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Introduction We evaluated the incidence of change in serial 12-lead electrocardiogram (ECG) diagnostic classifications in patients resuscitated from out-of-hospital (OH) cardiac arrest (OHCA) comparing OH to emergency department (ED) ECGs. Methods This retrospective case series included: 1) adults (≥ 18 years old), 2) resuscitated from OHCA, 3) ≥ 1 OH and 1 ED ECG/patient, and 4) emergency medical services (EMS) transport to the study hospital. OH and ED ECGs were classified as: 1) STEMI (ST-segment Elevation Myocardial Infarction), 2) Ischemic, and 3) Non-ischemic. Two ED physicians and one cardiologist independently classified all ECGs, then generated a consensus opinion classification for each ECG based on American Heart Association’s 2018 Expert Consensus criteria. The most ischemic OH ECG classification was compared with the last ED ECG classification. Results From 7/27/12 to 7/18/19, 176 patients were entered with a mean age of 61.2 ± 16.6 years; 102/176 (58%) were male. Overall, 504 OH and ED 12-lead ECGs were acquired (2.9 ECGs/patient). ECG classification inter-rater reliability kappa score was 0.63 ± 0.02 (substantial agreement). Overall, 86/176 (49%) changed ECG classification from the OH to ED setting; 69/86 (80%) of these ECGs changed from more to less ischemic classifications. Of 49 OH STEMI ECG classifications, 33/49 (67%) changed to a less ischemic (non-STEMI) ED ECG classification. Conclusions Change in 12-lead ECG classification from OH to ED setting in patients resuscitated from OHCA was common (49%). The OH STEMI classification changed to a less ischemic (non-STEMI) ED classification in 67% of cases.

Sedentary behavior is associated with cardiovascular disease (CVD) and mortality, independent of physical activity. The biological mechanisms underlying these associations are largely unknown. We hypothesized that obese subjects with sedentary desk jobs, when assigned a sit–stand desk, will reduce daily sedentary time, and show improvement in arterial flow-mediated dilation (FMD), an early indicator of CVD. Overweight and obese subjects without known CVD were recruited at our institution and given an adjustable sit–stand desk at work. Activities were quantified with an accelerometer for 7 days at baseline and during the intervention. FMD of the brachial and superficial femoral arteries, fasting lipids, insulin and glucose labs, and anthropometrics were measured at baseline, and 12 and 24 weeks. Repeated one-way ANOVA tests were used to compare measurements over time. Fifteen participants were enrolled (93% female, mean age 40 ± 5 years, mean body mass index [BMI] 33 ± 5). Mean daily sedentary time at work decreased by 90 minutes from baseline (385 ± 49 minutes) to 12 weeks (297 ± 80 minutes, p = 0.002) and 24 weeks (295 ± 127 minutes, p = 0.015). Femoral FMD increased from baseline (4.9 ± 1.7%) to 12 weeks (6.4 ± 2.3%, p = 0.043) and further to 24 weeks (8.1 ± 3.2%, p = 0.009). Significant improvement in fasting triglycerides and insulin resistance occurred. There was no change in brachial FMD, exercise activity, step counts, weight, or BMI. A significant reduction in sedentary time during working hours was identified with utilization of a sit–stand desk and sustained over 24 weeks. Improvements in FMD, triglycerides, and insulin resistance provide insight into mechanisms of adverse health risks associated with sedentary behavior.

Preeclampsia is a life-threatening pregnancy-associated cardiovascular disorder characterized by hypertension and proteinuria at 20 weeks of gestation. Though its exact underlying cause is not precisely defined and likely heterogenous, a plethora of research indicates that in some women with preeclampsia, both maternal and placental vascular dysfunction plays a role in the pathogenesis and can persist into the postpartum period. Potential abnormalities include impaired placentation, incomplete spiral artery remodeling, and endothelial damage, which are further propagated by immune factors, mitochondrial stress, and an imbalance of pro- and antiangiogenic substances. While the field has progressed, current gaps in knowledge include detailed initial molecular mechanisms and effective treatment options. Newfound evidence indicates that vasopressin is an early mediator and biomarker of the disorder, and promising future therapeutic avenues include mitigating mitochondrial dysfunction, excess oxidative stress, and the resulting inflammatory state. In this review, we provide a detailed overview of vascular defects present during preeclampsia and connect well-established notions to newer discoveries at the molecular, cellular, and whole-organism levels.

Female athletes display a high prevalence of hypothalamic amenorrhea as a result of energy imbalance. In these athletes with amenorrhea, decreased luteinizing hormone/follicule-stimulating hormone secretion leads to deficiency in endogenous estrogen. The severe estrogen deficiency in these athletes may increase cardiovascular risk similar to that in postmenopausal women. This review discusses the potential cardiovascular risk factors in athletes with amenorrhea as a result of hypoestrogenism, which include endothelial dysfunction and unfavorable lipid profiles. We also consider the potential to reverse the cardiovascular risk by restoring energy or hormonal imbalance along the reproductive axis in athletes with amenorrhea.

The vascular endothelium plays a crucial role to regulate vascular tone. Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) infection is known to cause vascular endothelial dysfunction. However, the long‐term effects of SARS‐CoV‐2 in resistance vessels remains unknown. This study is designed to test whether endothelium‐dependent vasodilation in human arterioles remains impaired after clearance of SARS‐CoV‐2 virus. Fresh human adipose tissues were obtained as discarded surgical specimens from control subjects (n=15, no SARS‐CoV‐2 exposure, 46.7±4 years) and previously SARS‐CoV‐2 positive subjects (PSPSs: n=8, 35.8±3.8 years). Among PSPSs, the time between positive and negative SARS‐CoV‐2 test results was ≤3 months (n=6) or 8 months (n=2). Isolated arterioles (100‐200 µm) were cannulated under 60 mmHg and examined for diameter changes to acetylcholine (ACh; 10−9 to 10−5 M) and sodium nitroprusside (SNP: 10−9 to 10−4 M) using videomicroscopy. Flow‐mediated dilation (FMD) was recorded at steady‐state during graded increases in intraluminal pressure gradients (5‐100 cm H2O). Dilation to ACh and FMD in arterioles from PSPSs was significantly reduced (ACh max. dilation at 10−5 M: 60±6% vs. 92.8±3.9% in control, n=7‐8, P

Objective The objective of this study was to measure flow‐mediated dilation (FMD) prior to and following transient increases in intraluminal pressure (IILP) in resistance arterioles isolated from subjects with and without coronary artery disease (CAD) (CAD and non‐CAD) and non‐CAD subjects with hypertension. Methods Arterioles were isolated from discarded surgical tissues (adipose and atrial) from patients without coronary artery disease (non‐CAD; ≤1 risk factor, excluding hypertension), with CAD, and non‐CAD patients with hypertension (hypertension as the only risk factor). To simulate transient hypertension, increased IILP was generated (150 mmHg, 30 min) by gravity. Arterioles were constricted with endothelin‐1, followed by FMD and endothelial‐independent dilation prior to and following exposure to IILP. Results IILP reduced FMD in non‐CAD and CAD arterioles relative to pre‐IILP (p

Objective: Coronary artery disease (CAD) is associated with a compensatory switch in mechanism of flow-mediated dilation (FMD) from nitric oxide (NO) to H 2 O 2 . The underlying mechanism responsible for the pathological shift is not well understood, and recent reports directly implicate telomerase and indirectly support a role for autophagy. We hypothesize that autophagy is critical for shear stress–induced release of NO and is a crucial component of for the pathway by which telomerase regulates FMD. Approach and Results: Human left ventricular, atrial, and adipose resistance arterioles were collected for videomicroscopy and immunoblotting. FMD and autophagic flux were measured in arterioles treated with autophagy modulators alone, and in tandem with telomerase-activity modulators. LC3B II/I was higher in left ventricular tissue from patients with CAD compared with non-CAD (2.8±0.2 versus 1.0±0.2-fold change; P 2 O 2 , while activation of autophagy restored NO-mediated vasodilation in CAD arterioles. In the presence of an autophagy activator, telomerase inhibitor prevented the expected switch (Control: 82±4%; NG-Nitro-l-arginine methyl ester: 36±5%; polyethylene glycol catalase: 80±3). Telomerase activation was unable to restore NO-mediated FMD in the presence of autophagy inhibition in CAD arterioles (control: 72±7%; NG-Nitro-l-arginine methyl ester: 79±7%; polyethylene glycol catalase: 38±9%). Conclusions: We provide novel evidence that autophagy is responsible for the pathological switch in dilator mechanism in CAD arterioles, demonstrating that autophagy acts downstream of telomerase as a common denominator in determining the mechanism of FMD.

Traditionally thought of primarily as the predominant regulator of myocardial perfusion, it is becoming more accepted that the human coronary microvasculature also exerts a more direct influence on the surrounding myocardium. Coronary microvascular dysfunction (CMD) not only precedes large artery atherosclerosis, but is associated with other cardiovascular diseases such as heart failure with preserved ejection fraction and hypertrophic cardiomyopathy. It is also highly predictive of cardiovascular events in patients with or without atherosclerotic cardiovascular disease. This review focuses on this recent paradigm shift and delves into the clinical consequences of CMD. Concepts of how resistance arterioles contribute to disease will be discussed, highlighting how the microvasculature may serve as a potential target for novel therapies and interventions. Finally, both invasive and non-invasive methods with which to assess the coronary microvasculature both for diagnostic and risk stratification purposes will be reviewed.

Although microvascular dysfunction (MVD) has been well characterized in individual organs as different disease entities, clinical evidence is mounting in support of an underlying systemic process. To address this hypothesis, we systematically searched PubMed and Medline for studies in adults published between 2014 and 2019 that measured blood biomarkers of MVD in three vital organs i.e. brain, heart, and the kidney. Of the 9706 unique articles 321 met the criteria, reporting 49 biomarkers of which 16 were common to the three organs. Endothelial dysfunction, inflammation including reactive oxidation, immune activation, and coagulation were the commonly recognized pathways. Triglyceride, C-reactive protein, Cystatin C, homocysteine, uric acid, IL-6, NT-proBNP, thrombomodulin, von Willebrand Factor, and uric acid were increased in MVD of all three organs. In contrast, vitamin D was decreased. Adiponectin, asymmetric dimethylarginine, total cholesterol, high-density and low-density cholesterol were found to be variably increased or decreased in studies. We review the pathways underlying MVD in the three organs and summarize evidence supporting its systemic nature. This scoping review informs clinicians and researchers in the multi-system manifestation of MVD. Future work should focus on longitudinal investigations to evaluate the multi-system involvement of this disease.

AIMS Cardiac contractility modulation (CCM) improves symptoms and exercise tolerance and reduces heart failure (HF) hospitalizations over 6-month follow-up in patients with New York Heart Association (NYHA) class III or IV symptoms, QRS

Introduction: Femoral artery atrophy and reduced endothelial function in the peripheral arteries of the affected lower limb contribute to reduced hyperemic blood flow in response to muscle contractions in chronic stroke survivors. These impairments could contribute to increased muscle weakness and exacerbate neuromuscular fatigue in stroke survivors. The time-course of these changes to the peripheral vasculature post-stroke have not been examined. Hypothesis: Superficial femoral artery atrophy and reduced blood flow to the affected limb occur in the subacute stroke period. Methods: This was a prospective, observational study which enrolled subacute stroke survivors admitted to inpatient rehabilitation at a single site. Maximum voluntary contractions (MVCs) of the paretic and non-paretic knee extensor muscles were assessed using a Biodex dynamometer. The superficial femoral artery was imaged in both legs using ultrasonography and arterial diameter was measured off-line with Brachial Analyzer software. Superficial femoral artery resting and hyperemic blood flow following MVCs was also quantified using ultrasonography. Results: Twelve subacute stroke survivors were enrolled in this study (7 men, 5 women). The mean age of all study participants was 65±10 years and the mean time since stroke was 12±6 days. Superficial femoral artery diameter was smaller in the affected leg compared to the non-affected leg (5.9±0.9 mm vs. 6.3±0.9 mm, respectively; p=0.006 paired t-test). Resting blood flow to the affected leg was also lower compared to the non-affected leg (164±68 ml/min vs. 205±105 ml/min, respectively; p=0.031 paired t-test). The MVC of the knee extensor muscles of the affected leg was less than the non-affected leg (103±63 Nm vs. 152±58 Nm, respectively; p=0.027, Wilcoxon signed rank test) and hyperemic blood flow was also reduced in the affected limb (248±94 ml/min vs. 428±203 ml/min, respectively; p2 =0.47, p=0.014). Conclusions: Superficial femoral artery atrophy and reduced limb blood flow occur in stroke survivors in the first weeks post-stroke and may contribute to limb weakness.

Heart failure (HF) is responsible for substantial morbidity and mortality and is increasing in prevalence. Although there has been remarkable progress in the treatment of HF with reduced ejection fraction (HFrEF), morbidity and mortality are still substantial. Cardiac contractility modulation (CCM) signals, consisting of biphasic high-voltage bipolar signals delivered to the right ventricular septum during the absolute refractory period, have been shown to improve symptoms, exercise tolerance and quality of life and reduce the rate of HF hospitalizations in patients with ejection fractions (EF) between 25% and 45%. CCM therapy is currently approved in the European Union, China, India, Australia and Brazil for use in symptomatic HFrEF patients with normal or slightly prolonged QRS duration. CCM is particularly beneficial in patients with baseline EF between 35% and 45%, which includes half the range of HF patients with mid-range EFs (HFmrEF). At the cellular level, CCM has been shown in HFrEF patients to improve calcium handling, to reverse the foetal myocyte gene programme associated with HF, and to facilitate reverse remodelling. This review highlights the preclinical and clinical literature related to CCM in HFrEF and HFmrEF and outlines the potential of CCM for HF with preserved EF, concluding that CCM may fill an important unmet need in the therapeutic approach to HF across the range of EFs.

BACKGROUND Sedentary behavior and obesity are major risk factors for cardiovascular disease. Regular physical activity has independent protective effects on the cardiovascular system, but the mechanisms responsible remain elusive. Recent studies suggest that the protein peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) participates in the response to exercise training. We hypothesized that the arterioles of athletes maintain dilation to flow despite combined inhibition of multiple vasodilators, but loss of PGC-1α renders these vessels susceptible to inhibition of a single vasodilator pathway. In addition, arterioles from overweight and obese individuals will display an an exercise-like phenotype when PGC-1α is activated. METHODS Isolated arterioles from exercise-trained (ET) and from mildly overweight or obese subjects (body mass index >25) were cannulated, and changes in lumen diameter in response to graded increases in flow were recorded in the absence and presence of compounds that inhibit various endothelium-dependent vasodilators. RESULTS Microvessels of ET subjects displayed robust dilation that could not be inhibited through targeting the combination of nitric oxide, prostaglandins, and hydrogen peroxide, but were inhibited via interference with membrane hyperpolarization. Loss of PGC-1α (siRNA) in the microcirculation of ET subjects eliminates this vasodilatory robustness rendering vessels susceptible to blockade of H2O2 alone. Pharmacological activation of PGC-1α with alpha-lipoic acid in isolated microvessels from sedentary, overweight, and obese subjects increases arteriolar resistance to vasodilator blockade and protects against acute increases in intraluminal pressure. CONCLUSIONS These findings suggest that the microvascular adaptations to exercise training, and the exercise-induced protection against acute vascular stress in overweight/obese subjects, are mediated by PGC-1α.

Purpose: The purpose of this study was to determine whether increased intraluminal pressure is the damaging factor that reduces flow-mediated dilation (FMD) in young, healthy subjects after resistance exercise to maximal exertion. Hypothesis: Attenuating the rise in brachial artery pressure during weight lifting by placing a blood pressure cuff on the upper arm prevents postexercise impairment of brachial artery FMD in sedentary individuals. Methods: Nine sedentary individuals who exercise once a week or less and six exercise-trained individuals who exercise three times a week or more performed leg press exercise to maximal exertion on two separate occasions. During one visit, a blood pressure cuff, proximal to the site of brachial artery measurement, was inflated to 100 mm Hg to protect the distal vasculature from the rise in intraluminal pressure, which occurs during resistance exercise. Brachial artery FMD was determined using ultrasonography before and 30 min after weight lifting. Results: Without the protective cuff, brachial artery FMD in sedentary individuals was reduced after weight lifting (9.0% ± 1.2% prelift vs 6.6% ± 0.8% postlift; P = 0.005), whereas in exercise-trained individuals, FMD was unchanged (7.4% ± 0.7% prelift vs 8.0% ± 0.9% postlift; P = 0.543). With the protective cuff, FMD no longer decreased but rather increased in sedentary individuals (8.7% ± 1.2% prelift vs 10.5% ± 1.0% postlift, P = 0.025). An increase in FMD was also seen in exercise-trained subjects when the cuff was present (6.6% ± 0.7% prelift vs 10.9% ± 1.5% postlift, P < 0.001). Conclusion: Protecting the brachial artery from exercise-induced hypertension enhances FMD in sedentary and exercise-trained individuals. These results indicate that increased intraluminal pressure in the artery contributes to the reduced FMD after heavy resistance exercise in sedentary individuals.

INTRODUCTION: Coronary microvascular dysfunction (CMD) is a complex disease, difficult to diagnose and often requires advanced imaging. We used mass spectrometry (MS) using discovery approach to search for serum proteins as potential biomarkers in these patients. METHODS: We used serum samples from 10 patients with CMD and 10 with normal coronary flow reserve (CFR) admitted to an observation unit where acute myocardial infarction was excluded. We identified CMD using (82)Rb positron emission tomography/computed tomography as CFR < 2 in response to regadenoson, in the absence of coronary calcification or regional perfusion defects. We used MS to identify potential protein biomarkers that were differentially expressed in cases and controls. RESULTS: Baseline characteristics were not different between cases and controls, except for beta-blocker use and which was higher in cases, and mean (SD) CFR which was lower in cases [1.19 (0.23) and 2.78 (0.78) in cases and controls respectively; p < 0.01]. We identified 5345 peptides corresponding to 209 proteins, and identified 197 proteins by peptides with suitable properties to infer relative quantitation values. While the calculated values for some proteins (e.g. vascular cell adhesion molecule-1, apolipoprotein C and Von Willebrand Factor) indicate fold-differences between groups, these are most likely a result of high values in only 1–2 patients and are not statistically significant. CONCLUSION: Mass spectrometry using discovery approach may not be an adequate method for quantitative assessment of serum proteins in CMD patients. Future MS studies should evaluate other approaches including tissue samples or serial measurements.

Background Elevated levels of ceramide, a sphingolipid known to cause a transition from nitric oxide (NO)– to hydrogen peroxide–dependent flow‐induced dilation ( FID ) in human arterioles, correlate with adverse cardiac events. However, elevations of ceramide are associated with changed concentrations of other sphingolipid metabolites. The effects of sphingolipid metabolites generated through manipulation of this lipid pathway on microvascular function are unknown. We examined the hypothesis that inhibition or activation of the ceramide pathway would determine the mediator of FID . Methods and Results Using videomicroscopy, internal diameter changes were measured in human arterioles collected from discarded adipose tissue during surgery. Inhibition of neutral ceramidase, an enzyme responsible for the hydrolysis of ceramide, favored hydrogen peroxide–dependent FID in arterioles from healthy patients. Using adenoviral technology, overexpression of neutral ceramidase in microvessels from diseased patients resulted in restoration of NO ‐dependent FID . Exogenous sphingosine‐1‐phosphate, a sphingolipid with opposing effects of ceramide, also restored NO as the mediator of FID in diseased arterioles. Likewise, exogenous adiponectin, a known activator of neutral ceramidase, or, activation of adiponectin receptors, favored NO ‐dependent dilation in arterioles collected from patients with coronary artery disease. Conclusions Sphingolipid metabolites play a critical role in determining the mediator of FID in human resistance arterioles. Manipulating the sphingolipid balance towards ceramide versus sphingosine‐1‐phosphate favors microvascular dysfunction versus restoration of NO ‐mediated FID , respectively. Multiple targets exist within this biolipid pathway to treat microvascular dysfunction and potentially improve patient outcomes.

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.

Background We developed a new left ventricular hypertrophy ( LVH ) criterion using a machine‐learning technique called Bayesian Additive Regression Trees ( BART ). Methods and Results This analysis included 4714 participants from MESA (Multi‐Ethnic Study of Atherosclerosis) free of clinically apparent cardiovascular disease at enrollment. We used BART to predict LV mass from ECG and participant characteristics using cardiac magnetic resonance imaging as the standard. Participants were randomly divided into a training set (n=3774) and a validation set (n=940). We compared the diagnostic/prognostic performance of our new BART ‐ LVH criteria with traditional ECG ‐ LVH criteria and cardiac magnetic resonance imaging– LVH . In the validation set, BART ‐ LVH showed the highest sensitivity (29.0%; 95% CI , 18.3%–39.7%), followed by Sokolow‐Lyon‐ LVH (21.7%; 95% CI , 12.0%–31.5%), Peguero–Lo Presti (14.5%; 95% CI , 6.2%–22.8%), Cornell voltage product (10.1%; 95% CI , 3.0%–17.3%), and Cornell voltage (5.8%; 95% CI , 0.3%–11.3%). The specificity was >93% for all criteria. During a median follow‐up of 12.3 years, 591 deaths, 492 cardiovascular disease events, and 332 coronary heart disease events were observed. In adjusted Cox models, both BART ‐ LVH and cardiac magnetic resonance imaging– LVH were associated with mortality (hazard ratio [95% CI ], 1.88 [1.45–2.44] and 2.21 [1.74–2.81], respectively), cardiovascular disease events (hazard ratio [95% CI ], 1.46 [1.08–1.98] and 1.91 [1.46–2.51], respectively), and coronary heart disease events (hazard ratio [95% CI ], 1.72 [1.20–2.47] and 1.96 [1.41–2.73], respectively). These associations were stronger than associations observed with traditional ECG ‐ LVH criteria. Conclusions Our new BART ‐ LVH criteria have superior diagnostic/prognostic ability to traditional ECG ‐ LVH criteria and similar performance to cardiac magnetic resonance imaging– LVH for predicting events.

Obesity is associated with microvascular dysfunction. While low-fat diet improves cardiovascular risk, its contributions on microvascular function, independent of weight loss, is unknown. We tested the hypothesis that nitric oxide (NO)-dependent vasodilation in microvessels is improved by low-fat diets designed for weight loss (LFWL) compared to low-fat weight maintenance (LFWM) diet. Obese adults were randomly assigned to either a LFWL diet (n = 11) or LFWM diet (n = 10) for six weeks. Microvessels were obtained from gluteal subcutaneous fat biopsies before and after the intervention for vascular reactivity measurements to acetylcholine (Ach) and flow, with and without L-NAME or indomethacin. Vascular and serum NO and C-reactive protein (CRP) were also measured. LFWL diet increased flow-induced (FID) and ACh-induced dilation (AChID), an effect that was inhibited by L-NAME. Conversely, LFWM diet did not affect FID or AChID. Indomethacin improved FID and AChID in the baseline and this effect was minimized in response to both diets. Serum NO or CRP did not change in response to either diet. In conclusion, LFWL diet improves microvascular reactivity compared to LFWM diet and increased vascular NO contribution to the improved microvascular dilation. These data suggest that weight reduction on low fat diet is critical for microvascular health.

Introduction: Brachial artery flow mediated dilation (FMD) is a well-established measure of vascular endothelial health and is pathologically low in chronic stroke survivors. Ischemic conditioning (IC) is a cardioprotective stimulus and has been shown to improve FMD and enhance motor function in healthy humans. We recently showed that IC can improve paretic muscle strength and increase self-selected walking speed in stroke survivors. These improvements could be, in part, mediated by improved peripheral vascular function and increased blood flow to the exercising muscle. The effects of IC on vascular endothelial function post-stroke have not been investigated. Hypothesis: Two weeks of IC on the paretic leg of chronic stroke survivors will improve FMD in the non-paretic brachial artery. Methods: This was a prospective, randomized, blinded and controlled pilot study. Twenty chronic stroke survivors (>1-year post-stroke) received either IC (cuff inflation on the paretic leg for five minutes to 225 mmHg) or Sham IC (cuff inflation to 10 mmHg) every other day for two weeks (five on-off cycles per session). Brachial artery FMD was assessed using ultrasonography within 48 hours of the beginning and end of the intervention period. Results: Eight men and twelve women participated in this study. The mean age was 59 ± 16 years and the mean time post-stroke was 9 ± 9 years. Brachial artery FMD increased in the IC group from 6.2 ± 4.9% to 8.9 ± 3.9% (n=10; p=0.023, 2-way Repeated Measures ANOVA) while no change was observed in the Sham IC group (pre- vs. post = 3.8 ± 3.9% vs. 2.7 ± 3.1%, respectively; p=0.32, n=10). Expressed as the mean change in FMD, IC increased FMD by 2.8 ± 3.7% while no change was observed in the Sham IC group (delta FMD = -1.1 ± 3.4%; p=0.024 IC vs. IC Sham, unpaired t-test). Conclusions: Two weeks of IC increases brachial artery FMD in chronic stroke survivors. Taken together with our previous work that shows IC increases paretic muscle strength and walking speed in chronic stroke survivors, IC has the potential to improve both motor and cardiovascular function post-stroke. Future larger studies are needed to evaluate the efficacy of IC to improve stroke recovery and to identify the pathways involved which confer benefit to both the nervous and cardiovascular systems.

Objective— This study examined vascular actions of angiotensin 1–7 (ANG 1–7) in human atrial and adipose arterioles. Approach and Results— The endothelium-derived hyperpolarizing factor of flow-mediated dilation (FMD) switches from antiproliferative nitric oxide (NO) to proatherosclerotic hydrogen peroxide in arterioles from humans with coronary artery disease (CAD). Given the known vasoprotective properties of ANG 1–7, we tested the hypothesis that overnight ANG 1–7 treatment restores the NO component of FMD in arterioles from patients with CAD. Endothelial telomerase activity is essential for preserving the NO component of vasodilation in the human microcirculation; thus, we also tested whether telomerase activity was necessary for ANG 1–7–mediated vasoprotection by treating separate arterioles with ANG 1–7±the telomerase inhibitor 2-[[(2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl1-yl]amino]benzoic acid. ANG 1–7 dilated arterioles from patients without CAD, whereas dilation was significantly reduced in arterioles from patients with CAD. In atrial arterioles from patients with CAD incubated with ANG 1–7 overnight, the NO synthase inhibitor NG-nitro- l -arginine methyl ester abolished FMD, whereas the hydrogen peroxide scavenger polyethylene glycol catalase had no effect. Conversely, in vessels incubated with ANG 1–7+2-[[(2E)-3-(2-naphthalenyl)-1-oxo-2-butenyl1-yl]amino]benzoic acid, NG-nitro- l -arginine methyl ester had no effect on FMD, but polyethylene glycol catalase abolished dilation. In cultured human coronary artery endothelial cells, ANG 1–7 significantly increased telomerase activity. These results indicate that ANG 1–7 dilates human microvessels, and dilation is abrogated in the presence of CAD. Furthermore, ANG 1–7 treatment is sufficient to restore the NO component of FMD in arterioles from patients with CAD in a telomerase-dependent manner. Conclusions— ANG 1–7 exerts vasoprotection in the human microvasculature via modulation of telomerase activity.

for senior cardiovascular scientists, it is well known and accepted that the American Journal of Physiology ( AJP ) -Heart and Circulatory Physiology publishes important and long-lasting cardiovascular science ([2][1]). Early career investigators and trainees may be less familiar with the history of

This pilot study examined whether ischemic conditioning (IC), a noninvasive, cost-effective, and easy-to-administer intervention, could improve gait speed and paretic leg muscle function in stroke survivors. We hypothesized that 2 wk of IC training would increase self-selected walking speed, increase paretic muscle strength, and reduce neuromuscular fatigability in chronic stroke survivors. Twenty-two chronic stroke survivors received either IC or IC Sham on their paretic leg every other day for 2 wk (7 total sessions). IC involved 5-min bouts of ischemia, repeated five times, using a cuff inflated to 225 mmHg on the paretic thigh. For IC Sham, the cuff inflation pressure was 10 mmHg. Self-selected walking speed was assessed using the 10-m walk test, and paretic leg knee extensor strength and fatigability were assessed using a Biodex dynamometer. Self-selected walking speed increased in the IC group (0.86 ± 0.21 m/s pretest vs. 1.04 ± 0.22 m/s posttest, means ± SD; P < 0.001) but not in the IC Sham group (0.92 ± 0.47 m/s pretest vs. 0.96 ± 0.46 m/s posttest; P = 0.25). Paretic leg maximum voluntary contractions were unchanged in both groups (103 ± 57 N·m pre-IC vs. 109 ± 65 N·m post-IC; 103 ± 59 N·m pre-IC Sham vs. 108 ± 67 N·m post-IC Sham; P = 0.81); however, participants in the IC group maintained a submaximal isometric contraction longer than participants in the IC Sham group (278 ± 163 s pre-IC vs. 496 ± 313 s post-IC, P = 0.004; 397 ± 203 s pre-IC Sham vs. 355 ± 195 s post-IC Sham; P = 0.46). The results from this pilot study thus indicate that IC training has the potential to improve walking speed and paretic muscle fatigue resistance poststroke. NEW & NOTEWORTHY This pilot study is the first to demonstrate that ischemic conditioning can improve self-selected walking speed and reduce paretic muscle fatigue in stroke survivors. Ischemic conditioning has been shown to be safe in numerous patient populations, can be accomplished at home or at the bedside in only 45 min, and requires no specialized training. Future larger studies are warranted to determine the efficacy of ischemic conditioning as a neurorehabilitation therapy poststroke.

To date, the major focus of diagnostic modalities and interventions to treat coronary artery disease has been the large epicardial vessels. Despite substantial data showing that microcirculatory dysfunction is a strong predictor of future adverse cardiovascular events, very little research has gone into developing techniques for in vivo diagnosis and therapeutic interventions to improve microcirculatory function. In this review, we will discuss the pathophysiology of coronary arteriolar dysfunction, define its prognostic implications, evaluate the diagnostic modalities available, and provide speculation on current and potential therapeutic opportunities.

Vascular endothelial dysfunction is an early event in the development of atherosclerosis. Flow-mediated dilation (FMD) can be used to identify such endothelial dysfunction which is characterized by a decrease of nitric oxide (NO). Indeed, in subjects with coronary artery disease (CAD), microvascular FMD switches from a NO-mediated to a H 2 O 2 -mediated mechanism with corresponding elevations in mitochondrial reactive oxygen species (ROS). Recent evidence has shown an increase circulating mitochondrial DNA Damage-Associated Molecular Patterns ( mt DAMPs) in Coronary Heart Disease subjects and has been linked to vascular dysfunction. mt DAMPs signaling can activate the inflammatory response directly through activation of Toll Like Receptors 9 (TLR9). The effect of mt DAMPs on the endothelial function in the human microcirculation and the potential role for TLR9- mtDNA signaling axis to affect microvascular FMD, is unknown. In this study, we hypothesized that increased levels of mt DAMPs result in changes in microvascular redox environment that promote a loss of NO mediated dilation and elevation in mitochondrial derived ROS The incubation of cultured endothelial cells (ECs) with mt DAMPs decreased the ratio peNOS:teNOS in a time-dependent manner supporting the idea that mt DAMPs reduce NO bioavailability. This effect was eliminated when the ECs were pre-incubated with TLR9-targeted si-RNA. Prolonged (15-20H) ex vivo exposure to low dose of mt DAMPs (1ug/mL) changed the mechanism of FMD from NO to compensatory increase in H 2 O 2 to preserve overall dilator capacity in non-CAD human adipose micro-arterioles (% Max Diameter: Control 84.7±8.2; + L-NAME: 89.4±5.5; + Peg-Cat 35.4±10.8*; N=5, *pmt DAMPs (2.5ug/mL), the magnitude of the FMD was however significantly altered (% Max Diameter: high dose: 42.8 ±9.1* vs. low dose of mt DAMPs 84.7±8.2; N=4; p Our data suggest a potential pathogenic role of mt DAMPs in microvascular function through TLR9 to reduce NO bioavailability and induce endothelial dysfunction.

Background A significant proportion of patients receiving CRT are non-responders. We evaluated the efficacy of Cardiac Contractility Modulation in subjects with reduced LVEF who, despite cardiac resynchronization therapy (CRT), continued to experience clinically significant symptoms. Methods This was a multi-center, open label, treatment-only, feasibility study of 17 CRT non-responders who received CCM therapy. Changes in NYHA class, ejection fraction (EF), Minnesota Living with Heart Failure Questionnaire (MLWHFQ) score, and exercise tolerance (6 minute walk test; 6MWT and peak VO2) were analyzed over 6 months. Mortality and hospitalization rates were determined. Results Patients (82% male) were 69.4 ± 9.6 years of age with baseline EF = 22.8 ± 6.5%. Among primary endpoints, peak VO2 increased 1.1 ± 1.6 ml/kg/min (p = 0.03) and MLWHFQ improved (−16 ± 16 points; p Conclusions Patients with heart failure and reduced ejection fraction who remain moderately to severely symptomatic despite use of CRT, may benefit from CCM therapy with improvement in quality of life and exercise tolerance. A larger prospective study in this population is warranted.

Objectives This study sought to confirm a subgroup analysis of the prior FIX-HF-5 (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure) study showing that cardiac contractility modulation (CCM) improved exercise tolerance (ET) and quality of life in patients with ejection fractions between 25% and 45%. Background CCM therapy for New York Heart Association (NYHA) functional class III and IV heart failure (HF) patients consists of nonexcitatory electrical signals delivered to the heart during the absolute refractory period. Methods A total of 160 patients with NYHA functional class III or IV symptoms, QRS duration Results The difference in peak Vo2 between groups was 0.84 (95% Bayesian credible interval: 0.123 to 1.552) ml O2/kg/min, satisfying the primary endpoint. Minnesota Living With Heart Failure questionnaire (p Conclusions CCM is safe, improves exercise tolerance and quality of life in the specified group of HF patients, and leads to fewer HF hospitalizations. (Evaluate Safety and Efficacy of the OPTIMIZER System in Subjects With Moderate-to-Severe Heart Failure; NCT01381172)

The postprandial state can negatively influence flow mediated dilation (FMD), a predictor of atherosclerosis and cardiovascular disease. This investigation was designed to determine the effect of regular aerobic and/or resistance exercise on postprandial FMD after a high sugar or high fat mixed meal. Forty-five healthy participants were recruited from one of four groups: lean sedentary (SED), runners, weight lifters, and cross-trainers. Participants were randomly crossed over to a high sugar meal (HSM) and a high fat mixed meal (HFMM; both fat and carbohydrate). Pre-and postprandial endothelial function was assessed for both meals using brachial artery FMD. Plasma lipids, insulin, glucose, hs-CRP, and SOD were also measured with both meals. Endothelium-independent dilation was determined via sublingual nitroglycerin. Brachial artery FMD was reduced in SED following the HSM (9.9 ± 0.9% at baseline, peak reduction at 60 min 6.5 ± 1.0%) and the HFMM (9.4 ± 0.9% at baseline, peak reduction at 120 min 5.9 ± 1.2%; P < 0.05 for both, Mean ± SEM). There was no change in FMD after either HSM or HFMM in runners, weight lifters, and cross-trainers. Post-prandial increases in blood glucose, insulin and triglycerides were less pronounced in the exercisers compared to SED. In addition, exercisers presented lower baseline plasma hs-CRP and higher SOD activity. Nitroglycerin responses were similar among groups. These results suggest that endothelial function is reduced in sedentary adults after a HSM or HFMM, but not in regular aerobic or resistance exercisers. This response may be due to favorable postprandial metabolic responses or lower postprandial levels of inflammation and oxidative stress. These findings may help to explain the cardioprotective effect of exercise.

Introduction: Weakness of the contralateral leg muscles commonly occurs following unilateral stroke. We and others have also shown that the femoral artery is atrophied in the paretic (P) limb of chronic stroke subjects (>6 months post-stroke) compared to the non-paretic (NP) limb, and that both resting and hyperemic blood flow to the exercising muscle are dramatically reduced. Further, the hyperemic response positively correlates with leg strength and clinical measures of leg function. It is unknown if these changes in femoral artery diameter and peripheral blood flow are present in the subacute phase of stroke ( Hypothesis: Femoral artery diameter is smaller, and resting and hyperemic blood flow to exercising muscle is reduced in the P limb in subjects in the subacute phase of stroke admitted to inpatient rehabilitation. Methods: Stroke patients were tested within three days of admission to inpatient rehabilitation in a hospital setting. Isometric knee extensor maximal voluntary contractions (MVCs) were measured in both legs using a Biodex dynamometer. Superficial femoral artery diameter and blood flow were measured at rest and immediately following MVCs using Doppler ultrasound. Results: A pilot group of four subjects (1 male, 3 female) aged 68 ± 4 years (range 56-75 years) completed all study procedures on average 13 ± 5 days post ischemic stroke (range 7-24 days). All subjects had infarcts of the middle cerebral artery (3 right, 1 left). P leg knee extensor MVCs were lower compared to the NP leg (93.8 ± 25.5 Nm vs. 160.4 ± 33.2 Nm, respectively; p Conclusions: We show feasibility of testing knee extensor muscle strength and peripheral blood flow in subacute stroke inpatients. Our preliminary data indicates that femoral artery atrophy has occurred in the P leg and that both resting and hyperemic blood flow to the P muscle are reduced.

Ischemic conditioning (IC) on the arm or leg has emerged as an intervention to improve strength and performance in healthy populations, but the effects on neurological populations are unknown. The purpose of this study was to quantify the effects of a single session of IC on knee extensor strength and muscle activation in chronic stroke survivors. Maximal knee extensor torque measurements and surface EMG were quantified in 10 chronic stroke survivors (>1 yr poststroke) with hemiparesis before and after a single session of IC or sham on the paretic leg. IC consisted of 5 min of compression with a proximal thigh cuff (inflation pressure = 225 mmHg for IC or 25 mmHg for sham) followed by 5 min of rest. This was repeated five times. Maximal knee extensor strength, EMG magnitude, and motor unit firing behavior were measured before and immediately after IC or sham. IC increased paretic leg strength by 10.6 ± 8.5 Nm, whereas no difference was observed in the sham group (change in sham = 1.3 ± 2.9 Nm, P = 0.001 IC vs. sham). IC-induced increases in strength were accompanied by a 31 ± 15% increase in the magnitude of muscle EMG during maximal contractions and a 5% decrease in motor unit recruitment thresholds during submaximal contractions. Individuals who had the most asymmetry in strength between their paretic and nonparetic legs had the largest increases in strength ( r2 = 0.54). This study provides evidence that a single session of IC can increase strength through improved muscle activation in chronic stroke survivors. NEW & NOTEWORTHY Present rehabilitation strategies for chronic stroke survivors do not optimally activate paretic muscle, and this limits potential strength gains. Ischemic conditioning of a limb has emerged as an effective strategy to improve muscle performance in healthy individuals but has never been tested in neurological populations. In this study, we show that ischemic conditioning on the paretic leg of chronic stroke survivors can increase leg strength and muscle activation while reducing motor unit recruitment thresholds.

Brachial artery flow–mediated vasodilation in exercise-trained (ET) individuals is maintained after a single bout of heavy resistance exercise compared with sedentary individuals. The purpose of this study was to determine whether vasodilation is also maintained in the microcirculation of ET individuals. A total of 51 sedentary and ET individuals underwent gluteal subcutaneous fat biopsy before and after performing a single bout of leg press exercise. Adipose arterioles were cannulated in an organ bath, and vasodilation to acetylcholine was assessed±the endothelial nitric oxide inhibitor l -NG-nitroarginine methyl ester, the cyclooxygenase inhibitor indomethacin, or the hydrogen peroxide scavenger polyethylene glycol catalase. Separate vessels (isolated from the same groups) were exposed to an intraluminal pressure of 150 mm Hg for 30 minutes to mimic the pressor response, which occurs with isometric exercise. Vasodilation to acetylcholine was reduced in microvessels from sedentary subjects after either a single weight lifting session or exposure to increased intraluminal pressure, whereas microvessels from ET individuals maintained acetylcholine-mediated vasodilation. Before weight lifting, vasodilation of microvessels from ET individuals was reduced in the presence of l -NG-nitroarginine methyl ester and indomethacin. After weight lifting or exposure to increased intraluminal pressure, polyethylene glycol catalase significantly reduced vasodilation, whereas l -NG-nitroarginine methyl ester and indomethacin had no effect. These results indicate that (1) endothelium-dependent vasodilation in the microvasculature is maintained after heavy resistance exercise in ET individuals but not in sedentary subjects and that (2) high pressure alone or during weight lifting may induce a mechanistic switch in the microvasculature to favor hydrogen peroxide as the vasoactive mediator of dilation.

Thirty years ago, Robert F. Furchgott concluded that nitric oxide, a compound traditionally known to be a toxic component of fuel exhaust, is in fact released from the endothelium, and in a paracrine fashion, induces relaxation of underlying vascular smooth muscle resulting in vasodilation. This discovery has helped pave the way for a more thorough understanding of vascular intercellular and intracellular communication that supports the process of regulating regional perfusion to match the local tissue oxygen demand. Vasoregulation is controlled not only by endothelial release of a diverse class of vasoactive compounds such as nitric oxide, arachidonic acid metabolites, and reactive oxygen species, but also by physical forces on the vascular wall and through electrotonic conduction through gap junctions. Although the endothelium is a critical source of vasoactive compounds, paracrine mediators can also be released from surrounding parenchyma such as perivascular fat, myocardium, and cells in the arterial adventitia to exert either local or remote vasomotor effects. The focus of this review will highlight the various means by which intercellular communication contributes to mechanisms of vasodilation. Paracrine signaling and parenchymal influences will be reviewed as well as regional vessel communication through gap junctions, connexons, and myoendothelial feedback. More recent modes of communication such as vesicular and microRNA signaling will also be discussed.

Angiogenesis can broadly be defined as the growth of new capillaries and blood vessels. A complex set of multiphasic signaling pathways regulate angiogenic blood vessel growth,1,2 and these pathways have been the target for both pro- and antiangiogenic therapies. Angiogenesis is a fundamental physiological process that is required for fetal development, wound healing, and tissue repair after ischemic damage. For these reasons, promoting proangiogenic pathways has therapeutic potential to combat diseases where tissue blood flow is compromised, such as peripheral artery disease, ischemic heart disease, or after ischemic stroke. Thus, quantitative methods to assess the degree of angiogenic growth are critical. Article, see p 1453 Typically, blood vessel density and the degree of angiogenic growth are quantified histologically by counting the number of capillaries observed in a defined cross section of tissue. When angiogenesis occurs, the ratio of capillaries per tissue surface area increases. Functional measures of angiogenesis include measuring perfusion to the tissue involved, and it is typically expected that these parameters (vascular density and perfusion) change in parallel. However, this is not always the case.1 In fact, injured tissue may demonstrate both an increase in capillary density and an increase in blood flow but still have underperfused areas. Such a discrepancy could be because of improper vasoregulation of new vessels, or creation of arteriovenous anastomoses that maintain overall tissue flow, …

[][1] On November 8, 2016, the greater medical community lost a visionary scientist, master clinician, a thought‐leader in echocardiography, and a pioneer in cardiac resuscitation. Richard E. Kerber will also be remembered as an accomplished clarinetist, opera aficionado, and avid

> “ But I think it [the Model] is more likely to change when, and because, far-reaching changes in the mental temper of our descendants demand that it should. The new Model will not be set up without evidence, but the evidence will turn up when the need for it becomes sufficiently great .” (222–223) The fate of biomedical research lies in the hands of future generations of scientists. In recent decades, the diversity of scientific career opportunities has exploded multidimensionally. However, the educational system for maintaining a pipeline of talented biomedical trainees remains unidimensional and has become outdated. This Viewpoint identifies inadequacies in training and offers potential solutions and implementation strategies to stimulate interest in science at a younger age and to better align individualized training pathways with career opportunities (precision training). Both interventions support of the ultimate goal of attracting the best possible future leaders in biomedical science . In his final published work, the eminent scholar C.S. Lewis describes the medieval model that dominated European intellectual life for centuries and explores how and why this model was replaced—because of discovery of dying stars, development of new scientific theories, and more. Aside from being a testament to an exceptional mind, C.S. Lewis’ The Discarded Image also contains wisdom directly relevant to the scientific milieu of the 21st century. Over the past 100 years, science and society have experienced unprecedented, dramatic change as a result of globalization, the Internet, advances in scientific capability, and an increasingly diverse and expanding scientific workforce. Such a large shift in the fabric of society has necessitated a corresponding shift in the environment in which we as scientists operate. However, scientific education lingers behind, using principles and processes that have not changed for many decades. The educational system responsible for training a new generation of …

Introduction: Individuals living with chronic stroke have weakness and increased neuromuscular fatigue in the paretic leg, which can limit walking ability and endurance. In cardiac and healthy populations, ischemic preconditioning (IPC) is a widely studied, effective, non-invasive stimulus which not only improves vascular function, but also motor performance. IPC occurs when the tissue of interest is exposed to repeated, short bouts of ischemia, which can improve motor function by enhancing vascular, neural and muscle function. IPC has not been tested as a method to improve motor function in individuals post-stroke. Hypothesis: Two weeks of IPC training on the paretic leg will improve leg strength and time-to-task failure (TTF) during a fatiguing muscle contraction. Methods: A feasibility study of 4 individuals (3 female, 1 male) with chronic stroke (20 ± 4 years) was conducted. A Biodex dynamometer was used to assess paretic leg knee extensor maximal voluntary contraction (MVC). To assess muscle fatigability, subjects maintained a sustained contraction equal to 30% of their MVC until failure using visual feedback. After baseline testing, subjects made six visits to the laboratory over a two week period to have IPC performed on their paretic leg. A blood pressure cuff was inflated on the thigh to 225 mmHg for five, five-minute bouts per session. Five minutes of rest was given between inflation cycles. After the last session, subjects returned within 48 hours to have MVC and TTF reassessed. Results: Three subjects completed all study procedures. One subject withdrew for medical reasons unrelated to the study. The IPC procedure was well tolerated by all subjects. After two-week IPC training, knee extensor MVC increased in the paretic leg (45.0 ± 2.7 Nm vs. 52.6 ± 5.7 Nm). Fatigability of the muscles was dramatically reduced after IPC training as TTF tripled (359 ± 180 seconds vs. 1097 ± 343 seconds). Conclusions: We are the first group to show that IPC is a well-tolerated and effective stimulus to improve paretic leg strength and reduce muscle fatigability in subjects with chronic stroke. The results of this pilot study warrant a larger study to determine whether IPC improves muscle performance post-stroke through neural, vascular, or muscle-related mechanisms.

In September 2011, the Centers for Disease Control and Prevention (CDC) convened a Ventilator-Associated Pneumonia (VAP) Surveillance Definition Working Group to organize a formal process for leaders and experts of key stakeholder organizations to discuss the challenges of VAP surveillance definitions and to propose new approaches to VAP surveillance in adult patients (Table 1). The charges to the Working Group were to (1) critically review a draft, streamlined VAP surveillance definition developed for use in adult patients; (2) suggest modifications to enhance the reliability and credibility of the surveillance definition within the critical care and infection prevention communities; and (3) propose a final adult surveillance definition algorithm to be implemented in the CDC's National Healthcare Safety Network (NHSN), taking into consideration the potential future use of the definition algorithm in public reporting, interfacility comparisons, and pay-for-reporting and pay-for-performance programs.

Objective:To develop and implement an objective, reliable approach to surveillance for ventilator-associated events in adult patients.Design:The Centers for Disease Control and Prevention (CDC) convened a Ventilator-Associated Pneumonia (VAP) Surveillance Definition Working Group in September 2011.

Small arterioles (40-150 μm) contribute to the majority of vascular resistance within organs and tissues. Under resting conditions, the basal tone of these vessels is determined by a delicate balance between vasodilator and vasoconstrictor influences. Cardiovascular homeostasis and regional tissue perfusion is largely a function of the ability of these small blood vessels to constrict or dilate in response to the changing metabolic demands of specific tissues. The endothelial cell layer of these microvessels is a key modulator of vasodilation through the synthesis and release of vasoactive substances. Beyond their vasomotor properties, these compounds importantly modulate vascular cell proliferation, inflammation, and thrombosis. Thus, the balance between local regulation of vascular tone and vascular pathophysiology can vary depending upon which factors are released from the endothelium. This review will focus on the dynamic nature of the endothelial released dilator factors depending on species, anatomic site, and presence of disease, with a focus on the human coronary microcirculation. Knowledge how endothelial signaling changes with disease may provide insights into the early stages of developing vascular inflammation and atherosclerosis, or related vascular pathologies.

The solitary pulmonary nodule (SPN) is frequently encountered on chest imaging and poses an important diagnostic challenge to clinicians. The differential diagnosis is broad, ranging from benign granulomata and infectious processes to malignancy. Important concepts in the evaluation of SPNs include the definition, morphologic characteristics via appropriate imaging modalities, and the calculation of pretest probability of malignancy. Morphologic differentiation of SPN into solid or subsolid types is important in the choice of follow-up and further management. In this first part of a two-part series, we describe the morphologic characteristics and various imaging modalities available to further characterize SPN. In Part 2, we will describe the determination of pretest probability of malignancy and an algorithmic approach to the diagnosis of SPN.