Alterations in vasoconstrictor responses to the endothelium-derived contracting factor uridine adenosine tetraphosphate are region specific in DOCA-salt hypertensive rats

Uridine adenosine tetraphosphate (Up(4)A) has been recently identified as a novel and potent endothelium-derived contracting factor and contains both purine and pyrimidine moieties, which activate purinergic P2X and P2Y receptors. The present study was designed to compare contractile responses to Up(4)A and other nucleotides such as ATP (P2X/P2Y agonist), UTP (P2Y(2)/P2Y(4) agonist), UDP (P2Y(6) agonist), and alpha,beta-methylene ATP (P2X(1) agonist) in different vascular regions [thoracic aorta, basilar, small mesenteric, and femoral arteries] from deoxycorticosterone acetate-salt (DOCA-salt) and control rats. In DOCA-salt rats [vs. control uninephrectomized (Uni) rats]: (1) in thoracic aorta, Up(4)A-, ATP-, and UP-induced contractions were unchanged; (2) in basilar artery, Up(4)A-, ATP-, UTP- and UDP-induced contractions were increased, and expression for P2X(1), but not P2Y(2) or P2Y(6) was decreased; (3) in small mesenteric artery, Up(4)A-induced contraction was decreased and UDP-induced contraction was increased; expression of P2Y(2) and P2X(1) was decreased whereas P2Y(6) expression was increased; (4) in femoral artery, Up(4)A-. UTP-, and UDP-induced contractions were increased, but expression of P2Y(2), P2Y(6) and P2X(1) was unchanged. The alpha,beta-methylene ATP-induced contraction was bell-shaped and the maximal contraction was reached at a lower concentration in basilar and mesenteric arteries from Uni rats, compared to arteries from DOCA-salt rats. These results suggest that Up(4)A-induced contraction is heterogenously affected among various vascular beds in arterial hypertension. P2Y receptor activation may contribute to enhancement of Up(4)A-induced contraction in basilar and femoral arteries. These changes in vascular reactivity to Up(4)A may be adaptive to the vascular alterations produced by hypertension. (C) 2011 Elsevier Ltd. All rights reserved.

Characterization of vascular wall progenitor cells and their role in therapeutic angiogenesis and Monckeberg's sclerosis

Recently, the existence of a capillary-rich vasculogenic zone has been identified in adult human arteries between the tunica media and adventitia; in this area it has been postulated that Mesenchymal Stem Cells (MSCs) may be present amidst the endothelial progenitors and hematopoietic stem cells. This hypothesis is supported by several studies claiming to have found the in vivo reservoir of MSCs in post-natal vessels and by the presence of ectopic tissues in the pathological artery wall. We demonstrated that the existence of multipotent progenitors is not restricted to microvasculature; vascular wall resident MSCs (VW-MSCs) have been isolated from multidistrict human large and middle size vessels (aortic arch, thoracic aorta and femoral artery) harvested from healthy multiorgan donors. Each VW-MSC population shows characteristics of embryonic-like stem cells and exhibits angiogenic, adipogenic, chondrogenic and leiomyogenic potential but less propensity to osteogenic ifferentiation. Human vascular progenitor cells are also able to engraft, differentiate into mature endothelial cells and support muscle function when injected in a murine model of hind limb ischemia. Conversely, VW-MSCs isolated from calcified femoral arteries display a good response to osteogenic commitment letting us to suppose that VW-MSCs could have an important role in the onset of vascular pathologies such as Mönckeberg sclerosis. Taken together these results show two opposite roles of vascular progenitor cells and underline the importance of establishing their in vivo pathological and regenerative potential to better understand pathological events and promote different therapeutic strategies in cardiovascular research and clinical applications.

Aortic arch morphometry in living humans

Anatomical features of the aortic arch such as its steepness, the take-off angles and the distances between its supra-aortic branches can influence the feasibility and difficulty of interventional and/or surgical maneuvers. These anatomical characteristics were assessed by means of 3D multiplanar reconstruction of thoracic angio-computed tomography scans of 92 living patients (79 males, 13 females, mean age 69.4 ± 9.9 years) carried out for various indications (gross pathology of the thoracic aorta excluded). There was a significant variation of all measured parameters between the subjects - a standard aortic arch (i.e. with all measured parameters within 2 SD) does not seem to exist. There were no significant differences between genders but some of the parameters correlated significantly to age.

Should intentional endovascular stent-graft coverage of the left subclavian artery be preceded by prophylactic revascularisation?

Thoracic endovascular aortic repair (TEVAR) has emerged as a promising therapeutic alternative to conventional open aortic replacement but it requires suitable proximal and distal landing zones for stent-graft anchoring. Many aortic pathologies affect in the immediate proximity of the left subclavian artery (LSA) limiting the proximal landing zone site without proximal vessel coverage. In patients in whom the distance between the LSA and aortic lesion is too short, extension of the landing zone can be obtained by covering the LSA's origin with the endovascular stent graft (ESG). This manoeuvre has the potential for immediate and delayed neurological and vascular symptoms. Some authors, therefore, propose prophylactic revascularisation of the LSA by transposition or bypass, while others suggest prophylactic revascularisation only under certain conditions, and still others see no requirement for prophylactic revascularisation in anticipation of LSA ostium coverage. In this review about LSA revascularisation in TEVAR patients with coverage of the LSA, we searched the electronic databases MEDLINE and EMBASE historically until the end date of May 2010 with the search terms left subclavian artery, covering, endovascular, revascularisation and thoracic aorta. We have gathered the most complete scientific evidence available used to support the various concepts to deal with this issue. After a review of the current available literature, 23 relevant articles were found, where we have identified and analysed three basic treatment concepts for LSA revascularisation in TEVAR patients (prophylactic, conditional prophylactic and no prophylactic LSA revascularisation). The available evidence supports prophylactic revascularisation of the LSA before ESG LSA coverage when preoperative imaging reveals abnormal supra-aortic vascular anatomy or pathology. We further conclude that elective patients undergoing planned coverage of the LSA during TEVAR should receive prophylactic LSA transposition or LSA-to-left-common-carotid-artery (LCCA) bypass surgery to prevent severe neurological complications, such as paraplegia or brain stem infarction.

Intravital microscopy reveals endothelial dysfunction in resistance arterioles in Angiotensin II-induced hypertension

It is known that hypertension is associated with endothelial dysfunction and that Angiotensin II (Ang II) is a key player in the pathogenesis of hypertension. We aimed to elucidate whether endothelial dysfunction is a specific feature of Ang II-mediated hypertension or a common finding of hypertension, independently of underlying etiology. We studied endothelial-dependent vasorelaxation in precapillary resistance arterioles and in various large-caliber conductance arteries in wild-type mice with Ang II-dependent hypertension (2-kidney 1-clip (2K1C) model) or Ang II-independent (volume overload) hypertension (1-kidney 1-clip model (1K1C)). Normotensive sham mice were used as controls. Aortic mechanical properties were also evaluated. Intravital microscopy of precapillary arterioles revealed a significantly impaired endothelium-dependent vasorelaxation in 2K1C mice compared with sham mice, as quantified by the ratio of acetylcholine (ACh)-induced over S-nitroso-N-acetyl-D,L-penicillamine (SNAP)-induced vasorelaxation (2K1C: 0.49±0.12 vs. sham: 0.87±0.11, P=0.018). In contrast, the ACh/SNAP ratio in volume-overload hypertension 1K1C mice was not significantly different from sham mice, indicating no specific endothelial dysfunction (1K1C: 0.77±0.27 vs. sham: 0.87±0.11, P=0.138). Mechanical aortic wall properties and endothelium-dependent vasorelaxation, assessed ex vivo in rings of large-caliber conductance (abdominal and thoracic aorta, carotid and femoral arteries), were not different between 2K1C, 1K1C and sham mice. Endothelial dysfunction is an early feature of Ang II- but not volume-overload-mediated hypertension. This occurs exclusively at the level of precapillary arterioles and not in conduit arteries. Our findings, if confirmed in clinical studies, will provide a better understanding of the pathophysiological mechanisms of hypertension.

Aortic root replacement does not affect outcome and quality of life

BACKGROUND: Different studies have analyzed the potential impact of the underlying pathologic process and the use of deep hypothermic circulatory arrest on outcome and quality of life after surgery on the thoracic aorta. The aim of this study is to analyze the impact of different surgical procedures on outcome and quality of life. METHODS: Between June 2001 and December 2003, 244 patients underwent surgery for various diseases of the ascending aorta with or without involvement of the aortic valve or root. They were divided according to the operative procedure: 76 patients (31.2%) underwent isolated replacement of the ascending aorta, 42 patients (17.2%) received separate aortic valve replacement and supracoronary replacement of the ascending aorta, 86 patients (35.2%) received a mechanical composite graft, and 40 patients (16.4%) received a biologic composite graft. All in-hospital data were assessed, and a follow-up was performed in all survivors after 26.6 +/- 8.8 months, focusing on outcome and quality of life (SF-36). RESULTS: Overall in-hospital mortality was 6.1%, and late mortality was 5.7%, with no significant difference between groups. Independent of the surgical technique and the extent of surgery, there was no difference in quality of life between the surgical collective and an age-matched and sex-matched standard population. CONCLUSIONS: Operations of the ascending aorta and aortic valve are very safe, with low in-hospital mortality and favorable midterm outcome regarding late mortality and morbidity. Quality of life after operations of the ascending aorta and aortic valve is equal to a standard population and is not affected by the surgical procedure. Liberal use of aortic root replacement is therefore justified to radically treat the diseased aortic segment.

Outcome and quality of life after surgical and endovascular treatment of descending aortic lesions

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) represents an attractive alternative to open aortic repair (OAR). The aim of this study was to assess outcome and quality of life in patients treated either by TEVAR or OAR for diseased descending thoracic aorta. METHODS: A post hoc analysis of a prospectively collected consecutive series of 136 patients presenting with surgical diseases of the descending aorta between January 2001 and December 2005 was conducted. Fourteen patients were excluded because of involvement of the ascending aorta. Assessed treatment cohorts were TEVAR (n = 52) and OAR (n = 70). Mean follow-up was 34 +/- 18 months. End points were perioperative and late mortality rates and long-term quality of life as assessed by the Short Form Health Survey (SF-36) and Hospital Anxiety and Depression Score questionnaires. RESULTS: Mean age was significantly higher in TEVAR patients (69 +/- 10 years versus 62 +/- 15 years; p = 0.002). Perioperative mortality rates were 9% (OAR) and 8% (TEVAR), respectively (p = 0.254). Accordingly, cumulative long-term mortality rates were similar in both cohorts. Overall quality-of-life scores were 93 (63-110, OAR) and 83 (60-112, TEVAR), respectively. Normal quality-of-life scores range from 85 to 115. Anxiety and depression scores were not increased after open surgery. CONCLUSIONS: Thoracic endovascular aortic repair and OAR both provide excellent long-term results in treatment of thoracic aortic disease. Long-term quality of life, however, is reduced after thoracic aortic repair. Interestingly, TEVAR patients did not score higher in overall quality of life despite all advantages of minimized access trauma. Similarly, anxiety and depression scores are not reduced by TEVAR, possibly reflecting a certain caution against the new technology.

Bronchial circulation after experimental lung transplantation: the effect of direct revascularization of a bronchial artery

Direct revascularization of a bronchial artery has been proposed as a measure to alleviate the problem of bronchial ischemia after lung transplantation. To assess the effect of restoration of arterial blood flow to the transplanted bronchus, bronchial mucosal blood flow was measured in a model of modified unilateral lung transplantation in pigs. Laser Doppler velocimetry (LDV) and radioisotope studies using radio-labeled erythrocytes (RI) were used to measure blood flow at the donor main carina (DC) and upper lobe carina (DUC) after 3 h of reperfusion. The recipient carina was used as a reference point; values obtained by LDV and RI were expressed as percentage of blood flow at the recipient carina. Two groups of animals were studied. In group 1 (n = 6) standard unilateral transplantation was performed; in group 2 (n = 6) a left bronchial artery was reimplanted into the descending thoracic aorta of the recipient. No differences were observed between the two groups with respect to preoperative or postoperative gas exchange or hemodynamics. In group 1, bronchial blood flow at the DC was 37.6 +/- 2.2% (LDV) and 44.1 +/- 14.8% (RI) of reference blood flow. At the DUC, blood flow was 54.9 +/- 7.7% (LDV) and 61.6 +/- 25.7% (RI) of normal flow. In group 2, blood flow was increased at the DC as measured by LDV (55.3 +/- 17.1%; p less than 0.05) and by RI (60.8 +/- 25.3%; p less than 0.2). A similar increase was found at the DUC (LDV: 81.8 +/- 19.3%; p less than 0.05; RI: 88.6 +/- 31.0%; p less than 0.2). It is concluded that there is a significant gradient of blood flow from intra- to extrapulmonary airways after lung transplantation. Reimplantation of a bronchial artery results in significant improvement of graft bronchial blood flow. Restoration of bronchial perfusion to normal levels, however, cannot be achieved, suggesting a possible defect in the microcirculation of the donor airways.

A longitudinal study of Type-B aortic dissection and endovascular repair scenarios: computational analyses

Conservative medical treatment is commonly first recommended for patients with uncomplicated Type-B aortic dissection (AD). However, if dissection-related complications occur, endovascular repair or open surgery is performed. Here we establish computational models of AD based on radiological three-dimensional images of a patient at initial presentation and after 4-years of best medical treatment (BMT). Computational fluid dynamics analyses are performed to quantitatively investigate the hemodynamic features of AD. Entry and re-entries (functioning as entries and outlets) are identified in the initial and follow-up models, and obvious variations of the inter-luminal flow exchange are revealed. Computational studies indicate that the reduction of blood pressure in BMT patients lowers pressure and wall shear stress in the thoracic aorta in general, and flattens the pressure distribution on the outer wall of the dissection, potentially reducing the progressive enlargement of the false lumen. Finally, scenario studies of endovascular aortic repair are conducted. The results indicate that, for patients with multiple tears, stent-grafts occluding all re-entries would be required to effectively reduce inter-luminal blood communication and thus induce thrombosis in the false lumen. This implicates that computational flow analyses may identify entries and relevant re-entries between true and false lumen and potentially assist in stent-graft planning.

Multi-phase postmortem CT angiography: recognizing technique-related artefacts and pitfalls

BACKGROUND AND PURPOSE Multi-phase postmortem CT angiography (MPMCTA) is increasingly being recognized as a valuable adjunct medicolegal tool to explore the vascular system. Adequate interpretation, however, requires knowledge about the most common technique-related artefacts. The purpose of this study was to identify and index the possible artefacts related to MPMCTA. MATERIAL AND METHODS An experienced radiologist blinded to all clinical and forensic data retrospectively reviewed 49 MPMCTAs. Each angiographic phase, i.e. arterial, venous and dynamic, was analysed separately to identify phase-specific artefacts based on location and aspect. RESULTS Incomplete contrast filling of the cerebral venous system was the most commonly encountered artefact, followed by contrast agent layering in the lumen of the thoracic aorta. Enhancement or so-called oedematization of the digestive system mucosa was also frequently observed. CONCLUSION All MPMCTA artefacts observed and described here are reproducible and easily identifiable. Knowledge about these artefacts is important to avoid misinterpreting them as pathological findings.

Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation.

AIMS In this work, we provide novel insight into the morphology of dissecting abdominal aortic aneurysms in angiotensin II-infused mice. We demonstrate why they exhibit a large variation in shape and, unlike their human counterparts, are located suprarenally rather than infrarenally. METHODS AND RESULTS We combined synchrotron-based, ultra-high resolution ex vivo imaging (phase contrast X-Ray tomographic microscopy) with in vivo imaging (high-frequency ultrasound and contrast-enhanced micro-CT) and image-guided histology. In all mice, we observed a tear in the tunica media of the abdominal aorta near the ostium of the celiac artery. Independently we found that, unlike the gradual luminal expansion typical for human aneurysms, the outer diameter increase of angiotensin II-induced dissecting aneurysms in mice was related to one or several intramural haematomas. These were caused by ruptures of the tunica media near the ostium of small suprarenal side branches, which had never been detected by the established small animal imaging techniques. The tear near the celiac artery led to apparent luminal dilatation, while the intramural haematoma led to a dissection of the tunica adventitia on the left suprarenal side of the aorta. The number of ruptured branches was higher in those aneurysms that extended into the thoracic aorta, which explained the observed variability in aneurysm shape. CONCLUSION Our results are the first to describe apparent luminal dilatation, suprarenal branch ruptures, and intramural haematoma formation in dissecting abdominal aortic aneurysms in mice. Moreover, we validate and demonstrate the vast potential of phase contrast X-ray tomographic microscopy in cardiovascular small animal applications.

Review of recent results using computational fluid dynamics simulations in patients receiving mechanical assist devices for end-stage heart failure

Many end-stage heart failure patients are not eligible to undergo heart transplantation due to organ shortage, and even those under consideration for transplantation might suffer long waiting periods. A better understanding of the hemodynamic impact of left ventricular assist devices (LVAD) on the cardiovascular system is therefore of great interest. Computational fluid dynamics (CFD) simulations give the opportunity to study the hemodynamics in this patient population using clinical imaging data such as computed tomographic angiography. This article reviews a recent study series involving patients with pulsatile and constant-flow LVAD devices in which CFD simulations were used to qualitatively and quantitatively assess blood flow dynamics in the thoracic aorta, demonstrating its potential to enhance the information available from medical imaging.

Noninvasive pressure difference mapping derived from 4D flow MRI in patients with unrepaired and repaired aortic coarctation.

PURPOSE To develop a method for computing and visualizing pressure differences derived from time-resolved velocity-encoded three-dimensional phase-contrast magnetic resonance imaging (4D flow MRI) and to compare pressure difference maps of patients with unrepaired and repaired aortic coarctation to young healthy volunteers. METHODS 4D flow MRI data of four patients with aortic coarctation either before or after repair (mean age 17 years, age range 3-28, one female, three males) and four young healthy volunteers without history of cardiovascular disease (mean age 24 years, age range 20-27, one female, three males) was acquired using a 1.5-T clinical MR scanner. Image analysis was performed with in-house developed image processing software. Relative pressures were computed based on the Navier-Stokes equation. RESULTS A standardized method for intuitive visualization of pressure difference maps was developed and successfully applied to all included patients and volunteers. Young healthy volunteers exhibited smooth and regular distribution of relative pressures in the thoracic aorta at mid systole with very similar distribution in all analyzed volunteers. Patients demonstrated disturbed pressures compared to volunteers. Changes included a pressure drop at the aortic isthmus in all patients, increased relative pressures in the aortic arch in patients with residual narrowing after repair, and increased relative pressures in the descending aorta in a patient after patch aortoplasty. CONCLUSIONS Pressure difference maps derived from 4D flow MRI can depict alterations of spatial pressure distribution in patients with repaired and unrepaired aortic coarctation. The technique might allow identifying pathophysiological conditions underlying complications after aortic coarctation repair.

Noninvasive 4D pressure difference mapping derived from 4D flow MRI in patients with repaired aortic coarctation: comparison with young healthy volunteers

To assess spatial and temporal pressure characteristics in patients with repaired aortic coarctation compared to young healthy volunteers using time-resolved velocity-encoded three-dimensional phase-contrast magnetic resonance imaging (4D flow MRI) and derived 4D pressure difference maps. After in vitro validation against invasive catheterization as gold standard, 4D flow MRI of the thoracic aorta was performed at 1.5T in 13 consecutive patients after aortic coarctation repair without recoarctation and 13 healthy volunteers. Using in-house developed processing software, 4D pressure difference maps were computed based on the Navier-Stokes equation. Pressure difference amplitudes, maximum slope of pressure amplitudes and spatial pressure range at mid systole were retrospectively measured by three readers, and twice by one reader to assess inter- and intraobserver agreement. In vitro, pressure differences derived from 4D flow MRI showed excellent agreement to invasive catheter measurements. In vivo, pressure difference amplitudes, maximum slope of pressure difference amplitudes and spatial pressure range at mid systole were significantly increased in patients compared to volunteers in the aortic arch, the proximal descending and the distal descending thoracic aorta (p < 0.05). Greatest differences occurred in the proximal descending aorta with values of the three parameters for patients versus volunteers being 19.7 ± 7.5 versus 10.0 ± 2.0 (p < 0.001), 10.9 ± 10.4 versus 1.9 ± 0.4 (p = 0.002), and 8.7 ± 6.3 versus 1.6 ± 0.9 (p < 0.001). Inter- and intraobserver agreements were excellent (p < 0.001). Noninvasive 4D pressure difference mapping derived from 4D flow MRI enables detection of altered intraluminal aortic pressures and showed significant spatial and temporal changes in patients with repaired aortic coarctation.

Identification of genetic variants that influence atherosclerosis in young persons

Atherosclerosis is widely accepted as a complex genetic phenotype and is the usual cause of cardiovascular disease, the world’s leading killer. Genetic factors have been proven to be important risk contributors for atherosclerosis and much work has been done to identify promising candidates that might play a role in the development of atherosclerosis. It is well known that many independent replications are needed to unequivocally establish a valid genotype-phenotype association across different populations before the findings are extended to clinical settings and to the expensive follow-up studies designed to identify causal genetic variants. Aiming to replicate the association with atherosclerosis in the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, we assessed the relationship of 32 atherosclerosis candidate SNPs to atherosclerosis in the PDAY cohort, consisting of AA and EA young people aged 15-34 years who died of non-medical causes. Two association studies, a whole sample study and a 1:1 matched case control study were performed by use of multiple linear regression and logistic regression analyses, respectively. For the whole sample association study, 32 SNPs among 2,650 individuals (1,369 AA and 1,281 EA) were tested for the association with six early atherosclerosis phenotypes: abdominal aorta fatty streaks, abdominal aorta raised lesions, right coronary artery fatty streaks, right coronary artery raised lesions, thoracic aorta fatty streaks, and thoracic aorta raised lesions. For the matched case-control association study, 337 case-control paired samples were included; cases were chosen with the highest total raised lesion scores from the studied population, while controls were randomly selected from individuals that had no raised lesions and matched to cases by age, gender and race. Sixteen SNPs in 13 genes were found to be significantly associated with atherosclerosis in at least one of the PDAY association studies. Among these 16 findings: eight SNPs (rs9579646, rs6053733, rs3849150, rs10499903, rs2148079, rs5073691, rs10116277, and rs17228212) successfully replicated previous results, six SNPs (rs17222814, rs10811661, rs7028570, rs7291467, rs16996148 and rs10401969) were reported as new findings exclusive to our study, the last two of the 16 SNPs, rs501120 and rs6922269, showed either intriguing or conflicting result. SNP rs17222814 in ALOX5AP and SNP rs3849150 in LRRC18 were consistently associated with atherosclerosis in both prior and the two PDAY association studies. SNP rs3849150 was also identified to be highly correlated with a non-synonymous coding SNP, rs17772611, which may damage the protein (polyphen score = 0.996), suggesting that SNP rs17772611 may be the causal functional variant.^ In conclusion, our study added more support for the association of these candidate genes with atherosclerosis. SNPs rs3849150 and rs17772611 of LRRC18, as well as SNP rs17222814 of ALOX5AP, were the most significant findings from our study, and may be ranked among the best for further study.^