Can ACAT inhibition limit the progression of atherosclerosis in patients with coronary artery disease?
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Comment↗
Biomedical subjects
Jean-Claude Tardif
Publications and source records attributed to Jean-Claude Tardif.
Role of probucol on endothelial dysfunction of epicardial coronary arteries associated with left ventricular hypertrophy.
The lipid-lowering agent probucol may be efficacious, through its antioxidant properties, to limit and reverse the vascular endothelial dysfunction associated with left ventricular hypertrophy (LVH). LVH was induced by performing an aortic banding (AB) on swine, except for controls (group 1). The untreated AB group received a placebo (group 2) whereas the treated groups received probucol (1000 mg/d orally); the third group began its treatment on the day of the banding (for 60 d), the fourth began on day 30 and the fifth on day 60 after AB (both for 30 d). Hypertrophy was assessed by echocardiography and histology. Coronary vascular reactivity was evaluated in organ chambers and endothelial function by quantification of NO2/NO3 and cyclic guanosine-3',5'-monophosphate. To assess oxidative stress, hydroperoxides and angiotensin II levels as well as superoxide dismutase activity were evaluated. After treatment with probucol, a significant decrease in left ventricle/body weight ratio was observed compared with the untreated group. Dose-response curves of the probucol groups showed an improvement in endothelium-dependent relaxations, associated with increased nitric oxide bioavailability and decreased angiotensin II and hydroperoxide levels. In conclusion, the antioxidant probucol limited the development and induced the regression of LVH and the associated coronary endothelial dysfunction.
Angiotensin II↗
Heart rate slowing versus other pharmacological antianginal strategies.
Relieving the symptoms of angina and improving the quality of life and functional status are important objectives in the management of patients with chronic stable angina. A high heart rate induces or exacerbates myocardial ischemia and angina because it both increases oxygen demand and decreases myocardial perfusion. Beta-Blockers are effective at reducing anginal symptoms largely by decreasing heart rate. Physician use and patient compliance may be limited by the side effects of Beta-blockers which include fatigue, depression and sexual dysfunction. Heart rate reduction can also be obtained by the calcium antagonists verapamil and diltiazem and by the new selective heart-rate-reducing agent ivabradine. Ivabradine (Procoralan) is a selective and specific I(f) inhibitor that acts on one of the most important ionic currents for the regulation of the pacemaker activity of sinoatrial node cells. Ivabradine has demonstrated dosedependent anti-ischemic and antianginal effects in a placebo-controlled study. The INITIATIVE trial is a large multicenter trial in which 939 patients with stable angina were randomized to ivabradine or atenolol. The noninferiority of ivabradine was shown in the INITIATIVE trial at all doses and for all criteria including time to limiting angina. The number of angina attacks per week was decreased by two thirds with both ivabradine and atenolol. In another trial of 1,195 patients, time to 1mm ST segment depression was increased by 45 s with ivabradine 7.5 mg b.i.d. and by 40 s with amlodipine 10 mg daily. Unlike beta-blockers, ivabradine is devoid of intrinsic negative inotropic effects and does not affect coronary vasomotion. A whole range of patients with angina may benefit from exclusive heart rate reduction with ivabradine, including those with contraindications or intolerance to the use of beta-blockers and patients that are insufficiently controlled by beta-blockers or calcium channel blockers.
Adrenergic beta-Antagonists↗
Inhaled milrinone: a new alternative in cardiac surgery?
The administration of milrinone through inhalation has been studied in only a few animal and human studies. Compared to the intravenous administration, inhaled milrinone has been shown to reduce pulmonary artery pressure without systemic hypotension. Therefore, this approach could represent an alternative to nitric oxide. This current state of knowledge of intravenous and inhaled milrinone is presented and summarized.
Administration, Inhalation↗
Relation of myocardial perfusion defects and nonsignificant coronary lesions by angiography with insights from intravascular ultrasound and coronary pressure measurements.
Several studies have demonstrated a correlation between myocardial ischemia and severity of coronary lesions as determined by intravascular ultrasound (IVUS) and fractional flow reserve (FFR) measurements. However, their value for the assessment of mild coronary stenoses that are associated with myocardial perfusion abnormalities has not been well studied. The objective of this study was to prospectively compare the results of myocardial perfusion as determined by exercise/dipyridamole myocardial single-photon emission computed tomography with IVUS and FFR measurements in patients who had angiographically mild coronary stenosis (< 50% diameter stenosis by quantitative coronary angiography). Forty-eight patients who had stable coronary disease (61 +/- 11 years of age; 6 women) were included. All had mild coronary stenosis in the proximal/middle segment of > or = 1 coronary artery and had undergone maximal exercise myocardial technetium-99m tetrofosmin single-photon emission computed tomography within 48 hours before coronary angiography. IVUS measurements included lesion lumen area, external elastic membrane area, lesion plaque burden (calculated as external elastic membrane minus lumen area, divided by external elastic membrane, and multiplied by 100), and lumen area stenosis (calculated as reference lumen area minus lesion lumen area, divided by reference lumen area, multiplied by 100). Fifty-three coronary lesions were studied, with a mean percent diameter stenosis of 34.9 +/- 7.9% on angiography. Myocardial perfusion defects were demonstrated by single-photon emission computed tomography in 11 patients (12 myocardial regions) with no differences in lesion percent diameter stenosis compared with those without perfusion defects. The presence of reversible perfusion defects was associated with a higher lesion plaque burden as evaluated by IVUS (67.4 +/- 8.1% vs 60.2 +/- 9.3%, p = 0.01). FFR values did not differ in the presence or absence of perfusion defects (0.90 +/- 0.06 vs 0.92 +/- 0.07, respectively; p = NS). In conclusion, plaque burden as determined by IVUS may partly explain the presence of myocardial perfusion defects in cases of angiographically nonsignificant coronary lesions. However, the high FFR values associated with these lesions suggest that other mechanisms, such as endothelial/microvascular dysfunction, might also account for perfusion abnormalities in these patients.
Blood Pressure↗
Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina.
AIMS: Ivabradine, a new I(f) inhibitor which acts specifically on the pacemaker activity of the sinoatrial node, is a pure heart rate lowering agent. Ivabradine has shown anti-ischaemic and anti-anginal activity in a placebo-controlled trial. The objective of this study was to compare the anti-anginal and anti-ischaemic effects of ivabradine and the beta-blocker atenolol. METHODS AND RESULTS: In a double-blinded trial, 939 patients with stable angina were randomized to receive ivabradine 5 mg bid for 4 weeks and then either 7.5 or 10 mg bid for 12 weeks or atenolol 50 mg od for 4 weeks and then 100 mg od for 12 weeks. Patients underwent treadmill exercise tests at randomization (M(0)) and after 4 (M(1)) and 16 (M(4)) weeks of therapy. Increases in total exercise duration (TED) at trough at M(4) were 86.8+/-129.0 and 91.7+/-118.8 s with ivabradine 7.5 and 10 mg, respectively and 78.8+/-133.4 s with atenolol 100 mg. Mean differences (SE) when compared with atenolol 100 mg were 10.3 (9.4) and 15.7 (9.5) s in favour of ivabradine 7.5 and 10 mg (P<0.001 for non-inferiority). TED at M(1) improved by 64.2+/-104.0 s with ivabradine 5 mg and by 60.0+/-114.4 s with atenolol 50 mg (P<0.001 for non-inferiority). Non-inferiority of ivabradine was shown at all doses and for all criteria. The number of angina attacks was decreased by two-thirds with both ivabradine and atenolol. CONCLUSION: Ivabradine is as effective as atenolol in patients with stable angina.
Adrenergic beta-Antagonists↗
Intensity of lipid lowering with statins and brachial artery vascular endothelium reactivity after acute coronary syndromes (from the BRAVER trial).
The time course and differential effects of statin regimens on endothelial function after acute coronary syndromes (ACSs) are unknown and could contribute to the superiority of a more intense strategy. A subset of subjects who were enrolled in the PROVE IT-TIMI 22 trial (n = 50) underwent evaluation of vascular reactivity by high-resolution brachial ultrasound. Endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent sublingual nitroglycerin-mediated dilation (NMD) were measured at baseline and at 48 hours, 1 month, and 4 months after the initiation of 40 mg of pravastatin (n = 26) or 80 mg of atorvastatin (n = 24). After 4 months, low-density lipoprotein cholesterol was decreased by 32% in the atorvastatin group but was not different from baseline after ACS in the pravastatin group. C-reactive protein decreased similarly in the 2 groups. Brachial artery diameters at rest were similar in the 2 groups and at each time point of the trial. FMD and NMD increased significantly after 4 months by 27% and 24%, respectively (p <0.05), with no difference between groups. There was no correlation between the change in FMD and the change in lipids or C-reactive protein. In subjects who had received previous statin therapy (n = 15), there was no significant variation in FMD (p = 0.140) and NMD (p = 0.129). In conclusion, initiation of statin therapy soon after ACS is associated with improvements in endothelium-dependent and independent vascular reactivities after 4 months.
Acute Disease↗
External beam radiation to prevent restenosis after superficial femoral artery balloon angioplasty.
BACKGROUND: Femoropopliteal percutaneous transluminal angioplasty (PTA) remains limited by restenosis. Although vascular brachytherapy may be effective in reducing restenosis, external beam radiation would be more practical to administer after PTA. METHODS AND RESULTS: After femoropopliteal PTA without stent placement, 99 patients were randomly assigned to 0 Gy (placebo; n=24), 7 Gy (n=24), 10.5 Gy (n=26), or 14 Gy (n=25) of external beam radiation of the PTA site (with a 3-cm margin at both extremities) in 1 session 24 hours after PTA. The primary end point was minimum lumen diameter on quantitative angiography 1 year after PTA. One year after PTA, the mean minimum lumen diameter was 1.92, 1.64, 1.92, and 2.91 mm, respectively, for the 0-, 7-, 10.5-, and 14-Gy groups (P=0.0072 for 0 versus 14 Gy). Mean luminal loss was 1.14, 1.27, 1.08, and 0.14 mm, respectively, for the 4 groups (P=0.0072 for 0 versus 14 Gy). Restenosis >50% was present in 50%, 65%, 48%, and 25% of patients, respectively, for the 0-, 7-, 10.5-, and 14-Gy groups (P=0.072). At 18 months, repeated revascularizations were required in 25% of patients in the 0-Gy group versus 12% of patients in the 14-Gy group (P=0.24). CONCLUSIONS: A single session of external beam radiation of 14 Gy of the femoropopliteal angioplasty site significantly reduces restenosis at 1 year.
Aged↗
Sustained elevation of serum CD40 ligand levels one month after coronary angioplasty predicts angiographic restenosis.
BACKGROUND: Percutaneous coronary intervention induces an early inflammatory reaction. The intensity of such a reaction as measured by high-sensitivity C-reactive protein has been correlated with recurrent ischemic events, but its association with restenosis remains uncertain. OBJECTIVES: To characterize the type and duration of the postangioplasty inflammatory reaction and to identify new inflammatory markers correlating with restenosis. METHODS: Fifty-three consecutive patients who underwent successful balloon angioplasty were studied. Levels of specific inflammatory markers were measured before intervention, and at one-month and six-month follow-up. Six-month clinical and angiographic follow-up was conducted in all patients, and quantitative coronary analysis was systematically performed. RESULTS: Levels of soluble CD40 ligand (sCD40L) and matrix metalloproteinase-2 showed a rise and fall pattern over six months, with peak levels measured at one month (P < 0.0001), while levels of soluble vascular cell adhesion molecule-1 increased after angioplasty and remained elevated at six months (P = 0.07). Plasma levels of sCD40L at one month correlated with angiographic late loss (r = 0.48, P = 0.001) and were predictive of six-month restenosis (area under receiver operating characteristic curve 0.75 [95% CI 0.61 to 0.88]). CONCLUSIONS: The results imply that inflammation persists for at least one month following angioplasty and that future therapeutic interventions targeting inflammation to prevent restenosis should be active during this period. Furthermore, the ability of sCD40L levels to predict restenosis at six months may indicate the relevance of this pathway as a therapeutic target for restenosis prevention.
Angioplasty, Balloon↗
Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease.
AIMS: Heart rate reduction is the cornerstone of the treatment of angina. The purpose of this study was to explore the prognostic value of heart rate in patients with stable coronary artery disease (CAD). METHODS AND RESULTS: We assessed the relationship between resting heart rate at baseline and cardiovascular mortality/morbidity, while adjusting for risk factors. A total of 24 913 patients with suspected or proven CAD from the Coronary Artery Surgery Study registry were studied for a median follow-up of 14.7 years. All-cause and cardiovascular mortality and cardiovascular rehospitalizations were increased with increasing heart rate (P<0.0001). Patients with resting heart rate > or =83 bpm at baseline had a significantly higher risk for total mortality [hazard ratio (HR)=1.32, CI 1.19-1.47, P<0.0001] and cardiovascular mortality (HR=1.31, CI 1.15-1.48, P<0.0001) after adjustment for multiple clinical variables when compared with the reference group. When comparing patients with heart rates between 77-82 and > or =83 bpm with patients with a heart rate < or =62 bpm, the HR values for time to first cardiovascular rehospitalization were 1.11 and 1.14, respectively (P<0.001 for both). CONCLUSION: Resting heart rate is a simple measurement with prognostic implications. High resting heart rate is a predictor for total and cardiovascular mortality independent of other risk factors in patients with CAD.
Arrhythmias, Cardiac↗
Long-term safety of intravascular ultrasound in nontransplant, nonintervened, atherosclerotic coronary arteries.
OBJECTIVES: The goal of this study was to demonstrate that intravascular ultrasound (IVUS) examination of native coronary arteries does not result in an acceleration of the atherosclerotic process. BACKGROUND: Intravascular ultrasound is increasingly used to assess the effects of pharmacologic agents on atherosclerosis. METHODS: Intravascular ultrasound examinations of one coronary artery and coronary angiography were performed in 525 patients at baseline. Patients then underwent a follow-up angiogram 18 to 24 months later. All end points were evaluated in IVUS-related and non-IVUS arteries using quantitative coronary analysis. The study end points were the coronary change score (per-patient mean of minimum lumen diameter changes for all lesions measured), occurrence of new coronary lesions, and progression of preexistent lesions at follow-up. Acute angiographic and clinical complications were also analyzed. RESULTS: Coronary change score was -0.06 +/- 0.23 mm and -0.05 +/- 0.21 mm for IVUS-related and non-IVUS arteries, respectively (p = 0.35). The increase in percent diameter stenosis from baseline to follow-up was 0.8 +/- 6.7% and 1.2 +/- 7.0% in the IVUS-related and non-IVUS arteries (p = 0.29). New lesions occurred in 3.6% and 3.9% of IVUS-related and non-IVUS arteries, respectively (p = 0.84). When all coronary lesions were considered, the incidence of lesion progression was not significantly different between IVUS-related (11.6%) and non-IVUS (9.8%) arteries. Coronary spasm occurred in 1.9% of IVUS procedures, and there was one case of acute occlusion with no long-term sequelae. CONCLUSIONS: Intravascular ultrasound does not significantly accelerate atherosclerosis in native coronary arteries and can be used safely to assess progression/regression in clinical trials.
Coronary Artery Disease↗
Antioxidants and atherosclerosis: emerging drug therapies.
Inflammation has a fundamental role in mediating all stages of atherosclerotic disease. The key role of oxidation in linking lipids and inflammation to atherosclerosis is compelling and supported by experimental evidence. However, the relevance of the antioxidant hypothesis for the treatment of patients with atherosclerosis has not been definitively proven. Probucol has reduced post-percutaneous coronary intervention (PCI) restenosis and progression of carotid atherosclerosis in clinical trials. The antioxidant/vascular protectant AGI-1067 has also been effective at preventing atherosclerosis in all tested animal models. The nonintervened reference coronary segments of the PCI vessel demonstrated improvements with AGI-1067 in the Canadian Antioxidant Restenosis Trial-1 (CART-1), evidence supportive of a clinical effect on slowing atherosclerosis progression. Results of randomized trials with the "antioxidant" vitamins have been disappointing, but there are potentially important problems associated with their use, including their potential pro-oxidant effects. Two important trials that test the antioxidant/anti-inflammatory hypothesis are ongoing with AGI-1067: CART-2, which assesses its value for the reduction of both atherosclerosis progression in non-PCI vessels and post-PCI restenosis; and Aggressive Reduction of Inflammation Stops Events (ARISE), which is evaluating the effects of AGI-1067 on hard cardiovascular outcomes.
Antioxidants↗
Effects of angiotensin-converting enzyme inhibitor plus irbesartan on maximal and submaximal exercise capacity and neurohumoral activation in patients with congestive heart failure.
BACKGROUND: In patients with symptomatic congestive heart failure receiving optimal therapy with an angiotensin-converting enzyme (ACE) inhibitor and a beta-blocker, the impact of using an angiotensin receptor blocker on submaximal exercise capacity and on neurohumoral activation at rest and during stress has not been investigated. METHODS: Thirty-three patients with congestive heart failure, New York Heart Association II or III symptoms, and left ventricular ejection fraction 25.5% +/- 7.2% treated with an ACE inhibitor and a beta-blocker were recruited. Patients were randomly assigned to receive irbesartan 150 mg per day (n = 22) or a placebo (n = 11) for 6 months. Maximal exercise capacity was assessed using a ramp protocol. Submaximal exercise duration was assessed using a constant load protocol, and plasma norepinephrine and angiotensin II (A-II) were measured in resting state, at 6 minutes, and at peak exercise. RESULTS: Patients treated with irbesartan presented a 26% increase in submaximal exercise time (+281 seconds, P = .08) whereas exercise duration increased by only 7% in patients treated with a placebo (+128 seconds, P = NS irbesartan vs placebo). Norepinephrine levels increased to a similar extent in both groups, whereas A-II levels did not increase or change in response to therapy. CONCLUSIONS: Dual A-II suppression with an ACE inhibitor plus irbesartan provides a small but a significant increase in submaximal exercise capacity. This beneficial effect is observed despite no significant changes in maximal exercise capacity, and in resting or exercise-induced increase in neurohumoral activation.
Adrenergic beta-Antagonists↗
Economic impact of the reduced incidence of atrial fibrillation in patients with heart failure treated with enalapril.
BACKGROUND: Atrial fibrillation (AF) in the setting of heart failure (HF) is linked to embolic stroke and exacerbation of HF. The rate of new-onset AF in patients with left ventricular dysfunction and mild to moderate HF enrolled in the SoLVD trials was significantly lower with enalapril than with placebo (5.4% vs 24% over 2.9 years, P < .0001). The objective of this study was to predict economic benefits over 5 and 10 years of reduced AF incidence in patients receiving enalapril for the treatment of HF from a Canadian third-party payer perspective. METHODS: Consequences of reduced incidence of AF in enalapril-treated patients were modeled using a Markov model. Patients were assigned to 1 health state: no AF, AF, poststroke, or death, and moved from one state to the other according to published incidence rates. It was assumed that most patients with AF would receive warfarin for stroke prevention. Resource use and costs were mostly retrieved from published Canadian studies. RESULTS: Reduced incidence of AF resulted in savings of 382 dollars and 525 dollars per patient treated with enalapril over 5 and 10 years, respectively, which stemmed mainly from reduced AF hospitalization and less need for warfarin and amiodarone. Sensitivity analyses demonstrated that enalapril becomes more cost saving as the baseline risk for embolic stroke in patients with AF increases and the use of warfarin prophylaxis decreases. CONCLUSIONS: Reduced incidence of AF with enalapril leads to significant clinical and economic advantages on top of the already well-established benefits of enalapril for patients with HF.
Atrial Fibrillation↗
Incidence and significance of abnormal hepatic venous Doppler flow velocities before cardiac surgery.
OBJECTIVE: The purpose of this study was to determine the incidence and significance of abnormal hepatic Doppler venous flow velocities as signs of an abnormal right ventricular filling pattern before cardiac surgery. DESIGN: Retrospective and prospective validation study. SETTING: Tertiary care hospital. PARTICIPANTS: Cardiac surgical patients (121 patients). INTERVENTIONS: Not applicable. MEASUREMENTS: Demographic, hemodynamic, and echocardiographic variables; vasoactive support; and difficult separation from bypass were compared between patients with or without abnormal hepatic venous Doppler flow. Logistic regression analysis was performed to identify predictors of difficult separation from bypass. Abnormal hepatic venous flow was observed in 23 (29%) and 17 patients (41%) in the retrospective and prospective study. Abnormal hepatic venous flow before surgery was associated with more vasoactive support in both the retrospective (p = 0.0362) and prospective study (p = 0.0163). In the prospective study, abnormal hepatic venous flow was associated with a higher Parsonnet score (p = 0.0005), more atrial fibrillation (p < 0.0001), pacemaker requirement (p = 0.0124), mitral valve replacement (p = 0.0325), reoperation (p = 0.0050), lower mean arterial pressure to pulmonary artery pressure ratio (p = 0.0127), higher wall motion score index (p = 0.0491), and higher incidence of abnormal right ventricular systolic function (p = 0.0139). Abnormal hepatic venous flow was not found to be an independent predictor of difficult separation from bypass. CONCLUSIONS: Abnormal hepatic venous flow velocities before cardiac surgery are frequent and are associated with increased need for vasoactive support after cardiopulmonary bypass. However, it is not an independent predictor of difficult separation from bypass and worse outcome.
Aged↗
Three-dimensional trajectory assessment of an IVUS transducer from single-plane cineangiograms: a phantom study.
The recovery of the three-dimensional (3-D) path of the transducer used during an intravascular ultrasound (IVUS) examination is of primary importance to assess the exact 3-D shape of the vessel under study. Traditionally, the reconstruction is done by simply stacking the images during the pullback, or more recently using biplane angiography to recover the vessel curvature. In this paper, we explain, how single-plane angiography can be used with two projection models, to perform this task. Two types of projection geometry are analyzed: weak-perspective and full-perspective. In weak-perspective projection geometry, the catheter path can be reconstructed without prior transducer depth information. With full-perspective projection geometry, precise depth location of reference points are needed in order to minimize the error of the recovered transducer angle of incidence. The transducer angulation reconstruction is based on the foreshortening effect as seen from the X-ray images. By comparing the measured to the true transducer length, we are able to get its incidence angle. The transducer trajectory is reconstructed by stitching together the different estimated angulations obtained from each image in a cineangiogram sequence. The method is described and validated on two helical vessel phantoms, giving on average a reconstructed path that is less than 2 mm distant from the true path when using full-perspective projection.
Catheterization↗
The drug-based pipeline against restenosis.
More than 1 million percutaneous coronary interventions (PCIs) are performed yearly worldwide. Restenosis is the recurrent narrowing that can occur within 6 months following an initially successful PCI. Although drug-eluting stents have accomplished remarkable success, restenosis has not been eliminated and optimisation of both the polymers and drugs associated with them is desirable. This article reviews the presently available and potential preventive approaches against restenosis, including the sirolimus and paclitaxel drug-eluting stents.
Anti-Inflammatory Agents↗
Are Canadian guidelines for cholesterol lowering in high-risk patients optimal?
Recent Canadian lipid guidelines recommend that all high-risk patients receive medication to reduce low density lipoprotein cholesterol (LDL-C) below 2.5 mmol/L. The recently published Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) and Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) studies compared strategies of cholesterol lowering with atorvastatin 80 mg versus pravastatin 40 mg. Atorvastatin halted the progression of atherosclerosis (whereas atherosclerosis progressed in the patients receiving pravastatin), and resulted in a 16% reduction in the primary composite end point (all-cause death, myocardial infarction, unstable angina, revascularization and stroke) compared with the pravastatin-treated group. In the PROVE IT trial, LDL-C was reduced by atorvastatin to 1.6 mmol/L and by pravastatin to 2.46 mmol/L. Although lower LDL-C levels are one explanation for the improved outcomes with atorvastatin, pleiotropic differences of the two statins, such as their effects on inflammation and coagulation, cannot be excluded. Until trials are completed that compare outcomes from LDL-C lowering to different targets with the same statin, it is premature to recommend changes to the current Canadian guidelines. However, future recommendations may suggest much lower LDL-C targets than those currently recommended.
Atorvastatin↗