Peroxisome Proliferator-Activated Receptor-α Agonism With Fenofibrate Does Not Suppress Inflammatory Responses to Evoked Endotoxemia.

BACKGROUND: Data conflict with regard to whether peroxisome proliferator-activated receptor-α agonism suppresses inflammation in humans. We hypothesized that in healthy adults peroxisome proliferator-activated receptor-α agonism with fenofibrate would blunt the induced immune responses to endotoxin (lipopolysaccharide [LPS]), an in vivo model for the study of cardiometabolic inflammation. METHODS AND RESULTS: In the Fenofibrate and omega-3 Fatty Acid Modulation of Endotoxemia (FFAME) trial, 36 healthy volunteers (mean age 26±7 years, mean body mass index 24±3 kg/m(2), 44% female, 72% white) were randomized to fenofibrate 145 mg or placebo daily. After 6 to 8 weeks of treatment, subjects underwent a low-dose LPS challenge. Clinical and blood measurements were collected at randomization, before LPS administration, and serially for 24 hours after LPS administration. We examined area under the curve for evoked responses by treatment group. Compared to placebo, but before LPS challenge, fenofibrate reduced total cholesterol and tended to decrease triglycerides, consistent with achieved therapeutic plasma levels of fenofibric acid. In the placebo group, LPS induced a modest inflammatory response with increased cytokines and chemokines (2- to 4-hour post-LPS 8-fold increase in tumor necrosis factor-α, 9-fold increase in interleukin-6, 9-fold increase in interleukin-10, and 10-fold increase in monocyte chemotactic protein-1; all P<0.001) and acute-phase reactants (24-hour post-LPS 15-fold increase in serum amyloid A and 9-fold increase in C-reactive protein; both P<0.001). Compared to placebo, however, fenofibrate did not significantly attenuate LPS-induced levels of plasma cytokines, chemokines, or acute-phase proteins. CONCLUSIONS: These data suggest a lack of systemic antiinflammatory properties of fenofibrate at clinically relevant dosing in humans. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov/ct2/show/NCT01048502. Unique identifier: NCT01048502. (J Am Heart Assoc. 2012;1:e002923 doi: 10.1161/JAHA.112.002923.).

Extended-release niacin acutely suppresses postprandial triglyceridemia.

OBJECTIVE: Postprandial triglyceridemia predicts cardiovascular events. Niacin might lower postprandial triglycerides by restricting free fatty acids. Immediate-release niacin reduced postprandial triglycerides, but extended-release niacin failed to do so when dosed the night before a fat challenge. The study aims were to determine whether extended-release niacin dosed before a fat challenge suppresses postprandial triglycerides and whether postprandial triglycerides are related to free fatty acid restriction. METHODS: A double-blinded, placebo-controlled, random-order crossover experiment was performed, in which healthy volunteers took 2 g extended-release niacin or placebo 1 hour before heavy cream. We sampled blood over 12 hours and report triglycerides and free fatty acid as means ± standard deviation for incremental area under the curve (AUC) and nadir. RESULTS: By combining 43 fat challenges from 22 subjects, postprandial triglycerides incremental AUC was +312 ± 200 mg/dL*h on placebo versus +199 ± 200 mg/dL*h on extended-release niacin (33% decrease, P=.02). The incremental nadir for free fatty acid was -0.07 ± 0.15 mmol/L on placebo versus -0.27 ± 0.13 mmol/L on extended-release niacin (P<.0001), and free fatty acid incremental AUC decreased from +2.9 ± 1.5 mmol/L*h to +1.5 ± 1.5 mmol/L*h on extended-release niacin (20% decrease, P=.0015). The incremental AUC for triglycerides was strongly related to the post-dose decrease in free fatty acid (r = +0.58, P=.0007). CONCLUSIONS: Given right before a fat meal, even a single dose of extended-release niacin suppresses postprandial triglyceridemia. This establishes that postprandial triglycerides suppression is an acute pharmacodynamic effect of extended-release niacin, probably the result of marked free fatty acid restriction. Further study is warranted to determine whether mealtime dosing would augment the clinical efficacy of extended-release niacin therapy.

Targets and delivery methods for therapeutic angiogenesis in peripheral artery disease.

Therapeutic angiogenesis utilizing genetic and cellular modalities in the treatment of arterial obstructive diseases continues to evolve. This is, in part, because the mechanism of vasculogenesis, angiogenesis, and arteriogenesis (the three processes by which the body responds to obstruction of large conduit arteries) is a complex process that is still under investigation. To date, the majority of human trials utilizing molecular, genetic, and cellular modalities for therapeutic angiogenesis in the treatment of peripheral artery disease (PAD) have not shown efficacy. Consequently, the current available knowledge is yet to be translated into novel therapeutic approaches for the treatment of PAD. The aim of this review is to discuss relevant scientific and clinical advances in therapeutic angiogenesis and their potential application in the treatment of ischemic diseases of the peripheral arteries. Additionally, this review article discusses past and recent developments, such as some unconventional approaches that have the potential to be applied as therapeutic targets. The article also includes advances in the delivery of genetic, cellular, and bioactive endothelial growth factors.

Personalized vascular medicine: individualizing drug therapy.

Personalized medicine refers to the application of an individual's biological fingerprint - the comprehensive dataset of unique biological information - to optimize medical care. While the principle itself is straightforward, its implementation remains challenging. Advances in pharmacogenomics as well as functional assays of vascular biology now permit improved characterization of an individual's response to medical therapy for vascular disease. This review describes novel strategies designed to permit tailoring of four major pharmacotherapeutic drug classes within vascular medicine: antiplatelet therapy, antihypertensive therapy, lipid-lowering therapy, and antithrombotic therapy. Translation to routine clinical practice awaits the results of ongoing randomized clinical trials comparing personalized approaches with standard of care management.

Combination antiplatelet therapy for secondary stroke prevention: enhanced efficacy or double trouble?

The evaluation of antithrombotic agents for secondary stroke prevention has focused on stroke reduction. The aim of this analysis was to focus specifically on the increase in bleeding risk. The annualized rates of total and major bleeding events in secondary stroke prevention trials of antithrombotics were assessed and cross compared. A Medline search for major randomized clinical studies with a follow-up duration of > or =1 year identified 13 studies. Pooled data sets were used to compare mean bleeding rates for aspirin (< or =325 mg/day), clopidogrel, anticoagulants (warfarin and other vitamin K antagonists), aspirin plus clopidogrel, and aspirin plus extended-release dipyridamole (ER-DP). Total bleeding occurred at mean rates of 4.8% with aspirin (< or =325 mg/day) alone, 2.9% with clopidogrel alone, 3.6% with aspirin plus ER-DP, 10.1% with aspirin plus clopidogrel, and 16.8% with anticoagulation. Major bleeding occurred at mean rates of 1% with aspirin (< or =325 mg/day) alone, 0.85% with clopidogrel, 0.93% with aspirin plus ER-DP, 1.7% with aspirin plus clopidogrel, and 2.5% with anticoagulation. In conclusion, the combination of aspirin and clopidogrel is associated with significantly greater bleeding than either aspirin (< or =325 mg/day) or clopidogrel alone. Aspirin plus ER-DP has a greater bleeding rate than clopidogrel but a lower rate than aspirin (< or =325 mg/day) alone.

New developments in anticoagulation for atrial fibrillation.

The incidence of stroke in patients with atrial fibrillation (AF) is five times greater than that in age-matched controls. Warfarin reduces this incidence by two thirds and is the most effective agent for this indication. However, despite its efficacy, warfarin management is tedious and is useful only in a subsegment of the population who needs anticoagulation and has no contraindications. Many agents are poised to replace warfarin as an effective anticoagulant for stroke prevention in AF. The direct thrombin inhibitor dabigatran is furthest along in clinical development, followed by the factor Xa inhibitors rivaroxaban and apixaban. All these agents seem effective, and none appears mechanistically superior over another. Dabigatran's advantage is that it was tested in two dosages in a phase 3 evaluation based on earlier phase 2 studies in patients with AF, whereas dosage data for the other agents were extrapolated from phase 2 programs for venous thromboembolism prevention. The vitamin K antagonist ATI-5923 offers clinical benefits similar to warfarin's, but with no or fewer drug-drug interactions, potentially greater time in therapeutic range, and probably less need for dose adjustment and laboratory monitoring. It challenges the newer mechanistic agents in efficacy and raises the bar for comparison in future head-to-head trials. Further analysis and clinical trial testing are still needed to determine whether one or all of these agents are effective anticoagulants for stroke prevention in patients with AF.

Age- and site-specific variation in the dermoscopic patterns of congenital melanocytic nevi: an aid to accurate classification and assessment of melanocytic nevi.

OBJECTIVES: To describe the dermoscopic features of congenital melanocytic nevi (CMN) and assess whether predominant dermoscopic patterns present in CMN are related to an individual's age (<12 years vs >or=12 years), sex, or lesional site (head, neck, and trunk vs extremities). DESIGN: Nonrandomized observational study. PATIENTS: A total of 77 consecutive patients, each with 1 CMN (n = 77 lesions), from an outpatient dermatology clinic. A diagnosis of CMN was established by (1) documentation of a melanocytic nevus during the first year of life or (2) by clinical examination and either clinical history or biopsy findings. MAIN OUTCOME MEASURES: Images of CMN were evaluated for specific dermoscopic structures and patterns. The distribution of patterns was assessed by age, sex, and lesional site. RESULTS: Most of the 77 lesions exhibited 1 of the following predominant dermoscopic patterns: reticular (18 lesions [23%]), globular (14 [18%]), or reticuloglobular (12 [16%]). Globular CMN were present in 5 of the 19 individuals who were younger than 12 years (26%) but in only 9 of the 58 individuals 12 years or older (16%). Reticular CMN were seen exclusively in the individuals who were 12 years or older. Congenital melanocytic nevi exhibiting no predominant pattern were more commonly present in the individuals younger than 12 years. Globular CMN were present in 11 head, neck, and trunk lesions (30%) compared with 3 extremity lesions (8%). Conversely, reticular CMN were present in 16 extremity lesions (40%) compared with 2 head, neck, and trunk lesions (5%). The predominant dermoscopic pattern did not vary based on sex. The most commonly observed dermoscopic structures were globules (in 64 lesions [83%]), hypertrichosis (in 61 [79%]), and reticular networks (in 55 [71%]). CONCLUSIONS: Our results suggest that the predominant dermoscopic patterns of CMN vary according to age and lesional site. These differences may inform future studies on the pathogenesis of CMN.

Abciximab and fatal pulmonary hemorrhage.

Abciximab, a platelet glycoprotein IIb/IIIa receptor blocker, is a well-known agent in percutaneous coronary intervention because of its antiplatelet, antithrombotic effects, which allow for good outcome. Major bleeding is a well-recognized complication of abciximab therapy, and pulmonary hemorrhage, although infrequent, is a serious, under-recognized, and often fatal complication. We describe a case of fatal pulmonary hemorrhage in a young woman who presented with acute myocardial infarction and cardiogenic shock and was treated with abciximab in conjunction with percutaneous coronary intervention. The possibility of diffuse pulmonary hemorrhage should be strongly suspected in the presence of hypoxemia, infiltrates on chest radiography, and a decrease in hemoglobin. Awareness about this complication of abciximab therapy on the part of physicians and health care professionals is strongly warranted. Therapy that may be used if diagnosis is promptly made includes bronchoscopic-guided balloon tamponade or iced saline lavage. These therapeutic interventions are still in the developmental stage, and to date there are no trials to document their efficacy and survival benefit.