Karina Gasbarrino

Circulating Chemerin Is Associated With Carotid Plaque Instability, Whereas Resistin Is Related to Cerebrovascular Symptomatology

Objective—The rupture of unstable carotid atherosclerotic plaques is one of the main causes of cerebrovascular ischemic events. There is need for circulating markers that can predict plaque instability and risk of stroke. Proinflammatory chemerin, leptin, and resistin, along with anti-inflammatory adiponectin, are adipokines with direct influence on vascular function. We investigated the association of circulating adipokines with carotid plaque instability and cerebrovascular symptomatology. Approach and Results—Neurologically symptomatic and asymptomatic patients (n=165) scheduled for carotid endarterectomy were recruited. Fasting blood samples were collected preoperatively; adiponectin and leptin levels were determined by radioimmunoassay; and chemerin and resistin levels were measured by enzyme-linked immunosorbent assays. The instability of plaque specimens was assessed using gold-standard histological classifications. Chemerin was significantly associated with plaque instability. The fully adjusted model, accounting for age, sex, body mass index, high-sensitivity C-reactive protein, type 2 diabetes mellitus, and circulating adiponectin, leptin, and resistin, yielded an odds ratio of 0.991 (95% confidence interval 0.985–0.998) for plaque instability per unit increase in chemerin. High leptin levels were significantly associated with presence of specific features of plaque instability. In subjects with type 2 diabetes mellitus, resistin levels were significantly elevated in symptomatic when compared with asymptomatic subjects (P=0.001) and increased the risk of cerebrovascular symptomatology (adjusted odds ratio 1.264, 95% confidence interval 1.004–1.594). Conclusions—Low chemerin and high resistin levels were associated with carotid disease severity, suggesting that these adipokines may act as potential markers for plaque instability and stroke risk. Future studies are needed to assess causation between circulating adipokines and plaque instability.

Circulating adiponectin levels in relation to carotid atherosclerotic plaque presence, ischemic stroke risk, and mortality: A systematic review and meta-analyses

BACKGROUND Low circulating levels of adiponectin, an anti-inflammatory and vasculoprotective adipokine, are associated with obesity, type 2 diabetes, and atherosclerotic disease. Presence of unstable plaques in the carotid artery is a known etiological factor causing ischemic strokes. Herein, we systematically reviewed the association between circulating adiponectin and progression of carotid atherosclerotic disease, particularly evaluating the occurrence of (1) carotid atherosclerotic plaques, (2) ischemic stroke, and (3) mortality in subjects who suffered a previous ischemic stroke. METHODS Medline, Embase, Biosis, Scopus, Web of Science, and Pubmed were searched for published studies and conference abstracts. The effect size and 95% confidence intervals (CIs) of the individual studies were pooled using fixed-effect or random-effect models. The quality of the eligible studies was evaluated using the Newcastle-Ottawa quality assessment scale. Sensitivity, subgroup, and meta-regression analyses were performed to address the impact of various risk factors on the association between adiponectin and ischemic stroke risk. RESULTS Twelve studies fulfilled the inclusion criteria for 3 independent meta-analyses. The association of increasing circulating adiponectin levels (5μg/mL-increment) with presence of carotid plaque was not conclusive (n=327; OR: 1.07; 95% CI: 0.85-1.35; 2 studies), whereas high adiponectin levels showed a significant 8% increase in risk of ischemic stroke (n=13,683; 7 studies), with a more sizable association observed among men compared to women. HDL was observed to have a marginal effect on the association between adiponectin and ischemic stroke, while other evaluated parameters were not found to be effect modifiers. A non-significant association of adiponectin with mortality was yielded (n=663; OR: 2.58; 95% CI: 0.69-9.62; 3 studies). Although no publication bias was evident, there was significant between-study heterogeneity in most analyses. CONCLUSION It appears that the direction of the relationship between adiponectin and carotid atherosclerotic plaque presence is dependent on the duration, severity, and nature of the underlying disease, while increased adiponectin levels were associated with an increase in risk for ischemic stroke. Lastly, the results from the mortality meta-analysis remain inconclusive. Future properly designed studies are necessary to further elucidate the role of adiponectin on atherosclerotic plaque development, and its related outcomes.

Mechanisms of radiation-induced sensorineural hearing loss and radioprotection

Patients that receive radiotherapy are at risk of late sensorineural hearing loss when the inner ear is included within the radiation field. Preclinical and human temporal bone studies have shown that there is differential damage to cochlear structures depending on the amount of dose delivered to the inner ear. In vitro studies have suggested that reactive oxygen species (ROS) are the main initial actors in radiation-induced damage. The interaction of ROS with different cellular components can result in different apoptotic pathways. Therefore, approaches to radioprotection are mainly aimed to reduce ROS production through antioxidants. This review summarizes recent research in the field that can improve the understanding and boost preventive efforts of this adverse effect.

Decreased Adiponectin-Mediated Signaling Through the AdipoR2 Pathway Is Associated With Carotid Plaque Instability

Background and Purpose— Adiponectin, the most abundantly secreted anti-inflammatory adipokine, protects against all stages of atherosclerotic plaque formation by acting on its receptors, AdipoR1 (adiponectin receptor 1) and AdipoR2 (adiponectin receptor 2). Through binding of AdipoR1, adiponectin leads to the activation of the AMPK (adenosine monophosphate–activated protein kinase) pathway, whereas stimulation of PPAR-&agr; (peroxisome proliferator–activated receptor-&agr;) is attributed to the binding of AdipoR2. However, the role of adiponectin and its receptors in plaque instability remains to be characterized. Thus, we aimed to investigate whether the adiponectin–AdipoR pathway is associated with carotid atherosclerotic plaque instability. Methods— The instability of plaque specimens obtained from patients who underwent a carotid endarterectomy (n=143) was assessed using gold standard histological classifications. Results— Using immunohistochemistry, we showed that adiponectin and AdipoR1/AdipoR2 are expressed in human carotid plaques and that their expression was localized most abundantly in areas of macrophage and foam cell accumulation. Unstable plaques expressed more adiponectin protein (Western blot, P<0.05) and less AdipoR2 mRNA (2.11-fold decrease, P<0.05) than stable plaques, whereas AdipoR1 expression remained similar between stable and unstable plaques. Beyond AdipoR1/AdipoR2 expression, a graded decrease in PPAR-&agr; protein levels was observed in relation to carotid plaque instability (P<0.001), whereas AMPK phosphorylation was increased (P<0.05). Our in vitro model of plaque instability, involving the induction of foam cells from human THP-1 (Tamm–Horsfall protein 1) macrophages treated with acetylated low-density lipoprotein, supported our in vivo conclusions. Conclusions— An overall abundance of adiponectin with a decrease in AdipoR2 expression and activity was observed in unstable plaques, suggesting that reduced signaling through the AdipoR2 pathway, and not through AdipoR1, may contribute to plaque instability.