Long term effects of nisoldipine on the progression of coronary atherosclerosis and the occurrence of clinical events: the NICOLE study.

BACKGROUND: Earlier angiographic studies have suggested that calcium antagonists may prevent the formation of new coronary lesions and the progression of minimal lesions. Conversely, a meta-analysis suggested that these drugs may increase cardiovascular mortality and morbidity in patients with coronary heart disease. OBJECTIVE: To investigate whether nisoldipine retards the progression of coronary atherosclerosis or reduces the occurrence of clinical events. DESIGN AND SETTING: The NICOLE study (NIsoldipine in COronary artery disease in LEuven) is a single centre, randomised, double blind, placebo controlled trial with coronary angiography at baseline, six months, and three years of follow up. PATIENTS: 826 patients who had undergone successful coronary angioplasty were randomised to nisoldipine 40 mg once daily or placebo. The intention to treat and per protocol population consisted of 819 and 578 patients, respectively. RESULTS: In the per protocol population, 625 of the nisoldipine treated and 655 of the placebo treated patients (NS) showed angiographic progression in at least one coronary arterial segment, defined as an increase in diameter stenosis of > or = 13%. The average minimum luminal diameter of the non-dilated lesions decreased by 0.163 mm and 0.167 mm in the nisoldipine and placebo groups, respectively (NS). The respective numbers of new lesions detected were 7 and 13 (NS). In the intention to treat population, the rates of death, stroke, and acute myocardial infarction were similar in both treatment groups. However, nisoldipine use was associated with fewer revascularisation procedures and thus the percentage of patients with any clinical event was lower (44.6% v 52.6%, p = 0.02). CONCLUSIONS: Nisoldipine has no demonstrable effect on the angiographic progression of coronary atherosclerosis or the risk of major cardiovascular events but its use is associated with fewer revascularisation procedures.

Optimal dosing of intravascular low-power red laser light as an adjunct to coronary stent implantation: insights from a porcine coronary stent model.

BACKGROUND: It is believed that restenosis following coronary interventions is the result of endothelial denudation that leads to thrombus formation, vascular remodeling, and smooth muscle cell proliferation. Low-power red laser light (LPRLL) irradiation enhances endothelial cell growth in vitro and in vivo, and reduces restenosis in animal models. The present study investigated the optimal dose of intravascular LPRLL therapy in the prevention of in-stent stenosis in a porcine coronary stent model. METHODS AND RESULTS: Selected right coronary artery segments were pretreated with a LPRLL balloon, delivering a dose of 0 mW during 1 min (group 1, n = 10), 50 mW during 1 min (group II, n = 10), or 100 mW during 1 min (group III, n = 10) before stenting. Quantitative coronary analysis of the stented vessel was performed before stenting, immediately after stenting, and at 6 weeks follow-up. The pigs were sacrificed, and histologic and morphometric analyses were conducted. At 6 weeks, minimal luminal stent diameter was significantly narrower in the control group compared to the 50-mW dose group (p < 0.05). These results were confirmed by morphometric analysis. Neointimal area was also significantly decreased in the 50-mW dose group. CONCLUSIONS: Intravascular LPRLL contributes to reduction of angiographic in-stent restenosis and neointimal hyperplasia in this animal model. The optimal dose using the LPRLL balloon system seems to be approximately 5 mW delivered during 1 min.

Intravascular low-power laser irradiation after coronary stenting: long-term follow-up.

BACKGROUND AND OBJECTIVE: A high restenosis rate remains a limiting factor for percutaneous transluminal coronary angioplasty and stenting. The objective of this study was to evaluate the effect of intravascular red laser therapy (IRLT) on restenosis after stenting procedures in de novo lesions. STUDY DESIGN/MATERIALS AND METHODS: A total of 68 consecutive patients were treated with IRLT in conjunction with coronary stenting procedures. Mean lesion length was 16.5 +/- 2.4 mm. Reference vessel diameter (RVD) and pre-minimal lumen diameter (MLD) were 2.90 +/- 0.15 mm and 1.12 +/- 0.26 mm, respectively. RESULTS: After treatment, MLD was 2.76 +/- 0.32 mm with no procedural complications or in-hospital adverse events. Angiographic follow-up (n = 61) revealed restenosis in nine patients (14.7%) with rate by artery size of > 3 mm (n = 21) 0%; 2.5--3.0 mm (n = 28) 14.2%; and < 2.5 mm (n = 12) 41.6%. CONCLUSION: Intravascular red light therapy is safe, feasible, and reduces expected restenosis rate after coronary stenting.

Usefulness of Nisoldipine for prevention of restenosis after percutaneous transluminal coronary angioplasty (results of the NICOLE study). NIsoldipine in COronary artery disease in LEuven.

The NIsoldipine in COronary artery disease in LEuven (NICOLE) study investigates (1) whether nisoldipine, a dihydropyridine calcium antagonist, reduces the progression of minor coronary arterial lesions in the long term, and (2) whether it reduces the restenosis rate after successful percutaneous transluminal coronary angioplasty (PTCA). The NICOLE study is a single-center, randomized, double-blind trial in 826 patients, who underwent a successful PTCA. Nisoldipine 40 mg coat-core or placebo was started the morning after the procedure and continued for 3 years. All coronary arterial segments were measured on preprocedural angiogram and on the second follow-up angiogram at 3 years. On the first follow-up angiogram at 6 months only the dilated segments were measured. Although the study is still ongoing until the primary end point is reached, we report in this study the angiographic restenosis data as well as the clinical events observed at 6-month follow-up. The per-protocol population consisted of 646 patients. Restenosis, defined as a > or =50% loss of the initial gain (National Heart, Lung, and Blood Institute criterion IV) occurred in 49% and 55% of the 308 nisoldipine-treated and the 338 placebo-treated patients, respectively (p = NS). At follow-up, the rates of death and myocardial infarction were low and similar in both groups, but in the nisoldipine group, less patients required early coronary angiography (18% vs 26%, p = 0.006) and subsequent revascularization procedures (32% vs 41%, p = 0.057). Thus, nisoldipine did not significantly reduce the angiographic restenosis rate after PTCA, but reduced the number of repeat revascularization procedures, which may be due to its antianginal action.

Intravascular low-power red laser light as an adjunct to coronary stent implantation: initial clinical experience.

Low-power red laser light (LPRLL) irradiation enhances endothelial cell growth in vitro and in vivo and reduces restenosis in animal models. The present study reports the preliminary clinical experience in our center. Eighty-one patients were treated with LPRLL, 30 mW/1 min, for in-stent restenosis (n = 27), elective stenting for recurrent restenosis (n = 16), and stenting for treatment of a suboptimal PTCA result (n = 38). All interventions were successful and no major adverse events due to LPRLL therapy were observed. At follow-up, 12 patients (14.8%) underwent an early control coronarogram due to target vessel restenosis. At 6 months, another 20 patients showed a significant restenosis of the target vessel. Preliminary clinical evaluation demonstrates that LPRLL is feasible and safe. The preliminary results suggest that LPRLL results in a decrease of in-stent restenosis when used during primary stenting.

Treatment of long dissections by use of a single long or multiple short stents: clinical and angiographic follow-up.

BACKGROUND: Recently, long (> or =20 mm) coronary stents were introduced for clinical use. They are intended as an alternative to multiple conventional stents to treat extensive dissections or suboptimal results of long lesions after balloon angioplasty. METHODS: In a total of 113 such consecutive vessels in 107 patients, the flexible Freedom stent was implanted. In 60 of these vessels, because of anatomic constraints, multiple overlapping short (16 mm) stents were implanted. The other 53 vessels were treated with a single long (> or =20 mm) stent. RESULTS: In the single stent group there were four implantation failures (8%) successfully managed by crossover to multiple overlapping short stents. During early follow-up, in-stent thrombosis was not observed, but three patients with a single long stent and two patients with multiple overlapping stents suffered myocardial infarction as a result of long lasting myocardial ischemia during a difficult angioplasty procedure. At 6-month follow-up, > or =50% restenosis was measured in 29% and 35% of the patients with a single long stent and in those with multiple overlapping stents, respectively (not significant). CONCLUSIONS: Compared with the alternative treatment modality (i.e., implantation of multiple short stents), no difference between in-hospital and 6-month outcome was observed. However, implantation of a single long stent, when technically feasible, reduces catheterization time, dye volume for the patient, and radiation exposure for both patient and operator during these embarrassing angioplasty procedures.

Clinical and angiographic outcome after implantation of a home-made stent for complicated coronary angioplasty.

To defray the escalating costs of coronary stenting, we handmade a balloon-expandable, stainless steel stent, which after experimental evaluation, was implanted in 156 patients undergoing PTCA complicated by a major dissection. The procedural success rate was 98%. The in-hospital course was characterized by a 1.3% cardiopulmonary mortality and a 4.5% nonfatal myocardial infarction rate, while emergency bypass surgery and early repeat PTCA were necessary in only one patient each (0.6%). Clinical 6-mo follow-up in 150 patients revealed no deaths and no myocardial infarctions, and the event-free survival rate was 82%. Six-month control angiography was performed in 93.3% of eligible patients and revealed a restenosis rate of 20%.

Comparison of clinical complications, angiographic results, and device usage of coronary angioplasty using low- and high-compliance balloons.

We randomized 800 patients in a prospective study comparing the angiographic results, device usage and in-hospital outcome of balloon angioplasty of primary stenoses of native coronary vessels with low-compliant and highly compliant balloons. The cumulative incidence of prespecified clinical endpoints was 8.0% in both treatment groups. The primary angiographic success rates were 83.9% and 78.9% in the high- and low-compliance group, respectively (P = 0.05). For the lesions dilated with one study balloon only, the quantitative angiographic findings were virtually identical in the two treatment groups. The total number of dissections was slightly but not significantly higher in the lesions treated with a highly compliant balloon. The global usage of angioplasty balloons was similar in both treatment groups. We conclude that, in general, there is no objective reason to prefer one balloon material to another on the basis of its compliance characteristics.

Concept of the homemade coronary stent: experimental results and initial clinical experience.

To defray the escalating cost of coronary stenting, we handmade a balloon expandable coil stent with stainless steel wire. Preliminary comparison with the Palmaz-Schatz stent showed that, when implanted in porcine iliac arteries, there was no difference in immediate angiographic results or in the degree of foreign body reaction at 6 wk. Subsequently, a total of 73 stents were implanted in 52 patients, either as a bailout device (54%) or for suboptimal angiographic results (46%). All but two implantations were successful. The postprocedural regimen consisted of heparin 1,000 IU/hr, aspirin 250 mg daily, and ticlopidine 500 mg daily. In-hospital complications were limited to two groin hematomas, one necessitating blood transfusion. Importantly, stent thrombosis was not observed. While 6-mo follow-up is pending, we already conclude that a balloon expandable coil stent can be handmade easily at low cost and implanted safely in patients.

Biocompatibility of biodegradable and nonbiodegradable polymer-coated stents implanted in porcine peripheral arteries.

PURPOSE: To investigate the neointimal response to poly(organo)phosphazene- and amphiphilic polyurethane-coated, oversized, stainless steel stents implanted in porcine peripheral arteries. METHODS: Nonarticulated, stainless steel, slotted-tube stents were coated with 1) a biodegradable poly-(organo)phosphazene with aminoacid ester side groups and 2) a biostable polyurethane prepared from an amphiphilic polyether, diphenyl methane-4,4'-diisocyanate and butane diol as chain extender. The stents were deployed in porcine peripheral arteries using an oversized balloon. RESULTS: The neonintimal response to amphiphilic polyurethane-coated stents was similar to the uncoated metallic stents. Poly(organo)phosphazene-coated stents, however, induced a severe histiolymphocytic and fibromuscular reaction resembling a foreign body reaction. CONCLUSIONS: Amphiphilic polyurethane is very promising as a biocompatible stent coating. Poly-(organo)phosphazene, however, appears unsuitable for this purpose.

Characteristics of creatine release during acute myocardial infarction, unstable angina, and cardiac surgery.

Creatine release was compared in various conditions of muscle damage: acute myocardial infarction (AMI), unstable angina, and cardiac surgery. After AMI, serum and urine creatine concentrations increased transiently. After cardiopulmonary resuscitation, serum creatine values were significantly higher because of impaired renal function, whereas urinary creatine concentrations were comparable. In 38 patients with unstable angina, no significant changes in serum and urine creatine concentrations were seen. In 37 of 92 AMI patients, secondary creatine peaks were observed 20.9 +/- 8.1 h after onset of symptoms. The magnitudes of the first and second peaks were correlated: Spearman r = 0.66. In 24 patients who underwent cardiac surgery, the changes in creatine concentration in serum during surgery were very small, despite the presence of muscle trauma.

Biocompatibility of polymer-coated oversized metallic stents implanted in normal porcine coronary arteries.

Polymer coatings have been suggested to decrease the thrombogenicity of metallic intravascular stents. The purpose of the present study was to investigate the intimal response to two different polymers when used as coatings for stents implanted in normal porcine coronary arteries. Non-articulated stainless steel-slotted tube stents were coated with either a biodegradable poly(organo)phosphazene with amino-acid ester side groups or a biostable polyurethane prepared from an amphiphilic polyether, dephenylmethane-4,4'-diisocyanate and butane diol as chain extender. In order to induce vascular wall injury, the stents were deployed using an oversized balloon. At 6 weeks follow-up, the angiographic luminal diameter measured in four polyurethane-coated stents and in six bare metallic stents was similar and 20% less than immediately post-stenting. However, in four polyphosphazene-coated stents the difference was 65% (P = 0.01 when compared to bare metal). At post-mortem morphometry the degree of luminal area stenosis was also similar in polyurethane-coated and in bare metallic stents (32 +/- 7.6% vs. 39 +/- 14%, NS) but reached 81 +/- 19% in polyphosphazene-coated stents (P < 0.03 when compared to bare metal). Thus, poly(organo)phosphazene induced a more pronounced histiolymphocytic and fibromuscular reaction than amphiphilic polyurethane, which appeared to be promising as biocompatible stent coating and, consequently, as a potential carrier for vasoactive drugs.

Intraarterial biocompatibility of polyethylene terephthalate self-expandable stents implanted in porcine peripheral arteries.

RATIONALE AND OBJECTIVES: We tested deployment feasibility and intraarterial biocompatibility of polyethylene terephthalate (PET) self-expandable vascular stents in a porcine peripheral artery model. METHODS: To assess the thrombogenicity and neointimal response to oversized PET self-expandable stents, we implanted 10 stents in porcine common iliac arteries, followed by a 6-mm balloon inflation to 6 atm. RESULTS: All pigs survived until the study termination 6 weeks after stent implantation. Control angiography revealed stent closure in three pigs. Minimal stent luminal diameter (MSLD) was measured using a semiautomated edge detection algorithm. The difference in MSLD after stent implantation and at control after 6 weeks was not significant (4.9 +/- 0.5 mm-->4.7 +/- 1.0 mm). Histopathologic examination showed signs of thrombotic occlusion and revascularization in occluded stents. In patient stents only a mild fibromuscular neointimal response was seen. CONCLUSION: PET self-expandable stents implanted in porcine iliac arteries are possibly thrombogenic but do not lead to a significant neointimal response.

The 'Ermenonville' classification of observations at coronary angioscopy--evaluation of intra- and inter-observer agreement. European Working Group on Coronary Angioscopy.

A European coronary angioscopy working group has been established to create and evaluate a classification system for angioscopic observation. The 'Ermenonville' classification features items, graded in 3-5 categories, such as lumen diameter, shape of narrowing, colours of surface, atheroma, dissection, thrombus, etc. Inter- and intra-observer agreement on the interpretation of angioscopic images, using this classification system, was studied within the working group. Kappa values for chance-corrected intra-observer agreement of the diagnostic items were 0.51-0.67. The mean kappa values for inter-observer agreement were very low at 0.13-0.29. The important items, such as red thrombus and dissection were studied after recoding as either present or absent. These items proved to have a good intra-observer agreement, and an acceptable inter-observer agreement after recoding. Other angioscopic diagnoses should be made with caution. Multicentre angioscopy studies should make use of an angioscopy core laboratory. A set of definitions for coronary angioscopy is proposed, and this working group will re-evaluate observer agreements using these definitions.

Immediate and 6-month follow-up results of coronary angioplasty for restenosis: analysis of factors predicting recurrent clinical restenosis.

To determine the results of coronary angioplasty for a first restenosis, the clinical, anatomic, and procedural data of 400 consecutive patients were compared with the data of 507 consecutive patients undergoing a first angioplasty. After angioplasty for restenosis, emergency redilatation had to be performed in only 0.7% of the patients versus 3.1% of the control group (p = 0.02); nevertheless, the major in-hospital event (death, myocardial infarction, emergency coronary surgery, cerebrovascular accident) rate for patients was only slightly lower (3.3% vs 4.2%, p = NS). During the 6-month follow-up period, there were no cardiac deaths and only two myocardial infarctions in the study group, but recurrent ischemia was more frequent (37% vs 31%, p = 0.05) and resulted in considerably more elective coronary surgery (16% vs 2.6%, p = 0.001). In the study group, stepwise discriminant analysis revealed four variables significantly related to the occurrence of a second restenosis: time interval between first and second angioplasty, male gender, severity of angina, and complexity of the restenotic lesions. However, their individual predictive power was low. In conclusion, compared with angioplasty for primary lesions, angioplasty for restenosis was associated with fewer periprocedural complications and, after a 6-month follow-up, serious cardiac events were almost nonexistent but recurrent ischemia was more frequent.

Cardiac ATP breakdown and mechanical function during recurrent periods of anoxia.

The effect of repeated short anoxic or ischemic periods on ATP breakdown and cardiac function remains controversial. To analyze this issue further and to study the regulation of adenine nucleotide breakdown during recurrent cardiac anoxia, we compared two different protocols of intermittent anoxia. Four rat hearts, perfused according to Langendorff, were exposed to 12 periods of anoxia, each lasting 1 minute, with reoxygenation periods of 3 minutes (protocol A). A second group of 8 hearts were made anoxic for 6 periods of anoxia, each lasting 1 minute, followed by 6 periods of anoxia, each lasting 2 minutes, with the same reoxygenation periods (protocol B). Adenosine production was studied with high performance liquid chromatography, ventricular contraction was monitored using a force transducer. During anoxia a substantial vasodilation and immediate fall in strength of ventricular contraction occurred. They were most pronounced during the first anoxic period and during the change from 1 to 2 minute periods of anoxia. Adenosine production was about 1 nmol/min during the first 1-minute anoxic period, decreasing during the following 1-minute anoxic periods. During the first 2-minute anoxic period, a new and much higher adenosine peak was observed (6 nmol/min), decreasing during the following 2-minute anoxic periods. Total purine release followed a pattern similar to that of adenosine. The concentration of ATP at the end of protocol B was 18.5 mumol/g dry tissue, which is significantly lower than that in protocol A (21.6 mumol/g). The results show that ATP breakdown during intermittent anoxia gradually decreases, notwithstanding the presence of substantial amounts of ATP.(ABSTRACT TRUNCATED AT 250 WORDS)

Stenting of venous bypass grafts: a new treatment modality for patients who are poor candidates for reintervention.

During a 2-year period, 136 self-expanding Wallstents were implanted in saphenous vein bypass grafts in 69 patients with end-stage coronary artery disease. All patients had severe symptoms and the majority were poor candidates for either repeat surgery or conventional bypass coronary angioplasty because of unfavorable native anatomy, impaired left ventricular function, or a high-risk bypass lesion anatomy for coronary angioplasty. All procedures were technically successful without major complications and a need for emergency bypass surgery. However, during the hospital stay acute thrombotic complications occurred in seven patients (10%) resulting in one death and acute myocardial infarction in five patients and necessitating emergency repeat PTCA in two patients and repeat CABG in four. Twenty-three patients had serious hemorrhagic complications directly related to the rigorous anticoagulation schedule. Two patients died of fatal cerebral bleeding. During follow-up, another five patients died accounting for a total mortality rate of 12%. At late angiographic follow-up (4.9 +/- 3.4 months, n = 53), 25 patients (47%) had a restenosis (greater than or equal to 50% DS) within or immediately adjacent to the stent, necessitating reintervention in 19 patients (PTCA, n = 12; repeat CABG, n = 7). In the group without stent-related restenosis (n = 28), 15 patients had progression of disease in either the native or bypass vessels leading to recurrence of major anginal symptoms within 1 to 24 months. Ten of these patients required further intervention (stent, n = 6; PTCA, n = 3; repeat CABG, n = 1). Stenting in saphenous coronary bypass grafts can be performed safely with excellent immediate angiographic and clinical results.(ABSTRACT TRUNCATED AT 250 WORDS)

Relative risk analysis of angiographic predictors of restenosis within the coronary Wallstent.

BACKGROUND: Late angiographic narrowing has been observed following coronary implantation of the Wallstent. To identify the angiographic variables that predict restenosis within the stented segment, a retrospective study of data from the European Wallstent core laboratory was performed. METHODS AND RESULTS: Follow-up angiograms (excluding patients with in-hospital occlusions) were analyzed for 214 lesions in 176 patients (78% restudy rate). The incidence of restenosis within the stented segment was 35% by lesion and 35% by patient for criterion 1 (greater than or equal to 0.72 mm loss in minimal luminal diameter) and 24% by lesion and 24% by patient for criterion 2 (diameter stenosis greater than or equal to 50% at follow-up). The association between 16 variables and restenosis was determined by a relative risk ratio assessment. Variables with significant risk ratios for restenosis with criterion 1 were use of multiple stents/lesion (relative risk, 1.56; 95% confidence interval [CI], 1.08-2.25) and oversized (unconstrained stent diameter exceeding reference diameter greater than 0.7 mm) stents (relative risk, 1.64; 95% CI, 1.10-2.45), and for criterion 2, oversizing by more than 0.70 mm (relative risk, 1.93; 95% CI, 1.13-3.31), bypass grafts (relative risk, 1.62; 95% CI, 0.98-2.66), use of multiple stents/lesion (relative risk, 1.61; 95% CI, 0.97-2.67) and residual diameter stenosis more than 20% post stenting (relative risk, 1.51; 95% CI, 0.91-2.50). CONCLUSIONS: It is concluded that several angiographic variables are significantly associated with late angiographic narrowing after stenting in the coronary arteries. We suggest that stent operators avoid excessive oversizing in the selection of stent diameter and the use of multiple stents per lesion to lessen the risk of late restenosis.

Humoral immune response against contractile proteins (actin and myosin) during cardiovascular disease.

Sensitive and highly specific ELISA assays were developed to determine humoral immune response against actin and myosin in 122 patients suffering from various cardiovascular diseases: acute viral myocarditis (n = 10, MYO), acute myocardial infarction (n = 28, AMI), valve surgery (n = 35, VALVE), coronary bypass surgery (n = 35, CABG), and peripheral vascular surgery (n = 14, VASC). Anti-actin and anti-myosin antibodies were determined on admission and serially during a period of 90 days. Anti-actin and anti-myosin immune response (IgG, IgM) was expressed comparing absorbance of the patients' serum with a reference serum. In the different patient groups significantly (P less than 0.01) higher anti-actin and anti-myosin antibody concentrations were found on admission compared with age-matched control groups. During follow-up, all patient groups except the vascular surgery group showed a significant immune response against actin and myosin, with an immune response ratio (peak/admission) for AMA IgG and IgM respectively of 2.12 and 2.40 in the VALVE group, 1.30 and 1.99 in the CABG group, 1.42 and 1.48 in the AMI group and 1.66 and 1.25 in the MYO group; and for AAA IgG and IgM respectively of 1.57 and 3.00 in the VALVE group, 1.54 and 1.64 in the CABG group, 1.25 and 1.07 in the AMI group, and 1.42 and 1.42 in the MYO group. A significant correlation between pre-cardiac injury and peak post-cardiac injury anti-myosin and anti-actin autoantibody levels could be demonstrated suggesting that pre-injury sensitization to these antigens plays an important role in evoking post-cardiac injury immune response.(ABSTRACT TRUNCATED AT 250 WORDS)