Comparison of Coapsys annuloplasty and internal reduction mitral annuloplasty in the randomized treatment of functional ischemic mitral regurgitation: impact on the left ventricle.

BACKGROUND: Functional mitral regurgitation is associated with both annular and ventricular distortion. Aggressive reduction annuloplasty for functional mitral regurgitation acts primarily at the annulus, with variable impact on the left ventricle. The Coapsys device externally reshapes the left ventricle to correct functional mitral regurgitation. Left ventricular reshaping was analyzed in a randomized study. METHODS: The RESTOR-MV study randomizes patients with coronary artery disease and functional mitral regurgitation to either reduction annuloplasty and coronary artery bypass grafting (the RA group) or Coapsys annuloplasty and bypass grafting (the CO group). The Coapsys device consists of epicardial pads connected by a cord. It was placed without cardiopulmonary bypass under echocardiographic guidance and sized to reduce annular dimension and improve leaflet coaptation. Internal reduction annuloplasty was performed by device placement. Intraoperative transesophageal echocardiograms were analyzed in 7 patients having reduction annuloplasty and 7 having Coapsys annuloplasty. RESULTS: Baseline mitral regurgitation (0-4 scale) was similar for the RA (3.0 +/- 0.6) and the CO groups (3.0 +/- 0.6). Intraoperative mitral regurgitation was reduced from 2.86 +/- 0.7 to 0.5 +/- 0.7 (P < .01 pre vs post) for the RA group and from 2.64 +/- 0.9 to 05 +/- 0.7 (P < .01 pre vs post) for the CO group. Annular anteroposterior diameter was reduced with both techniques: RA, 3.45 +/- 0.39 to 2.34 +/- 0.37 cm (P < .01 pre vs post); CO, 3.40 +/- 0.27 to 2.85 +/- 0.34 cm (P < .05 pre vs post). Long-axis dimensions were unchanged with both techniques. Short-axis dimensions measured at three levels were significantly reduced only in the CO patients: basal diameter 4.77 +/- 0.58 to 3.58 +/- 0.38 cm (P < .01 pre vs post); mid diameter 4.88 +/- 0.55 to 3.57 +/- 0.43 cm (P < .01 pre vs post); and apical diameter 4.39 +/- 0.46 to 3.38 +/- 0.34 cm (P < .01 pre vs post). CONCLUSIONS: Coapsys and reduction annuloplasty techniques both acutely reduce functional mitral regurgitation and annular dimension. The Coapsys device provided significantly greater left ventricular reshaping than did reduction annuloplasty. Further evaluation will assess the long-term valvular function and ventricular geometric stability associated with both techniques.

The role of annuloplasty in mitral valve repair.

Mitral valve repair surgery has progressed dramatically since its inception over 40 years ago. As techniques have evolved, complicated mitral valve reconstruction has become commonplace, with durable late results. Likewise, the value of concomitant annuloplasty during valve repair has been firmly established as contributing to late valve repair durability. This review discusses the evolution of annuloplasty techniques and the physiologic reasoning behind various approaches.

Opioids confer myocardial tolerance to ischemia: interaction of delta opioid agonists and antagonists.

BACKGROUND: Mammalian hibernation biology is now known to be mediated by delta opioids. The altered myocellular physiology of hibernation closely parallels that of hypothermic ischemia used to protect the heart for cardiac surgery. METHODS AND RESULTS: The present study examined the interaction of delta opioid agonists and antagonists on myocardial tolerance to ischemia. By means of a nonhibernating isolated rabbit heart model, functional and metabolic myocardial parameters were assessed during nonischemic baseline and postischemic recovery periods. Control hearts with standard cardioplegic protection alone were compared with those with cardioplegia plus preperfusion with a delta opioid agonist, a delta opioid antagonist, or both. All hearts were then subjected to 2 hours of global ischemia. Compared with cardioplegia alone, postischemic left ventricular developed pressure, coronary flows, and myocardial oxygen consumption were all increased with administration of delta opioid agonists and decreased below baseline with delta opioid antagonists. Functional recovery of left ventricular developed pressure was improved with opioids (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid agonist: 65 +/- 5 mm Hg, P <.01) and inhibited with antagonists (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid antagonist: 17 +/- 5 mm Hg, P <.05), and true to form, the protective opioid effect was negated when combined with an antagonist (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid agonist and delta opioid antagonist: 42 +/- 4 mm Hg, P = not significant). CONCLUSIONS: This study demonstrates that cardiac tolerance to ischemia may be mediated by delta opioids.

Increased rat cardiac allograft survival by the glycosaminoglycan pentosan polysulfate.

BACKGROUND: Modulation of the inflammatory response has proven to be of benefit in salvaging cardiac allografts at risk of irreversible injury. Pentosan polysulfate (PPS), like heparin, is a negatively charged sulfated glycosaminoglycan (GAG) that possesses anti-inflammatory properties including the ability to inhibit activation of the complement system. This study was conducted to determine the potential of PPS to prolong allograft survival in an experimental model of cardiac transplantation. MATERIALS AND METHODS: A heterotopic cardiac transplant was performed by implanting the heart from fetal Brown Norway rats into the ear pinnae of adult Lewis rats. Vehicle (saline) or PPS (30 mg/kg) was administered subcutaneously immediately after transplantation and daily thereafter (n = 6 in each group). Another GAG, heparin, was also analyzed to determine the effect of anticoagulation on transplant survival (n = 6). RESULTS: Treatment with PPS significantly (P < 0. 05) increased allograft survival time as compared to vehicle-treated animals (8.0 +/- 0.3 days vs 5.5 +/- 0.5 days). The results noted with PPS were similar to those observed in cyclosporine (10 mg/kg; n = 6)-treated animals (8.25 +/- 0.25 days). Treatment with heparin (300 U/kg/day) did not significantly prolong cardiac graft survival time, suggesting that anticoagulation is not sufficient to prolong transplant survival. Analysis of tissue histology showed diminished transplant rejection as evidenced by decreased white blood cell infiltration and cellular necrosis. CONCLUSIONS: The results of this study indicate that PPS possesses the ability to prolong cardiac transplant viability in a heterotopic cardiac transplant model, independent of its anticoagulant actions.

Anti-TNF antibody modulates cytokine and MHC expression in cardiac allografts.

Tumor necrosis factor-alpha (TNF) is a multifunctional cytokine evoked in response to alloantigen stimulation and may be involved in lymphocyte activation, adhesion molecule expression, and regulation of MHC class II antigens. Anti-TNF treatment prolongs cardiac allograft survival. We investigated the role of anti-TNF in the regulation of MHC class II antigens and cytokine mRNA expression of TNF, interferon-gamma (IFN), IL-2, IL-4, and IL-10 in cardiac allografts to elucidate its immunological mechanism. These in vivo studies were conducted using a rat MHC mismatch Brown-Norway to Lewis (BN to LEW) heterotopic cardiac transplant model. In control untreated rats, allografts were rejected at 6.8 +/- 0.6 days. Allograft survival was significantly prolonged to 12.7 +/- 1.4 days with anti-TNF treatment. MHC class II expression, analyzed by indirect immunofluorescence cytometry, demonstrated that MHC class II-positive cells increased by 25% in spleens of untreated allografted rats compared to naive rats, while anti-TNF-treated allografted rats had a similar percentage of MHC II cells as naives. Further, naive, untransplanted rats and both anti-TNF and untreated, transplanted rats had heart and spleens harvested on Day 5 post-transplant. Cytokine mRNA expression was determined by semiquantitative RT-PCR. In heart and spleen cells from naives, TNF mRNA expression was undetectable or very weak. However, in rejecting allografts and spleen cells from untreated recipients, TNF expression was remarkably increased, while anti-TNF attenuated this TNF expression in both heart graft and spleen cells. Furthermore, IL-2, IL-10, and IFN expression were absent in naive hearts. However, in untreated allografts IL-2, IL-10, and IFN were strongly expressed, which was markedly decreased after anti-TNF treatment. Finally, IL-4 expression was found equally in naive hearts, untreated allografts, and anti-TNF-treated allografts. These results suggest that anti-TNF antibody treatment may not only neutralize TNF activity but also play a role in altering cytokine mRNA expression and MHC class II expression.

Delta opioid receptors and low temperature myocardial protection.

BACKGROUND: Cardiac surgery continues to be limited by an inability to achieve complete myocardial protection. This may result from the use of hypothermic cardioplegia. Interestingly, the subcellular changes of animal hibernation parallel the altered biology of induced hypothermic myocardial ischemia, but are well tolerated by hibernated mammalian myocardium. Evidence indicates this protection is mediated by activation of the delta opioid receptor, which elicits profound metabolic effects at the whole animal, organ, and cell level. In this study, we sought to determine if pentazocine, with agonist activity at the delta opioid receptor, could improve myocardial recovery following global ischemia over a wide range of temperatures. METHODS: Isolated rabbit hearts received either standard cardioplegia or were pretreated with racemic, d or 1 isomer pentazocine. Hearts were then subjected to 2 hours at 34 degrees C, or 3.5 hours at 20 degrees C, or 4 hours at 10 degrees C of cardioplegic ischemia and reperfused. Functional recovery was compared to controls. RESULTS: Isovolumic developed pressure, coronary flow, oxygen consumption, and ultrastructural preservation were enhanced with pentazocine delta opioid mediated protection, which appears to be additive to standard cardioplegia, even at low temperatures. CONCLUSIONS: Teleologically, delta opioid protection parallels animal hibernation, which occurs from 34 degrees down to 0 degrees C. The use of delta opioid receptor agonists may have important clinical implications for cardiac surgery and deserves further study.

Long-term outcome following case management after coronary artery bypass surgery.

Patient outcome following coronary artery bypass grafting (CABG) has come under increasing governmental, social, and economic scrutiny. To insure quality patient outcome after CABG, many new policies and programs have been instituted. One of these, case management, was developed as a tool for identification and quantification of patient clinical sequences and resource utilization. This present study examines the influence of case management on length of stay and patient outcome following CABG. One hundred forty randomized, retrospectively analyzed CABG patients from 1990, prior to case management, were compared against 140 age-and case-matched randomly controlled CABG patients from 1994 after case management was in place. Patients' demographics were similar. The outcome data showed that intensive care unit (ICU) use and total length of stay were significantly decreased. Furthermore, resource utilization as monitored by chest X-ray, electrocardiography, and laboratory testing were decreased as well. Finally, mortality was decreased despite an increase in risk-adjusted acuity of the patients. There appeared to be no effect of gender or age on the benefit derived from case management. These data demonstrate that the influence of case management is beneficial for resource utilization and patient outcome following CABG and that these types of patient care policy advancements should be encouraged.

Insulin regulation of protein phosphorylation in H4 hepatoma cells. Examination of rapid effects using two-dimensional electrophoresis.

Activation of the insulin receptor tyrosine kinase is thought to initiate a chain of phosphorylation changes which regulate various metabolic and growth processes. Insulin has been shown to regulate some kinases by affecting their phosphorylation states; however, direct connections between activation of the receptor tyrosine kinase and subsequent altered phosphorylations of these kinases have yet to be established. To define the constituents of these regulated phosphorylation cascade systems, the time course of insulin-induced phosphorylation changes has been examined. 32P-Labeled H4IIE hepatoma cells were treated with insulin for 5-300 s, and then cell extracts were subjected to two-dimensional gel electrophoresis. Computer analysis of autoradiograms was employed to quantify insulin-induced phosphorylation changes. Phosphotyrosine was assessed by KOH digestion, by anti-phosphotyrosine immunoprecipitation, and by phenylarsine oxide treatment. Insulin induced a hierarchy of phosphorylation changes over the 300-s time course, with most increases being detectable within 10 s. Of these, only four did not undergo enhanced tyrosine phosphorylation. Eight proteins were found to undergo transient phosphorylation changes. Phenylarsine oxide elicited the appearance of novel low molecular weight phosphoproteins. These results support the concept of insulin-directed phosphorylation cascades, but indicate the magnitude of potential targets of the insulin receptor has been underestimated.

Rat liver insulin mediator which stimulates pyruvate dehydrogenase phosphate contains galactosamine and D-chiroinositol.

It has been established that insulin treatment of cells, isolated plasma membranes, or whole animals leads to the generation of low molecular weight mediators which serve as intermediates in the signalling pathway. At least two distinct classes of mediator have been described, based on differences in apparent molecular weight, isoelectric point and biological activity (Cheng, K., and Larner, J. (1985) Ann. Rev. Physiol. 45, 407-424). Recently, Saltiel's (Saltiel, A.R., and Cuatrecasas, P. (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 5793-5797) and Mato's (Mato, J.M., Kelly, K.L., Abler, A., and Jarett, L. (1987) J. Biol. Chem. 262, 2131-2137) laboratories have described an insulin "modulator" which was apparently derived from glycosylphosphoinositol linker, similar to those known to anchor proteins to the external surface of the cell membrane (Low, M.G. (1987) Bioch. J. 244, 1-13). In this paper, we report that highly purified preparations of the insulin mediator which stimulates pyruvate dehydrogenase phosphatase contain mannose, galactosamine, and D-chiroinositol. These determinations are based upon analyses using paper chromatography and gas chromatography/mass spectroscopy. Nitrous acid deamination of the mediator resulted in release of inositol phosphate, indicating that the galactosamine and D-chiroinositol are linked. Although the presence of chiroinositol in modulator from H35 hepatoma cells has been recently reported (Mato, J.M., Kelly, K.L., Abler, A., Jarett, L., Corkey, B.E., Cashel, J.A., and Zopf, D. (1987) Bioch. Biophys. Res. Comm. 146, 764-770), the optical identity of the inositol remained unknown until the present report. Likewise, the presence of galactosamine rather than glucosamine in insulin mediator is a novel finding. These findings, coupled with those of Saltiel and Mato's groups, provide clear evidence for the existence of multiple forms of insulin mediators. Additionally, the results presented here afford further confirmation for the formation of insulin mediators from glycosyl-phosphoinositol linkers.

A putative mediator of insulin action which inhibits adenylate cyclase and adenosine 3',5'-monophosphate-dependent protein kinase: partial purification from rat liver: site and kinetic mechanism of action.

A novel putative mediator of insulin action which acts to inhibit adenylate cyclase and cAMP-dependent protein kinase has been purified from livers of insulin-treated streptozotocin-diabetic rats. It was increased by short term (5-min) insulin injections in vivo and purified several thousand-fold by Sephadex and HPLC. Its mol wt was somewhat larger (2500) than previous mediators identified, and it was more hydrophobic in character. Its mechanism of action or adenylate cyclase was determined and found to be chiefly directed against the catalytic subunit. Its action on the cAMP-dependent protein kinase was found to be competitive with regard to protein substrate, but noncompetitive with regard to ATP and cAMP. Its relationship to other putative insulin mediators and the mechanism of insulin action is discussed.

Insulin-like and insulin-enhancing effects of the sulfonylurea glyburide on rat adipose glycogen synthase.

The effects of long-term exposure of cultured rat adipose tissue to glyburide were examined on glycogen synthase activity. Glyburide alone caused an increase in the activity ratio (low glucose-6-P/high glucose-6-P) of glycogen synthase, and enhanced insulin's activation of the enzyme. The glyburide effects were time dependent, requiring fat pieces to be exposed to the drug for at least 10-20 h. The glucose concentration in the culture medium was also important: optimal concentrations of glucose were 10-20 mM. Glyburide acted to shift the insulin dose-response curve to the left by a factor of 2.5, but did not enhance the effects of maximal concentrations of the hormone. The Ka of the glyburide effects was about 2.0 microM. If glucose was omitted during the 20-min incubation with or without insulin, the increase in the activity ratio of glycogen synthase by glyburide was unaffected, but the enhancement of insulin action was reduced. Because these data indicate that glyburide's actions are glucose dependent, we propose that the sulfonylurea is probably acting to increase glucose transport, thus allosterically increasing the activity of a synthase phosphatase by glucose-6-P. The net result of this would be increased dephosphorylation and activation of glycogen synthase.

Selective inhibition of the insulin-stimulated phosphorylation of the 95,000 dalton subunit of the insulin receptor by TAME or BAEE.

Added N alpha-p-tosyl-l-arginine methyl ester or N alpha-benzoyl-l-arginine ethyl ester inhibited the stimulation by insulin of phosphorylation of the 95,000 dalton subunit of the insulin receptor both in a partially purified insulin receptor fraction from rat adipocytes and in a highly purified insulin receptor preparation from human placenta. N-alpha-p-tosyl-l-lysine chloromethyl ketone, N alpha-p-tosyl-l-lysine methyl ester, or N-acetyl-l-phenylalanine ethyl ester were much less potent, while N-benzoyl-1-alanine methyl ester was without effect. Inhibition of the phosphorylation by the arginine analogues did not require preincubation of the insulin receptor with inhibitors in the presence of insulin prior to phosphorylation. Inhibition by N alpha-p-tosyl-l-arginine methyl ester was decreased by preincubation of the receptor fraction with cold ATP and MnCl2. These results suggest that N alpha-p-tosyl-l-arginine methyl ester inhibits an initial ATP and Mn2+ dependent reaction in insulin-stimulated phosphorylation process.

Properties of glycogen synthase and phosphorylase from Biomphalaria glabrata (mollusca).

Glycogen synthase and phosphorylase were characterized from the cephalopedal region of the snail, Biomphalaria glabrata. Glycogen synthase exhibited increases and decreases in its activity ratio (-G6P/+G6P) under conditions that are known to cause conversion of the two forms of the enzyme from mammalian systems, implying that the snail's synthase also possesses interconvertible forms. Each form had a distinct pH optimum, with the G6P-independent form (synthase alpha) exhibiting maximum activity at pH 7.4, whereas the G6P-dependent form (synthase beta) had optimal activity at pH 8.3. Both synthase alpha and beta displayed classical Michaelis-Menten kinetics for the substrates UDP-glucose and glycogen, and the beta form displayed sigmoidal kinetics for its modulator, G6P. Only UDP-glucose could function as a glucosyl donor in the synthase-catalyzed reaction. ADP, GDP, UDP, and ATP were all competitive inhibitors of synthase alpha, although at varying degrees of efficiency. Glycogen phosphorylase also demonstrated interconversion of its two forms (alpha and beta), as evidenced by changes in its activity ratio (-AMP/+AMP). AMP elicited hyperbolic kinetics from this enzyme. Concentrations of KF above 20 mM were found to inhibit glycogen synthase alpha while stimulating phosphorylase beta, thus causing erroneous activity ratios for both enzymes.