Organic nitrates play an important role in the therapy of ischemic heart disease, however, their clinical application is limited by the development of vascular nitrate tolerance. We have previously shown attenuation of the cardioprotective effect of preconditioning in vascular nitrate tolerance. Here we studied whether the development of vascular nitrate tolerance affects the infarct size limiting effect of ischemic postconditioning in the myocardium, and whether the activation of survival kinases plays a role in the molecular mechanism of postconditioning in the presence or absence of vascular nitrate tolerance. Male Wistar rats were treated with nitroglycerin/vehicle for 3 days to induce vascular nitrate tolerance. On the fourth day, isolated hearts were subjected to 30min coronary occlusion followed by 120min reperfusion with or without ischemic postconditioning. In non-tolerant hearts, postconditioning significantly decreased infarct size as compared to ischemia/reperfusion, however, postconditioning failed to decrease infarct size in hearts of nitrate tolerant rats. Phosphorylation of ERK 1/2, Akt or eNOS showed no significant differences between groups at the 10 min of reperfusion. Vascular nitrate tolerance interferes with the infarct size limiting effect of ischemic postconditioning. Activation of survival kinases is not crucial in the molecular mechanism of postconditioning which remains unaffected in nitrate tolerance.

BACKGROUND:

To assess acute effects of bevacizumab (anti-VEGF therapy) on cerebral microvessels and systemic cardiovascular regulation. DESIGN AND

SUBJECTS:

20 consecutive patients with colorectal cancer (median age: 60.4 years, range 45.5-73.9 years) received bevacizumab intravenously (5 mg/kg) uncoupled of chemotherapy. Prior to and within the first 24 hours after bevacizumab infusion, patients were investigated for retinal endothelial function. A series of a triple 24-hour ambulatory blood pressure measurement was conducted. Retinal endothelial function was determined as flicker light-induced vasodilation. The integrity of baroreflex arc and autonomic cardiovascular control was examined by stimulatory manoeuvres.

RESULTS:

Bevacizumab therapy significantly reduced the vasodilatory capacity of retinal arterioles in response to flicker light. A slight decrease in diastolic pressure and heart rate was observed after bevacizumab infusion but this was unrelated to changes in retinal function. The pressure response upon nitroglycerin was largely preserved after bevacizumab infusion. The proportion of patients with abnormal nocturnal blood pressure regulation increased under anti-angiogenic therapy. Autonomic blood pressure control was not affected by bevacizumab treatment.

CONCLUSIONS:

Bevacizumab acutely impairs microvascular function independent of blood pressure changes. Imaging of the retinal microcirculation seems a valuable tool for monitoring pharmacodynamic effects of bevacizumab.

TRIAL REGISTRATION:

NCT ID: NCT00740168.

Nitroglycerin (NG) is a toxic explosive found as a contaminant of soil and groundwater. Several microbial strains are capable of partially reducing the NG molecule to dinitro or mononitroesters. Recently, a strain capable of growing on NG as the sole source of carbon and nitrogen (Arthrobacter sp. strain JBH1) was isolated from contaminated soil. Despite the widespread presence of microbial strains capable of transforming NG in contaminated soils and sediments, the extent of NG biodegradation at contaminated sites is still unknown. In this study column experiments were conducted to investigate the extent of microbial degradation of NG in saturated porous media, specifically after bioaugmentation with JBH1. Initial experiments using sterile, low sorptivity sand, showed mineralization of NG after bioaugmentation with JBH1 in the absence of sources of carbon and nitrogen other than NG. Results could be modeled using a first order degradation rate of 0.14d(-1). Further experiments conducted using contaminated soil with high organic carbon content (highly sorptive) resulted in column effluents that did not contain NG although high dinitroester concentrations were observed. Bioaugmentation with JBH1 in sediments containing strains capable of partial transformation of NG resulted in complete mineralization of NG and faster degradation rates.

Vascular reactivity is a surrogate marker for atherosclerosis and is predictive of cardiovascular outcome. Noncardiovascular surgery is associated with perioperative cardiovascular complications in high risk patients. To evaluate the impact of noncardiovascular surgery on reactive hyperaemia and arterial endothelial function, and to investigate the relationships between invasive (laparotomy) versus minimally invasive (laparoscopic) surgery and endothelial dysfunction, we prospectively evaluated 106 patients undergoing abdominal surgery under general anaesthesia (71 laparotomy, 35 laparoscopy). Measurements of blood pressure, heart rate and pain (by visual analogue scale, VAS) were undertaken. Brachial endothelium-dependent flow-mediated dilation (FMD), endothelium-independent dilation(nitroglycerin-induced dilation, NTG)and reactive hyperaemia were measured with high resolution B-mode ultrasound at preoperative day 1 (baseline), and postoperatively at 2 hours, one day and 7 days. Blood pressure and heart rate were significantly higher 2 hours postoperatively. VAS were higher (P<0.01), and reactive hyperaemia and FMD were significantly lower (P<0.001) at 2 hours and one day post-opreation compared with baseline and with postoperative day 7. FMD at postoperative day 7 recovered to baseline level. Patients undergoing laparoscopic surgery had less FMD reduction at day 1 (7.5±1.5%) and day 7 (7.9±1.5%), compared with laparotomy (6.4±1.6%, p=0.001 and 7.0±1.6%, P=0.006 respectively), consistent with potential cardiovascular benefit. NTG responses were stable throughout. On backward multivariate linear regression analysis, FMD was independently related to age and VAS (model R=0.486, F value=6.4, P<0.001). Reactive hyperaemia and arterial endothelial function are significantly reduced in the early postoperative period, particularly after laparotomy compared with laparoscopy, which may be related to post-operative cardiovascular events. This article is protected by copyright. All rights reserved.

Background:

Perioperative hypertension affects 80% of cardiac surgery patients and is associated with an increased risk of complications.

Objective:

To determine the relationship between perioperative blood pressure (BP) control and hospital costs for cardiac surgery in the United States (US) and estimate the potential cost reductions associated with effective therapies.

Methods:

The analysis estimated hospitalization costs (2011 US dollars (USD)) for cardiac surgery when BP was controlled with intravenous (IV) antihypertensives. Patient characteristics, hospital length of stay, and clinical event rates during the initial hospitalization and post-discharge 30 days after study drug infusion were based on the ECLIPSE (Evaluation of CLevidipine In the Perioperative Treatment of Hypertension Assessing Safety Events) trials. These clinical trial data were combined with data from the Massachusetts Acute Hospital Case Mix Database 2007 - 2009 (MA Case Mix Database) to estimate total hospitalization costs.

Results:

Effective perioperative BP control in patients requiring IV antihypertensives was associated with a 7% decrease in hospital costs compared with less effective BP control. Reductions in total hospital costs associated with clevidipine versus other IV antihypertensives averaged $394 per patient overall. Cost savings with clevidipine exceeded $500 per patient versus sodium nitroprusside and nitroglycerin, but only $22 compared to nicardipine.

Conclusion:

Improved perioperative BP control may reduce hospital costs. Given the low cost of IV antihypertensives, the total hospital cost reductions may offset any incremental cost increases associated with newer, more effective therapies.

Migraine is a common disabling disorder with a significant genetic component, characterized by severe headache and often accompanied by nausea, vomiting, and light sensitivity. We identified two families, each with a distinct missense mutation in the gene encoding casein kinase Iδ (CKIδ), in which the mutation cosegregated with both the presence of migraine and advanced sleep phase. The resulting alterations (T44A and H46R) occurred in the conserved catalytic domain of CKIδ, where they caused reduced enzyme activity. Mice engineered to carry the CKIδ-T44A allele were more sensitive to pain after treatment with the migraine trigger nitroglycerin. CKIδ-T44A mice also exhibited a reduced threshold for cortical spreading depression (believed to be the physiological analog of migraine aura) and greater arterial dilation during cortical spreading depression. Astrocytes from CKIδ-T44A mice showed increased spontaneous and evoked calcium signaling. These genetic, cellular, physiological, and behavioral analyses suggest that decreases in CKIδ activity can contribute to the pathogenesis of migraine.

OBJECTIVES:

The study aimed to assess whether young binge drinkers have impaired macrovascular and microvascular function and cardiovascular (CV) disease risk factors compared to age-matched alcohol abstainers.

BACKGROUND:

Binge drinking rates are highest on college campuses and among 18- to 25-year-olds; however, macrovascular and microvascular endothelial function in young adults with a history of repeated binge drinking (≥5 standard drinks in 2 hrs. in men; ≥4 standard drinks in 2 hrs. in women) has not been investigated

METHODS:

We evaluated the cardiovascular profile, brachial artery endothelial-dependent flow mediated vasodilation (FMD), and flow independent nitroglycerin (NTG)-mediated dilation and vasoreactivity of resistance arteries (isolated from gluteal fat biopsies) in abstainers and binge drinkers.

RESULTS:

Men and women (18-25 years of age, abstainers [A] n = 17, binge drinkers [BD] n = 19) were enrolled. Among the BD group, past-month average number of binge episodes was 6 ± 1, and average duration of binge drinking behavior was 4 ± 0.6 years. FMD and NTG-mediated dilations were significantly lower in the BD (FMD: 8.4% ± 0.7, P = 0.022; NTG: 19.6% ± 2, P = 0.009) than the A group (FMD: 11 ± 0.7%; NTG: 28.6 ± 2%). ACh- and SNP-induced dilation in resistance arteries was not significantly different between the A and BD groups. However, ET-1-induced constriction was significantly enhanced in the BD group compared to the A group (P = 0.032). No differences between groups were found in blood pressure, lipoproteins, and C-reactive protein.

CONCLUSIONS:

Alterations in the macrocirculation and microcirculation may represent early clinical manifestations of CV risk in otherwise healthy young binge drinkers. This study has important clinical implications for screening young adults for a repeated history of binge drinking.

The purpose of this study was to investigate the association of visit-to-visit and 24-h blood pressure (BP) variability with markers of endothelial injury and vascular function. We recruited 72 African Americans who were non-diabetic, non-smoking and free of cardiovascular (CV) and renal disease. Office BP was measured at three visits and 24-h ambulatory BP monitoring was conducted to measure visit-to-visit and 24-h BP variability, respectively. The 5-min time-course of brachial artery flow-mediated dilation and nitroglycerin-mediated dilation were assessed as measures of endothelial and smooth muscle function. Fasted blood samples were analyzed for circulating endothelial microparticles (EMPs). Significantly lower CD31+CD42- EMPs were found in participants with high visit-to-visit systolic blood pressure (SBP) variability or high 24-h diastolic blood pressure (DBP) variability. Participants with high visit-to-visit DBP variability had significantly lower flow-mediated dilation and higher nitroglycerin-mediated dilation at multiple time-points. When analyzed as continuous variables, 24-h mean arterial pressure variability was inversely associated with CD62+ EMPs; visit-to-visit DBP variability was inversely associated with flow-mediated dilation normalized by smooth muscle function and was positively associated with nitroglycerin-mediated dilation; and 24-h DBP variability was positively associated with nitroglycerin-mediated dilation. All associations were independent of age, gender, body mass index and mean BP. In conclusion, in this cohort of African Americans visit-to-visit and 24-h BP variability were associated with measures of endothelial injury, endothelial function and smooth muscle function. These results suggest that BP variability may influence the pathogenesis of CV disease, in part, through influences on vascular health.Journal of Human Hypertension advance online publication, 25 April 2013; doi:10.1038/jhh.2013.33.

Untreated HIV may increase the risk of cardiovascular events. Our preliminary in vitro and in vivo research suggests that pentoxifylline (PTX) reduces vascular inflammation and improves endothelial function in HIV-infected persons not requiring antiretroviral therapy.We performed a randomized, placebo-controlled trial of PTX 400 mg orally thrice daily for 8 weeks in 26 participants. The primary endpoint was change in flow-mediated dilation (FMD) of the brachial artery after 8 weeks. Nitroglycerin-mediated dilation (NTGMD) and circulating markers of inflammation, cellular immune activation, coagulation, and metabolism were also assessed.The difference in mean absolute change (SD) in FMD after 8 weeks between the placebo [-1.06 (1.45)%] and PTX [-1.93 (3.03)%] groups was not significant (P = 0.44). No differences in NTGMD were observed. The only significant between-group difference in the changes in biomarkers from baseline to week 8 was in soluble tumor necrosis factor receptor-1 (sTNFRI) [-83.2 pg/mL in the placebo group vs. +65.9 pg/mL in the PTX group; P = 0.03]. PTX was generally well-tolerated.PTX did not improve endothelial function and unexpectedly increased the inflammatory biomarker sTNFRI in HIV-infected participants not requiring antiretroviral therapy. Additional interventional research is needed to reduce inflammation and cardiovascular risk in this population.ClinicalTrials.gov NCT00796822.

PURPOSE:

A case of accidental autoinjection of epinephrine is described.

SUMMARY:

A 47-year-old man arrived at the emergency department after accidental injection of epinephrine with an autoinjector into his left thumb. His vital signs were stable at admission. The patient was allergic to nuts and thought he may have eaten something containing a pine nut. The patient reported feeling itching in his throat but had no shortness of breath or swollen tongue. He tried to self-administer an epinephrine injection, but it did not inject. While he was checking the device, it accidently injected into his left thumb pad. A review of systems revealed throat discomfort, a tingling sensation of the tongue, and a left-thumb puncture with pain. Physical examination of the left thumb pad revealed a pale, cool thumb with diminished capillary refill and punctuate black discoloration at the site of injection. Topical nitroglycerin paste was applied but had no effect, so terbutaline was ordered. The terbutaline injection was prepared as a 1:1 preparation of terbutaline sulfate 1 mg/mL and 0.9% sodium chloride injection. The immediate effects were the return of color from pale white to red and observable perfusion to the area within seconds. After 20 minutes, the red color remained, with observable perfusion and warmth, in addition to complete neurosensory function. Sixty minutes after terbutaline administration, the patient was discharged home.

CONCLUSION:

A 47-year-old man who accidentally injected himself in the thumb with an epinephrine autoinjector was successfully treated with subcutaneous terbutaline. The treatment had an immediate effect, including revascularization and resolution of pain.