Fructose and Uric Acid: Is There a Role in Endothelial Function?

Population level data support that consumption of fructose and fructose-based sweeteners has dramatically increased and suggest that high dietary intake of fructose is an important factor in the development of the cardiorenal metabolic syndrome (CRS). The CRS is a constellation of cardiac, kidney and metabolic disorders including insulin resistance, obesity, metabolic dyslipidemia, high blood pressure, and evidence of early cardiac and kidney disease. The consequences of fructose metabolism may result in intracellular ATP depletion, increased uric acid production, oxidative stress, inflammation, and increased lipogenesis, which are associated with endothelial dysfunction. Endothelial dysfunction is an early manifestation of vascular disease and a driver for the development of CRS. A better understanding of fructose overconsumption in the development of CRS may provide new insights into pathogenesis and future therapeutic strategies.     

Mechanisms of Disease: Is Mitochondrial Function Altered in Heart Failure?

The human heart sustains an exceptional energy transfer rate, consuming more energy per gram weight than any other organ system. The healthy heart can rapidly adapt to changes in demand, while the failing heart cannot. Cardiac energy flux systems falter in the failing heart. The purpose of this review is to characterize the fundamental role of mitochondria in this energy transfer system and describe our local research on mitochondrial respiratory capacity in failing human hearts.     

Is Endothelial Function of the Radial Artery Altered in Human Essential Hypertension?

There is controversy over whether endothelial function is impaired in human essential hypertension. All studies to date have used measurements of forearm blood flow by plethysmography to assess endothelium-dependent vasodilation and endothelial function. In contrast to these studies, which have focused on resistance vessels, we have determined what effects the endothelium has on underlying smooth muscle cells in conduit arteries by measuring arterial compliance of the radial arteries (change in diameter of radial artery over pressure for each arterial pulse). In 13 normotensive healthy subjects and 11 young patients with essential hypertension, arterial compliance of the radial artery was assessed directly with a new high-precision ultrasonic device (NIUS 02) after infusion of acetylcholine (endothelium-dependent response) or sodium nitroprusside (endothelium-independent response). Arterial compliance of the radial artery was similar at baseline and with increasing doses of acetylcholine and sodium nitroprusside in normotensive and in hypertensive subjects. The increase in arterial compliance from baseline at each individual concentration of acetylcholine and sodium nitroprusside was the same in both normotensive and hypertensive subjects. However, after a single oral dose of a combination of the angiotensin converting enzyme inhibitor spirapril and the calcium entry blocker isradipine, the increase in arterial compliance in response to the maximum dose of intraarterial acetylcholine was enhanced in normotensives (0.38 ± 1.23 to 0.76 ± 1.01 mm²/mm Hg × 10⁻³, P < .05), but not in hypertensives (+0.41 ± 1.26 to 0.36 ± 1.31 mm²/mm Hg × 10⁻³, not significant), and differed significantly between normotensive and hypertensive subjects (P < .05). Thus, pharmacologic stimulation disclosed a blunted response of endothelium-dependent action in the arterial compliance of the conduit arteries in hypertensive subjects. This suggests an impaired endothelial function reserve in persons with essential hypertension.     

Endothelial Function in Hypertension: Victim or Culprit?

Far from simply lining the inner surface of blood vessels, the cellular monolayer that comprises the endothelium is a highly active organ that regulates vascular tone. In health, the endothelium maintains the balance between opposing dilator and constrictor influences, while in disease, it is the common ground on which cardiovascular risk factors act to initiate the atherosclerotic process. As such, it is the site at which cardiovascular disease begins and consequently acts as a barometer of an individual's likely future cardiovascular health. The vascular endothelium is a very active organ responsible for the regulation of vascular tone through the effects of locally synthesized mediators, predominantly nitric oxide (NO), endothelial NO synthase (eNOS), and superoxide. NO is abundantly evident in normally functioning vasculature where it acts as a vasodilator, inhibits inflammation, and has an antiaggregant effect on platelets. Its depletion is both a sign and cause of endothelial dysfunction resulting from reduced activity of eNOS and amplified production of nicotinamide adenine dinucleotide oxidase, which, in turn, results in raised levels of reactive oxygen species. This cascade is the basis for reduced vascular compliance through an imbalanced regulation of tone with a predominance of vasoconstrictive elements. Further, structural changes in the microvasculature are a critical early step in the loss of normal function. This microvascular dysfunction is known to be highly predictive of future macrovascular events and is consequently a very attractive target for intervention in the hypertensive population in order to prevent cardiovascular events.     

Does Lipoprotein(a) Impair Endothelial Function?

Objectives. This study was undertaken to test the hypothesis that lipoprotein(a) [Lp(a)] impairs endothelial function.Background. Elevated Lp(a) plasma levels have been demonstrated to be associated with an increased risk of coronary heart disease. In atherosclerosis, endothelial dysfunction is known to be an early indicator of vascular changes. However, the effect of Lp(a) on nitric oxide (NO)-dependent vasodilator response has not yet been determined. We therefore examined the influence of Lp(a) on basal and stimulated NO-mediated vasodilator response in the forearm vascular bed.Methods. Strain gauge plethysmography was used to measure changes in forearm blood flow produced by intraarterial infusion of increasing doses of acetylcholine (3, 12, 24 and 48 μg/min), sodium nitroprusside (200, 800 and 3,200 ng/min) and N-monomethyl l-arginine (l-NMMA) (1, 2 and 4 μmol/min) in 57 white subjects (mean age ± SD 37 ± 14 years). Lp(a) plasma concentrations were determined by rocket immunoelectrophoresis.Results. Endothelium-dependent vasodilation tested by intraarterial acetylcholine and endothelium-independent vascular relaxation tested by intraarterial sodium nitroprusside were not correlated with Lp(a). Similarly, no significant differences in forearm blood flow changes were observed when patients were classified into tertiles according to their individual Lp(a) concentration. In contrast, changes in forearm blood flow after intraarterial l-NMMA indicating basal production and release of NO differed significantly among tertiles. Patients in the highest Lp(a) tertile (49.2 ± 20.3 mg/dl) had a much greater vasoconstrictive response to l-NMMA than patients in the lowest Lp(a) tertile (4.8 ± 2.5 mg/dl): 2 μmol/min of l-NMMA, −23.6 ± 22.5% vs. −10.4 ± 9.1% (p < 0.02); 4 μmol/min of l-NMMA, −27.8 ± 10.3% vs. −17.6 ± 9.9% (p < 0.03). Lp(a) plasma level consistently correlated negatively with the forearm blood flow responses to 4 μmol/min of intraarterial l-NMMA (r = −0.38, p < 0.01). Multiple stepwise regression analysis of variables, including total and high and low density lipoprotein cholesterol, further confirmed that plasma Lp(a) remained a significant independent determinant of forearm blood flow changes in response to l-NMMA (p < 0.02).Conclusions. The endothelium-dependent vasoconstrictive response to l-NMMA was enhanced in subjects with relatively high Lp(a) plasma levels, suggesting an increased basal production and release of NO. This response seemed to reflect a compensatory mechanism of the endothelium to yet unknown Lp(a)-induced atherosclerotic effects.     

Effects of Estrogen Level on the Function of Vascular Endothelial Cells and Expression of Vascular Cell Adhesion Molecule-1(?)

Objectives To ob-serve the effect of different estrogen levels on the secretory function of vascular endothelial cells of female rats, and study the effect of modulation of estrogen level on the expression of vascular cell adhesion molecule - 1 and the concentration of estrogen receptor in vascular endothelial cells. Methods Radioim-munology was used to measure the serum concentration of endothelin and PGI2, and copper - cadmium reduction was employed to measure the serum content of nitrogen monoxide. Radioligand binding and flowcy-tometry were used to measure the expression of estrogen receptor and vascular cell adhesion molecule (VCAM - 1) of vascular endothelial cells respectively. Results 1. The serum concentration of nitric oxide and PGI2 decreased when the ovaries of female rats were removed. In ovariectomized rats, given estrogen, the concentration rose ( P < 0. 05), but the plasma concentration of endothelin was adverse to it. 2. The concentration of estrogen receptor of vascular endothelial cel     

Is Glucagonoma of the Pancreas a Curable Disease?

Background. Glucagonomas are rare neuroendocrine tumors of the pancreas. Because of its rarity, its natural history is not well understood. Aim. We evaluated the natural history of glucagonomas treated at a teritary care cancer center. Methods. A retrospective analysis of 12 patients during 1970 to 2000 was performed. Six patients (50%) had a tumor located in the head of the pancreas. Results. Abdominal pain (83%) and weight loss (75%) were the most common symptoms. Median tumor size was 6 cm (range 0.04–10). Seven patients (58%) had liver metastases. Five patients (42%) underwent curative resection. Overall median survival was 66 mo, and 5-yr overall survival was 66%. Five-yr overall survival was 83% for patients who had resection versus 50% for the non-resected patients (p=0.04). Patients who were disease-free had a complete resection of the primary tumor and no liver involvement. Conclusions. Glucagonomas generally present with liver metastases at the time of diagnosis. Cure is only possible if the disease is localized and completely resected.     

Is Red Cell Sodium Transport a Function of Pressure?

Sodium ef flux from normal red cells was measured as a function of pressure to test whether abnormal sodium transport in hypertension is a direct consequence of the increased arterial pressure. Red cells were loaded with ²²Na and sodium efflux was measured at 37°C while the samples were in a bomb at constant pressures of 200 mmHg or 517 mmHg. Control samples were incubated concurrently at atmospheric pressure and the same temperature. The effect of preincubation of blood at 200 mmHg for 3.5 h on sodium efflux was also measured.

²²Na efflux and first order efflux rate constants were similar in high and normal pressure samples in each case. These findings suggest that acute changes in pressure have no effect on erythrocyte sodium efflux, which in turn implies that abnormal membrane transport in hypertension is not a consequence of the raised arterial pressure.     

Is Vascular Mortality Increased in Hypopituitarism?

Hitherto four relevant cohort studies have been published on the life expectancy of patients with hypopituitarism, two from the UK and two from Sweden. In all four studies patients with acromegaly or Cushing's disease were excluded, and patients with GH replacement were not included. A crude meta-analysis, not considering differences in validity of the study designs, gives an overall Relative Risk (RR) of 1.47, with a relatively small 95% confidence interval of 1.27–1.70. The aim of this critical review was to assess whether lacking validity in the design of one or several of these studies indicates that the true RR might be higher or lower than indicated by meta-analyses. A high frequency of cranial irradiation in one of the Swedish cohorts may explain part of the very high observed RR for cerebrovascular mortality, but there remained a 40% risk increase for cardiac diseases that cannot be explained by irradiation. Some other validity problems, especially seen in the UK studies, will result in under-estimation of the true RR, but for others the direction of bias is uncertain due to lacking information in the original publications. According to our view, it is more probable that the observed overall 50% risk increase for vascular mortality is an under-estimation than an over-estimation of the true RR. This analysis is of a qualitative nature, and it is not possible to quantify to what extent the lacking validity may have affected the RR.     

Is Gluten a Cause of Gastrointestinal Symptoms in People Without Celiac Disease?

The avoidance of wheat- and gluten-containing products is a worldwide phenomenon. While celiac disease is a well-established entity, the evidence base for gluten as a trigger of symptoms in patients without celiac disease (so-called ‘non-celiac gluten sensitivity’ or NCGS) is limited. The problems lie in the complexity of wheat and the ability of its carbohydrate as well as protein components to trigger gastrointestinal symptoms, the potentially false assumption that response to a gluten-free diet equates to an effect of gluten withdrawal, and diagnostic criteria for coeliac disease. Recent randomized controlled re-challenge trials have suggested that gluten may worsen gastrointestinal symptoms, but failed to confirm patients with self-perceived NCGS have specific gluten sensitivity. Furthermore, mechanisms by which gluten triggers symptoms have yet to be identified. This review discusses the most recent scientific evidence and our current understanding of NCGS.