Assessment of cardiopulmonary point-of-care ultrasound objective structured clinical examinations in graduating anesthesiology residents across multiple residency programs.

STUDY OBJECTIVE: To implement and assess a cardiopulmonary point-of-care ultrasound (POCUS) objective structured clinical examination (OSCE) in a large cohort of graduating anesthesia residents. DESIGN: Observational cohort study. SETTING: University-affiliated hospitals. SUBJECTS: 150 graduating anesthesia residents in their last nine months of training. INTERVENTIONS: A standardized cardiopulmonary OSCE was administered to each resident. MEASUREMENTS: The cardiac views evaluated were parasternal long axis (PLAX), apical 4 chamber (A4C), and parasternal short axis (PSAX). The pulmonary views evaluated were pleural effusion (PLE) and pneumothorax (PTX). In addition, a pre- and post-exam survey scored on a 5-point Likert scale was administered to each resident. MAIN RESULTS: A4C view (mean 0.7 ± 0.3) scored a lower mean, compared to PSAX (mean 0.8 ± 0.3) and PLAX (mean 0.8 ± 0.4). Residents performed well on the PTX exam (mean 0.9 ± 0.3) but more poorly on the PLE exam (mean 0.6 ± 0.4). Structural identification across cardiac and pulmonary views were mostly high (means >0.7), but advanced interpretive skills and maneuvers had lower mean scores. Pre- and post- OSCE survey results were positive with almost all questions scoring >4 on the Likert scale. CONCLUSION: Our study demonstrates that a cardiopulmonary POCUS OSCE can be successfully implemented across multiple anesthesia training programs. While most residents were able to perform basic ultrasound views and identify structures, advanced interpretive skills and maneuvers performed lower.

Perioperative Management of Patients with Sepsis and Septic Shock, Part I: Systematic Approach.

Sepsis and septic shock are medical emergencies, with high associated mortality. The Surviving Sepsis Campaign has developed definitions and management guidelines, emphasizing the use of hour-1 care bundle. Anesthesiologists frequently encounter sepsis when source control is required. The authors summarize expected manifestations of organ dysfunction and state-of-the-art management of patients with sepsis and septic shock. They highlight an increasingly vital role point-of-care ultrasound examination in the recognition and management of hemodynamic derangements in this patient population. Supporting the role of anesthesiologists as perioperative physicians, the authors provide a framework for transitions of care between operating room and intensive care units.

Anesthesia for Patients with Concomitant Cardiac and Renal Dysfunction.

Renal disease and cardiovascular disease are commonly encountered in the same patient. The dynamic interactions between renal disease and cardiovascular disease have an impact on perioperative management. Renal failure is an independent risk factor for cardiovascular disease and the link between the two disease states remains to be fully elucidated.

Genome-wide association study for endothelial growth factors.

BACKGROUND: Endothelial growth factors including angiopoietin-2 (Ang-2), its soluble receptor Tie-2 (sTie-2), and hepatocyte growth factor play important roles in angiogenesis, vascular remodeling, local tumor growth, and metastatic potential of various cancers. Circulating levels of these biomarkers have a heritable component (between 13% and 56%), but the underlying genetic variation influencing these biomarker levels is largely unknown. METHODS AND RESULTS: We performed a genome-wide association study for circulating Ang-2, sTie-2, and hepatocyte growth factor in 3571 Framingham Heart Study participants and assessed replication of the top hits for Ang-2 and sTie-2 in 3184 participants of the Study of Health in Pomerania. In multivariable-adjusted models, sTie-2 and hepatocyte growth factor concentrations were associated with single-nucleotide polymorphisms in the genes encoding the respective biomarkers (top P=2.40×10(-65) [rs2273720] and 3.64×10(-19) [rs5745687], respectively). Likewise, rs2442517 in the MCPH1 gene (in which the Ang-2 gene is embedded) was associated with Ang-2 levels (P=5.05×10(-8) in Framingham Heart Study and 8.39×10(-5) in Study of Health in Pomerania). Furthermore, single-nucleotide polymorphisms in the AB0 gene were associated with sTie-2 (top single-nucleotide polymorphism rs8176693 with P=1.84×10(-33) in Framingham Heart Study; P=2.53×10(-30) in Study of Health in Pomerania) and Ang-2 (rs8176746 with P=2.07×10(-8) in Framingham Heart Study; P=0.001 in Study of Health in Pomerania) levels on a genome-wide significant level. The top genetic loci were explained between 1.7% (Ang-2) and 11.2% (sTie-2) of the interindividual variation in biomarker levels. CONCLUSIONS: Genetic variation contributes to the interindividual variation in growth factor levels and explains a modest proportion of circulating hepatocyte growth factor, Ang-2, and Tie-2. This may potentially contribute to the familial susceptibility to cancer, a premise that warrants further studies.

Circulating vascular growth factors and central hemodynamic load in the community.

Mean and pulsatile components of hemodynamic load are related to cardiovascular disease. Vascular growth factors play a fundamental role in vascular remodeling. The links between growth factors and hemodynamic load components are not well described. In 3496 participants from the Framingham Heart Study third generation cohort (mean age: 40±9 years; 52% women), we related 4 tonometry-derived measures of central arterial load (carotid femoral pulse wave velocity and forward pressure wave, mean arterial pressure, and the global reflection coefficient) to circulating concentrations of angiopoietin 2, its soluble receptor; vascular endothelial growth factor, its soluble receptor; hepatocyte growth factor; insulin-like growth factor 1; and its binding protein 3. Using multivariable linear regression models, adjusted for standard cardiovascular risk factors, serum insulin-like growth factor 1 concentrations were negatively associated with carotid femoral pulse wave velocity, mean arterial pressure, and reflection coefficient (P≤0.01 for all), whereas serum vascular endothelial growth factor levels were positively associated with carotid femoral pulse wave velocity and mean arterial pressure (P<0.04). Serum insulin-like growth factor binding protein 3 and soluble angiopoietin 2 receptor levels were positively related to mean arterial pressure and to forward pressure wave, respectively (P<0.05). In our cross-sectional study of a large community-based sample, circulating vascular growth factor levels were related to measures of mean and pulsatile hemodynamic load in a pattern consistent with the known physiological effects of insulin-like growth factor 1 and vascular endothelial growth factor.

Circulating neuregulin-1ß levels vary according to the angiographic severity of coronary artery disease and ischemia.

BACKGROUND: Coronary artery disease (CAD) is the leading killer in the United States. Patients with severe CAD and ischemia have worse prognosis. Therefore expansion of biomarker research, to identify at-risk individuals and explain the complex biology between cardiovascular growth factors and atherosclerosis is needed. Neuregulin-1ß (NRG-1ß) is a myocardial stress activated growth and survival factor released from endocardial and endothelial cells. NRG-1ß is essential for cardiovascular development and a regulator of angiogenesis. We postulated that plasma and serum levels of NRG-1ß would vary in relation to CAD severity and the presence of stress-induced ischemia. METHODS: We measured serum and plasma levels of NRG-1ß and vascular endothelial growth factor (VEGF) in 60 patients undergoing cardiac catheterization. CAD severity was calculated from angiographic results using a modified Duke jeopardy score. RESULTS: Serum NRG-1ß (sNRG-1ß), plasma NRG-1ß (pNRG-1ß), serum VEGF, and plasma VEGF were detectable in the majority of patients. The pNRG-1ß levels were approximately two-fold higher than sNRG-1ß. Both sNRG-1ß and pNRG-1ß correlated inversely with CAD severity. pNRG-1ß levels were statistically higher in patients with stress-induced ischemia denoted by a positive myocardial perfusion imaging study that correlated with angiographic findings (P=0.02). CONCLUSION: Both sNRG-1ß and pNRG-1ß correlated inversely with angiographic severity of CAD. pNRG-1ß levels were two-fold higher than serum and were higher in patients with stress-induced ischemia. Therefore we conclude that plasma is the optimal source for the further exploration of the biological significance of NRG-1ß as a biomarker of CAD severity and ischemia.

Identification of cis- and trans-acting genetic variants explaining up to half the variation in circulating vascular endothelial growth factor levels.

RATIONALE: Vascular endothelial growth factor (VEGF) affects angiogenesis, atherosclerosis, and cancer. Although the heritability of circulating VEGF levels is high, little is known about its genetic underpinnings. OBJECTIVE: Our aim was to identify genetic variants associated with circulating VEGF levels, using an unbiased genome-wide approach, and to explore their functional significance with gene expression and pathway analysis. METHODS AND RESULTS: We undertook a genome-wide association study of serum VEGF levels in 3527 participants of the Framingham Heart Study, with preplanned replication in 1727 participants from 2 independent samples, the STANISLAS Family Study and the Prospective Investigation of the Vasculature in Uppsala Seniors study. One hundred forty single nucleotide polymorphism (SNPs) reached genome-wide significance (P<5×10(-8)). We found evidence of replication for the most significant associations in both replication datasets. In a conditional genome-wide association study, 4 SNPs mapping to 3 chromosomal regions were independently associated with circulating VEGF levels: rs6921438 and rs4416670 (6p21.1, P=6.11×10(-506) and P=1.47×10(-12)), rs6993770 (8q23.1, P=2.50×10(-16)), and rs10738760 (9p24.2, P=1.96×10(-34)). A genetic score including these 4 SNPs explained 48% of the heritability of serum VEGF levels. Six of the SNPs that reached genome-wide significance in the genome-wide association study were significantly associated with VEGF messenger RNA levels in peripheral blood mononuclear cells. Ingenuity pathway analyses showed found plausible biological links between VEGF and 2 novel genes in these loci (ZFPM2 and VLDLR). CONCLUSIONS: Genetic variants explaining up to half the heritability of serum VEGF levels were identified. These new insights provide important clues to the pathways regulating circulating VEGF levels.

Neuregulin-1ß regulation of embryonic endothelial progenitor cell survival.

Endothelial progenitor cells (EPCs) are mobilized into the vascular space and home to damaged tissues, where they promote repair in part through a process of angiogenesis. Neuregulins (NRGs) are ligands in the epidermal growth factor family that signal through type I receptor tyrosine kinases in the erbB family (erbB2, erbB3, and erbB4) and regulate endothelial cell biology, promoting angiogenesis. Stimuli such as ischemia and exercise that promote EPC mobilization also induce cleavage and release of transmembrane NRG from cardiac microvascular endothelial cells (CMECs). We hypothesized that NRG/erbB signaling may regulate EPC biology. Using an embryonic (e)EPC cell line that homes to and repairs injured myocardium, we were able to detect erbB2 and erbB3 transcripts. Identical receptor expression was found in EPCs isolated from rat bone marrow and human whole blood. NRG treatment of eEPCs induces phosphorylation of kinases including Akt, GSK-3ß, and Erk1/2 and the nuclear accumulation and transcriptional activation of ß-catenin. NRG does not induce eEPC proliferation or migration but does protect eEPCs against serum deprivation-induced apoptosis. These results suggest a role for tissue-derived NRG in the regulation of EPC survival.

Circulating insulin-like growth factor-1 and its binding protein-3: metabolic and genetic correlates in the community.

OBJECTIVE: The metabolic and genetic correlates of circulating insulin-like growth factor-1 (IGF-1) and its main circulating carrier, IGF-1-binding-protein-3 (IGFBP-3), are unclear. METHODS AND RESULTS: We measured serum IGF-1 and IGFBP-3 concentrations in a sample of the Framingham Heart Study (N=3977, aged 40+/-9 years, 46% male) and evaluated their relations to cardiovascular risk factors using multivariable regression. Serum IGF-1 was inversely correlated with age, body mass index, total cholesterol, the presence of diabetes, alcohol consumption, and glomerular filtration rate (all P<0.01), whereas the ratio of IGF-1:IGFBP-3 was lower in women and inversely related to age, triglycerides, high-density lipoprotein cholesterol, systolic blood pressure, and alcohol consumption (all P<0.0001). Circulating IGF-1 correlated negatively with insulin resistance (homeostatic model assessment) (r=-0.1; P<0.0001) and was lower in participants with more components of the metabolic syndrome (Adult Treatment Panel III criteria) (P<0.0001). Additive genetic factors (heritability) accounted for 43% and 39% of the variation of IGF-1 and IGFBP-3, respectively (both P<10(-27)). CONCLUSIONS: Our cross-sectional observations in a large community-based sample link lower circulating IGF-1 to greater metabolic risk burden and underscore substantial genetic influences on IGF-1 concentrations. Prospective studies are warranted to elucidate whether lower IGF-1 concentrations predict greater metabolic risk longitudinally.

Clinical and genetic correlates of circulating angiopoietin-2 and soluble Tie-2 in the community.

BACKGROUND: Experimental studies suggest that endothelial growth factors play an important role in angiogenesis and vascular remodeling. The clinical and genetic correlates of circulating angiopoietin-2 (Ang-2) and its soluble receptor/regulator Tie-2 (sTie-2) have not been determined in a community-based sample. METHODS AND RESULTS: Serum Ang-2 and sTie-2 were assayed in 3778 third-generation cohort participants of the Framingham Heart Study (mean age, 40+/-9 years; 53% women). Clinical correlates and heritability of both biomarkers were assessed using generalized estimating equations and variance-component analyses. Ang-2 levels were higher and sTie-2 levels were lower in women than in men. Ang-2 was positively related to age, smoking, systolic blood pressure, hypertension treatment, and diabetes (P<0.05 for all) but was inversely associated with total cholesterol and diastolic blood pressure (P<0.0001 for both), and sTie-2 was positively associated with body mass index, diabetes, and triglycerides but was inversely related to age, alcohol consumption, and glomerular filtration rate (P<0.05 for all). Both Ang-2 and sTie-2 were higher in participants with metabolic syndrome (P<0.005), with stronger associations of Ang-2 with blood pressure traits and of sTie-2 with obesity-dyslipidemia components. Heritability estimates for Ang-2 and sTie-2 were 27% and 56%, respectively (P<0.0001). A region on chromosome 9 was significantly linked to circulating sTie-2 levels (logarithm of the odds score, 8.31). CONCLUSION: Circulating levels of Ang-2 and sTie-2 are heritable traits associated with cardiovascular disease risk factors, including the metabolic syndrome. These observations are consistent with the notion that angiogenesis and vascular remodeling are determined in part by genetic influences and associated with metabolic risk factors.

Neuregulin-1 beta is associated with disease severity and adverse outcomes in chronic heart failure.

BACKGROUND: Neuregulin-1 (NRG-1) is a paracrine factor released by microvascular endothelial cells that has cardioprotective effects in animal models of heart failure. However, circulating NRG-1 has not been studied in human heart disease. We used a novel immunoassay to test whether circulating NRG-1beta is associated with disease severity and clinical outcomes in chronic heart failure. METHODS AND RESULTS: Serum NRG-1beta was quantified in 899 outpatients in the Penn Heart Failure Study, a referral cohort representing a broad spectrum of systolic heart failure. Circulating NRG-1beta was significantly elevated in patients with worse disease severity (median, 6.2 ng/mL for New York Heart Association class IV versus 4.4 ng/mL for class I; P=0.002). In adjusted models, NRG-1beta was independently associated with an increased risk of death or cardiac transplantation over a median follow-up of 2.4 years (adjusted hazard ratio, 1.58; 95% confidence interval, 1.04 to 2.39; P=0.03 comparing fourth versus first NRG-1beta quartile). Associations with outcome differed by heart failure cause and symptom severity, with the strongest associations observed in patients with ischemic cardiomyopathy (interaction P=0.008) and New York Heart Association class III/IV symptoms (interaction P=0.01). These findings were all independent of brain natriuretic peptide, and assessment of NRG-1beta and brain natriuretic peptide jointly provided better risk stratification than each biomarker individually in patients with ischemic or New York Heart Association class III/IV heart failure. CONCLUSIONS: Circulating NRG-1beta is independently associated with heart failure severity and risk of death or cardiac transplantation. These findings support a role for NRG-1/ErbB signaling in human heart failure and identify serum NRG-1beta as a novel biomarker that may have clinical applications.

Vascular endothelial growth factor, its soluble receptor, and hepatocyte growth factor: clinical and genetic correlates and association with vascular function.

AIMS: Growth factors play an important role in regulating vascular function. Data are limited regarding clinical and genetic correlates of endothelial growth factors and their associations with vascular function. METHODS AND RESULTS: We evaluated clinical and genetic correlates of circulating vascular endothelial growth factor A (VEGF), its soluble receptor sFlt-1, and hepatocyte growth factor (HGF) in 3754 Framingham Study participants. We also related the growth factors to measures of brachial artery function. Serum VEGF and HGF were higher and sFLt-1 was lower in women and smokers. VEGF and HGF were associated positively with body mass index; both displayed strong positive associations with the metabolic syndrome (P < 0.001) and its components. The heritabilities of VEGF, sFlt-1, and HGF were 78, 13, and 38%, respectively. VEGF and HGF were related positively to baseline brachial diameter (P < 0.01) and to baseline mean flow velocity (P < 0.001) in age- and sex-adjusted models, but the multivariable models failed to reach significance. None of the growth factors were related to flow-mediated dilation. CONCLUSION: In our community-based sample, circulating VEGF and HGF demonstrated high heritabilities and a sexual dimorphism. Increased angiogenesis and greater endothelial cell turnover may underlie associations of these growth factors with risk factors including smoking.

Serum Neuregulin-1beta as a Biomarker of Cardiovascular Fitness.

PURPOSE: Neuregulins (NRG) are growth factors that bind to receptors of the erbB family, and are known to mediate a number of processes involved in diverse tissues. Neuregulin-1beta is expressed in skeletal muscle and is activated by exercise. We hypothesized that NRG-1beta might circulate in the bloodstream and increase as a consequence of physical activity. A study was conducted in healthy subjects to determine if NRG-1beta is immunodetectable in human serum, and if so whether levels relate acutely or chronically to exercise. METHODS: Nine healthy men underwent three bouts of exercise of varying degrees of intensity on a bicycle ergometer over a period of three weeks. Cardio-respiratory fitness was determined by measurement of maximal oxygen uptake (VO(2)max). Serum was sampled prior to and immediately after each session (up to 30 minutes post) and serum NRG-1beta was quantified utilizing an indirect sandwich ELISA assay developed in our lab. RESULTS: Across subjects, mean serum NRG-1beta levels ranged from 32 ng/mL to 473 ng/mL. Individual subjects showed relatively stable levels during the study period that did not change acutely after exercise. Serum NRG-1beta demonstrated a positive correlation with VO(2)max (r2=0.49, p =.044). CONCLUSIONS: These preliminary observations suggest that at least in healthy men, serum NRG-1beta is an indicator of cardio-respiratory fitness and does not change acutely with exercise.

Clinical and echocardiographic correlates of plasma procollagen type III amino-terminal peptide levels in the community.

BACKGROUND: Left ventricular remodeling is characterized by increased collagen deposition in the extracellular matrix. Levels of plasma procollagen type III amino-terminal peptide (PIIINP), a marker of collagen turnover, are elevated in the setting of recent myocardial infarction, heart failure, and cardiomyopathy. Whether plasma PIIINP levels are a useful indicator of subclinical left ventricular abnormalities in ambulatory individuals has not been studied. METHODS: We examined 967 Framingham Heart Study participants (mean age, 56 years; 60% women) who underwent routine echocardiography and measurement of plasma PIIINP levels. All participants were free of prior myocardial infarction or heart failure. Multivariable regression analyses were performed to examine the clinical and echocardiographic correlates of PIIINP levels. RESULTS: Plasma PIIINP levels increased with age and body mass index but did not significantly correlate with other cardiovascular risk factors including hypertension and diabetes. In multivariable models, there was no association between plasma PIIINP levels and left ventricular mass (P = .89), left ventricular fractional shortening (P = .15), left ventricular end-diastolic dimension (P = .51), or left atrial size (P = .68). Plasma PIIINP levels were positively correlated with tissue inhibitor of metalloproteinase-1 levels (multivariable-adjusted, P = .001). CONCLUSIONS: The use of biomarkers of extracellular matrix turnover has generated recent interest, with plasma PIIINP being the most commonly studied biomarker in acute settings. However, our findings in a large, community-based cohort suggest that plasma PIIINP has limited use for the detection of structural heart disease in ambulatory individuals.