Saccade selection and inhibition: motor and attentional components.

Motor responses are fundamentally spatial in their function and neural organization. However, studies of inhibitory motor control, focused on global stopping of all actions, have ignored whether inhibitory control can be exercised selectively for specific actions. We used a new approach to elicit and measure motor inhibition by asking human participants to either look at (select) or avoid looking at (inhibit) a location in space. We found that instructing a location to be avoided resulted in an inhibitory bias specific to that location. When compared with the facilitatory bias observed in the Look task, it differed significantly in both its spatiotemporal dynamics and its modulation of attentional processing. While action selection was evident in oculomotor system and interacted with attentional processing, action inhibition was evident mainly in the oculomotor system. Our findings suggest that action inhibition is implemented by spatially specific mechanisms that are separate from action selection. NEW & NOTEWORTHY We show that cognitive control of saccadic responses evokes separable action selection and inhibition processes. Both action selection and inhibition are represented in the saccadic system, but only action selection interacts with the attentional system.

Effect of Angiotensin II Type I Receptor Blockade with Valsartan on Carotid Artery Atherosclerosis: A Double Blind Randomized Clinical Trial Comparing Valsartan and Placebo (EFFERVESCENT).

BACKGROUND: Progression of atherosclerosis is associated with a greater risk for adverse outcomes. Angiotensin II plays a key role in the pathogenesis and progression of atherosclerosis. We aimed to investigate the effects of angiotensin II type-1 receptor blockade with Valsartan on carotid wall atherosclerosis, with the hypothesis that Valsartan will reduce progression of atherosclerosis. METHODS: Subjects (n = 120) with carotid intima-media thickness >0.65 mm by ultrasound were randomized (2:1) in a double-blind manner to receive either Valsartan or placebo for 2 years. Bilateral T2-weighted black-blood carotid magnetic resonance imaging was performed at baseline, 12 and 24 months. Changes in the carotid bulb vessel wall area and wall thickness were primary endpoints. Secondary endpoints included changes in carotid plaque thickness, plasma levels of aminothiols, C-reactive protein, fibrinogen, and endothelium-dependent and -independent vascular function. RESULTS: Over 2 years, the carotid bulb vessel wall area decreased with Valsartan (-6.7, 95% CI [-11.6, -1.9] mm(2)) but not with placebo (3.4, 95% CI [-2.8, 9.6] mm(2)), P = .01 between groups. Similarly, mean wall thickness decreased with Valsartan (-0.18, 95% CI [-0.30, -0.06] mm), but not with placebo (0.08, 95% CI [-0.07, 0.23] mm), P = .009 between groups. Furthermore, plaque thickness decreased with Valsartan (-0.35, 95% CI [-0.63, -0.08] mm) but was unchanged with placebo (+0.28, 95% CI [-0.11, 0.69] mm), P = .01 between groups. These findings were unaffected by statin therapy or changes in blood pressure. Notably, there were significant improvements in the aminothiol cysteineglutathione disulfide, and trends to improvements in fibrinogen levels and endothelium-independent vascular function. CONCLUSIONS: In subjects with carotid wall thickening, angiotensin II type-1 receptor blockade was associated with regression in carotid atherosclerosis. Whether these effects translate into improved outcomes in subjects with subclinical atherosclerosis warrants investigation.

Effects of clopidogrel therapy on oxidative stress, inflammation, vascular function, and progenitor cells in stable coronary artery disease.

BACKGROUND: Traditional cardiovascular risk factors lead to endothelial injury and activation of leukocytes and platelets that initiate and propagate atherosclerosis. We proposed that clopidogrel therapy in patients with stable coronary artery disease imparts a pleiotropic effect that extends beyond antiplatelet aggregation to other atheroprotective processes. METHODS: Forty-one subjects were randomized in a double-blind, placebo-controlled, crossover study to receive either clopidogrel 75 mg daily or placebo for 6 weeks and then transitioned immediately to the other treatment for an additional 6 weeks. We assessed (1) endothelial function as flow-mediated dilation of the brachial artery, (2) arterial stiffness and central augmentation index using applanation tonometry, (3) vascular function as fingertip reactive hyperemia index, (4) inflammation by measuring plasma CD40 ligand and serum high-sensitivity c-reactive protein levels, (5) oxidative stress by measuring plasma aminothiols, and (6) circulating progenitor cells, at baseline and at the end of each 6-week treatment period. RESULTS: Clopidogrel therapy resulted in a significant reduction in soluble CD40 ligand (P = 0.03), a prothrombotic and proinflammatory molecule derived mainly from activated platelets. However, clopidogrel therapy had no effect on endothelial function, arterial stiffness, inflammatory and oxidative stress markers, or progenitor cells. CONCLUSIONS: Our findings suggest a solitary antiplatelet effect of clopidogrel therapy in patients with stable coronary artery disease, with no effect on other subclinical markers of cardiovascular disease risk.

Inhibition of saccades elicits attentional suppression.

Visuospatial attention has been shown to have a central role in planning and generation of saccades but what role, if any, it plays in inhibition of saccades remains unclear. In this study, we used an oculomotor delayed match- or nonmatch-to-sample task in which a cued location has to be encoded and memorized for one of two very different goals-to plan a saccade to it or to avoid making a saccade to it. We measured the spatial allocation of attention during the delay and found that while marking a location as a future saccade target resulted in an attentional benefit at that location, marking it as forbidden to saccades led to an attentional cost. Additionally, saccade trajectories were found to deviate away more from the "don't look" location than from a saccade-irrelevant distractor confirming greater inhibition of an actively forbidden location in oculomotor programming. Our finding that attention is suppressed at locations forbidden to saccades confirms and complements the claim of a selective and obligatory coupling between saccades and attention-saccades at the memorized location could neither be planned nor suppressed independent of a corresponding effect on attentional performance.

Coronary artery wall shear stress is associated with progression and transformation of atherosclerotic plaque and arterial remodeling in patients with coronary artery disease.

BACKGROUND: Experimental studies suggest that low wall shear stress (WSS) promotes plaque development and high WSS is associated with plaque destabilization. We hypothesized that low-WSS segments in patients with coronary artery disease develop plaque progression and high-WSS segments develop necrotic core progression with fibrous tissue regression. METHODS AND RESULTS: Twenty patients with coronary artery disease underwent baseline and 6-month radiofrequency intravascular ultrasound (virtual histology intravascular ultrasound) and computational fluid dynamics modeling for WSS calculation. For each virtual histology intravascular ultrasound segment (n=2249), changes in plaque area, virtual histology intravascular ultrasound-derived plaque composition, and remodeling were compared in low-, intermediate-, and high-WSS categories. Compared with intermediate-WSS segments, low-WSS segments developed progression of plaque area (P=0.027) and necrotic core (P<0.001), whereas high-WSS segments had progression of necrotic core (P<0.001) and dense calcium (P<0.001) and regression of fibrous (P<0.001) and fibrofatty (P<0.001) tissue. Compared with intermediate-WSS segments, low-WSS segments demonstrated greater reduction in vessel (P<0.001) and lumen area (P<0.001), and high-WSS segments demonstrated an increase in vessel (P<0.001) and lumen (P<0.001) area. These changes resulted in a trend toward more constrictive remodeling in low- compared with high-WSS segments (73% versus 30%; P=0.06) and more excessive expansive remodeling in high- compared with low-WSS segments (42% versus 15%; P=0.16). CONCLUSIONS: Compared with intermediate-WSS coronary segments, low-WSS segments develop greater plaque and necrotic core progression and constrictive remodeling, and high-WSS segments develop greater necrotic core and calcium progression, regression of fibrous and fibrofatty tissue, and excessive expansive remodeling, suggestive of transformation to a more vulnerable phenotype. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00576576.

Coronary angiographic scoring systems: an evaluation of their equivalence and validity.

BACKGROUND: Multiple scoring systems have been devised to quantify angiographic coronary artery disease (CAD) burden, but it is unclear how these scores relate to each other and which scores are most accurate. The aim of this study was to compare coronary angiographic scoring systems (1) with each other and (2) with intravascular ultrasound (IVUS)-derived plaque burden in a population undergoing angiographic evaluation for CAD. METHODS: Coronary angiographic data from 3600 patients were scored using 10 commonly used angiographic scoring systems and interscore correlations were calculated. In a subset of 50 patients, plaque burden and plaque area in the left anterior descending coronary artery were quantified using IVUS and correlated with angiographic scores. RESULTS: All angiographic scores correlated with each other (range for Spearman coefficient [ρ] 0.79-0.98, P < .0001); the 2 most widely used scores, Gensini and CASS-70, had a ρ = 0.90 (P < .0001). All scores correlated significantly with average plaque burden and plaque area by IVUS (range ρ 0.56-0.78, P < .0001 and 0.43-0.62, P < .01, respectively). The CASS-50 score had the strongest correlation (ρ 0.78 and 0.62, P < .0001) and the Duke Jeopardy score the weakest correlation (ρ 0.56 and 0.43, P < .01) with plaque burden and area, respectively. CONCLUSIONS: Angiographic scoring systems are strongly correlated with each other and with atherosclerotic plaque burden. Scoring systems therefore appear to be a valid estimate of CAD plaque burden.

Effect of inlet velocity profiles on patient-specific computational fluid dynamics simulations of the carotid bifurcation.

Patient-specific computational fluid dynamics (CFD) is a powerful tool for researching the role of blood flow in disease processes. Modern clinical imaging technology such as MRI and CT can provide high resolution information about vessel geometry, but in many situations, patient-specific inlet velocity information is not available. In these situations, a simplified velocity profile must be selected. We studied how idealized inlet velocity profiles (blunt, parabolic, and Womersley flow) affect patient-specific CFD results when compared to simulations employing a "reference standard" of the patient's own measured velocity profile in the carotid bifurcation. To place the magnitude of these effects in context, we also investigated the effect of geometry and the use of subject-specific flow waveform on the CFD results. We quantified these differences by examining the pointwise percent error of the mean wall shear stress (WSS) and the oscillatory shear index (OSI) and by computing the intra-class correlation coefficient (ICC) between axial profiles of the mean WSS and OSI in the internal carotid artery bulb. The parabolic inlet velocity profile produced the most similar mean WSS and OSI to simulations employing the real patient-specific inlet velocity profile. However, anatomic variation in vessel geometry and the use of a nonpatient-specific flow waveform both affected the WSS and OSI results more than did the choice of inlet velocity profile. Although careful selection of boundary conditions is essential for all CFD analysis, accurate patient-specific geometry reconstruction and measurement of vessel flow rate waveform are more important than the choice of velocity profile. A parabolic velocity profile provided results most similar to the patient-specific velocity profile.

Localization of culprit lesions in coronary arteries of patients with ST-segment elevation myocardial infarctions: relation to bifurcations and curvatures.

BACKGROUND: Although culprit lesions in ST-segment elevation myocardial infarction (STEMI) cluster in the proximal coronary arteries, their relationship to bifurcations and curvatures, where blood flow is disturbed, is unknown. We hypothesized that (a) culprit lesions localize to disturbed flow distal to bifurcations and curvatures and (b) the distribution of culprit lesions in the left (LCA) and right coronary arteries (RCA) and resulting infarct size are related to the location of bifurcations and curvatures. METHODS: Emory University's contribution to the National Cardiovascular Data Registry was queried for STEMIs. Using quantitative coronary angiography, the distances from the vessel ostium, major bifurcations, and major curvatures to the culprit lesion were measured in 385 patients. RESULTS: Culprit lesions were located within 20 mm of a bifurcation in 79% of patients and closer to the bifurcation in the LCA compared with the RCA (7.4 ± 7.3 vs 17.7 ± 14.8 mm, P < .0001). Of RCA culprit lesions, 45% were located within 20 mm of a major curvature. Compared with those in the RCA, culprit lesions in the LCA were located more proximally (24.4 ± 16.5 vs 44.7 ± 28.8 mm, P = .0003) and were associated with larger myocardial infarctions as assessed by peak creatine kinase-MB (208 ± 222 vs 140 ± 153 ng/dL, P = .001) and troponin I (59 ± 62 vs 40 ± 35 ng/dL, P = .0006) and with higher in-hospital mortality (5.2% vs 1.1%, P = .04). CONCLUSIONS: In patients with STEMI, culprit lesions are frequently located immediately distal to bifurcations and in proximity to major curvatures where disturbed flow is known to occur. This supports the role of wall shear stress in the pathogenesis of STEMI.

Rheumatoid arthritis and cardiovascular disease.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease affecting approximately 1% of the adult general population. Cardiovascular disease is recognized as the leading cause of death in RA patients, accounting for nearly 40% of their mortality. Patients with RA are at a twofold increased risk for myocardial infarction and stroke, with risk increasing to nearly threefold in patients who have had the disease for 10 years or more. Congestive heart failure appears to be a greater contributor to excess mortality than ischemia. This increased cardiovascular disease risk in RA patients seems to be independent of traditional cardiovascular risk factors. Pathogenic mechanisms include pro-oxidative dyslipidemia, insulin resistance, prothrombotic state, hyperhomocysteinemia, and immune mechanisms such as T-cell activation that subsequently lead to endothelial dysfunction, a decrease in endothelial progenitor cells, and arterial stiffness, which are the congeners of accelerated atherosclerosis observed in RA patients. This paper discusses pathogenic mechanisms, effects of methotrexate, tumor necrosis factor antagonists, steroids, and statins, with a perspective on therapy.

Massive penny ingestion: the loot with local and systemic effects.

A 57-year-old schizophrenic woman presented with lethargy, nausea, vomiting, and anorexia after coin ingestion. She was found to have multiple organ dysfunction manifested as hepatitis, pancreatitis, severe anemia with markedly depressed bone marrow response, extravascular hemolysis, and acute renal failure. Prolonged exposure to zinc from massive coin ingestion was responsible. Zinc poisoning is an unusual consequence of coin ingestion in the adult human literature. A detailed discussion on zinc poisoning, as well as the pitfalls in radiological diagnosis of massive coin ingestion, is presented.

Four-extremity gangrene associated with crack cocaine abuse.

A 43-year-old woman with a history of cocaine abuse presented with decreased mental responsiveness and cyanosis of the extremities several hours after repeated use of "crack" cocaine. She developed bilateral hand compartment syndrome requiring emergency fasciotomy and gangrene of both hands and legs despite anticoagulant and antithrombotic therapy. Digital and above-knee amputations were performed. There was no evidence of an autoimmune disorder or vasculitis on laboratory evaluation and tissue histology. Peripheral vasospasm may have been the mechanism of toxicity in this case, and the use of intravenous vasodilators should be considered as potential additional therapy.

Herpes zoster ophthalmicus and syndrome of inappropriate antidiuretic hormone secretion.

Presented here is a case of syndrome of inappropriate antidiuretic hormone secretion (SIADH) that developed in an elderly woman with single dermatomal herpes varicella zoster ophthalmicus without evidence of varicella-zoster encephalitis or dissemination. This is only the third such case reported in the English language literature to date, and it affirms that SIADH can develop in patients with herpetic involvement of just a single dermatome and corrects with resolution of the herpetic lesions.

Atypical mediastinal lipomatosis.

We present an elderly, non-obese male with no significant medical history who presented with dyspnea on exertion. Chest radiography showed an enlarged cardiac silhouette with a retrocardiac shadow of increased lucency, resulting in a "double contour" effect. Transthoracic echocardiography raised the suspicion of a diffuse fatty infiltration in the pericardium severely distorting the left atrium. This was later confirmed on computed tomography of the chest by measuring radiodensity in Hounsfield units. The serum cortisol level ordered later was normal. To the authors' knowledge, this is only the second reported case of mediastinal lipomatosis that occurred in the absence of endogenous or exogenous steroid excess or obesity, with diffuse fatty infiltration, suspected on chest radiography and transthoracic echocardiography and confirmed by computed tomography of the chest.

Spindle cell hemangioendothelioma.

Prior to the 1980s, the term hemangioendothelioma (HE) loosely applied to a spectrum of vascular tumors ranging from benign tumors, such as capillary hemangiomas, to fully malignant angiosarcomas. In the early 1980s, the term epithelioid HE was used to describe a heterogeneous group of vascular tumors with an intermediate clinical course between hemangiomas and conventional angiosarcomas, thereby bringing to notice the borderline nature of these tumors. Since then, HEs have become a distinct entity, being further classified into spindle cell HE, retiform HE, kaposiform HE, and polymorphous HE. We present a case of spindle cell HE that began as an interdigital nodule and progressively became multifocal to involve the entire right upper extremity and chest wall, despite multiple surgical excisions, resulting in severe ongoing disfigurement of the patient.

Comprehensive Assessment of Coronary Plaque Progression With Advanced Intravascular Imaging, Physiological Measures, and Wall Shear Stress: A Pilot Double-Blinded Randomized Controlled Clinical Trial of Nebivolol Versus Atenolol in Nonobstructive Coronary Artery Disease.

BACKGROUND: We hypothesized that nebivolol, a ß-blocker with nitric oxide-mediated activity, compared with atenolol, a ß-blocker without such activity, would decrease oxidative stress and improve the effects of endothelial dysfunction and wall shear stress (WSS), thereby reducing atherosclerosis progression and vulnerability in patients with nonobstructive coronary artery disease. METHODS AND RESULTS: In this pilot double-blinded randomized controlled trial, 24 patients treated for 1 year with nebivolol 10 mg versus atenolol 100 mg plus standard medical therapy underwent baseline and follow-up coronary angiography with assessments of inflammatory and oxidative stress biomarkers, microvascular function, endothelial function, and virtual histology intravascular ultrasound. WSS was calculated from computational fluid dynamics. Virtual histology intravascular ultrasound segments were assessed for vessel volumetrics and remodeling. There was a trend toward more low-WSS segments in the nebivolol cohort (P=0.06). Low-WSS regions were associated with greater plaque progression (P<0.0001) and constrictive remodeling (P=0.04); conversely, high-WSS segments demonstrated plaque regression and excessive expansive remodeling. Nebivolol patients had decreased lumen and vessel areas along with increased plaque area, resulting in more constrictive remodeling (P=0.002). There were no significant differences in biomarker levels, microvascular function, endothelial function, or number of thin-capped fibroatheromas per vessel. Importantly, after adjusting for ß-blocker, low-WSS segments remained significantly associated with lumen loss and plaque progression. CONCLUSION: Nebivolol, compared with atenolol, was associated with greater plaque progression and constrictive remodeling, likely driven by more low-WSS segments in the nebivolol arm. Both ß-blockers had similar effects on oxidative stress, microvascular function, and endothelial function. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/. Unique identifier: NCT01230892.

Coronary microvascular dysfunction is associated with higher frequency of thin-cap fibroatheroma.

OBJECTIVE: Both coronary microvascular dysfunction and epicardial plaque vulnerability have been associated with adverse cardiovascular outcomes. However, whether microvascular dysfunction is a predictor of plaque vulnerability is not known. We hypothesized that microvascular dysfunction is associated with greater systemic inflammation and is a predictor of virtual histology-intravascular ultrasound (VH-IVUS)-defined coronary thin-cap fibroatheromas. METHODS: Invasive physiologic assessment and VH-IVUS were performed and serum high-sensitivity C-reactive protein (hs-CRP) was measured in 51 patients with non-obstructive CAD [fractional flow reserve (FFR)≥0.75]. Microvascular dysfunction was defined as coronary flow velocity reserve (CFVR)<2.0. Lumen area and plaque burden and composition were assessed in each VH-IVUS frame. Frequency of thin-cap fibroatheroma (TCFA) in each artery was defined as the percentage of VH-IVUS frames with plaque burden≥40% and confluent necrotic core≥10% in contact with lumen for at least 3 consecutive frames. RESULTS: Mean age was 57±12 years and 25% of patients presented with acute coronary syndrome. Despite similar amount of epicardial disease, characterized by lumen area (8.9±3.0 vs. 10.1±3.3mm(2), p=0.3) and FFR (0.90±0.08 vs. 0.92±0.07, p=0.2), patients with microvascular dysfunction had greater hs-CRP (4.2 [2.3, 7.6] vs. 1.0 [0.4, 4.2]ng/ml, p=0.006), greater plaque burden (47±10 vs. 36±13%, p=0.004), and higher frequency of TCFA (17±25 vs. 6±9%, p=0.02). After adjustment for cardiovascular risk factors, hs-CRP, and plaque burden, coronary microvascular dysfunction was an independent predictor of frequency of TCFA (ß=+0.42, p=0.033). CONCLUSION: In patients with non-obstructive CAD, coronary microvascular dysfunction is associated with higher serum hs-CRP and is an independent predictor of more TCFAs, a marker for increased epicardial plaque vulnerability.

Effect of intensive atorvastatin therapy on coronary atherosclerosis progression, composition, arterial remodeling, and microvascular function.

BACKGROUND: There is a discrepancy between the marked reduction in adverse events with statins and their modest effect on atheroma regression. We hypothesized that, in a Western population, high-dose atorvastatin will result in alterations in coronary atheroma composition, phenotype, and microvascular function. METHODS: Serial coronary radiofrequency intravascular ultrasound (VH-IVUS), coronary flow reserve (CFR), and hyperemic microvascular resistance (HMR) were performed at baseline and after 6 months of treatment with 80 mg atorvastatin in 20 patients with moderate coronary artery disease (CAD). For each VH-IVUS frame (n = 2249), changes in total plaque atheroma, composition, and phenotype (pathological intimal thickening, fibrotic plaque, fibroatheroma), and serial remodeling were assessed. RESULTS: Total serum cholesterol decreased from 186.0 mg/dL (interquartile range [IQR], 168.0 to 212.5 mg/dL) to 139.0 mg/dL (IQR, 124.3 to 151.3 mg/dL). Percent atheroma volume did not change significantly (-0.5% [IQR, -2.8% to 3.7%]; P=.90) and serial remodeling analysis demonstrated 40% constrictive, 24% incomplete, and 36% expansive patterns. There was a trend toward lower percent fibrous tissue (-3.47 ± 1.78%; P=.07) and percent fibro-fatty tissue (-2.52 ± 1.24%; P=.06) and increase in percent necrotic core (+2.74 ± 1.65%; P=.11) and percent dense calcium (+1.99 ± 0.81; P=.02), which translated into significantly less pathological intimal thickening (4% vs 12%; P<.0001) and more fibroatheromas (67% vs 57%; P<.0001) at follow-up compared to baseline. There were modest non-significant improvements in CFR (+0.26 [IQR, -0.37 to 0.76]; P=.23) and HMR (-0.22 [IQR, -0.56 to 0.28]; P=.12). CONCLUSIONS: In this pilot study of Western patients with moderate CAD, high-dose atorvastatin resulted in alterations in coronary atheroma composition with corresponding changes in plaque phenotype and modest improvement in coronary microvascular function.

Association of coronary wall shear stress with atherosclerotic plaque burden, composition, and distribution in patients with coronary artery disease.

BACKGROUND: Extremes of wall shear stress (WSS) have been associated with plaque progression and transformation, which has raised interest in the clinical assessment of WSS. We hypothesized that calculated coronary WSS is predicted only partially by luminal geometry and that WSS is related to plaque composition. METHODS AND RESULTS: Twenty-seven patients with coronary artery disease underwent virtual histology intravascular ultrasound and Doppler velocity measurement for computational fluid dynamics modeling for WSS calculation in each virtual histology intravascular ultrasound segment (N=3581 segments). We assessed the association of WSS with plaque burden and distribution and with plaque composition. WSS remained relatively constant across the lower 3 quartiles of plaque burden (P=0.08) but increased in the highest quartile of plaque burden (P<0.001). Segments distal to lesions or within bifurcations were more likely to have low WSS (P<0.001). However, the majority of segments distal to lesions (80%) and within bifurcations (89%) did not exhibit low WSS. After adjustment for plaque burden, there was a negative association between WSS and percent necrotic core and calcium. For every 10 dynes/cm(2) increase in WSS, percent necrotic core decreased by 17% (P=0.01), and percent dense calcium decreased by 17% (P<0.001). There was no significant association between WSS and percent of fibrous or fibrofatty plaque components (P=NS). CONCLUSIONS: IN PATIENTS WITH CORONARY ARTERY DISEASE: (1) Luminal geometry predicts calculated WSS only partially, which suggests that detailed computational techniques must be used to calculate WSS. (2) Low WSS is associated with plaque necrotic core and calcium, independent of plaque burden, which suggests a link between WSS and coronary plaque phenotype. (J Am Heart Assoc. 2012;1:e002543 doi: 10.1161/JAHA.112.002543.).