices. Using test conditions of maximum input compliance, effective orifice area for the roots was 1.69 cm2 compared with 1.47 cm2 for the stented valve. CONCLUSION: An appropriate physiological model for the hydrodynamic testing of compliant tissue roots has been established.

Distribution of hepatic venous blood in the total cavo pulmonary connection: an in vitro study into the effects of connection geometry.

The total cavo pulmonary connection, or TCPC, is a surgical correction to congenital heart defects. The geometry of this connection has been shown to determine the fluid power loss as well as the distribution of hepatic fluid that enters through the inferior vena cava. In vitro studies were performed to measure the power loss and hepatic fluid distribution in models of the TCPC with four different geometries. It was found that a zero offset straight geometry provided good hepatic fluid distribution but large power loss. A zero offset flared geometry provided low power loss but poor hepatic fluid distribution. The optimal geometry from those tested was found to be the zero offset cowl geometry whereby an enlargement was made on one side of the inferior and superior vena cava. So long as the cowl was directed toward the pulmonary artery of lowest flow rate, low power loss and relatively good distribution of hepatic flow could be obtained.

The in vitro hydrodynamic characteristics of the porcine pulmonary valve and root with regard to the ross procedure.

OBJECTIVE: The hydrodynamic parameters and leaflet motion of the porcine pulmonary root and valve and the performance of the pulmonary autograft implanted in subcoronary position or as a free-standing root were investigated at systemic and pulmonary pressures in vitro. METHODS: Ten fresh pulmonary and aortic roots (anulus diameter, 20-25 mm) were tested in a pulsatile flow simulator. Five free-sewn pulmonary valves were implanted in aortic roots in the subcoronary position, and 5 pulmonary roots were implanted as free-standing roots. The external diameter of the roots was measured at the sinotubular junction in a pressure range of 0 to 120 mm Hg. The transvalvular gradient and regurgitation were measured, and the effective orifice area was calculated. The leaflet motion was recorded on video tape. RESULTS: The fresh pulmonary roots were more compliant than their aortic counterparts (33% +/- 3. 0% vs 7% +/- 1.5% with dilatation at 0-30 mm Hg and 46% +/- 8.4% vs 35% +/- 7.8% with dilatation at 0-120 mm Hg). The pulmonary roots had a lower pressure drop at systemic than at pulmonary pressures. The pressure drops of the pulmonary roots were also lower than those of the aortic roots in the systemic pressure range. The leaflet opening of the pulmonary valve was triangular, with low bending deformation at all pressures. Implanting the free-sewn pulmonary valve in the subcoronary position or the pulmonary root as a free-standing root did not affect the hydrodynamic parameters and leaflet motion adversely. CONCLUSION: The pulmonary valve and root could easily withstand aortic pressures in vitro. A biphasic dilatation curve ensures that higher pressures did not overdilate the pulmonary root. Moreover, valve performance was better at systemic pressures.

The effect of sizing on the hydrodynamic parameters of the Medtronic freestyle valve in vitro.

BACKGROUND: An in vitro model has been established to investigate the effect of sizing on the hydrodynamic characteristics and leaflet motion of the Medtronic Freestyle valve. METHODS: The valves were tested in fresh porcine aortic roots. Two or three different sizes of valves were implanted in the same aortic root one after the other. The compliance of the fresh aortic and the composite roots was measured in the pressure range of 0 to 120 mm Hg, and the composite roots were then tested in a pulsatile flow simulator. The transvalvular gradient and degree of regurgitation were measured and the effective orifice area and performance index were calculated. Leaflet motion was recorded on video. RESULTS: The fresh aortic roots dilated by average 39.4% as the hydrostatic pressure rose from 0 to 120 mm Hg. Implantation of the Medtronic Freestyle valve did not change the distensibility of the aortic root significantly. The sizing protocol did not affect significantly the hydrodynamic performance. However, a significantly lower open leaflet bending deformation was found in the undersized valves. Regurgitation was found only at 2-mm undersized valves. CONCLUSIONS: Leaflet motion of the Medtronic Freestyle valve in vitro was best if 1 mm undersized, and this may be beneficial to long-term durability.

Distribution of hepatic venous blood in the total cavo-pulmonary connection: an in vitro study.

OBJECTIVES: The objective of this project was to quantify the effects of geometry on the distribution of hepatic blood to the lungs in patients with a total cavo-pulmonary connection. The basis for this work is the supposition that hepatic blood is necessary for proper lung function. METHODS: Plastic models of these connections were made with varying degrees of offset between the inferior and superior vena cava and attached to an in vitro flow loop. Dye was injected into the inferior vena cava and its concentration quantified in each pulmonary artery. These data were converted to percentage concentration and distribution of hepatic blood to each lung. RESULTS: With no offset between the vena cava, hepatic blood distribution and concentration to each lung was similar to normal. For an offset of one or more diameters, hepatic blood tended to flow preferentially towards the nearest pulmonary artery with the opposite pulmonary artery exhibiting a deficit (<10% of normal). CONCLUSIONS: Distribution of hepatic blood to each lung was found to be a function of vena cava offset and pulmonary artery flow split. Under normal conditions, 60% of blood towards the right pulmonary artery, the hepatic blood distribution to both lungs could be maintained above 50% of normal if the inferior vena cava was offset towards the left pulmonary artery. Offsetting the inferior vena cava towards the right pulmonary artery jeopardized the delivery of hepatic blood to one lung.

Mortality rates after surgery for congenital heart defects in children and surgeons' performance.

BACKGROUND: A public inquiry into surgery for paediatric congenital heart defects in Bristol, UK, underscored the need for reliable data on overall mortality rates, which would allow assessment of individual surgeons' performance. We aimed to gather and report such data for 1 year to provide information for clinicians, researchers, policy makers, and the general public. METHODS: We collected data on all operations (1378) for congenital heart defects done by 11 surgeons in five departments in the UK between April 1, 1997, and March 31, 1998. These operations represented about 36% of all operations done in the UK during that time. Clearly defined criteria were agreed to classify operations into subgroups. FINDINGS: The overall mortality rate for all operations was 4.0% (95% CI 3.0-5.2). No deaths occurred for 67 arterial-switch operations. Mortality rates for coarctation, ventricular septal defect, atrioventricular septal defect, Fallot, and truncus arteriosus operations were 1.1%, 0.6%, 3.6%, 2.3%, and 28.6%, respectively. Although overall mortality rates between surgeons varied (1.6-6.9%), no surgeon's were higher than the 95% CI. The numbers of operations done by individual surgeons were small, which led to wide confidence intervals and made the detection of differences in performance difficult. INTERPRETATION: The participating departments seemed to reach high standards of care for children with congenital heart defects, although more data would be needed to assess performance of individual surgeons. The development of quality standards will be difficult because of the complexity of defects, the different types of operations, and few patients in each subgroup. Collection of larger sets of data for more patients and centres are needed.

Repair of aortic atresia and hypoplastic left heart syndrome without using graft material.

We present a modification of the Norwood stage 1 operation, where the neo-aorta was reconstructed without using graft material. After extensive mobilization of the descending aorta the ductus arteriosus was excised and an end-to-end anastomosis was created between the main pulmonary artery and the distal ductal-aortic junction. The proximal ascending aorta was anastomosed side-to-side to the neo-aorta. Finally either a direct side-to-side anastomosis was created or a 3.5-mm Gore-Tex graft was implanted between the innominate artery and the right pulmonary artery. The first three patients had a favourable outcome: echocardiography showed good ventricular function and acceptable saturation (85%) at the follow up.

Subtype-specific kinetics of inhibitory adenosine receptor internalization are determined by sensitivity to phosphorylation by G protein-coupled receptor kinases.

Despite coupling to the same class of inhibitory G proteins and binding the same physiological ligand, the human A(1) and rat A(3) adenosine receptors (ARs) desensitize at different rates in response to sustained agonist exposure. This is due to the ability of the A(3)AR, but not the A(1)AR, to serve as a substrate for rapid phosphorylation and desensitization by members of the G protein-coupled receptor kinase (GRK) family. The aim of this study was to investigate whether these differences were also manifested in their abilities to undergo agonist-dependent receptor internalization. For the first time, we report that A(3)ARs internalize profoundly in response to short-term exposure to agonist but not activators of second messenger-regulated kinases. The A(3)AR-selective antagonist MRS1523 blocked both A(3)AR phosphorylation and internalization. Moreover, in contrast to the A(1)AR, which internalized quite slowly (t(1/2) = 90 min), A(3)ARs internalized rapidly (t(1/2) = 10 min) over a time frame that followed the onset of receptor phosphorylation. A nonphosphorylated A(3)AR mutant failed to internalize over a 60-min time course, suggesting that receptor phosphorylation was essential for rapid A(3)AR internalization to occur. In addition, fusion onto the A(1)AR of the A(3)AR C-terminal domain containing the sites for phosphorylation by GRKs conferred rapid agonist-induced internalization kinetics (t(1/2) = 10 min) on the resulting chimeric AR. In conclusion, these data suggest that GRK-stimulated phosphorylation of threonine residues within the C-terminal domain of the A(3)AR is obligatory to observe rapid agonist-mediated internalization of the receptor.

Cytokine and S100B levels in paediatric patients undergoing corrective cardiac surgery with or without total circulatory arrest.

OBJECTIVES: Neurological damage following cardiopulmonary bypass (CPB) is difficult to objectively evaluate in infants. In adults, serum elevations of astroglial S100B correlate with proven brain injury independent of operative temperature. The deleterious effects of inflammatory cytokines, generated during CPB, on the brain have not been studied in infants using S100B as a marker for cerebral injury. METHODS: Twelve neonates, weighing 3.3 +/- 0.2 kg (total circulatory arrest group (TCA)) and 12 infants weighing 7.0 +/- 1.0 kg (cardiopulmonary bypass group (CPB)) underwent corrective cardiac surgery for various pathologies. Serial blood samples on induction, at the end of CPB, 30 min, 2 h and 24 h after the administration of protamine, were taken. The resultant plasma was frozen to -80 degrees C and stored for batch analysis. Cytokines were measured using ELISAs and S100B using a luminometric assay. RESULTS: The TCA group were younger and experienced a longer perfusion time than the CPB group (137 +/- 8 vs. 113 +/- 7, P = 0.04). The mean TCA time was 23 +/- 4 min. The TCA group had significantly higher levels of IL-6 (P = 0.001), IL-8 (P = 0.005) and S100B (P = 0.002) at 24 h. C5b-9 levels were significantly lower in the TCA group: end of CPB (P = 0.001), 30 min (P < 0.001), 2 h (P = 0.002). There was a weak, but significant correlation between IL-6 levels at the end of CPB and S100B levels 2 h later (r = 0.55, P = 0.03). Long extubation times were associated with high 24-h S100B levels (r = 0.52, P = 0.01). CONCLUSIONS: (1) The TCA group have prolonged rises of IL-6, IL-8 and S100B. (2) The TCA group generates significantly lower complement. (3) Astroglial injury, seen after surgery, may, in part, be cytokine mediated.

The influence of size mismatch on the hemodynamic performance of the pulmonary autograft in vitro.

OBJECTIVES: We established an in vitro model to investigate the effect of size mismatch between the aortic and pulmonary root on the hydrodynamic performance and leaflet motion of the pulmonary autograft. METHODS: Ten fresh porcine pulmonary roots (annulus diameter: 19-25 mm) were tested in a pulsatile flow simulator. The autografts then were implanted in fresh porcine aortic roots (annulus diameter: 19-30 mm) and retested in the flow simulator. Three roots were oversized by 21-39%, three were undersized by 32-45% and there were four size for size implantations. The external diameter of the roots and autografts was measured at the sinotubular junction at hydrostatic pressures of 0 - 120 mmHg. The transvalvular gradient and regurgitation were also measured and the effective orifice area was calculated. The leaflet motion was recorded on video. RESULTS: The fresh pulmonary roots were more compliant than the fresh aortic roots (46 +/- 8.4% vs. 35 +/- 7.8% dilatation from 0 to 120 mmHg). The group of matching size autografts dilated by 43 +/- 4.9% in the same pressure range. The external diameter of the undersized autografts was 10 +/- 2.1% bigger than before implantation at 0 pressure and then the dilatation was 40 +/- 5.3% at 120 mmHg. The oversized implantation made the autografts 11 +/- 9.4% smaller in their relaxed state, but then they dilated by 65 +/- 11% as the pressure increased to 120 mmHg, resulting in a net dilatation of 54% over the original undilated state. The under or oversizing had little effect on the pressure gradient measured across the valves (5.6 +/- 2.57 mmHg before, 6.3 +/- 3.27 mmHg after implantation). Only the oversized valves showed significantly higher gradients than the native pulmonary valves. The effective orifice area of the undersized autografts was slightly bigger and the oversized autografts was slightly smaller after implantation, although the differences were not significant. The size mismatch did not cause regurgitation on the valves. The video images showed very low-open leaflet-bending deformation, both on the fresh pulmonary and the autograft valves. CONCLUSION: Under or oversizing the pulmonary autograft up to 40% of the annulus diameter did not affect the hydrodynamic parameters significantly. The compliance of the autograft root was able to compensate for the size mismatch without adversely influencing the valve performance.

Fate of the stented arterial duct.

BACKGROUND: The technical aspects of ductal stenting have been reported, but little is known of the fate of the duct after stent implantation. METHODS AND RESULTS: Nineteen patients underwent stent implantation to maintain ductal patency. Eight had hypoplastic left heart (HLH) syndrome, 10 had pulmonary atresia, and 1 had tricuspid atresia. Median survival with HLH was 57 (12 to 907) days. Stent implantation was successful in all cases of HLH, but there were no long-term survivors. Two well-palliated infants died at transplantation. Median survival with duct-dependent pulmonary flow was 183 (0 to 1687) days, with 3 patients well at latest follow-up (56, 55, and 9 months, respectively). There were 2 operative deaths due to ductal spasm and 4 late deaths, 1 due to duct thrombosis, 1 due to chronic lung disease, and 2 of unknown cause. Stent implantation failed in 4 of the 11 cases. Assessment of endothelialization was possible in 13 cases; the stent was partially covered in 3 and fully endothelialized in all 10 cases assessed >8 weeks after implantation. In patients stented for inadequate pulmonary flow, ductal intimal hyperplasia occurred by 9 months in all 3 survivors but responded to repeated dilation. CONCLUSIONS: Ductal stenting cannot be recommended. In patients with HLH, it provides only short-term palliation even when combined with pulmonary artery banding. With duct-dependent pulmonary blood flow, the procedure carries high risk, and duration of palliation is poor. In patients with bilateral ducts and absent central pulmonary arteries, good palliation may be achieved, but repeated angioplasty is necessary to counteract intimal hyperplasia.

The effect of sizing on the in vitro hydrodynamic characteristics and leaflet motion of the Toronto SPV stentless valve.

OBJECTIVES: We established an in vitro model to investigate the effects of valve sizing on the hemodynamic characteristics and leaflet motion of the Toronto SPV valve (St Jude Medical, Inc, St Paul, Minn). METHODS: Nine valves were first implanted in fresh porcine aortic roots and then retested in glutaraldehyde-treated porcine aortic roots. Three valves were 1- to 2-mm oversized, 3 were 1- to 2-mm undersized, and there were 3 size-for-size implantations. The elasticities of the aortic roots and the composite roots were measured in the pressure range between 0 and 120 mm Hg, and the composite roots were then tested in a pulsatile flow simulator. The transvalvular gradient and regurgitation were measured and the effective orifice area and performance index were calculated for each root. Leaflet motion was recorded on videotape. RESULTS: The external diameter of the fresh root increased by 35% as the hydrostatic pressure rose from 0 to 120 mm Hg, as compared with 11% for the glutaraldehyde-treated root. Valve implantation in the fresh root reduced the distensibility to 22% but did not change distensibility in the glutaraldehyde-treated root. The effective orifice area was dependent on the valve size, with the transvalvular gradient decreasing as the valve size increased. For the same size of valve the hydrodynamic parameters were slightly better if the valve was undersized by 1 mm. A significant difference in favor of the undersized valves was found in open-leaflet bending deformation. CONCLUSION: Leaflet motion of the stentless porcine aortic valve in vitro is improved if the valve is slightly undersized, and this may be beneficial to the long-term durability of the prosthesis.

Inflammatory mediators in adults undergoing cardiopulmonary bypass: comparison of centrifugal and roller pumps.

BACKGROUND: The nonocclusive centrifugal pump is used for cardiopulmonary bypass (CPB) and mechanical cardiac assistance. This study examined its impact on proinflammatory cytokine release. METHODS: Forty-one patients undergoing elective coronary artery bypass grafting were randomized prospectively to either a standard roller pump group (n = 21) or a centrifugal vortex pump group (n = 20) for CPB. The two groups were well matched in age, sex, severity of disease, and duration of CPB and aortic cross-clamping. Plasma levels of the cytokines tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, and interleukin-8, as well as terminal complement, neutrophil counts, and leukocyte elastase, were analyzed before, during, and after CPB. RESULTS: In both groups, traces of tumor necrosis factor-alpha were observed infrequently and interleukin-1beta was not detected. Plasma levels of interleukin-6 and interleukin-8 increased during and after CPB, reaching a peak at 2 hours after protamine administration in both groups before returning toward baseline at 24 hours. The release of interleukin-6 was significantly greater in the centrifugal group (p < 0.05), whereas the interleukin-8 concentration did not differ between the groups throughout the study period. Levels of terminal complement increased in both groups perioperatively, reaching a peak 30 minutes after protamine administration, whereas neutrophil counts and elastase peaked 2 hours after protamine administration. Plasma terminal complement, neutrophil counts, and elastase release were significantly higher in the centrifugal group (p < 0.05). Peak terminal complement correlated (r = 0.64, p < 0.01) with peak elastase in the centrifugal group only. CONCLUSIONS: This study confirms the proinflammatory nature of CPB in adults and demonstrates that use of the centrifugal pump induces a greater systemic inflammatory response than use of the standard roller pump.