Atherosclerotic Peripheral Arteries Research Articles

Comparative lipid profiling of murine and human atherosclerotic plaques using high-resolution MALDI MSI

The distribution of atherosclerotic lesions in the aorta and its branches of ApoE knockout (ApoE−/−) mice is like that of patients with atherosclerosis. By using high-resolution MALDI mass spectrometry imaging (MSI), we aimed at characterizing universally applicable physiological biomarkers by comparing the murine lipid marker profile with that of human atherosclerotic arteries. Therefore, the aorta or carotid artery of male ApoE−/− mice at different ages, human arteries with documented atherosclerotic changes originated from amputated limbs, and corresponding controls were analysed. Obtained data were subjected to multivariate statistical analysis to identify potential biomarkers. Thirty-one m/z values corresponding to individual lipid species of cholesterol esters, lysophosphatidylcholines, lysophosphatidylethanolamines, and cholesterol derivatives were found to be specific in aortic atherosclerotic plaques of old ApoE−/− mice. The lipid composition at related vessel positions of young ApoE−/− mice was more comparable with wild-type mice. Twenty-six m/z values of the murine lipid markers were found in human atherosclerotic peripheral arteries but also control vessels and showed a more patient-dependent diverse distribution. Extensive data analysis without marker preselection based on mouse data revealed lysophosphatidylcholine and glucosylated cholesterol species, the latter not being detected in the murine atherosclerotic tissue, as specific potential novel human atherosclerotic vessel markers. Despite the heterogeneous lipid profile of atherosclerotic peripheral arteries derived from human patients, we identified lipids specifically colocalized to atherosclerotic human tissue and plaques in ApoE−/− mice. These data highlight species-dependent differences in lipid profiles between peripheral artery disease and aortic atherosclerosis.

Recombinant Human Elastase Alters the Compliance of Atherosclerotic Tibial Arteries After Ex Vivo Angioplasty.

This study was designed to determine whether vonapanitase (formerly PRT-201), a recombinant human elastase, treatment can fragment the protein elastin in elastic fibers and cause dilation of atherosclerotic human peripheral arteries subjected to ex vivo balloon angioplasty. Seven patients undergoing lower limb amputation for peripheral artery disease or who died and donated their bodies to science donated 11 tibial arteries (5 anterior, 6 posterior) for this study. All arteries were atherosclerotic by visual inspection. The arteries underwent ex vivo balloon angioplasty and thereafter were cut into rings and studied on wire myographs where the rings were stretched and tension was recorded. After treatment with vonapanitase 2 mg/mL or vehicle control, myography was repeated and the rings were then subject to elastin content measurement using a desmosine radioimmunoassay and elastic fiber visualization by histology. The wire myography data were used to derive compliance, stress-strain, and incremental elastic modulus curves. Vonapanitase treatment reduced elastin (desmosine) content by 60% and decreased elastic fiber histologic staining. Vonapanitase-treated rings experienced less tension at any level of stretch and as a result had shifts in the compliance and stress-strain curves relative to vehicle-treated rings. Vonapanitase treatment did not alter the incremental elastic modulus curve. Vonapanitase treatment of atherosclerotic human peripheral arteries after ex vivo balloon angioplasty fragmented elastin in elastic fibers, decreased tension in the rings at any level of stretch, and altered the compliance and stress-strain curves in a manner predicting arterial dilation in vivo. Based on this result, local treatment of balloon angioplasty sites may increase blood vessel diameter and thereby improve the success of balloon angioplasty in peripheral artery disease.

Effects of recombinant human type I pancreatic elastase on human atherosclerotic arteries.

Rationale:At physiologic pressures, elastic fibers constrain artery diameter. Local treatment of atherosclerotic arteries with PRT-201, a recombinant type I elastase, could result in fragmentation and removal of elastin fibers and increased vessel diameter.Objective:To investigate the use of PRT-201 as a treatment for human atherosclerotic arteries.Methods and Results:Arteries were harvested from donor legs amputated due to severe peripheral artery disease or from recently deceased persons who donated their bodies to science. Three- to four-centimeter artery segments were studied on a perfusion myograph to obtain baseline diameter data. After treatment with PRT-201 3.6 mg/mL or saline for 30 minutes myography was repeated. PRT-201 treatment resulted in an increase in vessel diameter across a range of transmural pressures. Average anterior tibial artery diameter increased by 0.78 ± 0.21 mm (27% ± 12%), whereas average posterior tibial artery diameter increased by 0.58 ± 0.30 mm (21% ± 11%), both P < 0.001. Elastin content as measured by desmosine radioimmunoassay was reduced by approximately 50%, P < 0.001.Conclusions:The results suggest that PRT-201 treatment of atherosclerotic peripheral arteries in patients could increase artery diameter, and thus luminal area, possibly alleviating some of the symptoms of peripheral artery disease.

Wall morphology, blood flow and wall shear stress: MR findings in patients with peripheral artery disease

To investigate the influence of atherosclerotic plaques on femoral haemodynamics assessed by two-dimensional (2D) phase-contrast (PC) magnetic resonance imaging (MRI) with three-directional velocity encoding. During 1year, patients with peripheral artery disease and an ankle brachial index <1.00 were enrolled. After institutional review board approval and written informed consent, 44 patients (age, 70 ± 12years) underwent common femoral artery MRI. Patients with contra-indications for MRI were excluded. Sequences included 2D time-of-flight, proton-density, T1-weighted and T2-weighted MRI. Electrocardiogram (ECG)-gated 2D PC-MRI with 3D velocity encoding was acquired. A radiologist classified images in five categories. Blood flow, velocity and wall shear stress (WSS) along the vessel circumference were quantified from the PC-MRI data. The acquired images were of good quality for interpretation. There were no image quality problems related to poor ECG-gating or slice positioning. Velocities, oscillatory shear stress and total flow were similar between patients with normal arteries and wall thickening/plaque. Patients with plaques demonstrated regionally increased peak systolic WSS and enhanced WSS eccentricity. Combined multi-contrast morphological imaging of the peripheral arterial wall with PC-MRI with three-directional velocity encoding is a feasible technique. Further study is needed to determine whether flow is an appropriate marker for altered endothelial cell function, vascular remodelling and plaque progression. • Femoral plaques are associated with altered dynamics of peripheral blood flow. • Multi-contrast MRI can investigate the presence and type of atherosclerotic plaques. • Three-dimensional velocity-encoding phase-contrast MRI can investigate flow and wall shear stress. • Atherosclerotic peripheral arteries demonstrate increased systolic velocities and wall shear stress.

Tri-axial system using the Solitaire-FR and Penumbra Aspiration Microcatheter for acute mechanical thrombectomy

The Solitaire-FR (eV3/Covidien, Irvine, CA, USA) retrievable stent (SFR), designed for mechanical thrombectomy in acute ischemic stroke, recently received Food and Drug Administration approval in the USA. Clot retrieval is performed by deploying the SFR through a microcatheter directly into the thrombus, to capture the clot and restore perfusion. In order to perform this maneuver, a balloon guide catheter must be used to apply negative suction and reverse flow within the cervical arteries, thus minimizing the chance of antegrade blood flow dislodging the thrombus from the stent. This technique requires at least an 8-French system that can increase the risk of arterial injury at the access site particularly in older patients with smaller or highly atherosclerotic peripheral arteries, and may provide inadequate aspiration in the vertebrobasilar system where only one vertebral artery is accessed and aspirated. The author describes a technique whereby a 6-French tri-axial system is used to deliver the SFR through a Penumbra Aspiration Microcatheter (Penumbra, Inc., Alameda, CA, USA) to provide intracranial aspiration in close proximity to the stent.

Stresses in peripheral arteries following stent placement: a finite element analysis

The success of stents to restore blood flow in atherosclerotic peripheral arteries is low relative to coronary arteries. It has been shown that joint flexion induces a mechanical environment that makes stent placement in these arteries highly incompatible, and damage and destruction of stents has been recorded. However, the effect of this environment on the stresses in the arteries is unknown. It is hypothesised that the stresses induced in arteries as a result of this mechanical environment could be sufficient to explain the relatively low success rates. To investigate this hypothesis, a finite element model of the stent–artery interaction was developed. Following stent expansion, bending was simulated by applying a displacement boundary condition to the artery. It is found that high stresses occur at the proximal/distal ends of the stent. As high stress and vascular injury are hypothesised to cause restenosis, the results presented here suggest that the mechanical environment of peripheral arteries could be the predominant cause of high restenosis rates.

Ischemic nephropathy in an elderly patient

Congestive heart failure often occurs in patients with bilateral renal artery stenosis. Recently, Jacobson and Breyer, and Jacobson introduced the term "ischemic nephropathy", which implies critical bilateral involvement or global ischemia. Ischemic nephropathy is not only a cause of hypertension but also an important cause of end-stage renal disease. However, the aging kidney often show that the renal artery does not demonstrate stenosis of the main trunks, but stenosis of an atherosclerotic branch. We present a case of multiple atherosclerotic peripheral renal arteries, which might have caused ischemic nephropathy in an elderly hypertensive patient with advanced atherosclerosis.

Mechanism of Luminal Gain with Plaque Excision in Atherosclerotic Coronary and Peripheral Arteries: Assessment by Histology and Intravascular Ultrasound

Using intravascular ultrasound (IVUS) and histology, the purpose of this study was to evaluate the occurrence of arterial wall overstretch and Dotter effect following revascularization with a plaque excision (PE) catheter compared with balloon angioplasty. Previous studies have demonstrated the safety and feasibility of plaque excision for the treatment of de novo coronary and peripheral atherosclerotic disease. However, whether mechanical vessel dilatation related to catheter insertion contributes to gains in the final luminal diameter is uncertain. Treatment with PE was assessed in both a porcine model (6 lesions treated with balloon angioplasty or PE) using histology and in humans with IVUS. In the latter part of the study, IVUS study was performed before and immediately following PE in 21 patients with either coronary artery disease (N = 13) or femoral artery disease (N = 8). Ultrasound measures in the femoral artery group were then compared with a control group of atherosclerotic lesions treated with conventional angioplasty that was matched according to lesion location and vessel diameter. Among individuals with coronary and peripheral arterial lesions treated with PE, the relative increases in luminal area secondary to reductions in plaque volume were 89% and 83%, respectively, with minimal increase in vessel diameter. In contrast, balloon angioplasty was associated with significantly greater vessel expansion and less plaque volume reduction. Vessel dissection also tended to occur less frequently and to a lesser extent with PE. Improvement in luminal dimensions using PE is principally due to a reduction in plaque volume rather than mechanical vessel expansion. The potential to increase luminal area while minimizing arterial dissection and barotrauma merits further clinical study with this method of revascularization.

Regulator of G protein signaling 5 marks peripheral arterial smooth muscle cells and is downregulated in atherosclerotic plaque

Regulator of G protein signaling 5 (RGS5), an inhibitor of Galpha(q) and Galpha(i) activation, was recently identified among genes highly expressed in smooth muscle cells (SMCs) of aorta but not vena cava. This finding prompted the hypothesis that RGS5 provides long-term G protein inhibition specific to normal arterial SMC populations and that loss of expression may in turn contribute to arterial disease. To test this hypothesis we characterized RGS5 gene expression throughout the vasculature of nonhuman primates to determine whether RGS5 was restricted to arteries in other vascular beds and whether expression was altered in arterial disease. In situ hybridization localized RGS5 message to medial SMCs of peripheral arteries, including carotid, iliac, mammary, and renal arteries, but not accompanying veins. SMCs of many small arteries and arterioles also expressed RGS5, including glomerular afferent arterioles critical to blood pressure regulation. Differential expression persisted in culture, inasmuch as RGS5 message was significantly higher in SMCs derived from arteries than from veins at real-time polymerase chain reaction. It was remarkable that the only major arterial bed lacking RGS5 was the coronary circulation. In atherosclerotic peripheral arteries RGS5 was expressed in medial SMCs, but was sharply downregulated in plaque SMCs. These data identify RGS5 as a new member of a short list of genes uniquely expressed in peripheral arteries but not coronary arteries. Persistence of an arterial pattern of RGS5 expression in culture and lack of expression in coronary arteries support a unique SMC phenotype fixed by distinct lineage or differentiation pathways. The association between loss of expression and arterial wall disease has prompted the new hypothesis that prolonged inhibition by RGS5 of vasoactive or trophic G protein signaling is critical to normal peripheral artery function.

Is plaque formation in the common carotid artery representative for plaque formation and luminal stenosis in other atherosclerotic peripheral arteries? A post mortem study

The atherosclerotic carotid artery is easily accessible for non-invasive duplex investigation. The aim of the present post mortem study was to examine whether plaque accumulation and luminal stenosis in the common carotid artery is representative for atherosclerotic plaque accumulation and luminal stenosis in other peripheral arteries. A total of 3765 cross-sections were obtained at regular intervals from 240 arteries (24 individuals). Five types of peripheral arteries were investigated: common carotid, femoral, common iliac, external iliac and renal arteries. In each cross-section, the lumen area, vessel area, plaque area and maximal plaque thickness was measured. For each location, the percentage luminal stenosis and relative plaque area was calculated. Relative plaque area was defined as the percentage of the vessel area which was occupied by plaque. Weak correlations (r=0.41-0.59) were observed between percentage relative plaque area or maximal plaque thickness in the common carotid artery and percentage relative plaque area in other peripheral arteries. Neither plaque accumulation nor luminal stenosis in the common carotid artery correlated with the percentage luminal stenosis in other peripheral arteries (P > 0.05). We conclude that plaque area in the common carotid artery is weakly correlated with plaque area and not correlated with luminal stenosis in other peripheral arteries.

Localized drug delivery in atherosclerotic arteries via a new balloon angioplasty catheter with intramural channels for simultaneous local drug delivery.

A dual-purpose angioplasty catheter with intramural channels and exterior pores for local drug delivery ("channeled balloon") was studied in eight atherosclerotic human necropsy arteries and in 22 rabbits with atherosclerotic peripheral arteries, in which markers (0.005 microns to 15 microns) were infused locally at 2 atmospheres during simultaneous angioplasty at 6 atmospheres. Thirteen of the rabbits were sacrificed at 4 or 24 h after procedure to determine the intramural retention over time. Histology confirmed effective angioplasty and revealed presence of markers in the arterial wall in 29 of 43 treated arteries (67%), whereas all control segments without local delivery had no marker staining. majority of the ineffective local delivery (12/14) occurred when 15 micron particles were infused (12/13 arteries without intramural markers), especially when examined 4 or 24 h later. Thus, in atherosclerotic arteries, the channeled balloon enabled simultaneous local drug delivery at low pressure during effective angioplasty, although particle size may play a role in successful intramural impregnation and retention.

Direct argon laser exposure for recanalization of peripheral arteries: early results.

Direct laser light, in combination with percutaneous transluminal angioplasty (PTA), was used to recanalize atherosclerotic peripheral arteries. Argon laser energy was controlled with an optical assembly and aligned with a special centering/dilation balloon so that plaque tissue absorbed laser energy directly and was vaporized. A channel was thereby created with multiple 10-W laser exposures (2-10 seconds), and conventional angioplasty was then performed. Recanalization was achieved in 33 of 36 procedures (92%), in 23 femoropopliteal (mean length, 9 cm) and three iliac total occlusions and ten femoropopliteal high-grade stenoses, with the three failures occurring in the first group. Complications included two emboli, six moderate groin hematomas, and one laser perforation. While these results are preliminary (mean follow-up, 3 months), direct laser angioplasty appears to be a useful adjunct to PTA for treating atherosclerotic arteries.