Binh An P. Phan

MR Imaging of Carotid Plaque Composition During Lipid-Lowering Therapy: A Prospective Assessment of Effect and Time Course

OBJECTIVES The purpose of this study was to test the lipid depletion hypothesis and to establish the time course of change in carotid plaque morphology and composition during lipid therapy using high-resolution magnetic resonance imaging (MRI). BACKGROUND Lipid therapy is thought to improve plaque stability and reduce cardiovascular events by targeting the plaque rupture risk features such as large lipid core, thin fibrous cap, and high level of inflammatory infiltrates. However, the plaque stabilizing process during lipid therapy has not been clearly demonstrated in humans and in vivo. METHODS Subjects with coronary or carotid artery disease, apolipoprotein B ≥120 mg/dl, and lipid treatment history <1 year, were randomly assigned to atorvastatin monotherapy or to atorvastatin-based combination therapies with appropriate placebos for 3 years. All subjects underwent high-resolution, multicontrast bilateral carotid MRI scans at baseline and annually for 3 years. All images were analyzed for quantification of wall area and plaque composition blinded to therapy, laboratory results, and clinical course. RESULTS After 3 years of lipid therapy, the 33 subjects with measurable lipid-rich necrotic core (LRNC) at baseline had a significant reduction in plaque lipid content: LRNC volume decreased from 60.4 ± 59.5 mm(3) to 37.4 ± 69.5 mm(3) (p < 0.001) and %LRNC (LRNC area/wall area in the lipid-rich regions) from 14.2 ± 7.0% to 7.4 ± 8.2% (p < 0.001). The time course showed that %LRNC decreased by 3.2 (p < 0.001) in the first year, by 3.0 (p = 0.005) in the second year, and by 0.91 (p = 0.2) in the third year. Changes in LRNC volume followed the same pattern. Percent wall volume (100 × wall/outer wall, a ratio of volumes) in the lipid-rich regions significantly decreased from 52.3 ± 8.5% to 48.6 ± 9.7% (p = 0.002). Slices containing LRNC had significantly more percent wall volume reduction than those without (-4.7% vs. -1.4%, p = 0.02). CONCLUSIONS Intensive lipid therapy significantly depletes carotid plaque lipid. Statistically significant plaque lipid depletion is observed after 1 year of treatment and continues in the second year, and precedes plaque regression. (Using Magnetic Resonance Imaging to Evaluate Carotid Artery Plaque Composition in People Receiving Cholesterol-Lowering Medications [The CPC Study]; NCT00715273).

Original ResearchMR Imaging of Carotid Plaque Composition During Lipid-Lowering Therapy: A Prospective Assessment of Effect and Time Course

OBJECTIVES The purpose of this study was to test the lipid depletion hypothesis and to establish the time course of change in carotid plaque morphology and composition during lipid therapy using high-resolution magnetic resonance imaging (MRI). BACKGROUND Lipid therapy is thought to improve plaque stability and reduce cardiovascular events by targeting the plaque rupture risk features such as large lipid core, thin fibrous cap, and high level of inflammatory infiltrates. However, the plaque stabilizing process during lipid therapy has not been clearly demonstrated in humans and in vivo. METHODS Subjects with coronary or carotid artery disease, apolipoprotein B ≥120 mg/dl, and lipid treatment history <1 year, were randomly assigned to atorvastatin monotherapy or to atorvastatin-based combination therapies with appropriate placebos for 3 years. All subjects underwent high-resolution, multicontrast bilateral carotid MRI scans at baseline and annually for 3 years. All images were analyzed for quantification of wall area and plaque composition blinded to therapy, laboratory results, and clinical course. RESULTS After 3 years of lipid therapy, the 33 subjects with measurable lipid-rich necrotic core (LRNC) at baseline had a significant reduction in plaque lipid content: LRNC volume decreased from 60.4 ± 59.5 mm(3) to 37.4 ± 69.5 mm(3) (p < 0.001) and %LRNC (LRNC area/wall area in the lipid-rich regions) from 14.2 ± 7.0% to 7.4 ± 8.2% (p < 0.001). The time course showed that %LRNC decreased by 3.2 (p < 0.001) in the first year, by 3.0 (p = 0.005) in the second year, and by 0.91 (p = 0.2) in the third year. Changes in LRNC volume followed the same pattern. Percent wall volume (100 × wall/outer wall, a ratio of volumes) in the lipid-rich regions significantly decreased from 52.3 ± 8.5% to 48.6 ± 9.7% (p = 0.002). Slices containing LRNC had significantly more percent wall volume reduction than those without (-4.7% vs. -1.4%, p = 0.02). CONCLUSIONS Intensive lipid therapy significantly depletes carotid plaque lipid. Statistically significant plaque lipid depletion is observed after 1 year of treatment and continues in the second year, and precedes plaque regression. (Using Magnetic Resonance Imaging to Evaluate Carotid Artery Plaque Composition in People Receiving Cholesterol-Lowering Medications [The CPC Study]; NCT00715273).

Ezetimibe therapy: mechanism of action and clinical update

The lowering of low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay for LDL-C lowering, a significant percentage of patients prescribed these agents either do not achieve targets with statin therapy alone or have partial or complete intolerance to them. For such patients, the use of adjuvant therapy capable of providing incremental LDL-C reduction is advised. One such agent is ezetimibe, a cholesterol absorption inhibitor that targets uptake at the jejunal enterocyte brush border. Its primary target of action is the cholesterol transport protein Nieman Pick C1 like 1 protein. Ezetimibe is an effective LDL-C lowering agent and is safe and well tolerated. In response to significant controversy surrounding the use and therapeutic effectiveness of this drug, we provide an update on the biochemical mechanism of action for ezetimibe, its safety and efficacy, as well as the results of recent randomized studies that support its use in a variety of clinical scenarios.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition A New Therapeutic Mechanism for Reducing Cardiovascular Disease Risk

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the regulation of cholesterol homeostasis. By binding to hepatic low-density lipoprotein (LDL) receptors and promoting their lysosomal degradation, PCSK9 reduces LDL uptake, leading to an increase in LDL cholesterol concentrations. Gain-of-function mutations in PCSK9 associated with high LDL cholesterol and premature cardiovascular disease have been causally implicated in the pathophysiology of autosomal-dominant familial hypercholesterolemia. In contrast, the more commonly expressed loss-of-function mutations in PCSK9 are associated with reduced LDL cholesterol and cardiovascular disease risk. The development of therapeutic approaches that inhibit PCSK9 function has therefore attracted considerable attention from clinicians and the pharmaceutical industry for the management of hypercholesterolemia and its associated cardiovascular disease risk. This review summarizes the effects of PCSK9 on hepatic and intestinal lipid metabolism and the more recently explored functions of PCSK9 in extrahepatic tissues. Therapeutic approaches that prevent interaction of PCSK9 with hepatic LDL receptors (monoclonal antibodies, mimetic peptides), inhibit PCSK9 synthesis in the endoplasmic reticulum (antisense oligonucleotides, siRNAs), and interfere with PCSK9 function (small molecules) are also described. Finally, clinical trials testing the safety and efficacy of monoclonal antibodies to PCSK9 are reviewed. These have shown dose-dependent decreases in LDL cholesterol (44%-65%), apolipoprotein B (48%-59%), and lipoprotein(a) (27%-50%) without major adverse effects in various high-risk patient categories, including those with statin intolerance. Initial reports from 2 of these trials have indicated the expected reduction in cardiovascular events. Hence, inhibition of PCSK9 holds considerable promise as a therapeutic option for decreasing cardiovascular disease risk.

Cardiovascular Effects of Exposure to Cigarette Smoke and Electronic Cigarettes : Clinical Perspectives From the Prevention of Cardiovascular Disease Section Leadership Council and Early Career Councils of the American College of Cardiology

Cardiovascular morbidity and mortality as a result of inhaled tobacco products continues to be a global healthcare crisis, particularly in low- and middle-income nations lacking the infrastructure to develop and implement effective public health policies limiting tobacco use. Following initiation of public awareness campaigns 50 years ago in the United States, considerable success has been achieved in reducing the prevalence of cigarette smoking and exposure to secondhand smoke. However, there has been a slowing of cessation rates in the United States during recent years, possibly caused by high residual addiction or fatigue from cessation messaging. Furthermore, tobacco products have continued to evolve faster than the scientific understanding of their biological effects. This review considers selected updates on the genetics and epigenetics of smoking behavior and associated cardiovascular risk, mechanisms of atherogenesis and thrombosis, clinical effects of smoking and benefits of cessation, and potential impact of electronic cigarettes on cardiovascular health.

Reproducibility of Carotid Atherosclerotic Lesion Type Characterization Using High Resolution Multicontrast Weighted Cardiovascular Magnetic Resonance

PURPOSE Cardiovascular magnetic resonance (CMR) can characterize carotid atherosclerosis. The purpose of this study is to evaluate reader agreement of carotid atherosclerotic lesion types by CMR. METHODS Carotid arteries of 34 patients (29 men, 5 women; mean age, 53 years) were imaged on a 1.5-T scanner. Images with 4 contrast weightings (T1, T2, proton density, and 3-dimensional time-of-flight) were acquired on each axial slice of the carotid arteries. Modified AHA criteria were used for lesion type assessment on the 4 selected axial slices (1 from the common carotid artery, 1 from the carotid bifurcation, and 2 from the internal carotid artery). The modified AHA criteria are as follows: type I-II, near-normal wall thickness without calcification; type III, diffuse wall thickening or small eccentric plaque without calcification; type IV-V, plaque with a lipid rich necrotic core surrounded by fibrous tissue with possible calcification; type VI, complex plaque with a possible surface defect, hemorrhage, or thrombus; type VII, calcified plaque; and type VIII, fibrotic plaque without a lipid core and with possible small calcifications. RESULTS Of the 272 possible axial slices (34 patients x 2 arteries per patient x 4 slices per artery), 256 slices were available for lesion type assessment. The majority (94%) of the lesions were of type I-II and III. kappa was 0.80 and 0.60 for intra-reader and inter-reader agreement of lesion types, respectively. Inter-reader disagreement for type I-II and type III occurred in 82% of lesions. Weighted kappa was 0.92 and 0.83 for intra-reader and inter-reader agreement of lesion types, respectively. CONCLUSION The difference between type I-II and III lesions lies in the definition of the vessel wall. The moderate inter-reader agreement suggests further efforts such as establishment of normal carotid artery wall thickness by a quantitative measure are needed for carotid atherosclerotic lesion characterization.

Effects of Niacin on Glucose Levels, Coronary Stenosis Progression, and Clinical Events in Subjects With Normal Baseline Glucose Levels (<100 mg/dl): A Combined Analysis of the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), and Carotid Plaque Composition by MRI During Lipid-Lowering (CPC) Study

Although the effect of niacin on the glucose levels in subjects with diabetes mellitus has been investigated, niacins effects on the glucose levels and atherosclerosis in subjects with normal glucose levels have not been well established. We examined the effect of niacin on the glucose levels, coronary stenosis progression using quantitative coronary angiography, and clinical events in 407 subjects who had a baseline glucose level <100 mg/dl and were enrolled in the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), or Carotid Plaque Composition by MRI during lipid-lowering (CPC) study testing active niacin therapy. Although the fasting glucose levels increased significantly within 3 years in both subjects treated with niacin (from 85.6 ± 9.5 to 95.5 ± 19.7 mg/dl, p <0.001) and without niacin (from 85.2 ± 9.6 to 90 ± 17.9 mg/dl, p = 0.009), those treated with niacin had a significantly larger increase in glucose levels than those not taking niacin (9.88 vs 4.05 mg/dl, p = 0.002). Overall, 29% of subjects developed impaired fasting glucose within 3 years. Incident impaired fasting glucose was significantly more likely to be observed in subjects treated with niacin than in those who were not. However, the frequency of new-onset diabetes mellitus did not differ significantly between the 2 groups (5.6% vs 4.8%, p = 0.5). Niacin-treated subjects compared to untreated subjects had significantly less change in mean coronary stenosis (0.1 ± 0.3% vs 2 ± 12%, p <0.0001) and less major cardiovascular events (8% vs 21%, p = 0.001). In conclusion, the use of niacin for 3 years in subjects with normal baseline glucose levels was associated with an increase in blood glucose levels and the risk of developing impaired fasting glucose, but not diabetes mellitus, and was associated with a significantly reduced incidence of coronary stenosis progression and major cardiovascular events.

Dyslipidemia in women: etiology and management

Dyslipidemia is highly prevalent among women. The management of dyslipidemia is a cornerstone in the prevention of both primary and secondary cardiovascular events, such as myocardial infarction, ischemic stroke, and coronary death. All major international guidelines on the treatment of dyslipidemia recommend similar approaches to the management of dyslipidemia in both men and women. Estrogen replacement therapy should not be considered as a therapeutic option for managing dyslipidemia in women. The reduction of atherogenic lipoprotein burden (reducing low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol based on risk-stratified thresholds and treatment targets) provided the framework for managing dyslipidemia in the US, Europe, Canada, and elsewhere in the world. Very recently, new guidelines in the US have changed this paradigm, whereby rather than focusing on treatment targets, risk now defines the intensity of treatment with statin therapy, with no specific goals for what level of low-density lipoprotein cholesterol should be attained. It is not clear if this will lead to changes in lipid guidelines in other parts of the world. In the meantime, region-specific guidelines should be followed. Lipid lowering with statin therapy does correlate with reductions in cardiovascular event rates in women. The clinical impact of treating dyslipidemias in women with nonstatin drugs (eg, fibrates, nicotinic acid, bile acid-binding resins, omega-3 fish oils) is as yet not determined.

Effects of adding extended-release niacin and colesevelam to statin therapy on lipid levels in subjects with atherosclerotic disease

BACKGROUND The use of combination therapies is needed to treat dyslipidemia in patients with both elevated low-density lipoprotein cholesterol (LDL-C) and low high-density lipoprotein cholesterol (HDL-C). We conducted a study to assess the efficacy and safety of combination therapy with statin plus extended-release (ER) niacin and colesevelam, aimed at lowering LDL-C and raising HDL-C, in subjects with atherosclerotic disease. METHODS This 1-year study randomized 123 subjects with atherosclerotic disease to atorvastatin alone, double therapy with atorvastatin plus ER niacin, or triple therapy with atorvastatin, plus ER niacin and colesevelam. Target LDL-C was ≤80 mg/dL for single and double therapy, and ≤60 mg/dL for triple therapy. Target HDL-C was an increase of ≥10 mg/dL for double and triple therapy. RESULTS Single therapy, with mean atorvastatin dose 30 mg/day, had a 47% reduction in LDL-C (P < 0.001) from 148 ± 29 mg/dL to 77 ± 15 mg/dL. With the addition of ER niacin, the double therapy had a 25% increase in HDL-C, from 42 ± 11 mg/dL to 53 ± 16 mg/dL (P < 0.001). The triple therapy decreased LDL-C by 57%, from 157 ± 29 mg/dL to 66 ± 18 mg/dL (P < 0.001), and increased HDL-C by 29%, from 40 ± 9 mg/dL to 50 ± 14 mg/dL (P < 0.001). Double and triple therapy required a lower atorvastatin dose of 20 mg/day to reach the target LDL-C levels. On average, 75% and 67% of subjects reached the predefined LDL-C and HDL-C treatment targets. No related myopathy or hepatotoxicity required stopping the therapy. CONCLUSION This study demonstrated that combination therapy with atorvastatin plus ER niacin and colesevelam can safely and effectively treat dyslipidemia in subjects with atherosclerotic disease.

Effect of contrast enhancement on the measurement of carotid arterial lumen and wall volume using MRI.

To investigate whether gadolinium (Gd)‐based contrast enhancement (CE) affects high‐resolution magnetic resonance imaging (MRI) measurements of carotid arterial wall volume.