bluuebunny/crossref_metadata_2025 huggingface dataset:
E-013 Endovascular Management of Pseudoaneurysms Secondary to External Ventricular Drain Placement: Single Center Experience
Authors: Choudhri O , Gupta M , Heit J , Feroze A , Do H
Published: July 2014

Introduction

Placement of external ventricular drains is a common, life-saving neurosurgical procedure indicated across a variety of settings. While advances have made the procedure quite safe, the potential for iatrogenic morbidity and mortality continues. Herein, we document our experience with the endovascular management of three pseudoaneurysms associated with EVD placement.

Patients and methods

We performed a retrospective analysis to identify all EVDs placed from 2008 through 2013 at our institution,. In instances of EVD-associated cerebrovascular injury, all admission and subsequent radiographic studies were reviewed, including cerebral angiograms and computed tomography (CT) scans. Angiograms were reviewed to record the extent of vascular injury and angiographic outcomes after treatment.

Results

One female and two male patients (40–75 years) were found to have developed vascular injuries associated with EVD placement. Three pseudoaneurysms, namely of the posterior communicating artery (PCOM), pericallosal artery branch and the middle meningeal artery, were treated by coil and/or glue embolization.

Conclusions

Although EVD-associated cerebrovascular injury remains a rare phenomenon, such procedures are not entirely benign. Endovascular repair for such lesions proves a viable, effective option.

Abbreviations

arteriovenous fistula (AVF), computed tomography (CT), external ventricular drain (EVD), posterior communicating artery (PCOM), posterior cerebral artery (PCA)

Disclosures

O. Choudhri: None. M. Gupta: None. J. Heit: None. A. Feroze: None. H. Do: None.
E-014 Changes in Posterior Circulation Arterial Flows after Revascularization Surgery in Moyamoya Disease: A Quantitative MRI Study
Authors: Navarro R , Feroze A , Choudhri O , Lober R , Khan N , Steinberg G
Published: July 2014

Background and purpose

Moyamoya disease and syndrome are well known to affect the anterior cerebral circulation by progressive steno-occlusive disease of the supraclinoid internal carotid arteries. Less attention has been paid to changes in posterior arterial circulation hemodynamics in this condition. We sought to better understand the latter using a relatively novel noninvasive imaging technique, quantitative magnetic resonance angiography (qMRA). We assessed the diagnostic utility of qMRA for posterior arterial circulation flows before and after surgical revascularization.

Materials and methods

This retrospective review included patients who met the following inclusion criteria: (1) diagnosis of moyamoya disease or syndrome with revascularization surgery at Stanford University between September 2008 and March 2012; (2) preoperative and postoperative qMRA scans on record within a two-year time frame; and (3) high-quality qMRA images without motion artefact. Cerebral blood-vessel flow was quantified after non-contrast magnetic resonance imaging (MRI) through the use of a commercially available software tool, non-invasive optimal vessel analysis (NOVA, VasSol, Chicago, USA).

Results

A total of 191 patients underwent 281 surgeries during this period of time. Of these, a cohort of 64 patients (78% female, mean age 38.5 years, 55% unilateral disease) had pre- and post-operative qMRA studies. Preoperative arterial flows in the posterior circulation were markedly elevated compared to normal controls. These flows significantly decreased after revascularization (94% direct STA–MCA bypass) with right PCA flow 145 mL/min pre-surgery vs. 123 mL/min post-surgery (p = 0.005, n = 51) and basilar artery flow 264 mL/min pre-surgery vs. 222 mL/min post-surgery (p < 0.001, n = 58). A notable decrease in flow rates was also appreciated within the left PCA distribution, albeit not to a statistically significant degree (p = 0.121, n = 53). No statistically significant changes were noted in posterior communicating artery flows.

Conclusions

Quantitative MRA shows that posterior circulation arterial flows are markedly increased in patients with moyamoya disease. After revascularization, there is an overall decrease in these flows that is significant in the basilar artery and right posterior cerebral artery. Further use of qMRA might be warranted to better understand moyamoya hemodynamics before and after surgery.

Abbreviations

MMD = moyamoya disease NOVA = noninvasive optimal vessel analysis; qMRA = quantitative magnetic resonance angiography

Keywords

moyamoya disease, quantitative magnetic resonance angiography, cerebral blood flow

Disclosures

R. Navarro: None. A. Feroze: None. O. Choudhri: None. R. Lober: None. N. Khan: None. G. Steinberg: None.
E-017 Cerebrovascular Decision Making: Professional and Personal Preferences
Authors: Tanweer O , Wilson T , Kalhorn S , Golfinos J , Huang P , Kondziolka D
Published: July 2014

Introduction

It is known that physicians sometimes recommend treatment that, in a similar clinical scenario, they might not choose for themselves. We sought to understand this dynamic across cerebrovascular practice and examine how neurosurgeons value the procedures they offer.

Methods

We conducted an online survey sent to a large cohort of neurosurgeons in May 2013. Respondents were randomised to answer either as the surgeon or as the patient. The questions involved patients presenting with 1) an epidural hematoma (control), 2) un-ruptured anterior communicating artery aneurysm, 3) incidentally found right temporal AVM, 4) spontaneous intracranial and intraventricular haemorrhage in deep structure. Data on practice parameters and experience levels was also collected.

Results

We obtained 534 survey responses, 279 responding as the “neurosurgeon”, and 255 as the “patient,” with a response rate of 19.7%. Demographics amongst the two groups of survey takers was similar. There was no difference in the management of an epidural hematoma, as expected. For the unruptured aneurysm, the rates of opting for treatment was similar amongst respondees. However within the treatment group there was a trend for survey takers to more often chose coiling for themselves and clipping for patients (p = 0.056). Surgeons, however, with a greater than 30% open-cerebrovascular practice had less of a tendency to do so. For arteriovenous malformation management, there was no statistical difference between choosing treatment or conservative management. However, amongst the respondees who chose treatment, more respondees chose resection/embolization for their patient but radiosurgery for self (p = 0.001). In a case of a large spontaneous intracranial and intraventricular haemorrhage neurosurgeons were more likely to place a ventricular drain in a patient than himself or herself. Neurosurgeons in practice more than 10 years since residency were more likely to recommend against interventions for aneurysms, AVMs or intracranial haemorrhage.

Conclusions

In the majority of cases altering the role of the surgeon did not change the decision to pursue treatment or conservative treatment. In certain clinical scenarios, however, neurosurgeons choose treatment options for themselves that are different than what they would choose for their patients. For the management of an arteriovenous malformations, intracranial aneurysms, and hypertensive haemorrhage, responses favored less invasive interventions when the surgeon was the patient. These findings are likely a result of cognitive biases, previous training, experience, areas of expertise, and personal values.

Disclosures

O. Tanweer: None. T. Wilson: None. S. Kalhorn: None. J. Golfinos: None. P. Huang: None. D. Kondziolka: None.
E-018 Flow-Diversion for Complex Middle Cerebral Artery Aneurysms
Authors: Zanaty M , Chalouhi N , Tjoumakaris S , Gonzalez L , Rosenwasser R , Jabbour P
Published: July 2014

Objective

To evaluate the safety and efficacy of flow-diversion for treatment of large and complex middle cerebral artery (MCA) aneurysms

Method

We conducted a retrospective review of the clinical charts of all patients who underwent PED placement for aneurysm at our institution from October 2010 to October 2013. We included 10 patients of which 5 had large MCA aneurysms and 3 had giant ones. Fusiform unruptured aneurysms represented 7 of all 10 aneurysm. Angiographic and clinical follow-up were available for all patients mostly between 7 and 12 months.

Results

We had no technical complications, no periprocedural morbidity and mortality. On follow-up we had no hemorrhagic complication, no aneurysm rupture and only one clinically significant thromboembolic event in a patient who discontinued antiplatelet therapy against medical advice. One patient had completely occluded his diseased vessel but remained asymptomatic. The overall complication rate is 3/10. On follow-up complete occlusion occurred in 7 patients (7/9).

Conclusion

PED treatment for large, giant and bifurcation MCA aneurysms was feasible, with satisfying complete-occlusion rate, no mortality and reasonable morbidity rate.

Disclosures

M. Zanaty: None. N. Chalouhi: None. S. Tjoumakaris: None. L. Gonzalez: None. R. Rosenwasser: None. P. Jabbour: None.
E-019 Flow Diversion in the Setting of Subarachnoid Haemorrhage
Authors: Chalouhi N , Zanaty M , Hasan D , Tjoumarkis S , Rosenwasser R , Jabbour P
Published: July 2014

Objective

Flow diverters are increasingly used for treatment of intracranial aneurysms. In previous series, the Pipeline Embolization Device (PED) was used essentially for the treatment of unruptured aneurysms. Little is known about the use of the PED in ruptured aneurysms. We assess the safety and efficacy of the PED in the largest series of acutely ruptured aneurysms to date.

Methods

A total of 20 patients with freshly ruptured aneurysms were treated with the PED between May 2011 and September 2013. Patients were loaded with aspirin and clopidogrel 8 h before the procedure. Platelet function was closely monitored throughout hospitalization using P2Y12 assays. Data on procedural safety was prospectively collected.

Results

Mean aneurysm size was 6.6 mm. Fifteen aneurysms (75%) arose from the anterior circulation. The number of PEDs used was 1.0 per aneurysm. Treatment was staged (initial coiling followed by coiling 1–2 weeks later) in 4 patients (20%). Adjunctive coiling was used in 6 cases (30%). There was only 1 complication (5%) in the series; this was a fatal intraoperative aneurysm dome rupture that occurred during adjunctive coil deployment. At the latest follow-up (mean, 6.1 months), all but one aneurysm were completely occluded. No aneurysm required further treatment. All except one patient (95%) achieved a favorable outcome (mRS 0–2).

Conclusion

In this study, treatment of ruptured aneurysms with the PED was associated with low complication rates, high aneurysm occlusion rates, and excellent clinical outcomes. These findings suggest that the PED is a safe and effective alternative for ruptured aneurysms non amenable to conventional endovascular techniques or surgical clipping. A staged approach that entails initial aneurysm coiling followed by coiling 1–2 weeks later appears to be an adequate strategy in this setting.

Disclosures

N. Chalouhi: None. M. Zanaty: None. D. Hasan: None. S. Tjoumarkis: None. R. Rosenwasser: None. P. Jabbour: None.
E-022 Outcomes of Aneurysms Embolised with Coils which were Candidates for the Pipeline Flow Diversion Device
Authors: Crimmins M , Banihashemi A , Gobin P
Published: July 2014

Introduction

We assessed the outcome of aneurysms which were eligible for treatment using flow diversion device which were treated with detachable coils prior to the adoption of Pipeline.

Methods

Data was obtained from a retrospective database of endovascularly Cases were sorted into two groups for this study. Group one consisted of aneurysm with a dome ≥10 mm, aneurysm neck ≥ 4 mm, located in the internal carotid artery and its branches (such as the posterior communicating, anterior choroidal, superior hypophyseal, and ophthalmic arteries), in line with criteria set by the FDA for Pipeline utilization. Group two included cases beyond the FDA indication but within institutionally accepted usage criteria (aneurysms of any size located on the side wall of the branches of the carotid artery or middle cerebral (M1), basilar, vertebral and posterior cerebral artery, with an aneurysm neck ≥3 mm or a dome-to-neck-ratio < 1.5, no limits were placed on dome size). Exclusion for either group was a history of aneurysm rupture or previous neurosurgical procedures.

Results

Only 50% of the FDA group could be completely embolised with 27% requiring retreatment. 53% of institutional criteria patients were completely embolised with an 8.7% retreatment rate. Characteristics of the patients and aneurysms with the outcome of the procedure, both immediate and longer term outcome will be presented. The time from initial endovascular operation to re-treatment by endovascular means at our institution in the 12 cases requiring re-treatment was 12.4 ± 14.0 months.

Conclusion

Cases that met FDA criteria were significantly more likely to require recoiling than institutional criteria. Aneurysms that meet FDA or institutional criteria for a flow diverting stent are difficult to treat, often incompletely embolised with coiling alone and often need more than one embolization procedure. We present our experience with coil embolization in aneurysms that could have been treated with Pipeline flow diverter.

Disclosures

M. Crimmins: None. A. Banihashemi: None. P. Gobin: None.
E-026 Time and Pressure - Possible Reasons Behind Worse Outcomes For GETA Patients Undergoing Stroke Interventions
Authors: Rai A , Boo S , Domico J , Roberts T , Carpenter J
Published: July 2014

Background

Several publications have shown poor outcomes for GETA patients undergoing endovascular stroke interventions. Our goal was to examine the factors directly related to GETA that may impact procedural outcomes. Our hypothesis being that GETA patients are sicker, the procedure may take longer and there may be fluctuations in blood pressure.

Methodology

An IRB approved retrospective analysis was performed on patients that had undergone stroke interventions over the last 5-years and for whom anesthesia records were available. Blood pressure parameters and time intervals were recorded at multiple steps during a patient’s progress from the ER to the ICU. Patient demographic information and comorbidities were also recorded, as was 90-day clinical outcome.

Results

Out of 190 patients, GETA was administered in 108(56.8%) and non-GETA in 82(43.2%) patients. The mean age was 67.9(±16.2) years in the GETA and 67.1(±17) years in the non-GETA-group (p = 0.7). The mean NIHSS was 18.9(±8.7) in the GETA versus 13.4(6.8) in the non-GETA-group (p < 0.0001). Of the non-GETA group, 34(41.5%) patients were done under conscious sedation (CS) and 48(58.5%) under MAC. A favorable clinical outcome (mRS 0-2) was seen in 35.5% of the GETA-group versus 54.5% of the non-GETA-group (OR 0.4 95%CI: 0.25–0.83, p = 0.01). Mortality was observed in 40.2% of the GETA versus 21.5% of the non-GETA-group (OR 0.4 95%CI: 0.2–0.8, p = 0.006). The recanalization rate was not different across the groups. The intra-procedural pressure fluctuation defined as the difference between the maximum and minimum SBP was 60(±30) points in GETA and 47(±27) points in non-GETA-group (p = 0.02). For the GETA-group, the ΔSBP pre and post-induction was 11.5(±21) points for favorable and 20(±23) points for poor outcomes (p = 0.07). The time to groin puncture from angiography lab arrival time was significantly shorter, 36(±25) minutes in the non-GETA-group versus 53(±32) minutes in the GETA-group (p = 0.0006).

Conclusion

GETA was associated with worse outcomes and higher mortality, however, GETA patients had also presented with worse deficits and by itself was not an independent predictor of outcome when NIHSS, age and recanalization were taken into account. A significantly higher BP fluctuation was seen in GETA versus non-GETA groups and a higher difference in pre and post-induction SBP portended a poor outcome amongst the GETA-group. Lastly the interval between arrival and groin puncture was significantly longer in GETA patients. At times GETA may be a necessity in sick patients, however, by strictly controlling BP and introducing measures to reduce delay in procedure start time (such as invasive BP monitoring through the femoral sheath), the “adverse” effect of GETA may be countered in endovascular stroke interventions.

Disclosures

A. Rai: 2; C; Stryker Neurovascular, Codman Neuro. S. Boo: None. J. Domico: None. T. Roberts: None. J. Carpenter: None.
E-029 WEB Flow Disruption: Preliminary Results from WEBCAST trial
Authors: Pierot L , Spelle L , Costalat V , Szikora I , Klisch J , Herbreteau D , Holtmannspoetter M , Weber W , Liebig T , Cognard C , Bonafé A , Moret J , Byrne J , Molyneux A
Published: July 2014

Background and purpose

WEBCAST is a European study dedicated to the evaluation of the feasibility, safety, and efficacy of endovascular treatment with WEB of intracranial aneurysms.

Materials and methods

The study was conducted in 10 European centers. Inclusion criteria were aneurysms located at internal carotid artery bifurcation, middle cerebral artery, basilar artery, and anterior communicating artery with a neck ≥4 mm and a dome to neck ratio ≥ 1. Recanalized aneurysms were not included. Complications and safety data were independently evaluated. Aneurysm occlusion was evaluated at 6 months with DSA by an independent core lab. Aneurysm occlusion was evaluated stable at 6 months in case of complete occlusion, no modification or improvement of the occlusion (versus post-operative occlusion), and no retreatment was performed or foreseen.

Results

Fifty-one patients (36 females and 15 males) with 51 aneurysms were included between December 2011 and February 2014. Age was between 33 and 75 years (55.6 ± 1.5 years). Forty-eight aneurysms were unruptured and 3 ruptured. Aneurysm location was middle cerebral artery (28 aneurysms), basilar artery (12 aneurysms) internal carotid artery (6 aneurysms), and anterior communicating (5 aneurysms).

The feasibility, safety, and efficacy of the treatment is analyzed.

Conclusion

WEBCAST is the first prospective, multicenter trial evaluating the treatment of intracranial aneurysms with WEB Aneurysm Embolization System. Preliminary results are presented.

Disclosures

L. Pierot: 2; C; Sequent. L. Spelle: None. V. Costalat: None. I. Szikora: None. J. Klisch: None. D. Herbreteau: None. M. Holtmannspoetter: None. W. Weber: None. T. Liebig: None. C. Cognard: None. A. Bonafé: None. J. Moret: None. J. Byrne: None. A. Molyneux: None.
E-030 Endovascular Treatment with Flow Diverter of Recanalized and Multitreated Aneurysms Initially Treated by Endovascular Approach
Authors: Pierot L , Benaissa A , Januel A , Herbreteau D , Berge J , Aggour M , Cognard C
Published: July 2014

Background and purpose

To evaluate the feasibility, safety, and efficacy of endovascular treatment with flow diverters (FD) in patients with recanalised and multitreated aneurysms, in a retrospective, multicenter, single-arm study.

Materials and methods

The study included 29 patients with 29 recanalised aneurysms who were treated by FDs (Silk or Pipeline device). Per and post procedural complications and morbidity and mortality rates were evaluated. Additionally, functional outcomes (mRS) at 1 month (short-term) and 3–4 months (mid-term) were compared with pre-operative mRS (before the procedure). Mid-term angiographic follow-up was performed assessing aneurismal occlusion by a 3-grades scale (complete occlusion, neck remnant, aneurysm remnant).

Results

FD placement was achieved in all the patients. Two misdeployments of the FD necessitated balloon dilatation in two patients associated with stent delivery in one patient. Permanent morbidity related to treatment was 6.9% (2/29), transient morbidity was 10.3% (3/29) and mortality due to treatment was 0.0% (0/29). One patient died from a myocardial infarct four weeks after the procedure. 25/29 (86.2%) patients had final good functional outcome, 26/29 (89.7%) patients had unchanged functional outcome, whereas 2/29 (6.9%) patients had clinical worsening. Angiographic follow-up showed complete occlusion in 17/28 patients (60.7%), neck remnants in 6/28 patients (21.4%) and residual aneurysms in 5/28 subjects (17.9%).

Conclusion

Flow diverter placement is feasible and safe in patients with recanalised and multitreated aneurysms. The procedure is associated with a high percentage of good functional outcomes as well as good anatomical results at mid-term (82.1%).

Disclosures

L. Pierot: 2; C; Covidien, Microvention, Stryker. A. Benaissa: None. A. Januel: None. D. Herbreteau: None. J. Berge: None. M. Aggour: None. C. Cognard: None.
Numerical simulations of a light nonaqueous phase liquid (LNAPL) movement in variably saturated soils with capillary hysteresis
Authors: Pasha Amin Y. , Hu Liming , Meegoda Jay N.
Published: July 2014

The fate and transport of pollutants in the subsurface is usually predicted using numerical simulations. Comparisons of the simulation results with experimental data are required to validate the numerical codes. In this paper, the nonaqueous phase liquid (NAPL) simulator code was used to numerically simulate two centrifugal light nonaqueous phase liquid (LNAPL) transport experiments. The numerical predictions were compared with the centrifugal test results and the impact of capillary hysteresis was evaluated. It was concluded that the simulation with the nonhysteretic model slightly underestimated the LNAPL volume retained in the vadose zone, and the average error of the predicted LNAPL saturation in the vadose zone and along the plume centerline was approximately 5% to 10%. The application of capillary hysteresis for the numerical simulation of the second centrifuge test has eliminated this error. In addition, accounting for hysteresis in the numerical simulation of the second centrifuge test has considerably improved the predicted results with respect to the size of the lens-shaped plume within the capillary fringe. However, there were inconsistencies between the numerical and experimental results, especially with respect to the time for the LNAPL to reach the groundwater level. This was found to be due to overestimation of the simulated downward infiltration of the LNAPL in the capillary fringe. It was found that the pore-connectivity parameter with a value of 0.66 for the relative permeability–saturation model produced the best comparison with experimental results.
Efficiency of a faulted regional top seal, Lakes Entrance Formation, Gippsland Basin, SE Australia
Authors: Çiftçi N. Bozkurt , Langhi Laurent , Strand Julian , Divko Louise Goldie
Published: July 2014

Future geological CO
2
sequestration in the Gippsland Basin is contingent upon an effective regional top seal; potentially provided by the late Oligocene–early Miocene Lakes Entrance Formation. This study integrates various top-seal assessment methodologies into a workflow to estimate the efficiency of the Lakes Entrance Formation as a top seal. Factors related to, for example, top-seal lithology, shale volume, carbonate content and fracture density, and factors relating to the faults that cut the top seal, fault-zone shale content, strain, slip-tendency, etc., are compared to hydrocarbon leakage and seepage indicators reported in the study area. The factors that best correlate with reported leakage indicators are combined to map the spatial risk variation.

While the study indicated that the ultimate control on top-seal efficiency is the formation’s membrane seal capacity; it also highlighted the spatial correlation between leakage indicators and some fault-related factors, suggesting that faults are key to top-seal bypass in much of the Gippsland Basin. Fault-zone shale content proved the dominant fault-related factor; as such, it can be concluded in the Gippsland Basin, at least, that a fault-zone shale content of less than 0.3 is the dominant factor with regard to faults enabling fluids to bypass top seals.
Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection
Authors: See Hoe Louise E. , Schilling Jan M. , Tarbit Emiri , Kiessling Can J. , Busija Anna R. , Niesman Ingrid R. , Du Toit Eugene , Ashton Kevin J. , Roth David M. , Headrick John P. , Patel Hemal H. , Peart Jason N.
Published: July 2014

Cholesterol-rich caveolar microdomains and associated caveolins influence sarcolemmal ion channel and receptor function and protective stress signaling. However, the importance of membrane cholesterol content to cardiovascular function and myocardial responses to ischemia-reperfusion (I/R) and cardioprotective stimuli are unclear. We assessed the effects of graded cholesterol depletion with methyl-β-cyclodextrin (MβCD) and lifelong knockout (KO) or overexpression (OE) of caveolin-3 (Cav-3) on cardiac function, I/R tolerance, and opioid receptor (OR)-mediated protection. Langendorff-perfused hearts from young male C57Bl/6 mice were untreated or treated with 0.02–1.0 mM MβCD for 25 min to deplete membrane cholesterol and disrupt caveolae. Hearts were subjected to 25-min ischemia/45-min reperfusion, and the cardioprotective effects of morphine applied either acutely or chronically [sustained ligand-activated preconditioning (SLP)] were assessed. MβCD concentration dependently reduced normoxic contractile function and postischemic outcomes in association with graded (10–30%) reductions in sarcolemmal cholesterol. Cardioprotection with acute morphine was abolished with ≥20 μM MβCD, whereas SLP was more robust and only inhibited with ≥200 μM MβCD. Deletion of Cav-3 also reduced, whereas Cav-3 OE improved, myocardial I/R tolerance. Protection via SLP remained equally effective in Cav-3 KO mice and was additive with innate protection arising with Cav-3 OE. These data reveal the membrane cholesterol dependence of normoxic myocardial and coronary function, I/R tolerance, and OR-mediated cardioprotection in murine hearts (all declining with cholesterol depletion). In contrast, baseline function appears insensitive to Cav-3, whereas cardiac I/R tolerance parallels Cav-3 expression. Novel SLP appears unique, being less sensitive to cholesterol depletion than acute OR protection and arising independently of Cav-3 expression.
Repeated daily dosing with sildenafil provides sustained protection from endothelial dysfunction caused by ischemia and reperfusion: a human in vivo study
Authors: McLaughlin Kelsey , Lytvyn Yuliya , Luca Mary Clare , Liuni Andrew , Gori Tommaso , Parker John D.
Published: July 2014

Sildenafil and nitroglycerin (GTN) are effective pharmacological preconditioning agents, protecting from the adverse effects of ischemia and reperfusion (I/R). The objective of the present study was to determine whether repeated, daily administration of sildenafil or GTN provides sustained preconditioning from I/R in the human forearm vasculature. Thirty-six healthy volunteers participated in this investigator-blind, randomized, placebo-controlled trial. Subjects received transdermal GTN (0.6 mg/h, 2 h/day), sildenafil (50 mg once daily), or placebo. Twenty-four hours after the first dose of medication, subjects underwent an assessment of flow-mediated dilation (FMD) before and after I/R (15 min of upper arm ischemia followed by 15 min of reperfusion). Subjects continued their study medication for 7 days, at which point FMD measurements were repeated before and after I/R. Venous blood samples were obtained for the determination of myeloperoxidase, P-selectin, and myoglobin before and after each I/R episode. Twenty-four hours after the first dose, both sildenafil and GTN (but not placebo) provided protection from the adverse effects of I/R. After 7 days of repeated daily doses and 24 h after the last dose, FMD was significantly blunted after I/R in placebo- and GTN-treated groups. In contrast, repeated daily administration of sildenafil provided continued protection from the adverse effects of I/R on endothelial function. There was no significant change in plasma levels of myeloperoxidase, P-selectin, or myoglobin at any time point. In conclusion, the present study establishes, for the first time in humans, that sildenafil, but not GTN, provides sustained pharmacological preconditioning of the endothelium and protection from adverse I/R effects on vascular function.
Severe hemorrhage attenuates cardiopulmonary chemoreflex control of regional sympathetic outputs via NTS adenosine receptors
Authors: Minic Zeljka , Li Cailian , O'Leary Donal S. , Scislo Tadeusz J.
Published: July 2014

Selective stimulation of inhibitory A1 and facilitatory A2a adenosine receptor subtypes located in the nucleus of the solitary tract (NTS) powerfully inhibits cardiopulmonary chemoreflex (CCR) control of regional sympathetic outputs via different mechanisms: direct inhibition of glutamate release and facilitation of an inhibitory neurotransmitter release, respectively. However, it remains unknown whether adenosine naturally released into the NTS has similar inhibitory effects on the CCR as the exogenous agonists do. Our previous study showed that adenosine is released into the NTS during severe hemorrhage and contributes to reciprocal changes of renal (decreases) and adrenal (increases) sympathetic nerve activity observed in this setting. Both A1 and A2a adenosine receptors are involved. Therefore, we tested the hypothesis that, during severe hemorrhage, CCR control of the two sympathetic outputs is attenuated by adenosine naturally released into the NTS. We compared renal and adrenal sympathoinhibitory responses evoked by right atrial injections of 5HT3 receptor agonist phenylbiguanide (2–8 μg/kg) under control conditions, during hemorrhage, and during hemorrhage preceded by blockade of NTS adenosine receptors with bilateral microinjections of 8-(p-sulfophenyl) theophylline (1 nmol/100 nl) in urethane/chloralose anesthetized rats. CCR-mediated inhibition of renal and adrenal sympathetic activity was significantly attenuated during severe hemorrhage despite reciprocal changes in the baseline activity levels, and this attenuation was removed by bilateral blockade of adenosine receptors in the caudal NTS. This confirmed that adenosine endogenously released into the NTS has a similar modulatory effect on integration of cardiovascular reflexes as stimulation of NTS adenosine receptors with exogenous agonists.
Hemodynamic performance of the Fontan circulation compared with a normal biventricular circulation: a computational model study
Authors: Liang Fuyou , Senzaki Hideaki , Kurishima Clara , Sughimoto Koichi , Inuzuka Ryo , Liu Hao
Published: July 2014

The physiological limitations of the Fontan circulation have been extensively addressed in the literature. Many studies emphasized the importance of pulmonary vascular resistance in determining cardiac output (CO) but gave little attention to other cardiovascular properties that may play considerable roles as well. The present study was aimed to systemically investigate the effects of various cardiovascular properties on clinically relevant hemodynamic variables (e.g., CO and central venous pressure). To this aim, a computational modeling method was employed. The constructed models provided a useful tool for quantifying the hemodynamic effects of any cardiovascular property of interest by varying the corresponding model parameters in model-based simulations. Herein, the Fontan circulation was studied compared with a normal biventricular circulation so as to highlight the unique characteristics of the Fontan circulation. Based on a series of numerical experiments, it was found that 1) pulmonary vascular resistance, ventricular diastolic function, and systemic vascular compliance play a major role, while heart rate, ventricular contractility, and systemic vascular resistance play a secondary role in the regulation of CO in the Fontan circulation; 2) CO is nonlinearly related to any single cardiovascular property, with their relationship being simultaneously influenced by other cardiovascular properties; and 3) the stability of central venous pressure is significantly reduced in the Fontan circulation. The findings suggest that the hemodynamic performance of the Fontan circulation is codetermined by various cardiovascular properties and hence a full understanding of patient-specific cardiovascular conditions is necessary to optimize the treatment of Fontan patients.
Therapeutic angiogenesis by autologous adipose-derived regenerative cells: comparison with bone marrow mononuclear cells
Authors: Hao Changning , Shintani Satoshi , Shimizu Yuuki , Kondo Kazuhisa , Ishii Masakazu , Wu Hongxian , Murohara Toyoaki
Published: July 2014

Transplantation of adipose-derived regenerative cell (ADRC) enhances ischemia-induced angiogenesis, but the underlying mechanism remains unknown. Here, we compared the efficacy between ADRC and bone marrow mononuclear cell (BM-MNC) transplantation in rabbits model of hindlimb ischemia and examined the possible roles of alternative phenotypic macrophages polarization in ADRC-mediated angiogenesis using mice model of hindlimb ischemia. ADRCs and BM-MNCs were isolated from New Zealand White rabbits and C57BL/6J mice. In rabbit studies, our data showed that ADRCs could incorporate into the endothelial vasculature in vitro and in vivo. Both ADRC-conditioned media (CM) and BM-MNC-CM enhanced the migratory ability and interrupted the process of apoptosis in human umbilical vein endothelial cells. Four weeks after cell transplantation, augmentation of postnatal neovascularization was observed in the ischemic muscle injected with either ADRCs or BM-MNCs. In mice studies, we presented that ADRCs polarized into the IL-10-releasing M2 macrophages through PGE2-EP2/4 axis and suppressed the expressions of TNF-α and IL-6 in the ischemic muscle. Gene expressions of several angiogenic cytokines were amplified in the macrophages cultured in ADRC-CM rather than BM-MNC-CM. Blockade of IL-10 using neutralizing MAb attenuated the ADRC-mediated angiogenesis and caused muscle apoptosis in vivo. In conclusion, ADRC transplantation harvested similar effect of neovascularization augmentation compared with BM-MNC in experimental rabbit model of hindlimb ischemia; ADRC displayed a unique immunoregulatory manner of accelerating IL-10-releasing M2 macrophages polarization through the PGE2-EP2/4 axis.
The low frequency power of heart rate variability is neither a measure of cardiac sympathetic tone nor of baroreflex sensitivity
Authors: Martelli Davide , Silvani Alessandro , McAllen Robin M. , May Clive N. , Ramchandra Rohit
Published: July 2014

The lack of noninvasive approaches to measure cardiac sympathetic nerve activity (CSNA) has driven the development of indirect estimates such as the low-frequency (LF) power of heart rate variability (HRV). Recently, it has been suggested that LF HRV can be used to estimate the baroreflex modulation of heart period (HP) rather than cardiac sympathetic tone. To test this hypothesis, we measured CSNA, HP, blood pressure (BP), and baroreflex sensitivity (BRS) of HP, estimated with the modified Oxford technique, in conscious sheep with pacing-induced heart failure and in healthy control sheep. We found that CSNA was higher and systolic BP and HP were lower in sheep with heart failure than in control sheep. Cross-correlation analysis showed that in each group, the beat-to-beat changes in HP correlated with those in CSNA and in BP, but LF HRV did not correlate significantly with either CSNA or BRS. However, when control sheep and sheep with heart failure were considered together, CSNA correlated negatively with HP and BRS. There was also a negative correlation between CSNA and BRS in control sheep when considered alone. In conclusion, we demonstrate that in conscious sheep, LF HRV is neither a robust index of CSNA nor of BRS and is outperformed by HP and BRS in tracking CSNA. These results do not support the use of LF HRV as a noninvasive estimate of either CSNA or baroreflex function, but they highlight a link between CSNA and BRS.
Systemic microvascular shunting through hyperdynamic capillaries after acute physiological disturbances following cardiopulmonary bypass
Authors: Koning Nick J. , Simon Lotte E. , Asfar Pierre , Baufreton Christophe , Boer Christa
Published: July 2014

Previously we showed that cardiopulmonary bypass (CPB) during cardiac surgery is associated with reduced sublingual microcirculatory perfusion and oxygenation. It has been suggested that impaired microcirculatory perfusion may be paralleled by increased heterogeneity of flow in the microvascular bed, possibly leading to arteriovenous shunting. Here we investigated our hypothesis that acute hemodynamic disturbances during extracorporeal circulation indeed lead to microcirculatory heterogeneity with hyperdynamic capillary perfusion and reduced systemic oxygen extraction. In this single-center prospective observational study, patients undergoing cardiac surgery with ( n = 18) or without ( n = 13) CPB were included. Perioperative microcirculatory perfusion was assessed sublingually with sidestream darkfield imaging, and recordings were quantified for microcirculatory heterogeneity and hyperdynamic capillary perfusion. The relationship with hemodynamic and oxygenation parameters was analyzed. Microcirculatory heterogeneity index increased substantially after onset of CPB [0.5 (0.0–0.9) to 1.0 (0.3–1.3); P = 0.031] but not during off-pump surgery. Median capillary red blood cell (RBC) velocity increased intraoperatively in the CPB group only [1,600 (913–2,500 μm/s) vs. 380 (190–480 μm/s); P < 0.001], with 31% of capillaries supporting high RBC velocities (>2,000 μm/s). Hyperdynamic microcirculatory perfusion was associated with reduced arteriovenous oxygen difference and systemic oxygen consumption during and after CPB. The current study provides the first direct human evidence for a microvascular shunting phenomenon through hyperdynamic capillaries following acute physiological disturbances after onset of CPB. The hypothesis of impaired systemic oxygen offloading caused by hyperdynamic capillaries was supported by reduced blood arteriovenous oxygen difference and low systemic oxygen extraction associated with CPB.
Poldip2 controls vascular smooth muscle cell migration by regulating focal adhesion turnover and force polarization
Authors: Datla Srinivasa Raju , McGrail Daniel J. , Vukelic Sasa , Huff Lauren P. , Lyle Alicia N. , Pounkova Lily , Lee Minyoung , Seidel-Rogol Bonnie , Khalil Mazen K. , Hilenski Lula L. , Terada Lance S. , Dawson Michelle R. , Lassègue Bernard , Griendling Kathy K.
Published: July 2014

Polymerase-δ-interacting protein 2 (Poldip2) interacts with NADPH oxidase 4 (Nox4) and regulates migration; however, the precise underlying mechanisms are unclear. Here, we investigated the role of Poldip2 in focal adhesion turnover, as well as traction force generation and polarization. Poldip2 overexpression (AdPoldip2) in vascular smooth muscle cells (VSMCs) impairs PDGF-induced migration and induces a characteristic phenotype of long cytoplasmic extensions. AdPoldip2 also prevents the decrease in spreading and increased aspect ratio observed in response to PDGF and slightly impairs cell contraction. Moreover, AdPoldip2 blocks focal adhesion dissolution and sustains H2O2levels in focal adhesions, whereas Poldip2 knockdown (siPoldip2) significantly decreases the number of focal adhesions. RhoA activity is unchanged when focal adhesion dissolution is stimulated in control cells but increases in AdPoldip2-treated cells. Inhibition of RhoA blocks Poldip2-mediated attenuation of focal adhesion dissolution, and overexpression of RhoA or focal adhesion kinase (FAK) reverses the loss of focal adhesions induced by siPoldip2, indicating that RhoA and FAK mediate the effect of Poldip2 on focal adhesions. Nox4 silencing prevents focal adhesion stabilization by AdPoldip2 and induces a phenotype similar to siPoldip2, suggesting a role for Nox4 in Poldip2-induced focal adhesion stability. As a consequence of impaired focal adhesion turnover, PDGF-treated AdPoldip2 cells are unable to reduce and polarize traction forces, a necessary first step in migration. These results implicate Poldip2 in VSMC migration via regulation of focal adhesion turnover and traction force generation in a Nox4/RhoA/FAK-dependent manner.
A computational physiology approach to personalized treatment models: the beneficial effects of slow breathing on the human cardiovascular system
Authors: Fonoberova Maria , Mezić Igor , Buckman Jennifer F. , Fonoberov Vladimir A. , Mezić Adriana , Vaschillo Evgeny G. , Mun Eun-Young , Vaschillo Bronya , Bates Marsha E.
Published: July 2014

Heart rate variability biofeedback intervention involves slow breathing at a rate of ∼6 breaths/min (resonance breathing) to maximize respiratory and baroreflex effects on heart period oscillations. This intervention has wide-ranging clinical benefits and is gaining empirical support as an adjunct therapy for biobehavioral disorders, including asthma and depression. Yet, little is known about the system-level cardiovascular changes that occur during resonance breathing or the extent to which individuals differ in cardiovascular benefit. This study used a computational physiology approach to dynamically model the human cardiovascular system at rest and during resonance breathing. Noninvasive measurements of heart period, beat-to-beat systolic and diastolic blood pressure, and respiration period were obtained from 24 healthy young men and women. A model with respiration as input was parameterized to better understand how the cardiovascular processes that control variability in heart period and blood pressure change from rest to resonance breathing. The cost function used in model calibration corresponded to the difference between the experimental data and model outputs. A good match was observed between the data and model outputs (heart period, blood pressure, and corresponding power spectral densities). Significant improvements in several modeled cardiovascular functions (e.g., blood flow to internal organs, sensitivity of the sympathetic component of the baroreflex, ventricular elastance) were observed during resonance breathing. Individual differences in the magnitude and nature of these dynamic responses suggest that computational physiology may be clinically useful for tailoring heart rate variability biofeedback interventions for the needs of individual patients.
Rescuing ΔF508 CFTR with trimethylangelicin, a dual-acting corrector and potentiator
Authors: Collawn James F. , Fu Lianwu , Bartoszewski Rafal , Matalon Sadis
Published: July 2014

Since the discovery of the cystic fibrosis (CF) gene that encodes the CF transmembrane conductance regulator (CFTR) in 1989, there has been considerable progress in understanding the molecular defects associated with different mutations in the CFTR protein. Small molecule “potentiators” have led the way as a drug therapeutic approach for correcting channel gating mutations such as the G551D mutation. Therapies for correcting the most common folding mutation in CFTR, ΔF508, however, have proven to be much more challenging. The protein-folding problem appears to be associated with both nucleotide binding domain (NBD) instability and domain interface interactions that are caused by the loss of the phenylalanine residue in NBD 1. Given the inherent complexity in the sequential folding pathway for this very large multidomain protein, it has been suggested that correcting the proper folding, anion channel function, and cell surface stability of the ΔF508 CFTR protein will require a multidrug approach to fix each of these compounding problems. Here we discuss a recent publication (Favia M, Mancini MT, Bezzerri V, Guerra L, Laselva O, Abbattiscianni AC, Debellis L, Reshkin SJ, Gambari R, Cabrini G, Casavola V. Am J Physiol Lung Cell Mol Physiol 307: L48–L61, 2014), however, that offers hope that single drug therapies are still possible.
Glucose-6-phosphate dehydrogenase plays a critical role in hypoxia-induced CD133+progenitor cells self-renewal and stimulates their accumulation in the lungs of pulmonary hypertensive rats
Authors: Chettimada Sukrutha , Joshi Sachindra Raj , Alzoubi Abdallah , Gebb Sarah A. , McMurtry Ivan F. , Gupte Rakhee , Gupte Sachin A.
Published: July 2014

Although hypoxia is detrimental to most cell types, it aids survival of progenitor cells and is associated with diseases like cancer and pulmonary hypertension in humans. Therefore, understanding the underlying mechanisms that promote survival of progenitor cells in hypoxia and then developing novel therapies to stop their growth in hypoxia-associated human diseases is important. Here we demonstrate that the proliferation and growth of human CD133+progenitor cells, which contribute to tumorigenesis and the development of pulmonary hypertension, are increased when cultured under hypoxic conditions. Furthermore, glucose-6-phosphate dehydrogenase (G6PD) activity was increased threefold in hypoxic CD133+cells. The increased G6PD activity was required for CD133+cell proliferation, and their growth was arrested by G6PD inhibition or knockdown. G6PD activity upregulated expression of HIF1α, cyclin A, and phospho-histone H3, thereby promoting CD133+cell dedifferentiation and self-renewal and altering cell cycle regulation. When CD133+cells were cocultured across a porous membrane from pulmonary artery smooth muscle cells (PASMCs), G6PD-dependent H2O2production and release by PASMCs recruited CD133+cells to the membrane, where they attached and expressed smooth muscle markers (α-actin and SM22α). Inhibition of G6PD reduced smooth muscle marker expression in CD133+cells under normoxia but not hypoxia. In vivo, CD133+cells colocalized with G6PD+cells in the perivascular region of lungs from rats with hypoxia-induced pulmonary hypertension. Finally, inhibition of G6PD by dehydroepiandrosterone in pulmonary arterial hypertensive rats nearly abolished CD133+cell accumulation around pulmonary arteries and the formation of occlusive lesions. These observations suggest G6PD plays a key role in increasing hypoxia-induced CD133+cell survival in hypertensive lungs that differentiate to smooth muscle cells and contribute to pulmonary arterial remodeling during development of pulmonary hypertension.