Bileaflet aortic valve prosthesis pivot geometry influences platelet secretion and anionic phospholipid exposure.

The clinical histories of the Medtronic Parallel (MP) and St. Jude Medical (SJM) Standard valves suggest pivot geometry influences the thrombogenic characteristics of bileaflet prostheses. This work studied the effects of various pivot geometries on markers of platelet damage in a controlled, in vitro apparatus. The Medtronic Parallel valve, two St. Jude Medical valves, and two demonstration prostheses were used to study the effects of bileaflet pivot design, gap width, and size on platelet secretion and anionic phospholipid expression during leakage flow. A centrifugal pump was used to drive blood through a circuit containing a bileaflet prosthesis. Samples were taken at set time intervals after the start of the pump. These samples were analyzed by cell counting, flow cytometry, and enzyme-linked immunosorbant assay. No significant differences were observed in platelet secretion or anionic phospholipid expression between experiments with the SJM 27 Standard regular leaker, the SJM 20 regular leaker, and the MP 27 valves. Significant differences in platelet secretion and anionic phospholipid expression were observed between a SJM 27 Standard regular leaker and a SJM 27 high leaker valve. These studies suggest that leakage gap width within bileaflet valve pivots has a significant effect on platelet damage initiated by leakage flow.

Stereocontrolled synthesis of cis-dibenzoquinolizine chlorofumarates: curare-like agents of ultrashort duration.

The quaternizations of dibenzoquinolizines 9 and 14 with 3-halo-1-propanols are highly cis-selective (94-100% cis), results consistent with the N-methylation of O-methylcapaurine (7b), but in contrast to the proposed trans-stereochemistry of dibenzo[a,h]quinolizine methiodide 10 and the analogous quaternizations of 1-benzyl- and 1-phenylisoquinoline congeners 5b and 5c. In this report, we describe stereoselective preparation of the unique cis-dibenzoquinolizinium propanols 15 and 16and their transformation into bis- and mixed-onium chlorofumarates 19, 20ab, and 26. Dibenzo[a,g]quinolizinium propanol 15 was prepared enantioselectively in three steps from dihydroisoquinoline 11. Asymmetric transfer hydrogenation of 11 in the presence of triethylamine/formic acid and Noyori's chiral ruthenium catalyst 12 produced R-(-)-5',8-dimethoxynorlaudanosine (13) in 98% yield and 87% ee. Pictet-Spengler cyclization of 13 in formalin/formic acid afforded the dibenzo[a,g]quinolizine 14 in 65% yield. Quaternization of 14 with 3-chloro-1-propanol under Finkelstein conditions generated cis-dibenzoquinolizinium propanol 15 in 85% yield with >94% cis-selectivity. The cis-dibenzo[a,h]quinolizinium propanol 16 was obtained as a single stereoisomer by reaction of the known tetramethoxyquinolizine 9 with neat 3-iodo-1-propanol. Bis-onium chlorofumarates 18 and 19 and the mixed-onium derivative 20ab were prepared by a pool synthesis procedure from (1R)-trans-6a, 16, and chlorofumaryl chloride (17). Mixed-onium alpha-chlorofumarate 26 was synthesized from (1S)-trans-6d, 15 and (+/-)-trans-2,3-dichlorosuccinic anhydride (22), employing a recently disclosed chlorofumarate mixed-diester synthesis. The title compounds (19, 20ab, and 26) displayed curare-like effects of ultrashort duration in rhesus monkeys.

The sensitivity of indicators of thrombosis initiation to a bileaflet prosthesis leakage stimulus.

BACKGROUND AND AIM OF THE STUDY: The recent clinical history and experimental studies of the Medtronic Parallel (MP) valve suggest that bileaflet valve leakage flow is a primary initiator of thrombosis. These studies investigated the effects of physiologic leakage flow through a MP valve on various markers of blood damage. METHODS: A centrifugal pump was used to drive whole, human blood anticoagulated with PPACK through a circuit containing a MP 27 mm valve in the closed position (experimental runs) or a MP 27 mm valve in the open position (control runs). Samples were taken at set time intervals after the start of the pump. These samples were analyzed by cell counting, flow cytometry, and ELISA. RESULTS: Cell counts remained relatively constant in both the experimental and control runs. Increases in plasma hemoglobin concentration and the percentage of glycophorin A-positive fragments in the cell population were not significant in either the experimental or the control runs. Plasma platelet factor 4 activity and the percentage of the CD41-positive population which was positive for annexin V increased significantly (p <0.05) in the experimental runs compared with the control runs. CONCLUSION: The results indicate that bileaflet valve leakage flow causes significant platelet disruption, that erythrocytes are more resistant to disruption by leakage flow than platelets and granulocytes, and that annexin V binding to platelets and plasma platelet factor 4 activity are more sensitive markers of leakage induced blood damage than plasma hemoglobin concentration.

An in vitro study of the hinge and near-field forward flow dynamics of the St. Jude Medical Regent bileaflet mechanical heart valve.

The most widely implanted prosthetic valve is the mechanical bileaflet. Recent clinical experiences suggest that some designs are more prone to thromboembolic episodes than others. This study evaluated the hinge flow and near-field forward flow of the new St. Jude Medical Regent bileaflet mechanical heart valve. Laser Doppler velocimetry measurements were conducted within the hinge and near-field forward flow regions of the Regent valve. These pulsatile flow velocity measurements were animated in time to visualize the flow fields throughout the cardiac cycle. During forward flow, a recirculation region developed in the inflow pocket of the Regent hinge but was subsequently abolished by strong backflow during valve closure. Leakage velocities in the hinge region reached 0.72 m/s and Reynolds shear stresses reached 2,600 dyn/cm2. Velocities in the near-field region were highest in the lateral orifice jet, reaching 2.1 m/s. Small regions of separated flow were observed adjacent to the hinge region. Leaflet motion through the Regent hinge creates a washout pattern which restricts the persistence of stagnation zones in its hinge. Based upon the results of these studies, the hematological performance of the Regent series should be at least equivalent to the performance of the Standard series.

The hemodynamic effects of mechanical prosthetic valve type and orientation on fluid mechanical energy loss and pressure drop in in vitro models of ventricular hypertrophy.

BACKGROUND AND AIMS OF THE STUDY: When choosing a prosthetic replacement for a natural heart valve, one objective should be to minimize the workload placed on the heart. This workload can be raised by fluid mechanical energy losses imposed by the valve. For a patient with left ventricular hypertrophy, certain aortic valve types and orientations could be hemodynamically superior to others. METHODS: This study used a control volume analysis to investigate the effects of prosthetic mechanical aortic valve type and orientation on fluid mechanical energy losses in four in vitro models of the left ventricular outflow/aortic inflow tract in various degrees of hypertrophy. Flow visualization studies were performed to qualitatively validate this analysis. The two most commonly used mechanical valve designs were studied: the St. Jude Medical (SJM) bileaflet valve and the Medtronic Hall (MH) tilting disk valve. Experiments were performed in pulsatile flow at a constant heart rate of 60 beats per min for five valve type/orientation combinations. The stroke volume was varied between 40 and 120 ml in five increments for each model and valve/orientation studied. RESULTS: Valve type and orientation was found to have a significant effect on energy losses in these models (p < 0.05). Valve/orientation combinations with leaflets or disks approximately parallel to the proximal flow direction created lower energy losses than others. The MH valve in the 180 degrees orientation caused significantly less energy losses and pressure drops (orifice and recovered) than any of the SJM valve/orientations studied (p < 0.05). The SJM and MH valves in the 0 degree orientation were responsible for significantly more energy loss than other valve/orientations studied (p < 0.05). An aortic inflow tract model with severe (45 degrees) curvature created significantly more energy loss (p < 0.05) than those with less curvature (15 and 30 degrees). However, the insertion of an obstruction simulating a hypertrophic tissue outgrowth caused much more energy loss than increasing the severity of outflow tract curvature from 15 to 45 degrees. Both orifice pressure drop and recovered pressure drop had excellent linear correlations with energy losses found in these models. CONCLUSIONS: These results imply that: (i) prosthetic valve type and orientation should be considered when replacing the aortic valve of a hypertropic patient; (ii) removal of obstructions within the aortic inflow tract will decrease ventricular workload; and (iii) the Doppler-estimated pressure gradients commonly use by cardiologists to assess the performance of a prosthetic valve, correlate very well with left ventricular energy loss and work load.