Chemotherapy (CT) is a necessary treatment to prevent the growth and survival of cancer cells. However, CT has a well-established adverse impact on the cardiovascular (CV) system, even years after cessation of treatment. The effects of CT drugs on tumor vasculature have been the focus of much research, but little evidence exists showing the effects on the host microcirculation. Microvascular (MV) dysfunction is an early indicator of numerous CV disease phenotypes, including heart failure. The goal of this study was to evaluate the direct effect of doxorubicin (Dox) on human coronary MV function. To study the effect of CT on the cardiac MV function, flow-mediated dilation (FMD), pharmacologically-induced endothelial dependent dilation to acetylcholine (ACh), and smooth muscle-dependent dilation to papaverine were investigated. Vessels were freshly isolated from atrial appendages of adult patients undergoing cardiopulmonary bypass surgery or from cardiac tissue of pediatric patients, collected at the time of surgery to repair congenital heart defects. Isolated vessels were incubated in endothelial culture medium containing vehicle or Dox (100 nm, 15–20 h) and used to measure dilator function by video microscopy. Ex vivo treatment of adult human coronary microvessels with Dox significantly impaired flow-mediated dilation (FMD). Conversely, in pediatric coronary microvessels, Dox-induced impairment of FMD was significantly reduced in comparison with adult subjects. In both adult and pediatric coronary microvessels, ACh-induced constriction was reversed into dilation in the presence of Dox. Smooth muscle-dependent dilation remained unchanged in all groups tested. In vessels from adult subjects, acute treatment with Dox in clinically relevant doses caused significant impairment of coronary arteriolar function, whereas vessels from pediatric subjects showed only marginal impairment to the same stressor. This interesting finding might explain the delayed onset of future adverse CV events in children compared with adults after anthracycline therapy. NEW & NOTEWORTHY We have characterized, for the first time, human microvascular responses to acute ex vivo exposure to doxorubicin in coronary vessels from patients without cancer. Our data show an augmented impairment of endothelial function in vessels from adult subjects compared with pediatric samples.

Rationale TERT, (catalytic subunit of telomerase), is linked to development of coronary artery disease (CAD); however, whether the role of nuclear vs. mitcondrial actions of TERT are involved is not determined. Dominant-negative TERT splice variants contribute to decreased mitochondrial integrity and promote elevated ROS production. We hypothesize that a decrease in mitochondrial TERT would increase mtDNA damage, promoting a pro-oxidative redox environment. The goal of this study was to define whether mitochondrial TERT is sufficient to maintain NO as the underlying mechanism of FMD by preserving mtDNA integrity. Methods and Results Immunoblots and qPCR were used to show elevated levels of splice variants α- and β-deletion TERT tissue from subjects with and without CAD. Genetic, pharmacological, and molecular tools were used to manipulate TERT localization. Isolated vessel preparations and fluorescence-based quantification of mtH2O2 and NO showed that reduction of TERT in the nucleus increased flow induced NO and decreased mtH2O2 levels, while prevention of mitochondrial import of TERT augmented pathological effects. Further elevated mtDNA damage was observed in tissue from subjects with CAD and initiation of mtDNA repair mechanisms was sufficient to restore NO mediated dilation in vessels from patients with CAD. Conclusion The work presented is the first evidence that catalytically active mitochondrial TERT, independent of its nuclear functions, plays a critical physiological role in preserving NO-mediated vasodilation and the balance of mitochondrial to nuclear TERT is fundamentally altered in states of human disease that are driven by increased expression of dominant negative splice variants.

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Rational Women with preeclampsia (PE) have compromised endothelial function (assessed by brachial artery flow‐mediated dilation) compared to normal women. Placental and uterine spiral artery endothelial dysfunction is seen in PE pregnancies. Human studies remain incomplete, as most approaches have been unable to eliminate neural, humoral, paracrine influences on vessel response. Direct evaluation of the placental arterioles will allow a more direct analysis of vasodilatory responses as related to the endothelial dysfunction in PE. Objective To study placental endothelial function in preeclamptic (PE) and normal placental vessels. Methods To examine the impact of PE on the microvascular function, isolated vessels from placentas of healthy and PE pregnancies were used for videomicroscopy. Endothelial‐dependent dilation to flow (FMD), acetylcholine (ACh) and smooth muscle‐dependent dilation to papaverine were evaluated. Data are presented as a percentage of maximum diameter and were analyzed with 2‐way ANOVA RM with statistical significance set at *p<0.05; data are expressed as mean ± SE. Results Vessels from PE patients resulted in impairment of FMD (control 71.% ±6.6%, PE 31.6%±10.7%*) and dilation to Ach (control 63.6%±9.4, PE 32.7±8.83%*). Smooth muscle‐dependent dilation to papaverine was unchanged between the two groups (Figure ). Conclusion Preliminary studies show impaired endothelial function in placental vessels of subjects with PE, compared to healthy controls, while smooth muscle function was not affected. Understanding the underlying mechanism(s) of vasodilation in placental vasculature will further the understanding the pathophysiology of PE. Support or Funding Information The project described was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, Award NumberUL1TR001436. The content is solely the responsibility of the author(s) and does not necessarily represent the official views of the NIH. This project is funded by the Research and Education Program Fund, a component of the Advancing a Healthier Wisconsin Endowment at the Medical College of Wisconsin. Vessels from PE patients resulted in impairment of FMD and dilation to ACh. Smooth muscle‐dependent dilation to papaverine was unchanged between the two groups. Statistical significance denoted with *

Beclomethasone dipropionate (BDP) has been reformulated in a chlorofluorocarbon-free propellant, hydrofluoroalkane-134a (HFA), resulting in an extrafine aerosol which gives improved drug delivery to the airways. The objective of this 6 week, placebo-controlled study was to evaluate the clinical efficacy of HFA-BDP 400 micrograms day-1 in 256 adult patients with moderate asthma. This is a lower daily dose than that recommended for existing BDP inhalers in current treatment guidelines for moderate asthma (NIH publication 95-3659). Another objective was to evaluate whether delivering the 400 micrograms dose as four actuations of 50 micrograms twice daily (HFA-BDP 50 micrograms) provided equivalent asthma control to delivering the dose as two actuations of 100 micrograms twice daily (HFA-BDP 100 micrograms) without the use of a spacer or holding chamber. Both active treatments produced a significant change from baseline in morning peak expiratory flow (PEF), which was significantly larger than that in the placebo group (P < or = 0.017) throughout the study. The mean changes from baseline in morning PEF at weeks 5-6 were 47.0 l min-1 in the combined HFA-BDP group and 16.5 l min-1 in the HFA-placebo group. The two dose strengths were statistically equivalent (P = 0.017 for equivalence testing). The active treatments also produced significant improvements compared with placebo in evening PEF, forced expiratory volume in the first second, forced expiratory flow over 25-75% of vital capacity, sleep disturbance scores and daily beta-agonist use. The study medication was well tolerated, with a low incidence of adverse events. The results from this study demonstrate that a daily dose of 400 micrograms HFA-BDP (given in 50 micrograms and 100 micrograms strengths) provides dose proportionality and effective control in patients with moderate asthma.