Fadia Mayyas

Association of Left Atrial Endothelin-1 with Atrial Rhythm, Size and Fibrosis in Patients with Structural Heart Disease

Background—Atrial fibrillation (AF) promotes atrial remodeling and can develop secondary to heart failure or mitral valve disease. Cardiac endothelin-1 (ET-1) expression responds to wall stress and can promote myocyte hypertrophy and interstitial fibrosis. We tested the hypothesis that atrial ET-1 is elevated in AF and is associated with AF persistence. Methods and Results—Left atrial appendage tissue was studied from coronary artery bypass graft, valve repair, and/or Maze procedure in patients in sinus rhythm with no history of AF (SR, n=21), with history of AF but in SR at surgery (AF/SR, n=23), and in AF at surgery (AF/AF, n=32). The correlation of LA size with atrial protein and mRNA expression of ET-1 and ET-1 receptors (ETAR and ETBR)was evaluated. LA appendage ET-1 content was higher in AF/AF than in SR, but receptor levels were similar. Immunostaining revealed that ET-1 and its receptors were present both in atrial myocytes and in fibroblasts. ET-1 content was positively correlated with LA size, heart failure, AF persistence, and severity of mitral regurgitation. Multivariate analysis confirmed associations of ET-1 with AF, hypertension, and LA size. LA size was associated with ET-1 and MR severity. ET-1 mRNA levels were correlated with genes involved in cardiac dilatation, hypertrophy, and fibrosis. Conclusions—Elevated atrial ET-1 content is associated with increased LA size, AF rhythm, hypertension, and heart failure. ET-1 is associated with atrial dilatation, fibrosis, and hypertrophy and probably contributes to AF persistence. Interventions that reduce atrial ET-1 expression and/or block its receptors may slow AF progression.

Impact of aldosterone antagonists on the substrate for atrial fibrillation: Aldosterone promotes oxidative stress and atrial structural/electrical remodeling

Atrial fibrillation (AF), the most common cardiac arrhythmia, is an electrocardiographic description of a condition with multiple and complex underlying mechanisms. Oxidative stress is an important driver of structural remodeling that creates a substrate for AF. Oxidant radicals may promote increase of atrial oxidative damage, electrical and structural remodeling, and atrial inflammation. AF and other cardiovascular morbidities activate angiotensin (Ang-II)-dependent and independent cascades. A key component of the renin-angiotensin-aldosterone system (RAAS) is the mineralocorticoid aldosterone. Recent studies provide evidence of myocardial aldosterone synthesis. Aldosterone promotes cardiac oxidative stress, inflammation and structural/electrical remodeling via multiple mechanisms. In HF patients, aldosterone production is enhanced. In patients and in experimental HF and AF models, aldosterone receptor antagonists have favorable influences on cardiac remodeling and oxidative stress. Therapeutic approaches that seek to reduce AF burden by modulating the aldosterone system are likely beneficial but underutilized.

A Systematic Review of Oxymorphone in the Management of Chronic Pain

Opioids are recommended for control of moderate-to-severe, chronic, malignant, and nonmalignant pain. A controlled-release formulation of the opioid oxymorphone has recently been launched. The aim of this review was to assess the effectiveness of oxymorphone as an analgesic in chronic pain. A systematic search for published studies of oral oxymorphone in the management of chronic pain was conducted. The studies were evaluated for their internal validity according to standard criteria. They were also evaluated for their external validity and research ethic aspects. A meta-analysis was performed to examine the effect of oxymorphone compared with placebo. Nine studies were evaluated; three were excluded because of low quality. Six controlled studies (duration 2-12 weeks) included a total of 1489 subjects suffering from chronic low back pain, chronic pain from osteoarthritis, and chronic cancer pain. Three of the studies were of high quality and three of medium quality. External validity was assessed to be high, medium, and low (in one, three, and two studies, respectively). The meta-analysis suggests that daily doses of 40-100mg are superior to placebo; however, the estimate (reduction of pain intensity compared with placebo) of the treatment effect is imprecise (95% confidence interval -17.08, -8.69). Limited evidence suggests that oxymorphone is effective for pain control in patients with cancer. No significant differences between oxymorphone and oxycodone at equipotent doses were found. In conclusion, oxymorphone is superior to placebo. There is no evidence that the efficacy of oxymorphone differs from other opioids.

Level and significance of plasma myeloperoxidase and the neutrophil to lymphocyte ratio in patients with coronary artery disease

Inflammation plays a pivotal role in the etiology of coronary artery disease (CAD). Myeloperoxidase (MPO) is a potent inflammatory factor and a critical modulator of coronary inflammation and oxidative stress. The goal of this study was to determine the impact of the plasma MPO (pMPO) level and neutrophil/lymphocyte ratio on the clinical characteristics and outcomes of patients with CAD. Blood samples were collected from 210 patients with underlying chest pain or recent myocardial infarction (MI) prior to coronary angiography in order to measure pMPO levels. The pMPO levels and neutrophil/lymphocyte ratio were correlated with clinical characteristics and outcomes following catheterization. The pMPO level and neutrophil/lymphocyte ratio were higher in patients with recent MI than in patients with CAD (coronary occlusion ≥50%) or without CAD (coronary occlusion <50%). Patients with ST segment elevated MI (STEMI) had a higher neutrophil/lymphocyte ratio relative to patients with non-STEMI. The pMPO level was identified to correlate with the neutrophil/lymphocyte ratio and the need for coronary artery reperfusion by coronary artery bypass surgery or percutaneous coronary intervention. Patients who were taking aspirin had lower pMPO levels and neutrophil/lymphocyte ratio compared with those who were not taking aspirin. The plasma neutrophil/lymphocyte ratio was negatively associated with the left ventricular ejection fraction at baseline and the 30-day follow-up, whereas pMPO showed no correlation. Multivariate analysis indicated that the pMPO level was positively associated with MI, the neutrophil/lymphocyte ratio and coronary intervention. The preoperative use of aspirin was associated with a lower pMPO level and neutrophil/lymphocyte ratio. In conclusion, pMPO is positively associated with MI, the neutrophil/lymphocyte ratio and coronary intervention. The preoperative use of aspirin is associated with a lower pMPO level and neutrophil/lymphocyte ratio. pMPO may serve as a predictor of coronary intervention and as a potential therapeutic target for the reduction of inflammation in patients with CAD.

The significance of circulating endothelin-1 as a predictor of coronary artery disease status and clinical outcomes following coronary artery catheterization

BACKGROUND/OBJECTIVES Coronary artery disease (CAD) is responsible for significant morbidity and mortality. Inflammatory, pro-thrombotic and structural factors contribute to the etiology of CAD. This study sought to determine the relationship of plasma endothelin-1 (pET-1), a potent vasoconstrictor, mitogen and modulator of cardiac inflammation, to clinical characteristics and outcomes of CAD patients. METHODS Blood samples were collected from 336 patients with underlying chest pain or recent myocardial infarction (MI), prior to coronary catheterization. pET-1 was correlated with clinical characteristics and outcomes following catheterization and at 30-day follow-up. RESULTS pET-1 was higher in recent MI patients than in patients with CAD (coronary occlusion≥50%) or without CAD (<50%) (Mean±sem (pg/ml): 2.12±0.13, 1.51±0.10, 1.21±0.06; 95% confidence interval (1.85-2.38, 1.31-1.72, 1.07-1.32; respectively, P<.0001). Patients with ST elevation MI (STEMI) had higher pET-1 than non-STEMI (P=.008). pET-1 was associated with heart failure (HF) and low left ventricular ejection fraction (LVEF) and was highest in MI patients presented with acute HF. At 30-day follow up, pET-1 was not associated with the change in LVEF. In multivariate analysis, pET-1 was positively associated with age, smoking, HF, CAD status, and need for revascularization by coronary artery bypass surgery (CABG). pET-1 was negatively correlated with LVEF and preoperative statin use. CONCLUSIONS pET-1 is associated with recent MI, HF, age, smoking, CABG, and low LVEF. Preoperative statin use was associated with lower pET-1. pET-1 may serve as a risk marker and a potential therapeutic target in CAD patients.

An evaluation of the effect of pentoxifylline on blood pressure and myocardial oxidative status following intake of western diet

Abstract Background: Western diet (WD) has been known to promote cardiac oxidative stress in models of hypertension and obesity. Pentoxifylline (PTX) is a potent antioxidant. The impact of PTX and WD on cardiac oxidative status in healthy hearts is unclear. Aim: we aimed to determine the impact of WD and/or PTX on blood pressure and myocardial oxidative status in normal rat hearts. Method: Young adult Sprague Dawley rats were randomly assigned into four groups; conventional diet (control), WD, PTX, or simultaneous combination of WD + PTX for 10 weeks. Blood pressure, lipids levels, and cardiac levels of oxidants and antioxidants were measured. Result: WD was associated with an increase in triglyceride level and a mild increase in systolic blood pressure (SBP), whereas PTX reduced SBP. Relative to control, no changes were observed in levels of TNF alpha and glutathione (GSH) system, however, a significant decrease in thiobarbituric acid reactive substances (TBARS) level was observed in all groups with a parallel increase in catalase activities. Superoxide dismutase and catalase activities were increased in the PTX group. Relative to the WD group, the WD + PTX group was associated with a significant increase in the activities of GSH peroxidase and reductase. Conclusions: The decrease in TBARS levels and the increase in catalase activities suggest that normal hearts adapt compensatory mechanisms to prevent oxidative damage in response to the mild increase in SBP associated with WD. Use of PTX with WD further enhanced antioxidant activities probably to balance the potential increase in reactive oxygen species.

The role of multidrug resistance-1 (MDR1) variants in response to fexofenadine among Jordanians.

OBJECTIVE The MDR1 gene encodes for P-glycoprotein (P-gp), which is an efflux transporter at the cell membrane. The P-gp has wide substrate specificity for multiple medications, including the antiallergic drug fexofenadine. In this study, we investigated the possible association between three common MDR1 gene polymorphisms (G2677T, C3435T, and C1236T), and the anti-allergic effect of fexofenadine among Jordanians. MATERIALS AND METHODS An assessment of the severity of allergic rhinitis symptoms was performed for all patients (n = 260) pre- and 7 days into fexofenadine. MDR1 polymorphisms were genotyped using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). RESULTS Relative to baseline, fexofenadine treatment was associated with significant reduction in allergic individual and total scores (p < 0.0001). Male gender was associated with less mean reduction in total allergic rhinitis symptoms score than in female (p < 0.05). In multivariate analysis, male gender was negatively correlated with response to fexofenadine (p = 0.01). The MDR1 gene C1236T polymorphism showed significant correlation with changes in total symptoms score from baseline in males (p < 0.05) but not in females. No significant correlation between fexofenadine response parameters and G2677T or the C3435T polymorphism was observed. CONCLUSIONS The MDR1 gene polymorphism C1236T was associated with the anti-allergic effect of fexofenadine among male Jordanians.

Melatonin prevents memory impairment induced by high-fat diet: Role of oxidative stress

Consumption of high-fat diet (HFD) induces oxidative stress in the hippocampus that leads to memory impairment. Melatonin has antioxidant and neuroprotective effects. In this study, we hypothesized that chronic administration of melatonin can prevent memory impairment induced by consumption of HFD. Melatonin was administered to rats via oral gavage (100mg/kg/day) for 4 weeks. HFD was also instituted for the same duration. Behavioral studies were conducted to test spatial memory using the radial arm water maze. Additionally, oxidative stress biomarkers were assessed in the hippocampus. Results showed that HFD impaired both short- and long- term memory (P<0.05), while melatonin treatment prevented such effects. Furthermore, melatonin prevented HFD-induced reduction in levels of GSH, and ratio of GSH/GSSG, and increase in GSSG in the hippocampus. Melatonin also prevented reduction in the catalase activity in hippocampus of animals on HFD. In conclusion, HFD induced memory impairment and melatonin prevented this impairment probably by preventing alteration of oxidative stress in the hippocampus.

Impact of high fat/high salt diet on myocardial oxidative stress.

ABSTRACT Background: High fat high salt diet contributes to oxidative stress and cardiac diseases. Aims: To determine the impact of moderately high fat diet (HFD), high salt (HS) or their combination on blood pressure (Bp) and myocardial oxidants/antioxidants. Methods: Sprague Dawley rats were assigned into four groups; conventional diet (control, 5% fat, 0.5% NaCl), HFD (25% fat, 0.5% NaCl), HS (5% fat, 8% NaCl), or combined diet (HFD+HS) for 10 weeks. Bp and cardiac oxidants and antioxidants were measured. Result: HFD, HS, and their combination didn’t cause obesity or dyslipidemia. Both HS and combined diets resulted in an increase in the heart/body weight ratio accompanied by an increase in Bp. No changes were observed in levels of the glutathione (GSH) system or superoxide dismutase (SOD) activities. However, a significant decrease in TBARS levels was observed in the HFD and the combined diet with a parallel increase in catalase activity in all groups. Relative to HFD, the combined diet was associated with increases in GSH reductase/peroxidase and SOD activities. Conclusions: The lack of changes in the GSH system, the decrease in TBARS, and the increase in catalase activity suggest that normal hearts adapt compensatory mechanisms to prevent oxidative damage in response to HFD/and or HS.

Atorvastatin Reduces Plasma Inflammatory and Oxidant Biomarkers in Patients With Risk of Atherosclerotic Cardiovascular Disease

Background: Oxidative stress and inflammation are associated with endothelial injury and coronary artery disease. Inflammatory factors that promote oxidative damage include endothelin-1 (ET-1), myeloperoxidase (MPO), and C-reactive protein (CRP). Current guidelines recommend the use of statins in patients with risk of atherosclerotic cardiovascular disease (ASCVD). Aim: To assess the impact of atorvastatin on plasma inflammatory and oxidant biomarkers in patients with moderate to very high risk of ASCVD. Method: Two hundred ten patients presented to the cardiology clinic were included and stratified into low, moderate, high, and very high risk of ASCVD. Moderate- (20 mg/d) to high-intensity (40 mg/d) atorvastatin was prescribed. Plasma levels of lipids, ET-1, CRP, MPO, total nitrite, lipid peroxides (thiobarbituric acid reactive substances [TBARS]), and superoxide dismutase (SOD) activities were measured at baseline and 12 weeks after treatment. Result: Relative to low-risk patients, baseline plasma inflammatory markers of CRP, MPO, ET-1, and nitrite were higher in patients with very high risk of ASCVD, whereas plasma SOD was lower (all P < .05). Use of high and moderate atorvastatin therapy significantly reduced low-density lipoprotein and total cholesterol levels, as well as plasma levels of CRP, MPO, nitrite, and TBARS, and increased plasma SOD activity in patients with moderate to very high risk of ASCVD, independent of lipid-lowering effects. Conclusions: Key markers of oxidative stress/inflammation such as CRP, ET-1, total nitrite, and MPO are associated with an increased risk of ASCVD. Moderate- and high-intensity atorvastatin use reduces plasma oxidative stress and inflammation regardless of ASCVD risk and independent of its lipid-lowering effect.