Prior events predict cerebrovascular and coronary outcomes in the PROGRESS trial

<p><b>Background and Purpose:</b> The relationship between baseline and recurrent vascular events may be important in the targeting of secondary prevention strategies. We examined the relationship between initial event and various types of further vascular outcomes and associated effects of blood pressure (BP)–lowering.</p> <p><b>Methods:</b> Subsidiary analyses of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) trial, a randomized, placebo-controlled trial that established the benefits of BP–lowering in 6105 patients (mean age 64 years, 30% female) with cerebrovascular disease, randomly assigned to either active treatment (perindopril for all, plus indapamide in those with neither an indication for, nor a contraindication to, a diuretic) or placebo(s).</p> <p><b>Results:</b> Stroke subtypes and coronary events were associated with 1.5- to 6.6-fold greater risk of recurrence of the same event (hazard ratios, 1.51 to 6.64; P=0.1 for large artery infarction, P<0.0001 for other events). However, 46% to 92% of further vascular outcomes were not of the same type. Active treatment produced comparable reductions in the risk of vascular outcomes among patients with a broad range of vascular events at entry (relative risk reduction, 25%; P<0.0001 for ischemic stroke; 42%, P=0.0006 for hemorrhagic stroke; 17%, P=0.3 for coronary events; P homogeneity=0.4).</p> <p><b>Conclusions:</b> Patients with previous vascular events are at high risk of recurrences of the same event. However, because they are also at risk of other vascular outcomes, a broad range of secondary prevention strategies is necessary for their treatment. BP–lowering is likely to be one of the most effective and generalizable strategies across a variety of major vascular events including stroke and myocardial infarction.</p&gt

Design, data management, and population baseline characteristics of the PERFORM magnetic resonance imaging project

Quantitative information from magnetic resonance imaging (MRI) may substantiate clinical findings and provide additional insight into the mechanism of clinical interventions in therapeutic stroke trials. The PERFORM study is exploring the efficacy of terutroban versus aspirin for secondary prevention in patients with a history of ischemic stroke. We report on the design of an exploratory longitudinal MRI follow-up study that was performed in a subgroup of the PERFORM trial. An international multi-centre longitudinal follow-up MRI study was designed for different MR systems employing safety and efficacy readouts: new T2 lesions, new DWI lesions, whole brain volume change, hippocampal volume change, changes in tissue microstructure as depicted by mean diffusivity and fractional anisotropy, vessel patency on MR angiography, and the presence of and development of new microbleeds. A total of 1,056 patients (men and women ≥55 years) were included. The data analysis included 3D reformation, image registration of different contrasts, tissue segmentation, and automated lesion detection. This large international multi-centre study demonstrates how new MRI readouts can be used to provide key information on the evolution of cerebral tissue lesions and within the macrovasculature after atherothrombotic stroke in a large sample of patients

Rationale, design and population baseline characteristics of the PERFORM Vascular Project: an ancillary study of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) trial

<p><b>Purpose</b></p> <p>PERFORM is exploring the efficacy of terutroban versus aspirin for secondary prevention in patients with a history of ischemic stroke or transient ischemic attacks (TIAs). The PERFORM Vascular Project will evaluate the effect of terutroban on progression of atherosclerosis, as assessed by change in carotid intima-media thickness (CIMT) in a subgroup of patients.</p> <p><b>Methods and results</b></p> <p>The Vascular Project includes structural (CIMT, carotid plaques) and functional (carotid stiffness) vascular studies in all patients showing at least one carotid plaque at entry. Expected mean follow-up is 36 months. Primary endpoint is rate of change of CIMT. Secondary endpoints include emergent plaques and assessment of carotid stiffness. 1,100 patients are required for 90% statistical power to detect treatment-related CIMT difference of 0.025 mm. The first patient was randomized in April 2006.</p> <p><b>Conclusions</b></p> <p>The PERFORM Vascular Project will investigate terutroban’s effect on vascular structure and function in patients with a history of ischemic stroke or TIAs.</p&gt

Inunditos como análogos de reservatórios: um exemplo nos depósitos gonduânicos triássicos do Gráben Arroio Moirão, RS

O estudo de reservatórios de óleo e gás de sistemas continentais tem enfatizado, na última década, arenitos associados a inunditos, provenientes de fluxos hiperpicnais. Contudo, há poucos estudos para entender sua arquitetura e heterogeneidade, resultando em dificuldades de reconhecimento e de exploração. O presente trabalho visa à análise de pacotes triássicos da Bacia do Paraná pertencentes à Formação Santa Maria, que ocorrem como fragmentos isolados sobre o Escudo Sul-Rio-Grandense na região do Gráben Arroio Moirão (RS). Para tanto, fez-se uso de mapeamento sistemático, análise de heterogeneidade de fácies e estratigrafia de sequências, que incluem levantamento de perfis colunares, identificação de associações e sucessões de fácies e superfícies-chave. Além disso, classificaram-se os arenitos e qualificou-se a porosidade com base na análise petrográfica. Foi possível delimitar os principais depósitos de arenitos, no quais predomina geometria tabular, grãos mal selecionados e matriz argilosa. Distinguiram-se cinco ciclos deposicionais granodecrescentes ascendentes, limitados na base e no topo por superfícies erosivas, que marcam heterogeneidades recorrentes. As fácies-reservatório foram classificadas como subarcósios, de matriz argilosa oxidada, com agregados de caulinita, e porosidade intergranular do tipo shrinkage. A integração dos dados resultou na elaboração de um modelo de variação lateral e vertical de fácies de depósitos de inunditos. Nele, identificaram-se fácies constituídas por arenitos grossos a conglomeráticos, com estratificações cruzada tangencial e plano-paralela, como potenciais modelos análogos de reservatórios. Esses resultados possibilitam prospectar outros depósitos arenosos dessa unidade estratigráfica da Bacia do Paraná, para fins de dimensionar regionalmente o análogo de reservatório.The study of oil and gas reservoirs in continental systems has emphasized, in the last decade, sandstones associated with inundites, coming from hyperpicnal flows. However, there are few studies to understand its architecture and heterogeneity, resulting in difficulties for exploration and exploitation. The current work aims at the analysis of Triassic strata from the Paraná Basin belonging to the Santa Maria Formation, which occur as isolated fragments on the Sul-rio-grandense Shield in Arroio Moirão Graben (RS). For this, systematic mapping, facies heterogeneity analysis and sequence stratigraphy were used, including columnar profiles, identification of associations and sequences of facies and key surfaces. In addition, the sandstones were classified and the porosity was qualified based on the petrographic analysis. It was possible to define the main deposits of sandstones, in which predominate tabular geometry, poorly selected grains and clayey matrix. Five ascending granodecrescent depositional cycles were distinguished, limited at the base and at the top by erosive surfaces, which marked recurrent heterogeneities. The reservoir facies were classified as subarcósios, of oxidized clay matrix, with aggregates of kaolinite, and intergranular porosity of the shrinkage type. The integration of the data resulted in the elaboration of a model of lateral and vertical variation inundites deposits facies. In it, facies composed of conglomeratic thick sandstones were identified, with tangential cross stratification and planar stratification, as potential analog models of reservoirs. These results allow the prospection of other sandy deposits from this stratigraphic unit of the Paraná Basin, in order to size the reservoir analogue regionally

The EffecTs of Amlodipine and other Blood PREssure Lowering Agents on Microvascular FuncTion in Small Vessel Diseases (TREAT-SVDs) trial: Study protocol for a randomised crossover trial

Background: Hypertension is the leading modifiable risk factor for cerebral small vessel diseases (SVDs). Yet, it is unknown whether antihypertensive drug classes differentially affect microvascular function in SVDs. Aims: To test whether amlodipine has a beneficial effect on microvascular function when compared to either losartan or atenolol, and whether losartan has a beneficial effect when compared to atenolol in patients with symptomatic SVDs. Design: TREAT-SVDs is an investigator-led, prospective, open-label, randomised crossover trial with blinded endpoint assessment (PROBE design) conducted at five study sites across Europe. Patients aged 18 years or older with symptomatic SVD who have an indication for antihypertensive treatment and are suffering from either sporadic SVD and a history of lacunar stroke or vascular cognitive impairment (group A) or CADASIL (group B) are randomly allocated 1:1:1 to one of three sequences of antihypertensive treatment. Patients stop their regular antihypertensive medication for a 2-week run-in period followed by 4-week periods of monotherapy with amlodipine, losartan and atenolol in random order as open-label medication in standard dose. Outcomes: The primary outcome measure is cerebrovascular reactivity (CVR) as determined by blood oxygen level dependent brain MRI signal response to hypercapnic challenge with change in CVR in normal appearing white matter as primary endpoint. Secondary outcome measures are mean systolic blood pressure (BP) and BP variability (BPv). Discussion: TREAT-SVDs will provide insights into the effects of different antihypertensive drugs on CVR, BP, and BPv in patients with symptomatic sporadic and hereditary SVDs. Funding: European Union's Horizon 2020 programme

Discovery of novel GPVI receptor antagonists by structure-based repurposing.

Inappropriate platelet aggregation creates a cardiovascular risk that is largely managed with thienopyridines and aspirin. Although effective, these drugs carry risks of increased bleeding and drug 'resistance', underpinning a drive for new antiplatelet agents. To discover such drugs, one strategy is to identify a suitable druggable target and then find small molecules that modulate it. A good and unexploited target is the platelet collagen receptor, GPVI, which promotes thrombus formation. To identify inhibitors of GPVI that are safe and bioavailable, we docked a FDA-approved drug library into the GPVI collagen-binding site in silico. We now report that losartan and cinanserin inhibit GPVI-mediated platelet activation in a selective, competitive and dose-dependent manner. This mechanism of action likely underpins the cardioprotective effects of losartan that could not be ascribed to its antihypertensive effects. We have, therefore, identified small molecule inhibitors of GPVI-mediated platelet activation, and also demonstrated the utility of structure-based repurposing