The effect of per os colchicine administration in combination with fenofibrate and N-acetylcysteine on triglyceride levels and the development of atherosclerotic lesions in cholesterol-fed rabbits.

OBJECTIVE: Atherosclerosis is a chronic inflammatory disease promoted by pro-inflammatory cytokines produced by NOD-, LRR- and pyrin domain-containing protein 3 (NLRP 3) inflammasome. Colchicine is an anti-inflammatory agent that inhibits inflammasome's action and stabilizes atherosclerotic lesions. N-acetylcysteine (NAC) reduces low-density lipoprotein (LDL) oxidation, metalloproteinase levels, and foam cell count and volume. Fenofibrate also has antioxidant, anti-inflammatory, and anticoagulant properties while also having a beneficial effect on the vasomotor function of the endothelium. The purpose of this study is to investigate the effect of per os colchicine administration in combination with fenofibrate and NAC on triglyceride levels and the development of atherosclerotic lesions in cholesterol-fed rabbits. MATERIALS AND METHODS: Twenty-eight male, 2 months old New Zealand White rabbits were separated into four groups and were fed with different types of diet for 7 weeks: standard, cholesterol 1% w/w, cholesterol 1% w/w plus colchicine 2 mg/kg body weight plus 250 mg/kg body weight/day fenofibrate, and cholesterol 1% w/w plus colchicine 2 mg/kg body weight plus 15 mg/kg body weight/day NAC. Blood samples were drawn from all animals. Lipid profiles were assessed, and interleukin 6 (IL-6) measurements were performed using an enzyme-linked immunosorbent assay (ELISA) kit. Histologic examination was performed on aorta specimens stained with eosin and hematoxylin. Aortic intimal thickness was evaluated using image analysis. RESULTS: Colchicine administration in combination with fenofibrate or NAC statistically significantly reduced the extent of atherosclerotic lesions in aortic preparations. Co-administration of colchicine with NAC has a stronger anti-atherogenic effect than the colchicine plus fenofibrate regimen. Triglerycide levels were decreased in the colchicine plus fenofibrate group and the colchicine plus NAC group at the end of the experiment (p < 0.05), whereas the Cholesterol group had increased levels. A favorable significant lower concentration of IL-6 was detected in the colchicine plus NAC group vs. the other groups. CONCLUSIONS: In an experimental rabbit model, it appears that colchicine statistically significantly reduces the development of atherosclerosis of the aorta, especially in combination with NAC. Colchicine, as an NLRP3 inflammasome inhibitor, and NAC, as an agent that directly targets IL-6 signaling, can reduce the inflammatory risk. Fenofibrate enhances the attenuating role of colchicine on triglyceride levels. Clinical studies should investigate whether similar effects can be observed in humans.

Intravenous lipid emulsion as an antidote in clinical toxicology: a systematic review.

OBJECTIVE: Intravenous lipid emulsions (ILE) were developed many decades ago to supply nutritional requirements to patients unable to obtain adequate enteral nutrition. The utility of ILE was extended to therapeutics, facilitating the delivery of drugs. More recently, the potential for ILE to act as an antidote for inversion of drug toxicity has been recognized. This review aims to summarize the literature on ILE therapy as an antidote. Suggested mechanisms of action, safety profile, and recommendations on the administration of ILE in cases of drug intoxication are highlighted. MATERIALS AND METHODS: A complete literature survey was performed using the PubMed database search to collect available information regarding mechanisms of ILE action as an antidote, ILE administration for drug toxicity, and presentation of adverse events. RESULTS: A total of 102 studies met the selection criteria for inclusion in the review. Mainly used for local anesthetics toxicity, ILE therapy has been expanded in clinical toxicology involving overdose treatment of drugs other than local anesthetics. Partitioning in a lipid phase of fat droplets is a mechanism named the lipid sink phenomenon that has primarily been described to explain this action of ILE and remains the most widely accepted. At the same time, recent research has also revealed several molecular mechanisms that may contribute to ILE efficacy. CONCLUSIONS: ILE therapy comprises a recognized approach in clinical toxicology. Due to the lack of randomized clinical trials, recommendations on administration are based on animal studies and published cases. Thus, the constantly increased knowledge about ILE therapy supports the need for a detailed appraisal.

Changes in serum leptin levels as well as sICAM-1 and sVCAM-1 soluble adhesion molecules during carotid endarterectomy.

OBJECTIVE: Leptin is an adipokine, known to be associated with oxidative stress, inflammation, and atherogenesis. Leptin plays an essential role in atheromatosis-associated inflammatory cascade through stimulation of inflammatory mediators such as soluble intracellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1). However, little is known about this association in patients with atherosclerosis and severe internal carotid artery (ICA) stenosis undergoing carotid endarterectomy (CEA). Our objective was to evaluate the variations of serum leptin levels, as well as sICAM-1 and sVCAM-1 levels in these patients during the process of CEA and 24 hours postoperatively. PATIENTS AND METHODS: The study group enrolled 50 patients undergoing CEA for ICA stenosis (> 70%). Serum leptin, sICAM-1 and sVCAM-1 plasma concentration measurements were performed at 4 distinct time points: before clamping of the ICA, 30 minutes after clamping of the ICA, 60 minutes after declamping of ICA and 24 hours postoperatively. RESULTS: Leptin was significantly decreased during CEA, but an overshooting in its levels was observed at 24 hours after the operation. Both sICAM-1 and sVCAM-1 initially followed the pattern of leptin changes but after completing CEA and up to 24 hours postoperatively a steep increase in their levels was not established. sVCAM-1 and sICAM-1 correlated with indices of oxidative stress at peak inflammatory burden. CONCLUSIONS: Leptin is a circulating marker of carotid atherosclerosis. Oxidative stress and expression of sVCAM-1 and sICAM-1 on vascular endothelial cells are key features in the pathophysiological process of atherosclerosis.

Cardiac allograft vasculopathy after heart transplantation: current prevention and treatment strategies.

OBJECTIVE: Cardiac allograft vasculopathy (CAV) is a leading cause of mortality in heart transplantation patients. Despite optimal immunosuppression therapy, the rate of CAV post-transplantation remains high. In this review, we gathered all recent studies as well as experimental evidence focusing on the prevention and treatment strategies regarding CAV after heart transplantation. MATERIALS AND METHODS: A complete literature survey was performed using the PubMed database search to gather available information regarding prevention and treatment strategies of CAV after heart transplantation. RESULTS: Several non-immune and immune factors have been linked to CAV such as ischemic reperfusion injury, metabolic disorders, cytomegalovirus infection, coronary endothelial dysfunction, injury and inflammation respectively. Serial coronary angiography combined with intravascular ultrasound is currently the method of choice for detecting early disease. Biomarkers and noninvasive imaging can also assist in the early identification of CAV. Treatment strategies such as mammalian target of rapamycin inhibitors proceed to grow, but prevention remains the objective. CONCLUSIONS: Early detection is the key to therapy management. It enables early identification and diagnosis of patients with CAV, who would gain the most from prompt treatment. Further investigation is needed to elucidate the multifactorial pathophysiological process of CAV, develop detection methods and find treatments that prevent or slow disease progression.

Association of macronutrient consumption with arterial aging in adults without clinically overt cardiovascular disease: a 5-year prospective cohort study.

PURPOSE: There is limited and inconsistent evidence regarding longitudinal effects of macronutrients on blood pressure (BP) haemodynamics and arterial aging in populations without cardiovascular disease (CVD). We aimed to prospectively investigate potential association of dietary macronutrients with long-term changes in peripheral and central haemodynamics and arterial stiffness. METHODS: One hundred and fifteen subjects (46.7 ± 8.73 years, 70 women), free of clinically overt CVD were consecutively recruited. Dietary macronutrient intake was evaluated using 3-day food records at baseline. Aortic stiffness and arterial wave reflections were assessed at baseline and in one follow-up visit 5 years later by pulse wave velocity (PWV) and augmentation index (AI), respectively. RESULTS: Individuals with the highest consumption of saturated fatty acids (SFA) presented the highest rate of progression in PWV, AI and aortic diastolic BP (p < 0.05 for all) after adjustment for age, gender, smoking, body mass index, hyperlipidemia, insulin resistance, changes in systolic BP and treatment with antihypertensive and hypolipidemic drugs. After similar multivariable adjustments, high consumption of carbohydrates was associated with higher progression of AI, whereas high consumption of monounsaturated fatty acids (MUFA) and fibre with lower progression in aortic and peripheral systolic and diastolic BP (p < 0.05 for all). CONCLUSIONS: In subjects without CVD, high consumption of SFA is related to accelerated arterial stiffening, while high consumption of MUFA and fibre and low intake of carbohydrates is associated with attenuated progression in blood pressure and arterial wave reflections, respectively. These findings expand current knowledge on the association of macronutrient consumption with arterial aging in the general population.

The complex crosstalk between inflammatory cytokines and ventricular arrhythmias.

The network of cytokines consists one of the most extensively studied signaling systems of human body. Cytokines appear to modulate pathogenesis and progress of many different diseases in the human body, particularly in regards to cardiovascular system. However, their effects on the electrical system of the heart has been neglected. Over the past decade, attemps to understand this relationship led to the uncovering of the direct and indirect effects of cytokines on action potential propagation and cell depolarization. This relationship has been depicted in clinical practice as serum levels of cytokines are increasingly associated with prevalence of ventricular arrhythmias either isolated or secondary to either a heart condition or a systemic auto-immune disease. Thus, they present an appealing potential as a biomarker for prediction of arrhythmia generation, as well as the ourtcome of electrophysiological interventions.