Effects of fish oil on arteriosclerosis in the Japanese quail.

The effects of fish oil on the development of arteriosclerosis were assessed using a special susceptible strain (SEA) of Japanese quail (Coturnix coturnix japonica). Sixty four quail were randomly divided into two groups and placed on isocaloric and approximately isocholesterolic (2% by weight) diets. Group A (control) was supplemented with 10% beef tallow oil, while group B received 10% Menhaden fish oil. The birds were sacrificed at 10 weeks (early) and 15-16 weeks (late). Based on semiquantitative histological grading of the arteriosclerotic lesions in the proximal aorta and brachiocephalic arteries, a score from 1 (no lesion) to 5 (severe, diffuse lesions) was assigned. A total of 57 quail were evaluated (seven died prior to scheduled sacrifice). At the early period, the mean arteriosclerosis scores for group A (n = 8) and group B (n = 8) were 3.3 (SD 1.0) and 1.9(1.0) respectively (p less than 0.017); 63% of the quail in group A and 13% of those in group B had a score greater than or equal to 3 (p less than 0.25, NS). At the late period, the scores for group A (n = 20) and group B (n = 21) were 3.8(0.6) and 2.6(0.9), respectively (p less than 0.001); 95% of the birds in group A and 43% of those in group B had a score greater than or equal to 3 (p less than 0.005). Histopathological examination of the arteriosclerotic lesions revealed disruption of the innermost elastic lamina, increased proteoglycan deposition in the medial interlamellar spaces, and the distinct involvement of macrophage like cells. Compared to human disease, arteriosclerosis in the quail is marked by distinct similarities, as well as differences. The SEA strain of Japanese quail appears to be a practical model for the study of arteriosclerosis; fish oil reduces the severity of disease in these birds when fed a high cholesterol diet.

Relative contributions of the anterior and posterior mitral chordae tendineae to canine global left ventricular systolic function.

The relative importance of the anterior and posterior mitral chordae tendineae to global left ventricular performance, independent of load, was determined by sequentially measuring the slope of the left ventricular peak isovolumetric pressure-volume relation in a canine model with the chordae of both, either, and neither mitral leaflet(s) intact. The order in which the chordae were severed was randomly assigned. Compared to baseline values (both chordae intact), severing the chordae of the anterior leaflet (posterior leaflet chordae intact) reduced the slope of the pressure-volume relation by 27% (p = 0.005) in 10 dogs; the slope decreased by an additional 16% (p = 0.017) when the posterior chordae were subsequently severed in this group. In 10 dogs randomized to the reverse order, the slope of the pressure-volume relation decreased by 17% (p = 0.021) after the posterior chordae were severed (anterior leaflet chordae intact); an additional 24% decrease in the slope (p = 0.001) occurred when the chordae of the anterior leaflet were subsequently severed in this group. The chordae of the anterior and posterior mitral leaflets have an additive, but statistically indistinguishable (p = 0.140), influence upon global left ventricular systolic performance; however, the contribution of the anterior chordae tends to be more important. Thus preservation of the anterior mitral leaflet and its chordal attachments to the papillary muscles during mitral valve replacement may have an equal or greater impact upon postoperative left ventricular function than mitral valve replacement with preservation of the posterior chordae; however, severing either the anterior or posterior chordae appears to be detrimental.

Restoration of left ventricular systolic performance after reattachment of the mitral chordae tendineae. The importance of valvular-ventricular interaction.

Clinical studies suggest that chorda-sparing mitral valve replacement techniques are associated with superior postoperative outcome, and several animal experiments have shown that disruption of the mitral subvalvular apparatus is followed by deterioration of left ventricular systolic function. One essential element, however, underlying the importance of chordal integrity for left ventricular function remains unproved: All investigators heretofore have been unable to demonstrate that left ventricular systolic performance can be restored by chordal reattachment after disruption of annular-papillary continuity. Therefore, we studied the effects of chordal detachment and subsequent chordal reattachment on left ventricular systolic performance using an in situ, isovolumic heart preparation in 10 halothane-anesthetized swine. The slope and left ventricular volume intercept of the isovolumic peak pressure-volume relationship were measured to assess global left ventricular systolic performance independent of load. Coronary perfusion pressure was maintained constant (95 +/- 6 mm Hg [+/- standard deviation]), and heart rates were in the physiologic range (133 +/- 26 min-1). Slope changed significantly (repeated measures analysis of variance, p = 0.0002), decreasing by 29% (from 4.74 +/- 0.94 to 3.37 +/- 0.87 mm Hg/ml, p less than 0.001) after chordal detachment and then returning to baseline (6.05 +/- 2.38 mm Hg/ml, p = 0.001) after chordal reattachment. Slope after chordal reattachment was not significantly different from the baseline value (p = 0.074). Volume intercept did not change significantly (p = 0.44) at any time. We conclude that the acute decrease in left ventricular contractility associated with surgical interruption of annular-ventricular continuity can, in fact, be reversed by chordal reattachment in this experimental model (isovolumically contracting normal porcine hearts). These data provide concrete confirmation of the concept of valvular-ventricular interaction; if these findings can be corroborated in the dilated, human left ventricle, such would strongly support efforts to preserve the mitral chordae tendineae during clinical mitral valve replacement to optimize postoperative left ventricular function.

Myoventriculoplasty and neoventricle myograft cardiac augmentation to establish pulmonary blood flow. Preliminary observations and feasibility studies.

In 10 dogs, a latissimus dorsi muscle (myograft) was neuroelectrically stimulated at 120 cycles/min for as long as 80 days. The higher thresholds and multiple lead penetrations required of direct muscle stimulation for muscle conditioning were avoided. Vascular delay and protective wrapping of the myograft in four dogs resulted in rapid seroma and fibrous sheath formation, which precluded further study. Of the six other myografts that were stimulated, two were used as functional right ventricular myoventriculoplasties and four were employed as neoventricle myografts with inflow and outflow valved conduits that were used to provide total pulmonary blood flow. Myoventriculoplasty produced functional enlargement of the right ventricle with synchronously contractile muscle. Neoventricles provided hemodynamically stable total pulmonary blood flow for as long as 20 hours, until internal chamber thrombus formed. Transpulmonary blood pressure generation by the neoventricle was found to be programmable up to physiologic systemic pressures by modulation of chamber preload and burst stimulation frequency at 50 msec intervals, delivered 120 times per minute. Synchronization capabilities for implantable burst pulse generators would further improve the efficacy of these myograft techniques designed to augment or supplant ventricular function, particularly to provide transpulmonary blood flow at programmable pressures.

Inhibition of accelerated cardiac allograft arteriosclerosis by fish oil.

Accelerated coronary arteriosclerosis remains the most important factor limiting long-term survival of heart transplant recipients, and dietary fish oil supplementation with omega-3 polyunsaturated fatty acids has been suggested to have a protective effect against coronary disease in epidemiologic studies and to inhibit arteriosclerosis in animal experiments. Therefore we tested the hypothesis that fish oil administration inhibits the development of allograft coronary arteriosclerosis by using a heterotopic heart transplant model. Three groups of Lewis rats (n = 10 each) received heterotopic heart transplants from Brown-Norway donors and were treated with cyclosporine intraperitoneally on a tapering schedule. Group 1 received fish oil daily by gavage (2 ml/kg/day; Emulsified Super MaxEpa, Twin Labs, Ronkonkona, N.Y.). Group 2 received an equal amount of safflower oil, as well as aspirin (1 mg/kg/day) and dipyridamole (3 mg/kg/day). Group 3 received safflower oil only. All rats were put to death 110 days later, at which time there was no statistically significant difference in graft function as assessed by palpation (scale 0 to 4, mean = 3.7 +/- 0.5 [+/- standard deviation]; analysis of variance: p = 0.72) or in microscopic grade of rejection (scale, 0 = none to 3 = severe, mean 2.1 +/- 0.6; analysis of variance: p = 0.68) between any of the groups. The coronary arteries were histologically scored for the degree of arteriosclerosis (scale, 0 = normal to 3 = occluded), and a mean grade of coronary disease was calculated for each heart. The fish oil-treated group had significantly less severe allograft coronary arteriosclerosis (analysis of variance: p = 0.005) than did groups 2 and 3 (mean grade 0.23 +/- 0.22 versus 1.04 +/- 0.75 and 0.96 +/- 0.55 (p less than 0.05, Scheffe F test), whereas groups 2 and 3 had similar degrees of coronary disease (p = no significant difference). These data demonstrate that fish oil supplementation inhibited accelerated coronary arteriosclerosis in this cyclosporine-treated heart allograft rat model, whereas antiplatelet agents in these doses were ineffective. Although the mechanism of this protective effect remains incompletely understood, it does not appear to involve enhanced immunosuppression. Fish oil and specific omega-3 polyunsaturated fatty acids should be further investigated as potentially useful agents to ameliorate accelerated allograft coronary arteriosclerosis in other animal species and perhaps eventually in man.

Physiologic role of the mitral apparatus in left ventricular regional mechanics, contraction synergy, and global systolic performance.

In animal models, severing the chordae tendineae of the mitral valve reduces the maximum global left ventricular elastance (Emax,g), a load-independent measure of left ventricular systolic performance; moreover, chamber geometry is altered with systolic bulging in the region of the papillary muscle insertions. This suggests that forces transmitted by the mitral apparatus increase the regional volume elastance (Emax,r) of segments subtending the insertions of the papillary muscles, and these regions contribute substantially to overall left ventricular systolic function (Emax,g). To test this hypothesis, we developed a method to evaluate changes in the magnitude and uniformity of Emax,r as quantitated by the slopes (E'max,i) of regional left ventricular isovolumetric pressure-dimension relations. Such measurements were obtained before and after all chordal attachments of the mitral valve were surgically divided in seven open-chest swine preparations. Significant declines in E'max,i were limited to the region of the posteromedial papillary muscle insertion. Although the mean E'max,i of all ventricular regions (E'max,ave) was unchanged, regional left ventricular elastances were less uniform after the mitral chordae tendineae were severed, which indicated a less synergistic contraction, and Emax,g fell by 21% from 7.1 +/- 2.0 to 5.6 +/- 1.2 mm Hg/ml (p less than 0.05). These data demonstrate that the mitral apparatus contributes importantly to the magnitude and uniformity of regional left ventricular elastances and suggest that such alterations in regional mechanics underlie the deterioration in global left ventricular systolic performance (Emax,g) after excision of the mitral apparatus.

B-mode ultrasound scanning in the detection of proximal venous thrombosis after total hip replacement.

A prospective study of the accuracy of real-time B-mode ultrasonography in detecting deep venous thrombosis in the femoral and popliteal veins of the lower extremity was conducted on a consecutive series of patients who had had a total hip replacement. Ascending venography was used as a diagnostic standard. One hundred and forty-three patients had ultrasound studies of both lower extremities and a venographic study of the operatively treated lower extremity at an average of 7.6 days postoperatively. The two tests were done within twenty-four hours of each other. Both ultrasonography and venography were done on 152 extremities. Two paired studies were excluded from the analysis of results because the ultrasound scans could not be interpreted. In 131 extremities, both diagnostic tests were negative for proximal thrombosis. Eight extremities had isolated thrombosis of a vein in the calf that was detected only by venography. In nineteen extremities, old or fresh thrombosis was diagnosed by venography. In four extremities, an old thrombosis of the superficial femoral vein was detected by both studies. In four of the extremities that had a new thrombus in the common femoral vein and in nine that had a new thrombus in the superficial femoral vein, abnormal findings on ultrasound scans correlated with those on venograms. There were two false-negative ultrasound scans and one false-negative venogram. The sensitivity, specificity, and accuracy of ultrasonography were 89, 100, and 99 per cent for the diagnosis of thrombosis of the proximal veins of the lower limb and 63, 100, and 93 per cent for the diagnosis of thrombosis when the entire venous system of the limb was included.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional variability of prostacyclin biosynthesis.

To investigate the regional variability in arterial and venous endothelial prostacyclin (PGI2) biosynthesis, we obtained 1-cm segments of carotid arteries, external jugular veins, femoral arteries and veins, iliac arteries and veins, inferior venae cavae (IVC), and aortas from 17 dogs. Vessel luminal PGI2 production was measured in the basal state by radioimmunoassay of 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). A total of 90 arterial specimens (57, 19, and 14 segments, respectively, of femoral/carotid arteries, iliac arteries, and aorta) and 41 venous specimens (15, 10, and 16 segments, respectively, of femoral/jugular veins, iliac veins, and IVC) were analyzed. Overall, arterial endothelial 6-keto-PGF1 alpha was higher than venous (8.1 +/- 0.5 ng/ml vs. 4.9 +/- 0.7 ng/ml, p less than 0.0004); 6-keto-PGF1 alpha levels were greater in the arteries than in their corresponding veins [femoral/carotid arteries (6.3 +/- 0.4 ng/ml) vs. femoral/jugular vein (2.1 +/- 0.4 ng/ml), p less than 0.0002; iliac arteries (9.3 +/- 1.0 ng/ml) vs. iliac veins (4.8 +/- 0.9 ng/ml), p less than 0.005; aorta (14.0 +/- 1.6 ng/ml) vs. IVC (7.5 +/- 1.4 ng/ml), p less than 0.006].(ABSTRACT TRUNCATED AT 250 WORDS)

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)

Inhibition of vein graft intimal thickening by eicosapentanoic acid: reduced thromboxane production without change in lipoprotein levels or low-density lipoprotein receptor density.

Marine lipids containing omega-3 fatty acids (chiefly, eicosapentanoic acid [EPA] and docosahexanoic acid [DHA]) may inhibit the development of atherosclerotic vascular disease, but the mechanisms responsible for this putative beneficial effect are unknown. We investigated the effects of EPA and DHA in a canine model of accelerated vein graft arteriosclerosis during a 3-month period. Twenty-five dogs were divided into three dietary groups: group I (control), group II (2.5% cholesterol), and group III (2.5% cholesterol plus 2 gm EPA/day [as MaxEPA]). The effects of EPA on vein graft intimal thickening, platelet and vascular prostaglandin metabolism, lipid and lipoprotein receptor metabolism, and hematologic parameters were assessed. Cholesterol feeding caused a significant 54% increase in graft intimal thickness compared with control animals (124.9 +/- 50.4 vs 81.2 +/- 32.4 micron; p = 0.013), which was prevented by supplementation with EPA in group III (56.9 +/- 30.0 micron; p = 0.001 vs group II). Intimal thickness in group III was not significantly different from that of control. EPA supplementation was also associated with a 38% decline in serum thromboxane levels from 457.0 +/- 129.3 pg/0.1 ml in group II to 283.5 +/- 96.9 pg/0.1 ml in group III (p = 0.007). The alterations in lipoprotein metabolism associated with cholesterol feeding were not affected by EPA: in both groups II and III, serum cholesterol and high-density lipoproteins and liver cholesterol content were elevated and hepatic low-density lipoproteins (LDL) receptor content was reduced. There were no differences between the three groups in terms of vein graft or native vessel prostacyclin production, hematocrit, platelet count, or coagulation parameters. In this canine model, dietary supplementation with marine omega-3 fatty acids reduced the extent and magnitude of accelerated vein graft intimal thickening induced by hypercholesterolemia; moreover, this beneficial effect was associated with lower serum thromboxane production and appeared to be independent of alterations in lipoprotein metabolism or LDL receptor density.

Valvular-ventricular interaction: importance of the mitral apparatus in canine left ventricular systolic performance.

As the mitral valvular apparatus tenses during systole, forces transmitted along the chordae tendineae to the left ventricular chamber may influence left ventricular performance. To test this hypothesis, 10 dogs anesthetized with fentanyl were studied during cardiopulmonary bypass. The importance of the mitral apparatus in left ventricular systolic function was assessed independent of load by means of the slope of the contractile state-dependent left ventricular peak isovolumetric pressure-volume relationship (Emax), which was measured at constant heart rate and aortic pressure with a micromanometer inside a left ventricular intracavitary balloon before and immediately after all chordae tendineae were severed. Herniation of the balloon was prevented by a disk secured to the mitral anulus. Emax decreased from 11.97 +/- 3.35 (+/- SD) to 6.38 +/- 0.96 mm Hg/ml (p less than .001) with chordal severing. The volume intercept (Vo) was unchanged. Fluoroscopic studies of the balloon contour in eight additional dogs revealed dyskinesia in the area of the papillary muscle insertion and substantial alterations in chamber geometry during systole after the chordae were severed. Accordingly, we conclude that global left ventricular systolic performance is impaired when chordal attachments of the mitral valve are disrupted. Changes in left ventricular geometry or loss of inward force normally transmitted to the left ventricular wall as the valve tense may underlie these changes. These findings suggest that postoperative left ventricular dysfunction after mitral valve replacement may be attributable, in part, to excision of the native mitral apparatus at the time of surgery and support efforts to spare chordae during mitral valve surgery.