The glucoregulatory benefits of glucagon-like peptide-1 (7-36) amide infusion during intensive insulin therapy in critically ill surgical patients: a pilot study.

OBJECTIVES: Intensive insulin therapy for tight glycemic control in critically ill surgical patients has been shown to reduce mortality; however, intensive insulin therapy is associated with iatrogenic hypoglycemia and increased variability of blood glucose levels. The incretin glucagon-like peptide-1 (7-36) amide is both insulinotropic and insulinomimetic and has been suggested as an adjunct to improve glycemic control in critically ill patients. We hypothesized that the addition of continuous infusion of glucagon-like peptide-1 to intensive insulin therapy would result in better glucose control, reduced requirement of exogenous insulin administration, and fewer hypoglycemic events. DESIGN: Prospective, randomized, double-blind, placebo-controlled clinical trial. SETTING: Surgical or burn ICU. PATIENTS: Eighteen patients who required intensive insulin therapy. INTERVENTIONS: A 72-hour continuous infusion of either glucagon-like peptide-1 (1.5 pmol/kg/min) or normal saline plus intensive insulin therapy. MEASUREMENTS AND MAIN RESULTS: The glucagon-like peptide-1 cohort (n = 9) and saline cohort (n = 9) were similar in age, Acute Physiology and Chronic Health Evaluation score, and history of diabetes. Blood glucose levels in the glucagon-like peptide-1 group were better controlled with much less variability. The coefficient of variation of blood glucose ranged from 7.2% to 30.4% in the glucagon-like peptide-1 group and from 19.8% to 56.8% in saline group. The mean blood glucose coefficient of variation for the glucagon-like peptide-1 and saline groups was 18.0% ± 2.7% and 30.3% ± 4.0% (p = 0.010), respectively. The 72-hour average insulin infusion rates were 3.37 ± 0.61 and 4.57 ± 1.18 U/hr (p = not significant). The incidents of hypoglycemia (≤ 2.78 mmol/L) in both groups were low (one in the glucagon-like peptide-1 group, three in the saline group). CONCLUSIONS: Glucagon-like peptide-1 (7-36) amide is a safe and efficacious form of adjunct therapy in patients with hyperglycemia in the surgical ICU setting. Improved stability of blood glucose is a favorable outcome, which enhances the safety of intensive insulin therapy. Larger studies of this potentially valuable therapy for glycemic control in the ICU are justified.

GLP-1 (7-36) amide restores myocardial insulin sensitivity and prevents the progression of heart failure in senescent beagles.

BACKGROUND: We previously demonstrated that older beagles have impaired whole body and myocardial insulin responsiveness (MIR), and that glucagon-like peptide-1 (GLP-1 [7-36] amide) improves MIR in young beagles with dilated cardiomyopathy (DCM). Here, we sought to determine if aging alone predisposes to an accelerated course of DCM, and if GLP-1 [7-36] amide would restore MIR and impact the course of DCM in older beagles. METHODS: Eight young beagles (Young-Control) and sixteen old beagles underwent chronic left ventricle (LV) instrumentation. Seven old beagles were treated with GLP-1 (7-36) amide (2.5 pmol/kg/min) for 2 weeks prior to instrumentation and for 35 days thereafter (Old + GLP-1), while other 9 served as control (Old-Control). All dogs underwent baseline metabolic determinations and LV biopsy for mitochondria isolation prior to the development of DCM induced by rapid pacing (240 min-1). Hemodynamic measurements were performed routinely as heart failure progressed. RESULTS: At baseline, all old beagles had elevated non-esterifed fatty acids (NEFA), and impaired MIR. GLP-1 reduced plasma NEFA (Old-Control: 853 ± 34; Old + GLP-1: 531 ± 33 µmol/L, p < 0.02), improved MIR (Old-Control: 289 ± 54; Old + GLP-1: 512 ± 44 mg/min/100 mg, p < 0.05), and increased uncoupling protein-3 (UCP-3) expression in isolated mitochondria. Compared to the Young-Control, the Old-Controls experienced an accelerated course of DCM (7 days versus 29 days, p < 0.005) and excess mortality, while the Old + GLP-1 experienced increased latency to the onset of DCM (7 days versus 23 days, p < 0.005) and reduced mortality. CONCLUSION: Aging is associated with myocardial insulin resistance, which predispose to an accelerated course of DCM. GLP-1 treatment is associated with increased MIR and protection against an accelerated course of DCM in older beagles.

Incorporating Acute Conditions into Risk-Adjustment for Provider Profiling: The Case of the US News and World Report Best Hospitals Rankings Methodology.

Several years ago, the US News and World Report changed their risk-adjustment methodology, now relying almost exclusively on chronic conditions for risk adjustment. The impacts of adding selected acute conditions like pneumonia, sepsis, and electrolyte disorders ("augmented") to their current risk models ("base") for 4 specialties-cardiology, neurology, oncology, and pulmonology-on estimates of hospital performance are reported here. In the augmented models, many acute conditions were associated with substantial risks of mortality. Compared to the base models, the discrimination and calibration of the augmented models for all specialties were improved. While estimated hospital performance was highly correlated between the 2 models, the inclusion of acute conditions in risk-adjustment models meaningfully improved the predictive ability of those models and had noticeable effects on hospital performance estimates. Measures or conditions that address disease severity should always be included when risk-adjusting hospitalization outcomes, especially if the goal is provider profiling.

Potential effects of aggressive decongestion during the treatment of decompensated heart failure on renal function and survival.

BACKGROUND: Overly aggressive diuresis leading to intravascular volume depletion has been proposed as a cause for worsening renal function during the treatment of decompensated heart failure. If diuresis occurs at a rate greater than extravascular fluid can refill the intravascular space, the concentration of such intravascular substances as hemoglobin and plasma proteins increases. We hypothesized that hemoconcentration would be associated with worsening renal function and possibly would provide insight into the relationship between aggressive decongestion and outcomes. METHODS AND RESULTS: Subjects in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial limited data set with a baseline/discharge pair of hematocrit, albumin, or total protein values were included (336 patients). Baseline-to-discharge increases in these parameters were evaluated, and patients with >or=2 in the top tertile were considered to have evidence of hemoconcentration. The group experiencing hemoconcentration received higher doses of loop diuretics, lost more weight/fluid, and had greater reductions in filling pressures (P<0.05 for all). Hemoconcentration was strongly associated with worsening renal function (odds ratio, 5.3; P<0.001), whereas changes in right atrial pressure (P=0.36) and pulmonary capillary wedge pressure (P=0.53) were not. Patients with hemoconcentration had significantly lower 180-day mortality (hazard ratio, 0.31; P=0.013). This relationship persisted after adjustment for baseline characteristics (hazard ratio, 0.16; P=0.001). CONCLUSIONS: Hemoconcentration is significantly associated with measures of aggressive fluid removal and deterioration in renal function. Despite this relationship, hemoconcentration is associated with substantially improved survival. These observations raise the question of whether aggressive decongestion, even in the setting of worsening renal function, can positively affect survival.

Impact of worsening renal function during the treatment of decompensated heart failure on changes in renal function during subsequent hospitalization.

BACKGROUND: Worsening renal function (WRF) commonly complicates the treatment of acute decompensated heart failure. Despite considerable investigation in this area, it remains unclear to what degree WRF is a reflection of treatment- versus patient-related factors. We hypothesized that if WRF is significantly influenced by factors intrinsic to the patient, then WRF during an index hospitalization should predict WRF during subsequent hospitalization. METHODS: Consecutive admissions to the Hospital of the University of Pennsylvania with a discharge diagnosis of congestive heart failure were reviewed. Patients with >1 hospitalization were retained for analysis. RESULTS: In total, 181 hospitalization pairs met the inclusion criteria. Baseline patient characteristics demonstrated significant correlation between hospitalizations (P ≤ .002 for all) but minimal association with WRF. In contrast, variables related to the aggressiveness of diuresis were weakly correlated between hospitalizations but significantly associated with WRF (P ≤ .024 for all). Consistent with the primary hypothesis, WRF during the index hospitalization was strongly associated with WRF during subsequent hospitalization (odds ratio [OR] 2.7, P = .003). This association was minimally altered after controlling for traditional baseline characteristics (OR 2.5, P = .006) and in-hospital treatment-related parameters (OR 2.8, P = .005). CONCLUSIONS: A prior history of WRF is strongly associated with subsequent episodes of WRF, independent of in-hospital treatment received. These results suggest that baseline factors intrinsic to the patient's cardiorenal pathophysiology have substantial influence on the subsequent development of WRF.

Eliminating hospital acquired infections: is it possible? Is it sustainable? Is it worth it?

An estimated 2 million hospital-acquired infections (HAI) are now reported annually in the US, and are associated with an estimated $5 billion in additional health care costs. With this, the growing incidence of HAI has become "ground zero" in the campaign to improve patient safety and eliminate waste in health care.We studied the characteristics of high-performing organizations and their leaders outside of health care to determine how such organizations become "best in class." We then sought to apply the principles that led to this status to eliminating HAI associated with central venous catheters.Observations of the current condition of health care revealed multiple defects in various processes, that were breeding grounds for error. Redesign of these processes by the people involved in them under the guidance of a leader resulted in an 86% reduction in infections in the blood. Overall, financial performance improved by $5.1 million over a 2-year period. Mortality in intensive care units declined by 29%.Using methods borrowed from highly reliable industries and engaging workers at the point of care can have profound and sustainable effects in nearly eliminating HAI, with significant clinical and financial benefits.

Akt pathway is hypoactivated by synergistic actions of diabetes mellitus and hypercholesterolemia resulting in advanced coronary artery disease.

Atherosclerosis is an inflammatory process leading to enhanced cellular proliferation, apoptosis, and vasa vasorum (VV) neovascularization. While both diabetes mellitus (DM) and hypercholesterolemia (HC) predispose to atherosclerosis, the precise interaction of these risk factors is unclear. Akt is a central node in signaling pathways important for inflammation, and we hypothesized that DM/HC would lead to aberrant Akt signaling and advanced, complex atherosclerosis. DM was induced in pigs by streptozotocin and HC by a high-fat diet. Animals were randomized to control (non-DM, non-HC), DM only, HC only, and DM/HC groups. Coronary artery homogenates were analyzed by immunoblotting for proteins involved in the Akt pathway, including phosphorylated (p)-Akt (Ser473), p-GSK-3beta (Ser9), activated NF-kappaB p65, and VEGF. Immunohistochemical staining for Ki67 (cell proliferation), terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) (apoptosis), and von Willebrand factor (vWF) (neovascularization) was performed. Neovascularization was visualized with micro-computerized tomography (CT). Only DM/HC animals developed advanced atherosclerosis and showed decreased p-Akt (Ser473) and p-GSK-3beta (Ser9) levels (P < 0.01 and P < 0.05, respectively). DM/HC arteries demonstrated increased cellular proliferation (P < 0.001), apoptosis (P < 0.01), and activation of NF-kappaB p65 (P < 0.05). Induction of DM/HC also resulted in significant VV neovascularization by enhanced VEGF expression (P < 0.05), increased vWF staining (P < 0.01), and increased density by micro-CT. In conclusion, DM and HC synergistically resulted in complex atherosclerosis associated with attenuated p-Akt (Ser473) levels. Aberrant Akt signaling correlated with increased inflammation, cellular proliferation, apoptosis, and VV neovascularization. Our results revealed a synergistic effect of DM and HC in triggering abnormal Akt signaling, resulting in advanced atherosclerosis.

Worsening renal function defined as an absolute increase in serum creatinine is a biased metric for the study of cardio-renal interactions.

OBJECTIVES: Worsening renal function (WRF) during the treatment of decompensated heart failure, frequently defined as an absolute increase in serum creatinine >or=0.3 mg/dl, has been reported as a strong adverse prognostic factor in several studies. We hypothesized that this definition of WRF is biased by baseline renal function secondary to the exponential relationship between creatinine and renal function. METHODS: We reviewed consecutive admissions with a discharge diagnosis of heart failure. An increase in creatinine >or=0.3 mg/dl (WRF(CREAT)) was compared to a decrease in GFR >or=20% (WRF(GFR)). RESULTS: Overall, 993 admissions met eligibility. WRF(CREAT) occurred in 31.5% and WRF(GFR) in 32.7%. WRF(CREAT) and WRF(GFR) had opposing relationships with baseline renal function (OR = 1.9 vs. OR = 0.51, respectively, p < 0.001). Both definitions had similar unadjusted associations with death at 30 days [WRF(GFR) OR = 2.3 (95% CI 1.1-4.8), p = 0.026; WRF(CREAT) OR = 2.1 (95% CI 1.0-4.4), p = 0.047]. Controlling for baseline renal insufficiency, WRF(GFR) added incrementally in the prediction of mortality (p = 0.009); however, WRF(CREAT) did not (p = 0.11). CONCLUSIONS: WRF, defined as an absolute change in serum creatinine, is heavily biased by baseline renal function. An alternative definition of WRF should be considered for future studies of cardio-renal interactions.

Neonatal exendin-4 leads to protection from reperfusion injury and reduced rates of oxidative phosphorylation in the adult rat heart.

PURPOSE: Glucagon like peptide-1 (7-36) amide (GLP-1) is an incretin hormone with multiple salutary cardiovascular effects. A short course of the GLP-1 analogue Exendin-4 (Ex-4) in the neonatal period prevents the development of mitochondrial dysfunction and oxidative stress in a rat prone to obesity and diabetes. We sought to evaluate whether neonatal Ex-4 can exert the same effect in the normal rat heart, as well as whether Ex-4 could affect susceptibility to cardiac reperfusion injury. METHODS: After birth, Sprague Dawley rat pups were given either Ex-4 (1 nmole/kg body weight) or vehicle (1% BSA in 0.9% saline) subcutaneously for 6 days. Animals were studied at juvenile (4-6 weeks) and adult (8-9 months) ages. Using the Langendorff isolated perfused heart, cardiovascular function was assessed at baseline and following ischemia-reperfusion. Mitochondria were isolated from fresh heart tissue, and oxidative phosphorylation and calcium sequestration were analyzed. TBARS, MnSOD activity, and non-enzymatic anti-oxidant capacity were measured to assess the degree of oxidative stress present in the two groups. RESULTS: Both at the juvenile and adult age, Ex-4 treated rats demonstrated improved recovery from an ischemic insult. Rates of oxidative phosphorylation were globally reduced in adult, but not juvenile Ex-4 treated animals. Furthermore, mitochondria isolated from adult Ex-4 treated rats sequestered less calcium before undergoing the mitochondrial permeability transition. Oxidative stress did not differ between groups at any time point. CONCLUSION: A short course of Exendin-4 in the neonatal period leads to protection from ischemic injury and a preconditioned mitochondrial phenotype in the adult rat.

Interleukin-18 predicts atherosclerosis progression in SIV-infected and uninfected rhesus monkeys (Macaca mulatta) on a high-fat/high-cholesterol diet.

Interleukin (IL)-18 levels have been identified as important predictors of cardiovascular mortality and are often elevated in human immunodeficiency virus (HIV)-infected individuals. To investigate a possible function for IL-18 in atherogenesis in the context of early HIV infection, we used the simian immunodeficiency model of HIV infection. Acutely simian immunodeficiency virus-infected and uninfected rhesus monkeys (Macaca mulatta) on an atherogenic diet were evaluated prospectively for atherosclerotic lesion development relative to a panel of plasma markers including IL-18, IL-8, IL-1beta, IL-6, C-reactive protein, soluble vascular cell adhesion molecule-1, soluble E-selectin, and soluble intercellular adhesion molecule-1. Although no significant differences in lesion development were identified between groups after 35 days of infection, levels of plasma IL-18 measured 1 month before virus inoculation correlated significantly with atherosclerotic plaque cross-sectional area at the carotid bifurcation (P<0.001, R=0.946), common iliac bifurcation (P<0.01, R=0.789), and cranial abdominal aorta (P<0.01, R=0.747), as well as with extent of CD3+ and CD68+ cellular infiltration in vascular lesions (both P<0.001, R>or=0.835) in both groups. Atherosclerotic plaque area at the carotid and common iliac bifurcations also showed a weaker inverse correlation with baseline IL-8 levels, as did CD68+ signal area. Results implicate a strong role for IL-18 in early atherosclerosis progression and raise the possibility that the chronically elevated IL-18 levels seen in later stages of HIV infection may contribute significantly to accelerated atherogenesis in this population.

New insights into myocardial glucose metabolism: surviving under stress.

PURPOSE OF REVIEW: Myocardial glucose uptake and metabolism are essential for maintaining myocardial energetics under circumstances of stress, such as myocardial ischemia or hypertrophy. We will discuss new information as to the mechanisms of altered glucose uptake as a consequence of impaired insulin action as well as emerging alternative cellular signaling mechanisms that lead to increased noninsulin dependent glucose uptake and metabolism. We will also review provocative clinical data that demonstrate the limitations of tight glycemic control as a mechanism to confer myocardial protection in patients with type 2 diabetes and discuss potential mechanistic explanations for the paradoxical results. RECENT FINDINGS: New studies have shed important light on the distal mechanisms involved in insulin-mediated Glut 4 translocation. There are also important new insights into the role of AMP kinase and hypoxia-induced factor-1alpha in mediating myocardial glucose uptake while conferring cardioprotection. SUMMARY: The importance of understanding the link between glucose uptake and cardioprotection is underscored by recent clinical trials that have failed to demonstrate a benefit between tight glycemic control and reduced cardiovascular events. These data underscore the need for additional agents that affect both outcomes.

Glucagon-like peptide-1 and myocardial protection: more than glycemic control.

Pharmacologic intervention for the failing heart has traditionally targeted neurohormonal activation and ventricular remodeling associated with cardiac dysfunction. Despite the multitude of agents available for the treatment of heart failure, it remains a highly prevalent clinical syndrome with substantial morbidity and mortality, necessitating alternative strategies of targeted management. One such area of interest is the ability to modulate myocardial glucose uptake and its impact on cardioprotection. Glucose-insulin-potassium (GIK) infusions have been studied for decades, with conflicting results regarding benefit in acute myocardial infarction. Based on the same concepts, glucagon-like peptide-1-[7-36] amide (GLP-1) has recently been demonstrated to be a more effective alternative in left ventricular (LV) systolic dysfunction. This paper provides a review on the current evidence supporting the use of GLP-1 in both animal models and humans with ischemic and nonischemic cardiomyopathy.

Diabetic cardiomyopathy: the search for a unifying hypothesis.

Although diabetes is recognized as a potent and prevalent risk factor for ischemic heart disease, less is known as to whether diabetes causes an altered cardiac phenotype independent of coronary atherosclerosis. Left ventricular systolic and diastolic dysfunction, left ventricular hypertrophy, and alterations in the coronary microcirculation have all been observed, although not consistently, in diabetic cardiomyopathy and are not fully explained by the cellular effects of hyperglycemia alone. The recent recognition that diabetes involves more than abnormal glucose homeostasis provides important new opportunities to examine and understand the impact of complex metabolic disturbances on cardiac structure and function.

Effect of glucagon-like peptide-1 (GLP-1) on glycemic control and left ventricular function in patients undergoing coronary artery bypass grafting.

Increasing evidence suggests that tight glycemic control improves clinical outcomes after coronary artery bypass grafting (CABG). However, the risk for hypoglycemia with insulin often results in less aggressive glycemic control. Glucagon-like peptide-1 (GLP-1) is a naturally occurring peptide whose insulinotropic effects are predicated on the glucose concentration, minimizing the risk for hypoglycemia. This study was conducted to examine whether perioperative treatment with GLP-1 would affect glycemic control and improve hemodynamic recovery after CABG. Twenty patients with coronary heart disease and preserved left ventricular function who were scheduled to undergo CABG were randomized to receive standard therapy at the discretion of the surgeon or treatment with GLP-1 (1.5 pmol/kg/min) as a continuous infusion beginning 12 hours before CABG and continuing for 48 hours. Perioperative hemodynamics, the left ventricular ejection fraction, plasma glucose, and requirements for insulin drips and inotropic support were monitored. There were no differences between groups in the preoperative, postoperative, or 7-day left ventricular ejection fraction (GLP-1 61 +/- 4%, control 59 +/- 3%) or cardiac index at 18 hours (GLP-1 3.0 +/- 0.2 L/min/m(2), control 3.3 +/- 0.4 L/min/m(2)). However, the control group required greater use of inotropic and vasoactive infusions during the 48 hours after the operation to achieve the same hemodynamic result. There were also more frequent arrhythmias requiring antiarrhythmic agents in the control group. GLP-1 resulted in better glycemic control in the pre- and perioperative periods (GLP-1 95 +/- 3 mg/dl, control 140 +/- 10 mg/dl, p

Phenotypic variation in myocardial macrophage populations suggests a role for macrophage activation in SIV-associated cardiac disease.

Cardiac abnormalities are common in HIV-infected individuals, and have been especially well documented as contributors to mortality in HIV-infected children. Underlying pathogenetic mechanisms responsible for myocardial disease in HIV-infection remain imperfectly understood. SIV-infected rhesus monkeys develop a spectrum of cardiac lesions similar to those seen in HIV-infected people, providing an important model for pathogenesis studies. Retrospective analysis of cardiac tissue collected at necropsy from SIV-infected rhesus monkeys was performed to evaluate myocardial macrophage and dendritic cell populations as a function of previously quantitated lymphocytic inflammatory infiltrates and cardiomyocyte degeneration or necrosis. Variations in the size and phenotype of macrophage and dendritic cell populations were examined as possible contributors to the pathogenesis of SIV-associated inflammatory lesions. Macrophages labeling immunohistochemically for CD163 differed substantially from macrophages labeling for HAM56 in overall number, distribution across groups, involvement in inflammatory clusters, correlation with the DC-SIGN(+) subpopulation of macrophages, and correlation with numbers of SIV-infected cells. CD163(+) macrophages occurred in significantly higher numbers in uninflamed hearts from SIV-infected animals than in hearts from SIV-infected animals with myocarditis or uninfected controls (p < 0.01). Numbers of CD163(+) cells correlated positively with numbers of SIV-infected cells (p < 0.05) suggesting that the CD163(+) population was associated with decreased inflammatory infiltration and reduced control of virus within the heart. As CD163 has been associated with nonclassical macrophage activation and an antiinflammatory phenotype, these results suggest that a balance between classical and nonclassical activation may affect levels of inflammatory infiltration and of myocardial virus burden.

Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31.

PURPOSE: Trastuzumab is effective in treating human epidermal growth factor receptor 2 (HER2) -positive breast cancer, but it increases frequency of cardiac dysfunction (CD) when used with or after anthracyclines. PATIENTS AND METHODS: National Surgical Adjuvant Breast and Bowel Project trial B-31 compared doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel plus 52 weeks of trastuzumab beginning concurrently with paclitaxel in patients with node-positive, HER2-positive breast cancer. Initiation of trastuzumab required normal post-AC left ventricular ejection fraction (LVEF) on multiple-gated acquisition scan. If symptoms suggestive of congestive heart failure (CHF) developed, source documents were blindly reviewed by an independent panel of cardiologists to determine whether criteria were met for a cardiac event (CE), which was defined as New York Heart Association class III or IV CHF or possible/probable cardiac death. Frequencies of CEs were compared between arms. RESULTS: Among patients with normal post-AC LVEF who began post-AC treatment, five of 814 control patients subsequently had confirmed CEs (four CHFs and one cardiac death) compared with 31 of 850 trastuzumab-treated patients (31 CHFs and no cardiac deaths). The difference in cumulative incidence at 3 years was 3.3% (4.1% for trastuzumab-treated patients minus 0.8% for control patients; 95% CI, 1.7% to 4.9%). Twenty-seven of the 31 patients in the trastuzumab arm have been followed for > or = 6 months after diagnosis of a CE; 26 were asymptomatic at last assessment, and 18 remained on cardiac medication. CHFs were more frequent in older patients and patients with marginal post-AC LVEF. Fourteen percent of patients discontinued trastuzumab because of asymptomatic decreases in LVEF; 4% discontinued trastuzumab because of symptomatic cardiotoxicity. CONCLUSION: Administering trastuzumab with paclitaxel after AC increases incidence of CHF and lesser CD. Potential cardiotoxicity should be carefully considered when discussing benefits and risks of this therapy.

SIV-associated myocarditis: viral and cellular correlates of inflammation severity.

Myocarditis is a common finding in HIV-infected people. Cardiac inflammatory lesions and functional abnormalities similar to those documented in HIV infection are frequently seen in SIV infection of rhesus monkeys, suggesting a shared disease mechanism. A retrospective analysis of cardiac tissue collected at necropsy was performed to assess correlates of myocardial inflammation in SIV-infected rhesus monkeys. Intramyocardial SIV-infected cells were identified in 7 of 21 hearts from SIV-infected animals, with viral protein consistently colocalizing with the macrophage marker HAM 56. Productively infected cells occurred in low numbers, and did not correlate with the presence or quantity of inflammation or necrosis. Intramyocardial CMV was identified in 6 of 21 hearts from SIV+ animals, but also did not correlate with the presence or quantity of inflammation or necrosis. In contrast, T cell infiltration correlated inversely with DC-SIGN+ cell numbers, which occurred in significantly higher numbers in SIV+ animals with histologically normal myocardium than in SIV+ animals with active or borderline myocarditis or in uninfected controls (p < 0.001), suggesting an important immunoregulatory role for this population within the myocardium.

Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure.

BACKGROUND: Insulin resistance is present in the setting of congestive heart failure. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with both insulinotropic and insulinomimetic properties. METHODS AND RESULTS: We investigated the safety and efficacy of a 5-week infusion of GLP-1 (2.5 pmol/kg/min) added to standard therapy in 12 patients with New York Heart Association class III/IV heart failure and compared the results with those of 9 patients with heart failure on standard therapy alone. Echocardiograms, maximum myocardial ventilation oxygen consumption (VO2 max), 6-minute walk test, and Minnesota Living with Heart Failure quality of life score (MNQOL) were assessed. Baseline demographics, background therapy, and the degree of left ventricular dysfunction were similar between groups. GLP-1 significantly improved left ventricular ejection fraction (21 +/- 3% to 27 +/- 3% P < .01), VO2 max (10.8 +/- .9 ml/O2/min/kg to 13.9 +/- .6 ml/O2/min/kg; P < .001), 6-minute walk distance (232 +/- 15 m to 286 +/- 12 m; P < .001) and MNQOL score (64 +/- 4 to 44 +/- 5; P < .01). Benefits were seen in both diabetic and non-diabetic patients. There were no significant changes in any of the parameters in the control patients on standard therapy. GLP-1 was well tolerated with minimal episodes of hypoglycemia and gastrointestinal side effects. CONCLUSION: Chronic infusion of GLP-1 significantly improves left ventricular function, functional status, and quality of life in patients with severe heart failure.

Using real-time problem solving to eliminate central line infections.

BACKGROUND: An estimated 200,000 Americans suffer central line-associated bloodstream infections (CLABs) each year, with 15%-20% mortality. Two intensive care units (ICUs) redefined the processes of care through system redesign to deliver reliable outcomes free of the variations that created the breeding ground for infection. METHODS: The ICUs, comprising 28 beds at Allegheny General Hospital, employed the principles of the Toyota Production System adapted to health care--Perfecting Patient Care--and applied them to central line placement and maintenance. Intensive observations, which revealed multiple variances from established practices, and root cause analyses of all CLABs empowered the workers to implement countermeasures designed to eliminate the defects in the processes of central line placement and maintenance. RESULTS: New processes were implemented within 90 days. Within a year CLABs decreased from 49 to 6 (10.5 to 1.2 infections/1,000 line-days), and mortalities from 19 to 1 (51% to 16%), despite an increase in the use of central lines and number of line-days. These results were sustained during a 34-month period. DISCUSSION: CLABs are not an inevitable product of complex ICU care but the result of highly variable and therefore unreliable care delivery that predisposes to infection.

Economics of central line--associated bloodstream infections.

Hospital-acquired infections add considerable morbidity and mortality to patient care. However, a detailed economic analysis of these infections on an individual case basis has been lacking. The authors examined both the hospital revenues and expenses in 54 cases of patients with central line-associated bloodstream infections (CLABs) over 3 years in 2 intensive care units and compared these financial data with patients who were matched for age, severity of illness on admission, and principal diagnosis. The average payment for a case complicated by CLAB was $64 894, and the average expense was $91733 with gross margin of -$26 839 per case and a total loss from operations of $1 449 306 in the 54 cases. The costs of CLABs and the associated complications averaged 43% of the total cost of care. The elimination of these preventable infections constitutes not only an opportunity to improve patient outcomes but also a significant financial opportunity.