Masashi Komeda

Pilot study of the efficacy of a thrombin inhibitor for use during cardiopulmonary bypass

Heparin is normally used for anticoagulation during cardiopulmonary bypass (CPB), but its use is contraindicated in patients with a history of heparin-induced thrombocytopenia, heparin-provoked thrombosis, or both. Heparin therapy can also be ineffective due to heparin resistance. A short-acting, oligonucleotide-based thrombin inhibitor (thrombin aptamer) may potentially serve as a substitute for heparin in these and other clinical situations. We tested a novel thrombin aptamer in a canine CPB pilot study to determine its anticoagulant efficacy, the resultant changes in coagulation variables, and the aptamers clearance mechanisms and pharmacokinetics. Seven dogs were studied initially: Four received varied doses of the aptamer (to establish the pharmacokinetic profile) and 3 received heparin. Subsequently, 4 other dogs underwent CPB, receiving a constant infusion of the aptamer before CPB (to characterize the baseline coagulation status), with partial CPB and hemodilution, during 60 minutes of total CPB, and, finally, after a 2-hour recovery period. At a 0.5 mg.kg-1.min-1 dose, the activated clotting time rose with aptamer infusion from 106 +/- 12 seconds to 187 +/- 8 seconds (+/- 1 standard deviation) (p = 0.014), increased further with hemodilution (to 259 +/- 41 seconds; p = 0.017), and was even more prolonged during total CPB (> 1,500 seconds; p < 0.001). This later increase in the activated clotting time paralleled a rise in the plasma concentration of the thrombin aptamer during total CPB, as determined by high-performance liquid chromatography.(ABSTRACT TRUNCATED AT 250 WORDS)

Mitral annular size and shape in sheep with annuloplasty rings

BACKGROUND Mitral annuloplasty is an important element of most mitral repairs, yet the effects of various types of annuloplasty rings on mitral annular dynamics are still debated. Recent studies suggest that flexible rings preserve physiologic mitral annular area change during the cardiac cycle, while rigid rings do not. METHODS To clarify the effects of mitral ring annuloplasty on mitral annular dynamic geometry, we sutured 8 radiopaque markers equidistantly around the mitral anulus in 3 groups of sheep (n = 7 each: no ring, Carpentier-Edwards semi-rigid Physio-Ring [Baxter Healthcare Corp, Edwards Division, Santa Ana, Calif], and Duran flexible ring [Medtronic, Inc, Minneapolis, Minn]). Ring sizes were selected according to anterior leaflet area and inter-trigonal distance (Physio-Ring 28 mm, n = 7; Duran ring 31 mm, n = 5, and 29 mm, n = 2). After 8 +/- 1 days of recovery, the sheep were sedated and studied by means of biplane videofluoroscopy. Mitral annular area was calculated from 3-dimensional marker coordinates without assuming circular or planar geometry. RESULTS In the no ring group, mitral annular area varied during the cardiac cycle by 11% +/- 2% (mean +/- SEM; maximum = 7.6 +/- 0.2, minimum = 6.8 +/- 0.2 cm2; P </=.001). Mitral annular area was fixed in the Physio-Ring group (4. 6 +/- 0.1 cm2) and, surprisingly, also static in the Duran ring group (4.8 +/- 0.1 cm2; P =.26 vs Physio-Ring). Furthermore, mitral annular 3-dimensional shape changed in the no-ring group during the cardiac cycle, but not in the Physio-Ring or Duran groups. CONCLUSIONS Mitral annular area and shape did not change during the cardiac cycle after ring annuloplasty, regardless of ring type. Thus mitral annular area reduction, independent of intrinsic ring flexibility, is the chief mechanism responsible for the salutary effects of mitral ring annuloplasty.

Septal Function During Left Ventricular Unloading

BACKGROUND Left ventricular (LV) unloading with mechanical support devices alters biventricular geometry and impairs right ventricular (RV) contractility, but its effect on septal systolic function remains unknown. METHODS AND RESULTS To evaluate the effects of LV volume and pressure unloading on septal geometry and function, LV preload was abruptly reduced by clamping left atrial pressure between 0 and -2 mm Hg in seven open-chest, anesthetized dogs by use of a pressure-control servomechanism to withdraw blood from the left atrium. With left atrial pressure clamping, maximal LV pressure decreased 30 +/- 12% (mean +/- SD) (P < .0001) and LV end-diastolic cross-sectional area (determined by two-dimensional echocardiography) decreased by 53 +/- 16% (P < .0001). This caused the septum to shift toward the left (RV septal free-wall dimension increased; P < .004) and flatten (radius of curvature increased; P < .0002), while LV septal free-wall dimension fell (P < .0001). Septal end-diastolic thickness increased 23 +/- 15% (P < .0005), reflecting a decline in septal preload. Systolic septal thickening decreased (P < .002), while systolic septal output (Septal Output = Septal Thickening x Heart Rate) fell from 30 +/- 17 to 15 +/- 22 cm/min (P < .002). This was associated with movement along the septal Frank-Starling equivalent (septal output versus end-diastolic septal thickness [preload] relation) to a less productive portion of the curve. CONCLUSIONS LV unloading not only altered interventricular septal geometry but also reduced septal systolic thickening and output, all of which may contribute to impaired RV contractility during mechanical LV support.

Three-dimensional dynamics of the canine mitral annulus during ischemic mitral regurgitation

BACKGROUND It has been suggested that ischemic mitral regurgitation results, at least in part, from generalized end-systolic mitral annulus (MA) dilatation, but the role of the MA is incompletely understood and the segmental dynamics of the MA during left ventricular ischemia have not been described. METHODS We used radiopaque markers and simultaneous biplane videofluoroscopy to measure three-dimensional in vivo lengths of eight MA segments in 7 sedated dogs before and after induction of ischemic MR (produced by circumflex coronary artery balloon occlusion and verified by Doppler echocardiography). As viewed from the left atrium, the MA segment between markers 1 and 2 (S12) was defined as starting at the posteromedial commissure, and remaining segments were numbered sequentially clockwise around the MA (ie, the posterior MA encompassed S12, S23, S34, S45,; the anterior MA included S56, S67, S78, S81). Marker images obtained 7 to 12 days after implantation were used to construct x, y, and z coordinates of each marker at end-diastole and end-systole. RESULTS During regional (posterolateral walls) left ventricular ischemia, the end-systolic MA area increased (4.9 +/- 0.8 cm2 [control] versus 5.9 +/- 0.6 cm2; p = 0.005). End-systolic MA segment lengths were as follows (control, ischemia [mm, mean +/- standard deviation]): S12 = 9 +/- 2, 10 +/- 3; S23 = 10 +/- 2, 12 +/- 3; S34 = 13 +/- 1, 15 +/- 1; S45 = 8 +/- 2, 9 +/- 2; S56 = 11 +/- 2, 11 +/- 2; S67 = 12 +/- 2, 12 +/- 2; S78 = 10 +/- 3, 11 +/- 2; and S81 = 11 +/- 1, 12 +/- 1. Values for S12, S23, S34, and S81 were significant (p < or = 0.05 for control versus ischemia by paired t test). CONCLUSIONS During ischemic mitral regurgitation, the MA enlarged at end-systole, but in an asymmetric manner; most posterior annular segments lengthened, whereas most anterior annular segment lengths did not change. These data suggest that alterations in regional MA mechanics may be important in the pathogenesis of ischemic mitral regurgitation. Further three-dimensional studies of MA dynamics and shape should be conducted so that new knowledge may result in improved mitral valve surgical techniques.

Left Ventricular Function, Twist, and Recoil After Mitral Valve Replacement

BACKGROUND Preservation of the mitral subvalvular apparatus during mitral valve replacement (MVR) has become more popular, in part because of the clinically and experimentally demonstrated more optimal left ventricular (LV) performance after surgery; the mechanisms responsible for this beneficial influence, however, have not been clearly elucidated. METHODS AND RESULTS Fourteen dogs underwent placement of 26 myocardial markers into the LV and septum. One week later, the animals were studied while awake, sedated, and atrially paced (120 beats per minute) both under baseline conditions and after inotropic stimulation (calcium). The animals then underwent MVR and were randomized into either chord-sparing (MVR-Intact) or chord-severing (MVR-Cut) techniques. Two weeks later, the animals were studied under the same conditions. LV systolic function was assessed by the slope of the end-systolic pressure-volume relation (Ees); early LV diastolic filling was analyzed by the pressure-time constant of relaxation (tau). The instantaneous longitudinal gradient of torsional deformation for the LV (twist) was also calculated, as were the changes in twist with respect to time during systole and early diastole (LV recoil). Intergroup comparison showed a trend toward increased contractility (Ees, P = .061, before versus after MVR), as well as faster relaxation for the MVR-Intact group. Concurrent analysis of LV systolic function and the rate of systolic twist revealed a significant inverse relation, which disappeared after MVR when the chordae were severed. CONCLUSIONS These observations suggest that the mitral subvalvular apparatus acts as a modulator of LV systolic torsional deformation into LV pump (or ejection) performance.

Pitfalls in creation of left atrial pressure-area relationships with automated border detection

Creation of pressure-area relationships (loops) with automated border detection (ABD) involves correction for the variable inherent delay in the ABD signal relative to the pressure recording. This article summarizes (1) the results of in vitro experiments performed to define the range of, and factors that might influence, the ABD delay; (2) the difficulties encountered in evaluating a thin-walled structure like the left atrium in the dog model; and (3) the solutions to some of the difficulties found. The in vitro experiments showed that the ABD delay relative to high-fidelity pressure recordings ranges from 20 to 34 msec and 35 to 57 msec at echocardiographic frame rates of 60/sec and 33/sec, respectively. The delay was not influenced significantly by the type of transducer used, distance from the target area, or size of the target area. The delay in the ABD signal, relative to the echocardiographic image, ranges from nil to less than one frame duration, whereas it is delayed one to two frame durations relative to the electrocardiogram processed by the imaging system. In the dog model, inclusion of even small areas outside the left atrium rendered curves with apparent physiologic contour but inappropriately long delays of 90 to 130 msec. To exclude areas outside the left atrial cavity, time-gain compensation and lateral gain compensation were used much more extensively than during left ventricular ABD recording. By changing the type of sonomicrometers used in our experiments, we were able to record simultaneously ABD and ultrasonic crystal data. However, both spontaneous contrast originating from a right-sided heart bypass pump and electronic noise from the eletrocautery severely interferred with ABD recording.

Exploring better methods to preserve the chordae tendineae during mitral valve replacement

BACKGROUND It is not known how best to resuspend the mitral chordae tendineae during mitral valve replacement to optimize postoperative left ventricular (LV) systolic and diastolic function. METHODS Six different techniques to preserve the chordae during mitral valve replacement were compared in 12 dogs using a nondistorting isovolumic technique: conventional, all chordae severed; anterior, all chordae preserved anteriorly; partial, anterior papillary muscle chordae preserved anteriorly; posterior, all chordae preserved posteriorly; oblique, anterior papillary muscle chordae directed anteriorly and posterior papillary muscle chordae posteriorly; and counter, opposite of oblique chordal direction. Control measurements (no chordal tension) were recorded between each experimental condition. RESULTS The oblique method tended to have the best LV systolic function versus the conventional method (Emax = 4.0 +/- 1.8 versus 3.3 +/- 1.2 mm Hg/mL [mean +/- standard deviation]; p = 0.08 by repeated-measures analysis of variance; physiologic intercept Ees100 = 20.3 +/- 8.6 mL [p < 0.05 versus control]), with no major change in LV diastolic stiffness. The posterior method had a lower Emax (3.3 +/- 1.2 mm Hg/mL) than the oblique method, but a similar Ees100 (20.8 +/-8.1 mL; p < 0.05 versus control) and the best diastolic LV performance (LV diastolic stiffness = 0.46 +/- 0.23 mm Hg/mL). The counter method also had good systolic function (Emax = 3.8 +/- 1.2 mm Hg/mL; Ees100 = 19.7 +/- 7.5 mL; p < 0.05 versus control), but had less favorable diastolic properties (0.65 +/- 0.37 mm Hg/mL; p < 0.05 by repeated-measures analysis of variance versus posterior). CONCLUSIONS In this isovolumic preparation in normal canine hearts, the oblique method of chordal resuspension was associated with the best LV systolic function, whereas the counter technique impaired LV diastolic function. These preliminary results warrant further study in ejecting and failing hearts to determine conclusively which chordal orientation best preserves LV performance after mitral valve replacement.

Complete Unloading Alone May Not Adequately Protect the Left Ventricle

BACKGROUND The benefit of left ventricular (LV) unloading for preserving LV function is commonly accepted, but its efficacy remains incompletely defined. METHODS We studied the influence of complete LV unloading on LV systolic and diastolic mechanics using an in situ isovolumic preparation with two different coronary perfusion pressures (CPPs) in 12 dogs during prolonged normothermic cardiopulmonary bypass. RESULTS Multivariate analysis of covariance with time as a covariate revealed that a high CPP (143 +/- 36 mm Hg; n = 6) was associated with better preservation of systolic LV function over time as assessed by LV end-systolic elastance (p < 0.001) and the end-systolic pressure-volume relation physiologic intercept (p < 0.001) compared with a moderate CPP (107 +/- 18 mm Hg; p < 0.005 versus a high CPP by t-test; n = 6). Dobutamine (2 micrograms.kg-1.min-1) improved LV end-systolic elastance (p < 0.005) and LV physiologic intercept (p < 0.01) only in the high-CPP group. Conversely, impaired LV diastolic function (as measured by LV stiffness) was observed (p < 0.001) with a high CPP, but did not change with a moderate CPP. CONCLUSIONS These observations in canine hearts suggest that complete LV unloading may not preserve LV systolic function adequately over time when CPP is maintained in the accepted clinical range. A higher CPP is required to prevent deterioration over prolonged cardiopulmonary bypass times, but diastolic dysfunction still occurs.