Near normalisation of blood glucose improves the potentiating effect of GLP-1 on glucose-induced insulin secretion in patients with type 2 diabetes

Aims/hypothesis The ability of glucagon-like peptide-1 (GLP-1) to enhance beta cell responsiveness to i.v. glucose is impaired in patients with type 2 diabetes mellitus compared with healthy individuals. We investigated whether 4 weeks of near normalisation of blood glucose (BG) improves the potentiation of glucose-stimulated insulin secretion by GLP-1. Methods Nine obese patients with type 2 diabetes and inadequate glycaemic control (HbA_1c 8.0 ± 0.4%) were investigated before and after 4 weeks of near normalisation of BG using insulin treatment (mean diurnal blood glucose 6.4 ± 0.3 mmol/l, HbA_1c 6.6 ± 0.3%). Nine matched healthy participants were also studied. Beta cell function was investigated before and after insulin treatment using stepwise glucose infusions and infusion of saline or GLP-1 (1.0 pmol kg⁻¹ min⁻¹), resulting in supraphysiological total GLP-1 concentrations of approximately 200 pmol/l. The responsiveness to glucose or glucose+GLP-1 was expressed as the slope of the linear regression line relating insulin secretion rate (ISR) and plasma glucose concentration (pmol kg⁻¹ min⁻¹ [mmol/l]⁻¹). Results In the diabetic participants, the slopes during glucose+saline infusion did not differ before and after insulin treatment (0.33 ± 0.07 and 0.39 ± 0.04, respectively; p = NS). In contrast, near normalisation of blood glucose improved beta cell sensitivity to glucose during glucose+GLP-1 infusion (1.27 ± 0.2 before vs 1.73 ± 0.31 after; p < 0.01). In the healthy participants, the slopes during the glucose+saline and glucose+GLP-1 infusions were 1.01 ± 0.14 and 4.79 ± 0.53, respectively. Conclusions/interpretation A supraphysiological dose of GLP-1 enhances beta cell responses to glucose in patients with type 2 diabetes, and 4 weeks of near normalisation of blood glucose further improves this effect. ClinicalTrials.gov ID no.: NCT00612625     

Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes

Objective  The incretin effect is attenuated in patients with type 2 diabetes mellitus, partly as a result of impaired beta cell responsiveness to glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The aim of the present study was to investigate whether 4 weeks of near-normalisation of the blood glucose level could improve insulin responses to GIP and GLP-1 in patients with type 2 diabetes. Methods  Eight obese patients with type 2 diabetes with poor glycaemic control (HbA_1c 8.6 ± 1.3%), were investigated before and after 4 weeks of near-normalisation of blood glucose (mean blood glucose 7.4 ± 1.2 mmol/l) using insulin treatment. Before and after insulin treatment the participants underwent three hyperglycaemic clamps (15 mmol/l) with infusion of GLP-1, GIP or saline. Insulin responses were evaluated as the incremental area under the plasma C-peptide curve. Results  Before and after near-normalisation of blood glucose, the C-peptide responses did not differ during the early phase of insulin secretion (0–10 min). The late phase C-peptide response (10–120 min) increased during GIP infusion from 33.0 ± 8.5 to 103.9 ± 24.2 (nmol/l) × (110 min)⁻¹ (p < 0.05) and during GLP-1 infusion from 48.7 ± 11.8 to 126.6 ± 32.5 (nmol/l) × (110 min)⁻¹ (p < 0.05), whereas during saline infusion the late-phase response did not differ before vs after near-normalisation of blood glucose (40.2 ± 11.2 vs 46.5 ± 12.7 [nmol/l] × [110 min]⁻¹). Conclusions  Near-normalisation of blood glucose for 4 weeks improves beta cell responsiveness to both GLP-1 and GIP by a factor of three to four. No effect was found on beta cell responsiveness to glucose alone. ClinicalTrials.gov ID no.: NCT 00612950 Funding: This study was supported by The Novo Nordisk Foundation, The Medical Science Research Foundation for Copenhagen.     

Long-term Follow-up of Patients Undergoing Postconditioning During ST-Elevation Myocardial Infarction

Reperfusion injury may offset the optimal salvage of myocardium achieved during primary coronary angioplasty. Thus, coronary reperfusion must be combined with cardioprotective adjunctive therapies in order to optimize myocardial salvage and minimize infarct size. Forty-three patients with their first ST-elevation myocardial infarction were randomized to myocardial postconditioning or standard of care at the time of primary coronary angioplasty. Postconditioning was performed immediately upon crossing the lesion with the guide wire and consisted of four cycles of 30 s occlusion followed by 30 s of reperfusion. End-points included infarct size, myocardial perfusion grade (MPG), left-ventricular ejection fraction (LVEF), and long-term clinical events (death and heart failure). Despite similar ischemic times (≅4.5 h) (p = 0.9) a reduction in infarct size was observed among patients treated with the postconditioning protocol. Peak creatine phosphokinase (CPK), as well as its myocardial band (MB) fraction, was significantly lower in the postconditioning group when compared with the control group (CPK—control, 2,444 ± 1,928 IU/L vs. PC, 2,182 ± 1,717 IU/L; CPK-MB—control, 242 ± 40 IU/L vs. PC, 195 ± 33 IU/L; p = 0.64 and p < 0.01, respectively). EF in the postconditioning group was improved when compared with the control group (control, 43% ± 15 vs. PC, 52% ± 9; p = 0.05). After a mean follow-up of 3.4 years, a 6-point absolute difference in LVEF was still evident in the postconditioning group (p = 0.18). MPG was better among patients treated with the postconditioning protocol compared with control (2.5 ± 0.5 vs. 2.1 ± 0.6; p = 0.02). Due to the small sample size no significant differences in clinical events were detected (p value for death = 0.9; p value for heart failure = 0.2). A simple postconditioning protocol applied at the onset of mechanical reperfusion, resulted in reduction of infarct size, better epicardial and myocardial flow, and improvement in left ventricular function. The beneficial effects of postconditioning on cardiac function persist beyond 3 years.     

The Cardioprotective Effect of Necrostatin Requires the Cyclophilin-D Component of the Mitochondrial Permeability Transition Pore

Background Necrostatin (Nec-1) protects against ischemia–reperfusion (IR) injury in both brain and heart. We have previously reported in this journal that necrostatin can delay opening of the mitochondrial permeability transition pore (MPTP) in isolated cardiomyocytes. Aim The aim of the present study was to investigate in more detail the role played by the MPTP in necrostatin-mediated cardioprotection employing mice lacking a key component of the MPTP, namely cyclophilin-D. Method Anaesthetized wild type (WT) and cyclophilin-D knockout (Cyp-D−/−) mice underwent an open-chest procedure involving 30 min of myocardial ischemia and 2 h of reperfusion, with subsequent infarct size assessed by triphenyltetrazolium staining. Nec-1, given at reperfusion, significantly limited infarct size in WT mice (17.7 ± 3% vs. 54.3 ± 3%, P < 0.05) but not in Cyp-D−/− mice (28.3 ± 7% vs. 30.8 ± 6%, P > 0.05). Conclusion The data obtained in Cyp-D−/− mice provide further evidence that Nec-1 protects against myocardial IR injury by modulating MPTP opening at reperfusion.     

Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide,inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas

Aims/hypothesis  The glucose-lowering effect of glucagon-like peptide-1 (GLP-1) is based not only upon its potent insulinotropic actions but also on its ability to restrain glucagon secretion. Surprisingly, the closely related glucose-dependent insulinotropic peptide (GIP) stimulates glucagon release. We examined whether the islet hormone somatostatin, which strongly inhibits glucagon secretion, is involved in this divergent behaviour. Methods  At 1.5 mmol/l glucose and therefore minimal insulin secretion, the glucagon, insulin and somatostatin responses to 20 mmol/l glucose, GLP-1, GIP and somatostatin were studied in the presence of a high-affinity monoclonal somatostatin antibody and of a highly specific somatostatin receptor subtype 2 (SSTR2) antagonist (PRL-2903) in the isolated perfused rat pancreas. Results  In control experiments, GLP-1 at 1 and 10 nmol/l reduced glucagon secretion significantly to 59.0 ± 6.3% (p < 0.004; n = 5; SSTR2 series; each vs pre-infusion level) and to 48.0 ± 2.6% (p < 0.001; n = 6; somatostatin antibody series) respectively. During somatostatin antibody administration, GLP-1 still inhibited glucagon secretion significantly, but the effect was less pronounced than in control experiments (p < 0.018). Co-infusion of the SSTR2 antagonist completely abolished the GLP-1-induced suppression of glucagon secretion. In contrast, neither the GIP-induced stimulation of glucagon release nor its inhibition by 20 mmol/l glucose was altered by somatostatin antibody or SSTR2 antagonist administration. Conclusions/interpretation  We conclude that GLP-1 is capable of inhibiting glucagon secretion even in the absence of secretory products from the beta cell. It is highly likely that this is mediated via somatostatin interacting with SSTR2 on rat alpha cells. In contrast, GIP and glucose seem to influence the alpha cell independently of somatostatin secretion.     

Effect of catheter-based transendocardial delivery of stromal cell-derived factor 1α on left ventricular function and perfusion in a porcine model of myocardial infarction

Abstract Background Myocardial regeneration after myocardial infarction can occur via stem cell recruitment. Stromal cell-derived factor 1α (SDF-1α) has been shown to be critical for stem cell homing to injured tissue. Methods Myocardial infarction was induced in pigs via microembolization of the distal left anterior descending artery. Two weeks after myocardial infarction animals underwent catheter-based transendocardial injection of SDF-1α into the periinfarct myocardium (18 injections, 5 ìg per injection) (n = 12) or sham-intervention (n = 8). Tc99m sestamibi single-photon emission computed tomography (SPECT) and electromechanical mapping (EMM) of the left ventricle were performed two and seven weeks after myocardial infarction. Results Infarct size by tetrazolium staining was similar in both groups (8.9 ±1.2% of left ventricle vs. 8.9 ± 2.6%). Vessel density in the periinfarct area was significantly higher in SDF-1α treated animals than in controls (349 ± 17/mm² vs. 276 ± 21/mm², p < 0.05). Myocardial perfusion (SPECT) did not change in either group. Ejection fraction and stroke volume (EMM) decreased in SDF-1α animals and increased in controls (difference between groups p = 0.05 for ejection fraction and p < 0.05 for stroke volume). Linear local shortening (EMM) did not change in controls (11.4 ± 1.3% to 11.5 ± 0.5%) but decreased significantly in SDF-1α treated animals (12.1 ± 0.9% to 8.4 ± 0.9%, p < 0.05, p < 0.05 for difference between groups). SDF-1 delivery was associated with a substantial loss of collagen in the periinfarct area (32±5% vs. 61±6% in control animals, p < 0.005). Conclusion A strategy to augment stem cell homing by catheter-based transendocardial delivery of SDF-1α in experimental myocardial infarction increases periinfarct vessel density, fails to improve myocardial perfusion, is associated with loss of collagen in the periinfarct area and impairs left ventricular function. Drs. Koch and Schaefer contributed equally to this study.     

Necrostatin: A Potentially Novel Cardioprotective Agent?

Background Necrostatin-1 (Nec-1), a small tryptophan-based molecule, was recently reported to protect the cerebral cortex against ischemia-reperfusion (I/R) injury. We investigated the actions of Nec-1 and its so-called inactive analog, Nec-1i, in the setting of myocardial I/R injury. Materials and methods The actions of Nec-1 and Nec-1i were examined in cultured C2C12 and H9c2 myocytes, cardiomyocytes isolated from male Sprague–Dawley rats, Langendorff isolated perfused C57Bl/6J mouse hearts and an in vivo open-chest C57Bl/6J mouse heart model. Results Nec-1 at 30 μM and 100 μM (but not 100 μM Nec-1i) reduced peroxide-induced cell death in C2C12 cells from 51.2 ± 1.1% (control) to 26.3 ± 2.9% (p < 0.01 vs control) and 17.8 ± 0.9% (p < 0.001), respectively. With H9c2 cells cell death was also reduced from 73.0 ± 0.4% (control) to 56.7 ± 0% (30 μM Nec-1, p < 0.05) and 45.4 ± 3.3% (100 μM Nec-1, p < 0.01). In the isolated perfused heart Nec-1 (30 μM) reduced infarct size (calculated as a percentage of the risk area) from 48.0 ± 2.0% (control) to 32.1 ± 5.4% (p < 0.05). Nec-1i (30 μM) also reduced infarct size (32.9 ± 5.1%, p < 0.05). In anesthetized C57Bl/6J mice Nec-1 (1.65 mg/kg), given intraperitoneally to coincide with reperfusion following left anterior descending artery ligation (30 min), also reduced infarct size from 45.3 ± 5.1% (control) to 26.6 ± 4.0% (p < 0.05), whilst Nec-1i (1.74 mg/kg) was ineffective (37.8 ± 6.0%). Stimulus-induced opening of the mitochondrial permeability transition pore (MPTP) in rat cardiomyocytes, as reflected by the time until mitochondrial depolarisation, was unaffected by Nec-1 or Nec-1i at 30 μM but increased at 100 μM i.e. 91% (p < 0.05 vs control) and 152% (p < 0.001) for Nec-1 and Nec-1i, respectively. Conclusion This is the first study to demonstrate that necrostatins inhibit myocardial cell death and reduce infarct size, possibly via a mechanism independent of the MPTP.     

Serum from children with polyarticular juvenile idiopathic arthritis (pJIA) inhibits differentiation, mineralization and may increase apoptosis of human osteoblasts “in vitro”

We examined the effects of polyarticular juvenile idiopathic arthritis (pJIA) serum on proliferation, differentiation, mineralization, and apoptosis of human osteoblast cells (hOb) in culture. The hOb were cultured with 10% serum from active pJIA and healthy controls (CT) and were tested for DNA synthesis, alkaline phosphatase (AP) activity, osteocalcin (OC) secretion, calcium levels, caspase 3 activity, and DNA fragmentation. None of the patients had used glucocorticoids for at least 1 month before the study, or any other drug that can affect bone mineral metabolism. Human inflammatory cytokine levels (IL-6, IL-8, IL-10, IL-1β, TNF-α, and IL-12p70) were measured in pJIA and CT sera. Low levels of AP activity was observed in pJIA cultures compared with CT cultures (67.16 ± 53.35 vs 100.11 ± 50.64 μmol p-nitrophenol/h⁻¹ mg⁻¹ protein, P = 0.008). There was also a significant decrease in OC secretion (9.23 ± 5.63 vs 12.82 ± 7.02 ng/mg protein, P = 0.012) and calcium levels (0.475 ± 0.197 vs 0.717 ± 0.366 mmol/l, P = 0.05) in pJIA hOb cultures. No difference was observed in cell proliferation (323.56 ± 108.23 vs 328.91 ± 88.03 dpm/mg protein, P = 0.788). Osteoblasts cultured with JIA sera showed lower levels of DNA and increased fragmentation than osteoblasts cultured with CT sera. pJIA sera showed higher IL-6 values than CT (21.44 ± 9.31 vs 3.58 ± 2.38 pg/ml, P < 0.001), but no difference was observed related to IL-8, IL-10, IL-1β, TNF-α, and IL-12p70 between pJIA and controls. This study suggests that serum from children with pJIA inhibits differentiation, mineralization and may increase apoptosis of hOb cultures, and inflammatory cytokines such as IL-6 might be a mechanism in this find. These results may represent an alternative therapeutic target for prevention and treatment of bone loss in JIA.     

Residual myocardial ischaemia in first non-Q versus Q wave infarction: maximal exercise testing and ambulatory ST-segment monitoring

In a prospective study of 123 consecutive survivors of a firstmyocardial infarction (43 non-Q wave, 80 Q wave), we determinedthe total residual ischaemic burden by use of pre-dischargemaximal exercise testing and post-discharge 36 h ambulatoryST-segment monitoring initiated 11 ± 5 days after theinfarction. The prevalence of exercise-induced ischae-mic manifestations in the infarct types was similar: chest pain 14%vs 16% and ST-segment depression 54% vs 54%. The ischaemic thresholddid not differ either (heart rate at 1 mm of ST-segmnent depression120 ± 27 vs 119 ± 25 beats. min^–1). Duringearly post-discharge daily activities, more patients with non-Qwave infarction demonstrated transient episodes of ST-segmentdepression: 28% vs 14% (ns). Furthermore, ischaemic episodeswere significantly longer (42.5±50.1 vs 22.0 ±20.6 min; p <0.001), and the ischaemic threshold was significantlylower in non-Q wave infarction (heart rate at onset of ST-segmentdepression 84±11 vs 88±9 beats.min^–1; p<0.05). During 3.5±0.9 years of follow-up the proportionof patients with 1 ischaemic event (non-fatal reinfarction,angina pectoris, revascularization) was significantly higherin non-Q wave infarction (51%) as compared to Q wave infarction(31%) (P<005). In both infarct types the presence of ST-segmentdepression on ambulatory recording and exercise testing significantlypredicted the development of future angina pectoris, whereaspatients at increased risk for subsequent non-fatal reinfarctionor cardiac death were not identified.     

Efficacy and safety of radiofrequency catheter ablation in the elderly

Introduction Radiofrequency (RF) catheter ablation has not been widely undertaken in elderly patients. The aim of our study was to compare the success rate of radiofrequency ablation and the incidence of severe procedural complications in young-adult and elderly patients. Methods We enrolled all patients undergoing radiofrequency catheter ablation procedures for supraventricular and ventricular arrhythmias at our Cardiology Department from January 2000 to December 2005. The patients were divided into two groups according to age: patients aged <70 years (group A) and those aged ≥70 years (group B). Group B was then divided into two subgroups: B1 (age 70–79 years) and B2 (age ≥80 years). We recorded the incidence of procedural complications and the long-term efficacy (mean follow-up 46 ± 20 months). Results We studied 605 patients, 69% in group A and 31% in group B (24% in subgroup B1 and 7% in B2). The prevalence of structural heart disease was higher in elderly patients than in young adults (83 vs 37%, p < 0.01). The rate of procedural complications was 1.3%; no differences emerged between groups A and B (1.2 vs 1.5%, p = NS) or among groups A, B1 and B2 (1.2 vs 1.4 vs 2%, p = NS). The success rate of catheter ablation was 91%, with no differences between the age-groups (92 vs 88%, p = NS) or among groups A, B1 and B2 (92 vs 88 vs 88%, p = NS). Conclusion Catheter ablation in elderly and very elderly patients is as effective and safe as in young-adult subjects, at least in cases which do not require left heart catheterization.     

Effect of ABCB1 Genotype on Pre- and Post-Cardiac Transplantation Plasma Lipid Concentrations

Genetic variation of ATP-binding cassette subfamily B member 1 (ABCB1) which encodes P-glycoprotein (P-gp) has been associated with lipid levels and response to statins. Here, we studied these associations in patients with advanced heart failure who subsequently underwent transplantation. Fasting total cholesterol (TC), low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol and triglycerides (TG) concentrations in 268 adult heart transplant recipients were analysed retrospectively before and at 1 year after transplantation (n = 176). ABCB1 genotyping and haplotyping for C1236T, G2677T/A and C3435T was performed using polymerase chain reaction. Pre-transplant LDL cholesterol was found to be associated with the C3435T genotype and the G2677T/A-C3435T and C1236T-G2677T/A-C3435T haplotypes. T-allele carriers at all loci (n = 77) had higher LDL levels than non-T-allele carriers (n = 24, 3.5 ± 1.2 vs. 2.8 ± 1.2 mmol/L, respectively, p = 0.025). This association remained after adjustment for age, sex, body mass index, statin use and underlying ischaemic heart disease. ABCB1 genotype was not associated with post-transplant lipid parameters. Hypercholesterolaemia (TC >5.7 mmol/L) was more prevalent post-transplant than pre-transplant (51% vs. 30%, respectively) and was likely related to steroid and calcineurin inhibitor use. Muscle-related statin effects were only seen in patients possessing the T-haplotype. In conclusion, an association between ABCB1 haplotype and plasma fasting LDL cholesterol concentration was found in patients with advanced heart failure. This association was not seen 1 year after cardiac transplantation.     

Risk factors for cardiovascular disease and endothelin-1 levels in Takayasu arteritis patients

The objective of this study was to evaluate traditional risk factors for cardiovascular disease (CVD) and endothelin-1 (ET-1) levels in Takayasu arteritis (TA) patients. Twenty-two TA patients and 37 controls were evaluated. TA patients had a higher prevalence of hypertension (63.6% vs. 21.6%, p = 0.001) and higher levels of triglycerides (129.5 mg/dL ± 70.8 vs. 88.4 mg/dL ± 60.8, p = 0.017) than controls. Mean number of CVD risk factors was 1.64 ± 1.22 in TA patients and 1.03 ± 1.44 among controls, p = 0.030. More TA patients presented at least one CVD risk factor when compared to controls (77.2% vs. 51.3%, p = 0.048). ET-1 levels were higher in patients than in controls (1.49 pg/mL ± 0.45 vs. 1.27 pg/mL ± 0.32, p = 0.034), however no significant difference was found between patients with active and inactive disease. In this study, TA patients presented a higher prevalence of hypertension, higher levels of triglycerides, and ET-1 than controls.     

Nicorandil suppresses the increases in plasma level of matrix metalloproteinase activity and attenuates left ventricular remodeling in patients with acute myocardial infarction

Nicorandil, a hybrid K_ATP channel opener and nicotinamide nitrate, reduces no-reflow phenomenon and improves cardiac function in patients with acute myocardial infarction (AMI). We repoted that nicorandil suppresses radical formation in patients with AMI undergoing primary percutaneous coronary intervention (PCI). In the present study, we tested the hypothesis that nicorandil treatment suppresses MMP activities and predicts ventricular remodeling in AMI. Sixty-two patients with AMI were randomized into nicorandil pretreatment (n = 31) and control (n = 31) groups after admission and underwent primary PCI. Nicorandil was administered as a bolus injection (4 mg) followed by constant infusion (8 mg/h) for 24 h just after admission. On days 1, 2, and 14 after the onset of AMI, the plasma levels of matrix metalloproteinase (MMP)-2 and MMP-9 were measured by enzyme-linked immunosorbent assay and the activities by gelatin zymography. There were no differences in the baseline clinical characteristics between the two groups. On day 1, there were no differences in both MMP-2 and MMP-9 levels and their activities between the two groups. However, both MMP-2 and MMP-9 levels and their activities were significantly lower in nicorandil than in control group on day 2 (MMP-2 level, 1 014 ± 39 vs 1 174 ± 44 ng/ml; MMP-9 level, 17 ± 1 vs 23 ± 2 ng/ml; both P < 005) and on day l4 (MMP-2 level, 970 ± 38 vs 1 221 ± 44 ng/ml; MMP-9 level, 17 ± 1 vs 23 ± 1 ng/ml; both P < 0.05). Left ventricular end-diastolic volume index (LVEDVI) at acute phase was not different between the two groups. At 6 months after AMI, LVEDVI was significantly smaller in nicorandil than in the control group (83 ± 4 vs 96 ± 4 ml/m², P < 0.05). The change in LVEDVI from acute phase to 6 months was positively correlated with MMP-2 and MMP-9 levels and activities. Nicorandil suppresses the increases in MMP levels and activities and prevents the development of ventricular remodeling in AMI.     

Impaired short-term blood pressure regulation and autonomic dysbalance in children with type 1 diabetes mellitus

Aims Because reduction in baroreceptor sensitivity (BRS) has been associated with hypertension in the normal population and with increased cardiovascular morbidity and mortality in patients with diabetes mellitus, we measured BRS in a patient cohort of children with type 1 diabetes mellitus. Methods Two hundred and eight children (150 patients with type 1 diabetes mellitus, mean age 13.9 ± 2.8 years, 70 boys, mean HbA_1c 7.8 ± 1.4%; and 58 healthy controls, mean age 14.1 ± 3.1 years, 32 boys) were studied. BRS and heart rate variability (HRV) were analysed from a short-time ECG and BP recording using the sequence method (BRS) and the frequency domain method (HRV). Results There were 111 of 150 patients (74%) and 5 of 58 controls (8.6%) that showed impaired BRS. Mean BRS differed significantly between patients and controls (18.4 ± 7.2 vs 25.8 ± 8.2 ms/mm, p < 0.001). BRS correlated inversely with systolic BP (r = −0.23, p = 0.009) and was related to diabetes duration (r = −0.194, p = 0.027). Analysis of HRV showed greater sympathetic and less parasympathetic influence in patients than in controls (low frequency/high frequency ratio 1.3 ± 0.8 vs 0.9 ± 0.6, p < 0.05); the low frequency/high frequency ratio was inversely correlated with BRS (r = −0.28, p = 0.001). Conclusions/interpretation Diabetic children show reduced BRS. In our patient group, the single risk factor for this finding was found to be the disease duration. The degree of BRS impairment was related to the degree of autonomic dysbalance. R. Dalla Pozza and S. Bechtold contributed equally to this study.     

Pacing to Reduce Refractory Angina in Patients with Severe Coronary Artery Disease: A Crossover Pilot Trial

Biventricular pacing (BiV) has been shown to reduce wall stress and workload in regions near the pacing sites. This trial investigated if BiV near the ischemic region would reduce chest pain in patients with refractory angina due to severe coronary artery disease (CAD). Eleven patients were implanted with BiV devices with leads positioned at or adjacent to their ischemic regions as detected by single-photon emission computed tomography (SPECT) and randomized to either pacing turned ON or OFF for 3 months, and then crossed over for 3 months. With pacing turned ON, a Dynamic atrioventricular (AV) delay was set for approximately 90% and 70% of the intrinsic AV delay at the resting heart rate and at the onset of symptoms, respectively. One patient was excluded from the analysis due to a large amount of RV pacing during the OFF periods (24–64%) and due to an inability to properly deliver therapy because of an excessive number of ventricular premature complexes. Overall, with the device ON vs. OFF, the number of angina episodes (0.8 ± 0.4 vs. 1.2 ± 0.7 per week, P = 0.03) and amount of nitroglycerin used (0.2 ± 0.1 vs. 1.0 ± 0.7 per week, P = 0.11) was lower with BiV pacing. Furthermore, the treadmill exercise time to symptoms trended higher (427 ± 65 vs. 408 ± 64 s, P = 0.19), and the sum of fluorodeoxyglucose–positron emission tomography (FDG-PET) scores trended lower (7.9 ± 3.5 vs. 12.0 ± 4.0, P = 0.11) with the device ON vs. OFF. Nevertheless, there were no significant differences in SPECT myocardial perfusion scores, left ventricle ejection fraction, wall motion score index, and quality of life scores with device programmed ON vs. OFF (all P > 0.05). In conclusion, this pilot study demonstrated that BiV-P at or near the ischemic region was feasible and associated with significant reductions in angina in patients with severe CAD. Adequately powered prospective studies are needed to confirm these findings.     

An orientation session improves objective sleep quality and mask acceptance during positive airway pressure titration

The aim of this study was to determine whether an orientation session led by a polysomnography (PSG) technician during the night of positive airway pressure (PAP) titration can improve objective sleep quality and acceptance of nasal mask in patients referred to a sleep laboratory. Consecutive patients (n = 1,481), referred for PAP titration during PSG, were retrospectively evaluated. Patients were distributed in two groups: the control group, patients referred for PAP titration (n = 699) who did not undertake an orientation session led by a PSG technician, and the oriented group, patients referred to PAP titration (n = 782) who followed the orientation session. Demographic data were similar (p > 0.05) between groups (control vs oriented) for: male/female proportion (76:24 vs 75:25%), age (mean ± SD; 53 ± 12 vs 52 ± 12 years), Epworth Sleepiness Scale score (12 ± 6 vs 12 ± 6), and body mass index (31 ± 6 vs 31 ± 6 kg/m²). PSG data were different (p < 0.05) between the groups for: total sleep time (312 ± 81 vs 326 ± 85 min), sleep efficiency (74 ± 17 vs 77 ± 14%), sleep latency (22 ± 24 vs 18 ± 29 min), S1 (8 ± 8 vs 6 ± 5%), S3  4 (19 ± 11 vs 21 ± 13%), rapid eye movement sleep (17 ± 9 vs 18 ± 9%), and wake after sleep onset (106 ± 68 vs 93 ± 58 min). After the orientation session, the number of patients who did not accept nasal mask during PSG recording was higher in the control group than the oriented group (80 vs 44; p = 0.001). An orientation session led by a PSG technician can improve objective sleep quality and nasal mask acceptance during the night of PAP titration. Such an addition to PAP titration could be an efficient intervention to improve PAP compliance.     

Acute hyperglycaemia rapidly increases arterial stiffness in young patients with type 1 diabetes

Aims/hypothesis Augmentation index (AIx) and pulse wave velocity (PWV), both measures of arterial stiffness, constitute risk factors for cardiovascular disease. Notably, hyperglycaemia during an acute cardiovascular event is associated with poor prognosis. The objective of this study was to investigate whether acute hyperglycaemia increases arterial stiffness in patients with type 1 diabetes and in healthy subjects. Methods Twenty-two male patients with type 1 diabetes and thirteen healthy men, who were age-matched non-smokers and without any diabetic complications, underwent a 120 min hyperglycaemic clamp (15 mmol/l). AIx was calculated to assess arterial stiffness. Before and during the clamp, carotid-radial (brachial) and carotid-femoral (aortic) PWV was measured. Results At baseline there was a difference in the AIx between patients with type 1 diabetes and healthy volunteers (−5 ± 2.7 vs −20 ± 2.8%, p < 0.05). Acute hyperglycaemia rapidly increased AIx in patients with type 1 diabetes (−5 ± 2.7 vs 8 ± 2.5%, p < 0.001) and healthy volunteers (−20 ± 2.8 vs 6 ± 8.8%, p < 0.001). Brachial PWV increased during acute hyperglycaemia in patients with type 1 diabetes (7.1 ± 1.2 vs 8.0 ± 1.0 m/s, p < 0.001), but not in healthy men (7.4 ± 1.7 vs 7.3 ± 1.4 m/s, NS). Conclusions/interpretation Acute hyperglycaemia increases the stiffness of intermediate-sized arteries and resistance arteries in young patients with type 1 diabetes and consequently emphasises the importance of strict daily glycaemic control. No change was observed in aortic PWV during the clamp, indicating that acute hyperglycaemia does not affect the large vessels. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users.     

Oral Administration of Candesartan Improves the Survival of Mice with Viral Myocarditis through Modification of Cardiac Adiponectin Expression

Purpose We examined the effects of the angiotensin II receptor type1 blocker candesartan on myocarditis injury in a murine model of acute myocarditis. We hypothesized that candesartan improves cardiac damage by inducing cardiac expression of adiponectin. Methods and results We examined changes in heart failure caused by myocarditis in mice by candesartan based on induction of cardiac adiponectin expression. We intraperitoneally injected encephalomyocarditis virus in C3H mice, then orally administered candesartan (10 mg/kg/day) or vehicle (control). The 7 day survival rate was 18% in the control group, but 60% in the candesartan group. The heart weight/body weight ratio in the candesartan group was significantly lower than in the control group. Circulating adiponectin concentrations on day 7 were significantly higher in the candesartan group compared with the control group (7.91 ± 0.61 vs. 6.04 ± 2.26 μg/ml, P < 0.05). Comparative expression of cardiac adiponectin mRNA in the candesartan group was significantly higher than in the control group on day 7 (55.4 ± 41.3 vs. 5.3 ± 7.7, P < 0.05). Immunohistochemical staining and in situ hybridization showed that cardiac expression of adiponectin protein and mRNA was present in the candesartan group on day 7. Conclusion Oral administration of candesartan improves survival and decreases myocardial damage in mice with viral myocarditits and induces expression of cardiac adiponectin. The induction of adiponectin might provide cardioprotective effects against acute heart failure due to viral myocarditis.     

Secondary failure to treatment with recombinant human IL-1 receptor antagonist in Chinese patients with rheumatoid arthritis

The aim of this study is to assess the efficacy of anakinra, a recombinant human interleukin 1 receptor antagonist, plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) refractory to MTX therapy. A total of 54 patients with active RA, who were taking MTX at a stable dosage, were randomized to receive daily subcutaneous injections of anakinra (80 mg) or placebo. Clinical outcomes were assessed every 4 weeks for 24 weeks by using the criteria of the American College of Rheumatology. After 24 weeks, more patients achieved clinical benefits as determined by the ACR20 improvement treated with anakinra plus MTX compared with MTX alone (64% vs. 17%, P = 0.004). In the anakinra group, an ACR50 response was observed in 38% and an ACR70 response in 17%. None of the patients treated with MTX alone achieved ACR50 or ACR 70 improvement. However, nine of 42 (21.4%) patients in the anakinra group, who showed therapeutic response initially, had secondary drug failure to anakinra therapy thereafter. A significant increase in mean DAS28 from baseline was found in the non-responders to anakinra compared with placebo (0.83 ± 1.38 vs. −1.28 ± 0.78, P < 0.001). Anakinra is effective in the treatment of patients with active RA by blocking IL-1. However, the efficacy of anakinra is soon lost in about one fifth of patients in spite of initial good response.     

Repeated Low-dose of Erythropoietin is Associated with Improved Left Ventricular Function in Rat Acute Myocardial Infarction Model

Objective To evaluate the potential protective affects of Epo on left ventricular (LV) function and remodeling after acute myocardial infarction (MI). Methods Epo was injected into the peritoneum of male Wistar rats (250 g) during 6 weeks post induction of MI. Rats were divided into five groups: MI treated with single high dose (MT1, 5,000 U/kg, n = 10), single high dose (5,000 U/kg) and repeated high doses (MTHi, 1,000 U/kg twice a week; n = 8), or single high dose (5,000 U/kg) and repeated low doses (MTLo, 750 U/kg once a week, n = 10), MI non-treated (MNT, n = 10), sham (S, n = 5). Echocardiography was performed 3.6 ± 1.5 days and 43.7 ± 2.3 days post MI. Collagen deposition and infarct size were measured on histological sections using computerized image analysis. Apoptosis was assessed by ApopTag staining. Results Baseline fractional shortening (FS) was similar between groups. Six weeks after MI the FS of MTLo (26.9%) was significantly higher compared to MNT (17.8%), MT1 (19.5%) and MTH (22.3%) (p = 0.01). However, remodeling indices (end diastolic and end systolic areas, LV circumference) did not improve in the Epo groups, and even worsened in the MTHi group. There was significantly less collagen staining in non-infarct areas in MT1 and MTHi groups compared to MNT and MTLo (0.38 ± 0.3%, 0.49 ± 0.34%, vs 0.89 ± 0.41%, 0.95 ± 0.33%, respectively, p < 0.001). The number of ApopTag positive nucleus was significantly higher in the MNT group compared to the MT1, MTHi, MTLo groups (14.4 ± 8, 7.6 ± 4, 5.8 ± 7, 4.8 ± 5, respectively, p = 0.01 for trend). Conclusion Repeated low doses of Epo after MI improved LV function, but the role of Epo on remodeling is not clear. It did not reduce left ventricular indices, but reduces fibrosis and apoptosis. High Epo doses reduced LV function and aggravated remodeling.