The incidence and prevalence of cardiovascular (CV)-related morbidity and mortality significantly increase with age. In the elderly, hypercholesterolemia with elevated total and low-density-lipoprotein cholesterol is a significant predictor of incident and recurrent CV disease. Multiple lines of evidence have established the benefit of statin therapy to lower cholesterol levels and reduce the risk of CV events as well as prevent progression of subclinical atherosclerotic disease. Elderly patients, particularly those older than 75 years, have not been well represented in randomized clinical trials evaluating lipid lowering therapy. The limited available data from clinical trials do support the benefit of statin therapy in the elderly population. Based upon these data, cholesterol treatment guidelines endorse statin therapy as the primary treatment of hypercholesterolemia in elderly patients, though caution is recommended given the greater number of co-morbid conditions and concern for poly-pharmacy common in the elderly. Additional research is needed to better establish the benefit of statin therapy in the elderly within the context of reducing CV risk, minimizing side effects, and improving overall quality of life.
Dyslipidemia is highly prevalent among women. The management of dyslipidemia is a cornerstone in the prevention of both primary and secondary cardiovascular events, such as myocardial infarction, ischemic stroke, and coronary death. All major international guidelines on the treatment of dyslipidemia recommend similar approaches to the management of dyslipidemia in both men and women. Estrogen replacement therapy should not be considered as a therapeutic option for managing dyslipidemia in women. The reduction of atherogenic lipoprotein burden (reducing low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol based on risk-stratified thresholds and treatment targets) provided the framework for managing dyslipidemia in the US, Europe, Canada, and elsewhere in the world. Very recently, new guidelines in the US have changed this paradigm, whereby rather than focusing on treatment targets, risk now defines the intensity of treatment with statin therapy, with no specific goals for what level of low-density lipoprotein cholesterol should be attained. It is not clear if this will lead to changes in lipid guidelines in other parts of the world. In the meantime, region-specific guidelines should be followed. Lipid lowering with statin therapy does correlate with reductions in cardiovascular event rates in women. The clinical impact of treating dyslipidemias in women with nonstatin drugs (eg, fibrates, nicotinic acid, bile acid-binding resins, omega-3 fish oils) is as yet not determined.
Dyslipidemia is an established risk factor for the development of atherosclerotic cardiovascular disease. Statin therapy has been proven in a number of clinical trials to lower the risk of acute cardiovascular events and is the mainstay of cholesterol treatment. Despite current optimal treatment for dyslipidemia, many patients fail to reach adequate cholesterol treatment goals and remain at a significantly increased risk of cardiovascular events. Given this residual risk, there is a critical need for additional lipid therapies that could augment the ability of statins to lower the burden of atherogenic lipoproteins and, in some cases, raise levels of high-density lipoproteins. A number of novel lipid-altering therapies have been developed and are currently in clinical trials. In this review, we discuss these promising therapies, which include PCSK9 inhibitors, apolipoprotein B antisense oligonucleotides, microsomal transfer protein inhibitors, thyroid mimetics, and cholesteryl ester transfer protein inhibitors. Although statin therapy is the current recommended primary treatment for dyslipidemia, emerging novel agents may become adjuvant therapies in the treatment of atherosclerotic heart disease.
The purpose of this study was to test the lipid depletion hypothesis and to establish the time course of change in carotid plaque morphology and composition during lipid therapy using high-resolution magnetic resonance imaging (MRI).
Mechanical ventilation with hyperoxia is a necessary treatment for patients with respiratory distress. However, patients on mechanical ventilation have increased susceptibility to infection. Studies including ours have shown that reactive oxygen species (ROS), generated by exposure to prolonged hyperoxia, can cause a decrease in the phagocytic activity of alveolar macrophages. Hydrogen peroxide (H?O?) is a form of ROS generated under hyperoxic conditions. In this study, we examined whether treatment with H?O? directly affects macrophage phagocytic ability in RAW 264.7 cells that were exposed to either 21% O? (room air) or 95% O? (hyperoxia). Moderate concentrations (ranging from 10 to 250 ?M) of H?O? significantly enhanced macrophage phagocytic activity and restored hyperoxia-suppressed phagocytosis through attenuation of hyperoxia-induced disorganization of actin cytoskeleton and actin oxidation. These results indicate that H?O? at low-moderate concentrations can be beneficial to host immune responses by improving macrophage phagocytic activity.
Recently, a growing body of evidence has suggested that adiponectin, which is secreted by adipose tissues, plays a critical role in obesity-related and autoimmune diseases. We compared the concentrations of adiponectin among 26 normal subjects and 34 allogeneic stem cell transplantation recipients. The concentrations of adiponectin were significantly higher in recipients with chronic graft-versus-host disease (cGVHD) than those in subjects without cGVHD (21.7 ± 11.0 vs 9.1 ± 6.1 ?g/mL in females, P < .001; and 10.1 ± 6.8 vs 4.3 ± 2.9 ?g/mL in males, P = .003). Multivariate analysis revealed that a higher concentration of adiponectin was associated with female sex (?-coefficient 8.2, P < .0001) and the severity of cGVHD (?-coefficient 6.6, 12.7, and 15.6, P < .01, each for mild, moderate, and severe cGVHD, respectively). In addition, adiponectin levels increased as cGVHD progressed, decreased as cGVHD improved, and did not change with stable cGVHD. In conclusion, adiponectin was associated with the severity of cGVHD and might play a role in the pathophysiology of cGVHD.
The Vietnamese develop type 2 diabetes (T2D) and metabolic syndrome (MS) at a lower BMI than other ethnicities. Thus, biomarkers that identify subjects at an increased risk of T2D independently of obesity are being sought. Recent studies show that circulating NO metabolites (NOx) are increased in T2D. We investigated whether plasma NOx levels predict insulin resistance and glucose intolerance before the development of T2D, independently of obesity.
The reactions of substituted benzhydryl bromides Ar(2)CHBr with primary and secondary amines in DMSO yield benzhydryl amines Ar(2)CHNRR, benzophenones Ar(2)C=O, and benzhydrols Ar(2)CHOH. Kinetic investigations at 20 degrees C revealed the rate law -d[Ar(2)CHBr]/dt = (k(1) + k(2)[HNRR])[Ar(2)CHBr], where the amine independent term k(1) gave rise to the formation of Ar(2)C=O and Ar(2)CHOH and the amine-dependent term k(2)[HNRR] was responsible for the formation of Ar(2)CHNRR. Clear evidence for concomitant S(N)1 and S(N)2 processes was obtained. While the rate constants of the S(N)1 reactions correlate with Hammetts sigma(+) constants (rho = -3.22), the second-order rate constants k(2) for the S(N)2 reactions are not correlated with the electron releasing abilities of the substituents, indicating that the transition states of the S(N)2 reactions do not merge with the transition states of the S(N)1 reactions. The correlation equation log k(20 degrees C) = s(E + N), where nucleophiles are characterized by N and s and electrophiles are characterized by E (J. Am. Chem. Soc. 2001, 123, 9500-9512), was used to calculate the lifetimes of benzhydrylium ions in the presence of amines and DMSO. The change from S(N)1 to S(N)2 mechanism occurred close to the point where the calculated rate constant for the collapse of the benzhydrylium ions with the amines just reaches the vibrational limit; that is, the concerted S(N)2 mechanism was only followed when it was enforced by the lifetime of the intermediate. The nucleophile-specific parameters N and s needed for this analysis were determined by studying the kinetics of the reactions of a variety of amines with amino-substituted benzhydrylium tetrafluoroborates (Ar(2)CH(+)BF(4)(-)) of known electrophilicity E in DMSO. Analogously, the rates of the reactions of laser flash photolytically generated benzhydrylium ions Ar(2)CH(+) with DMSO in acetonitrile were employed to determine the nucleophile-specific parameters N and s of DMSO, and it is reported that DMSO is a significantly stronger O-nucleophile than water and ordinary alcohols.
Although the effect of niacin on the glucose levels in subjects with diabetes mellitus has been investigated, niacins effects on the glucose levels and atherosclerosis in subjects with normal glucose levels have not been well established. We examined the effect of niacin on the glucose levels, coronary stenosis progression using quantitative coronary angiography, and clinical events in 407 subjects who had a baseline glucose level <100 mg/dl and were enrolled in the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), or Carotid Plaque Composition by MRI during lipid-lowering (CPC) study testing active niacin therapy. Although the fasting glucose levels increased significantly within 3 years in both subjects treated with niacin (from 85.6 ± 9.5 to 95.5 ± 19.7 mg/dl, p <0.001) and without niacin (from 85.2 ± 9.6 to 90 ± 17.9 mg/dl, p = 0.009), those treated with niacin had a significantly larger increase in glucose levels than those not taking niacin (9.88 vs 4.05 mg/dl, p = 0.002). Overall, 29% of subjects developed impaired fasting glucose within 3 years. Incident impaired fasting glucose was significantly more likely to be observed in subjects treated with niacin than in those who were not. However, the frequency of new-onset diabetes mellitus did not differ significantly between the 2 groups (5.6% vs 4.8%, p = 0.5). Niacin-treated subjects compared to untreated subjects had significantly less change in mean coronary stenosis (0.1 ± 0.3% vs 2 ± 12%, p <0.0001) and less major cardiovascular events (8% vs 21%, p = 0.001). In conclusion, the use of niacin for 3 years in subjects with normal baseline glucose levels was associated with an increase in blood glucose levels and the risk of developing impaired fasting glucose, but not diabetes mellitus, and was associated with a significantly reduced incidence of coronary stenosis progression and major cardiovascular events.
Mechanical ventilation with supraphysiological concentrations of oxygen (hyperoxia) is routinely used to treat patients with respiratory distress. However, a significant number of patients on ventilators exhibit enhanced susceptibility to infections and develop ventilator-associated pneumonia (VAP). Pseudomonas aeruginosa (PA) is one of the most common species of bacteria found in these patients. Previously, we demonstrated that prolonged exposure to hyperoxia can compromise the ability of alveolar macrophages (AMs), an essential part of the innate immunity, to phagocytose PA. This study sought to investigate the potential molecular mechanisms underlying hyperoxia-compromised innate immunity against bacterial infection in a murine model of PA pneumonia. Here, we show that exposure to hyperoxia (? 99% O2) led to a significant elevation in concentrations of airway high mobility group box-1 (HMGB1) and increased mortality in C57BL/6 mice infected with PA. Treatment of these mice with a neutralizing anti-HMGB1 monoclonal antibody (mAb) resulted in a reduction in bacterial counts, injury, and numbers of neutrophils in the lungs, and an increase in leukocyte phagocytic activity compared with mice receiving control mAb. This improved phagocytic function was associated with reduced concentrations of airway HMGB1. The correlation between phagocytic activity and concentrations of extracellular HMGB1 was also observed in cultured macrophages. These results indicate a pathogenic role for HMGB1 in hyperoxia-induced impairment with regard to a hosts ability to clear bacteria and inflammatory lung injury. Thus, HMGB1 may provide a novel molecular target for improving hyperoxia-compromised innate immunity in patients with VAP.
The lowering of low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay for LDL-C lowering, a significant percentage of patients prescribed these agents either do not achieve targets with statin therapy alone or have partial or complete intolerance to them. For such patients, the use of adjuvant therapy capable of providing incremental LDL-C reduction is advised. One such agent is ezetimibe, a cholesterol absorption inhibitor that targets uptake at the jejunal enterocyte brush border. Its primary target of action is the cholesterol transport protein Nieman Pick C1 like 1 protein. Ezetimibe is an effective LDL-C lowering agent and is safe and well tolerated. In response to significant controversy surrounding the use and therapeutic effectiveness of this drug, we provide an update on the biochemical mechanism of action for ezetimibe, its safety and efficacy, as well as the results of recent randomized studies that support its use in a variety of clinical scenarios.
Pulmonary infection with Pseudomonas aeruginosa and neutrophilic lung inflammation significantly contribute to morbidity and mortality in cystic fibrosis (CF). High-mobility group box 1 protein (HMGB1), a ubiquitous DNA binding protein that promotes inflammatory tissue injury, is significantly elevated in CF sputum. However, its mechanistic and potential therapeutic implications in CF were previously unknown. We found that HMGB1 levels were significantly elevated in bronchoalveolar lavage fluids (BALs) of CF patients and cystic fibrosis transmembrane conductance regulator (CFTR )(-/-) mice. Neutralizing anti-HMGB1 monoclonal antibody (mAb) conferred significant protection against P. aeruginosa-induced neutrophil recruitment, lung injury and bacterial infection in both CFTR(-/-) and wild-type mice. Alveolar macrophages isolated from mice treated with anti-HMGB1 mAb had improved phagocytic activity, which was suppressed by direct exposure to HMGB1. In addition, BAL from CF patients significantly impaired macrophage phagocytotic function, and this impairment was attenuated by HMGB1-neutralizing antibodies. The HMGB1-mediated suppression of bacterial phagocytosis was attenuated in macrophages lacking toll-like receptor (TLR)-4, suggesting a critical role for TLR4 in signaling HMGB1-mediated macrophage dysfunction. These studies demonstrate that the elevated levels of HMGB1 in CF airways are critical for neutrophil recruitment and persistent presence of P. aeruginosa in the lung. Thus, HMGB1 may provide a therapeutic target for reducing bacterial infection and lung inflammation in CF.
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