Nateglinide and glibenclamide metabolic effects in naïve type 2 diabetic patients treated with metformin

Background and objective: Most antidiabetic agents target only one of several underlying causes of diabetes. The complementary actions of the glinides and the biguanides may give optimal glycemic control in patients with type 2 diabetes mellitus. The aim of the present study was to compare the effects of nateglinide plus metformin with glibenclamide plus metformin on glucose and lipid metabolism, and haemodynamic parameters in patients with type 2 diabetes mellitus. Methods: We enrolled 248 type 2 diabetic patients. Patients were randomly assigned to receive nateglinide (n = 124) or glibenclamide (n = 124), after 6 months of run‐in, in which we titrated nateglinide (starting dose 180 mg/day), glibenclamide (starting dose 7·5 mg/day), and metformin (starting dose 1500 mg/day). The final doses were (mean ± standard deviation), 300 ± 60, 12·5 ± 2·5, and 2500 ± 500 mg/day, respectively. We followed these patients for 1 year after titration. We assessed body mass index (BMI), fasting (FPG) and post‐prandial (PPG) plasma glucose, glycosylated haemoglobin (HbA_1c), fasting (FPI) and post‐prandial (PPI) plasma insulin, homeostasis model assessment (HOMA) index, and lipid profile [total cholesterol (TC), low density lipoprotein‐cholesterol (LDL‐C), high density lipoprotein‐cholesterol (HDL‐C), triglycerides (Tg), apolipoprotein A‐I (Apo A‐I), and apolipoprotein B (Apo B)], systolic blood pressure (SBP), and diastolic blood pressure (DBP). All variables were evaluated at baseline and after 3 and 6 months in the run‐in period, and at baseline, and after 3, 6, 9 and 12 months for both treatment groups. Results and discussion: Body mass index did not show any significant change during the study. We observed a significant improvement from baseline to 1 year on HbA_1c (P < 0·01 vs. baseline and vs. glibenclamide group, respectively), FPG (P < 0·01 vs. baseline), PPG (P < 0·01 vs. baseline), and on HOMA index (P < 0·05 vs. baseline) in the nateglinide group. In the glibenclamide group, we found significant changes in HbA_1c (P < 0·05 vs. baseline), FPG (P < 0·01 vs. baseline), PPG (P < 0·05 vs. baseline), and HOMA index (P < 0·05 vs. baseline). No significant change was observed in TC, LDL‐C, HDL‐C, Tg, Apo A‐I, Apo B, SBP, DBP and HR in either group after 3, 6, 9 and 12 months. These effects of nateglinide and glibenclamide on insulin‐resistance parameters are in agreement with previous reports. Contrarily to previous reports, we did not observe any significant BP change in patients treated with glibenclamide. Although both nateglinide and glibenclamide attenuated PPG and HOMA index, they did not have significant effects on lipid metabolism, as already shown in subjects with type 2 diabetes and good glycemic control. Conclusion: Nateglinide improved glycemic control better than glibenclamide in combination with metformin.     

WNK4 regulates airway Na+ transport: study of familial hyperkalaemia and hypertension

Background WNK [With No K (lysine)] kinases are essential for regulation of blood pressure and potassium homeostasis. WNK4 expression was recently found not only in the distal nephron but also in chloride‐transporting epithelia. To establish a physiological role for this distribution we studied patients with familial hyperkalaemia and hypertension (FHH), [pseudohypoaldosteronism type II (PHAII)], which is caused by mutations in WNK4. Design Measurement of nasal potential difference (NPD) and sweat electrolytes were performed in controls, in six subjects with FHH and ten subjects with cystic fibrosis (CF). Results Basal NPD was higher in FHH compared with controls (n = 20): 22·8 ± 5·7 vs. 16·2 ± 5·3 mV, respectively (P = 0·014). Maximal response to amiloride was also higher in FHH compared with controls: 14·8 ± 3·5 vs. 10·0 ± 4·8 mV, respectively (P = 0·03). In CF these values were 42·9 ± 9·3 and 29·9 ± 7·4 mV, respectively. The kinetics of the amiloride effect were faster in FHH, and as first reported here also in CF, compared with controls. At 30 s, amiloride‐inhibitable residual PD in FHH was 50 ± 30 vs. 81 ± 9% in controls (P = 0·0003) and 56 ± 7% in CF. The response to chloride‐free and isoproterenol solutions, which determines chloride transport activity, was similar in FHH compared with controls [16·0 ± 8·6 vs. 10·4 ± 5·9 mV (P = 0·08)]. Sweat conductivity in FHH was 49·7 ± 7·3 vs. 38·2 ± 8·1 mmol (NaCl eq) L^?1 in 16 controls (P = 0·007) and 94·0 ± 19·3 in CF. Conclusions Mutant WNK4 increases Na⁺ transport in airways, and therefore it is regulated by wild‐type WNK4. This may be caused by a regulation of ENaC or a K⁺ channel.     

Acute resistance exercise using free weights on aortic wave reflection characteristics

Aortic wave reflection characteristics such as the augmentation index (AIx), wasted left ventricular pressure energy (ΔE_w) and aortic haemodynamics, such as aortic systolic blood pressure (ASBP), strongly predict cardiovascular events. The effects of acute resistance exercise (ARE) using free‐weight exercises on these characteristics are unknown. Therefore, we sought to determine the effects of acute free‐weight resistance exercise on aortic wave reflection characteristics and aortic haemodynamics in resistance‐trained individuals. Fifteen young, healthy resistance‐trained (9 ± 3 years) individuals performed two randomized sessions consisting of an acute bout of free‐weight resistance exercise (ARE) or a quiet control (CON). The ARE consisted of three sets of 10 repetitions at 75% one repetition maximum for squat, bench press and deadlift. In CON, the participants rested in the supine position for 30 min. Measurements were made at baseline before sessions and 10 min after sessions. A two‐way ANOVA was used to compare the effects of condition across time. There were no significant interactions for aortic or brachial blood pressures. Compared to rest, there were significant increases in augmentation pressure (rest: 5·7 ± 3·0 mmHg; recovery: 10·4 ± 5·7 mmHg, P = 0·002), AIx (rest: 116·8 ± 4·2%; recovery: 123·2 ± 8·4%, P = 0·002), AIx normalized at 75 bpm (rest: 5·2 ± 7·6%; recovery: 27·3 ± 13·2%, P<0·0001), ΔE_w (rest: 1215 ± 674 dynes s cm^?2; recovery: 2096 ± 1182 dynes s cm^?2, P = 0·008), and there was a significant decrease in transit time of the reflected wave (rest: 150·7 ± 5·8 ms; recovery 145·5 ± 5·6 ms, P<0·001) during recovery from ARE compared to CON. These data suggest that ARE using free‐weight exercises may have no effect on aortic and brachial blood pressure but may significantly alter aortic wave reflection characteristics.     

Is arterial stiffening in Alström syndrome linked to the development of cardiomyopathy?

Background Alström syndrome (AS) is a rare autosomal recessive condition characterized by retinal degeneration, childhood obesity, and severe insulin resistance. Dilated cardiomyopathy of unknown aetiology is a well‐recognized and potentially lethal complication. The aim of this study was to investigate the relationship between vascular function, hyperinsulinaemia and cardiac performance in AS. Materials and methods Fifteen subjects with AS (mean age 21 years, range 10–35) were studied and compared with age‐, sex‐, and blood pressure‐matched healthy controls. Large artery stiffness and wave reflections were assessed in both groups by measuring aortic and brachial pulse wave velocity (PWV) (carotid‐femoral and carotid‐radial) and augmentation index (AIX) (Sphygmocor). In AS subjects, left ventricular function was assessed by echocardiography and metabolic parameters including fasting insulin, glucose, lipids and brain natriuretic peptide were also measured. Results Comparing AS subjects vs. controls (mean ± SD), AIX was elevated in AS subjects (18 ± 9% vs. 3 ± 11%, P < 0·0001). No significant changes in brachial PWV (8·1 ± 1·3 m s⁻¹ vs. 7·3 ± 1·1 m s⁻¹, P = 0·14) or aortic PWV (6·5 ± 1·1 m s⁻¹ vs. 6·0 ± 1·0 m s⁻¹, P = 0·26) were observed. AS subjects were hyperinsulinaemic and had disturbances in lipid profiles relative to controls. No correlations were observed between vascular, metabolic and echocardiographic parameters. Conclusions In AS there are alterations in the shape of the central arterial pressure waveform associated with augmented aortic systolic pressure and indicative of increased wave reflection. Unfavourable central arterial haemodynamics in AS may contribute to the development of cardiomyopathy but other aetiological factors are probably involved.     

Elevated VEGF-plasma levels in young patients with mild essential hypertension

Background Growing evidence shows that inflammation plays a pivotal role in the pathophysiology of essential hypertension (EH). Vascular endothelial cell growth factor (VEGF) is currently discussed as a possible mediator of inflammation. To investigate the hypothesis that VEGF plays a role as an inflammatory mediator in EH we performed the present pilot study of young patients in a very early stage of EH. Materials and methods 15 young patients with mild EH [33·8 ± 7·3 years, systolic blood pressure (SBP): 143·8 ± 10·5 mmHg, diastolic blood pressure (DBP): 88·2 ± 11·1 mmHg, mean arterial pressure (MAP) 106·6 ± 10·4 mmHg] and 15 healthy controls (31·7 ± 10·6 years) were examined. Blood was drawn from a peripheral vein and serum levels of VEGF, monocyte‐chemoattractant‐protein (MCP)‐1, high‐sensitivity C‐reactive protein (hsCRP), interleukin (IL)‐6, and tumour‐necrosis‐factor (TNF)‐α were measured via commercially available enzyme‐linked immunoassays. Results Hypertensives showed increased plasma levels of VEGF (P < 0·05) and MCP‐1 (P < 0·05). VEGF positively correlated with MAP (r = 0·46, P < 0·05) and MCP‐1 (r = 0·63, P < 0·01). Multivariate analysis demonstrated VEGF to be an independent predictor of MCP‐1 levels. Furthermore, hypertensives had higher levels of hsCRP (P < 0·01), IL‐6 (P < 0·001) and TNF‐α (P < 0·05). IL‐6 levels correlated with SBP (r = 0·59, P < 0·001), DBP (r = 0·67, P < 0·001) and MAP (r = 0·46, P < 0·001). A significant positive correlation was also found between hsCRP levels and SBP (r = 0·39, P < 0·05). Conclusions This pilot study demonstrates that in an early state of EH, inflammatory pathways have already been activated. Besides classical pro‐inflammatory cytokines, VEGF serum levels are significantly elevated. The positive correlation of VEGF with MCP‐1 is suggestive for the already described induction of MCP‐1 via VEGF.     

Impact of antiretroviral therapy on visfatin and retinol-binding protein 4 in HIV-infected subjects

Background To determine circulating levels of adipocytokines, especially the recently characterized visfatin, and the fat‐derived factor retinol‐binding protein‐4 (RBP‐4) in HIV‐infected subjects and their respective changes following treatment with highly active antiretroviral therapy (HAART). Materials and methods Fourteen HIV‐positive, HAART‐naïve subjects were compared with 10 HIV‐negative healthy controls and reassessed after a 1‐year treatment with HAART. Plasma visfatin and RBP‐4 were determined by ELISA, whereas leptin and adiponectin by RIA. Body composition was measured with dual X‐ray absorptiometry (DXA). Homeostasis model assessment (HOMA‐IR) was assessed using insulin and glucose levels. Results Visfatin and RBP‐4 levels in HIV‐positive subjects were comparable with those of HIV‐negative controls before treatment with HAART. Treatment with HAART for 12 months resulted in a 6·9‐fold and 7·1‐fold increase of visfatin and RBP‐4 levels (+54·0 ± 9·7 ng mL^?1, P < 0·0001 and +95·3 ± 31·7 ng mL^?1, P < 0·01), respectively. Leptin (?2·7 ± 1·6 ng mL^?1, P = 0·054) was unchanged and adiponectin (?2·8 ± 0·7 µg mL^?1, P < 0·01) decreased. Changes of visfatin concentrations correlated significantly with the increases of RBP‐4 (r = 0·78, P = 0·001), fat‐free mass (FFM, r = 0·75, P < 0·05) and change of HOMA‐IR (r = 0·64, P < 0·05). Parameters of glucose metabolism and body fat mass were unchanged during the observation period. Conclusions Treatment with HAART induced a pronounced increase of plasma visfatin and RBP‐4 as well as a decrease of adiponectin in HIV‐infected patients on HAART. Although body weight, fat mass and parameters of glucose metabolism remained stable, the changes in the adipocytokines might herald subsequent alterations of these parameters.     

Autonomic neuropathy precedes cardiovascular dysfunction in rats with diabetes

Background Our team previously demonstrated arterial stiffening and cardiac hypertrophy in type 2 diabetic rats at 8 but not 4 weeks after being administered streptozotocin (STZ) and nicotinamide (NA). The present study focused on investigating the effects of type 2 diabetes on cardiac autonomic nerve function in the STZ‐ and NA‐treated animals, using modern spectral estimation technique. Design An autoregressive process was performed to each detrended signal of heart rate and systolic blood pressure measured in the 4‐ and 8‐week STZ‐NA rats with anaesthesia. The power of low‐frequency and high‐frequency oscillations was automatically quantified with each spectral peak by computing the residuals. The closed‐loop baroreflex gain was estimated using the square root of the ratio between heart rate and systolic blood pressure powers in the low‐frequency band. Results Compared with the age‐matched controls, both the 4‐ and 8‐week STZ‐NA diabetic rats had significantly decreased low‐frequency oscillations of heart rate but not systolic blood pressure variability, showing a decline in baroreflex gain (0·451 ± 0·060 and 0·484 ± 0·056 vs. 1·196 ± 0·064 ms mmHg^?1, P < 0·05). On the other hand, the low frequency–high frequency power ratio of the heart period was also diminished in the two diabetic groups, indicating a shift in sympatho‐vagal balance of the heart control (0·472 ± 0·109 and 0·504 ± 0·090 vs. 1·857 ± 0·336, P < 0·05). Conclusions The cardiac autonomic dysfunction in the absence of any significant changes in vascular dynamics, 4 but not 8 weeks after induction of type 2 diabetes, suggests that the diabetic autonomic neuropathy may precede arterial stiffening and cardiac hypertrophy in the STZ‐ and NA‐treated rats.     

Ursodeoxycholic acid reduces lipid peroxidation and mucin secretagogue activity in gallbladder bile of patients with cholesterol gallstones

Background Recently it has been postulated that gallbladder mucin hypersecretion observed in the pathogenesis of cholesterol gallstone disease may be induced by biliary lipid peroxidation. Ursodeoxycholic acid treatment reduces mucin concentration and the formation of cholesterol crystals in the gallbladder bile of patients with cholesterol gallstones and this effect might be mediated by a decrease of biliary lipid peroxidation. Material and methods In a double‐blind, placebo‐controlled trial patients with symptomatic cholesterol gallstones received either ursodeoxycholic acid (750 mg daily) (n = 10) or placebo (n = 12) 10–12 days prior to cholecystectomy. As a marker for lipid peroxidation malondialdehyde was measured in bile together with mucin concentration. In addition, the mucin secretagogue activity of the individual bile samples was assessed in cultured dog gallbladder epithelial cells. Results Ursodeoxycholic acid therapy resulted in a significant reduction of lipid peroxidation in bile as determined by the biliary malondialdehyde concentration (1·36 ± 0·28 vs. 2·05 ± 0·38 µmol L^?1; P < 0·005) and the malondialdehyde (µmol L^?1)/total bile acid (mmol L^?1) ratio (0·02 ± 0·005 vs. 0·06 ± 0·01; P < 0·001). Furthermore, a decrease in mucin concentrations (0·7 ± 0·3 vs. 1·3 ± 0·5 mg mL^?1; P < 0·005) and of the mucin secretagogue activity of gallbladder bile (0·9 ± 0·2 vs. 2·2 ± 0·3 times control; P < 0·001) was observed. Conclusions The reduction of lipid peroxidation and mucin secretagogue activity of gallbladder bile induced by ursodeoxycholic acid treatment may contribute to the beneficial effects of this drug on gallbladder bile composition and symptoms in cholesterol gallstone patients.     

Middle cerebral artery blood flow velocity in response to lower body positive pressure

Lower body positive pressure (LBPP) has been used in the treatment of haemorrhagic shock and in offsetting g‐force induced fluid shifts. However, the middle cerebral artery blood flow velocity (MCAv) response to supine LBPP is unknown. Fifteen healthy volunteers (mean ± SD: age, 26 ± 5 year; body mass, 79 ± 10 kg; height, 174 ± 9 cm) completed 5 minutes of 20 and 40 mm Hg LBPP, in a randomized order, separated by 5 minutes rest (baseline). Beat‐to‐beat MCAv and blood pressure, partial pressure of end‐tidal carbon dioxide (P_ETCO₂) and heart rate were recorded and presented as the change from the preceding baseline. All measures were similar between baseline periods (all P>0·30). Mean arterial pressure (MAP) increased by 7 ± 6 (8 ± 7%) and 13 ± 7 mm Hg (19 ± 11%) from baseline during 20 and 40 mm Hg (P<0·01), respectively. The greater MAP increase at 40 mm Hg (P<0·01 versus 20 mm Hg) was mediated via a greater increase in total peripheral resistance (P<0·01), with heart rate, cardiac output (Model flow) and P_ETCO₂ remaining unchanged (all P>0·05) throughout. MCAv increased from baseline by 3 ± 4 cm s^?1 (5 ± 5%) during 20 mm Hg (P = 0·003), whilst no change (P = 0·18) was observed during 40 mm Hg. Our results indicate a divergent response, in that 20 mm Hg LBPP‐induced modest increases in both MCAv and MAP, yet no change in MCAv was observed at the higher LBPP of 40 mm Hg despite a further increase in MAP.     

Ovariectomy increases vascular calcification via the OPG/RANKL cytokine signalling pathway

Background Observational studies suggest a strong relationship between menopause and vascular calcification. Receptor activator of nuclear factor‐κΒ ligand (RANKL) and osteoprotegerin (OPG) are critical regulators of bone remodelling and modulate vascular calcification. We assessed the hypothesis that ovariectomy increases vascular calcification via the OPG/RANKL axis. Materials and methods Age‐matched sexually mature rabbits were randomized to ovariectomy (OVX, n = 12) or sham procedure (SHAM, n = 12). One month post‐procedure, atherosclerosis was induced by 15 months 0·2%‐cholesterol diet and endothelial balloon denudations (at months 1 and 3). Aortic atherosclerosis was assessed in vivo by magnetic resonance imaging (MRI) at months 9 and 15. At sacrifice, aortas were harvested for ex vivo microcomputed tomography (µCT) and molecular analysis of the vascular tissue. Results Vascular calcification density and calcific particle number were significantly greater in OVX than SHAM (8·4 ± 2·8 vs. 1·9 ± 0·6 mg cm^?3, P = 0·042, and 94 ± 26 vs. 33 ± 7 particles cm^?3, P = 0·046, respectively). Calcification morphology, as assessed by the arc angle subtended by the largest calcific particle, showed no difference between groups (OVX 33 ± 7° vs. SHAM 33 ± 5°, P = 0·99). By Western blot analysis, OVX increased the vascular OPG:RANKL ratio by 66%, P = 0·029, primarily by decreasing RANKL (P = 0·019). At month 9, MRI demonstrated no difference in atheroma volume between OVX and SHAM, and no significant change was seen by the end of the study. Conclusions In contrast to bone, vascular OPG:RANKL ratio increased in response to ovariectomy with a corresponding fourfold increase in arterial calcification. This diametrical organ‐specific response may explain the comorbid association of osteoporosis with calcifying atherosclerosis in post‐menopausal women.     

High-density lipoprotein cholesterol, C-reactive protein, and prevalence and severity of coronary artery disease in 5641 consecutive patients undergoing coronary angiography

Background Although high‐density lipoprotein cholesterol (HDL‐C) and C‐reactive protein (CRP) are well‐established predictors for future cardiovascular events, little information is available regarding their correlation with the prevalence and severity of angiographically evaluated coronary artery disease (CAD). Material and methods Five thousand six hundred forty‐one consecutive patients undergoing coronary angiography for the evaluation of CAD were analysed. Cardiovascular risk factors were assessed by routine blood chemistry and questionnaire. CAD severity was graded by visual estimation of lumen diameter stenosis with significant stenoses defined as lumen diameter reduction of ≥ 70%. Coronary angiograms were graded as one‐, two‐ or three‐vessel disease, as nonsignificant CAD (lumen irregularities < 70%) or non‐CAD. Results HDL‐C (60·3 ± 18·5 vs. 51·9 ± 15·3 mg dL^?1; P < 0·001) was higher and CRP was lower (0·65 ± 1·68 vs. 1·02 ± 2·38 mg dL^?1; P < 0·001) in non‐CAD (n = 1517) compared to overall CAD patients (n = 4124). CAD patients were older (65·2 ± 10·5 years vs. 59·9 ± 11·4 years), more often diabetics (19·2% vs. 10·6%) and hypertensives (79·2% vs. 66·0%) and included more smokers (18·8% vs. 16·5%) (all P < 0·005). Low‐density lipoprotein cholesterol (124·5 ± 38·3 vs. 126·0 ± 36·3 mg dL^?1; P = NS) was similar in overall CAD and non‐CAD patients with more statin users (43·4% vs. 27·9%; P < 0·001) among CAD patients. Comparing non‐CAD with different CAD severities using analysis of variance, results did not change substantially. In a multivariate analysis, HDL‐C and CRP remained independently associated with the prevalence of CAD. In addition, HDL‐C is also a potent predictor for the severity of CAD. Conclusions In this large consecutive patient cohort, HDL‐C and CRP are independently associated with the prevalence of CAD. In this analysis, HDL‐C is an even stronger predictor for CAD than some other major classical risk factors.     

Effect of set configuration on hemodynamics and cardiac autonomic modulation after high‐intensity squat exercise

The aim of this study was to compare the effect of two different high‐intensity resistance exercise (RE) set configurations on the following: systolic blood pressure (SBP), rate pressure product (RPP), heart rate (HR) variability (HRV), and HR complexity (HRC). Ten well‐trained males performed three parallel squat sets until failure (traditional training; TT) with the four repetitions maximum load (4RM), and a rest of 3 min between sets. Thereafter, participants performed a cluster training session (CT) of equated load but with resting time distributed between each repetition. Dependent variables were recorded before, during, and after RE. Mean SBP (25·7 versus 10·9% percentage increase; P = 0·016) and RPP (112·5 versus 69·9%; P = 0·01) were significantly higher in TT. The decrease in HRV after exercise and the drop of HRC during exercise were similar in CT and TT. Change of standard deviation of normal RR intervals after TT correlated with change in SBP (r = 0·803; P = 0·009) while the change of Sample Entropy during exercise correlated with the increment of RPP during CT (ρ = ?0·667; P = 0·05). This study suggests that set configuration influences acute cardiovascular responses during RE. When intensity, volume and work‐to‐rest ratio are equated, CT is less demanding in terms of SBP and RPP. A greater hemodynamic response during exercise would be associated with a faster parasympathetic recovery.     

Lipid peroxidation and mucin secretagogue activity in bile of gallstone patients

Background Chronic inflammation of the gallbladder wall and mucin hypersecretion are considered to be important factors in the pathogenesis of cholesterol gallstone disease. The aim of the study was to compare mucin concentration and mucin secretagogue activity with lipid peroxidation in gallbladder bile of patients with cholesterol or pigment stones. Material and methods We studied mucin concentration and, as a marker of lipid peroxidation, malondialdehyde concentration in 11 rapid (1 to 3 days) and eight non‐nucleating (> 21 days) gallbladder biles of patients with cholesterol or pigment stones. Furthermore, the mucin secretagogue activity of rapid and non‐nucleating gallbladder biles, as well as 1–5 µmol L⁻¹ malondialdehyde on cultured gallbladder epithelial cells, was determined. Results Our data show an increased malondialdehyde (7·2 ± 1·8 vs. 3·8 ± 0·5 µmol L⁻¹, P = 0·01) and mucin concentration (0·9 ± 0·09 vs. 0·41 ± 0·03 mg mL⁻¹, P = 0·01) and an increased mucin secretagogue activity (2·0 ± 0·5 vs. 1·1 ± 0·3 mucin secretion/control, P = 0·04) and cholesterol saturation index (1·2 ± 0·1 vs. 08 ± 0·1, P = 0·04) in rapid as compared to non‐nucleating gallbladder biles. Malondialdehyde stimulated mucin secretion of cultured gallbladder epithelial cells in a concentration dependent manner. Conclusions Our results support a promoting effect of gallbladder mucin hypersecretion by lipid peroxidation leading to rapid formation of cholesterol crystals in gallbladder bile. These findings suggest that besides hypersecretion of cholesterol in bile, chronic inflammation of the gallbladder wall is implicated in the pathogenesis of cholesterol gallstone disease.     

Cardiac troponin I and ventricular arrhythmia in patients with chronic heart failure

Background Both detectable serum cardiac troponin I (cTnI) and ventricular dysrhythmias are common in patients with chronic heart failure (CHF) and are paralleled with the severity of the CHF. However, the relationship between serum cTnI and ventricular arrhythmia severity in patients with CHF remains unknown; the mechanism of the ventricular arrhythmia in the CHF patients also remains unclear. Materials and methods The study group included 218 patients with CHF who had cTnI assay drawn at the time of initial presentation. Patients with acute myocardial infarction or myocarditis were excluded from the analysis. The patients were divided into two groups: cTnI‐positive with serum cTnI > 0·5 ng mL^?1 (n = 98) and cTnI‐negative with serum cTnI ≤ 0·5 ng mL^?1 (n = 120). The severity of ventricular dysrhythmias was assessed by 24‐h Holter monitoring, using prospectively defined measures of ventricular arrhythmic burden. Results Prevalence of risk factors for ventricular dysrhythmias was equal in both groups. All measures of ventricular ectopy were much higher in patients of the cTnI‐positive groups. Mean hourly ventricular pairs (13·59 ± 10·3 vs. 11·1 ± 6·01, P = 0·027), mean hourly repetitive ventricular beats (26·01 ± 13·67 vs. 22·01 ± 13·56, P = 0·032), and the frequency of ventricular tachycardia episodes per 24 h (12·54 ± 16·68 vs. 7·68 ± 11·54, P = 0·012) were higher in patients with detectable cTnI levels. After inclusion of clinical variables and drug therapies in a multivariate analysis, the positive relationship between cTnI and the frequency of ventricular pairs (P = 0·03), repetitive ventricular beats (P = 0·037), and ventricular tachycardia (P = 0·03) remained independent. In multivariate logistic regression, the risk of developing ventricular tachycardia was higher in patients with detectable cTnI levels with an adjusted odds ratio (OR) of 2·31 (95% CI, 1·22–2·65, P = 0·003). Conclusions In patients with CHF, serum cTnI is closely related to increased occurrence of ventricular dysrhythmias and could identify a subgroup of patients with ventricular tachycardia. The minimal myocardial injury detected by serum cTnI might be the abnormal substrate for ventricular dysrhythmias.     

Glucagon-like peptide-1 reduces the pulsatile component of testosterone secretion in healthy males

Background Glucagon‐like‐peptide‐1 (7–36) amide (GLP‐1), a potent regulator of glucose homeostasis, has been implicated in the control of hypothalamic‐pituitary function. In vivo it is a relevant neuroendocrine modulator of gonadotropin‐releasing hormone release, suggesting its possible role as a metabolic signal to the reproductive system. The present study was undertaken to establish its effect on luteinizing hormone (LH) and testosterone secretion in nine healthy male volunteers. Materials and methods Each subject underwent an oral glucose tolerance test to establish LH, testosterone, and GLP‐1 responses to glucose. Euglycaemic clamp experiments (6 h) were performed on two occasions with saline or with a constant infusion of GLP‐1 (0·4 pmol kg^?1 min ^?1). Blood samples were drawn at 10‐min intervals to measure the pulsatile pattern of LH and testosterone secretion. Results Ingestion of oral glucose resulted in a reduction in plasma testosterone levels at 30 min compared with baseline (P < 0·004) despite unaltered LH levels (P = 0·5). Constant GLP‐1 infusion resulted in no change in LH (P = 0·83), testosterone (P = 0·96), follicle stimulating hormone (FSH) (P = 0·86) and leptin levels (P = 0·3). Pulse analysis revealed no significant difference in the number (P = 0·1) or median absolute amplitude (P = 0·3) of the LH pulses. However, there was a significant decrease in the number (3·0 ± 0·6 vs. 1·3 ± 0·4; P < 0·05) and a tendency for increased duration of testosterone pulses (97·4  16·7 vs. 170  27·1 min; P = 0·06). Conclusion Oral glucose ingestion and intravenous GLP‐1 infusion reduce the pulsatile component of testosterone secretion by a mechanism independent of LH release.     

Effect of polymerized-type I collagen in knee osteoarthritis. II. In vivo study

Background Polymerized‐Type I Collagen (Polymerized‐Collagen) is an anti‐inflammatory and a tissue regenerator biodrug. The aim of the study was to evaluate the efficacy and safety of intra‐articular injections of Polymerized‐Collagen in patients with knee osteoarthritis (OA). Methods and design Patients (n = 53) were treated with 12 intra‐articular injections of 2 mL of Polymerized‐Collagen (n = 27) or 2 mL of placebo (n = 26) during 6 months. Follow up period was 6 months. The primary endpoints included Western Ontario and McMaster University Osteoarthritis Index, Lequesne index, and pain intensity on a visual analogue scale (VAS). Secondary outcomes were patient global score, investigator global score and drug evaluation. Clinical improvement was determined if the decrease in pain exceeds 20 mm on a VAS and patients achieved at least 20% of improvement from baseline. Urinary levels of C‐terminal crosslinking telopeptide of collagen type II (CTXII) and serum high‐sensitivity C‐reactive protein (hsCRP) were determined by enzyme immunoassays. Statistical analysis was performed by intention to treat. Results Polymerized‐Collagen was safe and well tolerated. Patients had a statistically significant improvement (P < 0·05) from baseline vs. Polymerized‐Collagen and vs. placebo at 6 months in: Lequesne Index (13·1 ± 0·5 vs. 7·1 ± 0·7 vs. 9·6 ± 0·8; P = 0·027), WOMAC (9·0 ± 0·5 vs. 4·0 ± 0·6 vs. 5·80 ± 0·8; P = 0·032), patient VAS (60·0 ± 2·6 vs. 20·6 ± 2·4 vs. 36·1 ± 4·5; P = 0·003), physician VAS (49·8 ± 1·9 vs. 16·8 ± 2·9 vs. 29·8 ± 2·9; P = 0·002), patient global score (1·08 ± 0·1 vs. 2·7 ± 0·1 vs. 1·9 ± 0·2; P = 0·028) and analgesic usage (30·1 ± 9·4 vs. 11·0 ± 3·4 vs. 17·9 ± 4·9; P = 0·001). This improvement was persistent during the follow up. A threefold increase in CTXII was determined in placebo group. No differences were found on hs CRP and incidence of adverse events between groups. Conclusion Polymerized‐Collagen is safe and effective in the treatment of knee OA.     

Radial pressure waveform dP/dt max is a poor indicator of left ventricular systolic function

Background The first derivative of left ventricular (LV) pressure over time (dP/dt max) is a marker of LV systolic function that can be assessed during cardiac catheterization and echocardiography. Radial artery dP/dt max has been proposed as a possible marker of LV systolic function and we sought to test this hypothesis. Materials and methods We compared simultaneously recorded radial dP/dt max (by high‐fidelity tonometry) with LV dP/dt max (by high‐fidelity catheter and echocardiography parameters analogous to LV dP/dt max). In study 1, beat‐to‐beat radial dP/dt max and LV dP/dt max were recorded at rest and during supine exercise in 12 males (aged 61 ± 12 years) undergoing cardiac catheterization. In study 2, 2D‐echocardiography and radial dP/dt max were recorded in 54 patients (separate to study 1; 39 men; aged 64 ± 10 years) at baseline and peak dobutamine‐induced stress. Three basal septum measures were taken as being analogous to LV dP/dt max: 1. Peak systolic strain rate; 2. Strain rate (SR‐dP/dt max) during isovolumic contraction (IVCT) and; 3. Tissue velocity during IVCT. Results In study 1 there was a significant difference between resting LV dP/dt max (1461 ± 383 mmHg s⁻¹) and radial dP/dt max (1182 ± 319 mmHg s⁻¹; P < 0·001), and a poor, but statistically significant, correlation between the variables (R² = 0·006; P < 0·05). Similar results were observed during exercise. In study 2 there were weak (R² = −0·12; P = 0·01) to non‐significant associations between radial dP/dt max and all echocardiographic measures analogous to LV dP/dt max at rest or peak stress. Conclusion Radial pressure waveform dP/dt max is not a reliable marker of LV systolic function.     

Gait performance in relation to aortic pulse wave velocity,carotid artery elasticity and peripheral perfusion in healthy older adults

Arterial stiffening is a widely known physiological change that occurs with ageing, but the functional consequences of vascular ageing are unclear. The purpose of this study was to determine whether carotid–femoral pulse wave velocity (PWV), mechanical properties of the carotid and femoral arteries and/or peripheral perfusion was associated with gait performance measured using a 400‐m walk test. Twenty‐one healthy older (68 ± 5 years) adults without cardiovascular disease participated in this study. Applanation tonometry was used to measure PWV, and Doppler ultrasound was used to measure arterial wall properties of the left common carotid and common femoral artery along with femoral blood flow. The median walk distance in the first 2 min of the test was 585 ft, and the overall gait speed was 1·5 m s^?1. Gait performance was inversely correlated with PWV (distance: r = ‐0·51; speed: r = ?0·48; P<0·05) and carotid artery stiffness index β (distance: r = ?0·56; speed: r =  ? 0·51; P<0·05) after adjustment for age, body mass index, waist circumference and systolic blood pressure. No significant correlations were found between gait performance and femoral artery stiffness index β or femoral artery blood flow. These results found higher central arterial stiffness, as assessed by segmental arterial stiffness or local arterial wall properties, is associated with lower gait performance in older adults independent of other confounders.     

Functional near‐infrared spectroscopy to probe sensorimotor region activation during electrical stimulation‐evoked movement

This study used non‐invasive functional near‐infrared spectroscopy (fNIRS) neuroimaging to monitor bilateral sensorimotor region activation during unilateral voluntary (VOL) and neuromuscular electrical stimulation (NMES)‐evoked movements. Methods. In eight healthy male volunteers, fNIRS was used to measure relative changes in oxyhaemoglobin (O₂Hb) and deoxyhaemoglobin (HHb) concentrations from a cortical sensorimotor region of interest in the left (LH) and right (RH) hemispheres during NMES‐evoked and VOL wrist extension movements of the right arm. Results. NMES‐evoked movements induced significantly greater activation (increase in O₂Hb and concomitant decrease in HHb) in the contralateral LH than in the ipsilateral RH (O₂Hb: 0·44 ± 0·16 μM and 0·25 ± 0·22 μM, P = 0·017; HHb: ?0·19 ± 0·10 μM and ?0·12 ± 0·09 μM, P = 0·036, respectively) as did VOL movements (0·51 ± 0·24 μΜ and 0·34 ± 0·21 μM, P = 0·031; HHb: ?0·18 ± 0·07 μΜ and ?0·12 ± 0·04 μΜ, P = 0·05, respectively). There was no significant difference between conditions for O₂Hb (P = 0·144) and HHb (P = 0·958). Conclusion. fNIRS neuroimaging enables quantification of bilateral sensorimotor regional activation profiles during voluntary and NMES‐evoked wrist extension movements.     

Impaired aortic elastic properties in patients with systemic sarcoidosis

Background Systemic sarcoidosis (Sar) is a granulomatous disorder involving multiple organs. Widespread vascular involvement and microangiopathy are common in patients with Sar. In addition, subclinical cardiac involvement is increasingly recognized in patients with Sar. However, data on the effect of Sar on the elastic properties of the arteries and myocardial performance are limited. In this study we looked for differences in aortic distensibility (AoD) which is an index of aortic elasticity, and myocardial performance of the ventricles, between patients with Sar and healthy subjects. In addition, we examined potential associations between AoD and clinical, respiratory and echocardiographic findings in patients with Sar. Materials and methods A total of 83 consecutive patients (26 male/57 female, mean age 51·1 ± 13·3 years) with Sar, without cardiac symptoms, were included. All patients underwent echocardiographic and respiratory evaluation including lung function tests. Additionally, 83 age‐ and sex‐matched healthy subjects served as controls. AoD was determined non‐invasively by ultrasonography. Results AoD was lower in the Sar compared to the control group (2·29 ± 0·26 vs. 2·45 ± 0·20 ·10^?6 cm²· dyn^?1, P < 0·01), while left ventricular mass (LVM) was higher in the Sar group (221·3 ± 50·2 vs. 195·6 ± 31·3 g, P = 0·007). Furthermore, myocardial performance of both ventricles was impaired in the Sar group. Multivariate linear regression analysis in the total sample population demonstrated a significant and independent inverse relationship between AoD and the presence of Sar (P < 0·001). The same analysis in the Sar patients showed that AoD was associated significantly and independently with the stage of Sar, age, systolic blood pressure, LVM and myocardial performance of both ventricles. No significant relationship was found between AoD and disease duration, pulmonary artery pressure or lung function tests. Conclusions Presence and severity of Sar are associated with reduced aortic distensibility, irrespective of the disease duration, pulmonary artery pressure and lung function. In addition, patients with Sar have increased LVM and impaired myocardial performance.