Anatomical variation of the aorta in the West of Scotland - A population with high cardiovascular disease burden. Implications for stent design and deployment.

The prevalence and complexity of cardiovascular disease (CVD) in the West of Scotland are high with the aortic arch and abdominal aorta, particularly at increased risk of cardiovascular pathology. Stent deployment can be key in preventing further cardiovascular events, however, current stent design does not account for complex advanced CVD in these areas. This cadaveric study aimed to provide anatomical measurements requested by manufacturers to improve stent design and deployment in this target population. Nine cadavers (six females and three males; age range = 82.7 ± 10.4 years) from the West of Scotland were dissected to expose the aortic arch and abdominal aorta. Digital callipers and protractors were used to collect data on vessel diameters (including taper), branch spacing, angles and presence of collaterals. CVD was present in all cadavers and ranged from mild plaque presence to aortic dissections. One possessed a bovine aortic arch variation. Supra-aortic vessels were approximately equally spaced, but the left common carotid had the most acute branching angle. Angulation of the arch from the coronal plane positively correlated with a deviation of the left subclavian artery (LSA) from the sternal midline (Spearman's coefficient r = 0.82, p = 0.01) which may impact surgical access. The origin of the vertebral artery on the LSA was also highly variable. The diameter of the descending aorta decreased along its length from the aortic hiatus to superior mesenteric by 21 ± 10% indicating a high degree of taper. The artery of Adamkiewicz was present in 33% and additional renal collaterals were present in 22%. 66% had tortuous vessels in the abdominal region. These results highlight the need for more data to aid the refinement of stent-graft design and deployment methods to ensure successful surgical intervention in this population.

Effects of dietary salt on gene and protein expression in brain tissue of a model of sporadic small vessel disease.

BACKGROUND: The effect of salt on cerebral small vessel disease (SVD) is poorly understood. We assessed the effect of dietary salt on cerebral tissue of the stroke-prone spontaneously hypertensive rat (SHRSP) - a relevant model of sporadic SVD - at both the gene and protein level. Methods: Brains from 21-week-old SHRSP and Wistar-Kyoto rats, half additionally salt-loaded (via a 3-week regime of 1% NaCl in drinking water), were split into two hemispheres and sectioned coronally - one hemisphere for mRNA microarray and qRT-PCR, the other for immunohistochemistry using a panel of antibodies targeting components of the neurovascular unit. Results: We observed differences in gene and protein expression affecting the acute phase pathway and oxidative stress (ALB, AMBP, APOH, AHSG and LOC100129193, up-regulated in salt-loaded WKY versus WKY, >2-fold), active microglia (increased Iba-1 protein expression in salt-loaded SHRSP versus salt-loaded WKY, p<0.05), vascular structure (ACTB and CTNNB, up-regulated in salt-loaded SHRSP versus SHRSP, >3-fold; CLDN-11, VEGF and VGF down-regulated >2-fold in salt-loaded SHRSP versus SHRSP) and myelin integrity (MBP down-regulated in salt loaded WKY rats versus WKY, >2.5-fold). Changes of salt-loading were more pronounced in SHRSP and occurred without an increase in blood pressure in WKY rats. CONCLUSION: Salt exposure induced changes in gene and protein expression in an experimental model of SVD and its parent rat strain in multiple pathways involving components of the glio-vascular unit. Further studies in pertinent experimental models at different ages would help clarify the short- and long-term effect of dietary salt in SVD.

Comparison of Statistical Methods for Assessing Spatial Correlations Between Maps of Different Arterial Properties.

Assessing the anatomical correlation of atherosclerosis with biomechanical localizing factors is hindered by spatial autocorrelation (SA), wherein neighboring arterial regions tend to have similar properties rather than being independent, and by the use of aggregated data, which artificially inflates correlation coefficients. Resampling data at lower resolution or reducing degrees-of-freedom in significance tests negated effects of SA but only in artificial situations where it occurred at a single length scale. Using Fourier or wavelet transforms to generate autocorrelation-preserving surrogate datasets, and thus to compute the null distribution, avoided this problem. Bootstrap methods additionally circumvented the errors caused by aggregating data. The bootstrap technique showed that wall shear stress (WSS) was significantly correlated with atherosclerotic lesion frequency and endothelial nuclear elongation, but not with the permeability of the arterial wall to albumin, in immature rabbits.

Differential gene expression in multiple neurological, inflammatory and connective tissue pathways in a spontaneous model of human small vessel stroke.

AIMS: Cerebral small vessel disease (SVD) causes a fifth of all strokes plus diffuse brain damage leading to cognitive decline, physical disabilities and dementia. The aetiology and pathogenesis of SVD are unknown, but largely attributed to hypertension or microatheroma. METHODS: We used the spontaneously hypertensive stroke-prone rat (SHRSP), the closest spontaneous experimental model of human SVD, and age-matched control rats kept under identical, non-salt-loaded conditions, to perform a blinded analysis of mRNA microarray, qRT-PCR and pathway analysis in two brain regions (frontal and mid-coronal) commonly affected by SVD in the SHRSP at age five, 16 and 21 weeks. RESULTS: We found gene expression abnormalities, with fold changes ranging from 2.5 to 59 for the 10 most differentially expressed genes, related to endothelial tight junctions (reduced), nitric oxide bioavailability (reduced), myelination (impaired), glial and microglial activity (increased), matrix proteins (impaired), vascular reactivity (impaired) and albumin (reduced), consistent with protein expression defects in the same rats. All were present at age 5 weeks thus predating blood pressure elevation. 'Neurological' and 'inflammatory' pathways were more affected than 'vascular' functional pathways. CONCLUSIONS: This set of defects, although individually modest, when acting in combination could explain the SHRSP's susceptibility to microvascular and brain injury, compared with control rats. Similar combined, individually modest, but multiple neurovascular unit defects, could explain susceptibility to spontaneous human SVD.

Potential animal models of lacunar stroke: a systematic review.

BACKGROUND AND PURPOSE: Lacunar ischemic stroke accounts for 25% of all ischemic strokes, but the exact etiology is unknown. Numerous pathophysiologies have been proposed, including atheroma and endothelial dysfunction. Models of any of these pathological features would aid understanding of the etiology and help develop treatments for lacunar stroke. We therefore aimed to assess the relevance of all available potential animal models of lacunar stroke. METHODS: We systematically reviewed the published literature for animal models that could represent lacunar stroke using validated search strategies. We included studies that could represent an aspect of lacunar stroke as well as those aiming to model conditions with potentially similar pathology and extracted data on species, induction method, and resulting brain and vessel lesions. RESULTS: From 5670 papers, 41 studies (46 papers) met inclusion criteria representing over 10 different classes of stroke induction. Important data like infarct size and animal numbers were often missing. Many models' infarcts were too large or affected the cortex. Emboli mostly caused cortical but not small subcortical lesions. Most models focused on creating ischemic lesions in brain tissue. Only one (spontaneous lesions in spontaneously hypertensive stroke-prone rats) also mimicked small vessel pathology. Here, the precursor to small vessel and brain damage was blood-brain barrier failure. CONCLUSIONS: Some animal models produce small subcortical infarcts, but few mimic the human small vessel pathology. Models of small vessel disease could help improve understanding of human lacunar disease, particularly to clarify factors associated with the small vessel morphological changes preceding brain damage. Much lacunar stroke may arise after blood-brain barrier disruption.

Mass transport properties of the rabbit aortic wall.

Uptake of circulating macromolecules by the arterial wall may be a critical step in atherogenesis. Here we investigate the age-related changes in patterns of uptake that occur in the rabbit. In immature aortas, uptake was elevated in a triangle downstream of branch ostia, a region prone to disease in immature rabbits and children. By 16-22 months, uptake was high lateral to ostia, as is lesion prevalence in mature rabbits and young adults. In older rabbits there was a more upstream pattern, similar to the disease distribution in older people. These variations were predominantly caused by the branches themselves, rather than reflecting larger patterns within which the branches happened to be situated (as may occur with patterns of haemodynamic wall shear stress). The narrow streaks of high uptake reported in some previous studies were shown to be post mortem artefacts. Finally, heparin (which interferes with the NO pathway) had no effect on the difference in uptake between regions upstream and downstream of branches in immature rabbits but reversed the difference in older rabbits, as does inhibiting NO synthesis directly. Nevertheless, examination of uptake all around the branch showed that changes occurred at both ages and that they were quite subtle, potentially explaining why inhibiting NO has only minor effects on lesion patterns in mature rabbits and contradicting the earlier conclusion that mechanotransduction pathways change with age. We suggest that recently-established changes in the patterns of haemodynamic forces themselves are more likely to account for the age-dependence of uptake patterns.

Change of direction in the biomechanics of atherosclerosis.

The non-uniform distribution of atherosclerosis within the arterial system has been attributed to pro-atherogenic influences of low, oscillatory haemodynamic wall shear stress (WSS) on endothelial cells (EC). This theory is challenged by the changes in lesion location that occur with age in human and rabbit aortas. Furthermore, a number of point-wise comparisons of lesion prevalence and WSS have failed to support it. Here we investigate the hypothesis that multidirectional flow-characterized as the average magnitude of WSS components acting transversely to the mean vector (transWSS)-plays a key role. Maps of lesion prevalence around aortic branch ostia in immature and mature rabbits were compared with equivalent maps of time average WSS, the OSI (an index characterizing oscillatory flow) and transWSS, obtained from computational simulations; Spearman's rank correlation coefficients were calculated for aggregated data and 95% confidence intervals were obtained by bootstrapping methods. Lesion prevalence correlated positively, strongly and significantly with transWSS at both ages. Correlations of lesion prevalence with the other shear metrics were not significant or were significantly lower than those obtained for transWSS. No correlation supported the low, oscillatory WSS theory. The data are consistent with the view that multidirectional near-wall flow is highly pro-atherogenic. Effects of multidirectional flow on EC, and methods for investigating them, are reviewed. The finding that oscillatory flow has pro-inflammatory effects when acting perpendicularly to the long axis of EC but anti-inflammatory effects when acting parallel to it may explain the stronger correlation of lesion prevalence with transWSS than with the OSI.

Pathology of lacunar ischemic stroke in humans--a systematic review.

Twenty-five percent of ischemic strokes are lacunar in type, but the cause remains unclear. Pathological descriptions of lacunar lesions are available but have not been systematically assessed. We therefore systematically summarized studies describing lacunar lesions by extracting data on the number of patients and lesions, clinical details, pathological methods, brain regions and/or vessels examined, and both parenchymal and vascular findings. Among 39 papers describing >4000 lesions (>50% from one study), 15 papers examined patients with a clinical lacunar syndrome. Terminology varied, many studies only reported macroscopic pathology and many lesions were cavitated (ie, old). Aside from symptomatic lesions occurring more often in the internal capsule or caudate nucleus, we found no other differences between symptomatic and asymptomatic patients. Perivascular edema and thickening, inflammation and disintegration of the arteriolar wall were common, whereas vessel occlusion was rare. The causal mechanisms of lacunar stroke remain poorly defined because of methodological inconsistencies and challenges. Standardised pathological definitions based on well-characterized post-mortem derived material supported by detailed clinical and imaging data are needed.

Etiology of stroke and choice of models.

Animal models of stroke contribute to the development of better stroke prevention and treatment through studies investigating the pathophysiology of different stroke subtypes and by testing promising treatments before trials in humans. There are two broad types of animal models: those in which stroke is induced through artificial means, modeling the consequences of a vascular insult but not the vascular pathology itself; and those in which strokes occur spontaneously. Most animal models of stroke are in rodents due to cost, ethical considerations, availability of standardized neurobehavioral assessments, and ease of physiological monitoring. While there are similarities in cerebrovascular anatomy and pathophysiology between rodents and humans, there are also important differences, including brain size, length and structure of perforating arteries, and gray to white matter ratio, which is substantially lower in humans. The wide range of rodent models of stroke includes models of global and focal ischemia, and of intracerebral and sub-arachnoid hemorrhage. The most widely studied model of spontaneous stroke is the spontaneously hypertensive stroke-prone rat, in which the predominant lesions are small subcortical infarcts resulting from a vascular pathology similar to human cerebral small vessel disease. Important limitations of animal models of stroke - they generally model only certain aspects of the disease and do not reflect the heterogeneity in severity, pathology and comorbidities of human stroke - and key methodological issues (especially the need for adequate sample size, randomization, and blinding in treatment trials) must be carefully considered for the successful translation of pathophysiological concepts and therapeutics from bench to bedside.

Is the spontaneously hypertensive stroke prone rat a pertinent model of sub cortical ischemic stroke? A systematic review.

The spontaneously hypertensive stroke prone rat is best known as an inducible model of large artery stroke. Spontaneous strokes and stroke propensity in the spontaneously hypertensive stroke prone rat are less well characterized; however, could be relevant to human lacunar stroke. We systematically reviewed the literature to assess the brain tissue and small vessel pathology underlying the spontaneous strokes of the spontaneously hypertensive stroke prone rat. We searched systematically three online databases from 1970 to May 2010; excluded duplicates, reviews, and articles describing the consequences of induced middle cerebral artery occlusion or noncerebral pathology; and recorded data describing brain region and the vessels examined, number of animals, age, dietary salt intake, vascular and tissue abnormalities. Among 102 relevant studies, animals sacrificed after developing stroke-like symptoms displayed arteriolar wall thickening, subcortical lesions, enlarged perivascular spaces and cortical infarcts and hemorrhages. Histopathology, proteomics and imaging studies suggested that the changes not due simply to hypertension. There may be susceptibility to endothelial permeability increase that precedes arteriolar wall thickening, degeneration and perivascular tissue changes; systemic inflammation may also precede cerebrovascular changes. There were very few data on venules or tissue changes before hypertension. The spontaneously hypertensive stroke prone rat shows similar features to human lacunar stroke and may be a good spontaneous model of this complex human disorder. Further studies should focus on structural changes at early ages and genetics to identify factors that predispose to vascular and brain damage.