Hamidreza Saber

The potential role of heat shock protein 27 in cardiovascular disease.

Heat shock proteins (Hsps) comprise several families of proteins expressed by a number of cell types following exposure to stressful environmental conditions that include heat, free radicals, toxins and ischemia, and are particularly involved in the recognition and renaturation of mis-folded proteins. Heat shock protein-27 (Hsp27) is a member of the small Hsp (sHsp) family with a molecular weight of approximately 27 KDa. In addition to its chaperoning functions, Hsp27 also appears to be involved in a diverse range of cellular functions, promoting cell survival through effects on the apoptotic pathway and plays important roles in cytoskeleton dynamics, cell differentiation and embryogenesis. Over the past two decades there has been an increasing interest in the relationship between Hsp27 and cardiovascular disease. Hsp27 is thought to exert an important role in the atherosclerotic process. Serum Hsp27 concentrations appear to be a biomarker of myocardial ischemia. In this review, we will focus on the possible protective and immuno-modulatory roles of Hsp27 in atherogenesis with special emphasis on their changes following acute coronary events and their potential as diagnostic and therapeutic targets.

Association between metabolic syndrome, BMI, and serum vitamin D concentrations in rheumatoid arthritis

Rheumatoid arthritis (RA) is the most common autoimmune arthritis. The impact of chronic inflammation on atherosclerosis and insulin resistance has been observed in several autoimmune diseases. On the other hand, metabolic syndrome (MetS); a cluster of traditional risk factors for atherosclerosis and diabetes seems to be prevalent in RA patients. It is reasonable to think that protective factors against inflammation can protect patients against atherosclerosis and diabetes, too. Vitamin D (Vit D), a novel immunomodulator, is recently considered to play a protective role against cardiovascular diseases, insulin resistance, and obesity. This cross-sectional study was designed to evaluate the impact of serum Vit D on MetS and body mass index (BMI). One hundred twenty RA patients were enrolled. MetS was assessed according to Adult Treatment Panel III criteria. All patients with known confounders influencing Vit D serum levels were excluded. Serum value of 25-hydroxyvitamin D (25(OH)D) was measured using a commercial ELISA kit. Data were analyzed by SPSS software. A logistic regression analysis stated that prednisolone dosage [p = 0.028, β = 0.177, odds ratio (OR) = 1.194, confidence interval (CI, 1.09–1.32)], age [p = 0.002, β = 0.146, OR = 1.57, CI (1.05–1.27)] and Vit D serum levels [p = 0.049, β = −3.766, OR = 0.023, CI (0.001–0.978)] are all significant predictors of MetS occurrence in RA patients. It was shown that 25(OH)D is a protective factor against MetS. It was also shown that there is a negative correlation between BMI and 25(OH)D serum levels (P = 0.037, rs = −0.266). In summary, this study suggested that 25(OH)D plays a protective role against MetS in RA patients. However, this cross-sectional study did not permit a power calculation on the causal relationship between Vit D and metabolic syndrome. On the other hand, Vit D has a negative correlation with BMI in these patients.

Incidence, recurrence, and long-term survival of ischemic stroke subtypes: A population-based study in the Middle East

Background Incidence, risk factors, case fatality and survival rates of ischemic stroke subtypes are unknown in the Middle East due to the lack of community-based incidence stroke studies in this region. Aim To characterize ischemic stroke subtypes in a Middle Eastern population. Methods The Mashad Stroke Incidence Study is a community-based study that prospectively ascertained all cases of stroke among the 450,229 inhabitants of Mashhad, Iran between 2006 and 2007. We identified 512 cases of first-ever ischemic stroke [264 men (mean age 65.5 ± 14.4) and 248 women (mean age 64.14 ± 14.5)]. Subtypes of ischemic stroke were classified according to the TOAST criteria. Incidence rates were age standardized to the WHO and European populations. Results The proportion of stroke subtypes was distributed as follows: 14.1% large artery disease, 15% cardioembolic, 22.5% small artery disease, 43.9% undetermined and 4.5% other. The greatest overall incidence rates were attributed to undetermined infarction (49.97/100,000) followed by small artery disease (25.54/100,000). Prevalence of hypertension, diabetes and atrial fibrillation differed among ischemic stroke subtypes. Overall, there were 268 (52.34%) deaths and 73 (14.25%) recurrent strokes at five years after incident ischemic stroke, with the greatest risk of recurrence seen in the large artery disease (35.6%) and cardioembolic (35.5%) subgroups. Survival was similar in men and women for each stroke subtype. Conclusions We observed markedly greater incidence rates of ischemic stroke subtypes than in other countries within the Mashad Stroke Incidence Study after age standardization. Our findings should be considered when planning prevention and stroke care services in this region.

Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts

Background and Purpose— The associations of individual long-chain n-3 polyunsaturated fatty acids with incident ischemic stroke and its main subtypes are not well established. We aimed to investigate prospectively the relationship of circulating eicosapentaenoic acid, docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with risk of total ischemic, atherothrombotic, and cardioembolic stroke. Methods— We measured circulating phospholipid fatty acids at baseline in 3 separate US cohorts: CHS (Cardiovascular Health Study), NHS (Nurses’ Health Study), and HPFS (Health Professionals Follow-Up Study). Ischemic strokes were prospectively adjudicated and classified into atherothrombotic (large- and small-vessel infarctions) or cardioembolic by imaging studies and medical records. Risk according to fatty acid levels was assessed using Cox proportional hazards (CHS) or conditional logistic regression (NHS, HPFS) according to study design. Cohort findings were pooled using fixed-effects meta-analysis. Results— A total of 953 incident ischemic strokes were identified (408 atherothrombotic, 256 cardioembolic, and 289 undetermined subtypes) during median follow-up of 11.2 years (CHS) and 8.3 years (pooled, NHS and HPFS). After multivariable adjustment, lower risk of total ischemic stroke was seen with higher DPA (highest versus lowest quartiles; pooled hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.58–0.92) and DHA (HR, 0.80; 95% CI, 0.64–1.00) but not eicosapentaenoic acid (HR, 0.94; 95% CI, 0.77–1.19). DHA was associated with lower risk of atherothrombotic stroke (HR, 0.53; 95% CI, 0.34–0.83) and DPA with lower risk of cardioembolic stroke (HR, 0.58; 95% CI, 0.37–0.92). Findings in each individual cohort were consistent with pooled results. Conclusions— In 3 large US cohorts, higher circulating levels of DHA were inversely associated with incident atherothrombotic stroke and DPA with cardioembolic stroke. These novel findings suggest differential pathways of benefit for DHA, DPA, and eicosapentaenoic acid.

Serum Insulin-Like Growth Factor 1 and the Risk of Ischemic Stroke: The Framingham Study

Background and Purpose— Low insulin-like growth factor 1 (IGF-1) has been associated with increased risk of atherosclerosis and atrial fibrillation in cross-sectional studies. Yet, prospective data linking IGF-1 levels to the development of ischemic stroke remain inconclusive. We examined prospectively the association between serum IGF-1 levels and incident ischemic stroke. Methods— We measured serum IGF-1 levels in 757 elderly individuals (mean age 79±5, 62% women), free of prevalent stroke, from the Framingham original cohort participants at the 22nd examination cycle (1990–1994) and were followed up for the development of ischemic stroke. Cox models were used to relate IGF-1 levels to the risk for incident ischemic stroke, adjusted for potential confounders. Results— During a mean follow-up of 10.2 years, 99 individuals developed ischemic stroke. After adjustment for age, sex, and potential confounders, higher IGF-1 levels were associated with a lower risk of incident ischemic stroke, with subjects in the lowest quintile of IGF-1 levels having a 2.3-fold higher risk of incident ischemic stroke (95% confidence interval, 1.09–5.06; P=0.03) as compared with those in the top quintile. We observed an effect modification by diabetes mellitus and waist–hip ratio for the association between IGF-1 and ischemic stroke (P<0.1). In subgroup analyses, the effects were restricted to subjects with diabetics and those in top waist–hip ratio quartile, in whom each standard deviation increase in IGF-1 was associated with a 61% (hazard ratio, 0.39; 95% confidence interval, 0.20–0.78; P=0.007) and 41% (hazard ratio, 0.59; 95% confidence interval, 0.37–0.95; P=0.031) lower risk of incident ischemic stroke, respectively. Conclusions— IGF-1 levels were inversely associated with ischemic stroke, especially among persons with insulin resistance.

Serum Leptin Levels and the Risk of Stroke: The Framingham Study.

Background and Purpose— Leptin is a major adipokine that regulates weight balance and energy homeostasis. There is inconsistent evidence linking circulating leptin levels to risk of stroke. We tested the hypothesis that leptin levels are associated with risk of incident stroke in an elderly community based sample. Methods— Serum leptin levels were assayed in 757 stroke free individuals (mean age, 79 years; 62% women) from the Framingham Original Cohort at the 22nd examination cycle (1990–1994). Incidence of all -stroke and ischemic stroke were prospectively ascertained. Results— During a mean follow up of 10 years, 119 individuals developed stroke (99 ischemic strokes). In multivariable Cox regression models, log leptin levels were not associated with incidence of all -stroke or ischemic stroke (hazard ratios per SD increment in log leptin 0.90 [0.73–1.09] and 0.89 [0.72–1.11], respectively). The results were suggestive for potential effect modification by waist/hip ratio for the association between leptin and stroke (P=0.03). Adjusting for age, sex, and established stroke risk factors, analysis stratified by waist/hip ratio quartiles revealed a lower incidence of first-ever all-stroke and ischemic stroke associated with higher leptin levels among only subjects in the top waist/hip ratio quartile (hazard ratio, 0.64 [0.43, 0.95] versus 0.98 [0.77, 1.25] for incident all-stroke and 0.61 [0.39, 0.95] versus 0.96 [0.74, 1.26] for ischemic stroke). Conclusions— Leptin levels were not directly related to the risk of incident stroke overall but there was an inverse association with stroke in the top waist/hip ratio quartile. Further investigations are required to confirm these findings and explore possible mechanisms for the observed association.

Mechanical thrombectomy for acute ischemic stroke with occlusion of the M2 segment of the middle cerebral artery: a meta-analysis

Background Endovascular thrombectomy has demonstrated benefit for patients with acute ischemic stroke from proximal large vessel occlusion. However, limited evidence is available from recent randomized trials on the role of thrombectomy for M2 segment occlusions of the middle cerebral artery (MCA). Methods We conducted a systematic review and meta-analysis to investigate clinical and radiographic outcomes, rates of hemorrhagic complications, and mortality after M2 occlusion thrombectomy using modern devices, and compared these outcomes against patients with M1 occlusions. Recanalization was defined as Thrombolysis in Cerebral Infarction (TICI) 2b/3 or modified TICI 2b/3. Results A total of 12 studies with 1080 patients with M2 thrombectomy were included in our analysis. Functional independence (modified Rankin Scale 0–2) rate was 59% (95% CI 54% to 64%). Mortality and symptomatic intracranial hemorrhage rates were 16% (95% CI 11% to 23%) and 10% (95% CI 6% to 16%), respectively. Recanalization rates were 81% (95% CI 79% to 84%), and were equally comparable for stent-retriever versus aspiration (OR 1.05; 95% CI 0.91 to 1.21). Successful M2 recanalization was associated with greater rates of favorable outcome (OR 4.22; 95% CI 1.96 to 9.1) compared with poor M2 recanalization (TICI 0–2a). There was no significant difference in recanalization rates for M2 versus M1 thrombectomy (OR 1.05; 95% CI 0.77 to 1.42). Conclusions This meta-analysis suggests that mechanical thrombectomy for M2 occlusions that can be safely accessed is associated with high functional independence and recanalization rates, but may be associated with an increased risk of hemorrhage.

Determination of Prooxidant–Antioxidant Balance during Uncomplicated Pregnancy Using a Rapid Assay

Summary Background: Oxidative stress is thought to be a major contributor to complications during pregnancy, for example preeclampsia. However, reports regarding prooxidant-antioxidant balance in uncomplicated pregnancy are inconsistent. In this study, we aimed to compare the levels of oxidative stress in non-pregnant women with apparently normal pregnant women during the first trimester and at delivery. Methods: An assay for the determination of prooxidant-antioxidant balance (PAB) was used in this study, in which the prooxidant burden and the antioxidant capacity were measured simultaneously in a single assay. The levels of oxidative stress were determined in 85 non-pregnant and 64 primigravid pregnant women. Results: Demographic data and biochemical indices did not differ significantly between the groups. Differences between PAB values were significant based on one-way ANOVA analysis (P<0.001). Using a post hoc test, we observed a statistically significant increase in PAB values during the first trimester and last trimester (P<0.001). Conclusions: Normal pregnancy is associated with a change in the measure of redox status, as assessed by the PAB assay. Kratak sadržaj Uvod: Veruje se da oksidativni stres u velikoj meri doprinosi komplikacijama u toku trudnoće, kao što je na primer preek- lampsija. Međutim, izveštaji o ravnoteži između prooksidanasa i antioksidanasa u trudnoći bez komplikacija se razlikuju. U ovoj studiji, cilj nam je bio da uporedimo nivoe oksidativnog stresa kod žena koje nisu trudne sa ženama u naizgled normal- noj trudnoći tokom prvog tromesečja i na porođaju. Metode: U studiji je za određivanje ravnoteže prooksidansi/ antioksidansi (PAB) korišćen test u kom se istovremeno mere prooksidantni balast i antioksidantni kapacitet, u jednom testu. Nivoi oksidativnog stresa određeni su kod 85 žena koje nisu bile trudne i 64 trudnice u prvoj trudnoći. Rezultati: Demografski podaci i biohemijski indeksi nisu se značajno razlikovali između grupa. Analiza ANOVA ukazala je na značajne razlike između vrednosti PAB (P<0,001). Pomoću post hoc testa uočili smo statistički značajan po- rast vrednosti PAB u toku prvog i poslednjeg tromesečja (P<0,001). Zaključak: Normalna trudnoća povezana je s promenom u meri redoks statusa, utvrđenoj na osnovu PAB testa.

Increased Serum Heat Shock Protein 27 Antibody Titers and Prooxidant-Antioxidant Balance in Patients with Beta-Thalassemia Major

Objective: Determination of the serum heat shock protein 27 (Hsp27) antibody titers and prooxidant-antioxidant balance (PAB) in patients with thalassemia as markers of cell and oxidative stress, respectively. Methods: Serum PAB and anti-Hsp27 antibody titers were measured in 140 patients with thalassemia major and 140 sex- and age-matched healthy volunteers. Results: A significantly higher serum PAB value was observed in patients in comparison to controls. In the patient group, anti-Hsp27 antibody titers were significantly higher than for the control group (p < 0.001). We found a weak negative correlation between anti-Hsp27 antibody concentrations and the PAB (p = 0.03), but these values were not correlated with serum superoxide dismutase activity in the thalassemic patients. Conclusions: Increased levels of serum PAB and Hsp27 antibodies may be involved in the pathological consequences of β-thalassemia major and may contribute to the development of endothelial injury.

Network meta-analysis of patent foramen ovale management strategies in cryptogenic stroke

Objective To compare the outcomes of patent foramen ovale (PFO) closure vs antiplatelet agent (APA) vs oral anticoagulation therapy (OAT) for secondary prevention of stroke in patients with cryptogenic stroke, using direct and indirect evidence from existing randomized data. Methods Relevant randomized controlled trials were identified by a systematic review. The efficacy outcome was stroke recurrence, and safety outcomes were atrial fibrillation and bleeding complications at the end of follow-up. Bayesian network meta-analysis was performed to calculate risk estimates and the rank probabilities using APA therapy as the reference. Results In a network meta-analysis of 6 randomized controlled trials consisting of 3,497 patients (1,732 PFO closure, 1,252 APA, 513 OAT), PFO closure and OAT were associated with lower rates of recurrent stroke (odds ratio [OR] 0.30, 95% credibility interval [CrI] 0.17–0.49 and OR 0.42, 95% CrI 0.22–0.78, respectively) with equal efficacy of OR 0.70 (95% CrI 0.37–1.49). PFO closure had the highest top rank probability of atrial fibrillation and OAT had the highest risk of bleeding complications. Conclusions These findings suggest that closure and OAT may be equally effective in recurrent stroke prevention in patients with PFO. There is an increased risk of atrial fibrillation and bleeding with closure and OAT therapy, respectively. A randomized trial is needed to identify patients who would benefit most from each strategy.