Most heart failure hospitalizations are due to volume overload; however, it is not easily evaluated by physical examination. Avoidance of diuresis in patients with fluid overload to avoid acute kidney injury increases morbidity in heart failure. We hypothesize that fractional excretion of urate can be used to guide diuresis. (Level of Difficulty: Advanced.).

Intracerebral hemorrhage (ICH) is one of the most devastating and costly diagnoses in the USA. ICH is a common diagnosis, accounting for 10–15 % of all strokes and affecting 20 out of 100,000 people. The CT angiography (CTA) spot sign, or contrast extravasation into the hematoma, is a reliable predictor of hematoma expansion, clinical deterioration, and increased mortality. Multiple studies have demonstrated a high negative predictive value (NPV) for ICH expansion in patients without spot sign. Our aim is to determine the absolute NPV of the spot sign and clinical characteristics of patients who had ICH expansion despite the absence of a spot sign. This information may be helpful in the development of a cost effective imaging protocol of patients with ICH. During a 3-year period, 204 patients with a CTA with primary intracerebral hemorrhage were evaluated for subsequent hematoma expansion during their hospitalization. Patients with intraventricular hemorrhage were excluded. Clinical characteristics and antithrombotic treatment on admission were noted. The number of follow-up NCCT was recorded. Of the resulting 123 patients, 108 had a negative spot sign and 7 of those patients subsequently had significant hematoma expansion, 6 of which were on antithrombotic therapy. The NPV of the CTA spot sign was calculated at 0.93. In patients without antithrombotic therapy, the NPV was 0.98. In summary, the negative predictive value of the CTA spot sign for expansion of ICH, in the absence of antithrombotic therapy and intraventricular hemorrhage (IVH) on admission, is very high. These results have the potential to redirect follow-up imaging protocols and reduce cost.

Left ventricular ejection fraction (LVEF) constitutes an important physiological parameter for the assessment of cardiac function, particularly in the settings of coronary artery disease and heart failure. This study explores the use of routinely and easily acquired variables in the intensive care unit (ICU) to predict severely depressed LVEF following ICU admission. A retrospective study was conducted. We extracted clinical physiological variables derived from ICU monitoring and available within the MIMIC II database and developed a fuzzy model using sequential feature selection and compared it with the conventional logistic regression (LR) model. Maximum predictive performance was observed using easily acquired ICU variables within 6 hours after admission and satisfactory predictive performance was achieved using variables acquired as early as one hour after admission. The fuzzy model is able to predict LVEF ≤ 25% with an AUC of 0.71 ± 0.07, outperforming the LR model, with an AUC of 0.67 ± 0.07. To the best of the authors' knowledge, this is the first study predicting severely impaired LVEF using multivariate analysis of routinely collected data in the ICU. We recommend inclusion of these findings into triaged management plans that balance urgency with resources and clinical status, particularly for reducing the time of echocardiographic examination.

Virtually all organisms seek to maximize fitness by matching fuel availability with energy expenditure. In vertebrates, glucose homeostasis is central to this process, with glucose levels finely tuned to match changing energy requirements. To discover new pathways regulating glucose levels in vivo, we performed a large-scale chemical screen in live zebrafish and identified the small molecule alexidine as a potent glucose-lowering agent. We found that alexidine inhibits the PTEN-like mitochondrial phosphatase PTPMT1 and that other pharmacological and genetic means of inactivating PTPMT1 also decrease glucose levels in zebrafish. Mutation of ptpmt1 eliminates the effect of alexidine, further confirming it as the glucose-lowering target of alexidine. We then identified succinate dehydrogenase (SDH) as a substrate of PTPMT1. Inactivation of PTPMT1 causes hyperphosphorylation and activation of SDH, providing a possible mechanism by which PTPMT1 coordinates glucose homeostasis. Therefore, PTPMT1 appears to be an important regulator of SDH phosphorylation status and glucose concentration.

Background: We recently performed metabolite profiling in 2,346 non-diabetic participants in the Framingham Offspring cohort. The glutamine/glutamate ratio was among the strongest predictors of the development of type II diabetes mellitus (DMII) during a 12-year follow-up period. Glutamate and glutamine are in a precursor-product relationship via the enzyme glutamine synthase (GS). Hypothesis: We hypothesized that inhibition of systemic GS activity would decrease the circulating glutamine/glutamate ratio and worsen glucose homeostasis in vivo. Methods: We administered 20 mg/kg of methionine sulfoximine (MSO), an irreversible inhibitor of GS, to 12 - 16 week old C57Bl6 mice intraperitoneally (i.p.) over 14 days (every other day for 7 injections). We then performed an intraperitoneal glucose tolerance test (IPGTT) with glucose measurements at 0, 30, 60, 90, 120 min from the tail vein. In a separate cohort of mice, we administered a single dose of 300 mg/kg of glutamine to both MSO-treated and control mice to assess reversibility of MSO effects. Results: Administration of MSO decreased circulating glutamine levels (n = 18, -64 ± 19% from baseline, p < 0.01), whereas glutamate levels increased significantly (n = 18, +25 ± 8, p = 0.03). The glutamine/glutamate ratio decreased from 2.16 ± 0.16 to 0.44 ± 0.03 (n = 12, p < 0.001). In the MSO-treated mice, the area under the curve of glucose excursion during the IPGTT increased markedly (n = 24, 12,098 ± 452 vs. 8,158 ± 368 AU, p < 0.001). In livers isolated from MSO-treated animals, we documented reduced liver GS activity by 94 ± 3% (n = 24, p < 0.001). Further, glutamine treatment of the MSO-treated animals at a dose of 300 mg/kg i.p. reversed the diabetogenic effects of MSO treatment (n = 12, 12,687 ± 568 vs 9,235 ± 399 AU, p < 0.01). Conclusion: Inhibition of systemic GS causes a reversal of the plasma glutamine/glutamate ratio and worsening of glucose tolerance. Glutamine administration rescues MSO-induced glucose intolerance. These studies implicate glutamine/glutamate metabolism in the control of glucose homeostasis. Further studies will focus on the mechanism of MSO-induced glucose intolerance and relate the murine findings to human pathology.

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) regulates metabolic genes in skeletal muscle and contributes to the response of muscle to exercise. Muscle PGC-1α transgenic expression and exercise both increase the expression of thermogenic genes within white adipose. How the PGC-1α-mediated response to exercise in muscle conveys signals to other tissues remains incompletely defined. We employed a metabolomic approach to examine metabolites secreted from myocytes with forced expression of PGC-1α, and identified β-aminoisobutyric acid (BAIBA) as a small molecule myokine. BAIBA increases the expression of brown adipocyte-specific genes in white adipocytes and β-oxidation in hepatocytes both in vitro and in vivo through a PPARα-mediated mechanism, induces a brown adipose-like phenotype in human pluripotent stem cells, and improves glucose homeostasis in mice. In humans, plasma BAIBA concentrations are increased with exercise and inversely associated with metabolic risk factors. BAIBA may thus contribute to exercise-induced protection from metabolic diseases.

INTRODUCTION:Whether red blood cell (RBC) transfusion is beneficial remains controversial. In both retrospective and prospective evaluations, transfusion has been associated with adverse, neutral, or protective effects. These varying results likely stem from a complex interplay between transfusion, patient characteristics, and clinical context. The objective was to test whether age, comorbidities, and clinical context modulate the effect of transfusion on survival.METHODS:By using the multiparameter intelligent monitoring in intensive care II database (v. 2.6), a retrospective analysis of 9,809 critically ill patients, we evaluated the effect of RBC transfusion on 30-day and 1-year mortality. Propensity score modeling and logistic regression adjusted for known confounding and assessed the independent effect of transfusion on 30-day and 1-year mortality. Sensitivity analysis was performed by using 3,164 transfused and non-transfused pairs, matched according the previously validated propensity model for RBC transfusion.RESULTS:RBC transfusion did not affect 30-day or 1-year mortality in the overall cohort. Patients younger than 55 years had increased odds of mortality (OR, 1.71; P < 0.01) with transfusion. Patients older than 75 years had lower odds of 30-day and 1-year mortality (OR, 0.70; P < 0.01) with transfusion. Transfusion was associated with worse outcome among patients undergoing cardiac surgery (OR, 2.1; P < 0.01). The propensity-matched population corroborated findings identified by regression adjustment.CONCLUSION:A complex relation exists between RBC transfusion and clinical outcome. Our results show that transfusion is associated with improved outcomes in some cohorts and worse outcome in others, depending on comorbidities and patient characteristics. As such, future investigations and clinical decisions evaluating the value of transfusion should account for variations in baseline characteristics and clinical context.

The aim of our study is to determine the short-term and long-term outcomes of intensive care unit (ICU) patients with minor troponin elevations. The retrospective study compared ICU patients with peak troponin elevation less than 0.1 ng/ml to those with only negative tests during their hospital stay. Data were gathered from ICUs at Beth Israel Deaconess Medical Center between 2001 and 2008. A total of 4224 patients (2547 controls and 1677 positives) were analysed. The primary outcome was mortality at one year. Secondary outcomes were 30-day mortality and hospital and ICU lengths of stay. After adjusting for age, sex, Simplified Acute Physiology Score, Sequential Organ Failure Assessment and combined Elixhauser score, we found that minor troponin elevations (peak troponin elevation between 0.01 and 0.09 ng/ml) were associated with a higher one-year mortality (Hazard Ratio 1.22, P <0.001 for binary troponin presence; Hazard Ratio 1.03, P <0.001 for each 0.01 ng/ml troponin increment). This relationship held for the subgroup of seven-day post-discharge survivors (Hazard Ratio 1.26, P <0.001). Minor elevations of troponin also significantly increased the net reclassification index over traditional risk markers for mortality prediction (net reclassification score 0.12, P <0.001). Minor troponin elevation was also associated with 30-day mortality (odds ratio 1.33, P=0.003). Importantly, troponin testing did not increase the adjusted mortality odds (P=0.9). Minor elevations in troponin substantially increase one-year, all-cause mortality in a stepwise fashion; it was also independently associated with 30-day mortality. We propose that minor elevations in troponin should not be regarded as clinically unimportant, but rather be included as a prognostic element if measured. We recommend prospective ICU studies to assess prognostic value of routine troponin determination.

Background To evaluate changes in endothelial progenitor cells (EPCs) and cytokines in patients with diabetic foot ulceration (DFU) in association with wound healing. Methods We studied healthy subjects, diabetic patients not at risk of DFU, at risk of DFU and with active DFU. We prospectively followed the DFU patients over a 12-week period. We also investigated similar changes in diabetic rabbit and mouse models of wound healing. Results All EPC phenotypes except the kinase insert domain receptor (KDR)+CD133+ were reduced in the at risk and the DFU groups compared to the controls. There were no major EPC differences between the control and not at risk group, and between the at risk and DFU groups. Serum stromal-cell derived factor-1 (SDF-1) and stem cell factor (SCF) were increased in DFU patients. DFU patients who healed their ulcers had lower CD34+KDR+ count at visits 3 and 4, serum c-reactive protein (CRP) and granulocyte-macrophage colony-stimulating factor (GM-CSF) at visit 1, interleukin-1 (IL-1) at visits 1 and 4. EPCs tended to be higher in both diabetic animal models when compared to their non-diabetic counterparts both before and ten days after wounding. Conclusions Uncomplicated diabetes does not affect EPCs. EPCs are reduced in patients at risk or with DFU while complete wound healing is associated with CD34+KDR+ reduction, suggesting possible increased homing. Low baseline CRP, IL-1α and GM-CSF serum levels were associated with complete wound healing and may potentially serve as prognostic markers of DFU healing. No animal model alone is representative of the human condition, indicating the need for multiple experimental models.

Improvements in metabolite-profiling techniques are providing increased breadth of coverage of the human metabolome and may highlight biomarkers and pathways in common diseases such as diabetes. Using a metabolomics platform that analyzes intermediary organic acids, purines, pyrimidines, and other compounds, we performed a nested case-control study of 188 individuals who developed diabetes and 188 propensity-matched controls from 2,422 normoglycemic participants followed for 12 years in the Framingham Heart Study. The metabolite 2-aminoadipic acid (2-AAA) was most strongly associated with the risk of developing diabetes. Individuals with 2-AAA concentrations in the top quartile had greater than a 4-fold risk of developing diabetes. Levels of 2-AAA were not well correlated with other metabolite biomarkers of diabetes, such as branched chain amino acids and aromatic amino acids, suggesting they report on a distinct pathophysiological pathway. In experimental studies, administration of 2-AAA lowered fasting plasma glucose levels in mice fed both standard chow and high-fat diets. Further, 2-AAA treatment enhanced insulin secretion from a pancreatic β cell line as well as murine and human islets. These data highlight a metabolite not previously associated with diabetes risk that is increased up to 12 years before the onset of overt disease. Our findings suggest that 2-AAA is a marker of diabetes risk and a potential modulator of glucose homeostasis in humans.

Background— Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes mellitus and cardiovascular disease, the underlying biological mechanisms remain poorly understood. Methods and Results— To identify pathways associated with cardiometabolic risk, we used liquid chromatography/mass spectrometry to determine the plasma concentrations of 45 distinct metabolites and to examine their relation to cardiometabolic risk in the Framingham Heart Study (FHS; n=1015) and the Malmö Diet and Cancer Study (MDC; n=746). We then interrogated significant findings in experimental models of cardiovascular and metabolic disease. We observed that metabolic risk factors (obesity, insulin resistance, high blood pressure, and dyslipidemia) were associated with multiple metabolites, including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. We observed strong associations of insulin resistance traits with glutamine (standardized regression coefficients, −0.04 to −0.22 per 1-SD change in log-glutamine; P<0.001), glutamate (0.05 to 0.14; P<0.001), and the glutamine-to-glutamate ratio (−0.05 to −0.20; P<0.001) in the discovery sample (FHS); similar associations were observed in the replication sample (MDC). High glutamine-to-glutamate ratio was associated with lower risk of incident diabetes mellitus in FHS (odds ratio, 0.79; adjusted P=0.03) but not in MDC. In experimental models, administration of glutamine in mice led to both increased glucose tolerance (P=0.01) and decreased blood pressure (P<0.05). Conclusions— Biochemical profiling identified circulating metabolites not previously associated with metabolic traits. Experimentally interrogating one of these pathways demonstrated that excess glutamine relative to glutamate, resulting from exogenous administration, is associated with reduced metabolic risk in mice.

INTRODUCTION:Despite advancements in management of cardiac arrest, mortality remains high and few severity of illness scoring systems have been calibrated in this population. The goal of the current investigation was to assess the Acute Physiology and Chronic Health Evaluation II score in post-cardiac arrest. MEASUREMENTS:This is a prospective observational study of adult post-cardiac arrest patients at a tertiary-care center. The primary outcome variable was in-hospital mortality and secondary outcome variable was neurologic outcome. APACHE II scores were used to predict outcomes using logistic modeling. MAIN RESULTS:A total of 228 subjects were included in the analysis. The median age of the cohort was 70 (IQR: 64-71) and 32% (72/228) of the patients were female. The median downtime was 15 min (IQR: 7-27) and initial lactate 5.9 mmol/L (IQR: 3.5-8.4). 71 (57%) of deaths occurred prior to the 72-h follow-up and overall in-hospital mortality was 55% (125/228). Discrimination of APACHE II score in all cardiac arrest patients increased in stepwise fashion from 0-h to 72-h follow-up (AUC: 0-h: 0.62; 24-h: 0.75; 48-h: 0.82; 72-h: 0.86). CONCLUSIONS:APACHE II score is a poor predictor of outcome at time zero for out-of-hospital cardiac arrest (OHCA) post-arrest patients consistent with the original development of the score in the critically ill. For in-hospital cardiac arrest (IHCA) at time zero and for both IHCA and OHCA at 24h and beyond, the APACHE II score was a modest indicator of illness severity and predictor of mortality/neurologic morbidity.

Background— Although randomized trials suggest that transfer for primary percutaneous coronary intervention (X-PCI) in ST-segment–elevation myocardial infarction is superior to onsite fibrinolytic therapy (O-FT), the generalizability of these findings to routine clinical practice is unclear because door-to-balloon (XDB) times are rapid in randomized trials but are frequently prolonged in practice. We hypothesized that delays resulting from transfer would reduce the survival advantage of X-PCI compared with O-FT. Methods and Results— ST-segment–elevation myocardial infarction patients enrolled in the National Registry of Myocardial Infarction (NRMI) within 12 hours of pain onset were identified. Propensity matching of patients treated with X-PCI and O-FT was performed, and the effect of PCI-related delay on in-hospital mortality was assessed. PCI-related delay was calculated by subtracting the XDB from the door-to-needle time in each matched pair. Conditional logistic regression adjusted for patient and hospital variables identified the XDB door-to-needle time at which no mortality advantage for X-PCI over O-FT was present. Eighty-one percent of X-PCI patients were matched (n=9506) to O-FT patients (n=9506). In the matched cohort, X-PCI was performed with delays >90 minutes in 68%. Multivariable analysis found no mortality advantage for X-PCI over O-FT when XDB door-to-needle time exceeded ≈120 minutes. Conclusion— PCI-related delays are extensive among patients transferred for X-PCI and are associated with poorer outcomes. No differential excess in mortality was seen with X-PCI compared with O-FT even with long PCI-related delays, but as XDB door-to-needle time times increase, the mortality advantage for X-PCI over O-FT declines.

Calcific aortic stenosis remains a major cause of mortality and morbidity in the aging population. Surgical replacement remains the treatment of choice for this disease. Balloon aortic valvuloplasty was introduced as a palliative procedure for these patients, but was tempered by a high rate of recurrence, which has limited its usefulness. However, the introduction of smaller-profile balloons, rapid pacing, and closure devices have brought it back as an alternative treatment strategy in selected patients who are at too high risk for surgery with repeat valvuloplasty as needed for recurrences. We report a case of prosthetic aortic valve stenosis treated with valvuloplasty with intracardiac and fluoroscopic guidance with recurrence treated with repeat valvuloplasty with promising intermediate-term outcome and describe the growing valve in valve procedures.

Introduction: Severity of illness scores can predict outcomes in critically ill patients. However, the calibration of previously established scores in post-cardiac arrest is poorly established. Objective: To assess the calibration of the Acute Physiology and Chronic Health Evaluation (APACHE II) score in out-of-hospital and in-hospital cardiac arrest. Methods: A prospective observational study of adult cardiac arrest at an urban tertiary care hospital during the period from 12/2007 to 12/2010. Inclusion criteria: 1. Adult (>18 years); 2. OHCA; 3. Return of spontaneous circulation (RSOC). Traumatic cardiac arrests were excluded. We recorded baseline demographics, arrest event characteristics, follow-up vitals and laboratory data, and in-hospital mortality. APACHE II scores were calculated at the time of ROSC, and at 24hrs, 48hrs, and 72hrs. We used simple descriptive statistics to describe the study population. Univariate logistic regression was used to predict mortality with APACHE II as a continuous predictor variable. Discrimination of APACHE II scores was assessed using the area under the curve (AUC) of the receiver operator characteristic (ROC) curve. Results: A total of 229 patients were analyzed. The median age was 70 years (IQR: 56 - 79) and 32% were female. APACHE II score was a significant predictor of mortality for both OHCA and IHCA at baseline and at all follow-up time points (all p < 0.01). Discrimination of the score increased over time and achieved very good discrimination after 24hrs (Table 1). Conclusion: The ability of APACHE II score to predict mortality improves over time in the 72-hours following cardiac arrest. These data suggest that after 24-hours, APACHE II scoring is a useful severity of illness score in all post-cardiac arrest patients.

Introduction: Severity of illness scores can predict outcomes in critically ill patients. However, the calibration of existing scoring systems in post-cardiac arrest patients is poorly established. Objective: To determine if the Simplified Acute Physiology Score (SAPS II) will predict mortality in out-of-hospital cardiac arrest (OHCA). Methods: An observational study of adult cardiac arrest at an urban tertiary care hospital during the period from 12/2007 to 12/2010. Data were collected prospectively and recorded in the Utstein style. Inclusion criteria: 1. Adult (>18 years); 2. OHCA; 3. Return of spontaneous circulation. Traumatic cardiac arrests were excluded. Patient demographics, co-morbid conditions, vital signs and laboratory data and in-hospital mortality were recorded. SAPS II scores were calculated. We used simple descriptive statistics to describe the study population and logistic regression to predict mortality with SAPS II as the predictor variable. Forward stepwise logistic regression selection was used to identify individual SAPS II variables that contribute to the sensitivity of the score. Discrimination was assessed using area under the curve (AUC) of the receiver operating characteristic (ROC) curve. Results: 115 patients were analyzed. The median age was 68 years (IQR: 55 - 79) and 28% were female. Median SAPS II score was 67 (IQR: 53 - 77) and 61% of patients died. Cumulative SAPS II score was a poor predictor of mortality (p = 0.19, OR: 1.012, 95% CI: 0.99 - 1.03) and demonstrated poor discrimination (AUC: 0.61). Stepwise selection identified the following individual SAPS II variables to predict mortality: HC03 (p = 0.006, OR: 1.46, 95%CI: 1.12 - 1.90), GCS (p = 0.03, OR: 1.12, 95%CI: 1.01 - 1.23), and age (p = 0.02, OR: 1.12, 95%CI: 1.02 - 1.23); together these are strong predictors of mortality: p = 0.02, AUC: 0.75. Conclusion: Cumulative SAPS II scoring fails to predict mortality in OHCA. The risk-score assigned to age, GCS and HC03 independently predict mortality and combined are good mortality predictors. These findings suggest that an alternative severity of illness score should be used in post-cardiac arrest patients. Future studies should determine optimal risk-scores of SAPS II variables in a larger cohort of OHCA.

Nitrite-hemoglobin reactions have been studied extensively in vitro, but there is a lack of information on the kinetics of nitrite and its metabolites in humans. In this study, we developed a nine-compartment physiological pharmacokinetic model to describe the in vivo erythrocytic uptake and release and disposition pathways of nitrite, nitrate, methemoglobin, and iron-nitrosyl hemoglobin in the human circulation. Our model revealed that nitrite entered erythrocytes rapidly with a rate constant of 0.256 min(-1) (i.e., half-life = 2.71 min). The formation of iron-nitrosyl hemoglobin from nitrite, which involves the reduction of nitrite by deoxyhemoglobin to generate nitric oxide (NO) and reaction of NO with deoxyhemoglobin to form iron-nitrosyl hemoglobin, occurred rapidly as well (k = 2.02 min(-1); half-life = 0.343 min = 21 s). The disposition kinetics of methemoglobin was complex. Nitrate formation occurred primarily in erythrocytes through the nitrite-oxyhemoglobin reaction and was higher when nitrite was administered intra-arterially than intravenously. Nitrate reduction was an insignificant metabolic pathway. This study is the first to comprehensively evaluate the kinetics of nitrite and its metabolites in humans and provides unique insights into the rapid equilibrium of nitrite into erythrocytes and conversion to NO in the red cell, which is kinetically associated with vasodilation.

Background: Randomized trials suggest that transfer for primary percutaneous coronary intervention (X-PCI) in STEMI is superior to onsite fibrinolytic therapy (O-FT), but the time dependent effect of this benefit in a less selected population has not been described. Transport and door-to-balloon times (DB) are rapid in randomized trials, but they are often prolonged in routine practice. We hypothesized that delays due to transfer would reduce the survival advantage compared with O-FT. Methods: Patients with STEMI on initial ECG and <12 hours after onset of pain enrolled in the National Registry of Myocardial Infarction receiving either O-FT or X-PPCI were identified. Propensity score matching was performed and the effect of PCI related delay on in-hospital mortality was assessed. PCI-related delay (DB-DN) was calculated by subtracting the door-to-needle time from the DB in the matched pair. Conditional logistic regression adjusting for patient and hospital variables was utilized identifying the DB-DN wher...