High-Density Lipoprotein Particle Subfractions in Heart Failure With Preserved or Reduced Ejection Fraction.

BACKGROUND: Circulating high-density lipoprotein particle (HDL-P) subfractions impact atherogenesis, inflammation, and endothelial function, all of which are implicated in the pathobiology of heart failure (HF). OBJECTIVES: The authors sought to identify key differences in plasma HDL-P subfractions between patients with HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) to determine their prognostic utility. METHODS: Patients with HFrEF (n = 782), HFpEF (n = 1,004), and no HF (n = 4,742) were identified in the CATHGEN (Catheterization Genetics) biorepository of sequential patients undergoing cardiac catheterization. Nuclear magnetic resonance-based lipoprotein profiling was performed on frozen fasting plasma obtained at catheterization. The authors used multivariable analysis of covariance to compare high-density lipoprotein particle (HDL-P) subfractions across groups, and Cox proportional hazards modeling to determine associations between HDL-P subfractions and time to death or major adverse cardiac events. RESULTS: Mean HDL-P size was greater in HFrEF than HFpEF, both of which were greater than in no HF (all 2-way p < 0.0001). By contrast, concentrations of small HDL-P and total HDL-P were lesser in HFrEF than HFpEF, which were both lesser than no HF (all 2-way p ≤ 0.0002). In both HFrEF and HFpEF, total HDL-P and small HDL-P were inversely associated with time to adverse events. These findings persisted after adjustment for 14 clinical covariates (including high-density lipoprotein cholesterol content, coronary artery disease, and the inflammatory biomarker GlycA), and in sensitivity analyses featuring alternate left ventricular ejection fraction definitions, or stricter inclusion criteria with diastolic dysfunction or left ventricular end-diastolic pressure thresholds. CONCLUSIONS: In the largest analysis of HDL-P subfractions in HF to date, derangements in HDL-P subfractions were identified that were more severe in HFrEF than HFpEF and were independently associated with adverse outcomes. These data may help refine risk assessment and provide new insights into the complex interaction of HDL and HF pathophysiology.

Improvement in insulin resistance after gastric bypass surgery is correlated with a decline in plasma 2-hydroxybutyric acid.

BACKGROUND: Gastric bypass surgery for weight reduction often corrects dysglycemia in diabetic patients, but a full understanding of the underlying biochemical pathways continues to be investigated. OBJECTIVES: To explore the effects of weight loss by surgical and dietary interventions on plasma metabolites using both targeted and discovery-oriented metabolomics platforms. SETTING: An academic medical center in the United States. METHODS: Improvement in homeostatic model assessment for insulin resistance (HOMA-IR), as an index of insulin resistance, was compared at 6 months in 11 patients that underwent Roux-en-Y gastric bypass against 11 patients that were matched for weight loss in the Weight Loss Maintenance (WLM) program. Metabolites in plasma were evaluated by nontargeted gas chromatography/mass spectrometry for the potential detection of >1100 biochemical markers. RESULTS: Among multiple metabolites detected, 2-hydroxybutyric acid (2-HBA) declined most significantly after 6 months in comparing patients that underwent Roux-en-Y gastric bypass with those in WLM (P < .001), corresponding with declines in HOMA-IR (P = .025). Baseline levels of 2-HBA for all patients were correlated with preintervention levels of HOMA-IR (R2 = .565, P < .001). Moreover, the changes in 2-HBA after 6 months were correlated with changes in HOMA-IR (R2 = .399, P = .0016). CONCLUSIONS: Correlation between insulin resistance and 2-HBA suggests the utility of the latter as an excellent biomarker for tracking glycemic improvement, and offers further insight into the pathways that control diabetes. This is the first report of a decline in 2-HBA in response to bariatric surgery.

Metabolites predict cardiovascular disease events in persons living with HIV: a pilot case-control study.

Introduction: Persons living with HIV (PLWH) are at higher risk for cardiovascular disease (CVD) events than uninfected persons. Current risk-stratification methods to define PLWH at highest risk for CVD events are lacking. Methods: Using tandem flow injection mass spectrometry, we quantified plasma levels of 60 metabolites in 24 matched pairs of PLWH [1:1 with and without known coronary artery disease (CAD)]. Metabolite levels were reduced to interpretable factors using principal components analysis. Results: Factors derived from short-chain dicarboxylacylcarnitines (SCDA) (p = 0.08) and glutamine/valine (p = 0.003) were elevated in CAD cases compared to controls. Conclusion: SCDAs and glutamine/valine may be valuable markers of cardiovascular risk among persons living with HIV in the future, pending validation in larger cohorts.

Brain-derived neurotrophic factor rs6265 (Val66Met) polymorphism is associated with disease severity and incidence of cardiovascular events in a patient cohort.

BACKGROUND: The rs6265 (Val66Met) single-nucleotide polymorphism in the BDNF gene has been related to a number of endophenotypes that have in turn been shown to confer risk for atherosclerotic cardiovascular disease (CVD). To date, however, very few studies have examined the association of the Val66Met single-nucleotide polymorphism with CVD clinical outcomes. METHODS: In a cohort of 5,510 Caucasian patients enrolled in the CATHeterization GENetics (CATHGEN) study at Duke University Hospital between 2001 and 2011, we determined the severity of coronary artery disease (CAD) and CVD event incidence through up to 11.8years of follow-up. We examined the association of Val66Met genotype with time-to-death or myocardial infarction, adjusting for age, sex, CAD risk variables, and CAD severity measures. RESULTS: The Val/Val genotype was associated with a higher risk than Met carriers for clinical CVD events (P=.034, hazard ratio 1.12, 95% CI 1.01-1.24). In addition, compared with Met carriers, individuals with the Val/Val genotype had a greater odds of having more diseased vessels (odds ratio 1.17, 95% CI 1.06-1.30, P=.002), and lower left ventricular ejection fraction (ß=-0.72, 95% CI, -1.42 to -0.02, P=.044). CONCLUSIONS: The Val/Val genotype was associated with greater severity of CAD and incidence of CVD-related clinical events in a patient sample. If these findings are confirmed in further research, intervention studies in clinical groups with the Val/Val genotype could be undertaken to prevent disease and improve prognosis.

A Novel Protein Glycan-Derived Inflammation Biomarker Independently Predicts Cardiovascular Disease and Modifies the Association of HDL Subclasses with Mortality.

BACKGROUND: Evidence suggests that systemic inflammation may adversely impact HDL function. In this study we sought to evaluate the independent and incremental predictive performance of GlycA-a novel serum inflammatory biomarker that is an aggregate measure of enzymatically glycosylated acute phase proteins-and HDL subclasses on adverse events in a retrospective observational study of a secondary prevention population and to understand a priori defined potential interactions between GlycA and HDL subclasses. METHODS: GlycA and HDL subclasses were measured using proton nuclear magnetic resonance spectroscopy in 7617 individuals in the CATHGEN (CATHeterization GENetics) cardiac catheterization biorepository. RESULTS: GlycA was associated with presence [odds ratio (OR) 1.07 (1.02-1.13), P = 0.01] and extent [OR 1.08 (1.03, 1.12) P < 0.0005] of coronary artery disease and with all-cause mortality [hazard ratio (HR) 1.34 (1.29-1.39), P < 0.0001], cardiovascular mortality [1.37 (1.30-1.45), P < 0.0001] and noncardiovascular mortality [1.46 (1.39-1.54) P < 0.0001] in models adjusted for 10 cardiovascular risk factors. GlycA and smaller HDL subclasses had independent but opposite effects on mortality risk prediction, with smaller HDL subclasses being protective [HR 0.69 (0.66-0.72), P < 0.0001]. There was an interaction between GlycA and smaller HDL subclasses-increasing GlycA concentrations attenuated the inverse association of smaller HDL subclasses with mortality. Adding GlycA and smaller HDL subclasses into the GRACE (Global Registry of Acute Coronary Events) and Framingham Heart Study Risk Scores improved mortality risk prediction, discrimination and reclassification. CONCLUSIONS: These findings highlight the interaction of systemic inflammation and HDL with clinical outcomes and may increase precision for clinical risk assessment in secondary prevention populations.

High-density lipoprotein subclass measurements improve mortality risk prediction, discrimination and reclassification in a cardiac catheterization cohort.

BACKGROUND AND AIMS: Recent failures of HDL cholesterol (HDL-C)-raising therapies to prevent cardiovascular disease (CVD) events have tempered the interest in the role of HDL-C in clinical risk assessment. Emerging data suggest that the atheroprotective properties of HDL depend on specific HDL particle characteristics not reflected by HDL-C. The purpose of this study was to determine the association of HDL particle concentration (HDL-P) and HDL subclasses with mortality in a high-risk cardiovascular population and to examine the clinical utility of these parameters in mortality risk discrimination and reclassification models. METHODS: Using nuclear magnetic resonance spectroscopy, we measured HDL-P and HDL subclasses in 3972 individuals enrolled in the CATHGEN coronary catheterization biorepository; tested for association with all-cause mortality in robust clinical models; and examined the utility of HDL subclasses in incremental mortality risk discrimination and reclassification. RESULTS: Over an average follow-up of eight years, 29.6% of the individuals died. In a multivariable model adjusted for ten CVD risk factors, HDL-P [HR, 0.71 (0.67-0.76), p = 1.3e-24] had a stronger inverse association with mortality than did HDL-C [HR 0.93 (0.87-0.99), p = 0.02]. Larger HDL size conferred greater risk and the sum of medium- and small-size HDL particles (MS-HDL-P) conferred less risk. Furthermore, the strong inverse relation of HDL-P levels with mortality was accounted for entirely by MS-HDL-P; HDL-C was not associated with mortality after adjustment for MS-HDL-P. Addition of MS-HDL-P to the GRACE Risk Score significantly improved risk discrimination and risk reclassification. CONCLUSION: HDL-P and smaller HDL subclasses were independent markers of residual mortality risk and incremental to HDL-C in a high-risk CVD population. These measures should be considered in risk stratification and future development of HDL-targeted therapies in high-risk populations.

Genetic variants associated with vein graft stenosis after coronary artery bypass grafting.

BACKGROUND: Vein graft stenosis after coronary artery bypass grafting (CABG) is common. Identifying genes associated with vein graft stenosis after CABG could reveal novel mechanisms of disease and discriminate patients at risk for graft failure. We hypothesized that genome-wide association would identify these genes. METHODS: We performed a genome-wide association study on a subset of patients presenting for cardiac catheterization for concern of ischemic heart disease, who also underwent CABG and subsequent coronary angiography after CABG for clinical indications (n = 521). Cases were defined as individuals with ≥50% stenosis in any vein graft on any cardiac catheterization, and controls were defined as those who did not have vein graft stenosis on any subsequent cardiac catheterization. Multivariable logistic regression was used to assess the association between single nucleotide polymorphisms (SNPs) and vein graft stenosis. RESULTS: Sixty-nine percent of patients had vein graft failure after CABG. Seven SNPs were significantly associated with vein graft stenosis, including intronic SNPs in the genes PALLD (Rs6854137, P = 3.77 × 10(-6)), ARID1B (Rs184074, P = 5.97 × 10(-6)), and TMEM123 (Rs11225247, P = 8.25 × 10(-6)); and intergenic SNPs near the genes ABCA13 (Rs10232860, P = 4.54 × 10(-6)), RMI2 (Rs9921338, P = 6.15 × 10(-6)), PRM2 (Rs7198849, P = 7.27 × 10(-6)), and TNFSF4 (Rs17346536, P = 9.33 × 10(-6)). CONCLUSIONS: We have identified novel genetic variants that may predispose to risk of vein graft failure after CABG, many within biologically plausible pathways. These polymorphisms merit further investigation, as they could assist in stratifying patients with multi-vessel coronary artery disease, which could lead to alterations in management and revascularization strategy.

Risk factors for 1-year mortality after thoracic endovascular aortic repair.

OBJECTIVE: Thoracic endovascular aortic repair, although physiologically well tolerated, may fail to confer significant survival benefit in some high-risk patients. In an effort to identify patients most likely to benefit from intervention, the present study sought to determine the risk factors for 1-year mortality after thoracic endovascular aortic repair. METHODS: A retrospective review was performed on prospectively collected data from all patients undergoing thoracic endovascular aortic repair from 2002 to 2010 at a single institution. Univariate analysis and multivariate Cox proportional hazards regression analysis were used to identify risk factors associated with mortality within 1 year after thoracic endovascular aortic repair. RESULTS: During the study period, 282 patients underwent at least 1 thoracic endovascular aortic repair; index procedures included descending aortic repair (n = 189), hybrid arch repair (n = 55), and hybrid thoracoabdominal repair (n = 38). The 30-day/in-hospital mortality was 7.4% (n = 21) and the overall 1-year mortality was 19% (n = 54). Cardiopulmonary pathologies were the most common cause of nonperioperative 1-year mortality (22%, n = 12). Multivariate modeling demonstrated 3 variables independently associated with 1-year mortality: age older than 75 years (hazard ratio, 2.26; P = .005), aortic diameter greater than 6.5 cm (hazard ratio, 2.20; P = .007), and American Society of Anesthesiologists class 4 (hazard ratio, 1.85; P = .049). A baseline creatinine greater than 1.5 mg/dL (hazard ratio, 1.79; P = .05) and congestive heart failure (hazard ratio, 1.87; P = .08) were also retained in the final model. These 5 variables explained a large proportion of the risk of 1-year mortality (C statistic = 0.74). CONCLUSIONS: Age older than 75 years, aortic diameter greater than 6.5 cm, and American Society of Anesthesiologists class 4 are independently associated with 1-year mortality after thoracic endovascular aortic repair. These clinical characteristics may help risk-stratify patients undergoing thoracic endovascular aortic repair and identify those unlikely to derive a long-term survival benefit from the procedure.

A functional polymorphism in the 5HTR2C gene associated with stress responses also predicts incident cardiovascular events.

Previously we have shown that a functional nonsynonymous single nucleotide polymorphism (rs6318) of the 5HTR2C gene located on the X-chromosome is associated with hypothalamic-pituitary-adrenal axis response to a stress recall task, and with endophenotypes associated with cardiovascular disease (CVD). These findings suggest that individuals carrying the rs6318 Ser23 C allele will be at higher risk for CVD compared to Cys23 G allele carriers. The present study examined allelic variation in rs6318 as a predictor of coronary artery disease (CAD) severity and a composite endpoint of all-cause mortality or myocardial infarction (MI) among Caucasian participants consecutively recruited through the cardiac catheterization laboratory at Duke University Hospital (Durham, NC) as part of the CATHGEN biorepository. Study population consisted of 6,126 Caucasian participants (4,036 [65.9%] males and 2,090 [34.1%] females). A total of 1,769 events occurred (1,544 deaths and 225 MIs; median follow-up time = 5.3 years, interquartile range = 3.3-8.2). Unadjusted Cox time-to-event regression models showed, compared to Cys23 G carriers, males hemizygous for Ser23 C and females homozygous for Ser23C were at increased risk for the composite endpoint of all-cause death or MI: Hazard Ratio (HR) = 1.47, 95% confidence interval (CI) = 1.17, 1.84, p = .0008. Adjusting for age, rs6318 genotype was not related to body mass index, diabetes, hypertension, dyslipidemia, smoking history, number of diseased coronary arteries, or left ventricular ejection fraction in either males or females. After adjustment for these covariates the estimate for the two Ser23 C groups was modestly attenuated, but remained statistically significant: HR = 1.38, 95% CI = 1.10, 1.73, p = .005. These findings suggest that this functional polymorphism of the 5HTR2C gene is associated with increased risk for CVD mortality and morbidity, but this association is apparently not explained by the association of rs6318 with traditional risk factors or conventional markers of atherosclerotic disease.

Matrix metalloproteinase-9 genetic polymorphisms and the risk for advanced pelvic organ prolapse.

OBJECTIVE: Matrix metalloproteinase-9 (MMP9) is a protease associated with degradation of collagen and elastin. Because increased MMP9 activity in vaginal tissue has been associated with pelvic organ prolapse (POP), we sought to comprehensively estimate MMP9 genetic variants and the risk for advanced prolapse. METHODS: This is a candidate gene association study of women with stage III-IV prolapse (case group, n=239) and women with stage 0-1 prolapse (control group, n=197). We attempted to oversample "extreme" phenotypes, including younger women with severe prolapse and older women without prolapse, in an attempt to concentrate the genetic effect. We used a linkage disequilibrium tagged approach to identify single nucleotide polymorphisms in MMP9 to evaluate in our study. To minimize potential confounding by race, our analysis focused on non-Hispanic white women. We performed multivariable logistic regression to estimate the association between MMP9 single nucleotide polymorphisms and case-control status, adjusting for age and vaginal parity. RESULTS: Women with advanced prolapse were slightly younger (64.8 ± 10.3 compared with 69.0 ± 10.2 years, P<.001) and more likely to have had one or more vaginal deliveries (96.6% compared with 82.2%, P<.001) when compared with control participants. Eight single nucleotide polymorphisms were assessed, which represented 93% coverage of the MMP9 gene. Of these, two were associated with advanced prolapse: 1) rs3918253 (adjusted odds ratio [OR] 0.64, 95% confidence interval [CI] 0.41-1.0, P=.05); and 2) rs3918256 (adjusted OR 0.64, 95% CI 0.41-1.01, P=.05). CONCLUSION: MMP9 is a biologically plausible candidate gene for POP given our results.

Comprehensive analysis of LAMC1 genetic variants in advanced pelvic organ prolapse.

OBJECTIVE: We sought to comprehensively evaluate the association of laminin gamma-1 (LAMC1) and advance pelvic organ prolapse. STUDY DESIGN: We conducted a candidate gene association of patients (n = 239) with stages III-IV prolapse and controls (n = 197) with stages 0-I prolapse. We used a linkage disequilibrium (LD)-tagged approach to identify single-nucleotide polymorphisms (SNPs) in LAMC1 and focused on non-Hispanic white women to minimize population stratification. Additive and dominant multivariable logistic regression models were used to test for association between individual SNPs and advanced prolapse. RESULTS: Fourteen SNPs representing 99% coverage of LAMC1 were genotyped. There was no association between SNP rs10911193 and advanced prolapse (P = .34). However, there was a trend toward significance for SNPs rs1413390 (P = .11), rs20563 (P = .11), and rs20558 (P = .12). CONCLUSION: Although we found that the previously reported LAMC1 SNP rs10911193 was not associated with nonfamilial prolapse, our results support further investigation of this candidate gene in the pathophysiology of prolapse.

Metabolic profiles predict adverse events after coronary artery bypass grafting.

OBJECTIVE: Clinical models incompletely predict the outcomes after coronary artery bypass grafting. Novel molecular technologies can identify biomarkers to improve risk stratification. We examined whether metabolic profiles can predict adverse events in patients undergoing coronary artery bypass grafting. METHODS: The study population comprised 478 subjects from the CATHGEN biorepository of patients referred for cardiac catheterization who underwent coronary artery bypass grafting after enrollment. Targeted mass spectrometry-based profiling of 69 metabolites was performed in frozen, fasting plasma samples collected before surgery. Principal components analysis and Cox proportional hazards regression modeling were used to assess the relation between the metabolite factor levels and a composite outcome of postcoronary artery bypass grafting myocardial infarction, the need for percutaneous coronary intervention, repeat coronary artery bypass grafting, and death. RESULTS: During a mean follow-up period of 4.3 ± 2.4 years, 126 subjects (26.4%) experienced an adverse event. Three principal components analysis-derived factors were significantly associated with an adverse outcome on univariate analysis: short-chain dicarboxylacylcarnitines (factor 2, P = .001); ketone-related metabolites (factor 5, P = .02); and short-chain acylcarnitines (factor 6, P = .004). These 3 factors remained independently predictive of an adverse outcome after multivariate adjustment: factor 2 (adjusted hazard ratio, 1.23; 95% confidence interval, 1.10-1.38; P < .001), factor 5 (odds ratio, 1.17; 95% confidence interval, 1.01-1.37; P = .04), and factor 6 (odds ratio, 1.14; 95% confidence interval, 1.02-1.27; P = .03). CONCLUSIONS: Metabolic profiles are independently associated with adverse outcomes after coronary artery bypass grafting. These profiles might represent novel biomarkers of risk that can augment existing tools for risk stratification of coronary artery bypass grafting patients and might elucidate novel biochemical pathways that mediate risk.

Effect of heparin administration on metabolomic profiles in samples obtained during cardiac catheterization.

BACKGROUND: Metabolic profiling holds promise for early detection of coronary artery disease and assessing risk for ischemic events. Heparin is frequently administered (1) to treat acute coronary syndromes; and (2) during routine cardiac catheterization procedures. Because it stimulates lipolysis, heparin is a potential confounder of metabolic profiling in these populations. METHODS AND RESULTS: Using mass spectrometry and conventional immunoassays, we evaluated how unfractionated heparin administration affected 69 peripheral blood metabolites (acylcarnitines, amino acids, nonesterified fatty acids and their oxidation byproducts, conventional lipids, glucose, and C-reactive protein) in samples obtained pre- and postcardiac catheterization from 19 patients who received heparin and 10 patients who did not. Using unpaired t tests, we compared the changes in mean metabolite levels before and after the procedure between the nonheparin and heparin groups. Clinical characteristics of the nonheparin and heparin groups, indication for cardiac catheterization, procedure performed, and other periprocedural variables were similar. The mean change between pre- and postprocedure ß-hydroxybutyrate (5.43 versus 66.84 µmol/L; P=0.009), ketones (21.17 versus 98.49 µmol/L; P=0.009), nonesterified fatty acids (0.37 versus 1.20 mmol/L; P=0.017), and triglycerides (-9.33 versus -36.50 mg/dL; P=0.007) was significantly different between the nonheparin and heparin groups, respectively. There were no significant differences between groups in the other metabolites measured. CONCLUSIONS: Heparin administration during cardiac catheterization induced changes in peripheral blood metabolites that were consistent with known lipolytic effects of heparin and define a metabolite signature associated with heparin administration. These findings are important for accurate interpretation of future metabolic profiling studies in populations exposed to heparin.

Complement factor 1 inhibitor improves cardiopulmonary function in neonatal cardiopulmonary bypass.

BACKGROUND: The inflammatory insult associated with cardiopulmonary bypass (CPB) continues to result in morbidity for neonates undergoing complex repair of congenital cardiac defects. Complement and contact activation are important mediating processes involved in this injury. Complement factor 1 esterase inhibitor (C1-inh), a natural inhibitor of complement, kallikrein, and coagulation pathways, may be decreased in children undergoing cardiac operations requiring CPB. We tested the hypothesis that C1-inh supplementation will ameliorate the cardiac and pulmonary dysfunction in a model of neonatal CPB. METHODS: Fifty-two neonatal pigs were randomly assigned to receive 0 IU (n = 22), 500 IU (n = 15), 1,000 IU (n = 8), or 1,500 IU (n = 7) of C1-inh. Doses were delivered 5 minutes before starting 90 minutes of normothermic CPB. Pulmonary and cardiovascular measures were taken before and 5, 30, and 60 minutes after CPB. RESULTS: Five animals did not survive CPB. The C1-inh concentration post-CPB increased monotonically with increasing dose (p < 0.001). Weight gain was significantly less in the 1,500 IU group (0.24 +/- 0.10 kg versus 0.38 +/- 0.09 kg, p = 0.001). Dynamic compliance increased with C1-inh dose from 0 to 500 IU by 23% +/- 4% (p < 0.001), but the increase leveled off at the higher doses. Alveolar-arterial O2 gradient decreased with C1-inh dose (p = 0.009). Time derivative of left ventricular pressure (dP/dt(max)) increased significantly with increasing dose (p = 0.016). At the highest dose of C1-inh, the time constant of isovolumic relaxation was increased (p = 0.018). CONCLUSIONS: The C1-inh supplementation results in improved pulmonary and systolic cardiac function in a model of neonatal CPB. The negative effect on diastolic function requires further investigation.

Setting positive end-expiratory pressure during jet ventilation to replicate the mean airway pressure of oscillatory ventilation.

BACKGROUND: High-frequency ventilation can be delivered with either oscillatory ventilation (HFOV) or jet ventilation (HFJV). Traditional clinician biases may limit the range of function of these important ventilation modes. We hypothesized that (1) the jet ventilator can be an accurate monitor of mean airway pressure (P (aw)) during HFOV, and (2) a mathematical relationship can be used to determine the positive end-expiratory pressure (PEEP) setting required for HFJV to reproduce the P (aw) of HFOV. METHODS: In phase 1 of our experiment, we used a differential pressure pneumotachometer and a jet adapter in-line between an oscillator circuit and a pediatric lung model to measure P (aw), PEEP, and peak inspiratory pressure (PIP). Thirty-six HFOV setting combinations were studied, in random order. We analyzed the correlation between the pneumotachometer and HFJV measurements. In phase 2 we used the jet as the monitoring device during each of the same 36 combinations of HFOV settings, and recorded P (aw), PIP, and DeltaP. Then, for each combination of settings, the jet ventilator was placed in-line with a conventional ventilator and was set at the same rate and PIP as was monitored during HFOV. To determine the appropriate PEEP setting, we calculated the P (aw) contributed by the PIP, respiratory rate, and inspiratory time set for HFJV, and subtracted this from the goal P (aw). This value was the PEEP predicted for HFJV to match the HFOV P (aw). RESULTS: The correlation coefficient between the pneumotachometer and HFJV measurements was r = 0.99 (mean difference 0.62 +/- 0.30 cm H(2)O, p < 0.001). The predicted and actual PEEP required were highly correlated (r = 0.99, p < 0.001). The mean difference in these values is not statistically significantly different from zero (mean difference 0.25 +/- 1.02 cm H(2)O, p > 0.15). CONCLUSIONS: HFJV is an accurate monitor during HFOV. These measurements can be used to calculate the predicted PEEP necessary to match P (aw) on the 2 ventilators. Replicating the P (aw) with adequate PEEP on HFJV may help simplify transitioning between ventilators when clinically indicated.

Insensible water loss from the medtronic minimax oxygenator: an In Vitro study.

The purposes of this study were to quantify the insensible water loss that occurs across the Medtronic Minimax oxygenator and to estimate the resultant rise in fluid sodium concentration.A Carmeda-coated extracorporeal membrane oxygenation circuit connected to a Medtronic Minimax Plus oxygenator was primed with normal saline and attached to a closed reservoir. The gas sweep was randomly assigned to one of three rates: 2, 5, or 10 LPM (liters per minute). Each sweep rate was run in triplicate. The sodium concentration of the circuit was assessed after 12 and 24 hours of each trial. At the end of each 24-hour run, the evaporative loss was calculated. The average insensible water losses were 6.9+/-0.4 ml/h, 16.6+/-1.5 ml/h, and 34.4+/-0.3 ml/h at gas sweep rates of 2, 5, and 10 LPM, respectively (p<0.0001). Daily evaporative water losses for the membrane can be estimated to be 82.7+/-2.2 ml for each 1 LPM of sweep gas flow for a normal saline pump flow of 300 ml/min. In a closed circuit, a faster sweep gas rate is associated with a more rapid rise in sodium concentration (p<0.0001).

A novel inhaled organic nitrate that affects pulmonary vascular tone in a piglet model of hypoxia-induced pulmonary hypertension.

Persistent pulmonary hypertension of the newborn is characterized by elevated pulmonary vascular resistance after birth leading to right-to-left shunting and systemic arterial hypoxemia. Inhaled nitric oxide (NO) is effective in reducing the need for extracorporeal membrane oxygenation, but it has potential toxicities, especially in an oxygen-rich environment. A number of other NO-based molecules have been given by inhalation, but their structure-function relationships have not been established. Recent studies have raised the idea that toxic and beneficial properties can be separated. We synthesized a novel organic nitrate [ethyl nitrate (ENO2)], tested it in vitro, and administered it to hypoxic piglets. ENO2 lowered pulmonary artery pressure and raised the Po2 in arterial blood but did not alter systemic vascular resistance or methemoglobin levels. In addition, we tested the effect of ENO2 in the presence of the thiol glutathione, both in vivo and in vitro, and found its action to be enhanced. Although ENO2 is less potent than inhaled NO on a dose-equivalency basis, pretreatment of hypoxic animals with glutathione, which may be depleted in injured lungs, led to a markedly enhanced effect (largely mitigating the difference in potency). These results suggest that ENO2 may hold promise as a safe alternative to NO, particularly in hypoxemic conditions characterized by thiol depletion.

Soluble alpha2-macroglobulin receptor is increased in endotracheal aspirates from infants and children after cardiopulmonary bypass.

OBJECTIVE: Cytokine dysregulation contributes to the systemic inflammatory response after cardiopulmonary bypass. Clearance of cytokine binding proteins may be important in the resolution of inflammation. Our aim was to determine whether the cytokine binding protein alpha 2 -macroglobulin and its soluble receptor were upregulated in endotracheal aspirates from infants and children undergoing cardiopulmonary bypass. METHODS: Seventy tracheal aspirates were collected before and after cardiopulmonary bypass from 35 infants and children undergoing surgical correction of congenital heart defects. alpha 2 -Macroglobulin and the soluble alpha 2 -macroglobulin receptor were identified by Western blot. With the use of multi-analyte cytokine profiling, pro-inflammatory and anti-inflammatory cytokines were quantified, normalized to total protein, and expressed as ratios. Paired t tests and Wilcoxon signed-rank tests were performed between prebypass and postbypass samples. Correlations were examined among alpha 2 -macroglobulin, soluble alpha 2 -macroglobulin receptor, cytokine ratios, and the clinical variables of cardiopulmonary bypass, aortic crossclamp, and circulatory arrest times. RESULTS: alpha 2 -Macroglobulin increased by 50% (mean densitometry increase 82,683 +/- 184,594, P = .012), and soluble alpha 2 -macroglobulin receptor increased by 17% (mean densitometry increase 506,148 +/- 687,037, P = .0001) after cardiopulmonary bypass. The ratio of interleukin-8/interleukin-4 increased by 136% ( P = .0001), and interleukin-8/interleukin-10 increased by 102% ( P = .001). The increase in soluble alpha 2 -macroglobulin receptor was positively correlated with the ratios of interleukin-8/interleukin-4 and interleukin-8/interleukin-10. There were no statistically significant positive correlations between the increase in alpha 2 -macroglobulin or soluble alpha 2 -macroglobulin receptor and measured clinical variables. CONCLUSIONS: We report for the first time the upregulation of alpha 2 -macroglobulin and soluble alpha 2 -macroglobulin receptor in tracheal aspirates after cardiopulmonary bypass in infants and children. Soluble alpha 2 -macroglobulin receptor correlates with increased alpha 2 -macroglobulin and a disproportionate increase in pro-inflammatory to anti-inflammatory cytokine ratios.

Carbon dioxide elimination and gas displacement vary with piston position during high-frequency oscillatory ventilation.

INTRODUCTION: Alterations in gas displacement in pediatric patients ventilated with the SensorMedics 3100A high-frequency oscillator are most commonly manipulated by adjusting the amplitude, frequency, and percent inspiratory time. The piston-position-and-displacement indicator is commonly centered and subsequently not adjusted. That practice may limit the clinician's ability to optimize carbon dioxide elimination. We hypothesized that varying the piston position would alter gas displacement and carbon dioxide elimination. METHODS: We conducted an observational study in a tertiary pediatric intensive care unit and a correlated bench study. In the clinical study, 24 patients were ventilated with a SensorMedics 3100A high-frequency oscillator. Transcutaneously measured carbon dioxide ((tCO(2))) values were documented with the piston-position-and-displacement indicator in left, center, and right positions. In the bench study the oscillator was set and maintained at: mean airway pressure 15 cm H(2)O, inspiratory time 33% of respiratory-cycle time, bias flow 20 L/min. A pneumotachometer attached to a respiratory mechanics monitor was placed between the ventilator circuit and a test lung. Data were collected with the piston-position-and-displacement indicator at the left, center, and right positions with frequencies of 4-14 Hz and amplitudes of 25-55 cm H(2)O. Data were collected over a 3-minute time period for each combination of frequency, amplitude, and piston-position-and-displacement-indicator position. We compared the data with repeated-measures analysis of variance. Pairwise comparisons were performed with a 2-tailed Student's test with Bonferroni correction. RESULTS: Among the 24 patients (tCO(2)) was significantly associated with the position of the piston (p < 0.007). In the bench study, gas displacement was higher when the piston-position-and-displacement indicator was positioned to the left (than when at the center position) 91.7% of the time (p < 0.0001). When the piston-position-and-displacement indicator was positioned to the right (as compared to the center position), gas displacement was lower 75% of the time (p < 0.0001). CONCLUSION: Adjusting the oscillator piston alters the volume of gas displaced and provides an additional means for titrating carbon dioxide elimination. .

Inhaled nitric oxide results in deteriorating hemodynamics when administered during cardiopulmonary bypass in neonatal swine.

OBJECTIVE: To evaluate if inhaled nitric oxide (iNO) has a lung-protective effect when it is delivered during the ischemic phase of neonatal cardiopulmonary bypass (CPB). DESIGN: Prospective, randomized, controlled study. SETTING: Surgical research laboratory in a university hospital. SUBJECTS: Thirty-five neonatal swine. INTERVENTIONS: One-week-old swine (2.1-3.4 kg) were exposed to cool, low-flow CPB bypass designed to mimic the bypass used during neonatal congenital heart repair. Animals were randomized to four groups: a) CPB without exposure to iNO (n = 9); b) iNO delivery only during CPB with discontinuation of iNO at the start of reperfusion (n = 7); c) iNO delivery both during CPB and during the 90-min post-CPB observation period (n = 7); and d) iNO delivery only after separation from CPB (n = 7). Each animal was placed on nonpulsatile CPB and cooled to a nasopharyngeal temperature of 18 degrees C (64 degrees F). Low-flow CPB (35 mL.kg(-1).min(-1)) was instituted for 90 mins. The blood flow then was returned to 100 mL.kg(-1).min(-1), and the animals were warmed to 36 degrees C (96.8 degrees F) before separation from CPB. Animals were followed 90 mins post-CPB. Lung tissue was harvested and evaluated for myeloperoxidase activity, wet/dry weight, and lung pathology. Five animals underwent sham protocol, receiving instrumentation but not exposure to CPB or iNO. MEASUREMENTS AND MAIN RESULTS: We measured pulmonary vascular resistance, right ventricular output, and pulmonary artery pressure in all animals at 30, 60, and 90 mins following separation from CPB. Study animals that received iNO during the ischemic period of CPB were not protected against CPB-induced lung injury. Those animals treated with iNO both during and after CPB trended worse than those receiving iNO only after CPB. Inhaled nitric oxide delivered only after separation from CPB improved the hemodynamic variables compared with all other groups. Differences in lung wet/dry weight, myeloperoxidase, and pathology were not significantly different among groups. CONCLUSIONS: The delivery of iNO during the ischemic period of CPB does not protect against CPB-induced lung injury in a neonatal piglet CPB model. Delivery of iNO during this phase of CPB may, in fact, worsen the post-CPB hemodynamic condition. Inhaled nitric oxide should be used with caution during periods of low pulmonary blood flow CPB. Inhaled nitric oxide remains effective for reducing pulmonary vascular resistance after CPB.