Plaque Characterization Using Intracoronary Imaging: Effects of Lipid-lowering Therapies

The clinical evidence on the efficacy of lipid lowering therapy in patients with coronary artery disease (CAD) is unequivocally established. However, the effects of these therapies on plaque composition and stability are less clear. The use of intracoronary imaging (ICI) technologies has emerged as a complement to conventional angiography to further characterize plaque morphology and detect high-risk plaque features related to cardiovascular events. Along with clinical outcomes studies, parallel imaging trials employing serial evaluations with intravascular ultrasound (IVUS) have shown that pharmacological treatment has the capacity to either slow disease progression or promote plaque regression, depending on the degree of lipid lowering achieved. Subsequently, the introduction of high-intensity lipid lowering therapy led to much lower levels of low-density lipoprotein cholesterol (LDL-C) levels than achieved in the past, resulting in greater clinical benefit. However, the degree of atheroma regression showed in concomitant imaging trials appeared more modest as compared to the magnitude of clinical benefit accrued from high-intensity statin therapy. Recently, new randomized trials have investigated the additional effects of achieving very low levels of LDL-C on high-risk plaque features-such as fibrous cap thickness and large lipid accumulation-beyond its size. This paper provides an overview of the currently available evidence of the effects of moderate to high-intensity lipid lowering therapy on high-risk plaque features as assessed by different ICI modalities, reviews data supporting the use of these trials, and analyse the future perspectives in this field.

Patients with peripheral artery disease (PAD) are at increased risk of major adverse limb events (MALE). Furthermore, MALE have several clinical implications and a poor prognosis, so prevention is a fundamental issue. The main objective of the present meta-analysis of randomized clinical trials is to evaluate the effect of different lipid-lowering therapies on MALE incidence in patients with PAD. A meta-analysis of randomized studies that evaluated the use of lipid-lowering therapy in patients with PAD and reported MALE was performed, after searching the PubMed/MEDLINE, Embase, ScieLO, Google Scholar, and Cochrane Controlled Trials databases. A fixed- or random-effects model was used. Five randomized clinical trials including 11,603 patients were identified and considered eligible for the analyses (5903 subjects were allocated to receive lipid-lowering therapy, while 5700 subjects were allocated to the respective placebo/control arms). The present meta-analysis revealed that lipid-lowering therapy was associated with a lower incidence of MALE (OR: 0.76, 95% confidence interval: 0.66-0.87; I2: 28%) compared to placebo/control groups. The sensitivity analysis shows that the results are robust. This study demonstrated that the use of lipid-lowering therapy compared with the placebo/control arms was associated with a marked reduction in the risk of MALE. Physicians involved in the monitoring and treatment of patients with PAD must work hard to ensure adequate lipid-lowering medication in these patients.

Since the publication of the JUPITER trial, attention has been focused on the adverse glycemic effects of statin therapy. Although the modest increase in the risk of new diabetes mellitus is outweighed by the reduction in cardiovascular events for statins, emerging biochemical and genetic links between lipid metabolism and glycemic control raise the prospect of a broader diabetogenic effect of lipid-lowering therapies. For the novel and powerful PCSK9-inhibitor class available evidence does not support a major glycaemic effect with the results of large scale trials awaited although preliminary genetic data does suggest a link. In contrast, there is clear evidence of a diabetogenic effect for the now outdated but well-studied niacin. For ezetimibe and fibrates, evidence is scarce but currently broadly unconcerning. For now, the glycemic effects of lipid-lowering therapies should have a limited influence on clinical decision-making. Further study in this topical area is needed.

In patients with coronary artery disease, lipid lowering therapy during 2–5 years is associated with less progression of coronary atherosclerosis in comparison to placebo [1, 2, 3, 4, 5, 6]. The effect of lipid lowering therapy on regional myocardial perfusion is less well known. We evaluated the effect of lipid lowering therapy during 2 years on myocardial perfusion by assessment of the hyperemic mean transit time (HMTT) of contrast passage by means of digital subtraction angiography [7,8]. This effect was studied in patients with coronary artery disease with normal to moderately elevated cholesterol levels within a substudy of the REgression GRowth Evaluation Statin Study (REGRESS), and in patients with extensive coronary artery disease and severe hypercholesterolemia in the LDL-Apheresis Atherosclerosis Regression Study (LAARS) [7,9]. The methodologic issues and results of both studies are summarized, and discussed in relation to each other.

Atherothrombosis is a systemic disease of the vessel wall that causes distinct clinical manifestations, depending on the affected circulatory bed and the characteristics of the individual lesions.1 These lesions may be quite heterogeneous.1 Thus, the clinical manifestations of atherothrombosis of the coronary arteries, of the arteries supplying the central nervous system, of the aorta, and of the peripheral circulation can be significantly different. Disruption-prone plaques in the coronary arteries, the so-called “vulnerable plaques,” tend to have a thin fibrous cap (cap thickness ≈65 to 150 μm) and a large lipid core (American Heart Association [AHA] plaque type IV-Va). Acute coronary syndromes often result from disruption of a modestly stenotic vulnerable plaque, not visible by x-ray angiography, which results in a thrombotic complication (AHA plaque type VI). During its evolution, a type Va plaque may also become fibrotic (AHA plaque type Vc) or calcified (AHA plaque type Vb).2,3⇓ In contrast to coronary artery vulnerable plaques characterized by high lipid content and a thin fibrous cap, high-risk plaques of the carotid arteries tend to be fibrotic and severely stenotic.3 ### Imaging of Atherothrombotic Disease Because there is striking heterogeneity in the composition of human atherothrombotic plaques, even within the same individual, reliable noninvasive imaging tools that can detect early atherothrombotic disease in the various regions and characterize the composition of the plaques are clinically desirable.3 Such imaging tools would improve our understanding of the pathophysiological mechanisms underlying atherothrombotic processes and allow us to better risk-stratify the disease. Additionally, such tools may permit optimal tailoring of treatment and allow direct monitoring of the vascular response. Presently, a number of imaging modalities are employed to study atherosclerosis; most identify luminal diameter or stenosis, wall thickness, and plaque volume.3 Two noninvasive imaging modalities, computed tomography and MRI, have been introduced to the study …

In this issue of Circulation , Nabulsi and coworkers1 from the Atherosclerosis Risk in Communities (ARIC) Study Group report their findings on the association of age, menopause status, and hormone replacement therapy with a single measure of atherosclerosis: the average carotid artery intima-media thickness determined by B-mode ultrasound. What they discovered in the ARIC cohorts was this: there was little or no relation between menopausal staus and carotid thickness in women aged 45 to 54 who had never used hormonal therapy and who had no evidence of coronary heart disease at entry. Furthermore, for slightly older (aged 55 to 64 years) postmenopausal women, there was no relation between the number of years since menopause and carotid thickness nor between hormone use and carotid thickness. All of these findings were unexpected. Data that have been accumulated over the past few years demonstrate strong clinical benefits from estrogen use for postmenopausal women. The ARIC investigators quite logically hypothesized that there would be significant relations between carotid thickness, menopause, and hormone therapy (or lack of it) in this community-wide study, but in fact their data did not provide support for this. The investigators speculate that the association of estrogen replacement therapy with a reduction in clinical cardiovascular events after menopause may not necessarily be due to a reduction in the amount of anatomic atherosclerotic disease or inhibition of its formation, at least during the early years after menopause, but might instead be more attributable to other beneficial physiological changes brought about by estrogen compounds. The present ARIC study has a number of limitations, as the authors themselves recognize. First, the upper age limit for ARIC was 64 years, and it was revealed that the duration of hormone use in women currently using hormones at entry was 9 years. It is possible that …

Coronary stenosis severity is both a powerful and a still debated predictor of prognosis in coronary artery disease. Coronary computed tomographic angiography (CCTA) has emerged as a noninvasive technique that enables anatomic visualization of coronary artery disease (CAD). CCTA with newer applications, plaque characterization and physiologic/functional evaluation, allows a comprehensive diagnostic and prognostic assessment of otherwise low-intermediate subjects for primary prevention. CCTA measures the overall plaque burden, differentiates plaque subtypes, and identifies high-risk plaque with good reproducibility. Research in this field may also advance towards an era of personalized risk prediction and individualized medical therapy. It has been demonstrated that statins may delay plaque progression and change some plaque features. The potential effects on plaque modifications induced by other medical therapies have also been investigated. Although it is not currently possible to recommend routinely serial scans to monitor the therapeutic efficacy of medical interventions, the plaque modulation, as a part of risk modification, appears a feasible strategy. In this review we summarize the current evidence regarding vulnerable plaque and effects of lipid lowering therapy on morphological features of CAD. We also discuss the potential ability of CCTA to characterize coronary atherosclerosis, stratify prognosis of asymptomatic subjects, and guide medical therapy.

Decades of post-mortem evaluations have demonstrated that the plaques triggering fatal myocardial infarction have certain distinct morphologic characteristics. As various intracoronary imaging techniques have been developed and brought to market, there has been a growing interest to apply these imaging modalities to detect specific plaque morphologic features that may indicate lesion vulnerability. The focus of this chapter will be to discuss plaque characterization using each of the intracoronary imaging modalities that are currently available for clinical use in the United States. These intracoronary imaging modalities include intravascular ultrasound (IVUS), optical coherence tomography (OCT), and near-infrared spectroscopy (NIRS). This chapter will provide an overview of these modalities in plaque characterization.

BackgroundIn studies where cross-sectional images of coronary arteries obtained with different imaging modalities are compared, the importance of correct co-localization and matching of images along the coronary artery longitudinal axis is obvious. However, it appears neglected that correct spatial orientation of the cross-sectional plane may not be obtainable just by rotating the images to ensure co-localization of identifiable landmarks such as sidebranches. A cross-section has two sides, one facing proximally and the other distally, and pairs of images reconstructed corresponding to these opposite points of view are mirror images of each other and not superimposable. This may be difficult if not impossible to recognize and unrecognized it will give rise to flawed results in the development and validation of imaging technologies aimed at plaque characterization (tissue mapping). We determined the imagined point of view for three commercially available intracoronary imaging systems used by invasive cardiologists and illustrate its importance in imaging modality validation.Methods and ResultsWe made an asymmetric phantom and investigated it with two different intravascular ultrasound (IVUS) systems and one optical coherence tomography (OCT) system. The asymmetry of the phantom allowed determination of the spatial orientation of the cross-sectional images. On all tested systems, an observer should imagine herself/himself standing proximal to the cross-section when looking at the intravascular images.ConclusionsThe tested intracoronary imaging modalities displayed cross-sectional images with a spatial orientation corresponding to a proximal point of view. Knowledge of the spatial orientation is mandatory when comparing and validating different imaging modalities aimed at plaque characterization.

Intracoronary Imaging for Percutaneous Coronary Intervention Guidance.

Aim . To analyze the associations of apolipoprotein E (APOE) gene polymorphisms (rs7412 and rs4420638) with the risk of coronary artery disease (CAD) and the effectiveness of lipid-lowering therapy with rosuvastatin. Material and methods . The study involved the analysis of deoxyribonucleic acid samples and phenotypic data of 1700 unrelated individuals of Slavic origin, natives of Central Russia. A pharmacogenetic testing included 205 patients with CAD. Patients were prescribed rosuvastatin with determination of lipid levels and intima-media thickness (IMT) after 6 and 12 months of follow-up. Results. Carriers of the minor T allele for rs7412 polymorphism of the APOE gene were characterized by a lower CAD risk and a higher baseline level of low-density lipoprotein cholesterol (LDL-C). Associations of this polymorphism depended on body mass index. An association with an increased CAD risk was typical for male carriers of the variant G allele for rs4420638 polymorphism of the APOE gene. When treating CAD patients with rosuvas-tatin, a more pronounced lipid-lowering effect on total cholesterol and LDL-C was characteristic of individuals homozygous for the minor T allele for rs7412 of the APOE gene after 1 month of therapy; decrease of the lipidlowering effect with respect to total cholesterol took place in carriers of the heterozygous A/G genotype of rs4420638 polymorphism of the APOE gene after 12 months of therapy. An association was found between the rs7412 polymorphism of the APOE gene and the changes of maximum IMT in CAD patients treated with rosuvastatin. It consisted of the absence of IMT regression in T allele carriers after 6 months of lipid-lowering therapy. Conclusion. Polymorphisms of the APOE gene are associated with parameters of cholesterol metabolism, the risk of CAD and the effectiveness of lipid-lowering therapy with rosuvastatin.

Aim . To analyze the associations of apolipoprotein E (APOE) gene polymorphisms (rs7412 and rs4420638) with the risk of coronary artery disease (CAD) and the effectiveness of lipid-lowering therapy with rosuvastatin. Material and methods . The study involved the analysis of deoxyribonucleic acid samples and phenotypic data of 1700 unrelated individuals of Slavic origin, natives of Central Russia. A pharmacogenetic testing included 205 patients with CAD. Patients were prescribed rosuvastatin with determination of lipid levels and intima-media thickness (IMT) after 6 and 12 months of follow-up. Results. Carriers of the minor T allele for rs7412 polymorphism of the APOE gene were characterized by a lower CAD risk and a higher baseline level of low-density lipoprotein cholesterol (LDL-C). Associations of this polymorphism depended on body mass index. An association with an increased CAD risk was typical for male carriers of the variant G allele for rs4420638 polymorphism of the APOE gene. When treating CAD patients with rosuvas-tatin, a more pronounced lipid-lowering effect on total cholesterol and LDL-C was characteristic of individuals homozygous for the minor T allele for rs7412 of the APOE gene after 1 month of therapy; decrease of the lipidlowering effect with respect to total cholesterol took place in carriers of the heterozygous A/G genotype of rs4420638 polymorphism of the APOE gene after 12 months of therapy. An association was found between the rs7412 polymorphism of the APOE gene and the changes of maximum IMT in CAD patients treated with rosuvastatin. It consisted of the absence of IMT regression in T allele carriers after 6 months of lipid-lowering therapy. Conclusion. Polymorphisms of the APOE gene are associated with parameters of cholesterol metabolism, the risk of CAD and the effectiveness of lipid-lowering therapy with rosuvastatin.

BACKGROUND: Elevated triglyceride levels—hypertriglyceridemia, representing an imbalance of lipid parameters—play a key role in contemporary lipid metabolism research and are associated with an increased risk of atherosclerotic cardiovascular disease. An insufficient response to lipid-lowering therapy is of major clinical importance in the management of cardiology patients and requires optimization under real-world clinical practice conditions. AIM: To evaluate the effectiveness of lipid-lowering therapy in a population of cardiology patients aged 18–90 years with hypertriglyceridemia in real-world clinical practice at an outpatient urban cardiology medical center. METHODS: This retrospective study included 693 cardiology patients aged 18–90 years with hypertriglyceridemia. Clinical diagnoses were established based on medical records, anthropometric measurements, and laboratory test results. RESULTS: Lipid-lowering therapy was administered to 459 patients (66.2%). Initiation of lipid-lowering therapy was required in 42 patients (6.1%). Adjustment of the therapeutic regimen was performed in 184 patients (36.7%) receiving pharmacological treatment. Target triglyceride levels were achieved in 309 patients (44.6%), total cholesterol targets in 106 (15.3%), low-density lipoprotein cholesterol targets in 201 (29.0%), high-density lipoprotein cholesterol targets in 362 (52.2%), and non-high-density lipoprotein cholesterol targets in 186 patients (26.8%). CONCLUSION: The effectiveness of lipid-lowering therapy among patients with hypertriglyceridemia was insufficient, indicating the need for more aggressive pharmacotherapy of this lipid metabolism disorder in the management of cardiology patients. Initiation and intensification of triglyceride-lowering therapy in routine clinical care, as well as increased physician awareness of hypertriglyceridemia, appear warranted.

Recent advances in coronary angioscopy

Angioscopy enables us macroscopic pathological diagnosis of cardiovascular diseases from the inside. This imaging modality has been intensively directed to characterizing vulnerable coronary plaques. Scoring of plaque color was developed, and based on prospective studies, dark yellow or glistening yellow plaques were proposed as vulnerable ones. Colorimetry apparatus was developed to assess yellow color of the plaques quantitatively. Effects of lipid-lowering therapies on coronary plaques were confirmed by angioscopy. However, since observation is limited to surface color and morphology, pitfalls of this imaging technology became evident. Near-infrared spectroscopy and near-infrared fluorescence angioscopy were developed for molecular imaging, and the latter method was successfully applied to patients. Color fluorescence angioscopy was also established for molecular and chemical basis characterization of vulnerable coronary plaques both in vitro and in vivo.