Relation between geometric dimensions of coronary artery stenoses and myocardial perfusion reserve in man.

To determine the relation between stenosis anatomy and perfusion in man, 31 patients had quantitative coronary arteriography and positron imaging (PET) with Rb-82 or N-13 ammonia at rest and after dipyridamole-handgrip stress. 10 patients were also studied after angioplasty (total stenoses = 41). Percent narrowing and absolute cross-sectional luminal area were related through a quadratic function to myocardial perfusion reserve determined with PET. Arteriographically determined coronary flow reserve was linearly related to relative myocardial perfusion reserve as expected, based on the derivation of equations for stenosis flow reserve. All of the correlations had considerable scatter, indicating that no single measurement derived by coronary arteriography was a good indicator of perfusion reserve by PET in individual patients. This study provides the relation between all anatomic dimensions of coronary artery stenoses and myocardial perfusion reserve in man, and suggests that PET indicates the functional significance of coronary artery stenoses for clinical purposes.

Final results of the Can Routine Ultrasound Influence Stent Expansion (CRUISE) study.

BACKGROUND: Intravascular ultrasound (IVUS) can assess stent geometry more accurately than angiography. Several studies have demonstrated that the degree of stent expansion as measured by IVUS directly correlated to clinical outcome. However, it is unclear if routine ultrasound guidance of stent implantation improves clinical outcome as compared with angiographic guidance alone. METHODS AND RESULTS: The CRUISE (Can Routine Ultrasound Influence Stent Expansion) study, a multicenter study IVUS substudy of the Stent Anti-thrombotic Regimen Study, was designed to assess the impact of IVUS on stent deployment in the high-pressure era. Nine centers were prospectively assigned to stent deployment with the use of ultrasound guidance and 7 centers to angiographic guidance alone with documentary (blinded) IVUS at the conclusion of the procedure. A total of 525 patients were enrolled with completed quantitative coronary angiography, quantitative coronary ultrasound, and clinical events adjudicated at 9 months for 499 patients. The IVUS-guided group had a larger minimal lumen diameter (2.9+/-0.4 versus 2.7+/-0. 5 mm, P<0.001) by quantitative coronary angiography and a larger minimal stent area (7.78+/-1.72 versus 7.06+/-2.13 mm(2), P<0.001) by quantitative coronary ultrasound. Target vessel revascularization, defined as clinically driven repeat interventional or surgical therapy of the index vessel at 9 month-follow-up, occurred significantly less frequently in the IVUS-guided group (8.5% versus 15.3%, P<0.05; relative reduction of 44%). CONCLUSIONS: These data suggest that ultrasound guidance of stent implantation may result in more effective stent expansion compared with angiographic guidance alone.

Regional myocardial function is not affected by severe coronary depressurization provided coronary blood flow is maintained.

It has been suggested that vasodilation distal to a stenosis may cause a profound decrease in perfusion pressure and adversely affect regional left ventricular function. This phenomenon could explain the clinical concept of reversal of regional dysfunction by coronary revascularization. To evaluate the hypothesis that regional myocardial function parallels regional coronary blood pressure in the absence of changes in coronary flow, dogs chronically instrumented with left circumflex coronary artery flow probes, cuff occluders, pressure catheters and segmental function sonomicrometers were studied. By decreasing regional coronary vascular resistance with selective intracoronary dipyridamole and controlling blood flow with a proximal coronary cuff occluder, the mean left circumflex artery pressure was reduced from 83 +/- 3 to 38 +/- 2 mm Hg while circumflex coronary blood flow was maintained constant. Regional contractile function as measured by circumflex sonomicrometers was unchanged at constant circumflex subendocardial blood flow as measured by radioactive microspheres. These findings suggest that regional contractile function is dependent on subendocardial blood flow and is independent of coronary perfusion pressure.

Patterns in visual interpretation of coronary arteriograms as detected by quantitative coronary arteriography.

In part 1 of a three-part study, 14 novice readers and 6 experienced cardiologists interpreted phantom images of known stenosis severity. No difference between the interpretations of experienced and novice readers was detectable. Visual estimates of "moderately" severe stenosis were 30% higher than actual percent diameter stenosis. In part 2 of the study, visual interpretation of percent diameter stenosis from 212 stenoses on 241 arteriograms was compared with quantitative coronary arteriographic assessment. The visual analysis overestimated disease severity in arteries with greater than or equal to 50% diameter stenosis (except for right coronary lesions) and underestimated severity in all arteries with less than 50% diameter stenosis. Of the 241 arteriograms, 40 had quantitative and visual analysis of all three coronary arteries for assessment of significant disease. In only 62% of the cases did visual and quantitative methods agree on the presence of severe disease; visual estimates diagnosed significantly (p less than 0.05) more three-vessel disease. In part 3 of the study, comparison of percent diameter stenosis by visual estimate with quantitative coronary arteriographic assessment before and after balloon angioplasty of 38 stenoses showed that visual interpretation significantly (p less than 0.001) overestimated initial lesion severity and underestimated stenosis severity after angioplasty.

Comparison of early systolic and early diastolic regional function during regional ischemia in a chronically instrumented canine model.

Depressed left ventricular function during the early part (first third) of both systole and diastole in the resting state have been reported to be sensitive indicators of coronary artery disease in patients with normal global function at rest. To evaluate the possible mechanisms of these findings, 11 dogs were chronically instrumented with segmental function sonomicrometers in the left circumflex and left anterior descending coronary artery distribution, circumflex coronary flow probes and cuff occluders, aortic flow probes and ventricular pressure transducers. Percent segmental function during the first third of systole and diastole was measured in the control state and with graded circumflex artery flow reductions. Significant decreases in early systolic function with ischemia in the circumflex artery distribution were partially offset by compensatory augmented shortening in the left anterior descending artery distribution. With ischemia in the circumflex distribution, there was prolonged contraction into diastole manifested as impaired relaxation. Simultaneously, in the left anterior descending artery distribution, there was minimal compensatory enhanced relaxation. These results suggest that early systolic dysfunction in ischemic segments may be offset by enhanced function in nonischemic segments, rendering minimal, if any, change in global systolic function. Early diastolic dysfunction in ischemic segments exceeds compensatory changes in nonischemic areas by two-to-four-fold. Hence, early diastolic functional indexes may be more sensitive indicators of ischemia at rest than early systolic functional indexes.

Reciprocal functional interaction of adjacent myocardial segments during regional ischemia: an intraventricular loading phenomenon affecting apparent regional contractile function in the intact heart.

The mechanism of the increase in function in myocardial segments adjacent to those subjected to regional ischemia is not known. To investigate the hypothesis that changes in regional loading are an important causative factor of this phenomenon, 17 dogs were instrumented with segmental shortening sonomicrometers in the left anterior descending and circumflex artery distributions, circumflex coronary flow probes and cuff occluders, as well as circumflex coronary pressure catheters. Additionally, the animals had aortic pressure catheters and ventricular pressure micromanometers. This animal model allowed modulation of regional inotropic state with regional ischemia or isoproterenol administration. With circumflex coronary bed ischemia, segmental shortening in the circumflex distribution decreased from 11.9 to 6.3% (p = 0.001) whereas left anterior descending regional shortening increased from 11.6 to 13.4% (p less than 0.001). These reciprocal changes occurred in the absence of changes in global afterload or heart rate. Systemic beta-receptor blockade did not change this response, suggesting that it was not reflex- or catecholamine-mediated. Infusing isoproterenol into the circumflex coronary artery resulted in an increase in circumflex regional shortening from 12.5 to 17.4% (p less than 0.02) whereas left anterior descending regional shortening decreased from 13.5 to 8.3% (p less than 0.001), again without change in heart rate or left ventricular or aortic pressure. These data suggest that reciprocal functional interaction between adjacent myocardial segments is a result of changes in regional afterload for the most part, with changes in local preload and timing of ejection also contributing to the observed effect.

Improved infarct-related arterial patency after high dose, weight-adjusted, rapid infusion of tissue-type plasminogen activator in myocardial infarction: results of a multicenter randomized trial of two dosage regimens.

To determine whether a weight-adjusted high dose (2 mg/kg body weight over 3 h) rapid infusion of recombinant tissue-type plasminogen activator (rt-PA) was more efficacious than a weight-adjusted standard dose (1.25 mg/kg over 3 h) in achieving reperfusion in the setting of acute myocardial infarction, 175 patients were entered into a randomized multicenter trial. Eighty-four patients were entered into the high dose group, receiving 1.2 mg/kg (10% given as a bolus injection) over 1 h, followed by 0.8 mg/kg over the next 2 h. Ninety-one patients were given 0.75 mg/kg (10% given as a bolus injection) in 1 h, followed by 0.5 mg/kg administered over the next 2 h. The median dose in the group that received 2 mg/kg dose was 145 mg, compared with 100 mg in the group that received 1.25 mg/kg. The 90 min patency rate in the group that received 2 mg/kg was 84% compared with 70% in the group that received 1.25 mg/kg (p = 0.003). Sixty-four percent of the patients in each group underwent coronary angioplasty at the time of cardiac catheterization. The infarct-related artery patency rate at the end of catheterization was 91% in the group that received 2 mg/kg compared with 83% in the group that received 1.25 mg/kg (p = 0.08). Among patients with a patent infarct-related coronary artery after catheterization, the 6 month mortality rate in the group that received 2 mg/kg was 2.9% compared with 9.8% in the group that received 1.25 mg/kg (p = 0.15). The bleeding complication rate in the two groups was similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Infrapopliteal transcatheter interventions for limb salvage in diabetic patients: importance of aggressive interventional approach and role of transcutaneous oximetry.

OBJECTIVES: This study sought to determine whether infrapopliteal transcatheter interventions can salvage ischemic limbs in diabetic patients referred for below the knee amputation at our institution. BACKGROUND: The value of transcatheter interventions in diabetic crural arteries is controversial. Tissue oxygen partial pressure (TCO2) levels < 40 mm Hg predict poor wound healing. METHODS: Percutaneous interventions were performed in 29 consecutive diabetic patients in need of limb salvage. Technical success was defined as < 20% residual vessel stenosis. Clinical success was defined as the avoidance of amputation and achievement of wound healing. At hospital discharge, patients were treated with Coumadin and aspirin. Ankle-brachial index (ABI) and TCO2 measurements were obtained before and after the intervention. RESULTS: After 12-month follow-up, six patients had presistent wounds, whereas 23 experienced wound healing. Forty of the 50 infrapopliteal arteries successfully dilated were occluded, with a mean (+/-SD) lesion length of 18.0 +/- 3.5 cm. After the procedure, TCO2 improved from 27.82 +/- 9.97 mm Hg (95% confidence interval [CI] 23.95 to 31.69) to 54.5 +/- 14.73 mm Hg (95% CI 48.79 to 60.21, p < 0.0001), whereas the ABI did not (p > 0.2). TCO2 predicted procedural and clinical success (p < 0.0182). CONCLUSIONS: Infrapopliteal transcatheter interventions in diabetic patients may salvage the majority of limbs doomed to amputation. Although TCO2 measurements are valuable in predicting wound healing and success after interventions, ABI measurements are not.

Transvalvular left ventricular assistance in cardiogenic shock secondary to acute myocardial infarction. Evidence for recovery from near fatal myocardial stunning.

OBJECTIVES: The purpose of this study was to test the hypothesis that transvalvular left ventricular assistance would support the circulation in patients with cardiogenic shock secondary to acute myocardial infarction and allow recovery of function in patients with a reversibly damaged (stunned) left ventricle. BACKGROUND: Cardiogenic shock occurs in 7.5% of patients presenting with acute myocardial infarction, resulting in survival of only 20%. Despite the use of aggressive interventional therapy in patients with shock secondary to anterior myocardial infarction, survival remains as low as 33%. METHODS: We studied 11 patients with acute myocardial infarction and cardiogenic shock, as defined by a cardiac index < 2 liters/min per m2, pulmonary capillary wedge pressure > 18 mm Hg and systolic blood pressure < 90 mm Hg during positive inotropic therapy. Patients were 57 +/- 13 years old (mean +/- SD) and had a mean left ventricular ejection fraction of 25 +/- 11%, mean arterial pressure of 69 +/- 13 mm Hg and mean cardiac index of 1.6 +/- 0.4 liters/min per m2 on admission to the study. RESULTS: During the 1st 24 h of left ventricular assistance, pulmonary capillary wedge pressure decreased from 26 +/- 4 to 16 +/- 4 mm Hg (p = 0.01), cardiac index increased from 1.6 +/- 0.4 to 2.4 +/- 0.4 liters/min per m2, and the dopamine hydrochloride dose decreased from 51 +/- 92 to 18 +/- 12 micrograms/kg body weight per min. In survivors, cardiac index improved to 3.2 +/- 0.5 liters/min per m2 (p = 0.01), and left ventricular ejection fraction improved to 34 +/- 5% (p < 0.05). The overall survival in the study group was 4 (36%) of 11 patients (95% confidence interval [CI] 8% to 65%), and 4 (66%) of 6 patients (95% CI 29% to 100%) with a Q wave anterior myocardial infarction survived. CONCLUSIONS: Transvalvular left ventricular support during cardiogenic shock complicating acute myocardial infarction is feasible and results in significant hemodynamic and functional improvement.

Percutaneous and surgical interventions for in-stent restenosis: long-term outcomes and effect of diabetes mellitus.

OBJECTIVE: We examined long-term outcomes of patients with in-stent restenosis (ISR) who underwent different percutaneous interventions at the discretion of individual operators: balloon angioplasty (BA), repeat stent or rotational atherectomy (RA). We also examined long-term outcomes of patients with ISR who underwent coronary artery bypass surgery (CABG). BACKGROUND: In-stent restenosis remains a challenging problem, and its optimal management is still unknown. METHODS: Symptomatic patients (n = 510) with ISR were identified using cardiac catheterization laboratory data. Management for ISR included BA (169 patients), repeat stenting (117 patients), RA (107 patients) or CABG (117 patients). Clinical outcome events of interest included death, myocardial infarction, target vessel revascularization (TVR) and a combined end point of these major adverse cardiovascular events (MACE). Mean follow-up was 19+/-12 months (range = 6 to 61 months). RESULTS: Patients with ISR treated with repeat stent had significantly larger average post-procedure minimal lumen diameter compared with BA or RA (3.3+/-0.4 mm vs. 3.0+/-0.4 vs. 2.9+/-0.5, respectively, p < 0.05). Incidence of TVR and MACE were similar in the BA, stent and RA groups (39%, 40%, 33% for TVR and 43%, 40%, 33% for MACE, p = NS). Patients with diabetes who underwent RA had similar outcomes as patients without diabetes, while patients with diabetes who underwent BA or stent had worse outcomes than patients without diabetes. Patients who underwent CABG for ISR, mainly because of the presence of multivessel disease, had significantly better outcomes than any percutaneous treatment (8% for TVR and 23% for MACE). CONCLUSIONS: In this large cohort of patients with ISR and in the subset of patients without diabetes, long-term outcomes were similar in the BA, repeat stent and RA groups. Tissue debulking with RA yielded better results only in diabetic patients. Bypass surgery for patients with multivessel disease and ISR provided the best outcomes.

Enhanced thrombolysis, reduced coronary reocclusion and limitation of infarct size with liposomal prostaglandin E1 in a canine thrombolysis model.

OBJECTIVES: The purpose of this study was to test the hypothesis that liposomal prostaglandin E1 (TLC C-53) would result in more rapid thrombolysis, less reocclusion and smaller infarct size when administered with heparin and streptokinase in a canine thrombolysis model. BACKGROUND: In experimental animals, prostaglandin E1 has been shown to augment thrombolysis, improve coronary flow and reduce infarct size when infused directly into the left atrium. TLC C-53 is a stable preparation of prostaglandin E1 bound by phospholipid microspheres that produces fewer adverse hemodynamic effects during intravenous use. METHODS: To investigate the effects of TLC C-53 on coronary patency and infarct salvage, we studied 30 conditioned open chest dogs. After coil-induced left anterior descending coronary artery occlusion and 1 h of clot maturation, the dogs were randomly assigned to receive a 10-min intravenous infusion of either TLC C-53 (2 micrograms/kg body weight) or placebo. Both groups then received intravenous heparin and streptokinase. Hemodynamic variables and Doppler coronary flow were monitored, and myocardial blood flow was determined using radioactive microspheres. Infarct size was assessed with triphenyltetrazolium chloride staining. RESULTS: Thrombolysis time was accelerated from 79 +/- 38 to 47 +/- 9 min (mean +/- SD), and coronary patency was greater (100% vs. 50%) with TLC C-53 than with placebo (p < 0.05). Moreover, for arteries that recanalized, coronary Doppler flow and myocardial perfusion were more severely impaired with placebo. Infarct size as a percent of the area at risk was higher (p < 0.05) with placebo (51 +/- 15%) than with TLC C-53 (33 +/- 14%). Neutrophil infiltration into ischemic myocardium determined by myeloperoxidase assay was also significantly greater in the placebo group. CONCLUSIONS: TLC C-53 administered intravenously before thrombolytic therapy resulted in a significant acceleration of thrombolysis time, improvement in coronary patency and blood flow during reperfusion and a reduction in infarct size.

Noninvasive assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilation. VIII. Clinical feasibility of positron cardiac imaging without a cyclotron using generator-produced rubidium-82.

The purpose of this study was to determine the clinical feasibility of diagnosing significant coronary artery disease by positron imaging of myocardial perfusion without a cyclotron, using generator-produced rubidium-82 (82Rb). Fifty patients underwent positron emission tomography of the entire heart using a multislice positron camera and intravenous 82Rb or nitrogen-13 ammonia (13NH3) before and after intravenous dipyridamole combined with handgrip stress. Images were read by two observers blinded as to clinical or arteriographic data. Automated quantitative coronary arteriography was obtained for the arteriographic determination of coronary flow reserve, previously demonstrated to be a single integrated measure of stenosis severity accounting for all its geometric dimensions of length, absolute diameter, percent narrowing and asymmetry by quantitative analysis of cine films. Significant coronary artery disease was defined as an arteriographically determined coronary flow reserve of less than 3.0 based on all stenosis dimensions. Any single geometric measure of stenosis severity alone was an inadequate reference standard for comparison with perfusion images. Sensitivity of identifying patients with coronary artery disease having an arteriographically determined coronary flow reserve of less than 3.0 was 95% by positron imaging with a specificity of 100%. The single case that was missed, studied with 13NH3, had a 43% diameter narrowing of a small ramus intermedius off the left coronary artery with no significant narrowing of the major coronary arteries. Positron emission tomography of myocardial perfusion before and after intravenous dipyridamole combined with handgrip stress utilizing generator-produced 82Rb provides sensitive and specific diagnosis of reduced coronary flow reserve due to coronary artery disease in humans.

Comparison of angioscopy, intravascular ultrasound imaging and quantitative coronary angiography in predicting clinical outcome after coronary intervention in high risk patients.

OBJECTIVES: The purpose of this study was to identify qualitative or quantitative variables present on angioscopy, intravascular ultrasound imaging or quantitative coronary arteriography that were associated with adverse clinical outcome after coronary intervention in high risk patients. BACKGROUND: Patients with acute coronary syndromes and complex lesion morphology on angiography are at increased risk for acute complications after coronary angioplasty. Newer devices that primarily remove atheroma have not improved outcome over that of balloon angioplasty. Intravascular imaging can accurately identify intraluminal and intramural histopathologic features not adequately visualized during coronary arteriography and may provide mechanistic insight into the pathogenesis of abrupt closure and restenosis. METHODS: Sixty high risk patients with unstable coronary syndromes and complex lesions on angiography underwent angioscopy (n = 40) and intravascular ultrasound imaging (n = 46) during interventional procedures. In 26 patients, both angioscopy and intravascular ultrasound were performed in the same lesion. All patients underwent off-line quantitative coronary arteriography. Coronary interventions included balloon (n = 21) and excimer laser (n = 4) angioplasty, directional (n = 19) and rotational (n = 6) atherectomy and stent implantation (n = 11). Patients were followed up for 1 year for objective evidence for recurrent ischemia. RESULTS: Patients whose clinical presentation included rest angina or acute myocardial infarction or who received thrombolytic therapy within 24 h of procedure were significantly more likely to experience recurrent ischemia after intervention. Plaque rupture or thrombus on preprocedure angioscopy or angioscopic thrombus after intervention were also significantly associated with adverse outcome. Qualitative or quantitative variables on angiography, intravascular ultrasound or off-line quantitative arteriography were not associated with recurrent ischemia on univariate analysis. Multivariate predictors of recurrent ischemia were plaque rupture on preprocedure angioscopy (p < 0.05, odds ratio [OR] 10.15) and angioscopic thrombus after intervention (p < 0.05, OR 7.26). CONCLUSIONS: Angioscopic plaque rupture and thrombus were independently associated with adverse outcome in patients with complex lesions after interventional procedures. These features were not identified by either angiography or intravascular ultrasound.

A multicenter, randomized, placebo-controlled trial of a new form of intravenous recombinant tissue-type plasminogen activator (activase) in acute myocardial infarction.

A new, predominantly single chain preparation of recombinant tissue-type plasminogen activator was evaluated to determine coronary thrombolytic efficacy in 100 patients with acute myocardial infarction. At 3.6 +/- 1.2 hours (mean +/- SD) from symptom onset, patients received either intravenous tissue plasminogen activator (1.25 mg/kg body weight over 3 hours) or placebo on a 3:1 randomized, double-blind basis. Coronary angiography, performed 68 +/- 13 minutes after initiation of the study drug infusion, demonstrated patency of the infarct-related artery in 40 (57%) of 70 patients in the tissue plasminogen activator group compared with 3 (13%) of 23 patients in the placebo group (p less than 0.001). Patients in the placebo group were then eligible to receive intracoronary streptokinase. At 90 minutes the patency was observed in 49 (69%) of 71 tissue plasminogen activator patients compared with 5 (24%) of 21 placebo patients (p less than 0.001). At 120 minutes patency was observed in 59 (79%) of 75 patients of the tissue plasminogen activator group and in 10 (40%) of 25 in the intracoronary streptokinase/placebo group. A nadir value of less than 100 mg/dl fibrinogen occurred in 8 (11%) of 73 patients receiving tissue plasminogen activator versus 8 (40%) of 20 patients treated with intracoronary streptokinase (p = 0.002). Moderate or severe bleeding episodes occurred in 39% of patients treated with tissue plasminogen activator compared with 32% of patients who received placebo/intracoronary streptokinase (p = NS). Thus, this tissue plasminogen activator preparation achieves a high rate of recanalization and, at the doses employed, exhibits increased fibrinogen sparing compared with intracoronary streptokinase.

Myocardial metabolism of fluorodeoxyglucose compared to cell membrane integrity for the potassium analogue rubidium-82 for assessing infarct size in man by PET.

Potassium loss from damaged myocardial cells is linearly related to CPK enzyme loss reflecting extent of necrosis. The potassium analog, rubidium-82 (82Rb), is extracted after i.v. injection and retained in viable myocardium but is not trapped or washed out of necrotic regions. To compare myocardial cell metabolism with membrane dysfunction as indicators of necrosis/viability, 43 patients with evolving myocardial infarction and coronary arteriography had positron emission tomography using fluorodeoxyglucose (FDG) and the potassium analog 82Rb. Percent of heart showing FDG defects and 82Rb washout on sequential images indicating failure to retain the potassium analogue were visually assessed and quantified by automated software. Infarct size based on rubidium kinetics correlated closely with size and location on FDG images (visual r = 0.93, automated r = 0.82), suggesting that loss of cell membrane integrity for trapping the potassium analog 82Rb parallels loss of intracellular glucose metabolism, both comparable quantitative markers of myocardial necrosis/viability.

Positron imaging of myocardial infarction with rubidium-82.

Positron imaging provides tomographic images of regional myocardial perfusion but has required an on-site cyclotron. Rubidium-82 (82Rb) is a short-lived (T1/2 = 75 sec) positron emitter available from a generator. In order to determine the feasibility for its use to image acute myocardial infarction, 18 patients with transmural infarctions who had coronary arteriography were given 30-40 mCi of 82Rb intravenously and positron tomographic imaging was carried out within 96 hr after onset of symptoms. Nine simultaneous transaxial slices were obtained for each patient with a positron camera. Images were also reconstructed in a long-axis, short-axis, and three-dimensional display. One study could not be interpreted because of excessive lung activity. Fourteen normals were also studied. The infarct related artery determined by angiography was correctly diagnosed by positron imaging in all 17 patients as were all three prior infarcts by readers blinded to the clinical data. No defects were observed in normals or in noninfarcted myocardial regions. This study indicates that 82Rb should be useful for perfusion imaging in patients with acute myocardial infarction. The short half-life of 82Rb should make it ideal for providing serial assessment of perfusion in patients undergoing thrombolytic therapy.

Changes in myocardial perfusion reserve after PTCA: noninvasive assessment with positron tomography.

The effect of percutaneous transluminal coronary angioplasty (PTCA) on myocardial perfusion reserve has not been previously determined. Accordingly, 11 patients underwent positron imaging with [13N]ammonia or 82Rb at rest and following dipyridamole + handgrip stress before and after PTCA. The ratio of stress to rest activity (S:R) was determined for each region of interest. Relative myocardial perfusion reserve by positron tomography (RMPR) was calculated by dividing S:R of the stenotic area by a corresponding value from a normal reference area of the same patient. Automated quantitative coronary arteriography was used to objectively measure the percent diameter (%D) and the percent area narrowing (%A) of the stenoses. In nine patients with successful PTCA, %D and %A improved (68 +/- 10 to 49 +/- 15% and 92 +/- 3 to 72 +/- 5%) and RMPR increased from 0.79 +/- 0.07 to 0.96 +/- 0.05. In the two patients in whom PTCA was unsuccessful, RMPR was unchanged. Changes in RMPR correlated inversely with changes in %D (r = -0.68) and %A (r = -0.92) and directly with improved coronary flow reserve derived from all stenosis measurements (r = 0.73, p less than 0.001 for each). This study suggests that dipyridamole + handgrip stress imaging with PET can be used to assess changes in myocardial perfusion reserve before and after PTCA with the potential for determining restenosis noninvasively.

Primary stenting for acute myocardial infarction.

Primary stenting for acute MI has been shown to be an improvement over PTCA alone. As with primary PTCA however there is an obligate delay in restoration of TIMI flow due to the time necessary for mobilization of the cath lab team. It is possible that a hybrid approach using partial thrombolysis plus early IIB/IIIA inhibitor administration followed by urgent angiography and stenting of the culprit lesion will be the ideal approach.

Molecular biology of plasminogen activators: what are the clinical implications of drug design?

The initial work on thrombolytic therapy for acute myocardial infarction (AMI) focused on intracoronary administration of streptokinase. Continuing research has given rise to the development of both second- and third-generation agents and consequent refinements in thrombolytic regimens. Intravenous recombinant tissue plasminogen activator (t-PA, or alteplase) proved superior to both intracoronary and intravenous streptokinase with regard to reperfusion efficacy and impact on survival. An accelerated dosage regimen was later devised to allow the administration of t-PA over a shorter period of time. Unfortunately, t-PA failed to lessen the risk of bleeding complications that had plagued the use of streptokinase. The wild-type t-PA molecule has since been modified in an attempt to achieve improved lytic characteristics with less bleeding risk. Among these third-generation agents is reteplase (r-PA); compared with alteplase, reteplase has a prolonged half-life and seems to offer more rapid thrombolysis. Promising results have been obtained in large, randomized trials of reteplase. Another new agent is the TNK mutant of t-PA, which also has a prolonged half-life and seems to produce more rapid and complete thrombolysis, as well as less risk of intracranial bleeding than with alteplase in animal models. Although large, randomized trials have not yet been conducted, encouraging results have emerged from preliminary dose-ranging trials with TNK. A third new agent, n-PA, has an even longer half-life and has shown improved lytic activity in animal models. A dose-ranging trial of n-PA is currently under way. Despite the fact that each of the third-generation drugs has shown considerable potential with regard to improving the efficacy of thrombolytic therapy, the risk of intracranial bleeding remains problematic and will need to be assessed in large, randomized trials.

Patency trials with reteplase (r-PA): what do they tell us?

Thrombolytic therapy has been shown to reduce mortality and morbidity after acute myocardial infarction. Therapeutic benefit seems to be directly correlated with completeness of reperfusion (Thrombolysis in Myocardial Infarction [TIMI] grade 3 flow) of the infarct-related coronary artery, as well as the timeliness of reperfusion. To determine which regimen of reteplase (r-PA), a deletion mutant of wild-type tissue plasminogen activator (t-PA), is most effective for clinical thrombolysis, several reteplase regimens were compared with the most successful standard regimens of recombinant t-PA (alteplase) in 2 large-scale, randomized studies. All patients received aspirin and intravenous heparin. In the Reteplase Angiographic Phase II International Dose Finding Trial (RAPID-1), results in 606 randomized patients showed that a 10 + 10 U double bolus of reteplase was more effective than a 15 U single bolus, a 10 + 5 double bolus, or conventional alteplase (100 mg over 3 hours). In the Reteplase versus Alteplase Patency Investigation During Acute Myocardial Infarction (RAPID-2) trial, results in 324 patients showed that significantly more patients achieved patency of the infarct-related artery (TIMI grade 2 or 3 flow) at 90 minutes with reteplase (10 + 10 U double bolus) than with accelerated alteplase (100 mg over 90 minutes): 83.4% versus 73.3%, respectively (p = 0.03). The incidence of complete patency (TIMI grade 3 flow) at 90 minutes was likewise greater with reteplase than with accelerated alteplase (59.9% vs 45.2%, respectively; p = 0.01). At 60 minutes, the incidence of TIMI grade 2 or 3 flow was also significantly higher with reteplase than with alteplase (81.8% vs 66.1%, respectively; p = 0.01), as was the incidence of TIMI grade 3 flow (51.2% vs 37.4%, respectively; p < 0.031). The 35-day mortality rate was 4.1% for reteplase and 8.4% for alteplase (p = not significant). Reteplase and alteplase did not differ significantly with regard to the occurrence of severe bleeding (12.4% vs 9.7%, respectively) or hemorrhagic stroke (1.2% vs 1.9%, respectively). The results of these trials show that reteplase, given as a 10 + 10 U double bolus, achieves significantly higher rates of early reperfusion of the infarct-related coronary artery and is associated with significantly fewer acute coronary interventions when compared with front-loaded alteplase. The benefits of reteplase are achieved without any apparent increased risk of complications.