To compare lipoprotein profiles of pre-diabetic to normoglycemic obese adolescents.
Cross-sectional study of 95 obese, pubertal adolescents (12–17 years), who underwent oral glucose tolerance test, lipid panel, and lipoprotein subclass particle analysis (NMR spectroscopy). Univariate and linear regression analyses compared pre-diabetic and normoglycemic groups.
22.1% (n=21) of adolescents had pre-diabetes. They were similar to normoglycemic adolescents (n=74) in age, race, BMI, standard lipids, total LDL-P, and total HDL-P. However, pre-diabetics had higher concentrations of small LDL-P (714.0±288.0 vs 537.7±266.5nmol/L, p=0.01) and smaller LDL-P size (20.73±0.41 vs 21.18±0.65nm, p=0.003), than normoglycemic youth. Pre-diabetics had higher small HDL-P (18.5±3.8 vs 16.6±3.9umol/L, p=0.046), lower large HDL-P (4.49±2.0 vs 6.32±2.6umol/L, p=0.004), and smaller HDL-P size (8.73±0.31 vs 9.01±0.39nm, p=0.003). After adjusting for demographics, Tanner stage, and BMI using multiple linear regression, all differences remained significant except for small HDL-P. After additional adjustment for HOMA-IR, only LDL-P size difference remained significant.
Obese pre-diabetic adolescents have a significantly more atherogenic lipoprotein profile compared with obese normoglycemic peers. Pre-diabetic adolescents may benefit from more aggressive interventions to decrease future cardiovascular risk.
impaired fasting glucose; impaired glucose tolerance; type 2 diabetes mellitus; lipoprotein subclass particle analysis; cardiovascular risk; body mass index; pediatrics; lipids; abnormal glucose tolerance
To introduce a new, efficient method for vessel-wall imaging of carotid and peripheral arteries by means of a flow-sensitive 3D water-selective SSFP-echo pulse sequence.
Periodic applications of RF pulses will generate two transverse steady states, immediately after and before an RF pulse; the latter being referred to as the SSFP-echo. The SSFP-echo signal for water protons in blood is spoiled as a result of moving spins losing phase coherence in the presence of a gradient pulse along the flow direction. Bloch equation simulations were performed over a wide range of velocities to evaluate the flow sensitivity of the SSFP-echo signal. Vessel walls of carotid and femoral and popliteal arteries were imaged at 3 T. In two patients with peripheral artery disease the femoral arteries were imaged bilaterally to demonstrate method’s potential to visualize atherosclerotic plaques. The method was also evaluated as a means to measure femoral artery flow-mediated dilation (FMD) in response to cuff-induced ischemia in four subjects.
The SSFP-echo pulse sequence, which does not have a dedicated blood signal suppression preparation, achieved low blood signal permitting discrimination of the carotid and peripheral arterial walls with in-plane spatial resolution ranging from 0.5 to 0.69 mm and slice thickness of 2 to 3 mm, i.e. comparable to conventional 2D vessel-wall imaging techniques. The results of the simulations were in good agreement with analytical solution and observations for both vascular territories examined. Scan time ranged from 2.5 to 5 s per slice yielding a contrast-to-noise ratio between the vessel wall and lumen from 3.5 to 17. Mean femoral FMD in the four subjects was 9%, in good qualitative agreement with literature values.
Water-selective 3D SSFP-echo pulse sequence is a potential alternative to 2D vessel-wall imaging. The proposed method is fast, robust, applicable to a wide range of flow velocities, and straightforward to implement.
Despite the significant morbidity and mortality attributable to cardiovascular disease (CVD), risk stratification remains an important challenge in the chronic kidney disease(CKD) population. We examined the discriminative ability of non-invasive measures of atherosclerosis, including carotid intima-media thickness(cIMT), carotid plaque, coronary artery calcification(CAC) and ascending and descending thoracic aorta calcification(TCAC), and Framingham Risk Score (FRS) to predict self-reported prevalent CVD.
Methods and Results
Participants were enrolled in the cIMT ancillary study of the Chronic Renal Insufficiency Cohort(CRIC) Study and also had all of the above measures within an 18 month period. CVD was present in 21% of study participants. C-statistics were used to ascertain the discriminatory power of each measure of atherosclerosis. The study population (n=220) was 64% male; 51% black and 45% white. The proportion of individuals with estimated glomerular filtration rate ≥60, 45–59, 30–44, and <30ml/min/1.73m2 was 21%, 41%, 28%, and 11%, respectively. In multivariable analyses adjusting for demographic factors, we failed to find a difference between CAC, carotid plaque, and cIMT as predictors of self-reported prevalent CVD (c-statistic 0.70, 95% confidence interval [CI]: 0.62–0.78; c-statistic 0.68, 95% CI: 0.60–0.75, and c-statistic 0.64, CI: 0.56–0.72, respectively). CAC was statistically better than FRS. FRS was the weakest discriminator of self-reported prevalent CVD (c-statistic 0.58).
There was a significant burden of atherosclerosis among individuals with CKD, ascertained by several different imaging modalities. We were unable to find a difference in the ability of CAC, carotid plaque, and cIMT to predict self-reported prevalent CVD.
carotid intima media thickness; coronary artery calcification; kidney; plaque
Personalized medicine refers to the application of an individual’s biological fingerprint – the comprehensive dataset of unique biological information – to optimize medical care. While the principle itself is straightforward, its implementation remains challenging. Advances in pharmacogenomics as well as functional assays of vascular biology now permit improved characterization of an individual’s response to medical therapy for vascular disease. This review describes novel strategies designed to permit tailoring of four major pharmacotherapeutic drug classes within vascular medicine: antiplatelet therapy, antihypertensive therapy, lipid-lowering therapy, and antithrombotic therapy. Translation to routine clinical practice awaits the results of ongoing randomized clinical trials comparing personalized approaches with standard of care management.
anticoagulants; antihypertensive agents; aspirin; statins; vascular diseases; warfarin
Therapeutic angiogenesis utilizing genetic and cellular modalities in the treatment of arterial obstructive diseases continues to evolve. This is, in part, because the mechanism of vasculogenesis, angiogenesis, and arteriogenesis (the three processes by which the body responds to obstruction of large conduit arteries) is a complex process that is still under investigation. To date, the majority of human trials utilizing molecular, genetic, and cellular modalities for therapeutic angiogenesis in the treatment of peripheral artery disease (PAD) have not shown efficacy. Consequently, the current available knowledge is yet to be translated into novel therapeutic approaches for the treatment of PAD. The aim of this review is to discuss relevant scientific and clinical advances in therapeutic angiogenesis and their potential application in the treatment of ischemic diseases of the peripheral arteries. Additionally, this review article discusses past and recent developments, such as some unconventional approaches that have the potential to be applied as therapeutic targets. The article also includes advances in the delivery of genetic, cellular, and bioactive endothelial growth factors.
cell therapy; gene therapy; neovascularization; peripheral artery disease; targeted delivery; therapeutic angiogenesis
The effect of weight loss on obesity-associated endothelial dysfunction is not clear because of conflicting data, demonstrating both improvement and no change in endothelial function after weight loss in obese subjects.
A two-year prospective study (n=121) was conducted to examine: 1) the effect of obesity and weight loss (either a low-carbohydrate or and low-fat diet) on flow mediated vasodilatation (FMD), a measure of endothelial function.
Participants reduced body weight by 7.1±4.4%, 8.7±6.8% 7.1±7.8% and 4.1±7.7% at 3, 6, 12 and 24 months, respectively with no significant differences between the low-fat and low-carbohydrate groups. Endothelial function was inversely correlated with waist circumference, triglyceride level, and directly correlated with leptin in obese persons prior to weight loss. These weight losses did not confer any improvements in FMD. There were no differences between the low-fat and low-carbohydrate diets in FMD at any time point. At 6 months (r = 0.26, p = 0.04) and one year (r = 0.28, p = 0.03), there were positive correlations between change in FMD and change in leptin but not at two years.
There was no significant improvement in endothelial function after 7.1±7.8% weight loss at one year and 4.1±7.7% at two years, achieved by either a low carbohydrate or a low fat diet.
Endothelium; Obesity; Leptin; Diet
Subjects with peripheral artery disease (PAD) are at increased risk of cardiovascular morbidity and mortality, perhaps in part, related to increased levels of inflammation, platelet activity, and lipids. We therefore sought to investigate the relationship between PAD and levels of inflammatory, platelet, and lipid biomarkers and the treatment effect of darapladib, a novel lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibitor.
This is a post hoc analysis of the 959 patients with coronary disease or their risk equivalent receiving atorvastatin who were randomized to receive darapladib or placebo to examine the effects of an Lp-PLA2 inhibitor on the biomarkers of cardiovascular risk. We conducted an exploratory analysis evaluating the levels of biomarkers in subjects with PAD (n = 172) compared with those without PAD (n = 787).
After adjustment for age, sex, smoking, body mass index, and diabetes, subjects with PAD had greater levels of matrix metalloproteinase-9 (between group comparisons 22%, 95% confidence interval [10–31], P < .01), myeloperoxidase (12% [2–20], P = .01), interleukin-6 (13% [4–21], P = .01), adiponectin (17% [7–26], P < .01), intercellular adhesion molecule-1 (7% [2–11], P < .01), osteoprotegrin (6% [1–10], P = .02), CD40 ligand (15% [1–28], P = .04), high-sensitivity C-reactive protein (17% [1–31], P = .04), and triglycerides (11% [0.2–21], P = .05). No significant difference was detected for Lp-PLA2 activity, P-selectin, urinary 11-dehydrothroboxane B2, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol between subjects with and without PAD. Darapladib produced highly significant inhibition of Lp-PLA2 activity when compared with placebo at weeks 4 and 12 (P < .01) in patients with and without PAD.
Subjects with PAD had elevated levels of matrix metalloproteinase-9, myeloperoxidase, interleukin-6, adiponectin, intercellular adhesion molecule-1, osteoprotegrin, CD40 ligand, high-sensitivity C-reactive protein, and triglycerides compared with those without PAD. Darapladib, a novel Lp-PLA2 inhibitor, was equally effective in reducing Lp-PLA2 activity levels in subjects with and without PAD.
Assessment of vascular disease has evolved from mere indirect and direct measurements of luminal stenosis to sophisticated imaging methods to depict millimeter structural changes of the vasculature. In the near future, the emergence of multimodal molecular imaging strategies may enable robust therapeutic and diagnostic (‘theragnostic’) approaches to vascular diseases that comprehensively consider structural, functional, biological and genomic characteristics of the disease in individualized risk assessment, early diagnosis and delivery of targeted interventions. This review presents a summary of recent preclinical and clinical developments in molecular imaging and theragnostic applications covering diverse atherosclerosis events such as endothelial activation, macrophage infammatory activity, plaque neovascularization and arterial thrombosis. The main focus is on molecular targets designed for imaging platforms commonly used in clinical medicine including magnetic resonance, computed tomography and positron emission tomography. A special emphasis is given to vascular ultrasound applications, considering the important role this imaging platform plays in the clinical and research practice of the vascular medicine specialty.
atherosclerosis plaque; imaging based therapeutic delivery systems; molecular imaging; theragnostics; thrombosis; vascular ultrasound
We sought to determine whether mean platelet volume (MPV) is associated with the prevalence of peripheral artery disease (PAD).
Platelets play a pivotal role in the pathogenesis of atherosclerosis and PAD. MPV, a measure of platelet size available in every blood count, is increasingly recognized as an important marker of platelet activity.
We analyzed data from 6354 participants aged 40 years and older from the 1999 to 2004 National Health and Nutrition Examination Survey (NHANES), a nationally representative sample of the US population. PAD was defined as an ankle brachial index ≤0.90 in either leg. Odds ratios and 95% confidence intervals were estimated by logistic regression.
The prevalence of PAD in the cohort was 5.7%. MPV was significantly associated with PAD prevalence (tertile 1 – 4.4%, tertile 2 – 6.1%, tertile 3 – 7.0%, P for trend = 0.003). After adjustment for age, sex, and race, the odds ratio of PAD comparing the highest tertile to the lowest tertile was 1.57 (95% confidence interval 1.15–2.13). After further adjustment for smoking status, hypertension, hypercholesterolemia, diabetes, glomerular filtration rate, body mass index, and platelet count the corresponding odds ratio was 1.58 (95% confidence interval 1.14–2.19). The addition of triglycerides, hemoglobin A1c, and C-reactive protein did not affect the results. The significant association between MPV and PAD was unchanged when MPV was used as a continuous variable.
Mean platelet volume is independently associated with PAD. These findings support the hypothesis that platelet size is an independent predictor of increased risk for PAD.
Mean platelet volume; Platelets; Peripheral artery disease; Epidemiology
The measurement of carotid intima-medial thickness is a well validated measure of cardiovascular risk. Although atherosclerosis occurs in the intima, this arterial layer is not measured alone due to limitation in ultrasound resolution with standard frequency probes.
We evaluated the feasibility of using a 55-MHz ultrasound system with high resolution to measure intima thickness in several vascular territories compared to a “standard” frequency probe.
The intima and medial thickness was measured in the brachial, radial and tibial arteries in 10 healthy subjects and 5 subjects with peripheral arterial disease. The high frequency ultrasound probe showed superior resolution compared to the standard frequency probe allowing for measurement of intima separately from media.
The intima can be measured independently of media with a high degree of reproducibility using a high frequency probe. This technology may allow for early detection of cardiovascular risk and extend knowledge about the physiological changes in the early atherosclerotic development.
Patients with chronic kidney disease (CKD) have an increased risk of developing peripheral arterial disease (PAD). We examined the cross-sectional association between novel risk factors and prevalent PAD among patients with CKD. A total of 3,758 patients with an estimated glomerular filtration rate (eGFR) of 20-70 mL/min/1.73 m2 who participated in the chronic renal insufficiency cohort (CRIC) study were included in the current analysis. PAD was defined as an ankle-brachial index <0.9 or a history of arm or leg revascularization. After adjustment for age, sex, race, cigarette smoking, physical activity, history of hypertension and diabetes, pulse pressure, high-density lipoprotein cholesterol, eGFR, and CRIC clinical sites, several novel risk factors were significantly associated with PAD. For example, odds ratios (95% confidence intervals) for a one standard deviation higher level of risk factors were 1.18 (1.08–1.29) for log-transformed high sensitivity-C reactive protein, 1.18 (1.08–1.29) for white blood cell count, 1.15 (1.05–1.25) for fibrinogen, 1.13 (1.03–1.24) for uric acid, 1.14 (1.02–1.26) for hemoglobin A1c, 1.11 (1.00–1.23) for log-transformed homeostasis model assessment-insulin resistance, and 1.35 (1.18–1.55) for cystatin C. In conclusion, these data indicate that inflammation, prothrombotic state, oxidative stress, insulin resistance, and cystatin C were associated with an increased prevalence of PAD in patients with CKD. Further studies are warranted to examine the causal effect of these risk factors on PAD in CKD patients.
peripheral arterial disease; novel risk factors; chronic kidney disease
The association between platelet activity, diabetes, and glucometabolic control is uncertain. We aim to investigate mean platelet volume (MPV), a marker of platelet size and platelet activity, with the prevalence of diabetes, metabolic syndrome, and degree of glycemic control.
RESEARCH DESIGN AND METHODS
This is a retrospective analysis of 13,021 participants in the National Health and Nutrition Examination Survey from 1999 to 2004. Prevalence of diabetes was defined as nonfasting glucose >200 mg/dL, fasting glucose ≥126 mg/dL, or treatment with hypoglycemic agents. Presence of metabolic syndrome was determined by the National Cholesterol Education Program Adult Treatment Panel III definition. Odds ratios and 95% CIs were estimated by logistic regression.
MPV was significantly higher in subjects with diabetes (8.20 vs. 8.06 femtoliter [fL], P < 0.01) but not in subjects with metabolic syndrome (8.09 vs. 8.07 fL, P = 0.24). For the metabolic syndrome components, MPV was significantly higher in abdominal obesity (P = 0.03) and low HDL (P = 0.04), and not different in high blood pressure (P = 0.07), abnormal glucose metabolism (P = 0.71), or hypertriglyceridemia (P = 0.46). There was a significant correlation between MPV and glucose (P < 0.0001) and between MPV and hemoglobin A1c (P < 0.0001) in subjects with diabetes. These correlations were no longer significant in those without diabetes. The adjusted odds of diabetes rose with increasing MPV levels and were most pronounced in subjects with MPV levels exceeding the 90th percentile (≥9.31 fL). The association between MPV and diabetes was most apparent in those with the poorest glucose control.
Mean platelet volume is strongly and independently associated with the presence and severity of diabetes.
The aim of this study was to develop and evaluate an integrated CMR method incorporating dynamic oximetry, blood flow and pulse-wave velocimetry to assess vascular reactivity in patients with peripheral artery disease (PAD) and healthy controls.
Methods and results
The study population consisted of young healthy subjects (YH, 30 ± 7 yrs, N = 19),PAD (71 ± 9 yrs, N = 38), and older healthy controls (OHC, 68 ± 9 yrs, N = 43). Peripheral vascular reactivity was evaluated with two methods, time-resolved quantification of blood flow velocity and oxygenation level in the femoral artery and vein, respectively, performed simultaneously both at rest and hyperemia. Aortic stiffness was assessed via pulse-wave velocity. Oximetric data showed that compared to OHC, the time-course of the hemoglobin oxygen saturation in PAD patients had longer washout time (28.6 ± 1.2 vs 16.9 ± 1.1 s, p < 0.0001), reduced upslope (0.60 ± 0.1 vs 1.3 ± 0.08 HbO2/sec, p < 0.0001) and lower overshoot (8 ± 1.4 vs 14 ± 1.2 HbO2, p = 0.0064). PAD patients also had longer-lasting antegrade femoral artery flow during hyperemia (51 ± 2.1 vs 24 ± 1.8 s, p < 0.0001), and reduced peak-to-baseline flow rate (3.1 ± 0.5 vs 7.4 ± 0.4, p < 0.0001). Further, the pulsatility at rest was reduced (0.75 ± 0.32 vs 5.2 ± 0.3, p < 0.0001), and aortic PWV was elevated (10.2 ± 0.4 vs 8.1 ± 0.4 m/s, p = 0.0048).
The proposed CMR protocol quantifies multiple aspects of vascular reactivity and represents an initial step toward development of a potential tool for evaluating interventions, extrapolating clinical outcomes and predicting functional endpoints based on quantitative parameters.
Peripheral arterial disease; Atherosclerosis; Microvascular function; Pulse-wave velocity; Blood oxygen saturation; Phase image; Magnetic resonance oximetry
Claudication is a common and disabling symptom of peripheral artery disease that can be treated with medication, supervised exercise or stent revascularization.
We randomly assigned 111 patients with aortoiliac peripheral artery disease to receive one of three treatments: optimal medical care [OMC], OMC plus supervised exercise [(SE], or OMC plus stent revascularization [ST]. The primary endpoint was the change in peak walking time (PWT) on a graded treadmill test at 6 months as compared with baseline. Secondary endpoints included free-living step activity, quality of life (QOL) using the Walking Impairment Questionnaire (WIQ) and Peripheral Artery Questionnaire (PAQ), and cardiovascular risk factors.
At six month follow-up, change in PWT (the primary endpoint) was greatest for SE, intermediate for ST, and least with OMC (mean change vs. baseline 5.8±4.6, 3.7±4.9, and 1.2±2.6 minutes, respectively; p<0.001 for the comparison of SE vs. OMC; p=0.02 for ST vs. OMC; and p=0.04 for SE vs. ST). Although disease-specific quality of life as assessed by the WIQ and PAQ also improved with both SE and ST compared with OMC, for most scales the extent of improvement was greater with ST than SE. Free-living step activity increased more with ST than with either SE or OMC alone (114±274 vs. 73±139 vs. −6±109 steps/hour) but these differences were not statistically significant.
Supervised exercise treatment results in superior treadmill walking performance than stent placement, even for those with aortoiliac PAD. The contrast between better walking performance for SE and better patient-reported QOL for ST warrants further study.
Approximately 13 percent of aortic valves removed from patients with end-stage aortic valve disease contain heterotopic ossification (HO). Recently, we identified a novel population of circulating osteogenic precursor (COP) cells which are derived from bone marrow and have the capability to form bone. These cells are identified by co-expression of osteogenic marker types 1 collagen or osteoclacin (OCN) and the hematopoietic marker CD45. We tested the hypothesis that these cells may contribute to heart valve stenosis.
Methods and Results
Quantification of CD45+ OCN+ COP cells by flow cytometry showed that they represent up to 1.1 percent of mononuclear cells. Clonally-derived COP cells produce bone morphogenetic proteins 2 and 4 by immunohistochemical analysis. We reviewed 105 cases of end-stage aortic valvular disease and confirmed HO in 13 archived specimens. Using immunohistochemistry, we identified COP cells by co-expression of CD45 and type 1 collagen. There was a statistically significant association between the presence of COP cells and early HO lesions. COP cells were negligible in regions of unaffected valve leaflets (no HO) from the same individuals.
This study provides the first evidence that osteogenic cells in the blood home to sites of vascular injury and are associated with HO formation in heart valves.
Heart valves; blood cells; pathology; aging; collagen
Coronary artery calcification (CAC) is associated with increased mortality risk in the general population. Although individuals with chronic kidney disease (CKD) are at markedly increased mortality risk, the incidence, prevalence, and prognosis of CAC in CKD is not well-understood.
Cross-sectional observational study.
Setting and Participants
Analysis of 1,908 participants who underwent coronary calcium scanning as part of the multi-ethnic CRIC (Chronic Renal Insufficiency Cohort) Study.
Estimated glomerular filtration rate (eGFR) computed using the Modification of Diet in Renal Disease (MDRD) Study equation, stratified by race, sex and diabetic status. eGFR was treated as a continous variable and a categorical variable compared to the reference range of >60 ml/min/1.73 m2
CAC detected using CT scans using either an Imatron C-300 electron beam computed tomography scanner or multi-detector CT scanner. CAC was computed using the Agatston score, as a categorical variable. Analyses were performed using ordinal logistic regression.
We found a strong and graded relationship between lower eGFR and increasing CAC. In unadjusted models, ORs increased from 1.68 (95% CI, 1.23–2.31) for eGFR from 50–59 to 2.82 (95% CI, 2.06–3.85) for eGFR of <30. Multivariable adjustment only partially attenuated the results (OR, 1.53; 95% CI, 1.07–2.20) for eGFR<30.
Use of eGFR rather than measured GFR.
We demonstrated a graded relationship between severity of CKD and CAC, independent of traditional risk factors. These findings supports recent guidelines that state that if vascular calcification is present, it should be considered as a complementary component to be included in the decision making required for individualizing treatment of CKD.
Clinical palpation of a pulsating abdominal mass alerts the clinician to the presence of a possible abdominal aortic aneurysm (AAA). Generally an arterial aneurysm is defined as a localized arterial dilatation ≥50 % greater than the normal diameter. Imaging studies are important in diagnosing the cause of a pulsatile abdominal mass and, if an AAA is found, in determining its size and involvement of abdominal branches. Ultrasound (US) is the initial imaging modality of choice when a pulsatile abdominal mass is present. Noncontrast computed tomography (CT) may be substituted in patients for whom US is not suitable. When aneurysms have reached the size threshold for intervention or are clinically symptomatic, contrast-enhanced multidetector CT angiography (CTA) is the best diagnostic and preintervention planning study, accurately delineating the location, size, and extent of aneurysm and the involvement of branch vessels. Magnetic resonance angiography (MRA) may be substituted if CT cannot be performed. Catheter arteriography has some utility in patients with significant contraindications to both CTA and MRA. The American College of Radiology Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.
Appropriateness criteria; Aortic aneurysm; Ultrasonography; Computed tomography; Magnetic resonance angiography; Catheter arteriography
The purpose of these guidelines is to recommend appropriate imaging for patients with blunt chest trauma. These patients are most often imaged in the emergency room, and thus emergency radiologists play a substantial role in prompt, accurate diagnoses that, in turn, can lead to life-saving interventions. The ACR Appropriateness Criteria® are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. Imaging largely focuses on the detection and exclusion of traumatic aortic injury; a large proportion of patients are victims of motor vehicle accidents. For those patients who survive the injury and come to emergency radiology, rapid, appropriate assessment of patients who require surgery is paramount.
Appropriateness criteria; Traumatic aortic injury; Thoracic aorta; Blunt trauma; CT; MRI
Quantitative measures are needed to identify diabetic patients at higher risk for CV events. Cell derived microparticles (MPs) are submicron membrane vesicles released from activated cells that are indicative of cell damage. Progenitor cells (PCs) including pro-angiogenic cells (PACs), often termed endothelial progenitor cells (EPCs), are mediators of reparative capacity. We examined whether the relationship of MPs to PCs/PACs could be used as an improved and clinically feasible index of vascular pathology.
Methods and Results
Plasma samples were collected from patients with early-stage (ES, Diagnosis<1yr) and long-term (LT, Diagnosis>5yrs,) type 2 diabetes and compared to age related healthy subjects (H). PC and MP subtypes were measured by a combination of flow cytometry and ELISA based methods. The ratio of pro-coagulant MPs/CD34+ PCs proved a valuable index to distinguish between subject groups (P=0.01). This index of compromised vascular function was highest in the LT group despite intensive statin therapy and was more informative than a range of soluble protein biomarkers.
This is the first report of a relationship between MPs and PCs in type 2 diabetes. This ratio may provide a quantitative and clinically feasible measurement of vascular dysfunction and cardiovascular risk in patients with diabetes.
Endothelial; progenitor; vascular; diabetes; microparticles
High-density lipoprotein (HDL) may provide cardiovascular protection by promoting reverse cholesterol transport from macrophages. We hypothesized that the capacity of HDL to accept cholesterol from macrophages would serve as a predictor of atherosclerotic burden.
We measured cholesterol efflux capacity in 203 healthy volunteers who underwent assessment of carotid artery intima–media thickness, 442 patients with angiographically confirmed coronary artery disease, and 351 patients without such angiographically confirmed disease. We quantified efflux capacity by using a validated ex vivo system that involved incubation of macrophages with apolipoprotein B–depleted serum from the study participants.
The levels of HDL cholesterol and apolipoprotein A-I were significant determinants of cholesterol efflux capacity but accounted for less than 40% of the observed variation. An inverse relationship was noted between efflux capacity and carotid intima–media thickness both before and after adjustment for the HDL cholesterol level. Furthermore, efflux capacity was a strong inverse predictor of coronary disease status (adjusted odds ratio for coronary disease per 1-SD increase in efflux capacity, 0.70; 95% confidence interval [CI], 0.59 to 0.83; P<0.001). This relationship was attenuated, but remained significant, after additional adjustment for the HDL cholesterol level (odds ratio per 1-SD increase, 0.75; 95% CI, 0.63 to 0.90; P = 0.002) or apolipoprotein A-I level (odds ratio per 1-SD increase, 0.74; 95% CI, 0.61 to 0.89; P = 0.002). Additional studies showed enhanced efflux capacity in patients with the metabolic syndrome and low HDL cholesterol levels who were treated with pioglitazone, but not in patients with hypercholesterolemia who were treated with statins.
Cholesterol efflux capacity from macrophages, a metric of HDL function, has a strong inverse association with both carotid intima–media thickness and the likelihood of angiographic coronary artery disease, independently of the HDL cholesterol level. (Funded by the National Heart, Lung, and Blood Institute and others.)
Fibrocalcific aortic stenosis (AS) results from an active process similar to atherosclerosis that involves basement membrane disruption, lipid deposition, inflammatory cell infiltration, and calcification. Consequently, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been extensively studied as potential therapeutic agents capable of slowing the progression of AS. However, two randomized trials, SALTIRE and the SEAS study, showed no benefit with statin therapy for AS. These results have shed doubt over the efficacy of statin therapy for AS, although their potential efficacy at early stages of aortic valve disease remains possible. In this article, we review the pathophysiology of fibrocalcific AS and discuss future directions for its nonsurgical management in the post-SEAS era.
Calcification; Aortic valve; Statin; Stenosis
Fetuin-A is an inhibitor of vascular calcification and a mediator of insulin resistance. This study evaluated the association of plasma fetuin-A and peripheral arterial disease (PAD).
RESEARCH DESIGN AND METHODS
A total of 738 individuals with type 2 diabetes (mean age 58.7 years, 37.1% female) without known cardiovascular or kidney disease were included in this cross-sectional analysis.
Subjects with PAD had a significantly lower fetuin-A (264.3 vs. 293.4 ng/dl, P < 0.001). In multivariable analysis, a 1-SD decrease in fetuin-A increased the odds of PAD (odds ratio 1.6, P = 0.02). Subgroup analysis revealed an increased odds even in subjects with glomerular filtration rate >80 (odds ratio 1.9, P = 0.05) or high-sensitivity C-reactive protein <3 mg/dl (odds ratio 2.7, P = 0.002).
Lower circulating fetuin-A is associated with PAD in type 2 diabetes beyond traditional and novel cardiovascular risk factors. Our findings suggest a potentially unique role for fetuin-A deficiency as a biomarker of PAD in patients with type 2 diabetes.
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a calcium-independent phospholipase A2 enzyme secreted by leukocytes and associated with circulating low-density lipoprotein and macrophages in atherosclerotic plaques. Until recently, the biological role of Lp-PLA2 in atherosclerosis was controversial, but now the preponderance of evidence demonstrates a proatherogenic role of this enzyme. Lp-PLA2 generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a major role in the development of atherosclerotic lesions and formation of a necrotic core, leading to more vulnerable plaques. These findings have opened the door to a potential novel therapeutic target, selective inhibition of Lp-LPA2. Recently, both animal models and human studies have shown that selective inhibition of Lp-PLA2 reduces plasma Lp-PLA2 activity, plaque area, and necrotic core area. This article reviews the most recent developments with Lp-PLA2 inhibitors.
Phospholipase; Lipoprotein; Atherosclerosis; Myocardial infarction; Atherothrombosis
To evaluate the role of membrane cholesterol on human neutrophil and HL-60 biomechanics, capture, rolling, and arrest to P-selectin or IL-1-activated endothelium.
Methods and Results
Methyl-β-cyclodextrin (MβCD) removed up to 73% and 45% of membrane cholesterol from HL-60 cells and neutrophils, while MβCD/cholesterol complexes resulted in maximum enrichment of 65% and 40%, respectively, above control levels. Cells were perfused at a venous wall shear rate of 100 s−1 over adherent P-selectin-coated 1-µm diameter beads, uncoated 10-µm diameter beads, P-selectin-coated surfaces, or activated endothelium. Elevated cholesterol enhanced capture efficiency to 1-µm beads and increased membrane tether growth rate by 1.5- to 2-fold, whereas cholesterol depletion greatly reduced tether formation. Elevated cholesterol levels increased tether lifetime by 17% in neutrophils and adhesion lifetime by 63% in HL-60 cells. Deformation of cholesterol-enriched neutrophils increased the contact time with 10-µm beads by 32% and the contact area by 7-fold. On both P-selectin surfaces and endothelial-cell monolayers, cholesterol-enriched neutrophils rolled more slowly, more stably, and were more likely to firmly arrest. Cholesterol depletion resulted in opposite effects.
Increasing membrane cholesterol enhanced membrane tether formation and whole cell deformability, contributing to slower, more stable rolling on P-selectin and increased firm arrest on activated endothelium.
neutrophils; cholesterol; cell adhesion; endothelium; membrane; inflammation