Jean Gregoire

Arterial Calcification and Not Lumen Stenosis Is Highly Correlated With Atherosclerotic Plaque Burden in Humans: A Histologic Study of 723 Coronary Artery Segments Using Nondecalcifying Methodology

OBJECTIVESnThis study was designed to evaluate whether calcium deposition in the coronary arteries is related to atherosclerotic plaque burden and narrowing of the arterial lumen.nnnBACKGROUNDnMany studies have recently documented the feasibility of electron beam computed tomography to detect and quantify coronary artery calcification in patients. Although these studies suggest a general relation between calcification and severity of coronary artery disease, the value of coronary calcium in defining atherosclerotic plaque and coronary lumen narrowing is unclear. Previous pathologic comparisons have failed to detail such a relation in identical histologic sections. This finding may be due to atherosclerotic remodeling.nnnMETHODSnA total of 37 nondecalcified coronary arteries were processed, sectioned at 3-mm intervals (723 sections) and evaluated by computer planimetry and densitometry.nnnRESULTSnA significant relation between calcium area and plaque area was found on a per-heart basis (n = 13, r = 0.87, p < 0.0001), per-artery basis (left anterior descending coronary artery [LAD]: n = 13, r = 0.89, p < 0.0001; left circumflex coronary artery [LCx]: n = 11, r = 0.7, p < 0.001; right coronary artery [RCA]: n = 13, r = 0.89, p < 0.0001) and per-segment basis (n = 723, r = 0.52, p < 0.0001). In contrast, a poor relation existed between residual histologic lumen area and calcium area for individual hearts (r = 0.48, p = NS), individual coronary arteries (LAD: r = 0.59, p = NS; LCx: r = 0.10, p = NS; RCA: r = 0.59, p = NS) and coronary segments (r = 0.07, p = NS). Longitudinal changes in external elastic lamina areas were highly correlated with changes in plaque area values (r = 0.60, p < 0.0001), whereas lumen area did not correlate with plaque size change (r = 0.01, p = NS).nnnCONCLUSIONSnCoronary calcium quantification is an excellent method of assessing atherosclerotic plaque presence at individual artery sites. Moreover, the amount of calcium correlates with the overall magnitude of atherosclerotic plaque burden. This study suggests that the remodeling phenomenon is the likely explanation for the lack of a good predictive value between lumen narrowing and quantification of mural calcification.

Effects of AGI-1067 and Probucol After Percutaneous Coronary Interventions

Background—AGI-1067, a metabolically stable modification of probucol, is an equipotent antioxidant to probucol but is pharmacologically distinct. In a multicenter trial, we studied whether AGI-1067 reduces restenosis assessed by intravascular ultrasound (IVUS) after percutaneous coronary intervention (PCI) compared with placebo and probucol used as a positive control. Methods and Results—Two weeks before PCI, 305 patients were randomly assigned to 1 of 5 treatment groups: placebo, probucol 500 mg BID, or AGI-1067 70, 140, or 280 mg once daily. Patients were treated for 2 weeks before and 4 weeks after PCI. Baseline and 6-month follow-up IVUS were interpreted by a blinded core laboratory. Stents were used in 85% of patients. Luminal area at the PCI site at follow-up was 2.66±1.58 mm2 for placebo, 3.69±2.69 mm2 for probucol, 2.75±1.76 mm2 for AGI-1067 70 mg, 3.17±2.26 mm2 for AGI-1067 140 mg, and 3.36±2.12 mm2 for AGI-1067 280 mg (P =0.02 for the dose-response relationship;P ≤0.05 for AGI-1067 280 mg and probucol versus placebo). There was a mean narrowing of 5.3 mm3 of reference segment lumen in the placebo group and an enlargement in the AGI-1067 140- and 280-mg groups at follow-up (P =0.05 for 140 mg). An increase in QTc interval >60 ms occurred in 4.8% of placebo patients, 17.4% of probucol patients, and 4.8%, 2.4%, and 2.5% of patients in the AGI-1067 groups (P =0.02). Conclusions—AGI-1067 and probucol reduce restenosis after PCI. In contrast to probucol, AGI-1067 did not cause prolongation of the QTc interval and improved lumen dimensions of reference segments, suggestive of a direct effect on atherosclerosis.

Treatment With 5-Lipoxygenase Inhibitor VIA-2291 (Atreleuton) in Patients With Recent Acute Coronary Syndrome

Background—Production of leukotrienes by 5-lipoxygenase (5-LO) has been linked to unstable atherosclerotic plaques and cardiovascular events. VIA-2291 is a potent 5-LO inhibitor. Methods and Results—In a double-blinded study, 191 patients were randomly assigned 3 weeks after an acute coronary syndrome to receive 25, 50, or 100 mg VIA-2291 or placebo daily for 12 weeks. The primary study end point, whole blood stimulated leukotriene LTB4 at trough drug level, was reduced in all VIA-2291 groups (P<0.0001) in a dose-dependent fashion, with approximately 80% inhibition in >90% of patients in the 100-mg group. A significant reduction of urine leukotriene LTE4 was obtained in all dose groups. No serious adverse events were considered related to study drug. A subset of 93 patients who had undergone a 64-slice coronary CT examination at baseline continued on study medication for a total of 24 weeks and underwent a repeat scan. Five of these patients withdrew or were noncompliant and 28 had nonevaluable scans. Among the 60 remaining patients, new coronary plaques were observed in 5 of 18 (27.8%) placebo-treated patients and in 2 of 42 (4.8%) VIA-2291–treated patients (P=0.01). A reduction in noncalcified plaque volume at 24 weeks versus placebo was observed in VIA-2291–treated groups in the 34 of these 60 patients in whom this end point was analyzable (P<0.01). Conclusions—VIA-2291 reduces leukotriene production at 12 weeks after an acute coronary syndrome. Preliminary data from the CT substudy suggest that such a reduction in leukotriene production may influence atherosclerosis; however, this requires confirmation in a larger study. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00358826.

Evaluation of coronary atheroma by 64-slice multidetector computed tomography: Comparison with intravascular ultrasound and angiography

BACKGROUNDnRecent improvements in multidetector computed tomography (MDCT) with 64-slice scanners have allowed acquisition of a coronary study in 5 s to 6 s, with good temporal and spatial resolution. Previous studies have reported an underestimation of plaque burden by MDCT. Whether shorter scan times can allow correct assessment of plaque volume requires comparison with intravascular ultrasound (IVUS).nnnMETHODSnPatients (n=30) scheduled for coronary angiography also underwent MDCT and IVUS examinations within 96 h. MDCT examination was performed with a 64-slice scanner. Nitroglycerin was administered before all imaging procedures. MDCT, quantitative coronary angiography (QCA) and IVUS analyses were performed by observers blinded to other results. Plaque volumes were determined by MDCT and IVUS in one vessel, and maximum percentage diameter stenosis was identified in each coronary segment by MDCT and QCA.nnnRESULTSnThe mean (+ or - SD) plaque volume was determined to be 179.1 + or - 78.9 mm(3) by MDCT and 176.1 + or - 87.9 mm(3) by IVUS. There was a strong positive correlation for plaque volume between MDCT and IVUS (r=0.84, P<0.0001). Percentage diameter stenosis assessed by MDCT and QCA also correlated well (r=0.88 per patient and r=0.87 per vessel, P<0.0001 for both). The maximum percentage diameter stenosis per vessel was 38.1 + or - 30.2% with MDCT and 34.1 + or - 27.6% with QCA. The sensitivity and specificity of MDCT in detecting stenoses above 50% per vessel were 100% and 91.0%, respectively.nnnCONCLUSIONSnPlaque volumes measured by 64-slice MDCT and IVUS correlate well, without systematic underestimation. The sensitivity and specificity of MDCT to detect stenoses greater than 50% by QCA are excellent with the administration of nitroglycerin before imaging.

Vascular protectants for the treatment of atherosclerosis

AGI1067, the monosuccinic acid ester of probucol, is a phenolic antioxidant member of a novel class of agents termed vascular protectants. It has strong antioxidant properties, equipotent to those of probucol, and anti-inflammatory properties. It inhibits gene expression of vascular cell adhesion molecule-1 and monocyte chemotactic protein1 and has been effective at preventing atherosclerosis in all tested animal models. It also improved luminal dimensions of reference segments in the percutaneous coronary intervention (PCI) vessels in the CART1 clinical trial, which suggests a direct anti-atherosclerosis effect. Two important trials that test the antioxidant/anti-inflammatory hypothesis are ongoing with AGI1067: the Canadian Atherosclerosis and Restenosis Trial, which assesses its value for the reduction of both atherosclerosis progression in non-PCI vessels and post-PCI restenosis, and the Aggressive Reduction of Inflammation Stops Events trial, which is evaluating the effects of AGI1067 on hard cardiovascular outcomes.

Updated guidelines for the management of dyslipidemia and prevention of cardiovascular disease by pharmacists

Cardiovascular (CV) disease continues to be a significant cause of morbidity and mortality—coronary disease and cerebrovascular disease are the second and third leading causes of death, respectively, in Canada.1 In 2007, a set of dyslipidemia guidelines tailored to pharmacists based on the 2006 Canadian Cardiovascular Society (CCS) recommendations was published in the Canadian Pharmacists Journal.2 Since then, pharmacists in many provinces have expanded their scope of practice, including in some cases the ability to independently prescribe or modify existing therapies and order laboratory tests. There is growing evidence that pharmacist intervention in the management of dyslipidemia leads to improvements in lipid management.3 Moreover, expanding evidence in the realm of dyslipidemia, including trials in previously understudied populations (chronic kidney disease), innovations in CV risk communication (Cardiovascular Age) and increased awareness of the adverse effect profile of statins led to the publication of the 2012 update of the CCS guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult.4 In this article, we provide an update based on the current CCS guidelines, with practical tips for pharmacists.

Short wave ultraviolet laser energy in porcine coronary arteries: medial cell death and neointimal formation.

Smooth muscle cell migration and proliferation from arterial media into the neointima are major factors in the restenosis process following coronary angioplasty. Because short wave ultraviolet (UV) radiation is cytotoxic for rat carotid artery smooth muscle cells, the aims of this study were to determine the effects of short wave UV irradiation on normal pig coronary arteries and to evaluate the efficacy of UV laser energy for reducing neointimal hyperplasia (NI).

Antioxidants and Restenosis — Human Studies

Since its inception in 1977, the use of percutaneous transluminal coronary angioplasty (PTCA) has increased to over one million cases per year worldwide. This explosive growth reflects the improvement in initial success rates, an acceptable safety profile, and the acceptance of PTCA as an alternative or adjunctive therapy to medical treatment and bypass surgery in patients with coronary artery disease [1,2]. Rapid advances in guidewires and balloon catheters, the introduction of intracoronary stents and other interventional devices as well as the accumulation of operator experience allow PTCA to be used in more complex lesions, smaller coronary arteries, and in patients with multi-vessel disease, with greater procedural success.

Biomechanics of Plaque Rupture: A Global Integration Approach

Myocardial infarction is mainly a process resulting from the rupture of the plaque protective fibrous cap in response to mechanical forces and physiological activity. Exposure of the blood to the prothrombotic content of the atheroma may result in the formation of a clot. A mechanical event is generally the trigger of a plaque rupture, where the plaque can no longer bear the different stresses. Plaque vulnerability to rupture can be evaluated with a finite-element analysis on a 3D model, obtained from intravascular ultrasound images, along with the mechanical properties of the coronary arterial wall evaluated from elastography analysis. Finite-element analysis of both fluid and wall and their interaction can be performed to evaluate plaque vulnerability and to select patients at higher risk who should undergo more aggressive therapies. This article presents the integration of intravascular imaging into the plaque rupture biomechanics study.

Restenosis and Remodeling: Is the Adventitia Involved?

Vascular remodeling has assumed great importance as a cause of coronary restenosis. Yet understanding of this complex phenomenon is only recently beginning to grow as more data has emerged. In its most fundamental form, remodeling may be defined as any change in vessel diameter (enlargement or constriction) in response to chronic changes in hemodynamic conditions or humoral factors [1]. With atherosclerosis or after vascular intervention, the coronary artery may exhibit three separate remodeling responses 1) compensatory enlargement, 2) absence of compensation or 3) vascular constriction/shrinkage [2]. Each has substantial implications for the artery lumen.