Large Artery Disease Research Articles

Systemic Hemodynamic Atherothrombotic Syndrome and Resonance Hypothesis of Blood Pressure Variability: Triggering Cardiovascular Events.

Blood pressure (BP) exhibits different variabilities and surges with different time phases, from the shortest beat-by-beat to longest yearly changes. We hypothesized that the synergistic resonance of these BP variabilites generates an extraordinarily large dynamic surge in BP and triggers cardiovascular events (the resonance hypothesis). The power of pulses is transmitted to the peripheral sites without attenuation by the large arteries, in individuals with stiffened arteries. Thus, the effect of a BP surge on cardiovascular risk would be especially exaggerated in high-risk patients with vascular disease. Based on this concept, our group recently proposed a new theory of systemic hemodynamic atherothromboltic syndrome (SHATS), a vicious cycle of hemodynamic stress and vascular disease that advances organ damage and triggers cardiovascular disease. Clinical phenotypes of SHATS are large-artery atherothombotic diseases such as stroke, coronary artery disease, and aortic and pheripheral artery disease; small-artery diseases, and microcirculation-related disease such as vascular cognitive dysfunction, heart failure, and chronic kidney disease. The careful consideration of BP variability and vascular diseases such as SHATS, and the early detection and management of SHATS, will achieve more effective individualized cardiovascular protection. In the near future, information and communication technology-based 'anticipation medicine' predicted by the changes of individual BP values could be a promising approach to achieving zero cardiovascular events.

The Effect of Small Artery Disease on the Occurrence and Management of Large Artery Disease.

blood have traditionally been divided anatomically into lesions that involve the extracranial large arteries and the intracranial large and small arteries. The rationale for this classification is that conditions that affect the large arteries within the neck and those that involve the large arteries in the head have somewhat different demographic, epidemiologic, and risk factor predilections and are often managed differently. Lesions in the small arteries are quite different morphologically from those in the large arteries and their epidemiologic factors and causes, as well as treatments, differ from conditions that affect the large arteries. There are multiple types of conditions that affect large arteries (atherosclerosis, dissections, fibromuscular lesions, dolichoectasia, aneurysms, vascular constrictions, and others). The classification of small artery disease is even more heterogeneous.

Intracranial arterial disease in CADASIL patients

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is characterized by the involvement of cerebral small arteries. Although cerebral large artery disease has been reported in CADASIL patients, the prevalence and location of relevant cerebral arterial disease have not been elucidated. In this study, we aim to characterize infarctions associated with cerebral large artery disease in CADASIL patients. MethodsWe retrospectively reviewed 49 consecutive symptomatic patients with genetically confirmed CADASIL, who visited the Asan Medical Center between December 2002 and December 2013. Infarctions located within the territory of a relevant, large cerebral artery were identified with the use of magnetic resonance imaging and magnetic resonance angiography. Patients with or without territorial patterns associated with large artery disease were compared. ResultsOut of a total of 49 patients, 23 patients had cerebral infarction. Among these, seven had infarction associated with cerebral large artery disease. The corresponding vascular lesions were located in the intracranial arteries in all seven patients. There were no differences between patients with or without territorial infarction in terms of vascular risk factors, microbleeds, white matter changes, or mutations involving cysteine. A literature review illustrates that symptomatic intracranial diseases are present in CADASIL patients at least in East Asia. ConclusionInfarction in association with intracranial arterial disease may be a manifestation of CADASIL. Further studies are needed to elucidate the pathologic characteristics and to see whether this occurs exclusively in East Asia.

Stroke Subtypes and Topographic Locations Associated with Neurological Deterioration in Acute Isolated Pontine Infarction

This study investigated predictors of neurological deterioration (ND) in acute isolated pontine infarction. Two hundred fifty-nine patients with acute isolated pontine infarctions identified using diffusion-weighted imaging were retrospectively analyzed. The patients were divided according to the presence/absence of ND, defined as increased (≥2 units) National Institutes of Health Stroke Scale scores 5 days after onset. Pontine infarctions comprised 3 stroke subtypes: vertebrobasilar large-artery disease, basilar artery branch disease (BABD), and small-artery disease (SAD), according to basilar artery atherosclerosis severity and lesion extent of the transverse axial plane. Topographic locations of longitudinal pontine infarctions in the axial plane were divided into upper, middle, lower, and whole. Of the 259 patients (male : female = 136:123, 68.84 ± 10.24), only 27.4% exhibited ND. The prevalence was significantly increased in females, whereas smoking was significantly decreased in patients with ND. BABD and lower pontine infarctions were significantly more frequent in patients with ND (70.4% and 43.7%, respectively) than in patients without ND (51.6% and 30.3%, respectively). SAD and upper pontine infarctions were significantly less frequent in patients with ND (16.9% and 7.0%, respectively) than in patients without ND (30.3% and 23.4%, respectively). BABD and lower pontine infarctions were positively related to ND. This is the first study to demonstrate that BABD and lower pons lesions are predictors of ND in acute isolated pontine infarction. These findings indicate the potential importance of early identification of stroke subtypes and topographic locations in the prevention of ND in patients with suspected pontine infarction.

Clinical, Laboratory, and Imaging Characteristics of Transient Ischemic Attack Caused by Large Artery Lesions: A Comparison between Carotid and Intracranial Arteries

Background/Aims: The aims of this study were to determine the differences in clinical characteristics and the risk of ischemic stroke between patients with transient ischemic attack (TIA) attributable to extracranial carotid and intracranial artery occlusive lesions. Methods: Among 445 patients admitted to our stroke care unit within 48 h of TIA onset between April 2008 and December 2013, 85 patients (63 men, mean age 69.4 years) with large artery occlusive lesions relevant to symptoms were included in this study. The primary endpoints were ischemic stroke at 2 and 90 days after TIA onset. Results: Twenty-eight patients had carotid artery occlusive lesions (extracranial group), and 57 patients had intracranial artery occlusive lesions (intracranial group). Patients in the intracranial group were significantly younger, had lower levels of fibrinogen, and were less likely to have occlusion when compared with those in the extracranial group. Eleven patients in the extracranial group and none in the intracranial group underwent revascularization procedures within 90 days of TIA onset. The 2-day risk (14.2 vs. 0%, p = 0.044) and the 90-day risk (17.1 vs. 0%, p = 0.020) of ischemic stroke after TIA onset were significantly higher in the intracranial group than in the extracranial group. Conclusions: Among our patients with TIA caused by large artery disease, patients with intracranial artery occlusive lesions were more frequent and were at higher risk of early ischemic stroke than those with extracranial carotid artery occlusive lesions. These data highlight the importance of prompt assessment of intracranial artery lesions in patients with TIA.

Lipin-1 contributes to modified low-density lipoprotein-elicited macrophage pro-inflammatory responses

Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries and the underlying cause of cardiovascular disease, a major cause of mortality worldwide. The over-accumulation of modified cholesterol-containing low-density lipoproteins (e.g. oxLDL) in the artery wall and the subsequent recruitment and activation of macrophages contributes to the development of atherosclerosis. The excessive uptake of modified-LDL by macrophages leads to a lipid-laden “foamy” phenotype and pro-inflammatory cytokine production. Modified-LDLs promote foam cell formation in part by stimulating de novo lipid biosynthesis. However, it is unknown if lipid biosynthesis directly regulates foam cell pro-inflammatory mediator production. Lipin-1, a phosphatidate phosphohydrolase required for the generation of diacylglycerol during glycerolipid synthesis has recently been demonstrated to contribute to bacterial-induced pro-inflammatory responses by macrophages. In this study we present evidence demonstrating the presence of lipin-1 within macrophages in human atherosclerotic plaques. Additionally, reducing lipin-1 levels in macrophages significantly inhibits both modified-LDL-induced foam cell formation in vitro, as observed by smaller/fewer intracellular lipid inclusions, and ablates modified-LDL-elicited production of the pro-atherogenic mediators tumor necrosis factor-α, interleukin-6, and prostaglandin E2. These findings demonstrate a critical role for lipin-1 in the regulation of macrophage inflammatory responses to modified-LDL. These data begin to link the processes of foam cell formation and pro-inflammatory cytokine production within macrophages.

Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study

SummaryBackgroundA third of transient ischaemic attacks (TIAs) and ischaemic strokes are of undetermined cause (ie, cryptogenic), potentially undermining secondary prevention. If these events are due to occult atheroma, the risk-factor profile and coronary prognosis should resemble that of overt large artery events. If they have a cardioembolic cause, the risk of future cardioembolic events should be increased. We aimed to assess the burden, outcome, risk factors, and long-term prognosis of cryptogenic TIA and stroke.MethodsIn a population-based study in Oxfordshire, UK, among patients with a first TIA or ischaemic stroke from April 1, 2002, to March 31, 2014, we compared cryptogenic events versus other causative subtypes according to the TOAST classification. We compared markers of atherosclerosis (ie, risk factors, coronary and peripheral arterial disease, asymptomatic carotid stenosis, and 10-year risk of acute coronary events) and of cardioembolism (ie, risk of cardioembolic stroke, systemic emboli, and new atrial fibrillation [AF] during follow-up, and minor-risk echocardiographic abnormalities and subclinical paroxysmal AF at baseline in patients with index events between 2010 and 2014).FindingsAmong 2555 patients, 812 (32%) had cryptogenic events (incidence of cryptogenic stroke 0·36 per 1000 population per year, 95% CI 0·23–0·49). Death or dependency at 6 months was similar after cryptogenic stroke compared with non-cardioembolic stroke (23% vs 27% for large artery and small vessel subtypes combined; p=0·26) as was the 10-year risk of recurrence (32% vs 27%; p=0·91). However, the cryptogenic group had fewer atherosclerotic risk factors than the large artery disease (p<0·0001), small vessel disease (p=0·001), and cardioembolic (p=0·008) groups. Compared with patients with large artery events, those with cryptogenic events had less hypertension (adjusted odds ratio [OR] 0·41, 95% CI 0·30–0·56; p<0·0001), diabetes (0·62, 0·43–0·90; p=0·01), peripheral vascular disease (0·27, 0·17–0·45; p<0·0001), hypercholesterolaemia (0·53, 0·40–0·70; p<0·0001), and history of smoking (0·68, 0·51–0·92; p=0·01), and compared with small vessel and cardioembolic subtypes, they had no excess risk of asymptomatic carotid disease (adjusted OR 0·64, 95% CI 0·37–1·11; p=0·11) or acute coronary events (adjusted hazard ratio [HR] 0·76, 95% CI 0·49–1·18; p=0·22) during follow-up. Compared with large artery and small vessel subtypes combined, patients with cryptogenic events also had no excess of minor-risk echocardiographic abnormalities (cryptogenic 37% vs 45%; p=0·18) or paroxysmal AF (6% vs 10%; p=0·17) at baseline or of new AF (adjusted HR 1·23, 0·78–1·95; p=0·37) or presumed cardioembolic events (1·16, 0·62–2·17; p=0·64) during follow-up.InterpretationThe clinical burden of cryptogenic TIA and stroke is substantial. Although stroke recurrence rates are comparable with other subtypes, cryptogenic events have the fewest atherosclerotic markers and no excess of cardioembolic markers.FundingWellcome Trust, Wolfson Foundation, UK Stroke Association, British Heart Foundation, Dunhill Medical Trust, National Institute for Health Research, Medical Research Council, and the NIHR Oxford Biomedical Research Centre.

Ischaemic stroke of undetermined cause

The definition of cryptogenic stroke or stroke of undetermined origin is affected by the current knowledge of the cause and pathogenesis of stroke and by the availability, comprehensiveness, quality, and timeliness of the ancillary investigations undertaken to discover the cause of the stroke. In The Lancet Neurology, Linxin Li and colleagues report findings from a populationbased study of the burden, outcome, risk factors, and long-term prognosis of cryptogenic stroke in patients with a first transient ischaemic attack (TIA) or ischaemic stroke. They found that of 2555 first ischaemic events, 812 (32%) were cryptogenic. The study shows that the prognosis of cryptogenic stroke and the risk of recurrence are similar to those of large artery disease and small vessel disease. For example, death or dependency at 6 months was similar after cryptogenic stroke compared with large artery and small vessel subtypes combined (23% vs 27%; p=0·26), as was the 10-year risk of recurrence (32% vs 27%; p=0·91). Secondary stroke prevention must be similarly aggressive and appropriate in stroke with and without identified cause. The findings from this Article question the role of paroxysmal atrial fibrillation as the major cause of cryptogenic stroke, which contrasts with the present enthusiasm for the use of technology to detect paroxysmal atrial fibrillation and for the possibility to prevent recurrent cryptogenic stroke with anticoagulants.

Isolated hippocampal infarcts: Vascular and neuropsychological findings

Background and PurposeThe hippocampus plays a role in the verbal and spatial memory processing, learning, and emotions. The purpose of this study was to determine clinical, etiological, and radiological features of isolated hippocampal infarcts. MethodsWe reviewed, 6800 patients with first-ever ischaemic stroke included in our Stroke Registry between 2004 and 2014. Among them we studied 19 patients with an acute isolated hippocampal infarct confirmed by MRI. ResultsAmong 6800 patients, 19 patients (0.03%) showed ischaemic lesions in the hippocampal artery territory, allowing us to delineate 5 variant distributions; (1) anterior hippocampal infarcts (4 patients [21%]) were present with altered consciousness, transient visual vivid hallucinations, and transient global amnesia with episodic and verbal memory deficits. (2) Posterior hippocampal infarcts (3 patients [16%]) developed dizziness and dullness at stroke onset, confusion, episodic and procedural memory deficit and verbal learning deficit. (3) Unilateral complete hippocampal infarcts were present (4 patients [21%]) with confusion, object specific hallucinations, intense mood states changes as well as impulsivity or depressive behaviour. Memory dysfunctions were found in all patients. (4) Bilateral hippocampal infarcts (3 patients [16%]) had cognitive deficits and memory deficits in all patients. All patients had difficulties retrieving specific autobiographical events and retrieving recent memory, and disturbances of learning in verbal and visual task. Hippocampal dementia was observed in 2 patients with severe immediate, delayed verbal and visual memory deficits, dysexecutive syndrome, deficits in responding to feedback and error correction with dull and aimless appearance lasting several months. (5) Small circumscribed (punctiform) hippocampal infarcts (5 patients [26%]) showed dizziness or dullness sensation and difficulties finding words or objects that they use everyday. Cardioembolism (10; 53%) and large-artery disease of the vertebrobasilar system (6; 32%) were the main stroke mechanisms. ConclusionsWe described topographic patterns of hippocampal infarction with distinct manifestations and etiologies. We thought that different patterns of hippocampal infarcts are the result of variation in hippocampal arterial supply or reflect a source of embolism.

Abstract 382: Lipin-1 Links Pro-inflammatory Responses and Foam Cell Formation by Oxidized-Low Density Lipoprotein-Elicited Macrophages

Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries and one of the underlying causes of cardiovascular disease (CVD). Macrophages participate decisively in the development and promotion of atherosclerosis. Macrophages infiltrate the arterial intima to ingest modified low density lipoproteins (e.g. oxLDLs) via scavenger receptors. The scavenging of oxLDLs results in foam cell formation due to enhanced lipid droplet biogenesis. These foam cells eventually release pro-inflammatory cytokines that promote atherosclerosis. However, it is currently unknown whether there is a link between lipid droplet biogenesis and pro-inflammatory cytokine production in macrophages that scavenge oxLDL. Lipin-1, a phosphatidate phosphohydrolase enzyme, partially contributes to macrophage pro-inflammatory cytokine production following stimulation with bacteria. Lipin-1 is also required for lipid droplet biogenesis in macrophages. Finally, we observed lipin-1 protein within macrophages from human atherosclerotic plaques. Thus, we hypothesized that lipid droplet biogenesis, via lipin-1 activity, directly contributes to foam cell pro-inflammatory cytokine production. To test this hypothesis we compared lipid droplet biogenesis and pro-inflammatory cytokine responses of oxLDL-stimulated wild type and lipin-1-depleted macrophages. Depletion of lipin-1 inhibited oxLDL-induced foam cell generation by reducing lipid droplet number, area, and staining intensity. There were no differences in scavenger receptor expression or uptake of oxLDL between wild type and lipin-1-depleted cells. In addition, depletion of lipin-1 also ablated oxLDL-elicited production of the pro-atherogenic cytokines tumor necrosis factor-α and interleukin-6. These findings demonstrate a critical role for lipin-1 in the regulation of macrophage inflammatory responses to oxLDL. Furthermore, these data begin to link foam cell formation, via lipid droplet biogenesis, and pro-inflammatory cytokine production within oxLDL stimulated macrophages. Thus, our studies suggest that lipid droplet biogenesis may be an ideal therapeutic target to inhibit inflammation associated with atherosclerosis to treat CVD.

STAT4 promotes atherosclerosis by supporting Tfh and plasma B cell development, T cell activation and CD11b+ cell accumulation in the aortic wall (LYM8P.632)

Abstract Atherosclerosis is an inflammatory disease of medium and large size arteries. Signal transducer and activator of transcription 4 (STAT4) is a transcription factor that supports the generation of cells with features of both follicular helper T cells (Tfh) and T helper 1 (Th1) cells. To date, the role of Stat-4 in atherosclerosis and the induction of Tfh cells in this disease has not been defined. To investigate the role of STAT4 in atherogenesis, we generated Stat-4-deficient low density lipoprotein-deficient (Stat4-/-Ldlr-/-) mice. Stat4 deficiency resulted in a significant reduction in atherosclerotic plaque burden within the aortas of Stat4-/-Ldlr-/- mice fed a high fat/high carbohydrate diet with added cholesterol (DDC) diet for 16 weeks compared to age and diet-matched Ldlr-/- control mice (p&amp;lt;0.01). Next we examined spleens and peripheral lymph nodes (PLNs) of Stat4-/-Ldlr-/ mice and found decreased number of CD19+ B cells (p&amp;lt;0.0001) and CD3+ T cells (p&amp;lt;0.05). Interestingly, the number of Tfh cells and plasma B cells (p&amp;lt;0.003) was also diminished in and spleens of Stat4-/-Ldlr-/- mice compared to Ldlr-/- mice. A significant reduction in CD11b+CD11c- cells and MHCII expression was detected in the aortas of Stat4-/-Ldlr-/- vs Ldlr-/- mice. Thus, the atherogenic effects of STAT4 are, at least partially, due to the modulation of the immune response via alterations of Tfh-dependent humoral response. Supported by R01 HL112605 and Suppl.Grant 02S1.

Abstract 171: Deficiency of the Co-stimulatory Molecule Cd27 Impairs Treg Development and Exacerbates Atherosclerosis.

Atherosclerosis, an inflammatory disease of large arteries, is - through its clinical manifestations stroke and myocardial infarction - the leading cause of morbidity and mortality in the industrialized world. Adaptive immunity and co-stimulatory signals play a pivotal role during all stages of the disease. Recently, regulatory T cells (Treg) were attributed an anti-inflammatory and anti-atherogenic role. The interaction of CD70, a member of the tumor necrosis factor super family with its receptor CD27 modulates Treg development but also affects T cell proliferation, differentiation, and activation at the sites of antigen priming and at effector function. We hypothesized an increased atherosclerotic burden and an exacerbation of disease upon CD27 deficiency. Cd27+/+Apoe-/- or Cd27-/-Apoe-/- bone marrow was transplanted into Apoe-/- recipient mice. After reconstitution, mice were fed a 0.15% high fat/cholesterol diet for 6 weeks. Plaque area at the aortic sinus was increased 2.3-fold in Cd27-/-Apoe-/- chimeras. Plaques contained high amounts of macrophages, which was accompanied by a reduced frequency of aortic (54.1%) and splenic (17.7%) Tregs. Similar results were obtained in 18 wk old Cd27-/-Apoe-/- on a normal chow diet, that also displayed an increase in atherosclerotic plaque area and a 2.5-fold higher plaque macrophage content. In addition, Cd27-/-Apoe-/-mice showed a significant decrease in the abundance of splenic (26%) and aortic (27%) Tregs. Remarkably, 28 week-old Cd27-/-Apoe-/- mice did not exhibit this phenotype, suggesting that CD27 only plays a role in earlier stages of atherosclerosis. Although Cd27-/-Apoe-/- Tregs did not show changes in suppressive or migratory capacity compared to Cd27+/+Apoe-/-, Cd27-deficiency did result in a marked increase in thymic Treg apoptosis. Taken together, our data reveal that deficiency for CD27 impairs thymic Treg development, which thereby exacerbates early and intermediate atherosclerosis by increasing plaque inflammation.

Early Stroke Risk after Transient Ischemic Attack in Patients without Large-Artery Disease or Atrial Fibrillation

Patients with transient ischemic attack (TIA) without large-artery disease (LAD) or atrial fibrillation (AF) on admission may be at higher risk of stroke than previously thought. The aim of this study was to investigate early stroke risk and its predictors in such patients. We studied 410 TIA patients admitted to our institute within 48 hours of onset. Urgent etiological workup revealed that 210 patients had neither symptomatic LAD nor AF. The outcome measure was the stroke occurrence within 7 days after admission. Stroke occurred within 7 days in 15 patients, 7.1% of patients without LAD or AF and 6.5% of those with LAD or AF, showing no statistical difference between the 2 groups. Twelve of the 15 patients were diagnosed with small-vessel disease as the stroke etiology. In multivariable regression analysis, motor lacunar symptoms (odds ratio [OR], 5.7; 95% confidence interval [CI], 1.4-41.1), high systolic blood pressure on admission of 183 mm Hg or greater (OR, 15.3; 95% CI, 3.8-80.2), and positive diffusion-weighted imaging findings (OR, 6.1; 95% CI, 1.6-28.1) were independent predictors for the stroke occurrence within 7 days in patients without LAD or AF. TIA patients should be cautiously managed, even when neither LAD nor AF are identified by urgent workup. Clinical findings as motor lacunar symptom or high admission blood pressure, besides diffusion-weighted imaging findings, may be helpful to predict early stroke in such patients.

Recent advances in atrial fibrillation and stroke

it is necessary to identify the underlying cause of the event, so that the appropriate therapy can be identified to maximally reduce risk of recurrence. Antiplatelet agents are not anticoagulants; they reduce the risk of stroke from embolisation of platelet aggregates, sometimes called ‘white thrombus’ (Fig. 1) in the setting of fast flow along the arterial wall or heart valves, but to prevent thrombus in the setting of stasis (‘redthrombus’, afibrin polymer with entrapped red cells), it is necessary to use anticoagulants. With recent improvements in blood pressure control and lipid-lowering therapy, the proportion of lacunar strokes due to small vessel disease and strokes due to large artery disease has declined significantly in the past 10 years, and in consequence the proportion of cardioembolic strokes has risen; our group found 2 that between 2002 and 2012, cardioembolic stroke increased from 26 to 56% of ischaemic stroke, among patients attending an ambulatory Urgent TIA Clinic. It is thus increasingly important for physicians to have a high index of suspicion for cardioembolic stroke, and to investigate patients intensively if they have no other apparent cause of stroke (‘cryptogenic stroke’). In the diagnosis of cardioembolic stroke, there are two sides to the coin: (1) negative evidence: the absence of other causes of stroke such as hypertension, large artery disease, dissection, or vasculitis; and (2) positive evidence such as the presence of cortical infarctions and/or TIA in multiple vascular territories, cardiac abnormalities such cardiomyopathy, a prosthetic or stenosed valve, a right-to-left shunt, evidence of atrial fibrillation, or clinical clues to paradoxical embolism. The latter includes a previous history of deep vein thrombosis (DVT), pulmonary embolism, the presence of venous insufficiency or varicose veins, a history of prolonged sitting (such as a long flight or sitting at a computer for many hours), dyspnoea or a Valsalva manoeuvre at the onset of the stroke, a history of sleep apnoea, or waking up with stroke. 3 A special case is atrial fibrillation (AF). This condition is particularly important because it is associated with larger strokes that are more disabling, is increasing in frequency because of the ageing of the population, is frequently missed by routine Holter recordings, andthere is aseriousproblemof under-use of anticoagulants, 4 particularly in the elderly, who are disproportionately more likely to benefit from anticoagulants. 5

Susceptibility Weighted MRI and Regional Cerebrovascular Reservoir Capacity in Angiography Proven Large Artery Disease in Acute Ischemic Stroke and Transient Ischemic Attack (P6.247)

Susceptibility Weighted MRI and Regional Cerebrovascular Reservoir Capacity in Angiography Proven Large Artery Disease in Acute Ischemic Stroke and Transient Ischemic Attack (P6.247)

Chemokines control mobilization, recruitment, and fate of monocytes in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease of large arteries and, among others, characterized by continuous influx of monocytes into the subendothelial space, subsequent macrophage accumulation, and foam cell formation. Chemokines and their receptors tightly orchestrate monocyte trafficking and fate from birth to death. This brief review summarizes our current understanding of the interplay between monocytes and chemokines entertaining crucial processes in atherosclerosis development, progression, and regression.

Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential interventions.

Small vessel disease encompasses lacunar stroke, white matter hyperintensities, lacunes and microbleeds. It causes a quarter of all ischemic strokes, is the commonest cause of vascular dementia, and the cause is incompletely understood. Vascular prophylaxis, as appropriate for large artery disease and cardioembolism, includes antithrombotics, and blood pressure and lipid lowering; however, these strategies may not be effective for small vessel disease, or are already used routinely so precluding further detailed study. Further, intensive antiplatelet therapy is known to be hazardous in small vessel disease through enhanced bleeding. Whether acetylcholinesterase inhibitors, which delay the progression of Alzheimer's dementia, are relevant in small vessel disease remains unclear. Potential prophylactic and treatment strategies might be those that target brain microvascular endothelium and the blood brain barrier, microvascular function and neuroinflammation. Potential interventions include endothelin antagonists, neurotrophins, nitric oxide donors and phosphodiesterase 5 inhibitors, peroxisome proliferator‐activated receptor‐gamma agonists, and prostacyclin mimics and phosphodiesterase 3 inhibitors. Several drugs that have relevant properties are licensed for other disorders, offering the possibility of drug repurposing. Others are in development. Since influencing multiple targets may be most effective, using multiple agents and/or those that have multiple effects may be preferable. We focus on potential small vessel disease mechanistic targets, summarize drugs that have relevant actions, and review data available from randomized trials on their actions and on the available evidence for their use in lacunar stroke.

Abstract W P114: Pure Pontine versus Pontine Plus Infarction Assessed by Diffusion Weighted MRI: Etiological and Clinical Differences

Pontine infarction is often associated with extrapontine infarcts. We aimed to elucidate differences in clinical characteristics and stroke mechanisms between the isolated pontine (IP) and pontine plus (PP) infarcts. We studied consecutively admitted patients with acute ischemic stroke (&lt; 7 days after the symptom) occurring in the pons between 2004 and 2013. All patients were assessed by diffusion weighted MRI (DWI) and MR angiography. According to DWI findings, we divided the patients into the IP and PP groups. In addition, pontine lesions were categorized as upper, middle and low according the previous report (Kim JS et al. Stroke 1995). Lesions were also categorized as focal vs. extensive and unilateral vs. bilateral. Functional outcome was measured by modified Rankin scale (mRS) at discharge. There were 834 (504 male) patients, 675 in the IP group and 159 in the PP group. The most commonly involved extrapontine territory was the posterior inferior cerebellar artery territory (54.1%) followed by superior cerebellar artery territory (42.1%) and occipital lobe (35.2%). As compared to the IP group, the pontine lesions in the PP group were more often located in the rostral (upper (67.3%), middle (61.6%), upper plus middle (40.3%)) level (p &lt; 0.001). Lesions involving more than 2 levels (40.3% vs. 10.5% p&lt;0.001), extensive (20.8% vs. 2.7%, &lt;0.001) and bilateral (37.1%, vs. 2.8%, p&lt;0.001) infarcts were more frequent in the PP group. The PP group had a higher prevalence of symptomatic stenosis (26.7% vs. 72.2%, p&lt;0.001), large artery disease (60.5% vs 25.9%) and cardioembolism (16.0% vs. 2.1%, &lt;0.001) than the IP group. In multivariable analysis, atrial fibrillation (OR: 3.87, 95% CI: 2.16-7.08) was significantly associated with PP. mRS at discharge was higher in the PP than IP group (median 3 (IQR 2-5) vs. 2 (IQR 1-3), &lt;0.001). PP groups have more extensive and rostral pontine lesions, and are more often associated with large artery artherosclerosis, cardioembolism, and worse functional outcome. Prevention and therapeutic strategies should differ between the two groups.

Abstract 134: Relative MTT Predicts Subsequent Stroke in Symptomatic Carotid Occlusion

Relative mean transit time (MTT) is readily obtainable from dynamic susceptibility contrast MRI of the brain. While it has received much attention in acute ischemic stroke as a possible means to identify patients for reperfusion therapies, little has been done to determine if it has clinical significance outside the acute setting. To determine if relative MTT could be used to identify patients who are at high risk for subsequent stroke, we analyzed data from the St. Louis Carotid Occlusion Study. This prospective study was carried out from 1992-1997 to determine if PET measurement of oxygen extraction fraction could identify medically treated patients with recently symptomatic carotid artery occlusion at high risk for subsequent stroke. Sixty-eight of the participants in the study had quantitative PET measurements of cerebral blood flow (CBF) and cerebral blood volume (CBV). From these we calculated the MTT (CBV/CBF) in each middle cerebral artery territory and determined the MTT ratio of the ipsilateral to the contralateral hemisphere (I/C MTT ratio). Nine of the 68 participants had a subsequent ipsilateral ischemic stroke during mean follow-up of 2.6 years (range .5 - 5 years). The I/C MTT ratio was significantly associated with subsequent stroke as a continuous variable by Cox regression analysis (HR 65, 95%CI 7-613, p &lt; .001). The maximum combination of sensitivity (.778) and specificity (.763) was obtained with a cutpoint of ≥ 1.387 which identified 7/9 subsequent strokes (PPV .333, NPV .957). Relative MTT shows great promise as a means to identify patients with large artery disease who are at high risk for subsequent stoke. These results need to be confirmed using MRI in a cohort receiving contemporary medical management.

Abstract T MP110: Central Retinal Artery Occlusion in Patients with Sickle Cell Disease

Objective: To determine the rate of and risk factors for incident central retinal artery occlusion (CRAO) among patients with sickle cell disease enrolled in a large cohort with longitudinal follow-up. Background: Sickle cell disease increases the risk of ischemic stroke among women but the risk of CRAO is not studied. Design/Methods: A total of 4085 patients from newborns to 77 years-old, were enrolled in Phase 1 of Cooperative Study of Sickle Cell Disease from 23 centers across the US. Participants underwent a baseline examination for assessment of demographics, prior medical history, lab assessments, and clinical data. Post baseline data included routine follow-up examinations, measures of organ damage, and collection of acute and chronic complications. The risk factors for CRAO were identified using Cox Proportional Hazards analysis. Results: A total of 9 (0.002%) of 4085 patients with sickle cell disease developed CRAO over a mean follow-up of 5.2 (95% CI 0.9 - 11.3) months, with an estimated incidence of 0.02 per 100 patient years. The incidence of CRAO was 0.03 per 100 patient years and 0.05 per 100 patient years in men and women, respectively. The history of previous stroke (2.6% versus 0.0%, p=0.7) and the proportion of patients diagnosed with large arterial occlusive disease (55.6% versus 7.7%, p=&lt;0.001) was greater in those who developed CRAO compared to those who did not develop CRAO. History of exchange transfusions (2.7 % versus 22.2 %, p=0.02) and cigarette smoking (13.7 % versus 22.2 %, p =0.4) were more common among patients who developed CRAO. The hematocrit (%) (mean ± SD) was similar between patients who did or did not develop CRAO (29.5 ± 9.6 versus 27.3 ± 5.6, p=0.3). At completion of follow-up, 22.2% (n=2) patients with CRAO reported disability compared with 11.1% (n=455) patients without CRAO (p=0.7) Conclusions: The incidence of CRAO is relatively high among patients with sickle cell disease and was associated with disability.