Response to exercise and mechanical efficiency in non-ischaemic stunning, induced by short-term rapid pacing in dogs: a role for calcium?

AIM: Rapid pacing (RP) is a regularly used model to induce heart failure in dogs. The aim of the study was to evaluate Ca2+ handling, left ventricular (LV) contractile response during Ca2+ administration compared to exercise, as well as oxygen consumption and mechanical efficiency after 48 h of RP. METHODS: Fifty-three mongrel dogs were instrumented to measure LV pressure, LV fractional shortening, regional wall thickening and coronary blood flow. Contractile reserve was measured with isoproterenol and intravenous (IV) Ca2+ administration. To assess the function of the sarcoplasmic reticulum (SR), post-extrasystolic potentiation (PESP) and SR Ca2+ uptake were measured. A graded treadmill test was performed in baseline and after RP (n = 14). In a separate group of animals (n = 5), myocardial performance and oxygen consumption were measured using a wide range of loading conditions. RESULTS: Left ventricular contractility was significantly decreased upon cessation of pacing. The contractile response to isoproterenol was blunted compared to a preserved response to IV Ca2+ . Post-extrasystolic potentiation was slightly increased after RP. Maximal velocity (Vmax ) of SR Ca2+ uptake was unchanged. Contractile response during exercise is attenuated after RP. External work is reduced, whereas oxygen consumption is preserved, provoking a reduced mechanical efficiency. CONCLUSION: Forty-eight-hours RP provokes a reversible LV dysfunction, while the SR function and response to exogenous Ca2+ are preserved. This is compatible with an intracellular functional remodelling to counteract Ca2+ overload provoked by RP. Left ventricular dysfunction is accompanied by a reduced contractile reserve, but an unchanged oxygen consumption, illustrating an alteration in oxygen utilization.

Argatroban for elective percutaneous coronary intervention: the ARG-E04 multi-center study.

UNLABELLED: The synthetic arginine-derived direct thrombin inhibitor argatroban is an attractive anticoagulant for percutaneous coronary intervention (PCI), because of its rapid onset and offset, and its hepatic elimination. Argatroban was approved for PCI in patients with heparin-induced thrombocytopenia (HIT). However, there are limited data about argatroban in non-HIT patients. The objective of this open-label, multiple-dose, controlled study was to examine the safety and efficacy of argatroban in patients undergoing elective PCI. METHODS AND RESULTS: Of 140 patients randomized to three argatroban dose groups (ARG250, ARG300, and ARG350 with 250, 300, or 350 µg/kg bolus, followed by 15, 20, or 25 µg/kg/min infusion) and one unfractionated heparin (UFH) group (70-100 IU/kg bolus), 138 patients were analyzed. Argatroban dose-dependently prolonged activated clotting time (ACT) with more patients reaching the minimum target ACT after the initial bolus injection (ARG250: 86.1%, ARG300: 89.5%, and ARG350: 96.8%) compared to 45.5% in UFH (p<0.001). The patient proportion who did not require additional bolus injections to start PCI was significantly higher in argatroban than in UFH (p ≤ 0.002). Consequently, the time to start of PCI was shortened in argatroban groups. Composite incidences of death, myocardial infarction, and urgent revascularization until day 30 were not significantly different between the groups (ARG250: 2.8%, ARG300: 0.0%, ARG350: 3.2% vs. UFH: 3.0%). Major bleeding was observed only in UFH (3.0%), while minor bleeding occurred in ARG350 (3.2%) and UFH (6.1%, n.s.). CONCLUSION: Argatroban dose-dependently increases coagulation parameters and, compared to UFH, demonstrates a superior predictable anticoagulant effect in patients undergoing elective PCI.

A large-scale multicentre study of patient skin doses in interventional cardiology: dose-area product action levels and dose reference levels.

For 318 patients in 8 different Belgian hospitals, the entire skin-dose distribution was mapped using a grid of 70 thermoluminescence dosimeters per patient, allowing an accurate determination of the maximum skin dose (MSD). Dose-area product (DAP) values, exposure parameters and geometry, together with procedure, patient and cardiologist characteristics, were also registered. Procedures were divided into two groups: diagnostic procedures (coronary angiography) and therapeutic procedures (dilatation, stent, combined procedures (e.g. coronary angiography + dilatation + stent)). The mean value of the MSD was 0.310 Gy for diagnostic and 0.699 Gy for therapeutic procedures. The most critical projection for receiving the MSD is the LAO90 (left anterior oblique) geometry. In 3% of cases, the MSD exceeded the 2 Gy dose threshold for deterministic effects. Action levels in terms of DAP values as the basis for a strategy for follow-up of patients for deterministic radiation skin effects were derived from measured MSD and cumulative DAP values. Two DAP action levels are proposed. A first DAP action level of 125 Gy cm(2) corresponding to the dose threshold of 2 Gy would imply an optional radiopathological follow-up depending on the cardiologist's decision. A second DAP action level of 250 Gy cm(2) corresponding to the 3 Gy skin dose would imply a systematic follow-up. Dose reference levels - 71.3 Gy cm(2) for diagnostic and 106.0 Gy cm(2) for therapeutic procedures - were derived from the 75 percentile of the DAP distributions. As a conclusion, we propose that total DAP is registered in patient's record file, as it can serve to improve the follow-up of patients for radiation-induced skin injuries.

Role of force--frequency relation during AV-block, sinus node block and beta-adrenoceptor block in conscious animals.

OBJECTIVE: Myocardial contractility is regulated by adrenergic stimulation, the strength-length relationship and the force-frequency relationship or Bowditch effect. The latter mechanism was clearly demonstrated in muscle strips, in the isolated heart as well as in in-vivo experiments. The aim of this study was to further investigate the role of the force-frequency effect on the contractile response to exercise or isoproterenol infusion in conditions of restricted increases in heart rate i.e., AV-block, sinus node block and beta-adrenoceptor block. METHODS: Nineteen dogs were instrumented with a left ventricular miniature pressure gauge, catheters in the aorta, pulmonary artery and left atrium and pacing leads on the left atrium and left ventricle. In order to control the chronotropic response during sympathetic stimulation, permanent AV-block was induced in nine dogs, sinus node block using UL-FS 49 and beta-adrenoceptor block using propranolol was studied in ten dogs. RESULTS: Adrenergic stimulation (isoproterenol 0.4 micro g/kg or exercise) after total AV-block failed to increase LVdP/dt. However, increasing LV pacing rate (from 50 up to 200 bpm) prior to adrenergic stimulation elicited a significant increase in LVdP/dt (4762 +/- 166 mmHg/s vs. 6485 +/- 381 mmHg/s, p < 0.05). In dogs in sinus rhythm, heart rate and LVdP/dt response to isoproterenol and exercise following pre-treatment with UL-FS 49 is significantly reduced, with heart rate increasing from 103 +/- 7 up to 154 +/- 5 bpm and LV dP/dt(max) from 2925 +/- 171 mmHg/s to 6249 +/- 400 mmHg/s compared to the response in control conditions (HR 220 +/- 3 bpm and LV dP/dt(max) 7473 +/- 616 mmHg/s) (p < 0.05). When heart rate is matched using atrial pacing, the LVdP/dt(max) response reached comparable values as observed in control conditions (7310 +/- 550 mmHg/s). Similar responses were obtained during exercise. Beta-adrenoceptor blockade attenuates considerably the heart rate and LVdP/dt response to sympathetic stimulation. Adjusting heart rate with atrial pacing restores only partially LVdP/dt(max). CONCLUSION: During sympathetic stimulation, the chronotropic response plays a major role for the concomitant full expression of the inotropic response. In conditions where increases in heart rate are absent or severely restricted such as in permanent AV-block, sinus node block and beta-adrenoceptor block, the inotropic response will also be impaired.

Myocardial stunning: an experimental act with a large clinical audience.

Myocardial stunning, a prolonged post-ischemic contractile dysfunction following single or multiple brief episodes of myocardial ischemia, was a fortuitous laboratory observation. Several years later it is obvious that myocardial stunning is a ubiquitous clinical finding and occurs whenever ischemia and reperfusion are present. Reperfusion, by restoring oxygen supply, which is beneficial and protective for the ischemic myocardium, induces at the same time a burst of oxygen free radicals complicated with intracellular Ca2+ overload, which is harmful for the contractile proteins. If it is a one-time episode, stunning is a benign condition which usually does not need treatment. If repetitive, it may lead first to chronic stunning and later to hibernating myocardium, characterised by permanent cellular injury and cell death through apoptosis with secondary reduction in myocardial perfusion. Patients with severe left ventricular dysfunction on the basis of hibernating myocardium carry an unfavourable prognosis when not revascularized. Further insight into molecular and genomic adaptation to ischemia and reperfusion will undoubtedly help improve our ability to fight ischemic heart disease.

Abnormal epicardial coronary resistance in patients with diffuse atherosclerosis but "Normal" coronary angiography.

BACKGROUND: Coronary arteries without focal stenosis at angiography are generally considered non-flow-limiting. However, atherosclerosis is a diffuse process that often remains invisible at angiography. Accordingly, we hypothesized that in patients with coronary artery disease, nonstenotic coronary arteries induce a decrease in pressure along their length due to diffuse coronary atherosclerosis. METHODS AND RESULTS: Coronary pressure and fractional flow reserve (FFR), as indices of coronary conductance, were obtained from 37 arteries in 10 individuals without atherosclerosis (group I) and from 106 nonstenotic arteries in 62 patients with arteriographic stenoses in another coronary artery (group II). In group I, the pressure gradient between aorta and distal coronary artery was minimal at rest (1+/-1 mm Hg) and during maximal hyperemia (3+/-3 mm Hg). Corresponding values were significantly larger in group II (5+/-4 mm Hg and 10+/-8 mm Hg, respectively; both P<0.001). The FFR was near unity (0.97+/-0.02; range, 0.92 to 1) in group I, indicating no resistance to flow in truly normal coronary arteries, but it was significantly lower (0.89+/-0.08; range, 0.69 to 1) in group II, indicating a higher resistance to flow. In 57% of arteries in group II, FFR was lower than the lowest value in group I. In 8% of arteries in group II, FFR was <0.75, the threshold for inducible ischemia. CONCLUSION: Diffuse coronary atherosclerosis without focal stenosis at angiography causes a graded, continuous pressure fall along arterial length. This resistance to flow contributes to myocardial ischemia and has consequences for decision-making during percutaneous coronary interventions.

Coronary thermodilution to assess flow reserve: experimental validation.

BACKGROUND: Fractional flow reserve (FFR) and coronary flow reserve (CFR) are indices of coronary stenosis severity that provide the clinician with complementary information on the contribution of epicardial arteries and microcirculation to total resistance to myocardial blood flow. At present, FFR and CFR can only be obtained by 2 separate guidewires. The present study tested the validity of the thermodilution principle in assessing CFR with one pressure-temperature sensor-tipped guidewire. METHODS AND RESULTS: In an in vitro model, absolute flow was compared with the inverse mean transit time (1/T(mn)) of a thermodilution curve obtained after a bolus injection of 3 mL of saline at room temperature. A very close correlation (r>0.95) was found between absolute flow and 1/T(mn) when the sensor was placed >/=6 cm from the injection site. In 6 chronically instrumented dogs (60 stenoses; FFR from 0.19 to 0.98), a significant linear relation was found between flow velocity and 1/T(mn). A significant correlation was found between CFR(Doppler), which was calculated from the ratio of hyperemic to resting flow velocities, and CFR(thermo), which was calculated from the ratio of resting to hyperemic T(mn) (r=0.76; SEE=0.24; P<0.001). CONCLUSION: The present findings demonstrate the validity of the thermodilution principle to assess CFR. Because the pressure-temperature sensor was mounted in a commercially available angioplasty guidewire, this technique permits simultaneous measurements of CFR and FFR.

Cardiovascular effects of beta 3-adrenoceptor stimulation in perinephritic hypertension.

BACKGROUND: A new beta 3-adrenoceptor (beta3-AR) has been shown to mediate peripheral vasodilation. This study was conducted to evaluate effects of the beta3-AR agonist, SR58611 in normal and hypertensive dogs. MATERIALS AND METHODS: In protocol 1, SR58611 was infused in normal dogs after placebo, after beta1/beta2 blockade with nadolol, after beta1/beta2/beta3 blockade with bupranolol and after combined autonomic blockade (CAB). In protocol 2, perinephritic hypertension was produced in dogs, which received SR58611 at 3 and 6 weeks of hypertension. Effects of SR58611 were evaluated at 7 weeks of hypertension after CAB. RESULTS: In normal dogs, SR58611 produced a dose-dependent decrease in mean aortic pressure (AOP) (from 116 +/- 19 to 100 +/- 19 mmHg, - 14%; P < 0.05) that was accompanied by baroreflex activation (heart rate increased by 70%; P < 0.01). This hypotensive effect resulting from peripheral vasodilation persisted after nadolol or CAB while baroreflex activation was blunted or abolished. A biphasic response of cardiac output, characterized by a rise and a decline (P < 0.05) reflected a reduction in after- and pre-load. After CAB, SR58611 did not modify cardiac contractility. SR58611 stimulated lipolysis as reflected by a 4-fold increase in blood free fatty acids (FFA) (P < 0.0005). Under CAB, the rise of FFA was reduced (P < 0.01). In hypertensive dogs, SR58611 produced a dose-dependent decrease in mean AOP (from 168 +/- 32 to 125 +/- 35 mmHg; - 26%, P < 0.0001), that was greater than in normal dogs (P < 0.05). Reflex-mediated tachycardia also occurred but at higher blood pressure values. Blood FFA rose similarly (P < 0.0001). Under CAB, heart rate remained unchanged but SR58611 still induced a decrease (P < 0.0001) in mean AOP concomitantly with a rise of (dP/dt)/DP40 (P < 0.005), an effect not observed in normal dogs. CONCLUSIONS: Beta3-AR stimulation exerts hypotensive effects, increases cardiac contractility and stimulates lipolysis in hypertensive dogs.

Fractional flow reserve in patients with prior myocardial infarction.

BACKGROUND: Fractional flow reserve (FFR), an index of coronary stenosis severity, can be calculated from the ratio of hyperemic distal to proximal coronary pressure. An FFR value of 0.75 can distinguish patients with normal and abnormal noninvasive stress testing in case of normal left ventricular function. The present study aimed at investigating the value of FFR in patients with a prior myocardial infarction. Methods and Results-- In 57 patients who had sustained a myocardial infarction >/=6 days earlier, myocardial perfusion single photon emission scintigraphy (SPECT) imaging and FFR were obtained before and after angioplasty. The sensitivity and specificity of the 0.75 value of FFR to detect flow maldistribution at SPECT imaging were 82% and 87%. The concordance between the FFR and SPECT imaging was 85% (P<0.001). When only truly positive and truly negative SPECT imaging were considered, the corresponding values were 87%, 100%, and 94% (P<0.001). Patients with positive SPECT imaging before angioplasty had a significantly lower FFR than patients with negative SPECT imaging (0.52+/-0.18 versus 0.67+/-0.16, P=0.0079) but a significantly higher left ventricular ejection fraction (63+/-10% versus 52+/-10%, P=0.0009) despite a similar degree of diameter stenosis (67+/-13% versus 68+/-16%, P=NS). A significant inverse correlation was found between LVEF and FFR (R=0.29, P=0.049). CONCLUSIONS: The present data indicate (1) that the 0.75 cutoff value of FFR to distinguish patients with positive from patients with negative SPECT imaging is valid after a myocardial infarction and (2) that for a similar degree of stenosis, the value of FFR depends on the mass of viable myocardium.

Continued benefit of coronary stenting versus balloon angioplasty: five-year clinical follow-up of Benestent-I trial.

OBJECTIVES: This study sought to establish whether the early favorable results in the Benestent-I randomized trial comparing elective Palmaz-Schatz stent implantation with balloon angioplasty in 516 patients with stable angina pectoris are maintained at 5 years. BACKGROUND: The size of the required sample was based on a 40% reduction in clinical events in the stent group. Seven months and one-year follow-up in this trial showed a decreased incidence of restenosis and clinical events in patients randomized to stent implantation. METHODS: Data at five years were collected by outpatient visit, via telephone and via the referring cardiologist. Three patients in the stent group and one in the percutaneous transluminal coronary angioplasty (PTCA) group were lost to follow-up at five years. Major clinical events, anginal status and use of cardiac medication were recorded according to the intention to treat principle. RESULTS: No significant differences were found in anginal status and use of cardiac medication between the two groups. In the PTCA group, 27.3% of patients underwent target lesion revascularization (TLR) versus 17.2% of patients in the stent group (p = 0.008). No significant differences in mortality (5.9% vs. 3.1%), cerebrovascular accident (0.8% vs. 1.2%), myocardial infarction (9.4% vs. 6.3%) or coronary bypass surgery (11.7% vs. 9.8%) were found between the stent and PTCA groups, respectively. At five years, the event-free survival rate (59.8% vs. 65.6%; p = 0.20) between the stent and PTCA groups no longer achieved statistical significance. CONCLUSIONS: The original 10% absolute difference in TLR in favor of the stent group has remained unchanged at five years, emphasizing the long-term stability of the stented target site.

Coronary pressure measurement to assess the hemodynamic significance of serial stenoses within one coronary artery: validation in humans.

BACKGROUND: When several stenoses are present within 1 coronary artery, the hemodynamic significance of each stenosis is influenced by the presence of the other(s), and the calculation of coronary and fractional flow reserve (CFR and FFR) for each individual stenosis is confounded. Recently, we developed and experimentally validated a method to determine the true FFR of each stenosis as it would be after the removal of the other stenosis; the true FFR can be reliably predicted by coronary pressures measured before treatment at specific locations within the coronary artery using equations accounting for stenosis interaction. The aim of the present study was to test the validity of these equations in humans. METHODS AND RESULTS: In this study of 32 patients with 2 serial stenoses in 1 coronary artery, relevant pressures were measured before the intervention, after the treatment of 1 stenosis, and after the treatment of both stenoses. The true FFR of each stenosis (FFR(true)) was directly measured after the elimination of the other stenosis and compared with the value predicted (FFR(pred)) from the initial pressure measurements before treatment. Although the hyperemic gradient across 1 stenosis increased significantly (from 10+/-7 to 19+/-11 mm Hg after treatment of the other stenosis), FFR(pred) was close to FFR(true) in all patients (0.78+/-0.12 versus 0.78+/-0.11 mm Hg; r=0.92; Delta%=4+/-0%). Without accounting for stenosis interaction, the value of FFR for each stenosis would have been significantly overestimated (0.85+/-0.08; P:<0.01). CONCLUSIONS: Coronary pressure measurements made by a pressure wire at maximum hyperemia provide a simple, practical method for assessing the individual hemodynamic significance of multiple stenoses within the same artery.

The ESSEX (European Scimed Stent Experience) study.

The aim of the study was to assess the safety and feasibility of implantation of the Scimed Radius stent. Secondary objectives were to assess the result of stent placement by quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS). The ESSEX study was a prospective, multicenter, observational study in which candidates for a single elective stent implantation, in a de novo or restenotic lesion, reference diameter 2.75-4.00 mm and target lesion < 14 mm in length, were enrolled. QCA at baseline, postprocedure, and 6-month follow-up was performed. IVUS was used to assess optimal stent implantation. One hundred and three patients were enrolled. Forty-four percent of the patients had unstable angina. Stent implantation was technically successful in all patients. Additional stents were implanted in 17 patients for procedural dissection (16) and spasm (1). Ninety-seven percent of patients were event-free at 1 month and 76% at 6-month follow-up. Angiographic restenosis rates for de novo lesions and for all patients were 19% and 21%, respectively. Clinical events occurred at 1- and 6-month follow-up in 2.9% and 24.3% of patients, respectively. No patients suffered subacute thrombosis. Retrospective analysis of peak balloon inflation pressure (< or = 12 and > 12 atm) as a determinant of clinical, QCA, and IVUS outcomes suggested no benefit or detrimental effect from optimization with high-pressure balloon inflation. Implantation of the self-expanding Radius stent is safe and efficacious. Based on registry data, clinical, angiographic, and IVUS, data comparable with modern balloon-expandable stents were obtained.

Pressure-derived fractional flow reserve to assess serial epicardial stenoses: theoretical basis and animal validation.

Background-Fractional flow reserve (FFR) is an index of stenosis severity validated for isolated stenoses. This study develops the theoretical basis and experimentally validates equations for predicting FFR of sequential stenoses separately. Methods and Results-For 2 stenoses in series, equations were derived to predict FFR (FFR(pred)) of each stenosis separately (ie, as if the other one were removed) from arterial pressure (P(a)), pressure between the 2 stenoses (P(m)), distal coronary pressure (P(d)), and coronary occlusive pressure (P(w)). In 5 dogs with 2 stenoses of varying severity in the left circumflex coronary artery, FFR(pred) was compared with FFR(app) (ratio of the pressure just distal to that just proximal to each stenoses) and to FFR(true) (ratio of the pressures distal to proximal to each stenosis but after removal of the other one) in case of fixed distal and varying proximal stenoses (n=15) and in case of fixed proximal and varying distal stenoses (n=20). The overestimation of FFR(true) by FFR(app) was larger than that of FFR(true) by FFR(pred) (0.070+/-0.007 versus 0.029+/-0.004, P<0.01 for fixed distal stenoses, and 0.114+/-0.01 versus 0.036+/-0. 004, P<0.01 for fixed proximal stenoses). This overestimation of FFR(true) by FFR(app) was larger for fixed proximal than for fixed distal stenoses. Conclusions-The interaction between 2 stenoses is such that FFR of each lesion separately cannot be calculated by the equation for isolated stenoses (P(d)/P(a) during hyperemia) applied to each separately but can be predicted by more complete equations taking into account P(a), P(m), P(d), and P(w).

Myocardial perfusion and oxygen consumption in reperfused noninfarcted dysfunctional myocardium after unstable angina: direct evidence for myocardial stunning in humans.

OBJECTIVES: To positively establish the diagnosis of myocardial stunning in patients with unstable angina and persistent wall motion abnormalities after reperfusion by coronary angioplasty. BACKGROUND: Although myocardial stunning is thought to occur in several clinical conditions, definite proof of its existence in humans is still lacking, owing to the difficulty of measuring myocardial blood flow (MBF) in absolute terms. METHODS: We studied 14 patients with unstable angina due to proximal left anterior descending coronary artery disease who presented persistent anterior wall motion abnormalities despite revascularization of the culprit lesion by percutaneous coronary angioplasty (PTCA) and who did not have clinical evidence of necrosis. Dynamic positron emission tomography (PET) with [13N]-ammonia and [11C]-acetate was performed 48 h after PTCA to determine absolute MBF and oxygen consumption (MVO2). Regional wall thickening and regional cardiac work were determined using two-dimensional echocardiography. Improvement of segmental wall motion abnormalities was followed for a median of 4 months (1.5 to 14 months). RESULTS: As judged from the changes in segmental wall motion score, regional dysfunction was spontaneously reversible in 12/14 patients and improved from 2.2 +/- 0.3 to 1.2 +/- 0.3 at late follow-up (p < 0.001). With PET, [13N]-ammonia MBF was similar among dysfunctional and remote normally contracting segments (85 +/- 29 vs. 99 +/- 20 ml x min (-1) x 100g(-1), p = not significant [n.s.]), thus demonstrating a perfusion-contraction mismatch. Despite the reduced contractile function, dysfunctional myocardium presented near normal levels of MVO2 (6.5 +/- 4.2 vs. 8.0 +/- 1.9 ml x min (-1)x 100g(-1), p = n.s.). Consequently, the regional myocardial efficiency (regional work divided by MVO2) of the dysfunctional myocardium was found to be markedly decreased as compared with normally contracting myocardium (6 +/- 6% vs. 26 +/- 6%, p < 0.001). CONCLUSIONS: This study demonstrates that human dysfunctional myocardium capable of spontaneously recovering contractile function after unstable angina endures a state of perfusion-contraction mismatch. These data for the first time provide unequivocal direct evidence for the existence of acute myocardial stunning in humans.

Carvedilol and lacidipine prevent cardiac hypertrophy and endothelin-1 gene overexpression after aortic banding.

Carvedilol and lacidipine have been shown to exert cardioprotective effects in rat models of chronic hypertension. We investigated their effects in an acute model of pressure overload produced by suprarenal aortic constriction, in which enhanced myocardial production of endothelin-1 could play a crucial role. In the absence of drug treatment, after 1 week, aortic banding provoked an increase in carotid pressure associated with left ventricular hypertrophy (29%; P<0.01). These changes were accompanied by increased myocardial expression of preproendothelin-1 (2.5 times; P<0.05) and skeletal alpha-actin (3.6 times; P<0.05), but the expression of cardiac alpha-actin was not modified. Oral administration of carvedilol at a dose of 30 mg. kg(-1). d(-1) to rats with aortic banding normalized carotid pressure and left ventricular weight as well as preproendothelin-1 and skeletal alpha-actin gene expression. Carvedilol at a lower dose (7.5 mg x kg(-1) x d(-1)) and lacidipine 1 mg x kg(-1) x d(-1) had only moderate and nonsignificant effects on carotid pressure but largely prevented left ventricular hypertrophy (P<0.01) and preproendothelin-1 overexpression (P<0.05). Labetalol (60 mg x kg(-1) x d(-1)) tended to exert similar effects but insignificantly. These results show that the antihypertrophic properties of carvedilol and lacidipine are partly independent of their antihypertensive effects and may be related to their ability to blunt myocardial preproendothelin-1 overexpression. Moreover, carvedilol at a dose of 7.5 mg x kg(-1) x d(-1) did not prevent myocardial overexpression of skeletal alpha-actin, which suggests that, in this model, reexpression of a fetal gene can be activated by pressure overload independently of cardiac hypertrophy.

Assessment of coronary angiograms prior to and after treatment with abciximab, and the outcome of angioplasty in refractory unstable angina patients. Angiographic results from the CAPTURE trial.

BACKGROUND: The CAPTURE study (c 7E3 A nti P latelet T herapy in U nstable Re fractory angina) was designed to assess outcome in patients with refractory angina undergoing angioplasty, receiving either abciximab or placebo. METHODS: One thousand two hundred and sixty-five patients with refractory unstable angina, defined as recurrent myocardial ischaemia despite medical treatment including heparin and nitrates were enrolled. After angiography, patients received an infusion of abciximab or placebo over 18-24 h preceding angioplasty, continuing until 1 h after the procedure. In 1197 patients undergoing angioplasty the angiographic committee centrally reviewed the baseline as well as the procedural angiograms. Coronary flow and lesion characteristics were assessed in the baseline angiogram as well as before intervention. Angiographic outcome, reason for failure as well as complications were assessed after angioplasty. RESULTS: At 30 days follow-up, patients receiving abciximab (n=595) compared with placebo (n=602) had a 30% reduction in the composite primary end-point death, myocardial infarction or urgent (re)intervention: 10.8% vs 15.4% (P=0.017). Baseline demographics were identical in the angiogram available group compared with the total study group. At 30 days, the non-angiogram available patients showed a higher incidence of events compared to those in whom the angiogram was reviewed: 19.4 vs 13.1% (P=ns). Lesion characteristics and coronary flow were not different at baseline between the placebo and abciximab groups. A primary end-point was reached in 9.6% of both placebo and abciximab patients with type A or B(1)lesions, in 17.0% vs 12.0% with type B(2)lesions, and in 19.1% vs 11.5% with type >B(2)or C lesions. Sixty-one percent of placebo and abciximab patients had TIMI 3 flow at baseline angiography. Pre-angioplasty TIMI 3 flow was observed in 69% and 72% respectively. The thrombus was resolved between the angiograms in 22% and 43% respectively, in the placebo and abciximab groups (P=0. 033). Angiographic success of the procedure was achieved in 88% and 94% in the placebo and abciximab patients, respectively (P<0.001). Stents were implanted in the ischaemia-related artery in 56 and 60 patients, respectively. However, failure of the stent procedure was more frequent in the placebo group than in the abciximab group, nine vs no patients (P=0.003). CONCLUSION: More frequent thrombus resolution was observed and a higher angiographic success rate was achieved in patients treated with abciximab before and during angioplasty compared with placebo. Patients with complex lesions as the underlying pathology reached fewer end-points if treated with abciximab before and during angioplasty.

Clopidogrel-rt-PA-heparin combination in the treatment of acute myocardial infarction.

The safety and tolerability of clopidogrel coadministration to patients with recent acute myocardial infarction (AMI) treated with recombinant tissue plasminogen activator (rt-PA) and heparin were assessed. Patients of either sex who had a recent uncomplicated AMI with ischemic pain lasting at least 20 minutes and ST-segment elevation, and with indication for thrombolysis were included. Treatment was started within 12 hours after the onset of pain. Clopidogrel 75 mg was administered within 3 hours of starting the rt-PA infusion, and was continued at 75 mg once daily over the next 6 days. Heparin was administered as a 5000 IU intravenous bolus followed by a 1000 IU/h infusion for at least 48 hours to maintain an activated partial thromboplastin time at 1.8 to 2.2 times the control value. rt-PA was administered as a 15 mg bolus injection, followed by a 0.75 mg/kg (up to 50 mg) infusion over 30 minutes and a subsequent 0.50 mg/kg (up to 35 mg) infusion over 60 minutes. The patients were hospitalized at least during the 7-day study period, after which they were followed for 10 days. The primary end point of the study was the occurrence of bleeding complications validated by a data monitoring and safety committee as severe (intracerebral or with substantial hemodynamic alteration requiring treatment), moderate (need for transfusion), or minor (other bleeding). Based on the statistical assumption, at alpha = 0.05 of a true probability of severe bleeding < or =0.06, the required minimum number of patients was calculated as 45, 65, or 94 if no, one, or two moderate-to-severe bleeding events occurred, respectively. Efficacy was assessed based on mortality, reinfarction, or need for emergency revascularization procedures. One intracranial hemorrhage occurred among the first 49 patients included, and one after the inclusion of 16 additional patients (total of 65). After further increase in the number of patients to 94, then to 116 in order to secure a number of 94 evaluable patients for safety, there were no additional cases of severe bleeding. Hence, the observed rate of moderate-to-severe bleeding was estimated at 1.7%, with a 95% probability that the underlying rate was below 7.5%. Deaths occurred in 3.6% compared to 6.3% in the GUSTO trial. Recurrent myocardial infarctions occurred in 4.5% and emergency revascularization procedures in 14.5% of the 110 patients deemed evaluable for efficacy, rates which are similar in this study and the GUSTO trial. The results of the study compare favorably with historical data showing a moderate-to-severe bleeding rate of 6% with aspirin given concomitantly with rt-PA and suggest that clopidogrel could be safely given as platelet aggrega

Audit and quality control in angioplasty in Europe: procedural results of the AQUA Study 1997: assessment of 250 randomly selected coronary interventions performed in 25 centres of five European countries. AQUA Study Group, Nucleus Clinical Issues, Working Group Coronary Circulation, of the European Society of Cardiology.

AIMS: Percutaneous transluminal coronary angioplasty (PTCA) has become the most widely used major intervention in western medicine. However, there is disparate use of this technique among different European countries and the U.S.A. In an attempt at quality assurance, the working group Coronary Circulation of the European Society of Cardiology has carried out a study on appropriateness, necessity, and performance of PTCA in Europe. The present paper reports on the procedural results of this survey. METHODS: In a multicentre case-control study in Europe, 750 patients (544 men, 206 women) with documented vascular disease of the From the countries participating in the European Registry of Coronary Intervention, the three countries with the highest absolute PTCA volume (Germany, France, and the United Kingdom) and two randomly selected countries (Belgium and Italy) were chosen for investigation. In these countries, five centres were selected at random according to the following criteria: one centre with >1000, three centres with 300-1000, and one centre with <300 procedures per year. In each of these, 10 cases from the first half of 1997 were randomly identified and all pertinent documentation was collected. RESULTS: In 250 cases, 325 stenoses were addressed as target lesions. Single vessel disease was present in 41%. History included stable angina in 49%, unstable angina in 32%, atypical chest pain in 6%, no anginal pain in 12%, and acute/subacute myocardial infarction in 13%. The percentage of patients with either positive stress test and/or unstable angina, acute/subacute infarction, previous infarction (within 6 months) or coronary revascularization amounted to 98%. Single vessel intervention accounted for 90%. In 41% balloon-only angioplasty was performed and in 54% at least one stent was implanted with considerable variation among countries. The use of other new devices amounted to only 3%. In 92%, the operators documented a successful procedure. Major complications (myocardial infarction, emergency bypass surgery, or death) were found in 4.8%. CONCLUSIONS: Based on scrutinized hospital and operator data, the present study revealed a satisfactorily high percentage of justifiable indications, an adequate procedural success rate, and an acceptably low complication rate. Further analysis by an expert panel will address appropriateness, necessity, and procedural performance of the individual cases.

Effects of dobutamine on coronary stenosis physiology and morphology: comparison with intracoronary adenosine.

BACKGROUND: The mechanisms leading to dobutamine-induced ischemia are not fully understood. In the present study, we investigated the effects of high-dose intravenous dobutamine on morphological and physiological indexes of coronary stenoses. METHODS AND RESULTS: Twenty-two patients with normal left ventricular function and isolated coronary stenoses were studied. At catheterization, mean aortic pressure (P(a)), mean distal coronary pressure (P(d)), and P(d)/P(a) as an index of myocardial resistance were recorded at rest, after intracoronary adenosine, and during intravenous infusion of dobutamine (10 to 40 micrograms . kg(-1). min(-1)). Reference vessel diameter and minimal luminal diameter, as assessed by coronary angiography, did not change during dobutamine infusion compared with baseline (2.84+/-0.49 versus 2.77+/-0.41 mm and 1.35+/-0.38 versus 1. 27+/-0.31 mm, respectively; both P=NS). During peak dobutamine infusion, P(d) and P(d)/P(a) reached similar levels as during adenosine infusion (60+/-18 versus 59+/-18 mm Hg and 0.68+/-0.18 versus 0.68+/-0.17, respectively; all P=NS). In 9 patients, an additional bolus of intracoronary adenosine given at the peak dose of dobutamine failed to further decrease P(d)/P(a). Furthermore, in patients with dobutamine-induced wall motion abnormalities, the maximal decrease in P(d)/P(a) was similar during dobutamine and adenosine infusions. CONCLUSIONS: High-dose intravenous infusion of dobutamine does not modify the dimensions of the epicardial coronary stenosis. However, much like the direct coronary vasodilator adenosine, dobutamine fully exhausts myocardial resistance regardless of the presence of mechanical dysfunction.