Noyan Gokce

Iron Chelation Improves Endothelial Function in Patients With Coronary Artery Disease

Background—Some epidemiological studies have shown that increased iron stores are associated with increased cardiovascular events. Redox-active iron may contribute to lipid peroxidation, endothelial cell activation, and generation of reactive oxygen species (especially hydroxyl radical, via Fenton chemistry). Increased oxidative stress is associated with impaired action of endothelium-derived nitric oxide in patients with atherosclerosis. Methods and Results—To test the hypothesis that reducing vascular iron stores would reverse endothelial dysfunction, we examined the effects of the iron chelator deferoxamine (500 mg intra-arterially over 1 hour) on vasomotor function in forearm resistance vessels of patients with coronary artery disease by venous occlusion plethysmography. Patients with coronary artery disease had impaired endothelium-dependent vasodilation in response to methacholine compared with healthy control subjects (P <0.001). Deferoxamine infusion decreased serum iron levels (P <0.001). Deferoxamine improved the blood flow response to methacholine in patients with coronary artery disease (P <0.01 by 2-way repeated-measures ANOVA) but had no effect on the response to sodium nitroprusside. In normal volunteers, deferoxamine had no effect on the response to methacholine. The nitric oxide synthase inhibitor NG-monomethyl-l-arginine abolished augmentation of the methacholine response associated with deferoxamine. The hydroxyl radical scavenger mannitol had no effect on the methacholine response. Conclusions—Deferoxamine improved nitric oxide–mediated, endothelium-dependent vasodilation in patients with coronary artery disease. These results suggest that iron availability contributes to impaired nitric oxide action in atherosclerosis.

l-Arginine and Hypertension

Hypertension is a major healthcare problem afflicting nearly 50 million individuals in the United States. Despite its strong causal association with cardiovascular disease complications including myocardial infarction, heart failure, and stroke, the majority of patients with hypertension do not achieve optimal blood pressure control. The prevalence of hypertension is expected to increase with the aging population, growing obesity epidemic, and rising incidence of metabolic syndrome. Endothelial dysfunction and reduced nitric oxide (NO) bioactivity represent prominent pathophysiological abnormalities associated with hypertensive cardiovascular disease. Individuals with hypertension exhibit blunted epicardial and resistance vascular dilation to endothelium-derived nitric oxide (EDNO) agonists in the peripheral and coronary circulation that likely contributes to mechanisms of altered vascular tone in hypertension. The amino acid L-arginine serves as the principal substrate for vascular NO production. Numerous studies, though not uniformly, demonstrate a beneficial effect of acute and chronic L-arginine supplementation on EDNO production and endothelial function, and L-arginine has been shown to reduce systemic blood pressure in some forms of experimental hypertension. This brief review discusses the potential role of L-arginine in hypertension, and reviews possible mechanisms of L-arginine action including modulation of EDNO production, alteration of asymmetrical dimethylarginine (ADMA):L-arginine balance, and possible improvement of insulin sensitivity. In view of the rising prevalence of hypertension, randomized human clinical studies investigating the potential therapeutic role of L-arginine may be warranted.

Effects of Black Race on Forearm Resistance Vessel Function

Presentation, response to therapy, and clinical outcome in hypertension differ according to race, and these observations could relate to differences in microvascular function. We examined forearm microvascular function in age-matched black (n=56) and white subjects (n=62) using intra-arterial agonist infusion and venous occlusion plethysmography. In normotensive subjects (n=70; 34 black and 36 white normotensives), methacholine-, sodium nitroprusside-, and verapamil-induced vasodilation was equivalent in black and white subjects. In hypertensive subjects (n=48; 22 black and 26 white hypertensives), the vasodilator response to methacholine was markedly lower in black subjects compared with white subjects (P <0.001). The vasodilator responses to sodium nitroprusside and verapamil, however, were equivalent in black and white hypertensive subjects. Acute ascorbic acid infusion improved the methacholine response equally in black and white hypertensive patients, suggesting that a difference in a rapidly reversible form of oxidative stress does not explain these findings. Thus, the present study demonstrates important racial differences in vascular function and a marked impairment in endothelial vasomotor function in black patients with hypertension. Further studies will be required to elucidate the mechanisms and determine whether these insights will lead to more appropriately tailored management of hypertension and its complications.

Acute effects of vasoactive drug treatment on brachial artery reactivity

OBJECTIVESnThe goal of this study was to investigate whether concomitant therapy with vasoactive medications alters the results of noninvasive assessment of endothelial function.nnnBACKGROUNDnUltrasound assessment of brachial artery flow-mediated dilation is emerging as a useful clinical tool. The current practice of withholding cardiac medications before ultrasound studies has unknown utility and would limit the clinical use of the methodology.nnnMETHODSnTo determine whether a single dose of a vasoactive drug influences brachial reactivity, we examined flow-mediated dilation and nitroglycerin-mediated dilation in 73 healthy subjects (age 27 +/- 6 years). Studies were completed at baseline and 3 h after randomized treatment with a single oral dose of placebo, felodipine (5 mg), metoprolol (50 mg), or enalapril (10 mg). To determine if holding vasoactive therapy for 24 h before study yields different results than continuation of clinically prescribed medications, we examined vascular function in 72 patients (age 57 +/- 10 years) with coronary artery disease. Ultrasound studies were performed 24 h after the last dose and again 3 h after patients took their clinically prescribed medications.nnnRESULTSnIn healthy subjects one dose of all three drugs lowered blood pressure, and metoprolol also lowered heart rate. However, there was no significant effect of treatment on brachial artery dilation. In patients with coronary artery disease on chronic treatment, taking prescribed medications reduced blood pressure and heart rate, but had no significant effect on brachial artery dilation.nnnCONCLUSIONSnRecent administration of commonly used nonnitrate vasoactive drugs has no significant effect on brachial reactivity. These findings suggest that current practice of withholding cardiac medications before testing endothelial function may not be necessary, making this methodology more practical for clinical use.

Obesity and Cardiovascular Disease

Case study: A 43-year-old man with a long history of obesity presented to our Weight Management Center 5 years after being disabled in a motor vehicle accident and gaining weight to a lifetime high of 269 kg and body mass index (BMI) of 85 kg/m2. His comorbidities were hypertension, obstructive sleep apnea, gastroesophageal reflux disease, gout, and osteoarthritis, and he had recently developed type 2 diabetes mellitus. Medications used included metformin, glyburide, losartan, hydrochlorothiazide, and diltiazem. He was motivated and met criteria for weight loss via a surgical intervention. Preoperatively, he was placed on a high-protein diet plus an appetite suppressant (phentermine) to achieve 10% weight loss. His weight declined, but he developed new-onset atrial fibrillation 3 weeks later, which was thought to be related to phentermine use and was cardioverted back to sinus rhythm.nnSeveral months later, the patient underwent gastric bypass bariatric surgery with a preoperative weight of 252 kg. His type 2 diabetes mellitus resolved immediately after surgery, as did his gastroesophageal reflux and hypertension. Ten months after surgery, his weight was down to 177 kg (BMI=56 kg/m2) with hemoglobin A1c of 5.9%, fasting blood glucose of 82 mg/dL, and blood pressure of 137/82 mm Hg, and he was no longer taking any medication.nnAlthough there are multiple long-term deleterious health effects of excess weight, obesity as defined by BMI ≥30 kg/m2 is associated with premature atherosclerosis, increased risk of myocardial infarction and heart failure, and decreased survival, largely because of cardiovascular deaths, particularly in extreme weight categories.1,2 Factors that contribute to cardiovascular disease in obesity are multifactorial and include metabolic dysregulation with increased prevalence of atherogenic risk factors, including insulin resistance, hypertension, and dyslipidemia; adverse cardiac remodeling characterized by hypertrophy, chamber enlargement, and impaired ventricular systolic and diastolic function; …

The A2b Adenosine Receptor Modulates Glucose Homeostasis and Obesity

Background High fat diet and its induced changes in glucose homeostasis, inflammation and obesity continue to be an epidemic in developed countries. The A2b adenosine receptor (A2bAR) is known to regulate inflammation. We used a diet-induced obesity murine knockout model to investigate the role of this receptor in mediating metabolic homeostasis, and correlated our findings in obese patient samples. Methodology/Principal Findings Administration of high fat, high cholesterol diet (HFD) for sixteen weeks vastly upregulated the expression of the A2bAR in control mice, while A2bAR knockout (KO) mice under this diet developed greater obesity and hallmarks of type 2 diabetes (T2D), assessed by delayed glucose clearance and augmented insulin levels compared to matching control mice. We identified a novel link between the expression of A2bAR, insulin receptor substrate 2 (IRS-2), and insulin signaling, determined by Western blotting for IRS-2 and tissue Akt phosphorylation. The latter is impaired in tissues of A2bAR KO mice, along with a greater inflammatory state. Additional mechanisms involved include A2bAR regulation of SREBP-1 expression, a repressor of IRS-2. Importantly, pharmacological activation of the A2bAR by injection of the A2bAR ligand BAY 60-6583 for four weeks post HFD restores IRS-2 levels, and ameliorates T2D. Finally, in obese human subjects A2bAR expression correlates strongly with IRS-2 expression. Conclusions/Significance Our study identified the A2bAR as a significant regulator of HFD-induced hallmarks of T2D, thereby pointing to its therapeutic potential.

Basic Research in Antioxidant Inhibition of Steps in Atherogenesis

Oxidised low-density lipoprotein (LDL) contributes to atherogenesis by a number of mechanisms, and antioxidants may act as antiatherogens. LDL oxidation is inhibited by LDL-associated antioxidants, particularly α-tocopherol (vitamin E), and water-soluble antioxidants present in LDLs biologic milieu, especially ascorbate (vitamin C). In addition to protecting LDL against oxidation, antioxidants may act at the level of the vascular cell by limiting cellular production of reactive oxygen species, and, thus, cell-mediated LDL oxidation. Cellular antioxidants can also protect against vascular cell dysfunction that would otherwise promote atherogenesis, such as increased adhesion molecule expression and monocyte recruitment, impaired production or release of nitric oxide, or bothe, and the proliferation of smooth muscle cells. Some of these processes are regulated by nuclear factor-κB or related transcription factors, which are redox-sensitive and inhibited by antioxidants. Furthermore, cellular antioxidants can limit cytotoxic effects of oxidised LDL and other oxidant insults, inhibiting vascular cell necrosis and lesion progression. Finally, some antioxidants, in particular α-tocopherol, may affect atherogenesis by inhibiting platelet function and mural thrombosis, although this effect appears to be explained by the inhibition of protein kinase C independent of α-tocopherols antioxidant activity.

Clinical assessment of endothelial function- ready for prime time?

The vascular endothelium plays a critical role in the regulation of arterial function through the synthesis and elaboration of a number of antiatherogenic factors such as nitric oxide (NO). “Endothelial dysfunction” represents a pathophysiological state in which normal homeostatic properties of the vasculature are impaired or lost, thereby supporting a vasospastic, prothrombotic, and proinflammatory atherogenic milieu.1 Impaired arterial function is associated with multiple cardiac risk factors and is detectable early in the progression of atherosclerosis, thus making it an ideal target for primary preventive intervention. It is also fundamental to mechanisms of advanced disease playing a critical role in the pathophysiology of acute cardiovascular syndromes such as myocardial infarction and stroke. The concept that endothelial phenotype serves as an overall barometer of vascular health and may shape clinical disease has prompted significant interest in its clinical assessment.2,3nnArticle see p 371nnClinical measurement of endothelial function is challenging, owing to its heterogeneous functions, because no single test provides a comprehensive physiological thumbprint of the entire vascular tree. As such, most studies have focused primarily on the regulation of arterial tone as a means of assessing vasoreactivity through interrogation of NO-mediated, endothelium-dependent vasodilator responses to specific agonists such as acetylcholine or shear stress that normally provoke vasodilation. Paradoxical constriction or attenuated dilator responses develop in disease states, reflecting impaired vasomotor function and reduced NO bioactivity. Although such studies were initially performed in coronary arteries, the technique has migrated to the surrogate forearm circulation, which permits more practical studies that are noninvasive and repeatable.4nnA number of noninvasive techniques are now available for assessment of forearm vascular reactivity, and presently the most frequently used method involves flow-mediated dilation (FMD) of the brachial artery, using ultrasound imaging. In this method, brachial diameter is measured at baseline and after …

Endothelial Dysfunction and Coronary Risk Reduction

There is growing evidence that improvement of endothelial function has the potential to reduce cardiovascular ris. This article reviews the impact of coronary risk factors on endothelial function and the benefits of risk factor reduction. Recent studies indicate that chronic exercise may directly improve endothelial function, thus providing an additional explanation for the benefits of increased physical activity.

The Endothelium in Atherothrombosis

Located at the interface between the vessel wall and circulating blood, the vascular endothelium plays a critical role in the homeo-static and physiologic functions of the vasculature. In response to biochemical and mechanical stimuli, endothelial cells synthesize and elaborate a number of factors that modulate vascular tone, inflammation, thrombosis, and vascular growth. Normal endothelium provides a fluid antiatherogenic environment that inhibits platelet and leukocyte adhesion, prevents vasospasm, promotes fibrinolysis, and inhibits vascular smooth muscle cell growth. Under pathologic conditions when homeostatic mechanisms are altered, the phenotypic changes that occur in endothelial cells support a vasospastic, prothrombotic, and proinflammatory milieu, and play a central role in the pathophysiology and clinical manifestations of cardiovascular disease [1].