Near-infrared spectroscopy-based microcirculatory assessment in acute atrial fibrillation.

Near-infrared spectroscopy is a means of assessing microcirculatory function, but has not been studied in atrial fibrillation (AF). We evaluated the effect of acute AF on thenar eminence near-infrared spectroscopy-derived microcirculatory variables. Stable patients presenting to the emergency department with acute onset AF underwent dynamic near-infrared spectroscopy assessment with a three minute vascular occlusion test (VOT). This was repeated after cardioversion to sinus rhythm (SR). Each assessment included baseline tissue oxygen saturation (StO2), slope of StO2 decrease during VOT, slope of StO2 increase post VOT, minimum and maximum StO2, amplitude of StO2 response and post-ischaemic hyperperfusion. Pre and post cardioversion values were compared by Wilcoxon signed-rank test. Twelve participants (seven male, five female) with a median age of 63 years (interquartile range 52 to 70 years) were enrolled. Median baseline StO2 was 74% before and 77% after cardioversion (P=0.03). The median slope of StO2 decrease during VOT was -0.19%/second and -0.16%/second (P=0.018) and the median slope of StO2 increase post VOT was 3.03%/second and 2.56%/second (P=0.002), pre and post cardioversion, respectively. Minimum StO2 was lower (39% versus 52%, P=0.002) and the amplitude of StO2 response greater (49% versus 40%, P=0.005) in AF, but there was no significant difference in maximum StO2 or the degree of reperfusion hyperaemia. In summary, baseline and minimum StO2 were lower with a greater ischaemic decrease in StO2 during AF, reflecting reduced tissue perfusion, compared with sinus rhythm. Recovery after ischaemia was higher in AF, suggesting normalisation of capillary recruitment during ischaemia.

Prevalence of pulmonary arterial hypertension in an Australian scleroderma population: screening allows for earlier diagnosis.

BACKGROUND: We sought to determine the prevalence of pulmonary complications and especially pulmonary arterial hypertension (PAH) in an Australian scleroderma population. METHODS: Between July 2005 and June 2007, physicians in Western Australia were asked to refer patients with scleroderma specifically for pulmonary hypertension screening. All patients were assessed for PAH and other respiratory conditions using echocardiography, lung function testing and clinical assessments. Right heart catheterization was carried out in patients with evidence of increased right ventricular systolic pressure. RESULTS: Of the 184 patients analysed, 44 had possible PAH on echocardiography. Right heart catheterization confirmed the diagnosis in 24 (13%). Diffuse interstitial lung disease was found in 32 patients representing a point prevalence of 17.4%. The severity of PAH at diagnosis varied according to whether the patients were referred for screening (group A) or for diagnostic (group B) purposes. The 6-min-walk test distance and median pulmonary vascular resistance were significantly worse in group B versus group A (324 vs 402 m; P= 0.02 and 884 dynes/s per cm(-5) vs 486 dynes/s per cm(-5); P < 0.01, respectively). CONCLUSION: Screening may result in earlier diagnosis of PAH with, in general more mild disease. This is important, given that early treatment for PAH while patients are less symptomatic is associated with improved exercise tolerance and pulmonary haemodynamics: indices indicative of disease progression and clinical worsening.

Oxidized LDL and small LDL particle size are independently predictive of a selective defect in microcirculatory endothelial function in type 2 diabetes.

AIM: To explore the associations of LDL (low-density lipoprotein) particle size and oxidized LDL with endothelium-dependent function of the forearm microcirculation in diabetes. METHODS: Endothelium-dependent function was examined in 43 middle-aged men and women with type 2 diabetes and 10 age-matched controls. All received aspirin to inhibit endothelial cyclo-oxygenase. Forearm blood flow (FBF) was measured using venous occlusion plethysmography with separate administration of acetylcholine (ACh) and bradykinin (BK) into the brachial artery. Endothelium-independent function was assessed using sodium nitroprusside (SNP). N(G)-monomethyl-L-arginine (L-NMMA) was co-infused with ACh (ACh + L-NMMA) and BK (BK + L-NMMA) to assess non-NO-mediated contributions to endothelium-dependent function. RESULTS: Subjects with diabetes had impaired endothelium-dependent and endothelium-independent function compared with controls (p < 0.01 for ACh, BK and SNP). In multivariate regression analysis, LDL size (r = 0.41 and p = 0.007), oxidized LDL (r = -0.41 and p = 0.007) and duration of diabetes (r = -0.37 and p = 0.02) predicted FBF response to ACh independently of age, gender and systolic blood pressure. There were no associations between LDL size, oxidized LDL, duration of diabetes and FBF response to BK, SNP, ACh + L-NMMA or BK + L-NMMA. CONCLUSION: In type 2 diabetes, small dense LDL particles, duration of diabetes and oxidized LDL may independently contribute to endothelial dysfunction of the microcirculation. These disturbances may occur via a selective defect, because ACh and BK activate endothelial NO synthase via different G-protein signal transduction pathways.

The vestibular control of balance after stroke.

OBJECTIVES: To examine vestibular control of balance in those who recovered the ability to stand after middle cerebral artery (MCA) stroke. METHODS: Sixteen patients with MCA stroke were compared with 10 age matched controls. Two additional patients were studied with isolated corticospinal tract lesions, one each at the level of the pons and medulla. Vestibular evoked postural responses were obtained using galvanic vestibular stimulation (GVS) while patients stood with their eyes closed and head facing forwards, equally loading both legs. The GVS response was characterised by measuring the amplitude of the stimulus evoked lateral forces acting through each leg and the lateral displacement of the axial skeleton. RESULTS: Lateral displacement and net lateral force following GVS were significantly larger after stroke. Unlike controls, the lateral forces in the stroke group were asymmetrical, being enhanced on the side of the non-paretic limb and small on the side of the paretic limb. The degree of GVS evoked asymmetry correlated with corticospinal damage assessed using transcranial magnetic stimulation. A similar asymmetrical response was seen in the patient with the pontine lesion but not the patient with the medullary lesion. CONCLUSIONS: MCA stroke may disrupt corticobulbar projections to brainstem output pathways involved in vestibular control of balance. These projections are either collaterals of the corticospinal tract or lie close to that tract and terminate in the pons/upper medulla. This hypothesis accounts for the association between corticospinal tract damage and GVS response asymmetry, and the lack of GVS evoked asymmetry with corticospinal lesions below the rostral medulla.

Dissociation of visual and haptic vertical in two patients with vestibular nuclear lesions.

The somatosensory (haptic) vertical (HV) and visual vertical (VV) were assessed in two patients with vestibular nuclear lesions. Patient 1 had paroxysmal nystagmus, and was tested "on" and "off." The HV was normal "on" and "off" but the VV was severely tilted during vestibular paroxysms. Patient 2, with a brainstem stroke, was tested at months 1 and 6. The VV was severely tilted on both occasions (>12 degrees) but the HV was marginally tilted (4 degrees) in the acute stage only. These VV-HV dissociations suggest that vestibular nuclear lesions influence gravity perception mostly via ocular torsional effects rather than by disrupting a single, internal representation of verticality.

Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes.

OBJECTIVE: Our objective was to assess effects of dietary supplementation with coenzyme Q10 (CoQ) on blood pressure and glycaemic control in subjects with type 2 diabetes, and to consider oxidative stress as a potential mechanism for any effects. SUBJECTS AND DESIGN: Seventy-four subjects with uncomplicated type 2 diabetes and dyslipidaemia were involved in a randomised double blind placebo-controlled 2x2 factorial intervention. SETTING: The study was performed at the University of Western Australia, Department of Medicine at Royal Perth Hospital, Australia. INTERVENTIONS: Subjects were randomly assigned to receive an oral dose of 100 mg CoQ twice daily (200 mg/day), 200 mg fenofibrate each morning, both or neither for 12 weeks. MAIN OUTCOME MEASURES: We report an analysis and discussion of the effects of CoQ on blood pressure, on long-term glycaemic control measured by glycated haemoglobin (HbA(1c)), and on oxidative stress assessed by measurement of plasma F2-isoprostanes. RESULTS: Fenofibrate did not alter blood pressure, HbA(1c), or plasma F2-isoprostanes. There was a 3-fold increase in plasma CoQ concentration (3.4+/-0.3 micro mol/l, P<0.001) as a result of CoQ supplementation. The main effect of CoQ was to significantly decrease systolic (-6.1+/-2.6 mmHg, P=0.021) and diastolic (-2.9+/-1.4 mmHg, P=0.048) blood pressure and HbA(1c) (-0.37+/-0.17%, P=0.032). Plasma F2-isoprostane concentrations were not altered by CoQ (0.14+/-0.15 nmol/l, P=0.345). CONCLUSIONS: These results show that CoQ supplementation may improve blood pressure and long-term glycaemic control in subjects with type 2 diabetes, but these improvements were not associated with reduced oxidative stress, as assessed by F2-isoprostanes. SPONSORSHIP: This study was supported by a grant from the NH&MRC, Australia.

Intra-ureteric capsaicin in loin pain haematuria syndrome: efficacy and complications.

OBJECTIVE: To evaluate the safety and efficacy of intra-ureteric capsaicin for loin pain haematuria syndrome (LPHS). PATIENTS AND METHODS: In an open prospective pilot study, four middle-aged patients (three women and one man) with LPHS resistant to therapies such as splanchnic nerve block, psychological treatment or renal autotransplantation (one) were assessed. An intra-ureteric infusion of capsaicin (30 mg/100 mL of 30% alcohol in saline) for 30 min with bladder irrigation was administered under general anaesthesia, with a subsequent intravenous patient-controlled narcotic analgesic pump for pain control. Double-concentration capsaicin was used for second infusions, if necessary when the response to the earlier infusion was inadequate or incomplete. RESULTS: The first patient had experienced reduced pain levels for the first 3 months only, with no benefit from the subsequent treatments with higher doses of capsaicin (60 mg). The second patient with recurrent pain in an autotransplanted kidney had no benefit from either a 30 or 60 mg capsaicin infusion a month apart, but developed a fibrotic stricture at the transplant pelvi-ureteric junction, requiring pyelocystoplasty. The third patient with concurrent depression had no benefit from a 30-mg infusion of capsaicin. The fourth patient experienced no pain relief from a 30 mg infusion of capsaicin but developed proteinuria secondary to mesangial proliferative glomerulonephritis, ureteric inflammation needing stenting within 7 days of treatment and subsequently nephrectomy for a nonfunctioning kidney at 3 months. CONCLUSION: Intra-ureteric capsaicin was neither effective nor safe in LPHS; the contribution of the alcohol diluent cannot be excluded.

Cognitive dysfunction after isolated brain stem insult. An underdiagnosed cause of long term morbidity.

Cognitive dysfunction adversely influences long term outcome after cerebral insult, but the potential for brain stem lesions to produce cognitive as well as physical impairments is not widely recognised. This report describes a series of seven consecutive patients referred to a neurological rehabilitation unit with lesions limited to brain stem structures, all of whom were shown to exhibit deficits in at least one domain of cognition. The practical importance of recognising cognitive dysfunction in this group of patients, and the theoretical significance of the disruption of specific cognitive domains by lesions to distributed neural circuits, are discussed.

Coenzyme Q(10) improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus.

AIM/HYPOTHESIS: We assessed whether dietary supplementation with coenzyme Q(10) improves endothelial function of the brachial artery in patients with Type II (non-insulin-dependent) diabetes mellitus and dyslipidaemia. METHODS: A total of 40 patients with Type II diabetes and dyslipidaemia were randomized to receive 200 mg of coenzyme Q(10) or placebo orally for 12 weeks. Endothelium-dependent and independent function of the brachial artery was measured as flow-mediated dilatation and glyceryl-trinitrate-mediated dilatation, respectively. A computerized system was used to quantitate vessel diameter changes before and after intervention. Arterial function was compared with 18 non-diabetic subjects. Oxidative stress was assessed by measuring plasma F(2)-isoprostane concentrations, and plasma antioxidant status by oxygen radical absorbance capacity. RESULTS: The diabetic patients had impaired flow-mediated dilation [3.8 % (SEM 0.5) vs 6.4 % (SEM 1.0), p = 0.016], but preserved glyceryl-trinitrate-mediated dilation, of the brachial artery compared with non-diabetic subjects. Flow-mediated dilation of the brachial artery increased by 1.6 % (SEM 0.3) with coenzyme Q(10) and decreased by -0.4 % (SEM 0.5) with placebo (p = 0.005); there were no group differences in the changes in pre-stimulatory arterial diameter, post-ischaemic hyperaemia or glyceryl-trinitrate-mediated dilation response. Coenzyme Q(10) treatment resulted in a threefold increase in plasma coenzyme Q(10) (p < 0.001) but did not alter plasma F(2)-isoprostanes, oxygen radical absorbance capacity, lipid concentrations, glycaemic control or blood pressure. CONCLUSION/INTERPRETATION: Coenzyme Q(10) supplementation improves endothelial function of conduit arteries of the peripheral circulation in dyslipidaemic patients with Type II diabetes. The mechanism could involve increased endothelial release and/or activity of nitric oxide due to improvement in vascular oxidative stress, an effect that might not be reflected by changes in plasma F(2)-isoprostane concentrations.

Improved analysis of brachial artery ultrasound using a novel edge-detection software system.

Brachial artery ultrasound is commonly employed for noninvasive assessment of endothelial function. However, analysis is observer dependent and susceptible to errors. We describe studies on a computerized edge-detection and wall-tracking software program to allow more accurate and reproducible measurement. In study 1, three purpose-built Perspex phantom arteries, 3.00, 4.00, and 6.00 mm in diameter, were measured with the software. There was a mean bias of 11 microm (P < 0.001 at each level) between known and measured values; the mean resolving power of the software was estimated as 8.3 microm. In study 2, the mean intraobserver coefficient of variation of repeated measures of flow-mediated dilation (FMD) using the software (6.7%) was significantly lower than that for traditional manual measurements using the intima-lumen interfaces (24.8%, P < 0.05) and intima-media interfaces (32.5%, P < 0.05). In study 3, 24 healthy volunteers underwent repeat testing twice within 1 wk; the coefficients of variation for between-visit reproducibility of FMD and response to glyceryl trinitrate using the software were 14.7 and 17.6%, respectively. Assuming 80% power and an alpha of 0.05, eight subjects with matched controls would be required, in a parallel designed study, to detect an absolute 2.5% change in FMD. In summary, we have developed a semiautomated computerized vascular ultrasound analysis system that will improve the power of clinical intervention studies to detect small changes in arterial diameter.

Vascular function of the peripheral circulation in patients with nephrosis.

BACKGROUND: Nephrotic syndrome is associated with abnormal lipoprotein metabolism and increased risk of coronary heart disease. Endothelial dysfunction, an early phase of atherogenesis that manifests as impaired flow-mediated dilation (FMD) of the peripheral circulation, may link these associations. METHODS: We examined endothelial function of the brachial artery and forearm resistance arteries in 15 patients with nephrosis (NP), 15 patients with primary hyperlipidemia (HL) alone, and 15 normolipidemic, nonproteinuric subjects (NC) matched for age, sex, and weight. The NP and HL groups had similar serum cholesterol and triglyceride concentrations. Post-ischemic FMD (endothelium-dependent) and glyceryl trinitrate-mediated dilation (GTNMD; endothelium-independent) of the brachial artery were studied using ultrasonography and computerized edge detection software. Postischemic forearm blood flow was also measured using plethysmography. RESULTS: Postischemic FMD of the brachial artery was significantly lower in the NP and HL groups compared with NC group (mean +/- SE): NP 4.91 +/- 0.8%, HL 4.53 +/- 0.6%, NC 8.45 +/- 0.5% (P < 0.001). There were no significant differences among the groups in baseline diameter and GTNMD of the brachial artery, nor in maximal forearm blood flow and flow debt repayment of the forearm microcirculation. Significant differences in FMD among the groups were principally related to differences in serum low-density lipoprotein cholesterol. CONCLUSIONS: Patients with NP have abnormal endothelium-dependent but preserved endothelium-independent dilation of the brachial artery following an ischemic stimulus. Postischemic forearm microcirculatory function is unimpaired. Dyslipoproteinemia is probably the principal cause of endothelial dysfunction of conduit arteries in patients with NP and the basis for their increased risk of cardiovascular disease.

Mitral valve prolapse: time for a fresh look.

To what extent is prolapse of the mitral valve associated with mitral regurgitation and the risk of infective endocarditis, rupture of the chordae tendineae, and sudden death? Earlier studies used differing definitions and criteria, and reported prevalence of this deformity varied widely, especially between referral and general population studies. Advances in echocardiography have clarified the diagnosis, allowing classification of prolapse into subtypes associated with different degrees of risk and prognoses.

Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: an hypothesis.

Endothelial dysfunction in non-insulin dependent (Type 2) diabetes mellitus (NIDDM) has implications for the pathogenesis of the two major complications, macrovascular disease and microangiopathy. Endothelial dysfunction is a consequence of a disturbance in the L-arginine/nitric oxide pathway. Its occurrence in NIDDM is well supported by both in vitro and in vivo studies. NIDDM results in diverse abnormalities in lipoprotein metabolism, the most significant being hypertriglyceridaemia which is associated with increased plasma concentrations of small dense LDL and low levels of HDL. Dysglycaemia results in hyperoxidative stress and increased formation of advanced-glycosylation endproducts, both of which enhance the oxidative modification of lipoprotein particles. Based on extensive in vitro studies and on human data, we generate the hypothesis that the development of endothelial dysfunction in NIDDM is a consequence of the effect of dyslipoproteinaemia, in particular increased circulatory concentrations of modified small dense LDL and of hyperoxidative stress on the formation, action and disposal of nitric oxide, by diverse molecular mechanisms; HDL is proposed to have a protective effect on these processes through its enzymic antioxidant properties. The hypothesis proposed is simple, testable and consistent with wide sources of evidence. The practical implications of the hypothesis and the existing opportunities for the prevention and reversal of endothelial dysfunction in NIDDM are also reviewed and discussed.

Special article: non-invasive measurement of endothelial function.

1. Endothelial dysfunction, due to reductions in nitric oxide (NO) action, is an early feature of macrovascular disease. 2. Non-invasive measurement of endothelial function may be assessed by postischaemic dilation of forearm vessels, using plethysmography, or flow-mediated dilatation of the brachial artery, using ultrasound. 3. Brachial flow-mediated dilatation reflects NO release and/or action more than forearm hyperaemia. 4. These techniques have been used as surrogate measures of coronary endothelial function. 5. Methodological, physiological and clinical aspects of the techniques are discussed.

Low-density lipoprotein size, high-density lipoprotein concentration, and endothelial dysfunction in non-insulin-dependent diabetes.

We examined endothelial function (nitric-oxide mediated) in 29 men with diet-treated non-insulin-dependent (Type 2) diabetes mellitus (NIDDM) and 18 male age-matched controls. Forearm blood flow was measured by venous occlusive plethysmography during intra-arterial administration of acetylcholine (ACh, 7.5 and 15 microg min(-1)) and sodium nitroprusside (SNP, 3 and 10 microg min(-1)). LDL particle size was estimated by non-denaturing gel electrophoresis. Serum lipids, blood pressure, and glycated haemoglobin were also measured. LDL particle size was smaller (p = 0.048) in the diabetic patients than controls. In the diabetic patients, LDL particle size was a significant positive predictor (p = 0.01) of the area under the dose-response curve for ACh, after adjusting for age, HbA1c, systolic BP, and cholesterol (R2 0.20). In stepwise regression including serum lipid and lipoprotein concentrations and LDL particle size, decreased HDL cholesterol was the best predictor of an impaired vasodilatory response to ACh. Vasodilatory responses to sodium nitroprusside were not significantly correlated with LDL particle size or serum lipid and lipoprotein concentrations. We conclude that in men with NIDDM, small, dense LDL particle size is associated with abnormal endogenous release of nitric oxide. The contribution of small, dense LDL particles to the development of endothelial dysfunction and early diabetic vasculopathy may not, however, be as great as decreased HDL cholesterol.

Management of lipid disorders in the elderly.

Cardiovascular disease has been inseparable from aging in developed societies and, as a result, it is the commonest cause of mortality in elderly populations. Atherosclerosis is associated with the progressive vascular accumulation of cholesterol-laden lipoproteins, and is linearly associated with the plasma level of low density lipoprotein (LDL) cholesterol. Clinical trials in patients aged < 65 years have conclusively shown that treatment of hypercholesterolaemia decreases the incidence of cardiovascular events and total mortality. However, few conclusive data are available regarding the treatment of hypercholesterolaemia in elderly patients. Extrapolation from clinical trials suggests that lipid lowering treatment in well selected elderly patients is effective in preventing cardiovascular events and is an efficient use of healthcare resources. In addition to cholesterol, high triglyceride and low high-density lipoprotein levels appear to be significant predictors of coronary artery disease in elderly patients. We do not advocate the indiscriminate screening of healthy elderly patients who have no other cardiovascular risk factors, because the marginal overall benefits are probably small and the costs of widespread screening and treatment high. On the other hand, chronological age itself cannot be considered a barrier to the screening and treatment of patients who have a good quality of life but have other cardiovascular risk factors and/or definite cardiovascular disease. Subgroup analysis of major clinical trials suggests that the aims of treatment should be to lower the LDL cholesterol level to 3.2 mmol/L (125 mg/dl), or the total cholesterol level to 5.2 mmol/L (200 mg/dl). Occasionally, multiple drug therapy is required to achieve this target, but statins (HMG-CoA reductase inhibitors) are the most commonly used first-line agents. With aggressive lowering of plasma lipid levels in this way, a reduction in clinical events is paralleled by regression of atheroma detectable by angiography, and an improvement in endothelial function. Global reduction of risk factors in elderly patients should always be undertaken, including dietary therapy, weight reduction in viscerally obese patients, postmenopausal estrogen replacement, smoking cessation, treatment of hypertension and control of diabetes mellitus. A secondary cause of dyslipidaemia should also be sought. The role of antioxidants is still not clear, but they are probably of little benefit in elderly patients. With the widespread use of effective, well tolerated treatments for lipid disorders in younger patients, significant improvements have already been attained in the morbidity and mortality associated with coronary artery disease. Since the current life expectancy at age 65 years is nearly 20 years in most Western countries, secondary prevention may increase the quality of life and the independent lifespan, even if eventual mortality is not delayed.

A biphasic sequence of myelination in the developing optic nerve of the frog.

We have examined the sequence of myelination along the optic nerve of the frog Litoria (Hyla) moorei from early tadpole life to adulthood. Myelinated axons were counted in electron micrographs of transverse sections taken from behind the eye, at the optic foramen and the chiasm. In tadpoles, myelinated axon numbers were significantly higher at the foramen than at the other levels. By metamorphic climax, numbers had risen at all three levels but more so behind the eye and at the chiasm to become approximately equal along the nerve. After metamorphosis, there was a dramatic increase in myelinated axon numbers, but another pattern was seen; in frogs of 5 cm and 7 cm body length, counts were significantly higher at the chiasm than at the foramen and lowest behind the eye. Thereafter, myelinated axon numbers stabilized at the chiasm but increased behind the eye and at the foramen so that in the most mature stage for this species, 9 cm adults, counts were again similar at the three levels. In addition, total axon numbers, that is, myelinated plus unmyelinated, were assessed from electron micrographs and increased from approximately 8,500 in early tadpoles to 0.65 million in fully mature adults. The proportion of axons that were myelinated showed two peaks, one before and the other after metamorphosis. Measurements of axon diameters from electron micrographs suggested that there was a critical diameter for myelination of 0.3 microns before, and of 0.5 microns after metamorphosis. The data indicate that there is a biphasic sequence of myelination of optic axons, the first phase being pre-metamorphic and the second post-metamorphic. The first phase is initiated at the foramen, and then extends both towards the eye and chiasm and continues until metamorphic climax. During the second phase, myelination originates at the chiasm, spreads towards the eye, and is complete only in the most mature adults. The critical diameter for myelination is smaller in the first phase than in the second.