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Background: Vasa vasorum (VV) vessels are critical in the genesis of atherosclerosis. Therefore, we assessed measures of carotid VV, intima-media thickness (CIMT), and patient risk factors in a primary prevention population., Methods: We used multivariable linear models to evaluate the relationship between baseline covariates and a measure of carotid VV (VV ratio) and CIMT among 324 diabetics and 141 nondiabetics., Results: Median CIMT (in mm) and VV ratio among nondiabetics were 0.82 ± 0.22 and 0.80 ± 0.19, respectively, and 1.06 ± 0.19 and 1.21 ± 0.26 among diabetics (P < 0.0001). Diabetes was associated with 36% (95% CI: 24.3-48.0, P < 0.001) higher VV ratio whereas a unit change in BMI was associated with ≈1% (95% CI: 0.5-1.4, P < 0.001) change in VV ratio. A 10-year increase in age was associated with 4% (95% CI: 1-7, P = 0.005) higher CIMT. Each 10 mmHg increase in mean systolic blood pressure was associated with 2% (95% CI: 1-4, P = 0.003) higher CIMT whereas diabetes conferred 31% (95% CI: 19.1-42.1, P < 0.001) higher CIMT. Female sex was associated with a 9% (95% CI: -12.9 to -4.1, P < 0.001) lower CIMT. Low density lipoprotein (LDL) cholesterol, blood pressure, and CIMT were not significantly associated with VV ratio., Conclusion: In this cohort of patients with low CIMT, VV ratio, and CIMT were distinctly unrelated, but each independently associated with diabetes. VV ratio and CIMT relationships warrant further investigation in large-scale studies and across a spectrum of atherosclerostic states., (© 2014, Wiley Periodicals, Inc.)

Introduction: The development of new surrogate markers of atherosclerosis is a crucial goal in the clinical setting, as they may allow physicians to recognize unstable lesions early and identify individuals with vulnerable or unstable lesions who bear an increased risk of future cardio--and cerebrovascular complications. These surrogate markers should be capable of being measured noninvasively using safe and reliable methods. Recently, Nambi et al. demonstrated how the combined measurement of carotid intima media thickness (CIMT) and occurrence of carotid plaques improves the risk prediction of cardiovascular outcomes. These results confirm the value of carotid ultrasound (US) when combined with traditional Framingham risk factors in assessing a patient's risk for atherosclerotic disease. Contrast-enhanced ultrasound (CEUS) is a new imaging approach that is evolving and may become a standard clinical tool for further atherosclerotic risk stratification in the future. The contrast agents used in US imaging are safe, commercially available, and approved for use in echocardiography by the FDA. Thus, CEUS is technically feasible with existing approved commercial equipment and can be performed at the bedside or in an outpatient setting. However, US contrast agents are not yet approved by the FDA for visualization and assessment of the carotid artery and its associated pathologies. The cost effectiveness of CEUS has been shown in the context of gastrointestinal imaging, and CEUS of carotid atherosclerotic lesions is emerging as an approach to complement unenhanced US imaging. By providing the direct visualization of adventitial vasa vasorum (VV) and intraplaque neovascularization, CEUS is capable of depicting two new surrogate markers of atherosclerosis - namely, adventitial VV and intraplaque neovascularization.

Carotid ultrasound measurement of carotid intima-media thickness (CIMT) and detection of plaques is a useful method to better assess cardiovascular disease risk status, especially in those at intermediate risk. We discuss the use CIMT and other emerging techniques such as contrast-enhanced carotid ultrasound imaging in the evaluation of the carotid artery and its value in cardiovascular disease.

Current developments in cardiovascular biology and imaging enable the noninvasive molecular evaluation of atherosclerotic vascular disease. Intraplaque neovascularization sprouting from the adventitial vasa vasorum has been identified as an independent predictor of intraplaque hemorrhage and plaque rupture. These intraplaque vasa vasorum result from angiogenesis, most likely under influence of hypoxic and inflammatory stimuli. Several molecular imaging techniques are currently available. Most experience has been obtained with molecular imaging using positron emission tomography and single photon emission computed tomography. Recently, the development of targeted contrast agents has allowed molecular imaging with magnetic resonance imaging, ultrasound and computed tomography. The present review discusses the use of these molecular imaging techniques to identify inflammation and intraplaque vasa vasorum to identify vulnerable atherosclerotic plaques at risk of rupture and thrombosis. The available literature on molecular imaging techniques and molecular targets associated with inflammation and angiogenesis is discussed, and the clinical applications of molecular cardiovascular imaging and the use of molecular techniques for local drug delivery are addressed.

Aim: To evaluate the agreement between contrast-enhanced ultrasound imaging and histopathology in an animal model of atherosclerosis., Methods and Results: Atherosclerosis was studied in both femoral arteries of four Rapacz familial hypercholesterolaemia (RFH) swine. Contrast-enhanced ultrasound imaging of the eight femoral arteries was performed at baseline and at 5, 12, 26, and 43 weeks follow-up after percutaneous transluminal stimulation of atherosclerosis to assess the progression of intima-media thickness (IMT) and the density and extent of the vasa vasorum network. Contrast-enhanced ultrasound imaging allowed an early detection of atherosclerosis and showed a significant gradual progression of atherosclerosis over time. IMT increased from 0.22 +/- 0.05 mm at baseline to 0.45 +/- 0.06 mm (P < 0.001) at follow-up. The density of the vasa vasorum network increased during follow-up and was significantly higher in advanced than in early atherosclerosis. The findings with contrast-enhanced ultrasound were confirmed by histopathological specimens of the arterial wall., Conclusion: Contrast-enhanced ultrasound is effective for in vivo detection of vasa vasorum in atherosclerotic plaques in the RFH swine model. After stimulation of atherosclerosis, contrast-enhanced ultrasound demonstrated a significantly increased IMT and significantly increased density of the vasa vasorum network in the developing atherosclerotic plaque, which was validated by histology.

Background and Purpose: Histological data associate proliferation of adventitial vasa vasorum and intraplaque neovascularization with vulnerable plaques represented by symptomatic vascular disease. In this observational study, the presence of carotid intraplaque neovascularization and adventitial vasa vasorum were correlated with the presence and occurrence of cardiovascular disease (CVD) and events (CVE)., Methods: The contrast-enhanced carotid ultrasound examinations of 147 subjects (mean age 64+/-11 years, 61% male) were analyzed for the presence of intraluminal plaque, plaque neovascularization (Grade 1=absent; Grade 2=present), and degree of adventitial vasa vasorum (Grade 1=absent, Grade 2=present). These observations were correlated with preexisting cardiovascular risk factors, presence of CVD, and history of CVE (myocardial infarction and transient ischemic attack/stroke)., Results: The presence of intraluminal carotid plaque was directly correlated to cardiovascular risk factors, CVD, and CVE (P<0.05). Adventitial vasa vasorum Grade 2 was associated with significant more subjects with CVD than vasa vasorum Grade 1 (73 versus 54%, P=0.029). Subjects with intraplaque neovascularization Grade 2 had significantly more often a history of CVE than subjects with intraplaque neovascularization Grade 1 (38 versus 20%, P=0.031). Multivariate logistic regression analysis revealed that presence of plaque was significantly associated with CVD (odds ratio 4.7, 95% CI 1.6 to 13.8) and intraplaque neovascularization grade 2 with CVE (odds ratio 4.0, 95% CI 1.3 to 12.6)., Conclusions: The presence and degree of adventitial vasa vasorum and plaque neovascularization were directly associated with CVD and CVE in a retrospective study of 147 patients undergoing contrast-enhanced carotid ultrasound.

Aims: Arterial vasa vasorum (VV) are known to be involved in the atherosclerotic process. The aim of the present study was to explore whether ultrasound imaging with contrast agent is able to visualize adventitial VV in human carotid atherosclerosis., Methods and Results: We studied with standard ultrasound 25 patients with carotid stenosis >50% (ATS group) and 15 patients without carotid artery plaques and an intima-media thickness (IMT) <1.0 mm (CTRL group). All patients underwent contrast ultrasound to evaluate periadventitial VV and B-flow imaging (BFI) modality was used to improve and measure periadventitial flow signal. On contrast-enhanced images, a fast microbubble flow and a homogeneous and linear periadventitial contrast signal using BFI were detectable in the adventitial area in all patients of both groups. Periadventitial signal thickness by BFI was higher in patients with atherosclerosis than in the control group (mean +/- SD: CTRL 0.80+/-0.06 mm; ATS 1.10+/-0.11 mm; P<0.001). Moreover, considering the whole study population, the adventitial signal thickness significantly correlated with IMT values (r=0.88, r(2)=0.77; P<0.0001)., Conclusion: Periadventitial contrast signal was detected in all patients and BFI thickness was higher in patient with carotid atherosclerosis and correlated with IMT.

Neovascularization of the arterial walls by adventitial vasa vasorum appears to participate in the process of atherosclerosis progression and destabilization. Although the biological mechanisms associated with plaque instability are still unclear, the uncontrolled formation of intraplaque neovessels appears to contribute to the development of complex atheromatous lesions. Recent reports have described the use of several ultrasound-based techniques for the real-time detection of intraplaque neovascularization. Preliminary studies in animal models have shown that the detection and characterization of adventitial neovascularization are technically feasible. The further development of these imaging techniques relies on the successful implementation of contrast microspheres capable of enhancing microvascular structures. These contrast agents serve as surrogate red blood cells and perform acoustically as true intravascular tracers providing, in real-time, the amount and distribution of neovessels within atherosclerotic lesions. Several ultrasound-based techniques are under development for the detection of adventitial vasa vasorum in the carotid and coronary vascular territories. Although still in early validation phases, these techniques might permit the early diagnosis and stratification of subclinical atherosclerosis, thus permitting aggressive preventive therapy. In the near future, innovative contrast agents using specific ligands are likely to expand the diagnostic and therapeutic possibilities of these emerging imaging techniques.

Cardiovascular disease is associated with the aging of the population, obesity, metabolic syndrome, and diabetes. Therefore, it is important to develop non-invasive imaging systems to detect "at-risk" populations. New data suggest that contrast-enhanced ultrasound (CU) imaging of the carotid arteries enhances luminal irregularities (i.e., ulcers and plaques), improves near-wall, carotid intima-media thickness, and uniquely permits direct, real-time visualization of neovasculature of the atherosclerotic plaque and associated adventitial vasa vasorum. With continued clinical investigation, CU imaging of the carotid artery may afford an effective means to non-invasively identify atherosclerosis in "at-risk" populations while providing new standard for therapeutic monitoring.