Abstract
Lipid peroxidation generates reactive dicarbonyls including isolevuglandins (IsoLGs) and malondialdehyde (MDA) that covalently modify proteins. Humans with familial hypercholesterolemia (FH) ...have increased lipoprotein dicarbonyl adducts and dysfunctional HDL. We investigate the impact of the dicarbonyl scavenger, 2-hydroxybenzylamine (2-HOBA) on HDL function and atherosclerosis in
Ldlr
−/−
mice, a model of FH. Compared to hypercholesterolemic
Ldlr
−/−
mice treated with vehicle or 4-HOBA, a nonreactive analogue, 2-HOBA decreases atherosclerosis by 60% in
en face
aortas, without changing plasma cholesterol.
Ldlr
−/−
mice treated with 2-HOBA have reduced MDA-LDL and MDA-HDL levels, and their HDL display increased capacity to reduce macrophage cholesterol. Importantly, 2-HOBA reduces the MDA- and IsoLG-lysyl content in atherosclerotic aortas versus 4-HOBA. Furthermore, 2-HOBA reduces inflammation and plaque apoptotic cells and promotes efferocytosis and features of stable plaques. Dicarbonyl scavenging with 2-HOBA has multiple atheroprotective effects in a murine FH model, supporting its potential as a therapeutic approach for atherosclerotic cardiovascular disease.
Naproxen ((S)-6-methoxy-α-methyl-2-naphthaleneacetic acid) is a powerful non-selective non-steroidal anti-inflammatory drug that is extensively used as a prescription and over-the-counter medication. ...Naproxen exhibits gastrointestinal toxicity, but its cardiovascular toxicity may be reduced compared with other drugs in its class. Despite the fact that naproxen has been marketed for many years, the molecular basis of its interaction with cyclooxygenase (COX) enzymes is unknown. We performed a detailed study of naproxen-COX-2 interactions using site-directed mutagenesis, structure-activity analysis, and x-ray crystallography. The results indicate that each of the pendant groups of the naphthyl scaffold are essential for COX inhibition, and only minimal substitutions are tolerated. Mutation of Trp-387 to Phe significantly reduced inhibition by naproxen, a result that appears unique to this inhibitor. Substitution of S or CH2 for the O atom of the p-methoxy group yielded analogs that were not affected by the W387F substitution and that exhibited increased COX-2 selectivity relative to naproxen. Crystallization and x-ray analysis yielded structures of COX-2 complexed to naproxen and its methylthio analog at 1.7 and 2.3 Å resolution, respectively. The combination of mutagenesis, structure analysis, and x-ray crystallography provided comprehensive information on the unique interactions responsible for naproxen binding to COX-2.
The oxidation hypothesis of atherogenesis has been the focus of much research over the past 2 decades. However, randomized placebo-controlled trials evaluating the efficacy of vitamin E in preventing ...cardiovascular events in aggregate have failed to show a beneficial effect. Implicit in these trials is that the dose of vitamin E tested effectively suppressed oxidative stress status but this was never determined. We defined the dose-dependent effects of vitamin E (
RRR-α-tocopherol) to suppress plasma concentrations of F
2-isoprostanes, a biomarker of free radical-mediated lipid peroxidation, in participants with polygenic hypercholesterolemia and enhanced oxidative stress, a population at risk for cardiovascular events. A time-course study was first performed in participants supplemented with 3200 IU/day of vitamin E for 20 weeks. A dose-ranging study was then performed in participants supplemented with 0, 100, 200, 400, 800, 1600, or 3200 IU/day of vitamin E for 16 weeks. In the time-course study, maximum suppression of plasma F
2-isoprostane concentrations did not occur until 16 weeks of supplementation. In the dose-ranging study there was a linear trend between the dosage of vitamin E and percentage reduction in plasma F
2-isoprostane concentrations which reached significance at doses of 1600 IU (35
±
2%,
p
<
0.035) and 3200 IU (49
±
10%,
p
<
0.005). This study provides information on the dosage of vitamin E that decreases systemic oxidant stress in vivo in humans and informs the planning and evaluation of clinical studies that assess the efficacy of vitamin E to mitigate disease.
2009 Focused Update Writing Group Members Mariell Jessup, MD, FACC, FAHA, Chair* William T. Abraham, MD, FACC, FAHAdagger Donald E. Casey, MD, MPH, MBAdouble dagger Arthur M. Feldman, MD, PhD, FACC, ...FAHA§ Gary S. Francis, MD, FACC, FAHA§ Theodore G. Ganiats, MD|| Marvin A. Konstam, MD, FACC¶ Donna M. Mancini, MD# Peter S. Rahko, MD, FACC, FAHAdagger Marc A. Silver, MD, FACC, FAHA** Lynne Warner Stevenson, MD, FACC, FAHAdagger Clyde W. Yancy, MD, FACC, FAHAdaggerdagger Task Force Members Sidney C. Smith, Jr, MD, FACC, FAHA, Chair Alice K. Jacobs, MD, FACC, FAHA, Vice-Chair Christopher E. Buller, MD, FACC Mark A. Creager, MD, FACC, FAHA Steven M. Ettinger, MD, FACC Harlan M. Krumholz, MD, FACC, FAHA Frederick G. Kushner, MD, FACC, FAHA Bruce W. Lytle, MD, FACC, FAHAdouble daggerdouble dagger Rick A. Nishimura, MD, FACC, FAHA Richard L. Page, MD, FACC, FAHA Lynn G. Tarkington, RN Clyde W. Yancy, MD, FACC, FAHA Table of Contents Preamble (UPDATED)...e3 Introduction (UPDATED)...e5 Evidence Review (UPDATED)...e5 Organization of Committee and Relationships With Industry (UPDATED)...e6 Review and Approval (NEW)...e6 Stages of Heart Failure (UPDATED)...e6 Characterization of Heart Failure as a Clinical Syndrome...e7 Definition of Heart Failure...e7 Heart Failure as a Symptomatic Disorder...e7 Heart Failure as a Progressive Disorder...e8 Initial and Serial Clinical Assessment of Patients Presenting With Heart Failure (UPDATED)...e8 Initial Evaluation of Patients...e10 Identification of Patients (UPDATED)...e10 Identification of a Structural and Functional Abnormality (UPDATED)...e11 Evaluation of the Cause of Heart Failure...e11 History and Physical Examination...e11 Laboratory Testing (UPDATED)...e12 Evaluation of the Possibility of Coronary Artery Disease...e13 Evaluation of the Possibility of Myocardial Disease...e13 Ongoing Evaluation of Patients...e14 Assessment of Functional Capacity...e14 Assessment of Volume Status...e14 Laboratory Assessment (UPDATED)...e15 Assessment of Prognosis (UPDATED)...e16 Therapy...e16 Patients at High Risk for Developing Heart Failure (Stage A)...e16 Control of Risk...e17 Treatment of Hypertension...e17 Treatment of Diabetes...e18 Management of the Metabolic Syndrome...e18 Management of Atherosclerotic Disease...e18 Control of Conditions That May Cause Cardiac Injury...e18 Other Measures...e19 Early Detection of Structural Abnormalities...e19 Patients With Cardiac Structural Abnormalities or Remodeling Who Have Not Developed Heart Failure Symptoms (Stage B)...e19 Prevention of Cardiovascular Events...e20 Patients With an Acute Myocardial Infarction...e20 Patients With a History of MI but Normal Left Ventricular Ejection Fraction...e20 Patients With Hypertension and Left Ventricular Hypertrophy...e20 Patients With Chronic Reduction of Left Ventricular Ejection Fraction but No Symptoms...e20 Patients With Severe Valvular Disease but No Symptoms...e20 Early Detection of Heart Failure...e21 Patients With Current or Prior Symptoms of HF (Stage C)...e21 Patients With Reduced Left Ventricular Ejection Fraction (UPDATED)...e21 General Measures (UPDATED)...e22 Drugs Recommended for Routine Use...e24 Diuretics...e24 Inhibitors of the Renin-Angiotensin-Aldosterone System...e25 Angiotensin Converting Enzyme Inhibitors in the Management of Heart Failure...e26 Angiotensin Receptor Blockers...e28 Aldosterone Antagonists...e29 Beta-Adrenergic Receptor Blockers...e31 Digitalis...e33 Ventricular Arrhythmias and Prevention of Sudden Death (UPDATED)...e35 Interventions to Be Considered for Use in Selected Patients...e37 Isosorbide Dinitrate...e37 Hydralazine...e37 Hydralazine and Isosorbide Dinitrate (UPDATED)...e37 Cardiac Resynchronization Therapy (UPDATED)...e38 Exercise Training...e39 Drugs and Interventions Under Active Investigation...e39 Techniques For Respiratory Support...e39 External Counterpulsation...e39 Vasopressin Receptor Antagonists...e40 Implantable Hemodynamic Monitors...e40 Cardiac Support Devices...e40 Surgical Approaches Under Investigation...e40 Nesiritide...e40 Drugs and Interventions of Unproved Value and Not Recommended...e40 Nutritional Supplements and Hormonal Therapies...e40 Intermittent Intravenous Positive Inotropic Therapy (UPDATED)...e41 Patients With Heart Failure and Normal Left Ventricular Ejection Fraction...e41 Identification of Patients...e42 Diagnosis...e43 Principles of Treatment...e43 Patients With Refractory End-Stage Heart Failure (Stage D) (UPDATED)...e44 Management of Fluid Status...e44 Utilization of Neurohormonal Inhibitors...e45 Intravenous Peripheral Vasodilators and Positive Inotropic Agents (UPDATED)...e45 Mechanical and Surgical Strategies...e46 The Hospitalized Patient (NEW)...e47 Diagnostic Strategies...e49 Treatment in the Hospital...e49 Diuretics: The Patient With Volume Overload...e49 Vasodilators...e50 Inotropes...e51 Other Considerations...e51 The Hospital Discharge...e52 Treatment of Special Populations (UPDATED)...e52 Women and Men...e53 Ethnic Considerations...e53 Elderly Patients...e54 Patients With Heart Failure Who Have Concomitant Disorders...e54 Cardiovascular Disorders...e55 Hypertension, Hyperlipidemia, and Diabetes Mellitus...e55 Coronary Artery Disease...e56 Supraventricular Arrhythmias (UPDATED)...e56 Prevention of Thromboembolic Events...e57 Noncardiovascular Disorders...e58 Patients With Renal Insufficiency...e58 Patients With Pulmonary Disease...e58 Patients With Cancer...e58 Patients With Thyroid Disease...e59 Patients With Hepatitis C and Human Immunodeficiency Virus...e59 Patients With Anemia...e59 End-of-Life Considerations...e59 Implementation of Practice Guidelines...e61 Isolated Provider Interventions...e61 Disease-Management Systems...e61 Performance Measures...e62 Roles of Generalist Physicians and Cardiologists...e62 References...e63 Appendix 1...e82 Appendix 2...e83 Appendix 3...e86 Appendix 4...e87 Appendix 5...e88 Preamble (UPDATED) It is important that the medical profession play a significant role in critically evaluating the use of diagnostic procedures and therapies as they are introduced and tested in the detection, management, or prevention of disease states.
The prevalence of some immune-mediated diseases (IMDs) shows distinct differences between populations of different ethnicities. The aim of this study was to determine if the age at diagnosis of ...common IMDs also differed between different ethnic groups in the UK, suggestive of distinct influences of ethnicity on disease pathogenesis.
This was a population-based retrospective primary care study. Linear regression provided unadjusted and adjusted estimates of age at diagnosis for common IMDs within the following ethnic groups: White, South Asian, African-Caribbean and Mixed-race/Other. Potential disease risk confounders in the association between ethnicity and diagnosis age including sex, smoking, body mass index and social deprivation (Townsend quintiles) were adjusted for. The analysis was replicated using data from UK Biobank (UKB).
After adjusting for risk confounders, we observed that individuals from South Asian, African-Caribbean and Mixed-race/Other ethnicities were diagnosed with IMDs at a significantly younger age than their White counterparts for almost all IMDs. The difference in the diagnosis age (ranging from 2 to 30 years earlier) varied for each disease and by ethnicity. For example, rheumatoid arthritis was diagnosed at age 49, 48 and 47 years in individuals of African-Caribbean, South Asian and Mixed-race/Other ethnicities respectively, compared to 56 years in White ethnicities. The earlier diagnosis of most IMDs observed was validated in UKB although with a smaller effect size.
Individuals from non-White ethnic groups in the UK had an earlier age at diagnosis for several IMDs than White adults.
This randomized, controlled trial shows that acetaminophen reduces kidney dysfunction and risk of developing acute kidney injury, particularly in severe malaria patients who present with high plasma ...hemoglobin, supporting the hypothesis that acetaminophen inhibits cell-free hemoglobin-mediated renal tubular oxidative damage.
Abstract
Background
Acute kidney injury independently predicts mortality in falciparum malaria. It is unknown whether acetaminophen's capacity to inhibit plasma hemoglobin-mediated oxidation is renoprotective in severe malaria.
Methods
This phase 2, open-label, randomized controlled trial conducted at two hospitals in Bangladesh assessed effects on renal function, safety, pharmacokinetic (PK) properties and pharmacodynamic (PD) effects of acetaminophen. Febrile patients (>12 years) with severe falciparum malaria were randomly assigned to receive acetaminophen (1 g 6-hourly for 72 hours) or no acetaminophen, in addition to intravenous artesunate. Primary outcome was the proportional change in creatinine after 72 hours stratified by median plasma hemoglobin.
Results
Between 2012 and 2014, 62 patients were randomly assigned to receive acetaminophen (n = 31) or no acetaminophen (n = 31). Median (interquartile range) reduction in creatinine after 72 hours was 23% (37% to 18%) in patients assigned to acetaminophen, versus 14% (29% to 0%) in patients assigned to no acetaminophen (P = .043). This difference in reduction was 37% (48% to 22%) versus 14% (30% to −71%) in patients with hemoglobin ≥45000 ng/mL (P = .010). The proportion with progressing kidney injury was higher among controls (subdistribution hazard ratio, 3.0; 95% confidence interval, 1.1 to 8.5; P = .034). PK-PD analyses showed that higher exposure to acetaminophen increased the probability of creatinine improvement. No patient fulfilled Hy's law for hepatotoxicity.
Conclusions
In this proof-of-principle study, acetaminophen showed renoprotection without evidence of safety concerns in patients with severe falciparum malaria, particularly in those with prominent intravascular hemolysis.
Clinical Trials Registration
NCT01641289.
Hemoproteins, hemoglobin and myoglobin, once released from cells can cause severe oxidative damage as a consequence of heme redox cycling between ferric and ferryl states that generates radical ...species that induce lipid peroxidation. We demonstrate in vitro that acetaminophen inhibits hemoprotein-induced lipid peroxidation by reducing ferryl heme to its ferric state and quenching globin radicals. Severe muscle injury (rhabdomyolysis) is accompanied by the release of myoglobin that becomes deposited in the kidney, causing renal injury. We previously showed in a rat model of rhabdomyolysis that redox cycling between ferric and ferryl myoglobin yields radical species that cause severe oxidative damage to the kidney. In this model, acetaminophen at therapeutic plasma concentrations significantly decreased oxidant injury in the kidney, improved renal function, and reduced renal damage. These findings also provide a hypothesis for potential therapeutic applications for acetaminophen in diseases involving hemoproteinmediated oxidative injury.
This trial evaluated the efficacy of acetaminophen in reducing oxidative injury, as measured by plasma F2-isoprostanes, in adult patients with severe sepsis and detectable plasma cell-free ...hemoglobin.
Single-center, randomized, double-blind, placebo-controlled phase II trial.
Medical ICU in a tertiary, academic medical center.
Critically ill patients 18 years old or older with severe sepsis and detectable plasma cell-free hemoglobin.
Patients were randomized 1:1 to enteral acetaminophen 1 g every 6 hours for 3 days (n = 18) or placebo (n = 22) with the same dosing schedule and duration.
F2-Isoprostanes on study day 3, the primary outcome, did not differ between acetaminophen (30 pg/mL; interquartile range, 24-41) and placebo (36 pg/mL; interquartile range, 25-80; p = 0.35). However, F2-isoprostanes were significantly reduced on study day 2 in the acetaminophen group (24 pg/mL; interquartile range, 19-36) when compared with placebo (36 pg/mL; interquartile range, 23-55; p = 0.047). Creatinine on study day 3, a secondary outcome, was significantly lower in the acetaminophen group (1.0 mg/dL; interquartile range, 0.6-1.4) when compared with that in the placebo (1.3 mg/dL; interquartile range, 0.83-2.0; p = 0.039). There was no statistically significant difference in hospital mortality (acetaminophen 5.6% vs placebo 18.2%; p = 0.355) or adverse events (aspartate aminotransferase or alanine aminotransferase > 400; acetaminophen 9.5% vs placebo 4.3%; p = 0.599).
In adults with severe sepsis and detectable plasma cell-free hemoglobin, treatment with acetaminophen within 24 hours of ICU admission may reduce oxidative injury and improve renal function. Additional study is needed to confirm these findings and determine the effect of acetaminophen on patient-centered outcomes.
PDF
