Citations

Pulmonary hypertension is common in patients with heart failure (HF); however, for a given degree of left ventricular dysfunction, the range in pulmonary artery pressures (PAP) is large. Polymorphisms of a number of candidate genes have been implicated in contributing to smooth muscle dysfunction and remodeling of the pulmonary vasculature, including the serotonin transporter (5HTT) gene. Patients with HF may have mild tissue hypoxia, which may alter expression of 5HTT. This study examined the influence of a repeat length polymorphism in the promoter region of the 5HTT gene on differences in PAP in HF patients. Ninety HF patients (age=55±14yrs; LVEF=28±10%; NYHA=2.0±0.9) and 90 age and gender matched controls (CTL, age=51±15yrs; LVEF=63±7%) were recruited. Heart failure and CTL subjects were divided into 3 genotype groups, SS‐homozygotes for the short variant, LL‐homozygotes for the long variant and LS‐heterozygous condition. For both HF and CTL, SS n=20; LS n=41; LL n=29). PAP was calculated from the tricuspid regurgitant velocity. Age and gender did not differ between HF and CTL or among genotype groups. PAP was higher in HF compared to CTL (38.9±12.5 vs 27.7±8.2 mmHg, p<0.01, respectively) with a significant genotype effect in HF (SS=34.2±8.6 vs LS=38.2±11.4 vs LL=43.2±15.2 mmHg, p<0.05), but not in CTL. The HF group also demonstrated elevated left atrial diameter compared to CTL (HF 48.0±8.7 vs 32.8±4.8 mm, p<0.01, respectively) although no difference was seen within the HF group across genotypes. These results suggest that the LL variant of 5HTT is associated with elevated PAP in HF but not CTL. HL71478 and HL07111.

Dietary sodium loading decreases β‐adrenergic receptor mediated vasodilation in hypertensive men, and paradoxically increases this dilation in normotensive men; no information exists in women. The purpose of this investigation was to test the hypothesis that dietary sodium loading and restriction influences β‐receptor mediated vasodilation in a sex‐dependent manner. Healthy normotensive subjects consumed a high (400 mmol/day, n=36, mean age±SEM 23±1 yr, 23 women) or low (10 mmol/day, n=30, 30±1 yr, 14 women) sodium diet for 5 days prior to study. Forearm blood flow (FBF, plethysmography) responses to brachial artery administration of isoproterenol (ISO: 1, 3, 6, 12 ng/100 ml tissue/min) were measured before and after endothelial NO synthase inhibition with N G ‐monomethyl‐L‐arginine (L‐NMMA). Consistent with prior reports, the FBF response to ISO was greater in men on high sodium compared to men on low sodium (p=0.03, ISO‐by‐sodium interaction). The highest response to ISO was 16.6±1.7 and 11.0±1.1 ml/100 ml tissue/min (high vs. low, p=0.01). After LNMMA the men's response to ISO did not differ based on sodium. In contrast, in women dietary sodium did not affect the response to ISO before or after LNMMA. We conclude that dietary sodium alters β‐adrenergic receptor mediated vasodilation in men, which appears to be dependent on NO. This is the first study to suggest that these mechanisms of vasodilation are resistant to dietary sodium in women. Support: HL‐089331, CTSA RR‐024150

Abstract Basilar artery occlusions (BAOs) are devastating ischemic strokes that account for 1% of all strokes with high morbidity and mortality; however, neuroendovascular techniques such as ADAPT have recently revolutionized the clinical outcomes of these patients. 1-3 Common underlying pathology in patients with BAO include intracranial atherosclerotic disease (ICAD) as well as thromboembolic origin. 4 Basilar artery ICAD in a setting of acute stroke portends a poor prognosis and post-thrombectomy residual critical flow limiting stenosis treatment options, including balloon angioplasty with or without stent placement. 5-7 We present a video illustration of neuroendovascular technique and challenges encountered when managing this pathology. Image at 5:42 reprinted with permission from Alawieh et al, Lessons learned over more than 500 stroke thrombectomies using ADAPT with increasing aspiration catheter size, Neurosurgery , 86(1), 2020, pp. 61-70, with permission from the Congress of Neurological Surgeons. 1

β 2 ‐adrenergic receptor (ADRB2) gene polymorphisms influence vasodilation, but studies investigating regional or systemic responses conflict, possibly due to counter‐regulatory baroreflex action during systemic β 2 ‐agonist infusion. We tested the hypothesis that ADRB2 gene variation would influence the SVR response to ADRB2 agonist terbutaline (TERB) during baroreflex inhibition. 40 healthy young adults were recruited according to the double homozygous haplotypes: Arg16+Gln27 (n=13), Gly16+Gln27 (n=6), and Gly16+Glu27 (n=21). Arterial pressure was measured by brachial arterial catheter, cardiac output by acetylene breathing. Lymphocytes were sampled for ex vivo analysis of ADRB2 density and binding conformation. Following baroreflex ablation with trimethaphan (3–7 mg/min), phenylephrine was titrated to restore blood pressure to baseline. TERB was infused i.v. at 33 and 67 ng/kg/min for 15 min/dose. There was partial evidence to suggest a main effect of haplotype on the change in SVR ( P = 0.06). For SNP position 16, the highest dose of TERB produced lower SVR in Gly16 vs Arg16 ( P = 0.03). Lymphocyte ADRB2 binding conformation was similar but receptor density was greater in Gly16 vs Arg16 ( P = 0.05). During baroreflex inhibition, the SVR response to systemic ADRB2 agonist is suggestive of augmented ADRB2 function in Gly16+Glu27 homozygotes, with greater influence from Gly16. Supported from NIH and DFG.

Abstract In-stent stenosis has a reported prevalence of 14% to 19% at 1-yr follow-up after carotid stenting and is associated with an increased risk of acute ischemic stroke. 1,2 Risk factors include female sex, diabetes, and dyslipidemia. Cutting balloon angioplasty is a safe and effective treatment modality for the treatment of carotid in-stent stenosis, and alternative treatment options include observation with medical management and placement of another stent. 3,4 The authors present the case of a 61-yr-old man with carotid in-stent restenosis and progressive worsening on serial imaging with ultrasound. The patient had a history of carotid stenting for symptomatic stenosis 6 mo prior and was maintained on aspirin and clopidogrel. In light of the progressive worsening, the in-stent stenosis was confirmed on computed tomography (CT) angiogram. The options were discussed with the patient and he consented for treatment with cutting balloon angioplasty. Final angiogram showed improvement of the luminal diameter with a residual stenosis of 15%. The patient tolerated the procedure well and was discharged home on postoperative day 1. Follow-up ultrasound demonstrated moderate improvement in peak systolic velocities, and the plan is to continue observation with a clinical follow-up and repeat carotid Dopplers at 3 mo.

1561 Background: Surgical interventions are studied less often than medical or radiation interventions in oncology clinical trials. We characterized surgical oncology trials registered on ClinicalTrials.gov, analyzed funding sources and identified features associated with early discontinuation and results reporting. Methods: We employed a cross-sectional study design with descriptive, logistic regression, cox regression, time series and survival analyses. We downloaded all 270,172 studies registered on the Aggregate Analysis of the ClinicalTrials.gov database from October 1, 2008 to March 9, 2020. After excluding non-interventional trials, applying cancer/oncology specific Medical Subject Heading terms to the remaining trials and excluding phase 1 trials, 27,915 trials were identified for manual review. Primary exposure variables were trial focus: neoplasia site and treatment modality (surgical interventions included investigations of outcomes from surgical resection or intra-operative/peri-operative changes), and funding: industry, U.S. government, academic. Results: 26,815 trials were found to have true oncology content; 1,661 (6.2%) involved surgical oncology, representing 311,789 patients. Funding sources were: 82.7% by academic institutions, 10.9% by industry, and 6.2% by U.S. government. The most studied neoplasia sites were colorectal (17.4% of trials), breast (10.7%), gastric (10.5%), hepatic (8.6%), lung (7.5%), brain/CNS (6.7%) and cervical (6.6%). U.S. government funded surgical oncology trials had the lowest risk of early discontinuation (adjusted HR 0.50, 95% CI: 0.26-0.99, p<0.047) and the highest odds of results reporting (adjusted OR 1.08, 95% CI: 0.55-2.11, p=0.83) (Table 1). Conclusions: There is a paucity of surgical oncology clinical trials compared to other treatment modalities, especially in context of surgery’s role in overall cancer care. From 2008-2020 only 6.2% of trials focused on surgical oncology, and U.S. government funded trials displayed the lowest hazard of early discontinuation and highest odds of results reporting. Stakeholders should look to government funded trials as models of improvement, but must increase representation and results dissemination of surgical oncology trials to guide treatment recommendations. Surgical oncology trial features and associated early discontinuation/results reporting. [Table: see text]

Abstract Breast cancer (BC) is a common cause of morbidity and mortality, particularly in women. Moreover, the discovery of diagnostic biomarkers for early BC remains a challenging task. Previously, we [Jasbiet al.J. Chromatogr. B.2019, 1105, 26−37] demonstrated a targeted metabolic profiling approach capable of identifying metabolite marker candidates that could enable highly sensitive and specific detection of BC. However, the coverage of this targeted method was limited and exhibited suboptimal classification of early BC (EBC). To expand the metabolome coverage and articulate a better panel of metabolites or mass spectral features for classification of EBC, we evaluated untargeted liquid chromatography quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) data, both individually as well as in conjunction with previously published targeted LC-triple quadruple (QQQ)-MS data. Variable importance in projection scores were used to refine the biomarker panel, whereas orthogonal partial least squares-discriminant analysis was used to operationalize the enhanced biomarker panel for early diagnosis. In this approach, 33 altered metabolites/features were detected by LC-QTOF-MS from 124 BC patients and 86 healthy controls. For EBC diagnosis, significance testing and analysis of the area under receiver operating characteristic (AUROC) curve identified six metabolites/features [ethyl (R)-3-hydroxyhexanoate; caprylic acid; hypoxanthine; and m/z 358.0018, 354.0053, and 356.0037] with p &lt; 0.05 and AUROC &gt; 0.7. These metabolites informed the construction of EBC diagnostic models; evaluation of model performance for the prediction of EBC showed an AUROC = 0.938 (95% CI: 0.895–0.975), with sensitivity = 0.90 when specificity = 0.90. Using the combined untargeted and targeted data set, eight metabolic pathways of potential biological relevance were indicated to be significantly altered as a result of EBC. Metabolic pathway analysis showed fatty acid and aminoacyl-tRNA biosynthesis as well as inositol phosphate metabolism to be most impacted in response to the disease. The combination of untargeted and targeted metabolomics platforms has provided a highly predictive and accurate method for BC and EBC diagnosis from plasma samples. Furthermore, such a complementary approach yielded critical information regarding potential pathogenic mechanisms underlying EBC that, although critical to improved prognosis and enhanced survival, are understudied in the current literature. All mass spectrometry data and deidentified subject metadata analyzed in this study have been deposited to Mendeley Data and are publicly available (DOI: 10.17632/kcjg8ybk45.1).

Abstract Embolic protection devices (EPDs) have become a standard of care during internal carotid artery revascularization. 1,2 This video is about a 57-yr-old-male who presented with a wake-up stroke with a left hemispheric syndrome. Head computed tomography angiography (CTA) revealed tandem occlusions of the proximal left internal carotid artery (ICA) and of the distal left middle cerebral artery (MCA) with an ASPECT (Alberta Stroke Program Early CT Score) score of 6. The patient underwent a cerebral angiogram and was treated with balloon angioplasty with a distal EPD and mechanical thrombectomy. The EPD became occluded with thrombus from the ICA and was retrieved through a 6-Fr Sofia (MicroVention) under continuous aspiration. Successful revascularization of the proximal ICA and distal MCA was achieved. No procedure-related complications occurred, and the patient's neurological exam improved. Tandem occlusions can occur in up to 15% of strokes. The optimal treatment can be controversial, but mechanical thrombectomy and ICA revascularization with a distal EPD appear to be safe and effective in selected patients. 3 Consent was obtained for the procedure and for the video production.

Introduction: Thiazide diuretics (TZDs) are the second most frequently prescribed class of antihypertensives. But <50% patients achieve goal blood pressure (BP) on TZD monotherapy, mostly because therapy is chosen overlooking the heterogeneity in patient responses. Circulating microRNAs (miRNAs) remain attractive as non-invasive biomarkers to predict drug response and tailor therapy for optimal outcomes. Hypothesis: Plasma miRNAs may play a role in TZD response; we aim to identify those associated with hydrochlorothiazide (HCTZ) response. Methods: We profiled 754 miRNAs in baseline (untreated) plasma samples of 36 uncomplicated hypertensive adults (18 Responders (R) and 18 Non-responders (NR) based on their diastolic BP (DBP) response to HCTZ therapy) from the Pharmacogenomic Evaluation of Antihypertensive Responses clinical trial, using the real-time qPCR based TaqMan OpenArray Human microRNA panel. We filtered out miRNAs with low amplification scores and Cq>38 and samples with low miRNA expression. Combination of miR-223 and miR-19b (identified as most stably expressed miRNAs by NormFinder Software) was used to normalize expression across samples. We used MannWhitney U test to identify microRNAs differentially expressed between R and NR; linear and logistic regressions for associations of miRNA expression with BP response. FDA corrected p<0.05 was used as significance threshold, unadjusted p<0.05 as suggestive threshold. Results: Mean systolic BP (SBP)/DBP change in R was 14/10 mmHg and in NR 0/1 mmHg. We found 77 miRNAs to be consistently expressed across samples, of which 11 were upregulated and 14 downregulated with >2-fold difference between R and NR. Though no miRNAs reached FDR p<0.05, miR-376a (fold change(fc)= 10.1, p= 0.035) and miR-17 (fc= -0.45, p= 0.017) were differentially expressed between R and NR and their expression associated with DBP and SBP change, along with miR-10b, miR-24, miR-134 associated with SBP change at p<0.05. Conclusions: In this first ever genome-wide miRNA study of antihypertensive drug response, we discovered circulating miRNAs associated with BP response to HCTZ. Future studies are planned to validate these findings in a larger cohort, across different race group and across different TZD.