Sex Differences in Plaque Composition and Morphology Among Symptomatic Patients With Mild-to-Moderate Carotid Artery Stenosis.

BACKGROUND AND PURPOSE: Incidence of ischemic stroke differs between men and women, with substantially higher rates in men. The underlying mechanism of this difference remains poorly understood but may be because of differences in carotid atherosclerosis. Using an in-depth imaging-based approach, we investigated differences between carotid plaque composition and morphology in male and female patients with stroke, taking into account differences in total plaque burden. Additionally, we investigated all possible within-artery combinations of plaque characteristics to explore differences between various plaque phenotypes. METHODS: We included 156 men and 68 women from the PARISK (Plaque At Risk) study, a prospective cohort study of patients with recent ischemic cerebrovascular symptoms and <70% ipsilateral carotid stenosis. Plaque characteristics (intraplaque hemorrhage [IPH], lipid-rich necrotic core [LRNC], calcifications, thin-or-ruptured fibrous cap, ulcerations, total plaque volume) were assessed with magnetic resonance imaging and multidetector-row computed tomography angiography. We used multivariable logistic and linear regression analyses to assess sex differences in plaque characteristics. RESULTS: We found significant difference in total plaque volume between men and women (ß=22.9 mm3 [95% CI, 15.4-30.5]; mean volume in men 1399±425 mm3, in women 1011±242 mm3). Additionally, men were more likely to have IPH (odds ratio [OR]=2.8 [95% CI, 1.3-6.3]; IPH proportion in men 49%, in women 16%) and LRNC (OR=2.4 [95% CI, 1.2-4.7]; LRNC proportion in men 73%, in women 41%) even after adjustment for total plaque volume. We found no sex-specific differences in plaque volume-corrected volumes of IPH, LRNC, and calcifications. In terms of coexistence of plaque characteristics, we found that men had more often a plaque with coexistence of calcifications, LRNC, and IPH (OR=2.7 [95% CI, 1.2-7.0]), with coexistence of thin-or-ruptured fibrous cap/ulcerations, LRNC, and IPH (OR=2.4 [95% CI, 1.1-5.9]), and with coexistence of all plaque characteristics (OR=3.0 [95% CI, 1.2-8.6]). CONCLUSIONS: In symptomatic patients with mild-to-moderate carotid stenosis, men are more likely to have a high-risk carotid plaque with IPH and LRNC than women, regardless of total plaque burden. Men also have more often a plaque with multiple vulnerable plaque components, which could comprise an even higher stroke risk. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01208025.

Combined Assessment of Elevated Plasma Lipoprotein-Associated Phospholipase A2 and Plaque Enhancement Improved Accuracy in the Risk of Acute Ischemic Stroke in Patients with Intracranial Artery Stenosis.

PURPOSE: We evaluated the relationship between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2) concentration and plaque characteristics in patients with intracranial artery stenosis and their clinical relevance in acute ischemic stroke. METHODS: Eighty-seven patients with intracranial atherosclerotic stenosis (66 males, 21 females) were retrospectively enrolled. Plasma Lp-PLA2 concentration was measured, and vessel wall magnetic resonance imaging (VW-MRI) was used to determine intracranial vascular stenosis and plaque characteristics, including plaque enhancement, surface morphology, and T1 hyperintensity. Binary logistic regression was used to evaluate the relationship between Lp-PLA2 concentration and plaque characteristics of intracranial artery after adjusting for demographic and confounding factors and to assess their diagnostic efficacy for the risk of acute ischemic stroke. RESULTS: After adjustment for demographic, medication and related lipid factors, Lp-PLA2 elevation was associated with plaque enhancement (odds ratio [OR]=12.7, 95% confidence interval [CI] 2.51-64.82, P=0.002) and surface irregularity (OR=2.9, 95% CI 1.06-7.98, P=0.038). Both Lp-PLA2 elevation (OR=8.8, 95% CI 1.64-47.72, P=0.011) and plaque enhancement (OR=34.3, 95% CI 5.88-200.4, P=0.001) were associated with acute ischemic stroke. Receiver operating characteristic curve analysis showed that the area under the curve for Lp-PLA2 concentration and plaque enhancement combined in the diagnosis of acute ischemic stroke was 0.884, significantly higher than that for Lp-PLA2 concentration (0.724) and plaque enhancement (0.794) alone. CONCLUSION: Elevated Lp-PLA2 is associated with plaque enhancement and plaque surface irregularity. Combined assessment of Lp-PLA2 concentration and plaque enhancement is of greater diagnostic value for the risk of acute ischemic stroke in patients with intracranial artery stenosis.

Assessment of Cardiovascular Safety of Anti-Osteoporosis Drugs.

The incidence of osteoporosis and cardiovascular disease increases with age, and there are potentially shared mechanistic associations between the two conditions. It is therefore highly relevant to understand the cardiovascular implications of osteoporosis medications. These are presented in this narrative review. Calcium supplementation could theoretically cause atheroma formation via calcium deposition, and in one study was found to be associated with myocardial infarction, but this has not been replicated. Vitamin D supplementation has been extensively investigated for cardiac benefit, but no consistent effect has been found. Despite findings in the early 21st century that menopausal hormone therapy was associated with coronary artery disease and venous thromboembolism (VTE), this therapy is now thought to be potentially safe (from a cardiac perspective) if started within the first 10 years of the menopause. Selective estrogen receptor modulators (SERMs) are associated with increased risk of VTE and may be related to fatal strokes (a subset of total strokes). Bisphosphonates could theoretically provide protection against atheroma. However, data from randomised trials and observational studies have neither robustly supported this nor consistently demonstrated the potential association with atrial fibrillation. Denosumab does not appear to be associated with cardiovascular disease and, although parathyroid hormone analogues are associated with palpitations and dizziness, no association with a defined cardiovascular pathology has been demonstrated. Finally, romosozumab has been shown to have a possible cardiovascular signal, and therefore post-market surveillance of this therapy will be vital.

Cost Effectiveness of Assessing Ultrasound Plaque Characteristics to Risk Stratify Asymptomatic Patients With Carotid Stenosis.

Background Imaging may play an important role in identifying high-risk plaques in patients who have carotid disease and who could benefit from surgical revascularization. We sought to evaluate the cost effectiveness of a decision-making rule based on the ultrasound imaging assessment of plaque echolucency in patients with asymptomatic carotid stenosis. Methods and Results We used a decision-analytic model to project lifetime quality-adjusted life years and costs for 5 stroke prevention strategies: (1) medical therapy only; (2) revascularization if both plaque echolucency and stenosis progression to >90% are present; (3) revascularization only if plaque echolucency is present; (4) revascularization only if stenosis progression >90% is present; or (5) either plaque echolucency or stenosis progression is present. Risks of clinical events, costs, and quality-of-life values were estimated based on published sources and the analysis was conducted from a healthcare system perspective for asymptomatic patients with 70% to 89% carotid stenosis at presentation. Patients who did not undergo revascularization had the highest stroke events (17.6%) and lowest life-years (8.45), while those who underwent revascularization on the basis of either presence of plaque echolucency on ultrasound or progression of carotid stenosis had the lowest stroke events (12.0%) and longest life-years (14.41). The either plaque echolucency or progression-based revascularization group had an incremental cost-effectiveness ratio of $110 000/quality-adjusted life years compared with the plaque echolucency-based strategy, which had an incremental cost-effectiveness ratio of $29 000/quality-adjusted life years compared with the joint echolucency and progression-based strategy. Conclusions Plaque echolucency on ultrasound can be a cost-effective tool to identify patients with asymptomatic carotid artery stenosis most likely to benefit from carotid endarterectomy.

Subclinical cardiovascular disease assessment and its relationship with cardiovascular risk SCORE in a healthy adult population: A cross-sectional community-based study.

INTRODUCTION: The aim of this study is to evaluate the relationship and the accuracy of SCORE (Systematic Coronary Risk Evaluation Project) risk correlated to multiple methods for determining subclinical cardiovascular disease (CVD) in a healthy population. MATERIAL AND METHODS: This cross-sectional study included 120 completely asymptomatic subjects, with an age range 35-75 years, and randomly selected from the general population. The individuals were evaluated clinically and biochemical, and the SCORE risk was computed. Subclinical atherosclerosis was assessed by various methods: carotid ultrasound for intima-media thickness (cIMT) and plaque detection; aortic pulse wave velocity (aPWV); echocardiography - left ventricular mass index (LVMI) and aortic atheromatosis (AA); ankle-brachial index (ABI). RESULTS: SCORE mean value was 2.95±2.71, with 76% of subjects having SCORE <5. Sixty-four percent of all subjects have had increased subclinical CVD changes, and SCORE risk score was correlated positively with all markers, except for ABI. In the multivariate analysis, increased cIMT and aPWV were significantly associated with high value of SCORE risk (OR 4.14, 95% CI: 1.42-12.15, p=0.009; respectively OR 1.41, 95% CI: 1.01-1.96, p=0.039). A positive linear relationship was observed between 3 territories of subclinical CVD (cIMT, LVMI, aPWV) and SCORE risk (p<0.0001). There was evidence of subclinical CVD in 60% of subjects with a SCORE value <5. CONCLUSIONS: As most subjects with a SCORE value <5 have subclinical CVD abnormalities, a more tailored subclinical CVD primary prevention program should be encouraged.

Prevalence and Risk Factors of Carotid Plaque Among Middle-aged and Elderly Adults in Rural Tianjin, China.

Carotid plaque (CP) is associated with cardiovascular and cerebrovascular events. However, population-based studies with a large sample are rare in China, particularly those in the low-income population. We aimed to determine the prevalence of CP and the associated risk factors in the rural areas of northern China. Between April 2014 and June 2014, we recruited 3789 residents aged ≥45 years. B-mode ultrasonography was performed to measure the extent of CP. The prevalence of CP was 40.3% overall, 47.1% in men, and 35.4% in women (P < 0.001). The prevalence of CP increased with increasing age (P < 0.001). The participants with CP were more likely to have hypertension, diabetes, high total cholesterol (TC) levels, and high low-density lipoprotein-cholesterol levels and be a current smoker; however, they were less likely to be obese. Multiple logistic regression analysis, adjusted for confounders, indicated that age, male sex, hypertension, diabetes, current smoking, and high LDL-C levels were the independent risk factors for CP. There was a lower risk of CP with alcohol consumption. The findings suggest that managing the conventional risk factors is crucial to reduce the burden of cardiovascular and cerebrovascular diseases in the low-income population in China.

Can and should carotid ultrasound be used in cardiovascular risk assessment?: the internist's perspective.

Cardiovascular risk management is a major and challenging task for internists. Risk scores using algorithms based on traditional risk factors are helpful in identifying patients in whom intensive prevention strategies are warranted. However there remains a need for more accurate screening tools to allow clinicians to individualize the primary prevention programs to their patients. Approximately 40-80% of apparently healthy, asymptomatic subjects exhibit increased thickness of the lamina intima-media of the carotid artery or have atherosclerotic carotid plaques. These abnormalities can be measured safely and at low cost by ultrasound. Subclinical carotid lesions are strongly associated with generalized atherosclerotic burden and the risk of future cardiovascular events. Although many cardiovascular risk management guidelines recommend the use of these parameters incorporation in clinical practice is still not commonplace. Based on the current literature it can be stated that in high risk patients there is no additional value of carotid ultrasound because even in the absence of carotid lesions these patients should receive an intensive risk reduction regime. In the large low-intermediate risk group however carotid ultrasound findings carry subtle but possibly clinically relevant information about cardiovascular risk profile. The effect of treatment decisions based on carotid ultrasound parameters has not been studied. Sequential measurements to monitor progression and evaluate treatment response on an individual basis are not sufficiently reproducible. We therefore recommend the use of carotid ultrasound in low to intermediate risk patients but emphasize the importance of interpreting the results in conjunction with all cardiovascular risk factors and avoid follow-up measurements.

Role of simultaneous carotid ultrasound in patients undergoing stress echocardiography for assessment of chest pain with no previous history of coronary artery disease.

BACKGROUND: We prospectively explored prevalence of carotid disease (CD), its independent association with coronary artery disease (CAD) and outcome as well as potential impact on management, in patients undergoing stress echocardiography (SE) for new onset chest pain without known CAD. METHODS: Accordingly, 591 consecutive patients referred for SE underwent carotid ultrasound. Carotid disease was defined as carotid intima-media thickness (C-IMT) >75th percentile for age and sex and/or presence of plaque. RESULTS: Myocardial ischemia was demonstrated in only a minority (11%), but there was a high prevalence of CD (70%). Incidence of CD was similar in patients with and without ischemia (76% versus 69%, P = .26). Carotid data led to reclassification of Framingham risk score categories in 65% of patients as well as more than a third of negative SE patients potentially benefitting from primary prevention therapy. Of the 83 patients undergoing coronary arteriography, 59 (71%) demonstrated coronary atherosclerosis (any atheroma) and 33 (40%) CAD. Positive predictive value of SE for CAD was 56%, but presence of carotid plaque improved it to 70%. Although both CD and plaque showed association with CAD and revascularization, after adjustment for conventional risk factors, only carotid plaque maintained significant association (P = .024 and P = .023, respectively). CONCLUSIONS: There is significantly higher prevalence of CD compared with myocardial ischemia in patients undergoing SE and carotid ultrasound for suspected CAD. This can lead to significant Framingham risk score reclassification with important primary prevention implications. Carotid plaque is superior to clinical assessment for the prediction of CAD and improves positive predictive value of SE for CAD in these patients.

Preoperative assessment of coronary arteries in patients undergoing thoraco-abdominal and noncoronary cardiovascular surgery with dual-source computed tomography angiography.

AIMS: To retrospectively evaluate coronary anomalies and coronary wall atheromatous changes by using dual-source computed tomography angiography (DSCTA) for preoperative assessment of patients with thoraco-abdominal and noncoronary cardiovascular disease. MATERIALS AND METHODS: One hundred and eighty-one patients scheduled for elective noncoronary cardiovascular surgery (heart valve disease group, HVD; arrhythmia group, Arrhy; or aortic aneurysm group, AA) underwent a DSCTA examination for preoperative preparation. Anomalous origin of coronary arteries, myocardial bridge (MB), coronary wall atheromatous changes, luminal stenosis, and types of plaques were evaluated and compared among the three groups. RESULTS: Anomalous origin of coronary arteries and MB were observed in 5.1% and 21.5% of patients. Anomalous origin of the coronary artery from the opposite sinus was most common (55.6%). MB was most frequently detected in the distal segment of the left anterior descending artery (LAD) (1.2%). Plaques were most common in the proximal segment of the LAD (16.4%) and LAD branches (42.2%). Diseased vessels and segments were more common in AA group, followed by Arrhy patients and finally HVD groups (p < 0.001 for each group). Multivessel involvement and significant stenosis of AA group were significantly more common than the other two groups. Noncalcified plaque and all grades of stenosis were more common in AA patients. CONCLUSION: DSCTA is useful for preoperative assessment of coronary arteries in patients undergoing thoraco-abdominal and noncoronary cardiovascular surgery. DSCTA detected higher prevalence of coronary artery disease in AA patients than in the other two groups of patients.

Assessment of subclinical atherosclerosis and intraplaque neovascularization using quantitative contrast-enhanced ultrasound in patients with familial hypercholesterolemia.

OBJECTIVE: Patients with heterozygous familial hypercholesterolemia (FH) are at severely increased risk of developing atherosclerosis at relatively young age. The aim of this study was to assess the prevalence of subclinical atherosclerosis and intraplaque neovascularization (IPN) in patients with FH, using contrast-enhanced ultrasound (CEUS) of the carotid arteries. METHODS: The study population consisted of 69 consecutive asymptomatic patients with FH (48% women, mean age 55 ± 8 years). All patients underwent carotid ultrasound to evaluate the presence and severity of carotid atherosclerosis, and CEUS to assess IPN. IPN was assessed in near wall plaques using a semi-quantitative grading scale and semi-automated quantification software. RESULTS: Carotid plaque was present in 62 patients (90%). A total of 49 patients had plaques that were eligible for the assessment of IPN: 7 patients (14%) had no IPN, 39 (80%) had mild to moderate IPN and 3 (6%) had severe IPN. Semi-automated quantification software showed no statistical significant difference in the amount of IPN between patients > 50 years and patients ≤ 50 years and between patients with a defective low-density lipoprotein receptor (LDLR) mutation and patients with a negative LDLR mutation. Plaques with irregular or ulcerated surface had significantly more IPN than plaques with a smooth surface (p < 0.05). CONCLUSION: Carotid ultrasound demonstrated atherosclerotic plaque in 90% of asymptomatic patients with FH without known atherosclerosis. IPN assessed with CEUS, was present in 86% of these patients. Irregular and ulcerated plaques exhibited significantly more IPN than plaques with a smooth surface.

Discordance between Framingham Risk Score and atherosclerotic plaque burden.

AIM: Clinical predictors are routinely used to identify individuals who may benefit from aggressive risk factor modification. However, clinical predictors cannot account for all genetic and environmental variables. The objective of this study is to investigate the association of Framingham Risk Score (FRS) with computed tomography angiography (CTA) measures of coronary atherosclerosis. METHODS AND RESULTS: Consecutive patients who underwent CTA were prospectively enrolled and categorized according to clinical predictors such as FRS and pre-test probability for obstructive coronary artery disease (CAD). Atherosclerotic calcific and non-calcific plaques were assessed. Of the 1507 patients without a history of diabetes mellitus, myocardial infarction, and not on statin therapy, coronary atherosclerosis was present in 63.5% of the patients. Of the 1173 patients with low and intermediate FRS, atherosclerotic plaque was visually present in 47.6 and 72.7% of the patients, respectively. A higher proportion of low FRS patients had isolated non-calcific plaque (14.8%) compared with patients in the intermediate (10.1%) or high (7.2%) FRS groups, and 11.7% of high FRS patients had no visual evidence of plaque. The correlation between FRS and plaque was fair (r = 0.48; P < 0.001). CONCLUSION: Although clinical variables are predictive of CAD events, CTA identified coronary atherosclerosis in a significant proportion of patients with low to intermediate FRS, and a small minority of patients with high FRS had no evidence of atherosclerosis. Prospective studies are required to determine the potential value of identifying coronary atherosclerosis using CTA and to assess whether modifying therapies based on these results are warranted.

Ultrasound assessment of brachial endothelial vasomotor function in addition to carotid plaque echolucency for predicting cardiovascular events in patients with coronary artery disease.

BACKGROUND: Single assessment of either flow-mediated vasodilatation of the brachial artery (FMD) or carotid plaque echolucency provides prognostic information for both cerebrovascular and coronary events. OBJECTIVES: This study tested the hypothesis that combined assessment using carotid plaque echolucency and FMD may have an additive effect when predicting cardiovascular events in patients with coronary artery disease (CAD). METHODS: Ultrasound assessment of carotid plaque echolucency with integrated backscatter (IBS) analysis (calibrated IBS=intima-media IBS value-adventitia IBS) and FMD was performed in 547 consecutive patients with CAD. All the study patients were followed up prospectively for a period of ≤ 60 months until the occurrence of one of the following cardiovascular events: cardiac death, non-fatal myocardial infarction, unstable angina requiring coronary revascularization, or ischemic stroke. RESULTS: During a mean follow-up period of 52 ± 10 months, 69 cardiovascular events occurred. A multivariate Cox proportional hazard model after 1000 bootstrapped resampling demonstrated that calibrated IBS and FMD were significant, independent predictors of future cardiovascular events after adjustment for known risk factors (calibrated IBS, HR 0.88, 95% CI 0.83-0.93; FMD, HR 0.76, 95% CI 0.68-0.85). The c-statistics, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) analyses showed that the combination of calibrated IBS and FMD values had a greater incremental effect on the predictive value of known risk factors for cardiovascular events. CONCLUSIONS: Combined assessment of brachial endothelial function and carotid plaque echolucency is an independent predictor of cardiovascular events and improves risk prediction when added to known risks.

Optical coherence tomography assessment of the spatial distribution of culprit ruptured plaques and thin-cap fibroatheromas in acute coronary syndrome.

AIMS: Plaque rupture and subsequent thrombosis is known to be the most important pathology leading to acute coronary syndrome (ACS). We investigated by optical coherence tomography (OCT) whether in ACS there is an association of the location of the culprit plaque in the coronary tree with plaque rupture and/or thin cap fibroatheroma (TCFA). METHODS AND RESULTS: We included 74 patients presenting with ACS that underwent OCT study of the culprit lesion. The distance of the culprit lesion from the ostium was measured angiographically, and the presence of rupture and/or TCFA was assessed by OCT. Sixty-seven patients were analysed. Forty-five ruptured plaques were identified by OCT (67.1%). The distance from the ostium was lower for culprit ruptured plaques versus culprit non-ruptured plaques (p<0.01), particularly in the left anterior descending (LAD) and the left circumflex (LCx) arteries. The majority of culprit ruptured plaques (68.9%) was located in the proximal 30 mm of the coronary arteries. A distance from the ostium of ≤30.54 mm predicted plaque rupture with 71.1% sensitivity and 68.2% specificity. Culprit lesions in the proximal 30 mm are associated with rupture (p<0.05), TCFA (p<0.05), and lower minimal cap thickness (p<0.05). CONCLUSIONS: Culprit ruptured plaques in ACS seem to be predominately located in the proximal segments of the coronary arteries.

Significance of noncalcified coronary plaque in asymptomatic subjects with low coronary artery calcium score: assessment with coronary computed tomography angiography.

We aimed to investigate the prevalence and severity of noncalcified coronary plaques (NCP) using coronary CT angiography (CCTA) and analyze predictors of significant coronary stenosis by NCP in asymptomatic subjects with low coronary artery calcium score (CACS). The institutional review board approved this retrospective study and all patients gave written, informed consent. The presence of plaque, severity of stenosis, plaque characteristics, and CACS were assessed in 7,515 asymptomatic subjects. We evaluated the prevalence and severity of NCP in subjects having low CACS (707 subjects; men with CACS from 1 to 50 and women from 1 to 10) in comparison to those having 0 CACS (6,040 subjects) as the reference standard. Conventional risk factors were assessed for predictors of NCP and significant stenosis by NCP. We also investigated the cardiac events of the patients through medical records. Compared to subjects with 0 CACS, those with low CACS showed higher prevalence of NCP (6.9% vs. 31.5%, P < 0.001) and significant stenosis caused by NCP (0.8% vs. 7.5%, P < 0.001). In the low CACS group, independent predictors for significant NCP included diabetes mellitus (DM), hypertension, and elevated low-density lipoprotein (LDL)-cholesterol (all P < 0.05). However, 47.2% of subjects with significant NCP were classified into the low to intermediate risk according to Framingham Risk Score. At the median follow up of 42 months (range: 3-60 months), cardiac events were significantly higher in the low CACS group compared to the 0 CACS group (2.6% vs. 0.27%, P < 0.001). In asymptomatic subjects having low CACS, the prevalence and severity of NCP were higher as compared to subjects having zero CACS and predictors of significant stenosis by NCP were DM, hypertension and LDL-Cholesterol. Therefore, CCTA may be useful for risk stratification of coronary artery disease as added value over CACS in selected populations with low CACS who have predictors of significant NCP.