Mitral valve replacement in dilated canine hearts with chronic mitral regurgitation. Importance of the mitral subvalvular apparatus.

The importance of the mitral subvalvular apparatus in terms of left ventricular (LV) mechanics and energetic efficiency in the chronically dilated canine heart was assessed in nine dogs with surgically induced mitral regurgitation. Miniature radiopaque tantalum markers were implanted into the myocardium to measure LV volume. Biplane cinefluoroscopic images obtained 1 week and 3 months after creation of mitral regurgitation confirmed the presence of LV dilatation. Mitral valve replacement with preservation of all chordae tendineae was then performed. LV systolic function and derived energetics were then assessed during transient caval occlusion both before and after chordal division by using exteriorized snares. Global LV systolic mechanics, as assessed by the slopes of the end-systolic pressure volume (Ees) and end-systolic stress volume (Ms) relations, fell by 46% (11.7 +/- 2.8 versus 6.3 +/- 1.4 mm Hg/ml, p less than 0.001) and 33% (17.8 +/- 4.0 versus 12.0 +/- 5.1 kdyne/cm5, p = 0.0001), respectively, when the chordae were divided. Chordal severing also increased systolic LV wall stress or LV afterload. In terms of calculated myocardial energetics, the slopes of the stroke work-end-diastolic volume and pressure volume area-end-diastolic volume relations declined significantly by 20% (85 +/- 14 versus 68 +/- 16 mm Hg) and 11% (116 +/- 20 versus 104 +/- 20 mm Hg) after cutting the chordae, thereby indicating reduced external stroke work and mechanical energy generated at any given level of preload. Moreover, the efficiency of energy transfer from pressure volume area to external stroke work fell by 19% (p less than 0.001). Since effective systemic arterial elastance (Ea) did not change, the Ea/Ees ratio (index of ventriculoarterial [V-A] coupling) increased from 0.93 +/- 0.27 to 1.67 +/- 0.62 (p = 0.006). Therefore, chordal division in dilated dog hearts due to chronic mitral regurgitation resulted not only in deterioration of systolic LV mechanics but also deleterious changes in calculated LV energetics and efficiency due to exacerbated mismatch in V-A coupling between the left ventricle and the systemic arterial bed, unfavorable loading conditions, and exhaustion of preload reserve. These observations in the low-pressure, volume-overloaded heart due to chronic mitral regurgitation underscore the importance of the mitral subvalvular apparatus for optimal LV systolic performance and energetic efficiency.

Importance of the mitral subvalvular apparatus for left ventricular segmental systolic mechanics.

The relative importance of the anterolateral (ANTLAT) and posteromedial (POSTMED) papillary muscle (PM) chordae tendineae for left ventricular (LV) segmental wall function was assessed in 12 in situ ejecting canine hearts. Pairs of piezoelectric crystals were placed in the regions subtending PM insertions and the ANTLAT LV free wall to measure wall thickness. After mitral valve replacement with complete preservation of the subvalvular apparatus, chordal attachments to either the ANTLAT PM or POSTMED PM were randomly severed using exteriorized snares, followed by subsequent division of the remaining chordae tendineae. Segmental wall function in each region was determined at each stage by segmental preload recruitable stroke work (sPRSW, slope of the segmental stroke work-end-diastolic wall thickness relation). The order in which the chordae were severed was unimportant (p greater than 0.530 in all regions). When the ANTLAT PM chordae were severed first, there were significant declines in sPRSW without a change in the wall thickness intercept in both the ANTLAT (-71.0 +/- 18.3 vs. -57.7 +/- 16.8 mmHg, p less than 0.05) and POSTMED (-81.8 +/- 23.1 vs. -65.4 +/- 17.3 mmHg, p less than 0.05) PM insertion sites. No further significant reductions in sPRSW in either region were detected after severing the remaining chordal attachments to the POSTMED PM. sPRSW in the ANTLAT LV free wall decreased progressively, reaching statistical significance when both sets of chordae tendineae were divided (-88.3 +/- 14.3 vs. -74.0 +/- 15.2 mm Hg, p less than 0.05). When the POSTMED PM chordae were severed first, no significant changes in sPRSW or the wall thickness intercept in either region of PM insertion were detected. Subsequent division of the ANTLAT PM chordal attachments reduced sPRSW significantly in both the ANTLAT PM (-65.9 +/- 21.1 vs. -56.1 +/- 22.1 mm Hg, p less than 0.05) and POSTMED PM (-78.8 +/- 24.7 vs. -67.2 +/- 24.0 mm Hg, p less than 0.05) insertion sites, without a shift in the wall thickness intercept. In the ANTLAT LV free wall, sPRSW again fell progressively, achieving statistical significance only when both chordal attachments were severed (-78.6 +/- 14.8 vs. -62.2 +/- 13.7 mm Hg, p less than 0.05). In conclusion, division of the chordae tendineae resulted in a decline in segmental LV function not only in the areas subtending PM insertions but also in remote LV regions. Furthermore, the influence of the ANTLAT PM chordae predominated local LV systolic function at both PM insertion sites.(ABSTRACT TRUNCATED AT 400 WORDS)

Global and regional left ventricular systolic performance in the in situ ejecting canine heart. Importance of the mitral apparatus.

The importance of the intact mitral apparatus in left ventricular (LV) systolic performance has been indirectly suggested by clinical studies of chordal-preserving mitral valve replacement (MVR) or reconstruction. The importance of the intact mitral apparatus has been clearly demonstrated in isovolumic experimental preparations but has not been demonstrated unequivocally in ejecting hearts. Therefore, this question was assessed independently of load in an in situ, open-chest ejecting canine heart preparation (n = 9). Three orthogonal LV dimensions were measured by sonomicrometry. During MVR with complete chordal preservation, snares were placed around the anterior and posterior papillary muscles. After the hearts were weaned from cardiopulmonary bypass, LV function was assessed by caval occlusion to alter LV preload abruptly. The slopes of the end-systolic--pressure-volume (end-systolic elastance, Ees) and stroke-work--end-diastolic volume (preload-recruitable stroke work, PRSW) relations were used to measure global LV systolic function; similarly, the slopes of the end-systolic--pressure-dimension (regional end-systolic elastance, rEes) and stroke-work--end-diastolic dimension changes in regional LV systolic performance. All chordae were then divided by pulling the snares. Immediate reassessment revealed deterioration of global LV function: Ees declined by 72% (14.1 +/- 11.2 mm Hg/ml [mean +/- SD] vs. 3.9 +/- 3.5 mm Hg/ml, p less than 0.001), and PRSW declined by 39% (129 +/- 37 vs. 79 +/- 29 mm Hg, p = 0.0001). Regional LV function was also adversely affected but somewhat selectively: rEes decreased significantly in all three LV dimensions (p less than or equal to 0.03), but rPRSW decreased significantly (-21%) only in the anteroposterior minor LV axis (89 +/- 19 vs. 70 +/- 15 mm Hg, p = 0.005) and in the septal-lateral axis (-19%, p = NS). These data demonstrate the importance of the intact mitral apparatus on LV systolic performance in ejecting hearts, particularly in the LV regions subtended by the papillary muscles.

Effects of aspirin, dipyridamole, and cod liver oil on accelerated myointimal proliferation in canine veno-arterial allografts.

The effects of the administration of aspirin (ASA), dipyridamole (DPM), and cod liver oil (CLO) on graft patency rate and degree of intimal hyperplasia were investigated in a canine, hypercholesterolemic veno-arterial allograft model in an attempt to modify this immunologically mediated vascular injury. The drug regimens were ASA 1 mg/kg/day, DPM 10 mg/kg/day, combined ASA and DPM (ASA + DPM), and CLO (1.8 g/day eicosapentanoic acid [EPA] and 1.2 g/day docosahexanoic acid [DHA]), and control. The early angiographic patency rate (1-3 weeks) was 81% +/- 10% (+/- 70% confidence limits); the 90-day overall patency rate was 60% +/- 4% (87/144), with no statistically significant differences among the groups (range 46 +/- 10-71 +/- 9%). Qualitatively, there was no difference in luminal thrombus, intimal hemorrhage, or lesion eccentricity. Considering the relatively short time of graft implantation, an extensive amount of microscopic disease was observed; quantitatively, the mean intimal thickness was 515 +/- 17 microgram overall but was not statistically different between the groups. The fraction of potential lumenal area occupied by intimal thickening was 0.37 +/- 0.01 but again did not differ significantly between the groups. These doses of ASA, DPM, ASA + DPM, and CLO did not alter graft occlusion or retard the marked degree of subintimal myointimal cell hyperplasia that was generated in this hypercholesterolemic canine veno-arterial allograft preparation. Possible explanations for these negative findings include inadequate dosage or form of omega-3 fatty acids and the antiplatelet drugs administered, excessive variability in graft response due to uncharacterized immunologic histocompatibility, and the possible influence of non-platelet-mediated mechanisms. Nevertheless, this preparation is attractive as a reproducible model of accelerated (immunologically mediated) experimental arteriosclerosis.

Incomplete biochemical adaptation of vein grafts to the arterial environment in terms of prostacyclin production.

Biochemical (or functional) adaptation of venoarterial grafts has been demonstrated recently. We reexamined one aspect of this biochemical "arterialization" process: prostacyclin (PGI2) production by canine venoarterial autologous grafts and the responsiveness of this biosynthetic pathway to maximal stimulation with substrate enhancement. Four reversed autologous grafts (femoral vein) were interposed into both carotid and femoral arteries in eight dogs. After 12 weeks, the grafts were removed, and radioimmunoassay was used to determine luminal surface production of 6-keto-PGF1 alpha (the stable metabolite of PGI2) in both the basal and stimulated (27 mumol/L arachidonic acid [AA]) states. PGI2 production by the venous autologous grafts was compared with that of control native artery and vein. We confirmed that PGI2 production (measured in nanograms per milliliter) by control artery was greater than vein under both basal conditions (5.8 +/- 0.4 [+/- SEM] vs. 2.7 +/- 0.5, p less than 0.001) and stimulated conditions (8.8 +/- 0.8 vs. 5.5 +/- 0.4, p = 0.002); moreover, AA stimulation significantly increased PGI2 production in both native artery and vein compared with basal PGI2 production. Under basal conditions, graft PGI2 production (6.3 +/- 1.6 ng/ml) was not significantly different than basal arterial levels (p = 0.8) but was higher than basal venous levels (p = 0.05). However, in marked contrast to both native artery and vein, the vein graft flow surface showed no significant response to substrate enhancement with AA: basal (6.3 +/- 1.6 ng/ml) vs. stimulated (5.9 +/- 0.9 ng/ml) (p = 0.8). These observations confirm that canine venoarterial autologous grafts undergo biochemical "arterialization"; however, this process appears to be an incomplete one.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological, hematological, and physiological effects of a new thromboxane synthetase inhibitor (CGS-13080) during cardiopulmonary bypass in dogs.

The hematological and pharmacological effects of a new thromboxane synthetase inhibitor, CGS-13080 (imidazo[1,5-alpha]pyridine-5-hexanoic acid), were investigated during cardiopulmonary bypass in a blinded, randomized manner in dogs. Compared with placebo, CGS-13080 suppressed thrombin-stimulated platelet thromboxane B2 production by 90% during cardiopulmonary bypass (p less than .001), an effect that persisted for two hours after stopping the infusion. In the CGS-13080-treated group, plasma 6-keto-prostaglandin F1 alpha levels significantly increased over time (p less than .03) and were somewhat higher when compared with those in the placebo-treated group. This observation suggests that an "endoperoxide shunt" may have occurred. In the control group, an inverse correlation between platelet count and level of thromboxane B2 per platelet following in vitro thrombin stimulation (r = .5, p less than .001) was apparent, but there was no correlation between these two variables (r = .18, p less than .10) in the CGS-13080-treated group. No adverse hemodynamic or other effects attributable to CGS-13080 occurred during or immediately following cardiopulmonary bypass. These results suggest that CGS-13080 is an effective inhibitor of thromboxane B2 production during cardiopulmonary bypass in dogs and has no adverse physiological effects.