The association of carotid plaque burden and composition and the coronary artery calcium score in intermediate cardiovascular risk patients.

Both the carotid ultrasound and coronary artery calcium (CAC) score quantify subclinical atherosclerosis and are associated with cardiovascular disease and events. This study investigated the association between CAC score and carotid plaque quantity and composition. Adult participants (n = 43) without history of cardiovascular disease were recruited to undergo a carotid ultrasound. Maximum plaque height (MPH), total plaque area (TPA), carotid intima-media thickness (CIMT), and plaque score were measured. Grayscale pixel distribution analysis of ultrasound images determined plaque tissue composition. Participants then underwent CT to determine CAC score, which were also categorized as absent (0), mild (1-99), moderate (100-399), and severe (400+). Spearman correlation coefficients between carotid variables and CAC scores were computed. The mean age of participants was 63 ± 11 years. CIMT, TPA, MPH, and plaque score were significantly associated with CAC score (ρ = 0.60, p < 0.0001; ρ = 0.54, p = 0.0002; ρ = 0.38, p = 0.01; and ρ = 0.49, p = 0.001). Echogenic composition features %Calcium and %Fibrous tissue were not correlated to a clinically relevant extent. There was a significant difference in the TPA, MPH, and plaque scores of those with a severe CAC score category compared to lesser categories. While carotid plaque burden was associated with CAC score, plaque composition was not. Though CAC score reliably measures calcification, carotid ultrasound gives information on both plaque burden and composition. Carotid ultrasound with assessment of plaque features used in conjunction with traditional risk factors may be an alternative or additive to CAC scoring and could improve the prediction of cardiovascular events in the intermediate risk population.

HEART + score: integrating carotid ultrasound to chest pain assessment in the emergency department.

OBJECTIVES: The HEART score is a clinical decision tool that stratifies patients into categories of low, moderate, and high-risk of major adverse cardiac events in the emergency department (ED) but cannot identify underlying cardiovascular disease in patients without prior history. The presence of atherosclerosis can easily be detected at the bedside using carotid ultrasound. Plaque quantification is well established, and plaque composition can be assessed using ultrasound grayscale pixel distribution analysis. This study aimed to determine whether carotid plaque burden and/or composition correlated with risk of events and could improve the sensitivity of the HEART score in risk stratifying ED patients with chest pain. METHODS: The HEART score was calculated based on history, electrocardiogram, age, risk factors, and initial troponin in patients presenting to the ED with chest pain (n = 321). Focused carotid ultrasound was performed, and maximum plaque height and total plaque area were used to determine plaque burden (quantity). Plaque composition (% blood, fat, muscle, fibrous, calcium-like tissue) was assessed by pixel distribution analysis. RESULTS: Carotid plaque height and area increased with HEART score (p < 0.0001). Carotid plaque % fibrous and % calcium also increased with HEART score. The HEART score had a higher area under the curve (AUC = 0.84) in predicting 30-day events compared to the plaque variables alone (AUCs < 0.70). Integrating plaque quantity into the HEART score slightly increased test sensitivity (62-69%) for 30-day events and reclassified 11 moderate-risk participants to high-risk (score 7-10). CONCLUSION: Plaque burden with advanced composition features (fibrous and calcium) was associated with increased HEART score. Integrating plaque assessment into the HEART score identified subclinical atherosclerosis in moderate-risk patients.

RéSUMé: OBJECTIFS: Le score HEART est un outil de décision clinique qui stratifie les patients en catégories de risque faible, modéré et élevé d'événements cardiaques indésirables majeurs à l'urgence (ED), mais ne peut pas identifier les maladies cardiovasculaires sous-jacentes chez les patients sans antécédents. La présence d'athérosclérose peut facilement être détectée au chevet du patient à l'aide de l'échographie carotide. La quantification de la plaque est bien établie et la composition de la plaque peut être évaluée à l'aide d'une analyse échographique de la distribution des pixels en niveaux de gris. Cette étude visait à déterminer si la charge et/ou la composition de la plaque carotidienne étaient corrélées avec le risque d'événements et pouvaient améliorer la sensibilité du score HEART chez les patients souffrant de douleurs thoraciques stratifiés. MéTHODES: Le score HEART a été calculé sur la base des antécédents, de l'électrocardiogramme, de l'âge, des facteurs de risque et de la troponine initiale chez les patients présentant une douleur thoracique à l'urgence (n = 321). L'échographie carotidienne focalisée a été effectuée, et la hauteur maximale de la plaque et la surface totale de la plaque ont été utilisées pour déterminer la charge de plaque (quantité). La composition de la plaque (% de sang, de graisse, de muscle, de tissu fibreux, de type calcique) a été évaluée par analyse de la distribution des pixels. RéSULTATS: La hauteur et la surface de la plaque carotide ont augmenté avec le score HEART (p<0,0001). Le pourcentage de plaque carotide fibreuse et le pourcentage de calcium ont également augmenté avec le score HEART. Le score HEART avait une zone plus élevée sous la courbe (ASC = 0,84) pour prédire les événements de 30 jours par rapport aux seules variables de la plaque (CCU < 0,70). L'intégration de la quantité de plaque dans le score HEART a légèrement augmenté la sensibilité au test (62 % à 69 %) pour les événements de 30 jours et a reclassé 11 participants à risque modéré à risque élevé (score de 7 à 10). CONCLUSION: La charge de plaque avec des caractéristiques de composition avancées (fibreuse et calcique) était associée à une augmentation du score HEART. Intégrer l'évaluation de la plaque dans le score HEART a identifié l'athérosclérose subclinique chez les patients à risque modéré.

Impact of transcatheter aortic valve implantation on circulating von Willebrand factor in patients with severe aortic stenosis.

INTRODUCTION: Severe aortic stenosis (AS) can lead to degradation of high molecular weight (HMW) von Willebrand factor (VWF) which can result in haemostatic abnormalities. While studies have explored changes in VWF profiles before and after surgical aortic valve replacement (SAVR), the longer-term changes in VWF profiles pre- and post-transcatheter aortic valve implantation (TAVI) are less understood. AIM: Our primary objective was to identify differences in VWF multimer profiles and VWF function pre-TAVI and 1-month post-TAVI. Our secondary objective was to correlate VWF markers with measures of AS severity. METHODS: Adult patients with severe AS referred for TAVI at our institution were prospectively enrolled in this cohort study. Blood samples were collected for plasma analysis at three time points for all patients: 1 day pre-TAVI, 3 days post-TAVI, and 1-month post-TAVI. VWF antigen, activity, propeptide, collagen binding, multimers, and factor VIII coagulant activity were determined at each time point. Correlations between VWF parameters and severity of AS were assessed. RESULTS: Twenty participants (15 males, five females) with severe AS were recruited for the study. There was a significant increase in HMW VWF between pre-procedure and 1-month post-TAVI (p < .05). There was a transient increase in VWF antigen levels and activity at 3-days post TAVI that decreased to pre-TAVI levels at 1-month. There were no statistically significant correlations between VWF markers and AS severity. CONCLUSIONS: This is the first study to elucidate longer-term (>1 week) improvements in HMW VWF after a TAVI procedure in severe AS patients.

Effect of pharmacologic anti-atherosclerotic therapy on carotid intraplaque neovascularization: A systematic review.

Intraplaque neovascularization (IPN), a key feature of vulnerable carotid plaque, is associated with adverse cardiovascular (CV) events. Statin therapy has been shown to diminish and stabilize atherosclerotic plaque, but its effect on IPN is uncertain. This review investigated the effects of common pharmacologic anti-atherosclerotic therapies on carotid IPN. Electronic databases (MEDLINE, EMBASE and Cochrane Library) were searched from inception until July 13, 2022. Studies evaluating the effect of anti-atherosclerotic therapy on carotid IPN among adults with carotid atherosclerosis were included. Sixteen studies were eligible for inclusion. Contrast-enhanced ultrasound (CEUS) was the most common IPN assessment modality (n=8), followed by dynamic contrast-enhanced MRI (DCE-MRI) (n=4), excised plaque histology (n=3) and superb microvascular imaging (n=2). In fifteen studies, statins were the therapy of interest and one study assessed PCSK9 inhibitors. Among CEUS studies, baseline statin use was associated with a lower frequency of carotid IPN (median OR = 0.45). Prospective studies showed regression of IPN after 6-12 months of lipid-lowering therapy, with more regression observed in treated participants compared to untreated controls. Our findings suggest that lipid-lowering therapy with statins or PCSK9 inhibitors is associated with IPN regression. However, there was no correlation between change in IPN parameters and change in serum lipids and inflammatory markers in statin-treated participants, so it is unclear whether these factors are mediators in the observed IPN changes. Lastly, this review was limited by study heterogeneity and small sample sizes, so larger trials are needed to validate findings.

Novel theranostic approaches to neovascularized atherosclerotic plaques.

As the global burden of atherosclerotic cardiovascular disease continues to rise, there is an increased demand for improved imaging techniques for earlier detection of atherosclerotic plaques and new therapeutic targets. Plaque lesions, vulnerable to rupture and thrombosis, are thought to be responsible for the majority of cardiovascular events, and are characterized by a large lipid core, a thin fibrous cap, and neovascularization. In addition to supplying the plaque core with increased inflammatory factors, these pathological neovessels are tortuous and leaky, further increasing the risk of intraplaque hemorrhage. Clinically, plaque neovascularization has been shown to be a significant and independent predictor of adverse cardiovascular outcomes. Microvessels can be detected through contrast-enhanced ultrasound (CEUS) imaging, however, clinical assessment in vivo is generally limited to qualitative measures of plaque neovascularization. There is no validated standard for quantitative assessment of the microvessel networks found in plaques. Advances in our understanding of the pathological mechanisms underlying plaque neovascularization and its significant role in the morbidity and mortality associated with atherosclerosis have made it an attractive area of research in translational medicine. Current areas of research include the development of novel therapeutic and diagnostic agents to target plaque neovascularization stabilization. With recent progress in nanotechnology, nanoparticles have been investigated for their ability to specifically target neovascularization. Contrast microbubbles have been similarly engineered to carry loads of therapeutic agents and can be visualized using CEUS. This review summarizes the pathogenesis, diagnosis, clinical significance of neovascularization, and importantly the emerging areas of theranostic tool development.

Focused carotid ultrasound to predict major adverse cardiac events among emergency department patients with chest pain.

BACKGROUND AND OBJECTIVE: Point-of-care focused vascular ultrasound (FOVUS), an assessment of carotid artery plaque, predicts coronary artery disease in outpatients referred for coronary angiography. Our primary objective was to determine the diagnostic accuracy of sonographer-performed FOVUS to predict major adverse cardiac events (MACE) within 30 days among patients with suspected cardiac ischemia in the emergency department (ED). METHODS: We conducted a prospective cohort study of patients with chest pain presenting to a tertiary care ED who had an electrocardiogram and cardiac troponin testing. The primary outcome was a composite of death, acute myocardial infarction, or re-vascularization at 30 days. A sonographer performed FOVUS scans in consenting eligible subjects. Emergency physicians, blinded to the sonographer FOVUS result, performed a second FOVUS on some subjects. RESULTS: We recruited 326 subjects (age 62.1 ± 13.5 years; 166 (52%) men), 319 of whom completed an FOVUS scan by the sonographer. Of these, 198 (62%) had a positive FOVUS scan and 41 (13%) had a 30-day MACE. The sensitivity was 83% (95% CI 71-94%), specificity 41% (95% CI 36-47%), positive-likelihood ratio 1.41 (95% CI 1.19-1.68), and negative-likelihood ratio 0.41 (95% CI 0.23-0.75). Among 71 subjects also scanned by an emergency physician, the Kappa was 0.50 (95% CI 0.31-0.70), suggesting moderate agreement between sonographer and emergency physician on the determination of significant carotid plaque. CONCLUSIONS: The presence of carotid plaque on sonographer-performed FOVUS is associated with 30-day MACE in ED patients presenting with chest pain. The prognostic performance of FOVUS is not sufficient to support its use as a stand-alone risk stratification tool in the ED. Future work should investigate FOVUS in conjunction with validated clinical decision rules for chest pain and the impact of enhanced training and quality improvement in the conduct of FOVUS by emergency physicians. REGISTRATION: This study was registered at clinicaltrials.gov (NCT02947360).

RéSUMé: CONTEXTE ET OBJECTIF: L'échographie vasculaire focalisée au point de service (FOVUS), une évaluation de la plaque de l'artère carotide, prédit la maladie coronarienne chez les patients externes référés pour une coronarographie. Notre objectif principal était de déterminer la précision diagnostique du FOVUS réalisé par un échographiste pour prédire les événements cardiaques indésirables majeurs (MACE) dans les 30 jours chez les patients présentant une suspicion d'ischémie cardiaque aux urgences. MéTHODES: Nous avons mené une étude de cohorte prospective de patients souffrant de douleurs thoraciques se présentant à un service d'urgence de soins tertiaires et ayant subi un électrocardiogramme et un test de troponine cardiaque. L'issue primaire était un critère composite de décès, d'infarctus aigu du myocarde ou de revascularisation à 30 jours. Un échographiste a effectué des scans FOVUS chez les sujets éligibles consentants. Les médecins urgentistes, aveuglés par le résultat FOVUS de l'échographiste, ont effectué un deuxième FOVUS sur certains sujets. RéSULTATS: Nous avons recruté 326 sujets (âge 62,1 ± 13,5 ans; 166 (52%) hommes), dont 319 ont effectué un examen FOVUS par l'échographiste. Parmi ceux-ci, 198 (62%) avaient un scan FOVUS positif et 41 (13%) avaient un MACE de 30 jours. La sensibilité était de 83% (IC à 95% 71%-94%), la spécificité de 41% (IC à 95% 36%-47%), le rapport de vraisemblance positif de 1,41 (IC à 95% 1,19­1,68) et le rapport de vraisemblance négatif de 0,41 (IC à 95% 0,23­0,75). Parmi les 71 sujets également examinés par un médecin urgentiste, le Kappa était de 0,50 (IC à 95%: 0,31­0,70), ce qui suggère une concordance modérée entre l'échographiste et le médecin urgentiste pour la détermination de la plaque carotide significative. CONCLUSIONS: La présence d'une plaque carotidienne sur un FOVUS effectué par un échographiste est associée à la MACE à 30 jours chez les patients des urgences présentant des douleurs thoraciques. La performance pronostique du FOVUS n'est pas suffisante pour justifier son utilisation comme outil autonome de stratification du risque dans les urgences. Des travaux futurs devraient étudier le FOVUS en conjonction avec des règles de décision clinique validées pour la douleur thoracique et l'impact d'une formation renforcée et d'une amélioration de la qualité dans la conduite du FOVUS par les médecins urgentistes. ENREGISTREMENT: Cette étude a été enregistrée sur clinicaltrials.gov (NCT02947360).

Progression of atherosclerosis with carnitine supplementation: a randomized controlled trial in the metabolic syndrome.

BACKGROUND: L-carnitine (L-C), a ubiquitous nutritional supplement, has been investigated as a potential therapy for cardiovascular disease, but its effects on human atherosclerosis are unknown. Clinical studies suggest improvement of some cardiovascular risk factors, whereas others show increased plasma levels of pro-atherogenic trimethylamine N-oxide. The primary aim was to determine whether L-C therapy led to progression or regression of carotid total plaque volume (TPV) in participants with metabolic syndrome (MetS). METHODS: This was a phase 2, prospective, double blinded, randomized, placebo-controlled, two-center trial. MetS was defined as ≥ 3/5 cardiac risk factors: elevated waist circumference; elevated triglycerides; reduced HDL-cholesterol; elevated blood pressure; elevated glucose or HbA1c; or on treatment. Participants with a baseline TPV ≥ 50 mm3 were randomized to placebo or 2 g L-C daily for 6 months. RESULTS: The primary outcome was the percent change in TPV over 6 months. In 157 participants (L-C N = 76, placebo N = 81), no difference in TPV change between arms was found. The L-C group had a greater increase in carotid atherosclerotic stenosis of 9.3% (p = 0.02) than the placebo group. There was a greater increase in total cholesterol and LDL-C levels in the L-C arm. CONCLUSIONS: Though total carotid plaque volume did not change in MetS participants taking L-C over 6-months, there was a concerning progression of carotid plaque stenosis. The potential harm of L-C in MetS and its association with pro-atherogenic metabolites raises concerns for its further use as a potential therapy and its widespread availability as a nutritional supplement. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02117661, Registered April 21, 2014, https://clinicaltrials.gov/ct2/show/NCT02117661 .

Increased carotid artery stiffness after preeclampsia in a cross-sectional study of postpartum women.

Preeclampsia (PE) is a hypertensive obstetrical complication associated with increased cardiovascular disease risk. Carotid artery functional assessments allow for identification of subclinical vascular dysfunction. This cross-sectional study measured carotid artery functional indices in healthy women with a recent pregnancy complicated by PE, versus women with a prior uncomplicated pregnancy. Women with a history of PE (N = 30) or an uncomplicated pregnancy (N = 30), were recruited between 6 months and 5 years postpartum. Left and right carotid artery ultrasound measured carotid intima media thickness, plaque burden, peak systolic velocity, end diastolic flow velocity and carotid far-wall circumferential strain (FWCS). Carotid FWCS is inversely related to vessel stiffness, where a decrease in FWCS indicates increased vessel stiffness. Right-side FWCS did not differ between women with a history of PE versus normotensive pregnancy. Left carotid artery FWCS was lower in formerly preeclamptic women after adjustment for diameter, pulse pressure, and heart rate compared to women following an uncomplicated pregnancy (3.35 ± 1.08 × 10-3 vs. 4.46 ± 1.40 × 10-3 ; p = 0.003). Those with prior severe PE had the greatest decrease in FWCS adjusted to diameter, pulse pressure, and heart rate compared to healthy controls (p = 0.02). Adjusted FWCS and total serum cholesterol were independent indicators of PE history when present in a logistic regression model with confounding variables including age, body mass index, and resting blood pressure. Further investigation is needed to elucidate if FWCS can be used as a risk stratification tool for future cardiovascular disease following a pregnancy complicated by PE. A history of PE is associated with decreased left FWCS (increased left carotid artery stiffness).

Femoral plaque burden by ultrasound is a better indicator of significant coronary artery disease over ankle brachial index.

The ankle-brachial index is a commonly used tool for identifying peripheral artery disease for cardiovascular risk stratification. An abnormal ankle-brachial index occurs only following extensive peripheral atherosclerosis occlusion, and thus has poor sensitivity for coronary atherosclerosis. There is a critical need for the development of tools that can detect risk prior to advanced stages of atherosclerosis. We sought to determine the sensitivity of femoral ultrasound for coronary artery disease. In this prospective, cross-sectional study, participants (n = 124) underwent ankle-brachial index measurement and femoral ultrasound for assessment of intima-media thickness, maximal plaque height, and total plaque area following coronary angiography. Receiver operating characteristic areas under the curve were plotted for identifying significant coronary artery disease (≥ 50% stenosis). Logistic regression was utilized to evaluate associations. 64% of participants had significant, angiography-confirmed coronary artery disease. Femoral ultrasound plaque area yielded the highest area under the curve for detecting significant coronary disease (area under the curve = 0.731). In contrast, an abnormal ankle-brachial index (≤ 0.90) produced an area under the curve of 0.568. Femoral ultrasound had a higher sensitivity (85%) than the ankle-brachial index (25%) for ruling out significant coronary artery disease. Both ankle-brachial index and femoral ultrasound have similar capacity to detect peripheral artery disease. Femoral ultrasound has a significantly greater discriminatory power than ankle-brachial index to detect clinically significant coronary artery disease. Ultrasound-captured femoral plaque burden directly delineates the extent of peripheral arterial disease and is better at ruling out significant coronary atherosclerosis than the ankle-brachial index.

Vascularized Carotid Atherosclerotic Plaque Models for the Validation of Novel Methods of Quantifying Intraplaque Neovascularization.

BACKGROUND: Intraplaque neovascularization (IPN) in advanced lesions of the carotid artery has been linked to plaque progression and risk of rupture. Quantitative measurement of IPN may provide a more powerful tool for the detection of such "vulnerable" plaque than the current visual scoring method. The aim of this study was to develop a phantom platform of a neovascularized atherosclerotic plaque within a carotid artery to assess new methods of quantifying IPN. METHODS: Ninety-two synthetic plaque models with various IPN architectures representing different ranges of IPN scoring were created and assessed using contrast-enhanced ultrasound. Intraplaque neovascularization volume was calculated from contrast infiltration in B mode. The plaque models were used to develop a testing platform for IPN quantification. A neovascularized enhancement ratio (NER) was calculated using commercially available software. The plaque model NERs were then compared to human plaque NERs (n = 42) to assess score relationship. Parametric mapping of dynamic intensity over time was used to differentiate IPN from calcified plaque regions. RESULTS: A positive correlation between NER and IPN volume (rho = 0.45; P < .0001) was found in the plaque models. Enhancement of certain plaque model types showed that they resembled human plaques, with visual grade scores of 0 (NER mean difference = 1.05 ± SE 2.45; P = .67), 1 (NER mean difference = 0.22 ± SE 3.26; P = .95), and 2 (NER mean difference = -0.84 ± SE 3.33; P = .80). An optimal cutoff for NER (0.355) identified grade 2 human plaques with a sensitivity of 95% and specificity of 91%. CONCLUSIONS: We developed a carotid artery model of neovascularized plaque and established a quantitative method for IPN using commercially available technology. We also developed an analysis method to quantify IPN in calcified plaques. This novel tool has the potential to improve clinical identification of vulnerable plaques, providing objective measures of IPN for cardiovascular risk assessment.

Maximum plaque height in carotid ultrasound predicts cardiovascular disease outcomes: a population-based validation study of the American society of echocardiography's grade II-III plaque characterization and protocol.

The presence of carotid arterial plaque by ultrasound enhances cardiovascular risk stratification beyond traditional risk factors. However, plaque quantification techniques require further outcomes-based investigation. The purpose of this study was to evaluate the utility of a focused carotid ultrasound protocol and novel plaque grading system developed by the American Society of Echocardiography (ASE). A retrospective analysis of 514 outpatients who were referred for coronary angiography between 2011 and 2014 was performed using a province-sponsored health database. All participants prospectively received a focused carotid ultrasound. Maximum plaque height (MPH) of arterial carotid plaque was quantified, using the Grade II-III plaque definition of MPH ≥ 1.5 mm for stratification, according to recent ASE recommendations. Participants were followed for 1.33-5.11 years (average follow-up = 3.60 ± 1.65 years) to identify the occurrence of cardiovascular events. Major events (death, myocardial infarction [MI], stroke, and transient ischemic attack [TIA]) were correlated to MPH. Participants with MPH ≥ 1.5 mm were more likely to experience stable angina, coronary artery bypass grafting, and stress testing at both 1-year and total follow-up. After adjusting for cardiac risk factors, increased MPH was shown to be predictive for TIA (odds ratio [OR] = 1.33, 95% confidence interval (CI) = 1.01-1.75); p = 0.04), whereas the odds of non-ST-elevation MI (OR = 1.55, 95% CI = 0.99-2.43; p = 0.06) approached significance. Using Kaplan-Meier survival analysis, MPH ≥ 1.5 mm demonstrated good separation for the composite outcome of death, MI, stroke, and TIA over total follow-up (p = 0.02). This rapid, office-based quantification of MPH in carotid ultrasound may serve as a stratification tool for predicting major cardiovascular events.

Combined Femoral and Carotid Plaque Burden Identifies Obstructive Coronary Artery Disease in Women.

BACKGROUND: It remains difficult to assess cardiovascular risk in symptomatic women. The development of femoral plaque precedes adverse cardiovascular events. However, associations of femoral plaque burden with coronary artery disease (CAD) severity and extent are unknown. The aim of this study was to determine sex-specific plaque quantification markers by vascular ultrasound for identifying significant, obstructive CAD. METHODS: In this cross-sectional study, 500 participants (34% women) underwent carotid and femoral ultrasound following coronary angiography. Maximal plaque height and total plaque area were quantified. Logistic regression was used to determine associations of plaque burden with significant, obstructive CAD (≥50% stenosis), when adjusted for age and cardiac risk factors. CAD prediction was evaluated using receiver operating characteristic areas under the curve (AUCs). RESULTS: Two hundred thirty-one men (70%) and 78 women (46%) had significant CAD. A combined assessment of femoral bifurcation and carotid maximal plaque height was the most accurate identifier of CAD in men (AUC = 0.773, cutoff ≥ 2.7 mm, 87% sensitivity, 53% specificity) but a poorer indicator of CAD in women (AUC = 0.659, P < .01). In contrast, the strongest identification of CAD in women was achieved by a combined analysis of common femoral and carotid total plaque area (AUC = 0.764, cutoff ≥ 42.0 mm2, 86% sensitivity, 53% specificity). At this value, more than half of women with false-positive stress test results were correctly identified as having no significant CAD. CONCLUSION: Combined femoral and carotid plaque burden assessments effectively ruled out significant disease in both sexes. Vascular ultrasound may have particular value for cardiovascular risk stratification in women, in whom traditional screening tools are less effective.

Carotid intraplaque neovascularization predicts coronary artery disease and cardiovascular events.

AIMS: It is thought that the majority of cardiovascular (CV) events are caused by vulnerable plaque. Such lesions are rupture prone, in part due to neovascularization. It is postulated that plaque vulnerability may be a systemic process and that vulnerable lesions may co-exist at multiple sites in the vascular bed. This study sought to examine whether carotid plaque vulnerability, characterized by contrast-enhanced ultrasound (CEUS)-assessed intraplaque neovascularization (IPN), was associated with significant coronary artery disease (CAD) and future CV events. METHODS AND RESULTS: We investigated carotid IPN using carotid CEUS in 459 consecutive stable patients referred for coronary angiography. IPN was graded based on the presence and location of microbubbles within each plaque (0, not visible; 1, peri-adventitial; and 2, plaque core). The grades of each plaque were averaged to obtain an overall score per patient. Coronary plaque severity and complexity was also determined angiographically. Patients were followed for 30 days following their angiogram. This study found that a higher CEUS-assessed carotid IPN score was associated with significant CAD (≥50% stenosis) (1.8 ± 0.4 vs. 0.5 ± 0.6, P < 0.0001) and greater complexity of coronary lesions (1.7 ± 0.5 vs. 1.3 ± 0.8, P < 0.0001). Furthermore, an IPN score ≥1.25 could predict significant CAD with a high sensitivity (92%) and specificity (89%). The Kaplan-Meier analysis demonstrated a significantly higher proportion of participants having CV events with an IPN score ≥1.25 (P = 0.004). CONCLUSION: Carotid plaque neovascularization was found to be predictive of significant and complex CAD and future CV events. CEUS-assessed carotid IPN is a clinically useful tool for CV risk stratification in high-risk cardiac patients.

Presence of Calcium-Like Tissue Composition in Carotid Plaque is Indicative of Significant Coronary Artery Disease in High-Risk Patients.

BACKGROUND: Grayscale pixel ranges from ultrasound images, indicating differences in atherosclerotic plaque echogenicity, have been shown to represent different tissue types. Our objective was to determine whether carotid plaque composition was correlated with severity of coronary artery disease (CAD) and risk of cardiovascular (CV) events. METHODS: A focused carotid ultrasound was performed in 522 participants who had recently undergone coronary angiography. In 468 participants found to have atherosclerotic plaque in at least one carotid artery, plaque composition was assessed for tissue-like types: grayscale ranges 0-4 (blood), 8-26 (fat), 41-76 (muscle), 112-196 (fibrous), and 211-255 (calcium). Logistic regression was used to evaluate correlations with significant CAD (≥50% stenosis). Cox proportional hazards models were used to determine risk for 5-year CV outcomes. RESULTS: Carotid plaque percent fibrous and percent calcium increased with severity of CAD (P < .02). When adjusted for age, sex, body mass index, estimated glomerular filtration rate, and traditional cardiac risk factors, maximum plaque height and percent calcium remained independent contributors of significant CAD (P < .01). Plaque height (≥2.74 mm), percent calcium (≥0.11%), and percent fat (11.6%) were associated with increased risk for CV events. Combined plaque height and percent fat gave the highest risk for events (risk ratio = 2.02; CI, 1.41-2.94, P = .0002). CONCLUSIONS: Carotid plaque fibrous and calcium-like tissues are correlated with increased CAD. Increased percent fat or percent calcium is associated with risk for CV events; however, a combination of plaque height, percent calcium, and/or percent fat increases risk for CV events. Incorporating ultrasound carotid plaque composition into screening practice may improve patient risk stratification for heart disease.

The Heart and Kidney: Abnormal Phosphate Homeostasis Is Associated With Atherosclerosis.

CONTEXT: Phosphate has gained recognition as a risk factor for adverse cardiovascular outcomes, potentially due to accelerated vascular calcification. Fibroblast growth factor-23 (FGF-23) is a counter-regulatory hormone that increases renal phosphate excretion to maintain normal levels. OBJECTIVE: The purpose of the study was to determine the association of phosphate and FGF-23 to atherosclerosis. DESIGN AND SETTING: A prospective cohort study (n = 204) of outpatients referred for coronary angiography over of a 1-year recruitment period at the Kingston General Hospital. INTERVENTION: Blood was collected, and a focused carotid ultrasound was performed. MAIN OUTCOME MEASURE: Degree of angiographic coronary artery disease was scored. Carotid maximum plaque height, total area, grayscale median, and tissue pixel distribution were measured. Plasma phosphate was assessed by mineral assay and FGF-23 by ELISA. RESULTS: Carotid plaque burden [total plaque area (TPA)] was associated with higher levels of phosphate (TPA, r = 0.20, P < 0.01) and FGF-23 (r = 0.19, P < 0.01). FGF-23 was associated with increased plaque % calcium-like tissue. Participants with no coronary artery disease had significantly lower phosphate levels. Phosphate was associated with higher grayscale median (GSM) in male subjects but with lower GSM in female subjects. FGF-23 was associated with increased plaque % fat in male subjects but increased plaque % calcium in female subjects. CONCLUSIONS: Phosphate was independently associated with the severity of atherosclerosis in terms of plaque burden and composition. FGF-23 was associated with plaque calcification. These findings suggest that abnormal phosphate homeostasis may play an under-recognized but potentially modifiable role in cardiovascular disease.

Handheld versus conventional vascular ultrasound for assessing carotid artery plaque.

BACKGROUND: Coronary Artery Disease (CAD) is the leading cause of death worldwide. Ultrasound-detected carotid plaque has been previously shown to predict significant CAD. Despite this evidence, carotid plaque assessment has not been implemented in cardiac risk screening, likely due to the cost associated with a formal carotid ultrasound examination. This study sought to determine whether a handheld vascular ultrasound device could be used as an accurate point-of-care imaging tool for the assessment of carotid artery plaque. METHODS: We performed a focused vascular ultrasound of the carotid arteries of 200 patients referred for coronary angiography using a handheld ultrasound device as well as a full-size conventional ultrasound system. For each participant, the maximum plaque height (MPH) and total plaque area (TPA) of the carotid artery bulbs were measured. RESULTS: Carotid plaque assessment using the handheld device was comparable to that of the conventional ultrasound system. We found a good correlation and no relevant bias between handheld and conventional ultrasound systems in measuring MPH (r = 0.84, p < 0.0001) and TPA (r = 0.94, p < 0.0001). Furthermore, there was good inter-rater reliability for online and offline measurements of MPH and offline measurements of TPA by handheld ultrasound (0.79, 0.76 and 0.85, respectively). CONCLUSIONS: This study demonstrates that a focused ultrasound of the carotid artery using a handheld device can be used to accurately measure MPH and TPA. This protocol has the potential to provide an expedited point-of-care assessment of carotid plaque.

Circulating Gas6 is associated with reduced human carotid atherosclerotic plaque burden in high risk cardiac patients.

OBJECTIVE: Pre-clinical studies suggest that growth arrest-specific protein 6 (Gas6), a member of the vitamin K dependent family of proteins, is implicated in atherosclerosis. A role for Gas6 in stabilizing atherosclerotic plaque has been suggested. Our aim was to determine the association between Gas6 and measures of carotid artery atherosclerosis in humans undergoing elective coronary angiography. Secondary aims were to determine the association between Gas6 and sex, diabetes, and obesity. METHODS: In 204 outpatients referred for coronary angiography, EDTA plasma was collected and a focused carotid ultrasound performed. Degree of angiographic coronary artery disease was scored. Carotid intima media thickness as well as maximum plaque height, plaque area, and grayscale median were measured by vascular sonography. Gas6 was assessed by enzyme-linked immunosorbent assay. RESULTS: We found that Gas6 concentrations were lower in males and were associated with diabetes, obesity, and lower kidney function. After adjustment for age, sex, kidney function, BMI and traditional cardiac risk factors; diabetes was associated with higher levels of Gas6, whilst there was a significant inverse relationship between Gas6 and total plaque area. Gas6 was inversely associated with maximum plaque height and total plaque area in adjusted multi-variable models. CONCLUSIONS: We observed higher levels of Gas6 in participantswith adverse cardiovascular risk profiles (e.g. diabetes, obesity) yet Gas6 was independently associated with reduced plaque height and total plaque area. These findings suggest that Gas6 may play a role in human atherosclerotic plaque remodeling.

Interatrial block predicts atrial fibrillation in patients with carotid and coronary artery disease.

BACKGROUND: Interatrial block (IAB) has been previously shown to predict atrial fibrillation (AF) in cardiac populations. This study sought to evaluate the relationship between IAB and new-onset AF in a population of patients undergoing clinically indicated coronary angiography who received carotid ultrasonography. METHODS: A population of 355 subjects undergoing coronary angiography and carotid ultrasound were retrospectively studied. Common carotid artery (CCA) far-wall intima-media thickness (CIMT), and total carotid plaque area were measured. Coronary artery disease was measured by angiography and IAB by electrocardiograph (ECG). RESULTS: The mean population age was 64.4 years, 70.4% male, mean BMI 29.9 kg/m2. IAB was a predictor of new-onset AF (OR =2.40, 95% CI: 1.33-4.29; P=0.003). There was a significant difference in AF free survival time between patients with IAB and without IAB via Cox proportional hazard analysis [52.9 months (95% CI: 47.1-58.7 months) vs. 62.6 months (95% CI: 58.8-66.5 months); P=0.006]. Patients with IAB had a significantly greater CIMT (0.883±0.193 vs. 0.829±0.192 mm; P=0.013) and a higher prevalence of significant (>70%) right coronary artery lesions than patients without (45.8% vs. 34.4%; P=0.026). Significant predictors of IAB on multivariate analysis were BMI ≥30 kg/m2 (OR =3.14, 95% CI: 1.14-6.71, P=0.003), male sex (OR =1.78, 95% CI: 1.05-3.03, P=0.034), increased mean CIMT (per 0.1 mm increase) (OR =1.75, 95% CI: 1.00-3.07, P=0.050) and increased age (per 10-year increase) (OR =1.46, 95% CI: 1.14-1.88, P=0.003). CONCLUSIONS: IAB is a predictor of new-onset AF in patients with carotid and coronary artery disease. Both carotid and coronary artery disease are associated with a higher prevalence of IAB.

Speckle tracking carotid artery circumferential strain is a marker of arterial sclerosis but not coronary atherosis.

PURPOSE: Circumferential speckle tracking carotid artery strain is a novel method of quantifying vessel wall stiffness. We hypothesized that carotid wall stiffness would be associated with carotid intimal medial thickening (a medial process associated with risk factors), but not coronary artery disease (an intimal process). METHODS: Bilateral carotid artery ultrasound was conducted on outpatients who had previously undergone elective coronary angiography. Mean carotid artery far wall circumferential strain (FWCS) was assessed for correlations with coronary angiographic stenosis, cardiac risk factors, carotid intima-media thickness (CIMT), and carotid plaque. RESULTS: One hundred and sixty five (165) patients were studied. No significant association was found between the presence of coronary artery disease on angiography and mean FWCS. FWCS was higher in current tobacco smokers. In addition, carotid strain was found to decrease with increased age (r = -0.33, P < 0.001). When adjusted for pulse pressure (PP), FWCS/PP was negatively correlated with mean CIMT (r = -0.29, P = 0.002) and bulb maximum plaque height (r = -0.27, P = 0.004). Hypertension and diabetes were associated with decreased FWCS/PP (increased wall stiffness). CONCLUSIONS: While no clear relationship between carotid strain and coronary artery disease was observed, increased CIMT, carotid plaque, and cardiac risk factors were associated with decreased carotid strain. Further work is required to explore the relationship between carotid strain and cardiovascular events.