Dextran sulfate modulates MAP kinase signaling and reduces endothelial injury in a rat aortic clamping model

OBJECTIVE: Mitogen-activated protein kinases (MAPKs), including JNK, p38, and ERK1/2, noticeably influence ischemia/reperfusion injury (IRI). The complement inhibitor dextran sulfate (DXS) associates with damaged endothelium denudated of its heparan sulfate proteoglycan (HSPG) layer. Other glycosaminoglycan analogs are known to influence MAPK signaling. Hypothetically therefore, targeted intravascular cytoprotection by DXS may function in part through influencing MAPK activation to reduce IRI-induced damage of the vasculature. METHODS: IRI of the infrarenal aorta of male Wistar rats was induced by 90 minutes clamping followed by 120 minutes reperfusion. DXS (5 mg/mL) or physiologic saline (NaCl controls) was infused locally into the ischemic aortic segment immediately prior to reperfusion. Ninety minutes ischemia-only and heparinase infusion (maximal damage) experiments, as well as native rat aorta, served as controls. Aortas were excised following termination of the experiments for further analysis. RESULTS: DXS significantly inhibited IRI-induced JNK and ERK1/2 activation (P = .043; P =.005) without influencing the p38 pathway (P =.110). Reduced aortic injury, with significant inhibition of apoptosis (P = .032 for DXS vs NaCl), correlated with decreased nuclear factor kappaB translocation within the aortic wall. DXS treatment clearly reduced C1q, C4b/c, C3b/c, and C9 complement deposition, whilst preserving endothelial cell integrity and reducing reperfusion-induced HSPG shedding. Protection was associated with binding of fluorescein labeled DXS to ischemically damaged tissue. CONCLUSIONS: Local application of DXS into ischemic vasculature immediately prior to reperfusion reduces complement deposition and preserves endothelial integrity, partially through modulating activation of MAPKs and may offer a new approach to tackle IRI in vascular surgical procedures. CLINICAL RELEVANCE: The purpose of the present study was to determine the role of dextran sulfate (DXS), a glycosaminoglycan analog and complement inhibitor, in modulating intracellular MAPK signaling pathways, reducing complement activation and ultimately attenuating ischemia/reperfusion injury (IRI) in a rat aortic-clamping model, in part a surrogate model to study the microvasculature. The study shows a role for DXS in ameliorating endothelial injury by reducing IRI-mediated damage and intravascular, local inflammation in the affected aortic segment. DXS may be envisaged as an endothelial protectant in vascular injury, such as occurs during vascular surgical procedures.

Increased splanchnic oxygen extraction because of routine nursing procedures

OBJECTIVE: Multiple organ failure is a common complication of acute circulatory and respiratory failure. We hypothesized that therapeutic interventions used routinely in intensive care can interfere with the perfusion of the gut and the liver, and thereby increase the risk of mismatch between oxygen supply and demand. DESIGN: Prospective, observational study. SETTING: Interdisciplinary intensive care unit (ICU) of a university hospital. PATIENTS: Thirty-six patients on mechanical ventilation with acute respiratory or circulatory failure or severe infection were included. INTERVENTIONS: Insertion of a hepatic venous catheter. MEASUREMENTS AND MAIN RESULTS: Daily nursing procedures were recorded. A decrease of >or=5% in hepatic venous oxygen saturation (Sho2) was considered relevant. Observation time was 64 (29-104) hours (median [interquartile range]). The ICU stay was 11 (8-15) days, and hospital mortality was 35%. The number of periods with procedures/patient was 170 (98-268), the number of procedure-related decreases in Sho2 was 29 (13-41), and the number of decreases in Sho2 unrelated to procedures was 9 (4-19). Accordingly, procedure-related Sho2 decreases occurred 11 (7-17) times per day. Median Sho2 decrease during the procedures was 7 (5-10)%, and median increase in the gradient between mixed and hepatic venous oxygen saturation was 6 (4-9)%. Procedures that caused most Sho2 decreases were airway suctioning, assessment of level of sedation, and changing patients' position. Sho2 decreases were associated with small but significant increases in heart rate and intravascular pressures. Maximal Sequential Organ Failure Assessment scores in the ICU correlated with the number of Sho2 decreases (r: .56; p < 0.001) and with the number of procedure-related Sho2 decreases (r: .60; p < 0.001). CONCLUSIONS: Patients are exposed to repeated episodes of impaired splanchnic perfusion during routine nursing procedures. More research is needed to examine the correlation, if any, between nursing procedures and hepatic venous desaturation.

Differences in coronary artery plaques between target and non-target vessels

We used intravascular ultrasound (IVUS) and virtual histology (VH) to assess the differences of plaque burden and composition between target coronary arteries containing the culprit lesion and non-target coronary arteries.

Everolimus dual effects of an area vasculosa angiogenesis and lymphangiogenesis

Recently approved as treatment for astrocytoma, kidney and pancreatic cancer, everolimus acts on tumor cells by inhibiting tumor cell growth and proliferation, as well as by inhibition of angiogenic activity by both direct effects on vascular cell proliferation and indirect effects on growth factor production. The effects of everolimus on early stages of normal vasculogenesis, angiogenesis and lymphangiogenesis are not yet available. We found increased development of intravascular pillars by using area vasculosa of the chick chorioallantoic membrane treated with everolimus. An active lymphangiogenic response was highlighted by the expression of Prospero homeobox protein 1 (Prox1) and podoplanin, together with vascular endothelial growth factor receptor C (Vegf-C) and vascular endothelial growth factor receptor 3 (Vegfr-3) expression on day 4 in the treated group. These findings suggest a potential role of everolimus in the activation of lymphangiogenesis.

Dynamics of vessel wall changes following the implantation of the Absorb everolimus-eluting bioresorbable vascular scaffold: a multi-imaging modality study at 6, 12, 24 and 36 months

Aims: To assess observations with multimodality imaging of the Absorb bioresorbable everolimus-eluting vascular scaffold performed in two consecutive cohorts of patients who were serially investigated either at 6 and 24 months or at 12 and 36 months. Methods and results: In the ABSORB multicentre single-arm trial, 45 patients (cohort B1) and 56 patients (cohort B2) underwent serial invasive imaging, specifically quantitative coronary angiography (QCA), intravascular ultrasound (IVUS), radiofrequency backscattering (IVUS-VH) and optical coherence tomography (OCT). Between one and three years, late luminal loss remained unchanged (6 months: 0.19 mm, 1 year: 0.27 mm, 2 years: 0.27 mm, 3 years: 0.29 mm) and the in-segment angiographic restenosis rate for the entire cohort B (n=101) at three years was 6%. On IVUS, mean lumen, scaffold, plaque and vessel area showed enlargement up to two years. Mean lumen and scaffold area remained stable between two and three years whereas significant reduction in plaque behind the struts occurred with a trend toward adaptive restrictive remodelling of EEM. Hyperechogenicity of the vessel wall, a surrogate of the bioresorption process, decreased from 23.1% to 10.4% with a reduction of radiofrequency backscattering for dense calcium and necrotic core. At three years, the count of strut cores detected on OCT increased significantly, probably reflecting the dismantling of the scaffold; 98% of struts were covered. In the entire cohort B (n=101), the three-year major adverse cardiac event rate was 10.0% without any scaffold thrombosis. Conclusions: The current investigation demonstrated the dynamics of vessel wall changes after implantation of a bioresorbable scaffold, resulting at three years in stable luminal dimensions, a low restenosis rate and a low clinical major adverse cardiac events rate.

The edge vascular response following implantation of the Absorb everolimus-eluting bioresorbable vascular scaffold and the XIENCE V metallic everolimus-eluting stent. First serial follow-up assessment at six months and two years: insights from the first-in-man ABSORB Cohort B and SPIRIT II trials

AIMS To assess serially the edge vascular response (EVR) of a bioresorbable vascular scaffold (BVS) compared to a metallic everolimus-eluting stent (EES). METHODS AND RESULTS Non-serial evaluations of the Absorb BVS at one year have previously demonstrated proximal edge constrictive remodelling and distal edge changes in plaque composition with increase of the percent fibro-fatty (FF) tissue component. The 5 mm proximal and distal segments adjacent to the implanted devices were investigated serially with intravascular ultrasound (IVUS), post procedure, at six months and at two years, from the ABSORB Cohort B1 (n=45) and the SPIRIT II (n=113) trials. Twenty-two proximal and twenty-four distal edge segments were available for analysis in the ABSORB Cohort B1 trial. In the SPIRIT II trial, thirty-three proximal and forty-six distal edge segments were analysed. At the 5-mm proximal edge, the vessels treated with an Absorb BVS from post procedure to two years demonstrated a lumen loss (LL) of 6.68% (-17.33; 2.08) (p=0.027) with a trend toward plaque area increase of 7.55% (-4.68; 27.11) (p=0.06). At the 5-mm distal edge no major changes were evident at either time point. At the 5-mm proximal edge the vessels treated with a XIENCE V EES from post procedure to two years did not show any signs of LL, only plaque area decrease of 6.90% (-17.86; 4.23) (p=0.035). At the distal edge no major changes were evident with regard to either lumen area or vessel remodelling at the same time point. CONCLUSIONS The IVUS-based serial evaluation of the EVR up to two years following implantation of a bioresorbable everolimus-eluting scaffold shows a statistically significant proximal edge LL; however, this finding did not seem to have any clinical implications in the serial assessment. The upcoming imaging follow-up of the Absorb BVS at three years is anticipated to provide further information regarding the vessel wall behaviour at the edges.

The Effect of Open-Irrigated Radiofrequency Catheter Ablation of Atrial Fibrillation on Left Atrial Pressure and B-Type Natriuretic Peptide

Background Open-irrigated radiofrequency catheter ablation (oiRFA) of atrial fibrillation (AF) imposes a volume load and risk of pulmonary edema. We sought to assess the effect of volume administration during ablation on left atrial (LA) pressure and B-type natriuretic peptide (BNP). Methods LA pressure was measured via transseptal sheath at the beginning and end of 44 LA ablation procedures in 42 patients. BNP plasma levels were measured before and after 10 procedures. Results A median of 3,255 (interquartile range [IQR], 2,014)-mL saline was administered during the procedure. During LA ablation, the median fluid balance was +1,438 (IQR, 1,109) mL and LA pressure increased by median 3.7 (IQR, 5.9) mm Hg (P < 0.001). LA pressure did not change in the 19 procedures with furosemide administration (median ΔP = −0.3 [IQR, 7.1] mm Hg, P = 0.334). The correlation of LA pressure and fluid balance was weak (rs = 0.383, P = 0.021). BNP decreased in all four procedures starting in AF or atrial tachycardia and then converting to sinus rhythm (P = 0.068), and increased in all six procedures starting and finishing in sinus rhythm (P = 0.028). After ablation, symptomatic volume overload responding to diuresis occurred in three patients. Conclusions A substantial intravascular volume load during oiRFA can be absorbed with little change in LA pressure, such that LA pressure is not a reliable indicator of the fluid balance. Subsequent redistribution of the volume load imposes a risk after the procedure. Conversion to sinus rhythm may improve ability to acutely accommodate the volume load.

Everolimus immunosuppression in de novo heart transplant recipients: What does the evidence tell us now?

The efficacy of everolimus with reduced cyclosporine in de novo heart transplant patients has been demonstrated convincingly in randomized studies. Moreover, everolimus-based immunosuppression in de novo heart transplant recipients has been shown in two randomized trials to reduce the increase in maximal intimal thickness based on intravascular ultrasound, indicating attenuation of cardiac allograft vasculopathy (CAV). Randomized trials of everolimus in de novo heart transplantation have also consistently shown reduced cytomegalovirus infection versus antimetabolite therapy. In maintenance heart transplantation, conversion from calcineurin inhibitors to everolimus has demonstrated a sustained improvement in renal function. In de novo patients, a renal benefit may only be achieved if there is an adequate reduction in exposure to calcineurin inhibitor therapy. Delayed introduction of everolimus may be appropriate in patients at high risk of wound healing complications, e.g. diabetic patients or patients with ventricular assist device. The current evidence base suggests that the most convincing reasons for use of everolimus from the time of heart transplantation are to slow the progression of CAV and to lower the risk of cytomegalovirus infection. A regimen of everolimus with reduced-exposure calcineurin inhibitor and steroids in de novo heart transplant patients represents a welcome addition to the therapeutic armamentarium.

Quantitative myocardial contrast echocardiography: a new method for the non-invasive detection of chronic heart transplant rejection

Chronic heart transplant rejection, i.e. cardiac allograft vasculopathy (CAV) is a major adverse prognostic factor after heart transplantation (HTx). This study tested the hypothesis that the relative myocardial blood volume (rBV) as quantified by myocardial contrast echocardiography accurately detects severe CAV as defined by coronary intravascular ultrasound (IVUS).

Natural history of optical coherence tomography-detected non-flow-limiting edge dissections following drug-eluting stent implantation

Aims: Angiographic evidence of edge dissections has been associated with a risk of early stent thrombosis. Optical coherence tomography (OCT) is a high-resolution technology detecting a greater number of edge dissections -particularly non-flow-limiting- compared to angiography. Their natural history and clinical implications remain unclear. The objectives of the present study were to assess the morphology, healing response, and clinical outcomes of OCT-detected edge dissections using serial OCT imaging at baseline and at one year following drug-eluting stent (DES) implantation. Methods and results: Edge dissections were defined as disruptions of the luminal surface in the 5 mm segments proximal and distal to the stent, and categorised as flaps, cavities, double-lumen dissections or fissures. Qualitative and quantitative OCT analyses were performed every 0.5 mm at baseline and one year, and clinical outcomes were assessed. Sixty-three lesions (57 patients) were studied with OCT at baseline and one-year follow-up. Twenty-two non-flow-limiting edge dissections in 21 lesions (20 patients) were identified by OCT; only two (9%) were angiographically visible. Flaps were found in 96% of cases. The median longitudinal dissection length was 2.9 mm (interquartile range [IQR] 1.6-4.2 mm), whereas the circumferential and axial extensions amounted to 1.2 mm (IQR: 0.9-1.7 mm) and 0.6 mm (IQR: 0.4-0.7 mm), respectively. Dissections extended into the media and adventitia in seven (33%) and four (20%) cases, respectively. Eighteen (82%) OCT-detected edge dissections were also evaluated with intravascular ultrasound which identified nine (50%) of these OCT-detected dissections. No stent thrombosis or target lesion revascularisation occurred up to one year. At follow-up, 20 (90%) edge dissections were completely healed on OCT. The two cases exhibiting persistent dissection had the longest flaps (2.81 mm and 2.42 mm) at baseline. Conclusions: OCT-detected edge dissections which are angiographically silent in the majority of cases are not associated with acute stent thrombosis or restenosis up to one-year follow-up.

Ultrasound-assessed non-culprit and culprit coronary vessels differ by age and gender

AIM To investigate age- and gender-related differences in non-culprit versus culprit coronary vessels assessed with virtual histology intravascular ultrasound (VH-IVUS). METHODS In 390 patients referred for coronary angiography to a single center (Luzerner Kantonsspital, Switzerland) between May 2007 and January 2011, 691 proximal vessel segments in left anterior descending, circumflex and/or right coronary arteries were imaged by VH-IVUS. Plaque burden and plaque composition (fibrous, fibro-fatty, necrotic core and dense calcium volumes) were analyzed in 3 age tertiles, according to gender and separated for vessels containing non-culprit or culprit lesions. To classify as vessel containing a culprit lesion, the patient had to present with an acute coronary syndrome, and the VH-IVUS had to be performed in a vessel segment containing the culprit lesion according to conventional coronary angiography. RESULTS In non-culprit vessels the plaque burden increased significantly with aging (in men from 37% ± 12% in the lowest to 46% ± 10% in the highest age tertile, P < 0.001; in women from 30% ± 9% to 40% ± 11%, P < 0.001); men had higher plaque burden than women at any age (P < 0.001 for each of the 3 age tertiles). In culprit vessels of the lowest age tertile, plaque burden was significantly higher than that in non-culprit vessels (in men 48% ± 6%, P < 0.001 as compared to non-culprit vessels; in women 44% ± 18%, P = 0.004 as compared to non-culprit vessels). Plaque burden of culprit vessels did not significantly change during aging (plaque burden in men of the highest age tertile 51% ± 9%, P = 0.523 as compared to lowest age tertile; in women of the highest age tertile 49% ± 8%, P = 0.449 as compared to lowest age tertile). In men, plaque morphology of culprit vessels became increasingly rupture-prone during aging (increasing percentages of necrotic core and dense calcium), whereas plaque morphology in non-culprit vessels was less rupture-prone and remained constant during aging. In women, necrotic core in non-culprit vessels was very low at young age, but increased during aging resulting in a plaque morphology that was very similar to men. Plaque morphology in culprit vessels of young women and men was similar. CONCLUSION This study provides evidence that age- and gender-related differences in plaque burden and plaque composition significantly depend on whether the vessel contained a non-culprit or culprit lesion.

High Resolution Vascular Imaging of the Rat Spine using Liposomal Blood Pool MR Agent

High resolution, vascular magnetic resonance imaging of the spine region in small animals poses several challenges. The small anatomical features, extravascular diffusion, and the low signal-to-noise ratio limit the use of conventional contrast agents. We hypothesize that a long circulating, intravascular liposomal-encapsulated MR contrast agent (liposomal-Gd) would facilitate visualization of small anatomical features of the perispinal vasculature not visible with conventional contrast agent (Gd-DTPA).

High-resolution vascular imaging of the rat spine using liposomal blood pool MR agent.

BACKGROUND AND PURPOSE: High-resolution, vascular MR imaging of the spine region in small animals poses several challenges. The small anatomic features, extravascular diffusion, and low signal-to-noise ratio limit the use of conventional contrast agents. We hypothesize that a long-circulating, intravascular liposomal-encapsulated MR contrast agent (liposomal-Gd) would facilitate visualization of small anatomic features of the perispinal vasculature not visible with conventional contrast agent (gadolinium-diethylene-triaminepentaacetic acid [Gd-DTPA]). METHODS: In this study, high-resolution MR angiography of the spine region was performed in a rat model using a liposomal-Gd, which is known to remain within the blood pool for an extended period. The imaging characteristics of this agent were compared with those of a conventional contrast agent, Gd-DTPA. RESULTS: The liposomal-Gd enabled acquisition of high quality angiograms with high signal-to-noise ratio. Several important vascular features, such as radicular arteries, posterior spinal vein, and epidural venous plexus were visualized in the angiograms obtained with the liposomal agent. The MR angiograms obtained with conventional Gd-DTPA did not demonstrate these vessels clearly because of marked extravascular soft-tissue enhancement that obscured the vasculature. CONCLUSIONS: This study demonstrates the potential benefit of long-circulating liposomal-Gd as a MR contrast agent for high-resolution vascular imaging applications.

Congenital thrombotic thrombocytopenic purpura caused by new compound heterozygous mutations of the ADAMTS13 gene

Upshaw-Schulman syndrome (USS) is due to severe congenital deficiency of von Willebrand factor (VWF)-cleaving protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 domains, nr 13) activity resulting in the presence of unusually large forms of VWF in the circulation, causing intravascular platelet clumping and thrombotic microangiopathy. Our patient, a 26-year-old man, had attacks of thrombotic thrombocytopenic purpura (TTP) with thrombocytopenia and a urine dipstick positive for hemoglobin (4+), often as the only sign of hemolytic activity. He had ADAMTS13 activity of <1% of normal plasma without the presence of inhibitors of ADAMTS13. ADAMTS13 deficiency was caused by two new mutations of the ADAMTS13 gene: a deletion of a single nucleotide in exon17 (c. 2042 delA) leading to a frameshift (K681C fs X16), and a missense mutation in exon 25 (c.3368G>A) leading to p.R1123H. This case report confirms the importance of the analysis of the ADAMTS13 activity and its inhibitor in patients who have episodes of TTP, with a very low platelet count and sometimes without the classic biochemical signs of hemolysis.

Septic mucormycosis in acute t-cell leucemia – pathogen detection in skin lesions

We report on a 43-year old patient with an acute T-Cell Leucemia, currently in Aplasia after Chemotherapy, showing five targetoid bluish skin lesions. Due to a three weeks history of septic symptoms he was under treatment with antibiotics and antifungals. Multiple septic foci were localized (N. caudatus, liver, kidneys, lung, spine and right psoas). Microbiology analyses of various blood cultures and of the aspirate of the psoas abscess showed initially negative results. Clinically the skin lesions were suspected to be of septic or thrombogenic origin. A 5 mm punch biopsy was performed and separated for microbiological diagnostic and conventional histology. Surprisingly large fungal agents in mostly intravascular distribution were seen histologically and identified as Lichtheimia corymbifera (syn. Absidia corymbifera) by PCR. Cultures remained negative. The patient died on the following day. Lichtheimia corymbifera is a fungus belonging to the family of mucormycosis. Aspergillosis and mucormycosis are the most common mold infections in patients with hematological malignancies, clinically often indistinguishable. However, the true incidence of mucormycosis is not known and probably underestimated because of difficulties in diagnosis. Mucormycosis typically causes acute, aggressive, and frequently angioinvasive infections presenting with solitary local skin necrosis. The fact that the pathogenic fungus was isolated from a very discrete skin lesion but was not detected in blood cultures, and only later in the PCR of the aspirate of the psoas abscess, makes this case exceptional.