Marius M. Rozek

Randomized, Placebo-Controlled Study for Immunosuppressive Treatment of Inflammatory Dilated Cardiomyopathy Two-Year Follow-Up Results

Background—Previous studies have shown disappointing results for immunosuppressive treatment in patients with dilated cardiomyopathy. Therefore, we studied the effectiveness of such therapy in patients with HLA upregulation on biopsy. Methods and Results—Of 202 patients with dilated cardiomyopathy, 84 patients with increased HLA expression were randomized to receive either immunosuppression or placebo for 3 months; they were then followed for 2 years. After 2 years, there were no significant differences in the primary end point (a composite of death, heart transplantation, and hospital readmission) between the 2 study groups (22.8% for the immunosuppression group and 20.5% for the placebo). The secondary efficacy end point included changes in ejection fraction, end-diastolic diameter, end-diastolic volume, end-systolic volume and NYHA class; left ventricular ejection fraction increased significantly in the immunosuppression group compared with the placebo group (95% CI, 4.20 to 13.12;P <0.001) after 3 months of follow-up. The early favorable effects of immunosuppressive therapy on left ventricular volume, left ventricular diastolic dimension, and New York Heart Association class were also present. This improvement was maintained in the immunosuppression group at 2 years (ejection fraction: 95% CI, 6.94 to 19.04;P <0.001). In addition, on the basis of the protocol-specified definition of improvement, 71.8% patients in the immunosuppression group versus 20.9% patients in the placebo group met the criteria of improvement after 3 months (P <0.001). At the end of the follow-up period, 71.4% patients from the immunosuppression group versus 30.8% patients from the placebo group were improved (P =0.001). Conclusions—These data demonstrate a long-term benefit of immunosuppressive therapy in patients with dilated cardiomyopathy and HLA upregulation on biopsy specimens. Thus, restoration of immunosuppressive therapy for such patients should be considered.

Pathogenesis of the Atherosclerotic Lesion: Implications for diabetes mellitus

In this review, we have highlighted pivotal cellular and molecular events in the initiation and progression of atherosclerosis. Key components of lesion initiation are an enhanced focal intimal influx and accumulation of lipoproteins, including LDL in hemodynamically determined lesion-prone areas, focal monocyte-macrophage recruitment, intimal generation of ROS, and oxidative modification of lipoproteins (including LDL [Ox-LDL]). Modified lipoproteins are taken up by the non-downregulating macrophage scavenger receptor, with foam cell formation and the development of the so-called fatty streak. One transitional event in lesion progression is foam cell necrosis, likely attributable to the cytotoxicity of both intimal free radicals and Ox-LDL, with development of an extracellular metabolically inert lipid core. Another is the migration to and proliferation within the intima of medial SMCs, leading to the synthesis of plaque collagens, elastin, and proteoglycans. Mural thrombosis plays a significant role in the late-stage progression of lesions. Regression of lesions is considered a function of the dynamic balance among components of initiation, progression, plaque stabilization, and removal of plaque constituents—the so-called regression quartet. Here, we critically examine how components of diabetes mellitus might impact not only lesion development, but also lesion regression. It is concluded that some components of diabetes mellitus augment key mechanisms in lesion initiation and progression and will likely retard the processes of plaque regression. Specifically, we focus on the various influences of diabetes mellitus on lipoprotein influx and accumulation, free radical generation and Ox-LDL, monocyte-macrophage recruitment, thrombosis and impaired fibrinolysis, and the reverse cholesterol transport system. The importance of nonenzymatic protein glycosylation in modifying a number of these processes is emphasized.

Atherosclerosis as an inflammatory process. The roles of the monocyte-macrophage

In this brief review, we have addressed the roles of the monocyte-macrophage in atherogenesis, with emphasis on the recruitment to the arterial wall. We have presented summary data on the SMC-derived chemoattractant protein and also on the temporal evolution of monocyte-derived macrophages into cholesteryl ester-rich foam cells. The concept of atheroma as an inflammatory process has also been discussed.

Local Delivery of Enoxaparin to Decrease Restenosis After Stenting: Results of Initial Multicenter Trial Polish-American Local Lovenox NIR Assessment Study (The POLONIA Study)

Background—Enoxaparin inhibits smooth muscle cell proliferation in experimental models. Intimal hyperplasia has been found to be the principal cause of restenosis after coronary stent implantation. We sought to determine whether the intramural delivery of enoxaparin before stenting of de novo lesions decreases restenosis. Methods and Results—One hundred patients who were undergoing stenting were randomly assigned to either local administration of enoxaparin during predilation with reduced systemic heparinization or stenting with standard, systemic heparinization. All patients were treated with the same type of stent (NIR). The primary study end point was late luminal loss. The secondary end points were major adverse cardiac events, target lesion revascularization, and angiographic restenosis at 6 months. Angiographic follow-up at 6 months was completed in all except 1 patient. Late luminal loss was reduced to 0.76±0.42 mm in the local enoxaparin delivery group versus 1.07±0.49 mm in the systemic heparinization group (P <0.001). Restenosis, using a binary definition, occurred in 10% of patients in the enoxaparin group and in 24% of patients in the systemic heparinization group (P <0.05). Target lesion revascularization rates occurred in 8% of the enoxaparin group and 22% of the systemic heparinization group (P <0.05). There were no deaths and no emergent CABGs were performed. The only subacute stent closure and non–Q-wave infarction occurred in a patient assigned to the systemic heparinization group. Conclusions—This is the first prospective randomized trial in which the local delivery of a drug, enoxaparin, resulted in significant reduction in late luminal loss and restenosis after stent implantation in de novo coronary lesions.

Characterization of monocyte chemotactic protein-1 binding to human monocytes

Monocyte chemotactic protein-1 (MCP-1) stimulates chemotaxis of peripheral blood monocytes. In order to understand the biologic basis of this specific activity, binding studies of 125I-MCP-1 were undertaken. MCP-1 showed saturable binding to monocytes. Scatchard analysis of the monocyte binding data indicate that there are approximately 1,600 high affinity binding sites per monocyte with a Kd = 1.1 nM. Studies with synthetic peptides constructed according to the MCP-1 amino acid sequence indicate that a synthetic peptide, MCP-1[13-35], stimulates monocyte migration and competes with native MCP-1 for binding sites. Inhibition of MCP-1 binding was tested with chemotactic connective tissue proteins. No inhibition of MCP-1 binding was observed with either collagen, elastin-derived peptides or fibronectin. These results identify a single class of unique high affinity MCP-1 binding sites that are likely to recognize a peptide domain on MCP-1 which include the amino acids within the region, 13-35.

Novel approach to rotational atherectomy results in low restenosis rates in long, calcified lesions: Long‐term results of the San Antonio rotablator study (SARS)

Ablation technique and adjunctive strategy may affect restenosis after rotational atherectomy. To minimize trauma to the vascular wall, we changed the technique of rotablation as follows: the RPM range was decreased to 140,000–160,000 RPM, the ablation was performed using a repetitive pecking motion, avoiding a decrease in the rotational speed of the burr greater than 3,000 RPM, long lesions were divided into segments and each segment was separately ablated, and the burr‐to‐artery ratio was intended to be approximately 0.75. To prevent coronary spasm, before and after each pass, 100–200 μg nitroglycerin and 100–200 μg verapamil i.c. boluses were administered. Adjunctive PTCA was performed using a closely sized 1.1:1 balloon‐to‐artery ratio with a noncompliant balloon at low pressures for 120 sec. The study incorporated 111 patients with a combined total of 146 calcified lesions.

Acute directional coronary atherectomy prior to stenting in complex coronary lesions: ADAPTS Study.

The purpose of this study was to determine the results of directional coronary atherectomy (DCA) combined with stenting in a high-risk patient population. The use of stenting or DCA alone for aorto-ostial lesions, total chronic occlusions, long lesions, and lesions containing thrombus is associated with lowered success and a relatively high restenosis rate. Between July 1993 and October 1996, we treated 89 lesions with the combined approach of DCA and stenting in 60 consecutive patients. Thirty-one (51.7%) patients were treated because of unstable angina, 11 (18.3%) for post-myocardial infarction (MI) angina, 3 (5.0%) for acute MI, and 15 (25.0%) patients for stable angina. A total of 43 (71.7%) patients had multivessel disease, 19 (31.7%) had undergone previous coronary artery bypass graft (CABG), and 17 (28.3%) patients had undergone multivessel revascularization. The procedure was successful in all patients; and no postprocedural deaths or emergent CABG occurred. Two patients (3.3%) had non-Q-wave MI after the procedure and 1 patient (1.7%) experienced Q-wave MI due to subacute stent closure 7 days after the procedure. During follow-up ranging from 6 months to 3 years, 2 (3.3%) patients died, 2 (3.3%) required CABG surgery, 1 (1.7%) patient had an MI, and 6 patients (10.0%) required target vessel revascularization. By the quantitative coronary angiography, the initial minimal luminal diameter (MLD) averaged 0.91+/-0.45 mm (74.7+/-11.8% stenosis) increasing to 3.80+/-0.44 mm (-6.7+/-12.1%) after the combined approach procedure. Thirty patients (50.0%) met criteria for late (> or =6 months) angiographic follow-up. Late MLD loss averaged 1.13+/-1.07 mm, for a mean net gain of 1.61+/-1.23 mm. Available angiographic follow-up evaluation showed a restenosis rate of 13.3%. A combined approach, defined as the use of both DCA and stenting, is safe and yields a low restenosis rate in high-risk patients who have lesions known to respond less favorably to stenting or DCA alone.

Bilateral carotid stenting combined with three-vessel percutaneous coronary intervention in single setting

We describe a patient who underwent bilateral internal carotid artery stenting and three‐vessel percutaneous coronary intervention during the same procedure. Stenting of carotid arteries was performed employing our innovative technique combining coronary and peripheral devices. No complications occurred. The patient was discharged home 1 day after the intervention and remains asymptomatic, leading a fully active life. To our knowledge, unstaged bilateral carotid stenting combined with three‐vessel coronary intervention has not been reported previously. Cathet Cardiovasc Intervent 2001;52:100–104.

Influence of the acyl-CoA:cholesterol O-acyltransferase inhibitor, CL 277082, on cholesteryl ester accumulation in rabbit macrophage-rich granulomas and hepatic tissue

The influence of the acyl-CoA: cholesterol O-acyltransferase (ACAT) inhibitor, CL 277082, on macrophage cholesteryl ester accumulation in a rabbit carrageenan granuloma macrophage-foam cell model was studied. Diets were supplemented with 0.3% cholesterol and 6% peanut oil with or without the inhibitor (0.25%) for 4 weeks prior to granuloma induction, and macrophage-rich granuloma tissue was harvested 14 days after carrageenan injection. Serum cholesterol was monitored biweekly, and plasma lipoproteins were isolated terminally. Total, free and esterified cholesterol contents were measured in hepatic and granuloma tissue. In hepatic tissue, administration of CL 277082 resulted in an 80% reduction in the content of total cholesterol, a 37% decrease in free cholesterol, and a 90% decrease in esterified cholesterol. Similarly, in macrophage-rich granuloma tissue, total cholesterol content was decreased by 44%, and esterified cholesterol content by 61%, with no change in free cholesterol. Additionally, CL 277082 was shown to inhibit granuloma tissue ACAT activity by 45%, VLDL mass was decreased slightly, LDL mass increased 3.4-fold and HDL mass was similar in both the inhibitor-treated and control animals. CL 277082 resulted in a 57% decrease in VLDL cholesteryl ester content and a 4.5-fold increase in triacylglycerol. Cholesteryl ester content in LDL was decreased by 31% and LDL triacylglycerol was increased 5.2-fold, while the only change in HDL composition was a 3.5-fold increase in triacylglycerol. The reductions in both hepatic tissue and macrophage-rich granuloma tissue esterified cholesterol accumulation are considered to be due largely to cellular ACAT inhibition, and the altered distribution and composition of the plasma lipoproteins.