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See detailEffects of increased afterload on left ventricular performance and mechanical efficiency are not baroreflex-mediated
Kolh, Philippe ULg; Ghuysen, Alexandre ULg; Tchana-Sato, Vincent ULg et al

in European Journal of Cardio - Thoracic Surgery (2003), 24(6), 912-919

Objective: To assess baroreflex intervention during increase in left ventricular afterload, we compared the effects of aortic banding on the intact cardiovascular system and under hexamethonium infusion ... [more ▼]

Objective: To assess baroreflex intervention during increase in left ventricular afterload, we compared the effects of aortic banding on the intact cardiovascular system and under hexamethonium infusion. Methods: Six open-chest pigs, instrumented for measurement of aortic pressure and flow, left ventricular pressure and volume, were studied under pentobarbital-sufentanil anesthesia. Vascular arterial properties were estimated with a four-element windkessel model. Left ventricular contractility was assessed by the slope of end-systolic pressure-volume relationship. Results: The effects of aortic banding on mechanical aortic properties were unaffected by autonomic nervous system inhibition. However, increase in peripheral arterial vascular resistance and in heart rate were prevented by hexamethonium. Aortic banding increased left ventricular contractility and stroke work. Left ventricular-arterial coupling remained unchanged, but mechanical efficiency was impaired. These ventricular changes were independent of baroreflex integrity. Conclusions: Our results demonstrate that an augmentation in afterload has a composite effect on left ventricular function. Left ventricular performance is increased, as demonstrated by increase in contractility and stroke work, but mechanical efficiency is decreased. These changes are observed independently of baroreflex integrity. Such mechanisms of autoregulation, independent of the autonomic nervous system, are of paramount importance in heart transplant patients. (C) 2003 Elsevier B.V. All fights reserved. [less ▲]

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See detailLeft ventricular preload-adjusted maximal power: Clinically useful marker of LV contractility ?
Segers, P.; Tchana-Sato, Vincent ULg; Leather, H. A. et al

in Circulation (2003, October 28), 108(17, Suppl. S), 396-396

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See detailEffects of endotoxic shock on right ventricular systolic function and mechanical efficiency
Lambermont, Bernard ULg; Ghuysen, Alexandre ULg; Kolh, Philippe ULg et al

in Cardiovascular Research (2003), 59(2), 412-418

Objective: To investigate the effects of endotoxin infusion on right ventricular (RV) systolic function and mechanical efficiency. Methods: Six anesthetized pigs (Endo group) received a 0.5 mg/kg ... [more ▼]

Objective: To investigate the effects of endotoxin infusion on right ventricular (RV) systolic function and mechanical efficiency. Methods: Six anesthetized pigs (Endo group) received a 0.5 mg/kg endotoxin infusion over 30 min and were compared with six other anesthetized pigs (Control group) receiving placebo for 5 h. RV pressure-volume (PV) loops were obtained by the conductance catheter technique and pulmonary artery flow and pressure were measured with high-fidelity transducers. Results: RV adaptation to increased afterload during the early phase of endotoxin-induced pulmonary hypertension (T30) was obtained by both homeometric and hetereometric regulations: the slope of the end-systolic PV relationship of the right ventricle increased from 1.4+/-0.2 mmHg/ml to 2.9+/-0.4 mmHg/ml (P<0.05) and RV end-diastolic volume increased from 56+/-6 ml to 64+/-11 ml (P<0.05). Consequently, right ventricular-vascular coupling was maintained at a maximum efficiency. Ninety minutes later (T120), facing the same increased afterload, the right ventricle failed to maintain its contractility to such an elevated level and, as a consequence, right ventricular-vascular uncoupling occurred. PV loop area, which is known to be highly correlated with oxygen myocardial consumption, increased from 1154+/-127 mmHg/ml (T0) to 1798+/-122 mmHg/ml (T180) (P<0.05) while RV mechanical efficiency decreased from 63+/-2% (T0) to 45+/-5% (T270) (P<0.05). Conclusions: In the very early phase of endotoxinic shock, right ventricular-vascular coupling is preserved by an increase in RV contractility. Later, myocardial oxygen consumption and energetic cost of RV contractility are increased, as evidenced by the decrease in RV efficiency, and right ventricular-vascular uncoupling occurs. Therefore, therapies aiming at restoring right ventricular-vascular coupling in endotoxic shock should attempt to increase RV contractility and to decrease RV afterload but also to preserve RV mechanical efficiency. (C) 2003 European Society of Cardiology. Published by Elsevier B.V. All rights reserved. [less ▲]

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See detailBM-573, a dual thromboxane synthase inhibitor and thromboxane receptor antagonist, prevents pig myocardial infarction induced by coronary thrombosis
Rolin, S.; Petein, M.; Tchana-Sato, Vincent ULg et al

in Journal of Pharmacology and Experimental therapeutics (2003), 306(1), 59-65

The aim of this study was to characterize the effects of BM-573 [N-terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a novel dual thromboxane A 2 receptor antagonist and thromboxane ... [more ▼]

The aim of this study was to characterize the effects of BM-573 [N-terbutyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl] urea], a novel dual thromboxane A 2 receptor antagonist and thromboxane synthase inhibitor, on myocardial infarction induced by topical ferric chloride (FeCl3) application to the left anterior descending (LAD) coronary artery in anesthetized pigs. All control animals (n = 6) developed an occlusive thrombus in the LAD coronary artery. The mean infarct size, revealed by triphenyl tetrazolium chloride (TTC), and the area at risk, evidenced by Evans blue, corresponded to 35.3 +/- 2.2 and 36.9 +/- 2.1% of the left ventricular mass, respectively. In the BM-573-treated group (n = 6), a drug infusion (10 mg . kg(-1) . h(-1)) started 30 min before FeCl3 application and continued throughout the experimentation. Among the BM-573-treated group, four pigs did not develop coronary artery thrombus and their myocardium appeared healthy. Histopathological examination of FeCl3-injured coronary artery revealed an occlusive and adherent thrombus in control group, while pretreatment with BM-573 prevented thrombus formation. In infarcted zones, lack of desmin staining and muscle structure disorganization were obvious. Depletion of myocardial ATP content was observed in the myocardial necrotic region of the control group, but not in myocardial samples of BM-573-treated pigs that did not develop myocardial infarction. When BM-573 prevented LAD artery occlusion, the area under the curve of plasmatic troponin T was reduced by 77% over 6 h. These data suggest that BM-573 could be useful for the prevention of myocardial infarction. [less ▲]

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See detailEffects of U-46619 on Pulmonary Hemodynamics before and after Administration of Bm-573, a Novel Thromboxane A2 Inhibitor
Lambermont, Bernard ULg; Kolh, Philippe ULg; Dogné, Jean-Michel ULg et al

in Archives of Physiology & Biochemistry (2003), 111(3), 217-23

We studied the effects on pulmonary hemodynamics of U-46619, a thromboxane A2 (TXA2) agonist, before and after administration of a novel TXA2 receptor antagonist and synthase inhibitor (BM-573). Six ... [more ▼]

We studied the effects on pulmonary hemodynamics of U-46619, a thromboxane A2 (TXA2) agonist, before and after administration of a novel TXA2 receptor antagonist and synthase inhibitor (BM-573). Six anesthetized pigs (Ago group) received 6 consecutive injections of U-46619 at 30-min interval and were compared with six anesthetized pigs (Anta group) which received an increasing dosage regimen of BM-573 10 min before each U-46619 injection. Consecutive changes in pulmonary hemodynamics, including characteristic resistance, vascular compliance, and peripheral vascular resistance, were continuously assessed during the experimental protocol using a four-element Windkessel model. At 2 mg/kg, BM-573 completely blocked pulmonary hypertensive effects of U-46619 but pulmonary vascular compliance still decreased. This residual effect can probably be explained by a persistent increase in the tonus of the pulmonary vascular wall smooth muscles sufficient to decrease vascular compliance but not vessel lumen diameter. Such molecule could be a promising therapeutic approach in TXA2 mediated pulmonary hypertension as it is the case in pulmonary embolism, hyperacute lung rejection and endotoxinic shock. [less ▲]

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See detailEffects of Bm-573, a Novel Thromboxane A2 Inhibitor, on Pulmonary Hemodynamics in Endotoxic Shock
Lambermont, Bernard ULg; Ghuysen, Alexandre ULg; Dogné, Jean-Michel ULg et al

in Archives of Physiology & Biochemistry (2003), 111(3), 224-31

Thromboxane A2 is considered to be partially responsible for the increase in pulmonary vascular resistance observed after endotoxin administration and to participate in proinflammatory reactions. The ... [more ▼]

Thromboxane A2 is considered to be partially responsible for the increase in pulmonary vascular resistance observed after endotoxin administration and to participate in proinflammatory reactions. The effects of a novel dual TXA2 synthase inhibitor and TXA2 receptor antagonist (BM-573) on pulmonary hemodynamics were investigated in endotoxic shock. 30 mins before the start of a 0.5 mg/kg endotoxin infusion, 6 pigs (Endo group) received a placebo infusion and 6 other pigs (Anta group) received a BM-573 infusion. In Endo group, pulmonary artery pressure increased from 25 +/- 1.8 (T0) to 42 +/- 2.3 mmHg (T60) (p < 0.05) after endotoxin infusion while, in Anta group, it increased from 23 +/- 1.6 (T0) to 25 +/- 1.5 mmHg (T60). This difference is due to a reduction in pulmonary vascular resistance in Anta group while pulmonary arterial compliance changes in Endo group remained comparable with the evolution in Anta group. In Endo group, PaO2 decreased from 131 +/- 21 (T0) to 74 +/- 12 mmHg (T300) (p < 0.05), while in Anta group, PaO2 was 241 +/- 31 mmHg at the end of the experimental period (T300). These results demonstrate that TXA2 plays a major role in pulmonary vascular changes during endotoxin insult. Concomitant inhibition of TXA2 synthesis and of TXA2 receptors by BM-573 inhibited the pulmonary vasopressive response during the early phase of endotoxin shock as well as the deterioration in arterial oxygenation. [less ▲]

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See detailAlteration of left ventriculo-arterial coupling and mechanical efficiency during acute myocardial ischemia
Kolh, Philippe ULg; Lambermont, Bernard ULg; Ghuysen, Alexandre ULg et al

in International Angiology (2003), 22(2), 148-158

AIM: Myocardial revascularisation being frequently performed during acute myocardial ischemia, in a hostile hemodynamic environment, we evaluated left ventriculo-arterial (VA) coupling, left ventricular ... [more ▼]

AIM: Myocardial revascularisation being frequently performed during acute myocardial ischemia, in a hostile hemodynamic environment, we evaluated left ventriculo-arterial (VA) coupling, left ventricular (LV) mechanical efficiency, and the mechanical properties of the systemic vasculature during acute myocardial ischemia. METHODS: In 6 pigs, vascular properties [characteristic impedance (R(1)), peripheral resistance (R(2)), compliance (C), inductance (L), arterial elastance (E(a))] were estimated with a windkessel model. LV function was assessed by the slope (E(es)) of end-systolic pressure-volume relationship (ESPVR), and stroke work (SW) - end-diastolic volume (EDV) relation. Pressure-volume area (PVA) was referred to as myocardial oxygen consumption. VA coupling was defined as E(es)/E(a), and mechanical efficiency as SW/PVA. After baseline recordings, the left anterior descending coronary artery was ligated and hemodynamic measures obtained every 30 minutes for 3 hours. Data are expressed as mean (SEM). RESULTS: Coronary occlusion induced an ESPVR rightward shift, and decreased E(es) from 3.67 (0.33) to 1.92 (0.20) mmHg/ml and the slope of the SW - EDV relationship from 72.3 (3.4) to 40.4 (4.5) mmHg (p<0.001), while E(a) increased from 3.33 (0.56) to 4.65 (0.29) mmHg/ml (p<0.005). This was responsible for a dramatic alteration of VA coupling from 1.22 (0.11) to 0.44 (0.07), (p<0.001). While R2 increased from 1.72 (0.30) to 2.38 (0.16) mmHg x s x ml(-1) (p<0.05) and C decreased from 0.78 (0.16) to 0.46 (0.08) ml/mmHg (p<0.05), R(1) and L were unchanged. Coronary occlusion decreased SW from 4056 (223) to 2580 (122) mmHg.ml (p<0.001), while PVA and SW/PVA decreased from 5575 (514) to 4813 (317) mmHg x ml (NS), and from 0.76 (0.04) to 0.57 (0.03) (p<0.001), respectively. CONCLUSION: Acute myocardial ischemia severely altered left ventriculo-arterial coupling and LV mechanical efficiency. Impaired left VA coupling was due to a combination of augmented arterial elastance, secondary to early vasoconstriction later associated with decreased arterial compliance, and decreased LV contractility. [less ▲]

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See detailDeterminants of left ventricular preload-adjusted maximal power
Segers, Patrick; Tchano-Sato, Vincent; Leather, H. Alex et al

in American Journal of Physiology - Heart and Circulatory Physiology (2003), 284(6), 2295-2301

Maximal left ventricular (LV) hydraulic power output (PWRmax), corrected for preload as PWRmax/(V-ed)(beta) (where V-ed is the end-diastolic volume and beta is a constant coefficient), is an index of LV ... [more ▼]

Maximal left ventricular (LV) hydraulic power output (PWRmax), corrected for preload as PWRmax/(V-ed)(beta) (where V-ed is the end-diastolic volume and beta is a constant coefficient), is an index of LV contractility. Whereas preload-adjusted maximal power (PAMP) is usually calculated with beta = 2, there is uncertainty about the optimal value of beta (beta = 1 for the normal LV and 2 for the dilated LV). The aim of this work is to study the determining factors of beta. The data set consisted of 245 recordings (steady state and vena cava occlusion) in 10 animals in an ischemic heart pig model. The occlusion data yielded the slope (E-es; 2.01 +/- 0.77 mmHg/ml, range 0.71-4.16 mmHg/ml) and intercept (V-0; -11.9 +/- 22.6 ml; range -76 to 39 ml) of the end-systolic pressure-volume relation, and the optimal beta-factor (assessed by fitting an exponential curve through the V-ed-PWRmax relation) was 1.94 +/- 0.88 (range 0.29-4.73). The relation of beta with V-ed was weak [beta = 0.60 + 0.02(V-ed); r(2) = 0.20]. In contrast, we found an excellent exponential relation between V-0 and beta [beta = 2.16e(0.0189(V0)), r(2) = 0.70]. PAMP, calculated from the steady-state data, was 0.64 +/- 0.40 mW/ml(2) (range 0.14-2.83 mW/ml(2)) with a poor correlation with E-es (r = 0.30, P < 0.001). An alternative formulation of PAMP as PWRmax/(V-ed - V-0)(2), incorporating V-0, yielded 0.47 +/- 0.26 mW/ml(2) (range 0.09-1.42 mW/ml(2)) and was highly correlated with E-es (r = 0.89, P < 0.001). In conclusion, correct preload adjustment of maximal LV power requires incorporation of V-0 and thus of data measured under altered loading conditions. [less ▲]

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See detailPharmacological evaluation of the novel thromboxane modulator BM-567 (I/II). Effects of BM-567 on platelet function
Dogne, J. M.; de Leval, X.; Kolh, Philippe ULg et al

in Prostaglandins, Leukotrienes, and Essential Fatty Acids (2003), 68(1), 49-54

The aim of this work was to evaluate the effects of BM-567 ( N-pentyl-N'-[(2-cyclohexylamino-5-nitrobenzene)sulfonyl]urea), a torasemide derivative. on both thromboxane A(2) (TXA(2)) receptors (TP) and ... [more ▼]

The aim of this work was to evaluate the effects of BM-567 ( N-pentyl-N'-[(2-cyclohexylamino-5-nitrobenzene)sulfonyl]urea), a torasemide derivative. on both thromboxane A(2) (TXA(2)) receptors (TP) and thromboxane synthase of human platelets. The drug affinity for TP receptors of human washed platelets has been determined. In this test BM-567 showed a high affinity (IC50: 1.1+/-0.1 nM) for the TP receptors in comparison with BM-531 (IC50: 7.8+/-0.7 nM) and sulotroban (IC50: 931+/-85 nM), two TXA(2) antagonists. We also demonstrated that BM-567 prevented platelet aggregation induced by arachidonic acid (AA) (600 muM) (ED100: 0.20+/-0.10muM), U-46619, a stable TXA(2) agonist (1 muM) (ED50: 0.30+/-0.04 muM) and collagen (1 mug ml(-1)) (% of inhibition: 44.3+/-4.3% at 10 muM) and inhibited the second wave of ADP (2 muM). Moreover, when BM-567 was incubated in whole blood from healthy donors, the closure time measured by the Platelet Function analyzer (PFA-100) was significantly prolonged (closure time: 215+/-21 s) by using collagen/epinephrine cartridges. Finally, at the concentration of 1 muM, BM-567 completely reduced the TXB2 production from human platelets stimulated with AA (600 muM). These results indicate that BM-567 is a novel combined TXA(2) receptor antagonist and thromboxane synthase inhibitor characterized by a powerful antiplatelet potency. (C) 2002 Elsevier Science Ltd. All rights reserved. [less ▲]

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See detailRight ventricular diastolic function in acute pulmonary embolism
Morimont, Philippe ULg; segers, P.; Ghuysen, Alexandre ULg et al

Poster (2003)

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See detailA dual thromboxane inhibitor and thromboxane receptor antagonist prevents pig myocardial infarction induced by coronary thrombosis
Rolin, S.; Petein, M.; Tchana-Sato, Vincent ULg et al

in European Heart Journal (2003), 24(Suppl. S), 325

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See detailProsthetic vascular infection complicated or not by aortoenteric fistula: comparison of treatment with and without cryopreserved allograft (homograft).
Lavigne, Jean-Paul ULg; Postal, Alain ULg; Kolh, Philippe ULg et al

in European Journal of Vascular and Endovascular Surgery (2003), 25(5), 416-23

OBJECTIVES: in patients with vascular prosthesis infection, to compare surgical outcome and long-term results of cryopreserved allograft implantations to conventional surgery. DESIGN: retrospective study ... [more ▼]

OBJECTIVES: in patients with vascular prosthesis infection, to compare surgical outcome and long-term results of cryopreserved allograft implantations to conventional surgery. DESIGN: retrospective study. MATERIAL AND METHODS: two asynchronous series of 44 [series I: 1980-1994; 8 patients with aortoenteric fistula (AEF)] and 22 (series II: 1994-1997; 4 patients with AEF) patients were treated for prosthesis infection. All patients had prosthesis excision. In series I, there were 4 in situ reparations, 26 extra-anatomic bypass, 13 excision only, and one death at laparotomy. In series II, in situ cryopreserved allografts were implanted in all patients. RESULTS: operative mortality was 16% in series I and 13.6% in series II. For AEF patients, mortality was 37% in series I and 50% in series II. Among hospital survivors, infection-related late mortality was 13.5% in series I and 5% in series II. For AEF patients, late mortality was 20% in series I and 50% in series II. Incidence of reoperations was 54% in series I and 10.5% in series II (p<0.01). Hospital stay was 47.2+/-26.4 days in series I and 16.6+/-11.5 days in series II (p<0.001). CONCLUSIONS: compared to conventional treatment, incidence of reoperations and length of hospital stay are significantly decreased after cryopreserved allograft implantation. However, closure of aortic stump and extra-anatomic bypass gives better results for patients with AEF. [less ▲]

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See detailPharmacological evaluation of the novel thromboxane modulator BM-567 (I/II). Effects of BM-567 on platelet function
Dogné, Jean-Michel ULg; De Leval, X.; Kolh, Philippe ULg et al

in Prostaglandins, Leukotrienes, and Essential Fatty Acids (2003)

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See detailUpdate on GPIIb/IIIa antagonists
Hanson, Julien ULg; De Leval, X.; Kolh, Philippe ULg et al

in Expert Opinion on Therapeutic Patents (2003), 13

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