Victor A. Umans

A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty

BACKGROUND The likelihood of restenosis is a major limitation of coronary angioplasty. We studied whether hirudin, a highly selective inhibitor of thrombin with irreversible effects, would prevent restenosis after angioplasty. We compared two regimens of recombinant hirudin with heparin. METHODS We randomly assigned 1141 patients with unstable angina who were scheduled for angioplasty to receive one of three treatments: (1) a bolus dose of 10,000 IU of heparin followed by an intravenous infusion of heparin for 24 hours and subcutaneous placebo twice daily for three days (382 patients), (2) a bolus dose of 40 mg of hirudin followed by an intravenous infusion of hirudin for 24 hours and subcutaneous placebo twice daily for three days (381 patients), or (3) the same hirudin regimen except that 40 mg of hirudin was given subcutaneously instead of placebo twice daily for three days (378 patients). The primary end point was event-free survival at seven months. Other end points were early cardiac events (within 96 hours), bleeding and other complications of the study treatment, and angiographic measurements of coronary diameter at six months of follow-up. RESULTS At seven months, event-free survival was 67.3 percent in the group receiving heparin, 63.5 percent in the group receiving intravenous hirudin, and 68.0 percent in the group receiving both intravenous and subcutaneous hirudin (P = 0.61). However, the administration of hirudin was associated with a significant reduction in early cardiac events, which occurred in 11.0, 7.9, and 5.6 percent of patients in the respective groups (combined relative risk with hirudin, 0.61; 95 percent confidence interval, 0.41 to 0.90; P = 0.023). The mean minimal luminal diameters in the respective groups on follow-up angiography at six months were 1.54, 1.47, and 1.56 mm (P = 0.08). CONCLUSIONS Although significantly fewer early cardiac events occurred with hirudin than with heparin, hirudin had no apparent benefit with longer-term follow-up.

Functional recovery after acute myocardial infarction: comparison between angiography, electrocardiography, and cardiovascular magnetic resonance measures of microvascular injury.

OBJECTIVES We examined the relation between angiographic, electrocardiographic, and gadolinium-enhanced cardiovascular magnetic resonance (CMR) characteristics of microvascular obstruction (MVO), and their predictive value on functional recovery after acute myocardial infarction (AMI). BACKGROUND Microvascular obstruction on CMR has been shown to predict left ventricular (LV) remodeling, but it is not well known how it compares with commonly used criteria of microvascular injury, and earlier reports have produced conflicting results on the significance and extent of MVO. METHODS Thrombolysis In Myocardial Infarction (TIMI) flow grade, myocardial blush grade (MBG), and ST-segment resolution were assessed in 60 patients with AMI treated with primary stenting. Cardiovascular magnetic resonance was performed between 2 and 9 days after revascularization to determine early MVO on first-pass perfusion imaging, late MVO on late gadolinium-enhanced imaging, and infarct size and transmural extent. Cine imaging was used to determine LV volumes and global and regional function at baseline and 4-month follow-up. RESULTS Early and late MVO were both related to incomplete ST-segment resolution (p = 0.002 and p = 0.01, respectively), but not to TIMI flow grade and MBG. Of all angiographic, electrocardiographic, and CMR variables, late MVO was the strongest parameter to predict changes in end-diastolic volume (beta = 0.53; p = 0.001), end-systolic volume (beta = 8.67; p = 0.001), and ejection fraction (beta = 3.94; p = 0.006) at follow-up. Regional analysis showed that late MVO had incremental diagnostic value to transmural extent of infarction (odds ratio: 0.18; p < 0.0001). CONCLUSIONS In patients after revascularized AMI, late MVO proved a more powerful predictor of global and regional functional recovery than all of the other characteristics, including transmural extent of infarction.

Impaired glucose metabolism predicts mortality after a myocardial infarction

Diabetes is a risk factor for increased mortality after a myocardial infarction. Whether this applies for patients with hyperglycemia during the acute phase of a acute myocardial infarction is unclear. Therefore we determined the relation between admission plasma glucose level and mortality in a prospectively collected series of 336 consecutive AMI patients. Patients were divided in four groups based on WHO criteria for glucose levels: I: <5.6 mmol/l, II: 5.6--8.3 mmol/l, III: 8.4--11.0 mmol/l, IV: 11.1 mmol/l. The average age was 68+/-11 years with a peak CK of 1378+/-160 U/l, 34% were anterior wall AMIs and 52% were treated with thrombolysis. All patients had a long-term follow-up control at an average of 14.2 months. One year mortality rate was 19.3% and rose to 44% in patients with glucose levels >11.1 mmol/l. The mortality was higher in diabetic patients than in non-diabetic patients (40 vs. 16%; P<0.05). Multivariate analysis revealed an independent effect of glucose level on mortality. In conclusions, our study in an unselected patient population demonstrates that admission plasma glucose level independently predicts 1 year mortality even in absence of diagnosed diabetes mellitus. Further studies evaluating the effect of acute insulin intervention in reducing mortality are warranted.

Quantitative assessment with intracoronary ultrasound of the mechanisms of restenosis after percutaneous transluminal coronary angioplasty and directional coronary atherectomy

The mechanisms of immediate and late changes after percutaneous transluminal coronary angioplasty (PTCA) and directional coronary atherectomy (DCA) were assessed by serial ultrasound imaging in 18 patients treated with PTCA and 16 treated with DCA before, immediately after, and 6 months after coronary interventions. A reduction in plaque area was the main operative mechanism of DCA, explaining 66% of lumen enlargement. In the PTCA group, the increase in lumen area was the result of a more balanced combination of plaque reduction (52% of lumen increase) and increase in total lumen area (48%); p < 0.05 versus DCA. In the PTCA group, this last mechanism was prevalent (p < 0.05) in the lesions showing wall fracture or dissection after treatment and in the lesions with a mixed or calcific composition. In the PTCA group, concentric lesions showed a greater plaque compression than eccentric lesions (p < 0.02). Plaque increase was responsible for 92% and 32% of the late lumen loss after DCA and after PTCA, respectively (p < 0.05). In PTCA patients, a chronic reduction in total vessel area was the main operative mechanism of lumen reduction (67%) and was prevalent in lesions with a mixed or calcific composition. (p < 0.05).

Directional atherectomy for treatment of restenosis within coronary stents: clinical, angiographic and histologic results

OBJECTIVES The safety and long-term results of directional coronary atherectomy in stented coronary arteries were determined. In addition, tissue studies were performed to characterize the development of restenosis. METHODS Directional coronary atherectomy was performed in restenosed stents in nine patients (10 procedures) 82 to 1,179 days after stenting. The tissue was assessed for histologic features of restenosis, smooth muscle cell phenotype, markers of cell proliferation and cell density. A control (no stenting) group consisted of 13 patients treated with directional coronary atherectomy for restenosis 14 to 597 days after coronary angioplasty, directional coronary atherectomy or laser intervention. RESULTS Directional coronary atherectomy procedures within the stent were technically successful with results similar to those of the initial stenting procedure (2.31 +/- 0.38 vs. 2.44 +/- 0.35 mm). Of five patients with angiographic follow-up, three had restenosis requiring reintervention (surgery in two and repeat atherectomy followed by laser angioplasty in one). Intimal hyperplasia was identified in 80% of specimens after stenting and in 77% after coronary angioplasty or atherectomy. In three patients with stenting, 70% to 76% of the intimal cells showed morphologic features of a contractile phenotype by electron microscopy 47 to 185 days after coronary intervention. Evidence of ongoing proliferation (proliferating cell nuclear antigen antibody studies) was absent in all specimens studied. Although wide individual variability was present in the maximal cell density of the intimal hyperplasia, there was a trend toward a reduction in cell density over time. CONCLUSIONS Although atherectomy is feasible for the treatment of restenosis in stented coronary arteries and initial results are excellent, recurrence of restenosis is common. Intimal hyperplasia is a nonspecific response to injury regardless of the device used and accounts for about 80% of cases of restenosis. Smooth muscle cell proliferation and phenotypic modulation toward a contractile phenotype are early events and largely completed by the time of clinical presentation of restenosis. Restenotic lesions may be predominantly cellular, matrix or a combination at a particular time after a coronary procedure.

Proliferation and extracellular matrix synthesis of smooth muscle cells cultured from human coronary atherosclerotic and restenotic lesions

OBJECTIVES The purpose of this study was to examine the proliferative capacity and extracellular matrix synthesis of human coronary plaque cells in vitro. BACKGROUND Common to both primary atherosclerosis and restenosis are vascular smooth muscle cell proliferation and production of extracellular matrix proteins. The applicability to humans of experimental animal models of these processes has been questioned. METHODS Primary atherosclerotic and restenotic lesions were excised by percutaneous directional coronary atherectomy in 93 patients. Smooth muscle cells were cultivated by an explant technique and identified by their morphology in culture, ultrastructural features under electron microscopy and immunostaining using monoclonal antibodies to smooth muscle cell alpha-actin. Proliferation in secondary culture was assessed with growth curves and the synthesis of collagen and sulfated glycosaminoglycans by the incorporation of 3H-proline and 35S-sulfate, respectively. These studies were also performed in cells derived from human umbilical artery media. RESULTS Success rates for primary (45%) and secondary (12%) culture of coronary cells were not influenced by clinical variables or lesion category. Primary culture success was improved by the presence of organized thrombus in the plaque and in relation to increased maximal cell density of the atherectomy specimen. Restenotic cells displayed more rapid growth than did cells of primary atherosclerotic origin, which grew in a manner similar to that of umbilical artery cells. Mean calculated population-doubling times for the three cell groups were 52 h (95% confidence interval [CI] 48 to 58 h), 71 h (95% CI 62 to 83 h) and 74 h (95% CI 65 to 84 h), respectively. Restenotic and primary atherosclerotic cells did not differ in the synthesis of collagen ([mean +/- SEM] 0.034 +/- 0.004 vs. 0.033 +/- 0.004 nmol isotope.microgram protein-1, p = NS) or sulfated glycosaminoglycans (11.47 +/- 1.07 vs. 15.37 +/- 3.10 nmol isotope.microgram protein-1, p = NS), but the coronary cells synthesized significantly more collagen and sulfated glycosaminoglycans than did umbilical artery cells (0.019 +/- 0.004 and 5.43 +/- 1.00 nmol isotope.microgram protein-1, respectively, both p < 0.05). CONCLUSIONS These data indicate that increased smooth muscle cell proliferation contributes to coronary restenosis in humans and support the concept that the extracellular matrix synthesis of adult smooth muscle cells is important to lesion formation.

Prognostic value of predischarge dobutamine stress echocardiography in chest pain patients with a negative cardiac troponin T

OBJECTIVES We prospectively studied the prognostic value of predischarge dobutamine stress echocardiography (DSE) in low-risk chest pain patients with a normal or nondiagnostic electrocardiogram (ECG) and a negative serial troponin T. BACKGROUND Noninvasive stress testing is recommended before discharge or within 72 h in patients with low-risk chest pain. The prognostic value of immediate DSE has not been studied in a blinded, prospective fashion. METHODS Patients presenting at the emergency room within 6 h of symptom onset and a normal or nondiagnostic ECG were eligible. Dobutamine stress echocardiography was performed after unstable coronary artery disease was ruled out by a standard rule-out protocol and a negative serial troponin T; the occurrence of any new wall motion abnormality was considered positive. Results were kept blinded. End points were cardiac death, myocardial infarction, rehospitalization for unstable angina or revascularization. RESULTS In total, 377 patients were included. There were 2 deaths, 2 myocardial infarctions, 8 rehospitalization for unstable angina, and 10 revascularizations at six-month follow-up. The end points occurred in 8/26 (30.8%) patients with a positive versus 14/351 (4.0%) patients with a negative DSE (odds ratio, 10.7; 95% confidence interval, 4.0 to 28.8; p < 0.0001). By multivariate analysis, DSE remained a predictor of end points (p < 0.0001). CONCLUSIONS A predischarge DSE had important, independent prognostic value in low-risk, troponin negative, chest pain patients.

Assessment of Microvascular Obstruction and Prediction of Short-term Remodeling after Acute Myocardial Infarction: Cardiac MR Imaging Study

PURPOSE To evaluate which cardiac magnetic resonance (MR) imaging technique for detection of microvascular obstruction (MVO) best predicts left ventricular (LV) remodeling after acute myocardial infarction (MI). MATERIALS AND METHODS This study had local ethics committee approval; all patients gave written informed consent. Sixty-three patients with first acute MI, treated with primary stent placement and optimal medical therapy, underwent cine MR imaging at 4-7 days and at 4 months after MI. Presence of MVO was qualitatively evaluated at baseline by using three techniques: (a) a single-shot saturation-recovery gradient-echo first-pass perfusion sequence (early hypoenhancement), mean time, 1.09 minutes +/- 0.07 (standard deviation) after contrast material administration; (b) a three-dimensional segmented saturation-recovery gradient-echo sequence (intermediate hypoenhancement), mean time, 2.17 minutes +/- 0.26; and (c) a two-dimensional segmented inversion-recovery gradient-echo late gadolinium enhancement sequence (late hypoenhancement), mean time, 13.32 minutes +/- 1.26. Contrast-to-noise ratios (CNRs) were calculated from the signal-to-noise ratios of the infarcted myocardium and MVO areas. Univariable linear regression analysis was used to identify the predictive value of each MR imaging technique. RESULTS Early hypoenhancement was detected in 44 (70%) of 63 patients; intermediate hypoenhancement, in 39 (62%); and late hypoenhancement, in 37 (59%). Late hypoenhancement was the strongest predictor of change in LV end-diastolic and end-systolic volumes over time (beta = 14.3, r = 0.40, P = .001 and beta = 11.3, r = 0.44, P < .001, respectively), whereas intermediate and late hypoenhancement had comparable predictive values of change in LV ejection fraction (beta = -3.1, r = -0.29, P = .02 and beta = -2.8, r = -0.27, P = .04, respectively). CNR corrected for spatial resolution was significantly superior for late enhancement compared with the other sequences (P < .001). CONCLUSION By using cardiac MR imaging, late hypoenhancement is the best prognostic marker of LV remodeling, with highest CNR between the infarcted myocardium and MVO regions.

Late Gadolinium-Enhanced Cardiovascular Magnetic Resonance Evaluation of Infarct Size and Microvascular Obstruction in Optimally Treated Patients after Acute Myocardial Infarction

PURPOSE Cardiovascular magnetic resonance (CMR) is considered the standard imaging modality in clinical trials to monitor patients after acute myocardial infarction (AMI). However, limited data is available with respect to infarct size, presence, and extent of microvascular injury (MVO), and changes over time, in relation to cardiac function in these optimally treated patients. In this study, we prospectively investigate the change of infarct size over time, and the incidence and significance of MVO in a uniform, optimally treated patient group after AMI. METHODS Forty patients underwent cine and late gadolinium-enhanced CMR within 9 days and at 4 months after primary stenting. Left ventricular ejection fraction (LVEF), infarct size (IS) and MVO size were calculated. RESULTS IS decreased with 19.0% at follow-up (p<0.01). The 23 (57.5%) patients with MVO had larger infarct size, higher left ventricular volumes and lower LVEF and more involution of IS at follow-up. Overall, LVEF improved from 42.3+/-9.8% to 44.0+/-9.8% (p=0.06), irrespective of presence or size of MVO. CONCLUSION Infarct size reduces over time by 19.0% in optimally treated patients after AMI. Despite optimal reperfusion, MVO was found in the majority of patients. Although patients with MVO had larger infarcts and worse indices of left ventricular remodelling, functional change at follow-up was comparable to patients without MVO.

Elevated troponin T and C-reactive protein predict impaired outcome for 4 years in patients with refractory unstable angina, and troponin T predicts benefit of treatment with abciximab in combination with PTCA

AIMS Treatment with the glycoprotein IIb/IIIa receptor antagonist abciximab before and during coronary intervention in refractory unstable angina improves early outcome. We collected 4-year follow-up data to assess whether this benefit is sustained. Additionally, we investigated the predictive value of baseline troponin T and CRP for long-term cardiovascular events. METHODS AND RESULTS Of 1265 patients enrolled in the CAPTURE trial follow-up was available in 94% of the patients alive after 6 months (median 48 months). Survival was similar in both groups. Both elevated troponin T and CRP were associated with impaired outcome, independently of other established risk factors, but with a different time course. Elevated troponin was associated with increased procedure related risk, and elevated CRP with increased risk for subsequent events. Lower rates of the composite end-point of death or myocardial infarction with abciximab vs. placebo were sustained during long-term follow up: 15.7% vs 17.2% at 4 years (P=ns), particularly in patients with elevated troponin T: 16.9% with abciximab vs 28.4% with placebo: P=0.015. Elevated CRP was not associated with specific benefit of abciximab. CONCLUSION Troponin T as a marker of thrombosis and CRP as a marker of inflammation are independent predictors of impaired outcome at 4 years follow-up. The initial benefit from abciximab with regard to death and myocardial infarction was preserved at 4 years. No specific benefit with abciximab was observed for patients with elevated CRP, suggesting that a chronic inflammatory process is not affected by abciximab. In contrast the benefit of treatment in patients with elevated troponin T implies that the acute thrombotic process in refractory unstable angina is treated effectively.