Designing a Multilevel Strategy to Enhance Secondary Prevention of Heart Disease.

Background Coronary artery calcification (CAC), the presence and severity of which strongly predict underlying coronary artery disease (CAD), can be seen on dedicated cardiac imaging studies or incidentally on noncardiac ones; however, the latter findings are commonly managed by primary care clinicians without clear accompanying recommendations and may represent an underrecognized opportunity to optimize secondary prevention of CAD. Methods Standardized practice guidelines and a multilevel implementation strategy for improving secondary prevention of cardiovascular disease through incidentally identified CAC were developed by an interdisciplinary committee. Evidence-based implementation strategies were selected and included integrating practice guidelines into radiology reports within the electronic medical records.

Fractional Excretion of Urate for Diuresis Management in Heart Failure and Cardiorenal Syndrome.

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.

Negative spot sign in primary intracerebral hemorrhage: potential impact in reducing imaging.

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.

Fuzzy Modeling to Predict Severely Depressed Left Ventricular Ejection Fraction following Admission to the Intensive Care Unit Using Clinical Physiology.

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.

PTPMT1 Inhibition Lowers Glucose through Succinate Dehydrogenase Phosphorylation.

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.

The effect of age and clinical circumstances on the outcome of red blood cell transfusion in critically ill patients.

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.

β-Aminoisobutyric acid induces browning of white fat and hepatic β-oxidation and is inversely correlated with cardiometabolic risk factors.

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.

Role of endothelial progenitor cells and inflammatory cytokines in healing of diabetic foot ulcers.

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.

2-Aminoadipic acid is a biomarker for diabetes risk.

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.

APACHE II scoring to predict outcome in post-cardiac arrest.

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.

Metabolite profiling identifies pathways associated with metabolic risk 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.

Benefit of transferring ST-segment-elevation myocardial infarction patients for percutaneous coronary intervention compared with administration of onsite fibrinolytic declines as delays increase.

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.

Repeated successful balloon valvuloplasty of a bioprosthetic aortic valve in a nonagenerian.

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.

Characterization of erythrocytic uptake and release and disposition pathways of nitrite, nitrate, methemoglobin, and iron-nitrosyl hemoglobin in the human circulation.

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.

Nitrite infusion in humans and nonhuman primates: endocrine effects, pharmacokinetics, and tolerance formation.

Background: The recent discovery that nitrite is an intrinsic vasodilator and signaling molecule at near-physiological concentrations has raised the possibility that nitrite contributes to hypoxic vasodilation and to the bioactivity of nitroglycerin and mediates the cardiovascular protective effects of nitrate in the Mediterranean diet. However, important questions of potency, kinetics, mechanism of action, and possible induction of tolerance remain unanswered.

Methods And Results: In the present study, we performed biochemical, physiological, and pharmacological studies using nitrite infusion protocols in 20 normal human volunteers and in nonhuman primates to answer these questions, and we specifically tested 3 proposed mechanisms of bioactivation: reduction to nitric oxide by xanthine oxidoreductase, nonenzymatic disproportionation, and reduction by deoxyhemoglobin.

A novel method of measuring reduction of nitrite-induced methemoglobin applied to fetal and adult blood of humans and sheep.

The reaction of nitrite with deoxyhemoglobin results in the production of nitric oxide and methemoglobin, a reaction recently proposed as an important oxygen-sensitive source of vasoactive nitric oxide during hypoxic and anoxic stress, with several animal studies suggesting that nitrite may have therapeutic potential. Accumulation of toxic levels of methemoglobin is suppressed by reductase enzymes present within the erythrocyte. Using a novel method of measuring methemoglobin reductase activity in intact erythrocytes, we compared fetal and adult sheep and human blood.

Endothelial progenitor cell mobilization and increased intravascular nitric oxide in patients undergoing cardiac rehabilitation.

Purpose: We investigated whether cardiac rehabilitation participation increases circulating endothelial progenitor cells (EPCs) and benefits vasculature in patients already on stable therapy previously shown to augment EPCs and improve endothelial function.

Methods: Forty-six of 50 patients with coronary artery disease completed a 36-session cardiac rehabilitation program: 45 were treated with HMG-CoA reductase inhibitor (statin) therapy > or = 1 month (average baseline low-density lipoprotein cholesterol = 81 mg/dL). Mononuclear cells isolated from blood were quantified for EPCs by flow cytometry (CD133/VEGFR-2 cells) and assayed in culture for EPC colony-forming units (CFUs).

Recent methodological advances in the analysis of nitrite in the human circulation: nitrite as a biochemical parameter of the L-arginine/NO pathway.

Nitric oxide (NO) plays a pivotal role in the modulation of multiple physiological processes. It acts as a messenger molecule within the cardiovascular system. NO is a highly unstable free radical in circulating blood and is oxidized rapidly to nitrite and nitrate.

The reductase NCB5OR is responsive to the redox status in beta-cells and is not involved in the ER stress response.

The novel reductase NCB5OR (NADPH cytochrome b5 oxidoreductase) resides in the ER (endoplasmic reticulum) and may protect cells against ER stress. Levels of BiP (immunoglobulin heavy-chain-binding protein), CHOP (CCAAT/enhancer-binding protein homologous protein) and XBP-1 (X-box-binding protein-1) did not differ in WT (wild-type) and KO (Ncb5or-null) tissues or MEFs (mouse embryonic fibroblasts), and XBP-1 remained unspliced. MEFs treated with inducers of ER stress demonstrated no change in Ncb5or expression and expression of ER-stress-induced genes was not enhanced.

The measurement of blood and plasma nitrite by chemiluminescence: pitfalls and solutions.

There are a number of difficulties involved in the quantification of nitrite in biological systems. These difficulties result from oxidation of nitrite (within minutes) by heme proteins, such as hemoglobin, myoglobin, cytoglobin, and neuroglobin; its low levels in vivo; and its ubiquitous presence in laboratory buffers and glassware. The goal of this review is to present an assay suitable for the sensitive and specific measurement of intravascular nitrite in mammals using the chemiluminescence-based nitric oxide analyzer and to inform the reader on how to evade the pitfalls pertinent to nitrite determination in biological matrices.

Lopinavir-ritonavir: effects on endothelial cell function in healthy subjects.

To differentiate between the effects that antiretroviral drugs have on the endothelium and the secondary effects that they have on immune function, viral load, and dyslipidemia, 6 non-human immunodeficiency virus-infected human subjects were treated with lopinavir-ritonavir for 1 month and, on the basis of forearm blood flow, the treatment's effects on endothelial cell function were measured. Surprisingly, after exposure to lopinavir-ritonavir, absolute forearm blood-flow responses to the endothelium-dependent vasodilator, acetylcholine, increased significantly (P=.03), and forearm blood flow decreased to a greater extent during specific inhibition of NO synthase by N(G)-monomethyl-L-arginine.

Plasma nitroso compounds are decreased in patients with endothelial dysfunction.

Objectives: We investigated whether plasma nitros(yl)ated species (RXNOs) that mediate systemic nitric oxide (NO) bioactivity are depleted in individuals with cardiovascular risk factors and endothelial dysfunction.

Background: Endothelium-derived NO acts not only as a regional messenger but exerts significant systemic effects via formation of circulating RXNOs delivering NO to sites of impaired production.

Methods: Endothelial function was assessed in 68 patients with one to four major cardiovascular risk factors (RF) and 39 healthy control subjects (C) by measurement of flow-mediated dilation (FMD) of the brachial artery using high-resolution ultrasound.

Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans.

A reduced nitric oxide availability is a hallmark of endothelial dysfunction occurring early in atherosclerosis. Recently, we have shown that plasma nitrite mirrors acute changes in endothelial nitric oxide synthase activity in various mammals, including humans. Here, we examined the hypothesis that plasma nitrite levels are reduced in humans with endothelial dysfunction and the decrease is correlated with increasing numbers of cardiovascular risk factors (RF).

Red blood cells express a functional endothelial nitric oxide synthase.

The synthesis of nitric oxide (NO) in the circulation has been attributed exclusively to the vascular endothelium. Red blood cells (RBCs) have been demonstrated to carry a nonfunctional NO synthase (NOS) and, due to their huge hemoglobin content, have been assumed to metabolize large quantities of NO. More recently, however, RBCs have been identified to reversibly bind, transport, and release NO within the cardiovascular system.