Randomized comparison of angioplasty of complex coronary lesions at a single center. Excimer Laser, Rotational Atherectomy, and Balloon Angioplasty Comparison (ERBAC) Study.

BACKGROUND: The purpose of this study was to test whether coronary revascularization with ablation of either excimer laser or rotational atherectomy can improve the initial angiographic and clinical outcomes compared with dilatation (balloon angioplasty) alone. METHODS AND RESULTS: At a single center, a total of 685 patients with symptomatic coronary disease warranting elective percutaneous revascularization for a complex lesion were randomly assigned to balloon angioplasty (n = 222), excimer laser angioplasty (n = 232), or rotational atherectomy (n = 231). The primary end point was procedural success (diameter stenosis < 50%, absence of death, Q-wave myocardial infarction, or coronary artery bypass surgery). The patients who underwent rotational atherectomy had a higher rate of procedural success than those who underwent excimer laser angioplasty or conventional balloon angioplasty (89% versus 77% and 80%, P = .0019), but no difference was observed in major in-hospital complications (3.2% versus 4.3% versus 3.1%, P = .71). At the 6-month follow-up, revascularization of the original target lesion was performed more frequently in the rotational atherectomy group (42.4%) and the excimer laser group (46.0%) than in the angioplasty group (31.9%, P = .013). CONCLUSIONS: Procedural success of rotational atherectomy is superior to laser angioplasty and balloon angioplasty; however, it does not result in better late outcomes. The role of plaque debulking before balloon dilatation in percutaneous coronary revascularization remains to be fully defined.

Cholinergic and alpha-adrenergic coronary vasomotion [corrected] with increasing ischemia-reperfusion injury.

Ischemia-reperfusion-induced injury of the coronary vasculature could result in an attenuated vasodilator or increased vasoconstrictor tone that might impact on myocardial recovery and viability. In 30 open-chest dogs the left circumflex coronary artery was occluded for 15 or 60 min and then reperfused, and responses to intracoronary acetylcholine, the alpha 1-adrenergic agonist methoxamine, and the alpha 2-adrenergic agonist BHT-933 (n = 10 each) were measured. In the experiments with 60 min of occlusion, triphenyltetrazolium chloride (TTC) staining was used to distinguish reversibly (TTC+) and irreversibly (TTC-) injured myocardium. After 15 min of occlusion, the vasodilator response to acetylcholine was not altered but was significantly reduced in TTC+ subendocardium and midmyocardium after 60 min of occlusion and was further reduced in TTC- subendocardium, midmyocardium, and also in subepicardium. The vasoconstrictor responses to methoxamine and BHT-933 were not altered after 15 or 60 min of occlusion in both TTC+ and TTC- myocardium. Posterior wall thickening was not affected by acetylcholine, methoxamine, or BHT-933. Thus, in reversibly injured myocardium after 15 min of occlusion, cholinergic and alpha-adrenergic coronary vasomotor responses are unchanged. With increasing duration of ischemia, reversibly and even more so irreversibly injured reperfused myocardium are characterized by an impaired cholinergic coronary vasodilation but not an enhanced alpha-adrenergic coronary vaso-constriction.

Attenuation of myocardial stunning by the ACE inhibitor ramiprilat through a signal cascade of bradykinin and prostaglandins but not nitric oxide.

BACKGROUND: Attenuation of myocardial stunning by several angiotensin-converting enzyme (ACE) inhibitors has been demonstrated. However, the signal cascade mediating such protective effect has not been analyzed in detail so far. METHODS AND RESULTS: In a first protocol, we addressed the role of bradykinin and analyzed the effect of the ACE inhibitor ramiprilat without and with added bradykinin B2 receptor antagonist HOE 140 on regional myocardial blood flow (colored microspheres) and function (sonomicrometry). Thirty-two enflurane/N2O-anesthetized open-chest dogs were subjected to 15 minutes of occlusion of the left circumflex coronary artery (LCx) and 4 hours of subsequent reperfusion. Eight dogs served as placebo controls (group 1), and 8 dogs received ramiprilat (20 micrograms/kg IV) before LCx occlusion (group 2). Eight dogs received a continuous intracoronary infusion of HOE 140 [0.5 ng/(mL.min) IC] during ischemia and reperfusion (group 3), and in 8 dogs HOE 140 was infused continuously during ischemia and reperfusion, starting 45 minutes before the administration of ramiprilat (group 4). Mean aortic pressure was kept constant with an intra-aortic balloon, and heart rate did not change throughout the experimental protocols. Under control conditions and during myocardial ischemia, posterior transmural blood flow (BF) and systolic wall thickening (WT) were not different in the four groups of dogs. However, at 4 hours of reperfusion, WT was still depressed in groups 1 (-10 +/- 20% of control [mean +/- SD]), 3 (-18 +/- 12% of control), and 4 (-12 +/- 21% of control), whereas WT in group 2 had recovered to 55 +/- 20% of control (P < .05 versus group 1). BF at 4 hours of reperfusion was not different in the four groups of dogs. Thus, the beneficial effect of ramiprilat on the functional recovery of stunned myocardium was obviously mediated by bradykinin. Since bradykinin stimulates the formation of both prostaglandins and nitric oxide, we tested in a second protocol which of these mediators was further involved in the beneficial effects of ramiprilat. Twenty-four additional dogs were subjected to 15 minutes of LCx occlusion and 4 hours of reperfusion. Six dogs received the cyclooxygenase inhibitor indomethacin (10 mg/kg IV) (group 5) and 6 dogs a combination of indomethacin with ramiprilat (group 6) before LCx occlusion. Six dogs received the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) (20 mg/kg IV) (group 7) and 6 dogs a combination of L-NAME with ramiprilat (group 8) before LCx occlusion. BF and WT before and during myocardial ischemia were not different in groups 5 and 6 and groups 7 and 8. However, at 4 hours of reperfusion, WT was still depressed in groups 5 (-10 +/- 38% of control), 6 (-7 +/- 18% of control), and 7 (-12 +/- 14% of control), whereas WT in group 8 had recovered to 47 +/- 28% of control (P < .05 versus group 7). BF at 4 hours of reperfusion was not different in the four groups of dogs. CONCLUSIONS: In summary, the attenuation of stunning by the ACE inhibitor ramiprilat involves a signal cascade of bradykinin and prostaglandins but not nitric oxide.

Characterization of the inotropic and arrhythmogenic action of the sodium channel activator BDF 9148: a comparison to its S-enantiomer BDF 9196, to its congener DPI 201-106, to norepinephrine, and to ouabain.

Positive inotropic substances which enhance the myocardial cAMP level or inhibit the Na+/K(+)-ATPase are known for their proarrhythmic side-effects. This study was performed to investigate the inotropic and arrhythmogenic action of the Na(+)-channel activator BDF 9148 (racemate) in comparison to its S-enantiomer BDF 9196, its congener DPI 201-106 (racemate), to norepinephrine, and to ouabain. In 30 open-chest dogs, the effects of these substances on the first derivative of left ventricular pressure (dP/dt, Millar-tip catheter) and anterior systolic wall thickening (AWT, sonomicrometry) were studied. Concomitantly, myocardial excitability, conduction times, and refractory period were assessed with a transmural, three-dimensional, 16-electrode array in the anterior wall. For the study of the Na(+)-channel activators, alpha- and beta-adrenergic and muscarinic receptors were blocked. A first set of measurements was performed during normoperfusion with administration of BDF 9148 (1 mg/kg, n = 8), BDF 9196 (0.5 mg/kg, n = 8), and DPI 201-106 (1 mg/kg, n = 8), respectively. A second set of measurements was performed with administration of the threefold dosage of either substance. With a severe stenosis on the left anterior descending coronary artery, a final set of measurements was performed, again using the higher dosage of either substance. For the study of norepinephrine (0.5 micrograms/kg/min i.v., n = 6) and ouabain (40 micrograms/kg i.v., n = 4), measurements were performed during normoperfusion in additional animals. Under normal conditions, either Na(+)-channel activator induced increases in dP/dtmax (lower dosage: 45-84%, higher dosage: by 93-117%) and AWT (lower dosage: by 24-37%, higher dosage: by 19-56%). Under ischemic conditions, either drug increased dP/dtmax by 60-98% and AWT by 45-102%. Excitability, conduction times, and refractory period did not change significantly in response to the Na(+)-channel activators, neither under normal nor under ischemic conditions. There was no significant difference in the incidence of spontaneous ventricular extrasystoles before and after administration of either Na(+)-channel activator. In contrast, an equi-inotropic dosage of norepinephrine (increases in dP/dtmax by 148% and AWT by 42%) increased excitability, decreased conduction times and refractory period, and increased the incidence of spontaneous ventricular extrasystoles. Ouabain induced only a moderate increase in dP/dtmax by 56% and AWT by 24%, but elicited sustained and complex ventricular arrhythmias. Excitability was markedly increased, whereas conduction times and refractory period changed only little.(ABSTRACT TRUNCATED AT 400 WORDS)

Impact of alpha-adrenergic coronary vasoconstriction on the transmural myocardial blood flow distribution during humoral and neuronal adrenergic activation.

Increased heart rate and left ventricular pressure during humoral and neuronal adrenergic activation act to restrict blood flow preferentially in the subendocardium. The hypothesis was advanced that alpha-adrenergic coronary vasoconstriction preferentially in the subepicardium may counterbalance the enhanced extravascular compression in the subendocardium and serve to maintain blood flow transmurally uniform. In 40 anesthetized dogs, regional myocardial blood flow was determined with colored microspheres; wall function, with sonomicrometry. Humoral adrenergic activation (HAA) was induced by a combination of intravenous atropine, intravenous norepinephrine, and atrial pacing during baseline coronary vasomotor tone (group 1, n = 6) and in the presence of maximal coronary vasodilation with intravenous dipyridamole (group 2, n = 6). In an additional group, HAA was induced by intravenous norepinephrine in the presence of dipyridamole but without atropine and atrial pacing in order to increase end-diastolic left ventricular pressure (group 3, n = 6). Measurements were performed at rest, during HAA, and during ongoing HAA with the intracoronary infusion of the alpha-antagonist phentolamine (Phen). At unchanged mean aortic pressure, Phen improved blood flow particularly to the inner layers as follows: from 1.42 +/- 0.40 (mean +/- SD) to 1.90 +/- 0.40 mL/(min.g) (group 1, P < .05), from 4.99 +/- 2.31 to 5.53 +/- 2.56 mL/(min.g) (group 2, P < .05), and from 6.01 +/- 1.41 to 6.29 +/- 1.27 mL/(min.g) (group 3, P < .05), associated with a decrease in outer layer blood flow in groups 2 and 3. In 16 additional dogs, beta-adrenoceptors were blocked by propranolol and muscarinic receptors by atropine. Neuronal adrenergic activation (NAA) was induced by cardiac sympathetic nerve stimulation (CSNS) during baseline coronary vasomotor tone (group 4, n = 8) and in the presence of maximal vasodilation (group 5, n = 8). Measurements were performed at rest, during a first CSNS, and 20 minutes later during a second CSNS+Phen. The reproducibility of two consecutive episodes of CSNS 20 minutes apart was demonstrated in a separate set of experiments (n = 6). At matched mean aortic pressures, Phen improved blood flow to all myocardial layers in group 4, whereas in group 5, Phen induced a redistribution of myocardial blood flow toward subepicardial layers [from 4.44 +/- 0.96 to 4.81 +/- 0.83 mL/(min.g), P < .05] at the expense of inner layers. With the addition of Phen, there was no change in regional wall function in any group of dogs studied. Thus, during HAA, alpha-adrenergic coronary vasoconstriction does not exert a beneficial effect on transmural blood flow distribution. During NAA, a beneficial effect of alpha-adrenergic coronary vasoconstriction becomes apparent only under conditions of maximal coronary vasodilation.

Local and neurohumoral control of coronary blood flow.

The powerful local metabolic regulation adjusting coronary blood flow to myocardial oxygen consumption under normal conditions is beyond doubt. However, despite substantial experimental efforts the responsible mediators are still largely unknown. Adenosine, a purported mediator of local metabolic control of coronary blood flow, is probably only involved in transient flow adaptations, but not in steady-state coronary autoregulation. Even below the autoregulatory range a substantial vasodilator reserve persists. Recruitment of such vasodilator reserve results in improved regional myocardial blood flow and attenuated regional ischemic dysfunction. beta-adrenergic coronary dilation is of minor functional importance. alpha-adrenergic coronary constriction acts to attenuate increases in coronary blood flow during sympathetic activation under normal conditions, such that myocardial oxygen extraction increases to match the increased oxygen consumption. alpha-adrenergic coronary constriction remains operative in ischemic myocardium, thus precipitating or contributing to acute myocardial ischemia during sympathetic activation and exercise in experimental animals as well as in patients with stable angina. The vagal transmitter acetylcholine--upon exogenous intracoronary infusion--induces critical constriction of epicardial coronary arteries with endothelial dysfunction and atherosclerosis. However, a vagal initiation of coronary spasm or myocardial ischemia has not been documented so far. Similarly, peptide hormones/transmitters such as NPY, vasopressin, and angiotensin can induce myocardial ischemia upon exogenous administration. Their pathophysiological role in myocardial ischemia and reperfusion, however, remains to be established.