Noninvasive assessment of human microvascular function in health and disease using incident dark-field microscopy.

Reduced peripheral microvascular reactivity is associated with an increased risk for major adverse cardiac events (MACEs). Tools for noninvasive assessment of peripheral microvascular function are limited, and existing technology is poorly validated in both healthy populations and patients with cardiovascular disease (CVD). Here, we used a handheld incident dark-field imaging tool (CytoCam) to test the hypothesis that, compared with healthy individuals (no risk factors for CVD), subjects formally diagnosed with coronary artery disease (CAD) or those with ≥2 risk factors for CAD (at risk) would exhibit impaired peripheral microvascular reactivity. A total of 17 participants (11 healthy, 6 at risk) were included in this pilot study. CytoCam was used to measure sublingual microvascular total vessel density (TVD), perfused vessel density (PVD), and microvascular flow index (MFI) in response to the topical application of acetylcholine (ACh) and sublingual administration of nitroglycerin (NTG). Baseline MFI and PVD were significantly reduced in the at-risk cohort compared with healthy individuals. Surprisingly, following the application of acetylcholine and nitroglycerin, both groups showed a significant improvement in all three microvascular perfusion parameters. These results suggest that, despite baseline reductions in both microvascular density and perfusion, human in vivo peripheral microvascular reactivity to both endothelial-dependent and -independent vasoactive agents remains intact in individuals with CAD or multiple risk factors for disease.NEW & NOTEWORTHY To our knowledge, this is the first study to comprehensively characterize in vivo sublingual microvascular structure and function (endothelium-dependent and -independent) in healthy patients and those with CVD. Importantly, we used an easy-to-use handheld device that can be easily translated to clinical settings. Our results indicate that baseline microvascular impairments in structure and function can be detected using the CytoCam technology, although reactivity to acetylcholine may be maintained even during disease in the peripheral microcirculation.

Impact of Sublingual Nitroglycerin on the Assessment of Computed Tomography-derived Fractional Flow Reserve: An Intraindividual Comparison Study.

OBJECTIVE: The aim of this study was to investigate the impact of nitroglycerin (NTG) on the assessment of computed tomography-derived fractional flow reserve (CT-FFR). MATERIALS AND METHODS: Seventy-seven patients with suspected coronary artery disease were recruited, and they underwent computed tomography angiography (CCTA) before and after NTG administration. The CT-FFRs were compared at 2 CCTAs. The difference was compared using the Wilcoxon signed rank test. Patients were divided into normal and stenosis groups according to CCTA results. Vessels in the stenosis group were further divided into different groups based on coronary artery calcium score (CACS) and stenosis degree. The poststenotic CT-FFR differences before and after NTG (DCT-FFR) were calculated to evaluate the impact of stenosis degree and CACS. Terminal CT-FFRs derived from CCTAs before and after NTG in total and vessel-specific levels were compared in the normal group. RESULTS: Of 47 patients in the stenosis group, poststenotic CT-FFR was significantly increased after NTG at per-vessel level. By taking CT-FFR of 0.75 or lower as the threshold, 5 and 4 patients showed abnormal CT-FFR before and after NTG, respectively. No significant differences were noted among the various stenosis degree and CACS groups regarding DCT-FFR. Of 30 patients in the normal group, terminal CT-FFR was significantly increased after NTG in total level and vessel-specific level of left anterior descending and right coronary artery, but not in the left circumflex. CONCLUSIONS: Both post lesion and distal vessel CT-FFR significantly improved after the administration of GTN with the degree of change not affected by stenosis severity or CACS.

Quantifying the Effect of Topical Nitroglycerin on Random Pattern Flap Perfusion in a Rodent Model: An Application of the ViOptix Intra.Ox for Dynamic Flap Perfusion Assessment and Salvage.

BACKGROUND: Near-infrared spectroscopy can detect changes in tissue oxygenation postoperatively that predict flap necrosis. The authors hypothesized that this technology can be applied along with topical nitroglycerin to measure an improvement in tissue oxygenation that correlates with tissue salvage. METHODS: Dorsal, random pattern flaps measuring 10 × 3 cm were raised using Sprague-Dawley rats. Tissue oxygenation was measured after flap elevation in 10 locations using the ViOptix Intra.Ox. Animals were divided into three groups that received 30 mg of topical nitroglycerin daily, twice-daily, or not at all. Oxygenation measurements were repeated on postoperative day 1 and animals were euthanized on day 7 and evaluated for tissue necrosis. RESULTS: Tissue necrosis was greatest in controls (51.3 mm) compared to daily (28.8 mm) and twice-daily nitroglycerin (18.8 mm; p = 0.035). Three flap perfusion zones were identified: healthy (proximal, 50 mm), necrotic (distal, 20 mm), and watershed. Immediate postoperative tissue oxygenation was highest in healthy tissue (57.2 percent) and decreased to 33.0 and 19.3 percent in the watershed and necrotic zones, respectively (p < 0.001). One day after treatment with nitroglycerin, oxygenation in the healthy zone did not increase significantly (mean difference, -1.5 percent). The watershed (17.8 percent; p < 0.001) and necrotic zones (16.3 percent; p <0.001) did exhibit significant improvements that were greater than those measured in control tissues (7.9 percent; both p < 0.001). CONCLUSIONS: Serial perfusion assessment using the ViOptix Intra.Ox measured a significant improvement in flap oxygenation after treatment with topical nitroglycerin. Within the watershed area of the flap, this increase in tissue oxygenation was associated with the salvage of ischemic tissue.

Quantitative Assessment of the Hemodynamic Effects of Intra-Arterial Nitroglycerin on Hepatocellular Carcinoma using Two-Dimensional Perfusion Angiography.

PURPOSE: To determine the hemodynamic effects of intra-arterial nitroglycerin on hepatocellular carcinoma (HCC) using 2-dimensional (2D) perfusion angiography. MATERIALS AND METHODS: Two-dimensional perfusion angiograms obtained prior to radioembolization from September 2019 to February 2020 were retrospectively reviewed. The inclusion criteria were the presence of Liver Imaging Reporting and Data System-5 tumors and angiographically distinguishable tumor and background liver. The exclusion criteria were previously treated tumors and motion-degraded studies. Thirteen patients with 2D perfusion angiograms obtained before and 2 minutes ± 1 after the administration of intra-arterial nitroglycerin were analyzed. The mean patient age was 72 years ± 9 and 11 of 13 (85%) had cirrhosis. The mean maximum tumor dimension was 4.6 cm ± 2.1. Eight tumors were in the right lobe and 5 were in the left lobe. The tumor and background liver 2D perfusion data were processed and the areas under the time-density curves were calculated. The relative perfusion of HCC to background liver was compared before and after nitroglycerin administration using a 2-tailed paired t-test. RESULTS: The mean rate of contrast administration was 1.4 mL/s ± 0.7 and the mean volume administered was 7.1 mL ± 3.3. The mean nitroglycerin dose was 281 µg ± 69. Ten of 13 patients (77%) demonstrated a relative increase in tumor perfusion. The mean HCC to background liver area under the curve ratio was 1.94 ± 0.76 before and 2.40 ± 0.89 after nitroglycerin administration (P < .05). CONCLUSIONS: Intra-arterial nitroglycerin increases previously untreated HCC perfusion relative to background liver as measured by 2D perfusion angiography, but this effect is variable among patients and should be validated with 3-dimensional imaging techniques.

Comparative analysis of cost-effectiveness between isosorbide-5-mononitrate and isosorbide: a retrospective real-world evaluation.

Aim: The cost-effectiveness of isosorbide-5-mononitrate (5-ISMN) and isosorbide dinitrate (ISDN) in real-world use in patients with coronary heart disease (CHD; either angina pectoris or myocardial infarction) was retrospectively compared. Method: In this retrospective real-world evaluation, patients with established CHD satisfying the following criteria were selected from information system of two tertiary hospitals in China: with pharmacy claiming for at least one injection of 5-ISMN or ISDN between July 2008 and May 2017; and, CHD patients. By using propensity score matching (PSM), we compared clinical aspects of efficacy, safety, length of hospital stay and cost during hospitalization between 5-ISMN and ISDN group. All data were processed by R statistical package v.2.13.1 (R Foundation for Statistical Computing, Vienna, Austria). Result: Of 5609 patients selected, 4047 received 5-ISMN and 1562 received ISDN. After PSM, we acquired 1555 pairs based on balancing of age, sex, insurance and comorbidities on admission. The frequency (4.2 ± 6.6-times vs 6.5 ± 9.5-times; p < 0.05) and total dosage (47.5 ± 153.4 vs 136.4 ± 261.0 mg; p < 0.05) of sublingual nitroglycerin use decreased and hypotension incidence lowered (8.0 vs 13.0%; p < 0.05) in 5-ISMN group compared with ISDN group. Hospital stay (16.0 ± 11.3 days vs 17.7 ± 13.2; p < 0.05) and hospitalization expenditure ([the ratio of cost in the study to the average hospitalization cost in the city] [odds ratio: 2.5 vs 2.6; p < 0.05]) were reduced in 5-ISMN group as with that of ISDN group. Moreover, the main component of hospitalization cost was medical consumables and medications in both the groups. Conclusion: In the present retrospective real-world evaluation, by using PSM analysis, we found that newer injection agent of 5-ISMN was associated with fewer use of sublingual nitroglycerin, less hypotension incidence, shorter length of hospital stay and less hospitalization expenditure related to its comparator ISDN in patients with established CHD. Further evaluation and clinical experience are need in different circumference for the usage of ISDN.

Assessment Of Spanlastic Vesicles Of Zolmitriptan For Treating Migraine In Rats.

OBJECTIVE: To develop and evaluate zolmitriptan spanlastics (Zol SLs) as a brain-targeted antimigraine delivery system. Spanlastics (SLs) prepared using span 60: tween 80 (70:30%, respectively) gave the highest percentage of entrapment efficiency (EE%). MATERIALS AND METHODS: A total of 60 adult male Wistar albino rats were divided into six groups (n=10 rats/group). Group 1 (Control) comprised rats serving as a negative control. Group 2 was treated with glyceryl trinitrate (NTG) and served as the positive control. Groups 3 (NTG+Zol com), Group 4 (NTG+Zol sol) and Group 5 (NTG+Zol SLs) received commercial zolmitriptan orally, zolmitriptan solution intranasally and Zol SLs F5 intranasally, respectively, 30 min before NTG. Group 6 (Zol SLs) comprised normal rats that received only Zol SLs intranasally. RESULTS: We found decreased Tmax, increased Cmax, AUC0-6, AUC0-∞ and ameliorated behaviour in rats (head scratching) treated with intranasal SLs compared to oral commercial zolmitriptan. CONCLUSION: Our study substantiates the enhanced efficacy of Zol SLs in brain targeting for migraine treatment.

Impact of sublingual nitroglycerin dosage on FFRCT assessment and coronary luminal volume-to-myocardial mass ratio.

OBJECTIVES: Fractional flow reserve computed tomography (FFRCT) depends upon nitroglycerin (NTG) inducing maximal hyperemia. However, the impact of NTG dosages on FFRCT analysis including coronary volume-to-mass ratio (V/M) is unknown. METHODS: Eighty patients with repeat coronary CT angiograms (CCTAs) with different sublingual spray NTG doses (0.4 mg and 0.8 mg) were retrospectively analyzed with 45 patients excluded. Patient and scan demographics, post-stenosis and nadir FFRCT values, coronary volume, and coronary volume-to-mass ratio (V/M) were compared at initial CCTA (0.4 mg NTG) and follow-up CCTA (0.8 mg NTG). Differences were compared by Wilcoxon signed-rank test. RESULTS: Thirty-five patients were included (time between CCTAs, 3.9 ± 1.6 years). Segment involvement score was 2.4 ± 3.3 and 2.8 ± 3.4 at initial and repeat CCTA (0.4 and 0.8 mg NTG), respectively (p = 0.004). There was similar image quality (4.1 ± 0.7 vs 4.1 ± 0.8; p = 0.51). Nadir FFRCT values did not differ in the left (0.4 mg, 0.80 ± 0.08 vs 0.8 mg, 0.80 ± 0.03; p = 0.66), right (0.4 mg, 0.90 ± 0.04 vs 0.8 mg, 0.90 ± 0.06; p = 0.25), or circumflex coronaries (0.4 mg, 0.87 ± 0.06 vs 0.8 mg, 0.88 ± 0.06; p = 0.34). Post-stenosis FFRCT values did not differ (p = 0.65). Coronary volume increased with 0.8 mg of NTG (2639 ± 753 mm3 vs 2844.8 ± 827 mm3; p = 0.009) but V/M ratio did not (p = 0.20). CONCLUSIONS: Use of 0.8 mg versus 0.4 mg of NTG in routine clinical CCTAs significantly increased coronary volume determined from FFRCT analysis but did not alter FFRCT or V/M. Further evaluation of repeat CCTAs in a more contemporaneous fashion using varied nitrate doses and disease severity is needed. KEY POINTS: • Fractional flow reserve from computed tomography (FFRCT) is a noninvasive method for evaluating the coronary arteries and relies on nitroglycerin (NTG) to induce coronary vasodilation, but the impact of different NTG dosages is unknown. • Retrospective analysis evaluated use of different NTG doses on FFRCT. • Increased NTG dose increased coronary luminal volume on FFRCTanalysis, but did not change FFRCTvalues.

Glyceryl trinitrate to reduce the need for manual removal of retained placenta following vaginal delivery: the GOT-IT RCT.

BACKGROUND: Retained placenta is associated with postpartum haemorrhage and can lead to significant maternal morbidity if untreated. The only effective treatment is the surgical procedure of manual removal of placenta, which is costly, requires skilled staff, requires an operative environment and is unpleasant for women. Small studies suggest that glyceryl trinitrate may be an effective medical alternative. OBJECTIVE: To determine the clinical effectiveness and cost-effectiveness of sublingual glyceryl trinitrate spray compared with placebo in reducing the need for manual removal of placenta in women with retained placenta after vaginal delivery following the failure of current management. DESIGN: A group-sequential randomised double-blind placebo-controlled trial with a cost-effectiveness analysis. SETTING: There were 29 obstetric units in the UK involved in the study. PARTICIPANTS: There were 1107 women (glyceryl trinitrate group, n = 543; placebo group, n = 564) randomised between October 2014 and July 2017. INTERVENTIONS: Glyceryl trinitrate spray was administered to 541 women in the intervention group, and a placebo was administered to 563 women in the control group. MAIN OUTCOME MEASURES: Four primary outcomes were defined: (1) clinical - the need for manual removal of placenta, (2) safety - measured blood loss, (3) patient sided - satisfaction with treatment and side effects and (4) economic - cost-effectiveness of both treatments using the UK NHS perspective. Secondary clinical outcomes included a > 15% decrease in haemoglobin level, time from randomisation to delivery of placenta in theatre, the need for earlier manual removal of placenta than planned, increase in heart rate or decrease in blood pressure, requirement for blood transfusion, requirement for general anaesthesia, maternal pyrexia, and sustained uterine relaxation requiring additional uterotonics. RESULTS: No difference was observed between the glyceryl trinitrate group and the control group for the placenta remaining undelivered within 15 minutes of study treatment (93.3% vs. 92%; odds ratio 1.01, 95% confidence interval 0.98 to 1.04; p = 0.393). There was no difference in blood loss of > 1000 ml between the glyceryl trinitrate group and the control group (22.2% vs. 15.5%; odds ratio 1.14, 95% confidence interval 0.88 to 1.48; p = 0.314). Palpitations were more common in the glyceryl trinitrate group than in the control group after taking the study drug (9.8% vs. 4.0%; odds ratio 2.60, 95% confidence interval 1.40 to 4.84; p = 0.003). There was no difference in any other measures of patient satisfaction between the groups. There was no difference in costs to the health service between groups (mean difference £55.30, 95% confidence interval -£199.20 to £309.79). Secondary outcomes revealed that a fall in systolic or diastolic blood pressure, or an increase in heart rate, was more common in the glyceryl trinitrate group than in the control group (odds ratio 4.9, 95% confidence interval 3.7 to 6.4; p < 0.001). The need for a blood transfusion was also more common in the glyceryl trinitrate group than in the control group (odds ratio 1.53, 95% confidence interval 1.04 to 2.25; p = 0.033). CONCLUSIONS: Glyceryl trinitrate spray did not increase the delivery of retained placenta within 15 minutes of administration when compared with the placebo, and was not cost-effective for medical management of retained placenta. More participants reported palpitations and required a blood transfusion in the glyceryl trinitrate group. Further research into alternative methods of medical management of retained placenta is required. TRIAL REGISTRATION: Current Controlled Trials ISRCTN88609453. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 70. See the NIHR Journals Library website for further project information.

A retained placenta is diagnosed when, following the birth of a baby, the placenta is not delivered. When this situation occurs, women are at risk of bleeding heavily. The only way to treat a retained placenta is for a trained doctor to remove it by an operation in theatre. This procedure can be painful and upsetting. Furthermore, the timing of the operation can interrupt mother­baby bonding immediately after giving birth. The study tested if the use of glyceryl trinitrate spray, given as two puffs under the woman's tongue following the diagnosis of retained placenta, may help the placenta to deliver without an operation. The study also tested if glyceryl trinitrate was safe, assessed what women thought about the treatment and compared the costs of glyceryl trinitrate with those of current operative management. This study included 1107 women diagnosed with retained placenta following the birth of their baby. Half of the women were treated with glyceryl trinitrate spray and the other half were treated with a dummy spray, which looked identical but did not contain the active treatment. If the placenta delivered within 15 minutes of the study treatment being taken, this was considered a success. However, if the placenta did not deliver within 15 minutes and the woman had to have her placenta removed by an operation, then this was viewed as unsuccessful. Neither the woman nor the clinical staff knew if the treatment given was the glyceryl trinitrate spray or the dummy spray. The results indicate that, although women were happy to be involved in the trial and the treatment was safe, the use of glyceryl trinitrate spray did not reduce the need for the placenta to be manually removed by an operation in theatre. Furthermore, glyceryl trinitrate spray was not cost-effective.

A pragmatic group sequential, placebo-controlled, randomised trial to determine the effectiveness of glyceryl trinitrate for retained placenta (GOT-IT): a study protocol.

INTRODUCTION: A retained placenta is diagnosed when the placenta is not delivered following delivery of the baby. It is a major cause of postpartum haemorrhage and treated by the operative procedure of manual removal of placenta (MROP). METHODS AND ANALYSIS: The aim of this pragmatic, randomised, placebo-controlled, double-blind UK-wide trial, with an internal pilot and nested qualitative research to adjust strategies to refine delivery of the main trial, is to determine whether sublingual glyceryl trinitrate (GTN) is (or is not) clinically and cost-effective for (medical) management of retained placenta. The primary clinical outcome is need for MROP, defined as the placenta remaining undelivered 15 min poststudy treatment and/or being required within 15 min of treatment due to safety concerns. The primary safety outcome is measured blood loss between administration of treatment and transfer to the postnatal ward or other clinical area. The primary patient-sided outcome is satisfaction with treatment and a side effect profile. The primary economic outcome is net incremental costs (or cost savings) to the National Health Service of using GTN versus standard practice. Secondary outcomes are being measured over a range of clinical and economic domains. The primary outcomes will be analysed using linear models appropriate to the distribution of each outcome. Health service costs will be compared with multiple trial outcomes in a cost-consequence analysis of GTN versus standard practice. ETHICS AND DISSEMINATION: Ethical approval has been obtained from the North-East Newcastle & North Tyneside 2 Research Ethics Committee (13/NE/0339). Dissemination plans for the trial include the Health Technology Assessment Monograph, presentation at international scientific meetings and publication in high-impact, peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISCRTN88609453; Pre-results.

Nitroglycerin-Derived Pd/Pa for the Assessment of Intermediate Coronary Lesions.

OBJECTIVES: To assess the predictive value of Pd/Pa after nitroglycerin administration (Pd/Pa[N]) as compared with standard fractional flow reserve (FFR). METHODS: Consecutive patients with intermediate coronary lesions assessed by FFR between January 2014 and October 2015 were included. We measured Pd/Pa at baseline, Pd/Pa(N), and Pd/Pa after incremental doses of intracoronary adenosine. RESULTS: A total of 134 patients (27% females; mean age, 65 years) were included. The diagnostic performance of Pd/Pa(N) and identification of cut-off value for Pd/Pa(N) compared with FFR threshold of 0.8 using receiver-operating characteristic (ROC) area under the curve analysis was between 0.98 (95% confidence interval, 0.95-1.00; P<.05) for 48 µg and 0.86 (95% confidence interval, 0.79-0.94; P<.05) for 240 µg adenosine. Pd/Pa(N) ≤0.8 had 100% positive predictive value. Pd/Pa(N) ≥0.94 provided 100% negative predictive value with a high sensitivity (>92%). Optimal diagnostic accuracy of Pd/Pa(N) was achieved for values ≤0.84. The Pearson's correlation between Pd/Pa(N) and FFR varied between 0.89 for 24 µg adenosine and 0.77 for 240 µg (P<.01). CONCLUSION: Pd/Pa(N) values can be used for diagnosis of hemodynamically significant lesions. Pd/Pa(N) correlates well with standard FFR. Pd/Pa(N) cut-off of ≤0.8 can be considered significant without need for adenosine injection. The value of using adenosine whenever Pd/Pa(N) is ≥0.94 is limited.

The Assessment of short-term effect of L-Citrulline on endothelial function via FMD to NMD ratio in known CAD patients: A randomized, cross-over clinical trial (Clinical trial number: NCT02638727).

BACKGROUND: Recent studies have confirmed the essential and paramount role of the L-Citrulline on the nitric oxide regulation and the endothelial function improvement. MATERIALS AND METHODS: In this cross-over clinical trial, thirty patients, diagnosed with coronary artery disease (CAD) and flow mediated dilation to nitroglycerin dependent vasodilation (FMD/NMD) ratio less than 1, were included. The patients were randomly divided into two groups of 15 patients and underwent treatment by L-Citrulline or placebo for 15 days, in 2 step protocol. The indicators of assessment in the current study were the ratio of the FMD/NMD and FMD value. RESULTS: In the current cross-over clinical trial, the mean of FMD to NMD ratio and mean FMD value of all patients before starting the protocol were 0.91 ± 0.08 and 4.04 ± 0.51 mm, respectively. The final results of study showed that following L-Citrulline administration, mean FMD to NMD ratio and mean FMD value were enhanced to: 1.03 ± 0.09 and 4.96 ± 0.72 mm, respectively, which were statistically significant (P<0.001 and P<0.001, respectively). However, following placebo administration, mean FMD to NMD ratio and mean FMD value were receded to: 0.92 ± 0.09 and 4.06 ± 0.22 mm, respectively, which were not statistically significant (P = 0.75 and P = 0.89, respectively). Moreover, the improvement of mean FMD to NMD ratio (0.12 ± 0.02) and mean FMD value (0.92 ± 0.16 mm), following L-Citrulline administration, were statistically significant in comparison with the change of mean FMD to NMD ratio (0.01 ± 0.002) and mean FMD value (0.02 ± 0.003), following placebo administration (P<0.001 and P<0.001, respectively). CONCLUSION: L-Citrulline treatment can lead to improvement of the endothelial function in patients diagnosed with CAD which are assessed via FMD to NMD ratio FMD value enhancements.

[18F]FDG PET/CT-based response assessment of stage IV non-small cell lung cancer treated with paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches.

PURPOSE: Nitroglycerin (NTG) is a vasodilating drug, which increases tumor blood flow and consequently decreases hypoxia. Therefore, changes in [18F] fluorodeoxyglucose positron emission tomography ([18F]FDG PET) uptake pattern may occur. In this analysis, we investigated the feasibility of [18F]FDG PET for response assessment to paclitaxel-carboplatin-bevacizumab (PCB) treatment with and without NTG patches. And we compared the [18F]FDG PET response assessment to RECIST response assessment and survival. METHODS: A total of 223 stage IV non-small cell lung cancer (NSCLC) patients were included in a phase II study (NCT01171170) randomizing between PCB treatment with or without NTG patches. For 60 participating patients, a baseline and a second [18F]FDG PET/computed tomography (CT) scan, performed between day 22 and 24 after the start of treatment, were available. Tumor response was defined as a 30 % decrease in CT and PET parameters, and was compared to RECIST response at week 6. The predictive value of these assessments for progression free survival (PFS) and overall survival (OS) was assessed with and without NTG. RESULTS: A 30 % decrease in SUVpeak assessment identified more patients as responders compared to a 30 % decrease in CT diameter assessment (73 % vs. 18 %), however, this was not correlated to OS (SUVpeak30 p = 0.833; CTdiameter30 p = 0.557). Changes in PET parameters between the baseline and the second scan were not significantly different for the NTG group compared to the control group (p value range 0.159-0.634). The CT-based (part of the [18F]FDG PET/CT) parameters showed a significant difference between the baseline and the second scan for the NTG group compared to the control group (CT diameter decrease of 7 ± 23 % vs. 19 ± 14 %, p = 0.016, respectively). CONCLUSIONS: The decrease in tumoral FDG uptake in advanced NSCLC patients treated with chemotherapy with and without NTG did not differ between both treatment arms. Early PET-based response assessment showed more tumor responders than CT-based response assessment (part of the [18F]FDG PET/CT); this was not correlated to survival. This might be due to timing of the [18F]FDG PET shortly after the bevacizumab infusion.

In vivo assessment of endothelial function in human lower extremity arteries.

OBJECTIVE: Endothelial function has been measured in preclinical studies in human brachial and coronary arteries but not in lower extremity arteries affected by atherosclerosis. We describe a novel, first-in-man evaluation of endothelial function of the superficial femoral arteries (SFAs) in patients with peripheral arterial disease (PAD). METHODS: Enrolled were 25 patients with PAD requiring lower extremity angiography. Endothelial-dependent relaxation was measured using intravascular ultrasound (IVUS) imaging and a Doppler flow wire after the infusion of acetylcholine (Ach). IVUS-derived virtual histology of the same vessel was calculated. Endothelial-independent relaxation was measured with an infusion of nitroglycerin (200 µg). Levels of nitric oxide and serum nitric oxide metabolites were determined by laboratory analysis. RESULTS: Patients (48% male; mean age, 62 years) had a history of hypertension (80%), coronary disease (36%), and diabetes (40%). The mean SFA diameter was 5.2 ± 1 mm (range, 3.2-6.9 mm). Patients tolerated Ach infusion with no adverse events. Endothelial-dependent relaxation increased over baseline for all patients with Ach infusion of 10(-6) to 10(-4). At Ach 10(-4), diameter (0.5%) and area (1.8%) changes in the diseased SFAs were modest and insignificant; however, average peak velocity of blood flow significantly increased 26%, 46%, and 63% with an Ach 10(-6) to 10(-4) infusion. Calculations of limb volumetric flow (68% at Ach 10(-4)) were significantly increased after Ach infusion. Lower extremity nitric oxide levels were slightly lower than systemic venous levels (P = .04). Nitroglycerin infusion indicated normal smooth muscle responsiveness (3% diameter, 9% area, and 116% velocity change over baseline). IVUS-virtual histology plaque stratification indicated predominantly fibrous morphology (46%; necrotic core, 29%; calcium, 18%). Atheroma burden was 14.9 ± 5.5 mm(3)/cm and did not correlate with endothelial responsiveness. CONCLUSIONS: Endothelial function can be measured directly in human lower extremity arteries at the sites of vascular disease. Despite extensive atherosclerosis, endothelial function is still intact. These data support the application of regional endothelial-specific biologic therapies in patients with PAD.

Nitroglycerine use in transcatheter arterial (chemo)embolization in patients with hepatocellular carcinoma and dual-energy CT assessment of Lipiodol retention.

OBJECTIVES: To investigate whether the addition of nitroglycerine to transcatheter arterial (chemo)embolization (TAE/TACE) can increase the delivery and effectiveness of TAE/TACE in patients with hepatocellular carcinoma (HCC) by dual-energy CT. METHODS: HCC patients (BCLC stage A or B) were randomized to (n = 51) or not to (n = 50) receive nitroglycerine and an emulsion of Lipiodol with or without doxorubicin, followed by embolization with Gelfoam pledgets. Dual-energy CT was performed pre- and 1 to 3 months post-embolization to assess changes in tumour diameter and Lipiodol levels in tumours. RESULTS: Median tumour diameter decreased from baseline in both groups with and without nitroglycerine (7.11 % vs. 12.5 %, respectively), and was statistically significant in the group receiving nitroglycerine (P = 0.023). There was no difference between the two groups in disease response (P = 0.237). The concentration and percentage of Lipiodol retained in tumours were significantly greater in patients treated with nitroglycerine compared to those without (median concentration 15.05 mg/mL vs. 4.40 mg/mL, respectively, P < 0.001; median percentage 82.01 % vs. 36.75 %, respectively, P < 0.001). CONCLUSIONS: Nitroglycerine increased delivery of the Lipiodol emulsion via TAE/TACE to HCC tumours with significant tumour reduction. Dual-energy CT can accurately quantify the amount of Lipiodol deposited in tumours. KEY POINTS: • Nitroglycerine improves delivery of tumour-targeted therapy via enhanced permeability and retention. • In hepatocellular carcinoma, nitroglycerine added to TAE/TACE showed greater tumour reduction. • Dual-energy CT can reliably quantify the amount of Lipiodol in TAE/TACE.

Cost-effectiveness of transdermal nitroglycerin use for preterm labor.

OBJECTIVE: The objective of this study was to determine the cost-effectiveness of using transdermal nitroglycerin (GTN) for cases of preterm labor. METHODS: The study included 153 women with clinical preterm labor, who were randomly allocated to either a GTN or placebo arm. All randomized cases were included in the final economic analysis. Differences between the two arms in gestational age at delivery, neonatal intensive care unit (NICU) admission, length of NICU stay, and NICU cost were assessed. Costs for non-NICU cases were calculated using Ottawa Hospital data through the Ontario Case Costing Initiative (OCCI). Cost-effectiveness and sensitivity analyses using a hospital perspective were both conducted. RESULTS: In the 153 randomized cases, 55 babies were admitted to NICU (GTN = 24; placebo = 31). We found no significant differences between the two arms in gestational age at delivery, NICU admission rate (32.4% vs. 39.2%), NICU length of stay (42.7 days vs. 52.8 days), or NICU cost (CAN $34,306 vs. CAN $44,326). Overall, (based on all randomized cases) the cost-effectiveness analyses showed that the GTN arm was the dominant strategy, with both lower cost (CAN $13,397 vs. CAN $18,427) and higher NICU admission avoided rate (67.6% vs. 60.8%) compared to the placebo arm. This dominance persisted in all sensitivity analyses. CONCLUSION: The use of GTN patch for preterm labor could reduce NICU costs, while improving important neonatal outcomes.

Assessment of endothelial function in patients with fibromyalgia--cardiac ultrasound study.

In patients with fibromyalgia (FM) syndrome, stress and pain may chronically enhance sympathetic activity, altering cardiovascular response and inducing endothelial dysfunction. We investigated endothelial function in FM patients using echocardiography and analyzed whether endothelial function was affected by the clinical parameters of FM. Fifty-five postmenopausal women with FM and 35 healthy controls were included. Endothelial function was examined by brachial artery flow-mediated dilatation (FMD, endothelium dependent) and response to 40 µg of sublingual nitroglycerine (NTG-induced dilatation, endothelium independent). FM patients underwent manual tender point survey and completed visual analogue scale (VAS) of pain and fibromyalgia impact questionnaire (FIQ). The study participants were subdivided into two groups based on the sum of the FIQ score (group A, FIQ ≥ 50, group B, <50). The FMD value (5.7 ± 3.9% vs. 7.0 ± 1.4%, P = 0.008) and NTG-induced dilatation (12.5 ± 5.1% vs. 14.7 ± 2.5%, P = 0.006) were significantly lower in FM group than healthy control. There were no significant differences in FMD between groups A and B (5.4 ± 3.3% vs. 6.6 ± 3.5%, P = 0.19). However, significant decreases were noted in NTG-induced dilatation values of group A compared with those of group B (11.0 ± 4.4% vs. 14.3 ± 3.8%, P = 0.004). FMD and NTG-induced dilatation showed a significant inverse association with pain VAS and FIQ. Pain exerts a negative effect on endothelial function in FM patients, and that effect was significantly different according to the FIQ score.

Left atrial flow propagation velocity: a new approach for assessment of left atrial reservoir function.

To assess the feasibility of left atrial flow propagation velocity (LAFPV) measurement and to evaluate the influence of preload alterations on this new parameter of left atrial (LA) reservoir function as compared to conventional echocardiographic indices. 30 healthy volunteers (26 ± 5 years, 20 males) underwent echocardiographic examination at rest, during passive leg lifting and after sublingual administration of nitroglycerine with subsequent Valsalva maneuver. LA reservoir function was assessed by conventional indices including LA expansion index, peak velocity and velocity-time integral of pulmonary venous systolic flow. As well, LAFPV was measured by color M-mode in an apical 4-chamber view as the slope of the transatrial flow wave during LA reservoir phase. LAFPV measurement was feasible in 25 subjects (83%). All conventional parameters of LA reservoir function were significantly altered from resting values by both load-modifying conditions. However, LAPFV was not significantly altered by such maneuvers (228 ± 28 cm s⁻¹ at rest vs. 238 ± 3 cm s⁻¹ during leg lifting, P = NS, vs. 218 ± 38 cm s(-1) after nitroglycerin with Valsalva maneuver, P = NS vs. rest, P < 0.01 vs. leg lifting). LAFPV can be measured in a majority of subjects and represents a new, less load-dependent index of LA reservoir function that may more appropriately reflect LA compliance.

Assessment of coronary flow parameters by transesophageal echocardiography in patients with isolated coronary artery ectasia: effect of intravenous nitroglycerin.

BACKGROUND: We sought to assess coronary flow parameters in patients with isolated coronary artery ectasia (CAE) as compared to subjects with normal coronaries. METHODS: Consecutively, we enrolled 30 patients with ectasia of the left anterior descending (LAD) coronary artery (study group), and 10 subjects with normal coronaries (control group). All patients underwent transesophageal echocardiography to visualize the LAD. Spectral recordings of proximal LAD flow velocities were made and velocity time integrals were calculated. The diameter of the proximal LAD was measured and LAD blood flow was calculated. Nitroglycerin (0.3 mg) was administered intravenously and measurements were repeated 5 minutes later. RESULTS: The mean age of the whole series was 48.6 ± 8 years, 39 (97.5%) being males. A significantly higher baseline systolic, diastolic, and total coronary blood flow was found in the study group as compared to the control group (46.1 ± 34.3 vs. 23.1 ± 8.2, 123.9 ± 73.3 vs. 68.1 ± 21.6, 170.1 ± 97.9 vs. 91.1 ± 26.8 cm(3) /min, respectively, P < 0.05 for all). Within the study group, nitroglycerin administration caused a significant decrease in peak diastolic velocity; systolic, diastolic, and total velocity time integrals; and both diastolic and total coronary blood flow (P < 0.05 for all). Meanwhile, within the control group, nitroglycerin administration caused a significant increase in the total coronary blood flow (P < 0.05). CONCLUSIONS: Patients with CAE have higher resting coronary blood flow in comparison with subjects with normal coronaries. Intravenous nitroglycerin administration causes significant reduction of coronary blood flow in ectatic coronary arteries.

Changes in abdominal aortic diameter in response to the cold pressor test and nitroglycerin: a new noninvasive model for the assessment of endothelial-dependent and endothelial-independent vascular relaxation.

Coronary vascular responses to the cold pressor test (CPT) have been shown to parallel changes caused by infusion of acetylcholine. Whereas the CPT is a method of assessing endothelial-dependent vasodilation, nitroglycerin produces endothelial-independent vasodilation. We performed histological studies on autopsy specimens of abdominal aorta and demonstrated that it is predominantly muscular artery. To test the hypothesis that vasodilatory responses of the abdominal aorta to interventions would parallel those of peripheral vessels, 33 normal males without hypertension, diabetes, or hyperlipidemia, and 10 younger male smokers had ultrasound imaging of the abdominal aorta conducted in the control state, 2 minutes after immersion of the hand in cold water and 10 minutes after rewarming the hand (i.e., cold pressor test). The internal diameter of the abdominal aorta at the onset of the QRS complex was determined for each intervention by averaging 4 beats. It was found that the cold pressor test and nitroglycerin resulted in similar degrees of dilation of the abdominal aorta in nonsmoking subjects, and that these responses were attenuated in smokers. Thus, both endothelial-dependent and endothelial-independent vascular relaxation were impaired in smokers.