Timothy A. Sanborn

Early revascularization in acute myocardial infarction complicated by cardiogenic shock

BACKGROUND The leading cause of death in patients hospitalized for acute myocardial infarction is cardiogenic shock. We conducted a randomized trial to evaluate early revascularization in patients with cardiogenic shock. METHODS Patients with shock due to left ventricular failure complicating myocardial infarction were randomly assigned to emergency revascularization (152 patients) or initial medical stabilization (150 patients). Revascularization was accomplished by either coronary-artery bypass grafting or angioplasty. Intraaortic balloon counterpulsation was performed in 86 percent of the patients in both groups. The primary end point was mortality from all causes at 30 days. Six-month survival was a secondary end point. RESULTS The mean age of the patients was 66+/-10 years, 32 percent were women and 55 percent were transferred from other hospitals. The median time to the onset of shock was 5.6 hours after infarction, and most infarcts were anterior in location. Ninety-seven percent of the patients assigned to revascularization underwent early coronary angiography, and 87 percent underwent revascularization; only 2.7 percent of the patients assigned to medical therapy crossed over to early revascularization without clinical indication. Overall mortality at 30 days did not differ significantly between the revascularization and medical-therapy groups (46.7 percent and 56.0 percent, respectively; difference, -9.3 percent; 95 percent confidence interval for the difference, -20.5 to 1.9 percent; P=0.11). Six-month mortality was lower in the revascularization group than in the medical-therapy group (50.3 percent vs. 63.1 percent, P=0.027). CONCLUSIONS In patients with cardiogenic shock, emergency revascularization did not significantly reduce overall mortality at 30 days. However, after six months there was a significant survival benefit. Early revascularization should be strongly considered for patients with acute myocardial infarction complicated by cardiogenic shock.

Angiogenesis Gene Therapy Phase I Assessment of Direct Intramyocardial Administration of an Adenovirus Vector Expressing VEGF121 cDNA to Individuals With Clinically Significant Severe Coronary Artery Disease

BACKGROUND Therapeutic angiogenesis, a new experimental strategy for the treatment of vascular insufficiency, uses the administration of mediators known to induce vascular development in embryogenesis to induce neovascularization of ischemic adult tissues. This report summarizes a phase I clinical experience with a gene-therapy strategy that used an E1(-)E3(-) adenovirus (Ad) gene-transfer vector expressing human vascular endothelial growth factor (VEGF) 121 cDNA (Ad(GV)VEGF121.10) to induce therapeutic angiogenesis in the myocardium of individuals with clinically significant coronary artery disease. METHODS AND RESULTS Ad(GV)VEGF121.10 was administered to 21 individuals by direct myocardial injection into an area of reversible ischemia either as an adjunct to conventional coronary artery bypass grafting (group A, n=15) or as sole therapy via a minithoracotomy (group B, n=6). There was no evidence of systemic or cardiac-related adverse events related to vector administration. In both groups, coronary angiography and stress sestamibi scan assessment of wall motion 30 days after therapy suggested improvement in the area of vector administration. All patients reported improvement in angina class after therapy. In group B, in which gene transfer was the only therapy, treadmill exercise assessment suggested improvement in most individuals. CONCLUSIONS The data are consistent with the concept that direct myocardial administration of Ad(GV)VEGF121.10 to individuals with clinically significant coronary artery disease appears to be well tolerated, and initiation of phase II evaluation of this therapy is warranted.

Biologic bypass with the use of adenovirus-mediated gene transfer of the complementary deoxyribonucleic acid for vascular endothelial growth factor 121 improves myocardial perfusion and function in the ischemic porcine heart☆☆☆★

OBJECTIVES Vascular endothelial growth factor (VEGF), a potent angiogenic mediator, can be delivered to targeted tissues by means of a replication-deficient adenovirus (Ad) vector. We hypothesized that direct administration of Ad vector expressing the VEGF121 complementary deoxyribonucleic acid (AdGVVEGF121.10) into regions of ischemic myocardium would enhance collateral vessel formation and improve regional perfusion and function. METHODS Yorkshire swine underwent thoracotomy and placement of an Ameroid constrictor (Research Instruments & MFG, Corvallis, Ore.) on the circumflex coronary artery. Three weeks later, myocardial perfusion and function were assessed by single photon emission computed tomography imaging (SPECT) with 99mTc-labeled sestamibi and by echocardiography during rest and stress. AdGVVEGF121.10 (n = 7) or the control vector, AdNull (n = 8), was administered directly into the myocardium at 10 sites in the circumflex distribution (10(8) pfu/site). Four weeks later, these studies were repeated and ex vivo angiography was performed. RESULTS SPECT imaging 4 weeks after vector administration demonstrated significant reduction in the ischemic area at stress in AdGVVEFG121.10-treated animals compared with AdNull control animals (p = 0.005). Stress echocardiography at the same time demonstrated improved segmental wall thickening in AdGVVEGF121.10 animals compared with AdNull control animals (p = 0.03), with AdGVVEGF121.10 animals showing nearly normalized function in the circumflex distribution. Collateral vessel development assessed by angiography was also significantly greater in AdGVVEGF121.10 animals than in AdNull control animals (p = 0.04), with almost complete reconstitution of circumflex filling in AdGVVEGF121.10 animals. CONCLUSIONS An Ad vector expressing the VEGF121 cDNA induces collateral vessel development in ischemic myocardium and results in significant improvement in both myocardial perfusion and function. Such a strategy may be useful in patients with ischemic heart disease in whom complete revascularization is not possible.

Impact of thrombolysis, intra-aortic balloon pump counterpulsation, and their combination in cardiogenic shock complicating acute myocardial infarction : A report from the shock trial Registry

OBJECTIVES We sought to investigate the potential benefit of thrombolytic therapy (TT) and intra-aortic balloon pump counterpulsation (IABP) on in-hospital mortality rates of patients enrolled in a prospective, multi-center Registry of acute myocardial infarction (MI) complicated by cardiogenic shock (CS). BACKGROUND Retrospective studies suggest that patients suffering from CS due to MI have lower in-hospital mortality rates when IABP support is added to TT. This hypothesis has not heretofore been examined prospectively in a study devoted to CS. METHODS Of 1,190 patients enrolled at 36 participating centers, 884 patients had CS due to predominant left ventricular (LV) failure. Excluding 26 patients with IABP placed prior to shock onset and 2 patients with incomplete data, 856 patients were evaluated regarding TT and IABP utilization. Treatments, selected by local physicians, fell into four categories: no TT, no IABP (33%; n = 285); IABP only (33%; n = 279); TT only (15%; n = 132); and TT and IABP (19%; n = 160). RESULTS Patients in CS treated with TT had a lower in-hospital mortality than those who did not receive TT (54% vs. 64%, p = 0.005), and those selected for IABP had a lower in-hospital mortality than those who did not receive IABP (50% vs. 72%, p < 0.0001). Furthermore, there was a significant difference in in-hospital mortality among the four treatment groups: TT + IABP (47%), IABP only (52%), TT only (63%), no TT, no IABP (77%) (p < 0.0001). Patients receiving early IABP (< or = 6 h after thrombolytic therapy, n = 72) had in-hospital mortality similar to those with late IABP (53% vs. 41%, n = 64, respectively, p = 0.172). Revascularization rates differed among the four groups: no TT, no IABP (18%); IABP only (70%); TT only (20%); TT and IABP (68%, p < 0.0001); this influenced in-hospital mortality significantly (39% with revascularization vs. 78% without revascularization, p < 0.0001). CONCLUSIONS Treatment of patients in cardiogenic shock due to predominant LV failure with TT, IABP and revascularization by PTCA/CABG was associated with lower in-hospital mortality rates than standard medical therapy in this Registry. For hospitals without revascularization capability, a strategy of early TT and IABP followed by immediate transfer for PTCA or CABG may be appropriate. However, selection bias is evident and further investigation is required.

Platelet accumulation in experimental angioplasty: time course and relation to vascular injury.

Since platelet accumulation may be an important determinant of restenosis after angioplasty, the time course of 51Cr-labeled platelet accumulation after experimental angioplasty was evaluated in a deendothelialized, hypercholesterolemic rabbit preparation of atherosclerosis. Marked platelet accumulation (39.5 +/- 8.7 X 10(6) platelets/1 cm vessel length) was observed at 30 min and remained active until 4 hr after angioplasty. Total accumulation over 24 hr was 56.4 +/- 4.7 X 10(6) platelets/1 cm length. Histologic dissection was directly related to the degree of platelet accumulation, with 64 +/- 15 X 10(6) platelets/1 cm in the group with marked dissection and 8.7 +/- 3.7 X 10(6) platelets/1 cm in the group with minimal dissection (p less than .05). Increasing angiographic dissection also resulted in a trend toward increased platelet accumulation, and angiographic change in luminal diameter showed a significant correlation with platelet accumulation. It is concluded that marked platelet accumulation occurs early after transluminal angioplasty and is related to the extent of dissection. Restenosis may result from a complex interaction of platelet accumulation, vascular damage, and blood flow.

A multicenter randomized trial comparing a percutaneous collagen hemotasis device with conventional manual compression after diagnostic angiography and angioplasty

OBJECTIVES A new percutaneous collagen hemostasis device was compared with conventional compression techniques after diagnostic catheterization and angioplasty. BACKGROUND Peripheral vascular complications after diagnostic catheterization or more complex interventional procedures, as well as the discomfort of manual compression and prolonged bed rest, represent significant morbidity for invasive cardiac procedures. METHODS A prospective, multicenter, randomized trial was designed to compare the hemostasis time in minutes and the incidence of vascular complications in patients receiving a vascular hemostasis device with those undergoing conventional compression techniques. RESULTS After diagnostic catheterization, hemostasis time was significantly less with the vascular hemostasis device than with conventional manual compression (4.1 +/- 2.8 min [n = 90 patients] vs. 17.6 +/- 9.2 min [n = 75], p < 0.0001). This difference was greater in patients undergoing angioplasty and was unrelated to the anticoagulation status (4.3 +/- 3.7 min [n = 71 not receiving heparin], 7.6 +/- 11.6 min [n = 85 receiving heparin], 33.6 +/- 24.2 min [n = 134 control patients not receiving heparin], p < 0.0001 vs. control patients). The time from the start of the procedure to ambulation was slightly less after diagnostic catheterization in patients treated with the device (13.3 +/- 12.1 h vs. 19.2 +/- 17.8 h, p < 0.05). It was also less in patients who underwent angioplasty when the device was used after discontinuation of anticoagulation (23.0 +/- 11.1 h, without heparin), as compared with control compression techniques (32.7 +/- 18.8 h, p < 0.0001). Time to ambulation was even shorter (16.1 +/- 11.1 h, p < 0.0001) in patients in whom the device was placed immediately after angioplasty while they were still fully anticoagulated with a prolonged activated clotting time (336 +/- 85 s). There were no major complications (surgery or transfusion) after diagnostic catheterization and a low incidence of major complications in patients who underwent angioplasty (0.7% in control patients, 1.4% with the device without heparin, 1.2% with the device and heparin, p = NS). After angioplasty, there was a trend toward fewer hematomas when the device was used in the absence of heparin (4.2% vs. 9.7% in control patients, p = 0.14). CONCLUSIONS A new vascular hemostasis device can significantly reduce the puncture site hemostasis time and the time to ambulation without significantly increasing the risk of peripheral vascular complications. The role of this technology in reducing complications, length of hospital stay and cost remains to be determined.

PERCUTANEOUS LASER THERMAL ANGIOPLASTY: INITIAL CLINICAL RESULTS WITH A LASER PROBE IN TOTAL PERIPHERAL ARTERY OCCLUSIONS

A metal-tipped laser fibre was used during percutaneous angioplasty of femoral/popliteal or iliac artery occlusions in 56 patients. Primary success was achieved in 50 (89%) of these total occlusions, providing a channel for subsequent balloon dilatation. Before the procedure, 18 lesions had been judged untreatable by conventional angioplasty and four of the six failures were in these. Complications directly attributable to the laser probe were one case of vessel perforation and two cases of entry into vessel walls; these had no sequelae. Other acute complications were a distal thrombosis in a non-heparinised patient, requiring local streptokinase treatment, and two reocclusions and one transient peripheral embolic episode in the first 24 hours. The laser probe technique has potential for increasing the proportion of patients suitable for angioplasty.

Percutaneous coronary intervention for cardiogenic shock in the SHOCK trial

OBJECTIVES We examined the clinical, angiographic, and procedural characteristics determining survival after percutaneous coronary intervention (PCI) for cardiogenic shock. BACKGROUND The SHOCK (SHould we emergently revascularize Occluded coronaries for Cardiogenic shocK?) trial prospectively enrolled patients with shock complicating acute myocardial infarction (MI). Patients were randomized to a strategy of early revascularization or initial medical stabilization. METHODS Patients randomized to early revascularization underwent PCI or bypass surgery on the basis of predefined clinical criteria. Patients randomized to early revascularization who underwent PCI and had angiographic films available for analysis are the subject of this report (n = 82). RESULTS The median time from MI to PCI was 11 h. The majority of patients had occluded culprit arteries (Thrombolysis In Myocardial Infarction [TIMI] grade 0 or 1 flow in 62%) and multivessel disease (81%). One-year mortality in PCI patients was 50%. Mortality was 39% if PCI was successful but 85% if unsuccessful (p < 0.001). Mortality was 38% if TIMI flow grade 3 was achieved, 55% with TIMI grade 2 flow, and 100% with TIMI grade 0 or 1 flow (p < 0.001). Mortality was 67% if severe mitral regurgitation was documented. Independent correlates of mortality were as follows: increasing age (p < 0.001), lower systolic blood pressure (p = 0.009), increasing time from randomization to PCI (p = 0.019), lower post-PCI TIMI flow (0/1 vs. 2/3) (p < 0.001), and multivessel PCI (p = 0.040). CONCLUSIONS Restoration of coronary blood flow is a major predictor of survival in cardiogenic shock. Benefit appears to extend beyond the generally accepted 12-h post-infarction window. Surgery should be considered in shock patients with severe mitral insufficiency or multivessel disease not amenable to relatively complete percutaneous revascularization.

Comparison of Percutaneous Coronary Intervention and Coronary Artery Bypass Grafting After Acute Myocardial Infarction Complicated by Cardiogenic Shock Results From the Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) Trial

Background—The Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) trial demonstrated the survival advantage of emergency revascularization versus initial medical stabilization in patients developing cardiogenic shock after acute myocardial infarction. The relative merits of coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) in patients with shock have not been defined. The objective of this analysis was to compare the effects of PCI and CABG on 30-day and 1-year survival in the SHOCK trial. Methods and Results—Of the 302 trial patients, 128 with predominant left ventricular failure had emergency revascularization. The selection of revascularization procedures was individualized. Eighty-one patients (63.3%) had PCI, and 47 (36.7%) had CABG. The median time from randomization to intervention was 0.9 hours (interquartile range [IQR], 0.3 to 2.2 hours) for PCI and 2.7 hours (IQR, 1.3 to 5.5 hours) for CABG. Baseline demographics and hemodynamics were similar, except that there were more diabetics (48.9% versus 26.9%; P=0.02), 3-vessel disease (80.4% versus 60.3%; P=0.03), and left main coronary disease (41.3% versus 13.0%; P=0.001) in the CABG group. In the PCI group, 12.3% had 2-vessel and 2.5% had 3-vessel interventions. In the CABG group, 84.8% received ≥2 grafts, 52.2% received ≥3 grafts, and 87.2% were deemed completely revascularized. The survival rates were 55.6% in the PCI group compared with 57.4% in the CABG group at 30 days (P=0.86) and 51.9% compared with 46.8%, respectively, at 1 year (P=0.71). Conclusions—Among SHOCK trial patients randomized to emergency revascularization, those treated with CABG had a greater prevalence of diabetes and worse coronary disease than those treated with PCI. However, survival rates were similar. Emergency CABG is an important component of an optimal treatment strategy in patients with cardiogenic shock, and should be considered a complementary treatment option in patients with extensive coronary disease.

Restenosis following transluminal angioplasty in experimental atherosclerosis.

Percutaneous transluminal angioplasty has received considerable attention in the treatment of obstructive atherosclerotic lesions in humans. However, restenosis frequently occurs and has limited the long-term effectiveness of this procedure. To study restenosis, a model of atherosclerosis was developed in 16 New Zealand rabbits. Atherosclerosis was induced in one or both iliac vessels by balloon deendothelialization followed by a 2% cholesterol diet for 6 weeks. Angiographic lesions were demonstrable in all animals. Fourteen iliac vessels served as controls, and nine underwent successful angioplasty with an increase in luminal diameter from 1.0 +/- 0.2 to 1.9 +/- 0.4 mm (p less than 0.01). After 4 weeks on a high cholesterol diet, all animals had another angiogram, which documented significant progression of disease in only six of 14 control iliac vessels, but in all nine dilated vessels. The average decrease in luminal diameter was 0.2 +/- 0.3 mm for the control group compared with 1.6 +/- 0.5 mm for the dilated group (p less than 0.01). Histopathological correlates revealed further remodeling of at various stages of organization and recanalization. In summary, this study demonstrates that restenosis occurs following transluminal angioplasty and is significantly more frequent than the natural progression of disease in a rabbit model of atherosclerosis. The mechanism of this restenosis appears to be related to intraluminal thrombosis and acceleration of atherosclerosis. Evaluation of antiplatelet drugs in the prevention of restenosis seems warranted.