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.

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.

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.

Developmental origins of pregnancy-induced cardiac changes: establishment of a novel model using the atrial natriuretic peptide gene-disrupted mice.

Pregnancy evokes many challenges on the maternal cardiovascular system that may unmask predispositions for future disease. This is particularly evident for women who develop pregnancy-related disorders, for example, pre-eclampsia and gestational diabetes or hypertension. Such pregnancy-related syndromes increase the risk for cardiovascular disease (CVD) postpartum. As a result, pregnancy has been termed as a cardiovascular stress test and an indicator or marker to predict the development of CVD later in life. In addition, pregnancy-related disorders impact the development of offspring also placing them at a higher risk for disease. Utilizing pregnancy as a physiological stressor, the current investigation sought to determine whether the cardiovascular system of offspring exposed to gestational hypertension in utero would respond adversely to the stress of pregnancy. Heterozygous atrial natriuretic peptide gene-disrupted (ANP+/-) offspring were generated by either crossing male wildtype ANP+/+ with female knockout ANP-/- to produce ANP+/-KO mice or crossing female wildtype ANP+/+ with male knockout ANP-/- to produce ANP+/-WT mice. To study the cardiovascular stress induced by pregnancy, female ANP+/-WT and ANP+/-KO mice were mated with male wildtype ANP+/+ mice to initiate pregnancy. Cardiac size and molecular expression of the renin-angiotensin (RAS) and natriuretic peptide systems (NPS) were compared between offspring groups. Our data demonstrate that gestational hypertension and lack of maternal ANP did not significantly impact the progression and regression of pregnancy-induced cardiac hypertrophy over gestation and postpartum in ANP+/- offspring. Additionally, the molecular cardiac expression of the RAS and NPS did not differ between offspring groups. Future investigation should assess potential differences in cardiac function and the impact of fetal-programming on offspring cardiovascular adaptations during pregnancy in more severe models of pregnancy-related hypertensive syndrome such as angiotensin II or isoproterenol infusion.

Relationship between carotid artery atherosclerosis and bulb geometry.

The carotid bifurcation is a common site of atherosclerotic plaque. Plaque development is thought to occur preferentially at geometrically predisposed areas such as arterial branch points. The aim of this study was to investigate the geometric and anatomical variables that contribute to the development of carotid plaque using three-dimensional (3D) ultrasound. Sixty-seven consecutive outpatients referred for elective coronary angiography underwent 3D carotid ultrasound scans for the purpose of carotid plaque quantification. Geometric quantification of the left and right carotid bulbs were performed retrospectively on this study population. Geometric values such as angle, area and length of the carotid bulb and the bifurcation were determined using QLAB software (Philips Healthcare). Plaque volume within the carotid bulb and artery branches was quantified using the stacked contour method. Pearson's correlation and linear regression analysis were used to determine the relationship between anatomical variables and plaque volume. The mean age for the total patient population was 65.9 ± 11.5 years. Carotid bulb inflow area (BIA) (r = 0.28, p = 0.001), bulb volume (BV) (r = 0.21, p = 0.01) and bifurcation angle (BifA) (r = 0.18, p = 0.04) showed a positive linear relationship with plaque volume. In contrast, internal carotid artery angle (ICAA) (r = - 0.18, p = 0.04) and bulb flare (r = - 0.20, p = 0.02) displayed a negative linear relationship with plaque volume. When adjusting for age and sex, only the BIA remained significant (ß = 0.18, p = 0.04). Geometric variables were identified as potential risk factors associated with plaque volume in the carotid bulb. Further analysis of the evolution of the BIA as well as the relationship to other geometric variables could create a stronger predictive model of atherosclerosis as well as assist in preoperative planning.

Sex Differences of the Natriuretic Peptide Polymorphism Associated With Angiographic Coronary Atherosclerosis.

BACKGROUND: Polymorphisms within natriuretic peptide (NP) genes have been associated with clinical outcomes for cardiovascular disease (CVD), but no previous study has compared the effect of these polymorphisms between men and women. This study aimed to investigate the association between single nucleotide polymorphisms (SNPs) in key genes of the NP system and coronary angiographic outcomes, with the focus on the sexual dimorphism in the effects of these SNPs. METHODS: Patients undergoing clinically indicated coronary angiography (n = 513, 328 men and 185 women) were consented and genotyped for NPPA rs5065, NPPB rs198389 and NPR2 rs10758325. Patients were stratified into having normal coronaries, non-obstructive coronary artery disease (CAD) or obstructive CAD, based on the highest stenosis in any epicardial artery. Average luminal narrowing across all four arteries was derived to represent the overall atherosclerotic burden. RESULTS: The frequency of NPPB rs198389 AA genotype was significantly higher in women with obstructive CAD (P = 0.014). The same association was not observed in males. With respect to atherosclerotic burden, an association was found between the AA genotype and average luminal narrowing in women (P = 0.005), but not in men. CONCLUSIONS: The current study identified an association between an SNP of the NPPB gene and coronary atherosclerotic burden through angiographic evidence in women but not in men. These results suggest that B-type natriuretic peptide (BNP) may have more important involvement in the development of CAD in women compared to men, and as such, genotyping of the NPPB gene may serve as a potential biomarker to identify women with high risk for CAD.

Novel Ultrasound Methods to Investigate Carotid Artery Plaque Vulnerability.

Features of vulnerable plaque include a high lipid content, an irregular shape, a thin fibrous cap, and neovascularization, but such lesions often fall into the category of nonstenotic, despite being at high risk for rupture, and therefore may be overlooked. In this review, the authors describe state-of-the-art investigative ultrasound methods to assess the activity, quality, and morphology of atherosclerotic plaque to determine vulnerability. Specifically, the authors focus on carotid artery plaque, describing the assessment of plaque activity through the detection of neovascularization using contrast-enhanced ultrasound, the characterization of plaque quality by advanced grayscale and integrated backscatter analysis methods, and the assessment of plaque morphology using three-dimensional ultrasound.

Onset and Regression of Pregnancy-Induced Cardiac Alterations in Gestationally Hypertensive Mice: The Role of the Natriuretic Peptide System.

Pregnancy induces cardiovascular adaptations in response to increased volume overload. Aside from the hemodynamic changes that occur during pregnancy, the maternal heart also undergoes structural changes. However, cardiac modulation in pregnancies complicated by gestational hypertension is incompletely understood. The objectives of the current investigation were to determine the role of the natriuretic peptide (NP) system in pregnancy and to assess alterations in pregnancy-induced cardiac hypertrophy between gestationally hypertensive and normotensive dams. Previously we have shown that mice lacking the expression of atrial NP (ANP; ANP(-/-)) exhibit a gestational hypertensive phenotype. In the current study, female ANP(+/+) and ANP(-/-) mice were mated with ANP(+/+) males. Changes in cardiac size and weight were evaluated across pregnancy at Gestational Days 15.5 and 17.5 and Postnatal Days 7, 14, and 28. Nonpregnant mice were used as controls. Physical measurement recordings and histological analyses demonstrated peak cardiac hypertrophy occurring at 14 days postpartum in both ANP(+/+) and ANP(-/-) dams with little to no change during pregnancy. Additionally, left ventricular expression of the renin-angiotensin system (RAS) and NP system was quantified by real-time quantitative polymerase chain reaction. Up-regulation of Agt and AT(1a) genes was observed late in pregnancy, while Nppa and Nppb genes were significantly up-regulated postpartum. Our data suggest that pregnancy-induced cardiac hypertrophy may be influenced by the RAS throughout gestation and by the NP system postpartum. Further investigations are required to gain a complete understanding of the mechanistic aspects of pregnancy-induced cardiac hypertrophy.