The aim of this study was to demonstrate the early effects of statin treatment on plaque composition according to plaque stability on Intravascular Ultrasound-Virtual Histology at 6 months after a coronary event. Previous trials have demonstrated that lipid lowering therapy with statins decreases plaque volume and increases plaque echogenicity in patients with coronary artery disease.
Materials and Methods
Fifty-four patients (54 lesions) with acute coronary syndrome were prospectively enrolled. We classified and analyzed the target plaques into two types according to plaque stability: thin-cap fibroatheroma (TCFA, n=14) and non-TCFA (n=40). The primary end point was change in percent necrotic core in the 10-mm subsegment with the most disease.
After 6 months of statin therapy, no change was demonstrated in the mean percentage of necrotic core (18.7±8.5% to 20.0±11.0%, p=0.38). There was a significant reduction in necrotic core percentage in patients with TCFA (21.3±7.2% to 14.4±8.9%, p=0.017), but not in patients with non-TCFA. Moreover, change in percent necrotic core was significantly correlated with change in high-sensitivity C-reactive protein levels (r=0.4, p=0.003). Changes in low-density lipoprotein cholesterol levels and lipid core percentage demonstrated no significant associations.
A clear reduction of lipid core was observed only for the TCFA plaque type, suggesting that changes in plaque composition following statin therapy might occur earlier in vulnerable plaque than in stable plaque; the effect may be related to the anti-inflammatory effects of statins.
Acute coronary syndromes; statin; IVUS-VH
We investigated correlations of coronary plaque composition determined by virtual histology (VH) intravascular ultrasound (IVUS) and blood levels of biomarkers that represent the vulnerability of coronary plaques.
Materials and Methods
Pre- and postprocedural blood levels of high sensitivity C-reactive protein, soluble CD40 ligand (sCD40L), matrix metalloproteinase-9, and neopterin were measured in 70 patients with stable angina (SA) or unstable angina (UA) who were undergoing percutaneous coronary intervention (PCI) for single lesions. We evaluated the data for correlations between these biomarkers and necrotic core contents in PCI target lesions analyzed by VH.
Clinical characteristics, IVUS, VH, and biomarker blood levels were not different between the SA and the UA group except for more frequent previous statin use (52.3% vs. 23.1%, p=0.017) and lower remodeling index in the SA group (0.98±0.09 vs. 1.10±0.070, p<0.001). Among the biomarkers evaluated, only pre-PCI neopterin level showed a weakly significant correlation with the absolute volume of the necrotic core (r=0.320, p=0.008). Pre- and post-PCI blood levels of sCD40L (r=0.220, p=0.072; r=0.231, p=0.062) and post-PCI blood level of neopterin (r=0.238, p=0.051) showed trends toward weakly positive correlations with the absolute volume of necrotic core.
We found a weakly positive correlation between the pre-PCI neopterin level and necrotic core volume in the PCI-target lesion. The clinical implications of our findings need to be investigated in further studies.
Atherosclerosis; coronary artery disease; inflammation; intravascular ultrasound
Endothelial dysfunction and plaque formation are features of atherosclerosis. Inhibition of L-type calcium channels or HMG-CoA pathway improves endothelial function and reduces plaque size. Thus, we investigated in stable coronary artery disease (CAD) the effects of a calcium antagonist on coronary endothelial function and plaque size.
Methods and results
In 454 patients undergoing PCI, acetylcholine (10−6 to 10−4 M) was infused in a coronary segment without significant CAD. Changes in coronary diameter were measured and an intravascular ultrasound examination (IVUS) was performed. On top of statin therapy, patients were randomized in a double-blind fashion to placebo or nifedipine GITS 30–60 mg/day and followed for 18–24 months.
Blood pressure was lower on nifedipine than on placebo by 5.8/2.1 mmHg (P < 0.001) as was total and LDL cholesterol (4.8 mg/dL; P = 0.495), while HDL was higher (3.6 mg/dL; P = 0.026). In the most constricting segment, nifedipine reduced vasoconstriction to acetylcholine (14.0% vs. placebo 7.7%; P < 0.0088). The percentage change in plaque volume with nifedipine and placebo, respectively, was 1.0 and 1.9%, ns.
The ENCORE II trial demonstrates in a multi-centre setting that calcium channel blockade with nifedipine for up to 2 years improves coronary endothelial function on top of statin treatment, but did not show an effect of nifedipine on plaque volume.
Acetylcholine; Angiography; Endothelium; IVUS; Plaque
Statin treatment in patients with coronary heart disease is associated with a reduced incidence of short-term adverse events and endpoint cardiac events. However, the effects of statin treatment on atherosclerotic plaques, particularly stable plaques, remain poorly defined. In total, 228 consecutive patients with stable atherosclerotic plaques who had undergone coronary arteriography (CAG) and intravascular ultrasound (IVUS) were randomly assigned to receive placebo (placebo group, n=54) or atorvastatin (ATOR) at a single daily dose of 10 mg (ATOR 10 mg group, n=47), 20 mg (ATOR 20 mg group, n=45), 40 mg (ATOR 40 mg group, n=43) or 80 mg (ATOR 80 mg group, n=39). Endpoints, including serum lipids, serum inflammation, plaque volume and percentage of plaque necrosis were assessed after 3–6 months. At baseline, mean low-density lipoprotein (LDL), high-density lipoprotein (HDL) and high-sensitivity C-reactive protein (hs-CRP) levels, as well as plaque volumes and percentages of plaque necrosis, were similar between all groups. At 6 months of follow-up, the LDL levels in the ATOR groups were below those at their respective baselines (P<0.01). HDL levels in the ATOR 80 mg group following treatment were significantly higher compared with baseline (P=0.001). Additionally, they were significantly higher compared with those in the placebo, ATOR 10, 20 and 40 mg groups (P<0.01, P=0.001, P=0.048, P=0.047, respectively). Hs-CRP levels in the placebo group following treatment were higher compared with baseline levels (6.87±2.62 vs. 5.07±1.80, P<0.01), but hs-CRP levels in the ATOR 80 mg group following treatment were lower compared with baseline (3.59±1.07 vs. 6.10±2.12, P<0.01). According to the virtual histology (VH) of IVUS, the percentages of plaque necrosis following treatment in the placebo and ATOR 10 mg groups rose above baseline levels (15.51±12.56 vs. 7.69±1.31%, 13.54±11.76 vs. 7.83±1.43%, P<0.01) and conformed to the diagnostic criteria for unstable plaques (15.51±12.56, 13.54±11.76%). By contrast, in the ATOR 20, 40 and 80 mg groups, percentages of plaque necrosis remained stable following treatment compared with baseline (P=0.069, 0.846 and 0.643, respectively). Plaque volumes following treatment in the placebo, ATOR 10 and 20 mg groups were similar to baseline levels. However, in the ATOR 40 and 80 mg groups, plaque volumes decreased following treatment compared with baseline plaque volumes (30.69±8.12 vs. 37.09±12.01 mm3, 24.99±1.01 vs. 36.47±14.68 mm3, P=0.019, P<0.01, respectively). ATOR (20 mg/day) is able to lower LDL to standard levels while ATOR 40 mg/day was superior to 20 mg/day and had similar effects to 80 mg/day. Only ATOR 80 mg/day was able to increase HDL levels. Hs-CRP in patients without ATOR was higher and ATOR 80 mg/day decreased levels. ATOR ≥20 mg/day is able to stabilize plaques and ATOR 80 mg/day was superior to 20 and 40 mg/day. Thus, ATOR 40–80 mg/day reduces the volume of plaques.
dose-ranging; atorvastatin; serum lipids; serum inflammation; plaque morphology; stable atherosclerotic plaques
It is still controversial whether borderline lesions with a vulnerable plaque should be stented early or simply treated pharmacologically. No data exist concerning the potential effects of statin therapy on borderline vulnerable lesions in patients with acute coronary syndrome (ACS).
Material and methods
Fifty patients with ACS whose culprit lesions were classified as “borderline lesions” were enrolled. All patients were treated with atorvastatin (20 mg) for 12 months. Intravascular ultrasound (IVUS) was performed and matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), and high-sensitive C-reactive protein (hsCRP) levels were measured at baseline and 12-month follow-up.
At 12-month follow-up, we found: 1) IVUS revealed that minimal lumen cross-sectional area (CSA) increased but plaque/media (P&M) area and plaque burden decreased. A total of 25 soft plaques (50%) were transformed into fibrous plaques. 2) ApoB, MMP-9 and hsCRP levels decreased, but TIMP-1 level increased. 3) Stepwise multivariate linear regression analysis showed that the independent predictors for changes in P&M area/year were the decrease in MMP-9 and hsCRP levels.
Atorvastatin therapy stabilized borderline vulnerable plaques and reversed atherosclerosis progression in patients with ACS. Reversal of this progression was accompanied by a decrease in the levels of plasma MMP-9 and hsCRP. Changes in MMP-9 and hsCRP could predict vulnerable plaque stabilization.
intravascular ultrasound; atorvastatin; acute coronary syndrome; vulnerable plaque
The Japan Assessment of Pitavastatin and Atorvastatin in Acute Coronary Syndrome (JAPAN-ACS) trial demonstrated that early aggressive statin therapy in patients with ACS significantly reduces plaque volume (PV). Advanced glycation end products (AGEs) and the receptors of AGEs (RAGE) may lead to angiopathy in diabetes mellitus (DM) and may affect on the development of coronary PV. The present sub-study of JAPAN-ACS investigates the association between AGEs and RAGE, and PV.
Intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) was undertaken, followed by the initiation of statin treatment (either 4 mg/day of pitavastatin or 20 mg/day of atorvastatin), in patients with ACS. In the 208 JAPAN-ACS subjects, PV using IVUS in non-culprit segment > 5 mm proximal or distal to the culprit lesion and, serum levels of AGEs and soluble RAGE (sRAGE) were measured at baseline and 8–12 months after PCI.
At baseline, no differences in the levels of either AGEs or sRAGE were found between patients with DM and those without DM. The levels of AGEs decreased significantly with statin therapy from 8.6 ± 2.2 to 8.0 ± 2.1 U/ml (p < 0.001), whereas the levels of sRAGE did not change. There were no significant correlations between changes in PV and the changes in levels of AGEs as well as sRAGE. However, high baseline AGEs levels were significantly associated with plaque progression (odds ratio, 1.21; 95% confidence interval, 1.01 - 1.48; p = 0.044) even after adjusting for DM in multivariate logistic regression models.
High baseline AGEs levels were associated with plaque progression in the JAPAN-ACS trial. This relationship was independent of DM. These findings suggest AGEs may be related to long-term glucose control and other oxidative stresses in ACS.
Advanced glycation end products; Acute coronary syndrome; Intravascular ultrasound; Plaque; Statins
Recent lipid guidelines recommend aggressive low-density lipoprotein (LDL) cholesterol lowering in patients with coronary artery disease. To clarify the evidence for this recommendation, we conducted a meta-analysis of randomized controlled trials that compared different intensities of statin therapy.
We searched electronic databases (MEDLINE, EMBASE, Cochrane Central Registery of Controlled Trials, Web of Science) for randomized controlled trials published up to July 19, 2007, that compared statin regimens of different intensities in adults with coronary artery disease and that reported cardiovascular events or mortality. Data were pooled using random-effects models to calculate odds ratios (OR).
A total of 7 trials (29 395 patients) were included. Compared with less intensive statin regimens, more intensive regimens further reduced LDL levels (0.72 mmol/L reduction, 95% confidence interval [CI] 0.60–0.84 mmol/L), and reduced the risk of myocardial infarction (OR 0.83, 95% CI 0.77–0.91) and stroke (OR 0.82, 95% CI 0.71–0.95). Although there was no effect on mortality among patients with chronic coronary artery disease (OR 0.96, 95% CI 0.80–1.14), all-cause mortality was reduced among patients with acute coronary syndromes treated with more intensive statin regimens (OR 0.75, 95% CI 0.61–0.93). Compared with lower intensity regimens, more intensive regimens were associated with small absolute increases in rates of drug discontinuation (2.5%), elevated levels of aminotransferases (1%) and myopathy (0.5%), and there was no difference in noncardiovascular mortality. All 7 trials reported events by randomization arm rather than by LDL level achieved. About half of the patients treated with more intensive statin therapy did not achieve an LDL level of less than 2.0 mmol/L, and none of the trials tested combination therapies.
Our analysis supports the use of more intensive statin regimens in patients with established coronary artery disease. There is insufficient evidence to advocate treating to particular LDL targets, using combination lipid-lowering therapy to achieve these targets or for using more intensive regimens in patients without established coronary artery disease.
Gray-scale intravascular ultrasound (IVUS) is the modality that has been established as the golden standard for in vivo imaging of the vessel wall of the coronary arteries. The use of IVUS in clinical practice is an important diagnostic tool used for quantitative assessment of coronary artery disease. This has made IVUS the de-facto invasive imaging method to evaluate new interventional therapies such as new stent designs and for atherosclerosis progression-regression studies. However, the gray-scale representation of the coronary vessel wall and plaque morphology in combination with the limited resolution of the current IVUS catheters makes it difficult, if not impossible, to identify qualitatively (e.g. visually) the plaque morphology similar as that of histopathology, the golden standard to characterize and quantify coronary plaque tissue components. Meanwhile, this limitation has been partially overcome by new innovative IVUS-based post-processing methods such as: virtual histology IVUS (VH-IVUS, Volcano Therapeutics, Rancho Cordova, CA, USA), iMAP-IVUS (Bostoc Scientific, Santa Clara, CA, USA), Integrated Backscatter IVUS (IB-IVUS) and Automated Differential Echogenicity (ADE).
Intravascular ultrasound; Radiofrequency data analysis; Atherosclerosis; Tissue characterization
Combined hyperlipidemia results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins in association with reduced lipoprotein lipase activity. Thus, this condition is typically characterized by concurrent elevations in total cholesterol and triglycerides with decreased high-density lipoprotein cholesterol. High levels of apolipoprotein B-containing lipoproteins, most prominently carried by low-density lipoprotein (LDL) particles, are an important risk factor for coronary heart disease. Statin therapy is highly effective at lowering LDL cholesterol. Despite the benefits of statin treatment for lowering total and LDL cholesterol, many statin-treated patients still have initial or recurrent coronary heart disease events. In this regard, combined therapy with statins and fibrates is more effective in controlling atherogenic dyslipidemia in patients with combined hyperlipidemia than either drug alone. Furthermore, statins and fibrates activate PPARα in a synergistic manner providing a molecular rationale for combination treatment in coronary heart disease. Endothelial dysfunction associated with cardiovascular diseases may contribute to insulin resistance so that there may also be additional beneficial metabolic effects of combined statin/fibrates therapy. However, there has been little published evidence that combined therapy is synergistic or even better than monotherapy alone in clinical studies. Therefore, there is a great need to study the effects of combination therapy in patients. When statins are combined with gemfibrozil therapy, this is more likely to be accompanied by myopathy. However, this limitation is not observed when fenofibrate, bezafibrate, or ciprofibrate are used in combination therapy.
Statins; Fibrates; Endothelial function; Insulin resistance; Combined hyperlipidemia; Safety
Although intensive lipid lowering by statins can enhance plaque stability, few data exist regarding how early statins change plaque composition and morphology in clinical setting. Therefore, to examine early changes in plaque composition and morphology by intensive lipid lowering with statins, we evaluate coronary plaques from acute coronary syndrome (ACS) before and 3 weeks after lipid lowering by coronary CT angiography. We enrolled 110 patients with suspected ACS and underwent coronary CT. We defined plaque as unstable when CT number of plaque< 50HU and remodeling index (lesion diameter/reference diameter) >1.10. Rosuvastatin (5 mg/day) or atorvastatin (20 mg/day) were introduced to reduce low density lipoprotein cholesterol (LDL-C). Then, CT was again performed by the same condition 3 weeks after lipid lowering therapy. Total 10 patients (8 men, mean age 72.0 years), in whom informed consent regarding serial CT examination was obtained, were analyzed. Among them, 4 patients who denied to have intensive lipid lowering were served as controls. In remaining 6 patients, LDL-C reduced from 129.5±26.9 mg/dl to 68.5±11.1 mg/dl after statin treatment. Under these conditions, CT number of the targeted plaque significantly increased from 16.0±15.9 to 50.8±35.0 HU (p<0.05) and remodeling index decreased from 1.22±0.11 to 1.11±0.06 (p<0.05), although these values substantially unchanged in controls. These results demonstrate that MDCT-determined plaque composition as well as volume could be changed within 3 weeks after intensive lipid lowering. This may explain acute effects of statins in treatment of acute coronary syndrome.
Computed tomography; HMG-CoA reductase inhibitor; plaques; acute coronary syndrome
Statins reduce LDL cholesterol and prevent vascular events, but their net effects in people at low risk of vascular events remain uncertain.
This meta-analysis included individual participant data from 22 trials of statin versus control (n=134 537; mean LDL cholesterol difference 1·08 mmol/L; median follow-up 4·8 years) and five trials of more versus less statin (n=39 612; difference 0·51 mmol/L; 5·1 years). Major vascular events were major coronary events (ie, non-fatal myocardial infarction or coronary death), strokes, or coronary revascularisations. Participants were separated into five categories of baseline 5-year major vascular event risk on control therapy (no statin or low-intensity statin) (<5%, ≥5% to <10%, ≥10% to <20%, ≥20% to <30%, ≥30%); in each, the rate ratio (RR) per 1·0 mmol/L LDL cholesterol reduction was estimated.
Reduction of LDL cholesterol with a statin reduced the risk of major vascular events (RR 0·79, 95% CI 0·77–0·81, per 1·0 mmol/L reduction), largely irrespective of age, sex, baseline LDL cholesterol or previous vascular disease, and of vascular and all-cause mortality. The proportional reduction in major vascular events was at least as big in the two lowest risk categories as in the higher risk categories (RR per 1·0 mmol/L reduction from lowest to highest risk: 0·62 [99% CI 0·47–0·81], 0·69 [99% CI 0·60–0·79], 0·79 [99% CI 0·74–0·85], 0·81 [99% CI 0·77–0·86], and 0·79 [99% CI 0·74–0·84]; trend p=0·04), which reflected significant reductions in these two lowest risk categories in major coronary events (RR 0·57, 99% CI 0·36–0·89, p=0·0012, and 0·61, 99% CI 0·50–0·74, p<0·0001) and in coronary revascularisations (RR 0·52, 99% CI 0·35–0·75, and 0·63, 99% CI 0·51–0·79; both p<0·0001). For stroke, the reduction in risk in participants with 5-year risk of major vascular events lower than 10% (RR per 1·0 mmol/L LDL cholesterol reduction 0·76, 99% CI 0·61–0·95, p=0·0012) was also similar to that seen in higher risk categories (trend p=0·3). In participants without a history of vascular disease, statins reduced the risks of vascular (RR per 1·0 mmol/L LDL cholesterol reduction 0·85, 95% CI 0·77–0·95) and all-cause mortality (RR 0·91, 95% CI 0·85–0·97), and the proportional reductions were similar by baseline risk. There was no evidence that reduction of LDL cholesterol with a statin increased cancer incidence (RR per 1·0 mmol/L LDL cholesterol reduction 1·00, 95% CI 0·96–1·04), cancer mortality (RR 0·99, 95% CI 0·93–1·06), or other non-vascular mortality.
In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/L reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered.
British Heart Foundation; UK Medical Research Council; Cancer Research UK; European Community Biomed Programme; Australian National Health and Medical Research Council; National Heart Foundation, Australia.
This secondary analysis from the Stop Atherosclerosis in Native Diabetics Study examines the effects of lowering low-density lipoprotein cholesterol (LDL-C) with statins alone versus statins plus ezetimibe (E) on common carotid artery intimal medial thickness (CIMT) in patients with type 2 diabetes and no prior cardiovascular event.
It is unknown whether the addition of E to statin therapy affects subclinical atherosclerosis.
Within an aggressive group (target LDL-C ≤70mg/dL; non-high-density lipoprotein [non-HDL]-C ≤<100 mg/dL; systolic blood pressure [SBP] ≤115mmHg), change in CIMT over 36mos was compared in diabetic individuals >40 yrs receiving statins plus E versus statins alone. CIMT changes in both aggressive subgroups were compared with changes in the standard subgroups (target LDL-C ≤<100mg/dL; non-HDL-C ≤ 130 mg/dL; SBP ≤130mmHg).
Mean (95%CI) LDL-C was reduced by 31 (23, 37)mg/dL and 32 (27, 38)mg/dL in the aggressive group receiving statins plus E and statins alone, respectively, compared with changes of 1 (−3, 6) mg/dL in the standard group (p<0.0001 vs both aggressive subgroups. Within the aggressive group, mean IMT at 36mos regressed from baseline similarly in the E (−.025 [−05,.003] mm) and non-E subgroups (−.012 [−.03,.008] mm) but progressed in the standard treatment arm (0.039 [0.02, 0.06] mm), intergroup p<0.0001.
Reducing LDL-C to aggressive targets resulted in similar regression of CIMT in patients who attained equivalent LDL-C reductions from a statin alone or statin plus E. CIMT increased in those achieving standard targets.
ezetimibe; CIMT; atherosclerosis
Effective LDL-cholesterol (LDL-C) reduction improves vascular function and can bring about regression of atherosclerosis. Alterations in endothelial function can occur rapidly, but changes in atherosclerosis are generally considered to occur more slowly. Vascular magnetic resonance imaging (MRI) is a powerful technique for accurate non-invasive assessment of central and peripheral arteries at multiple anatomical sites. We report the changes in atherosclerosis burden and arterial function in response to open label statin treatment, in 24 statin-naïve newly diagnosed stable coronary artery disease patients. Patients underwent MRI before, and 3 and 12 months after commencing treatment. Mean LDL-C fell by 37% to 70.8 mg/dL (P < 0.01). The plaque index (normalised vessel wall area) showed reductions in the aorta (2.3%, P < 0.05) and carotid (3.1%, P < 0.05) arteries at 3 months. Early reductions in atherosclerosis of aorta and carotid observed at 3 months were significantly correlated with later change at 12 months (R2 = 0.50, P < 0.001; R2 = 0.22, P < 0.05, respectively). Improvements in aortic distensibility and brachial endothelial function that were apparent after 3 months treatment were sustained at the 12-month time point.
Statin; Magnetic resonance imaging; Aorta; Carotid; Atherosclerosis
The aim of this study was to assess the effects of a usual dose of simvastatin (20 mg/day) on plaque regression and vascular remodeling at the peri-stent reference segments after bare-metal stent implantation.
We retrospectively investigated serial intravascular ultrasound (IVUS) findings in 380 peri-stent reference segments (184 proximal and 196 distal to the stent) in 196 patients (simvastatin group, n = 132 vs. non-statin group, n = 64). Quantitative volumetric IVUS analysis was performed in 5-mm vessel segments proximal and distal to the stent.
IVUS follow-up was performed at a mean of 9.4 months after stenting (range, 5 to 19 months). No significant differences were observed in the changes in mean plaque plus media (P&M) area, mean lumen area, and mean external elastic membrane (EEM) area from post-stenting to follow-up at both proximal and distal edges between the simvastatin and non-statin group. Although lumen loss within the first 3 mm from each stent edge was primarily due to an increase in P&M area rather than a change in EEM area, and lumen loss beyond 3 mm from each stent edge was due to a combination of increased P&M area and decreased EEM area, no significant differences in changes were observed in P&M, EEM, and lumen area at every 1-mm subsegment between the simvastatin and non-statin group.
A usual dose of simvastatin does not inhibit plaque progression and lumen loss and does not affect vascular remodeling in peri-stent reference segments in patients undergoing bare-metal stent implantation.
Atherosclerosis; Ultrasonography, interventional; Lipids; Plaque
Intravascular photoacoustic (IVPA) imaging is a catheter-based, minimally invasive, imaging modality capable of providing high-resolution optical absorption map of the arterial wall. Integrated with intravascular ultrasound (IVUS) imaging, combined IVPA and IVUS imaging can be used to detect and characterize atherosclerotic plaques building up in the inner lining of an artery. In this paper, we present and discuss various representative applications of combined IVPA/IVUS imaging of atherosclerosis, including assessment of the composition of atherosclerotic plaques, imaging of macrophages within the plaques, and molecular imaging of biomarkers associated with formation and development of plaques. In addition, imaging of coronary artery stents using IVPA and IVUS imaging is demonstrated. Furthermore, the design of an integrated IVUS/IVPA imaging catheter needed for in vivo clinical applications is discussed.
Atherosclerosis; contrast agent; imaging catheter; intravascular photoacoustic (IVPA) imaging; intravascular ultrasound (IVUS) imaging; molecular imaging; stent; vulnerable plaque
Soft, lipid-containing carotid plaques, which appear echolucent on ultrasound imaging, have been associated with increased risk of ischemic stroke. We sought to investigate the effect of short-term treatment with atorvastatin on the change of carotid plaque echodensity. We treated 40 stroke-free and statin-naive subjects with 80 mg atorvastatin daily for 30 days. Computer assisted gray-scale densitometry (GSD) index was calculated at baseline and 30 days after treatment from the normalized plaque images. A multiple logistic regression was used to assess the effect modification of low-density lipoprotein (LDL) cholesterol on plaque stabilization after adjusting for age, sex, and smoking. The average number of carotid plaques at baseline was 2 (range: 0–5; 27 subjects with carotid plaque) and did not change 30 days following atorvastatin treatment. The mean GSD index significantly increased from 73±16 (range: 1–125) at baseline to 89±15 (range: 1–137) at 30 days after treatment (P<0.05). The adjusted odds ratio for the positive GSD plaque index change (vs. no change or decreased gray-scale median (GSM) index) was 1.71 (95% confidence interval: 1.1–7.6, P<0.01). In conclusion, we observed decreased echolucency (increased echodensity) of carotid artery plaques after short-term treatment with atorvastatin.
Carotid arteries; Carotid ultrasound; Atherosclerotic plaque; Echolucency; Statins
Background and Objectives
Non-invasive detection and characterization of plaque composition may constitute an important step in risk stratification and monitoring of the progression of coronary atherosclerosis. Multislice computed tomography (MSCT) allows for accurate, non-invasive detection and characterization of atherosclerotic plaques, as well as determination of coronary artery stenosis. The aim of this study was to determine the usefulness of MSCT for characterizing non-calcified coronary plaques previously classified by intravascular ultrasound (IVUS).
Subjects and Methods
Seventy-one plaques were evaluated in 42 patients undergoing MSCT and IVUS. Coronary plaques were classified as hypoechoic or hyperechoic based on IVUS echogenicity. On MSCT, CT attenuation was measured using circular regions of interest (ROI) and represented as Hounsfield units (HU).
MSCT attenuation in hypoechoic plaques was significantly lower than it was in hyperechoic plaques (52.9±24.6 HU vs. 98.6±34.9 HU, respectively, p<0.001). When comparing CT attenuation between hypoechoic and hyperechoic plaques, 60.2 HU was the cut-off value for differentiating between the two, with a 90.7% sensitivity and a 78.6% specificity.
MSCT might be a useful tool for non-invasively evaluating the characteristics of coronary artery plaques.
Atherosclerosis; Coronary arteries; X-ray computed tomography
Both statins and ezetimibe lower LDL-C, but ezetimibe’s effect on atherosclerosis is controversial. We hypothesized that lowering LDL-C cholesterol by adding ezetimibe to statin therapy would regress atherosclerosis measured by magnetic resonance imaging (MRI) in the superficial femoral artery (SFA) in peripheral arterial disease (PAD).
– Atherosclerotic plaque volume was measured in the proximal 15–20 cm of the SFA in 67 PAD patients (age 63±10, ABI 0.69±0.14) at baseline and annually x 2. Statin-naïve patients (n=34) were randomized to simvastatin 40mg (S, n=16) or simvastatin 40mg + ezetimibe 10mg (S+E, n=18). Patients already on statins but with LDL-C>80 mg/dl had open-label ezetimibe 10mg added (E, n=33). Repeated measures models estimated changes in plaque parameters over time and between-group differences.
– LDL-C was lower at year 1 in S+E (67±7mg/dl) than S (91±8mg/dl, p<0.05), but similar at year 2 (68±10 vs. 83±11mg/dl, respectively). Plaque volume did not change from baseline to year 2 in either S+E (11.5±1.4cm3 to 10.5±1.3cm3, p=NS) or S (11.0±1.5cm3 to 10.5±1.4cm3, p=NS). In E, plaque progressed from baseline to year 2 (10.0±0.8 cm3 to 10.8±0.9, p<0.01) despite a 22% decrease in LDL-C.
– Statin initiation with or without ezetimibe in statin-naïve patients halts progression of peripheral atherosclerosis. When ezetimibe is added to patients previously on statins, peripheral atherosclerosis progressed. Thus, ezetimibe’s effect on peripheral atherosclerosis may depend upon relative timing of statin therapy.
Clinical Trial Registration Information
- NCT00587678 http://clinicaltrials.gov/ct2/show/NCT00587678
peripheral vascular disease; lipids; magnetic resonance imaging; plaque; atherosclerosis
Non-invasive assessment of plaque volume and composition is important for risk stratification and long-term studies of plaque stabilisation. Our aim was to evaluate dual-source computed tomography (DSCT) and colour-coded analysis in the quantification and classification of coronary atheroma. DSCT and virtual histology intravascular ultrasound (IVUS-VH) were prospectively performed in 14 patients. 22 lesions were compared in terms of plaque volume, maximal per cent vessel stenosis and percentages of fatty, fibrous or calcified components. Plaque characterisation was performed with software that automatically segments luminal or outer vessel boundaries and uses CT attenuation for a colour-coded plaque analysis. Good correlation was found for per cent vessel stenosis in DSCT (53 ± 13%) and IVUS (51 ± 14%; r2 = 0.70). Mean volumes for entire plaque and non-calcified atheroma were 68.5 ± 33 mm3 and 56.7 ± 30 mm3, respectively, in DSCT and 60.8 ± 29 mm3 and 55.8 ± 26 mm3, respectively, in IVUS. Mean percentages of fatty, fibrous or calcified components were 28.2 ± 6%, 53.2 ± 9% and 18.7 ± 13%, respectively, in DSCT and 29.9 ± 5%, 55.3 ± 12% and 14.4 ± 9%, respectively, in IVUS-VH. Significant overestimation was present for the entire plaque and the volume of calcified plaque (p = 0.03; p = 0.0004). Although good correlation with IVUS was obtained for the entire plaque (r2 = 0.76) and non-calcified plaque volume (r2 = 0.84), correlation proved very poor and insignificant for percentage plaque composition. Interclass correlation coefficients for non-calcified plaque volume and percentages of fatty, fibrous or calcified components were 0.99, 0.99, 0.95 and 0.98, respectively, and intraclass coefficients were 0.98, 0.93, 0.98 and 0.99, respectively. We found that using Hounsfield unit-based analysis, DSCT allows for accurate quantification of non-calcified plaque. Although percentage plaque composition proves highly reproducible, it is not correlated with IVUS-VH.
Serial intravascular ultrasound virtual histology (IVUS-VH) after implantation of metallic stents has been unable to show any changes in the composition of the scaffolded plaque overtime. The everolimus-eluting ABSORB scaffold potentially allows for the formation of new fibrotic tissue on the scaffolded coronary plaque during bioresorption. We examined the 12 month IVUS-VH changes in composition of the plaque behind the struts (PBS) following the implantation of the ABSORB scaffold. Using IVUS-VH and dedicated software, the composition of the PBS was analyzed in all patients from the ABSORB Cohort B2 trial, who were imaged with a commercially available IVUS-VH console (s5i system, Volcano Corporation, Rancho Cordova, CA, USA), immediately post-ABSORB implantation and at 12 month follow-up. Paired IVUS-VH data, recorded with s5i system, were available in 17 patients (18 lesions). The analysis demonstrated an increase in mean PBS area (2.39 ± 1.85 mm2 vs. 2.76 ± 1.79 mm2, P = 0.078) and a reduction in the mean lumen area (6.37 ± 0.90 mm2 vs. 5.98 ± 0.97 mm2, P = 0.006). Conversely, a significant decrease of 16 and 30% in necrotic core (NC) and dense calcium (DC) content, respectively, were evident (median % NC from 43.24 to 36.06%, P = 0.016; median % DC from 20.28 to 11.36%, P = 0.002). Serial IVUS-VH analyses of plaque located behind the ABSORB struts at 12-month demonstrated an increase in plaque area with a decrease in its NC and DC content. Larger studies are required to investigate the clinical impact of these findings.
Bioresorbable vascular scaffold; Coronary plaque; IVUS-VH; Everolimus; Necrotic core
Although intravascular ultrasound (IVUS) is widely used, there is limited published data on its accuracy in defining plaque characteristics in vivo. Optical coherence tomography (OCT) is a high-resolution imaging technique that takes advantage of the pronounced optical contrast between the components of normal and diseased vessels. The aim of this study was to evaluate the ability of conventional grey-scale IVUS in identifying in vivo coronary plaque characteristics, in particular lipid content as a marker of the vulnerable plaque, when compared to OCT.
Methods and results
In patients undergoing cardiac catheterisation, IVUS and OCT imaging was performed. Detailed qualitative analysis of lipid-rich plaque, calcific plaque, and plaque disruption were performed at corresponding sites using both modalities. A total of 146 matched sites were available for analysis. When compared to OCT, sensitivity of IVUS for identification of lipid pools was low (24.1%) but specificity was high (93.9%). The sensitivity and specificity of IVUS for detection of calcific plaque and plaque disruption were respectively 92.9%; 66.4%, and 66.7%; 96.1%.
Conventional grey-scale IVUS may not be a reliable imaging modality for detection of lipid-rich and hence vulnerable plaques. This has important implications in using conventional grey-scale IVUS to identify the vulnerable plaque.
Intravascular; ultrasound; optical; coherence tomography; coronary plaques
Atherosclerosis is a systemic disease that affects most vascular beds. The gold standard of atherosclerosis imaging has been invasive intravascular ultrasound (IVUS). Newer noninvasive imaging modalities like B-mode ultrasound, cardiac computed tomography (CT), positron emission tomography (PET), and magnetic resonance imaging (MRI) have been used to assess these vascular territories with high accuracy and reproducibility. These imaging modalities have lately been used for the assessment of the atherosclerotic plaque and the response of its volume to several medical therapies used in the treatment of patients with cardiovascular disease. To study the impact of these medications on atheroma volume progression or regression, imaging modalities have been used on a serial basis providing a unique opportunity to monitor the effect these antiatherosclerotic strategies exert on plaque burden. As a result, studies incorporating serial IVUS imaging, quantitative coronary angiography (QCA), B-mode ultrasound, electron beam computed tomography (EBCT), and dynamic contrast-enhanced magnetic resonance imaging have all been used to evaluate the impact of therapeutic strategies that modify cholesterol and blood pressure on the progression/regression of atherosclerotic plaque. In this review, we intend to summarize the impact of different therapies aimed at halting the progression or even result in regression of atherosclerotic cardiovascular disease evaluated by different imaging modalities.
Statin treatment markedly reduces the incidence of acute coronary events in patients with coronary atherosclerosis. Although imaging studies have indirectly shown the beneficial effects of statins on plaque morphology, there has to our knowledge been no reported histologic comparison of the morphology of coronary plaque in statin-treated versus untreated patients who had substantial coronary artery atherosclerosis.
We retrospectively studied arterial sections from the native hearts of patients who had experienced end-stage ischemic heart disease and subsequent cardiac transplantation. Of 44 qualified patients, 33 study patients had received pre-transplantation statin therapy, and 11 control patients had not.
Pathologic examination of each explanted heart confirmed coronary artery disease and previous myocardial infarction in all patients. Diabetes mellitus was more prevalent in the study group. The groups were similar in levels of total and low-density lipoprotein cholesterol, and in the available number of arterial cross-sections per patient.
All patients had plaques. High-grade lesions were found in 66.3% of cross-sections in the control group, and in 34.6% in the study group (P=0.011). Conversely, the degree of inflammation was markedly lower in the study group: low-grade fibrous plaques occurred in 45.7% of cross-sections in the study group, versus 11.3% in the control group (P=0.006).
The study group had significantly fewer high-grade plaques and more fibrous plaques than did the control group at the time of transplantation. Our findings show that statin therapy substantially enhances plaque stabilization. We further suggest that reduction of plaque inflammation is an important aspect of this stabilization.
Antilipemic agents/therapeutic use; arteriosclerosis/drug therapy; coronary artery disease/classification/complications/drug therapy/pathology/prevention & control; coronary vessels/pathology; hydroxymethylglutaryl-CoA reductase inhibitors/therapeutic use; hyperlipidemias/blood/complications/drug therapy; immunohistochemistry; inflammation/drug therapy/physiopathology; macrophages/drug effects/pathology; muscle, smooth, vascular/drug effects/pathology; vascular patency/drug effects
Mixed dyslipidemia is a common lipid disorder characterized by the presence of an atherogenic lipoprotein phenotype due to abnormalities in various atherogenic and anti-atherogenic lipoproteins. Despite the link between the decrease of LDL-cholesterol by statin treatment and the prevention of cardiovascular disease, a high residual risk is observed in statin trials. This residual risk is partly explained by lipoprotein abnormalities other than LDL. Fenofibrate exerts a favorable effect on the atherogenic lipid profile of mixed dyslipidemia and can effectively reduce cardiovascular disease in patients with mixed dyslipidemia. Fenofibrate may offer important treatment alternatives as a second-line therapy in several circumstances: in combination with a statin for patients with mixed dyslipidemias not at goals on statin mono-therapy; in monotherapy for patients intolerant or with contraindication to statin therapy; and in combination with other drugs (ezetimibe, colesevelam) for patients with mixed dyslipidemias, known intolerance, or contraindication to statin and not at goals on fenofibrate monotherapy. However, the role of fenofibrate-statin therapy and of other therapies involving fenofibrate in cardiovascular risk reduction strategies remains to be established.
fenofibrate; mixed dyslipidemia; triglycerides; LDL-cholesterol; HDL-cholesterol
Reducing low-density lipoprotein cholesterol (LDL-C) is associated with reduced risk for major coronary events. Despite statin efficacy, a considerable proportion of statin-treated hypercholesterolemic patients fail to reach therapeutic LDL-C targets as defined by guidelines. This study compared the efficacy of ezetimibe added to ongoing statins with doubling the dose of ongoing statin in a population of Taiwanese patients with hypercholesterolemia.
This was a randomized, open-label, parallel-group comparison study of ezetimibe 10 mg added to ongoing statin compared with doubling the dose of ongoing statin. Adult Taiwanese hypercholesterolemic patients not at optimal LDL-C levels with previous statin treatment were randomized (N = 83) to ongoing statin + ezetimibe (simvastatin, atorvastatin or pravastatin + ezetimibe at doses of 20/10, 10/10 or 20/10 mg) or doubling the dose of ongoing statin (simvastatin 40 mg, atorvastatin 20 mg or pravastatin 40 mg) for 8 weeks. Percent change in total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C) and triglycerides, and specified safety parameters were assessed at 4 and 8 weeks.
At 8 weeks, patients treated with statin + ezetimibe experienced significantly greater reductions compared with doubling the statin dose in LDL-C (26.2% vs 17.9%, p = 0.0026) and total cholesterol (20.8% vs 12.2%, p = 0.0003). Percentage of patients achieving treatment goal was greater for statin + ezetimibe (58.6%) vs doubling statin (41.2%), but the difference was not statistically significant (p = 0.1675). The safety and tolerability profiles were similar between treatments.
Ezetimibe added to ongoing statin therapy resulted in significantly greater lipid-lowering compared with doubling the dose of statin in Taiwanese patients with hypercholesterolemia. Studies to assess clinical outcome benefit are ongoing.
Registered at ClinicalTrials.gov: NCT00652327
Ezetimibe; Simvastatin; Atorvastatin; Pravastatin