Rivaroxaban compared with low-dose aspirin in individuals with type 2 diabetes and high cardiovascular risk: a randomised trial to assess effects on endothelial function, platelet activation and vascular biomarkers.

AIMS/HYPOTHESIS: Individuals with type 2 diabetes mellitus and subclinical inflammation have stimulated coagulation, activated platelets and endothelial dysfunction. Recent studies with the direct factor Xa inhibitor rivaroxaban in combination with low-dose aspirin demonstrated a significant reduction of major cardiovascular events, especially in individuals with type 2 diabetes and proven cardiovascular disease. Therefore, we asked the question of whether treatment with rivaroxaban could influence endothelial function, arterial stiffness and platelet activation. METHODS: We conducted a multi-centre, prospective, randomised, open-label trial in 179 participants with type 2 diabetes (duration 2-20 years), subclinical inflammation (high-sensitivity C-reactive protein 2-10 mg/l) and at least two traits of the metabolic syndrome to compare the effects of the direct factor Xa inhibitor rivaroxaban (5 mg twice daily) vs aspirin (100 mg every day) on endothelial function (assessed by forearm occlusion plethysmography), skin blood flow (assessed by laser-Doppler fluxmetry), arterial stiffness (assessed by pulse wave velocity) and serum biomarkers of endothelial function and inflammation. Furthermore, we investigated phosphorylation of vasodilator-stimulated phosphoprotein (VASP) in platelets, the concentration of platelet-derived microparticles (PMPs) and the effects of isolated PMPs on HUVEC proliferation in vitro. RESULTS: Rivaroxaban treatment for 20 weeks (n = 89) resulted in a significant improvement of post-ischaemic forearm blood flow (3.6 ± 4.7 vs 1.0 ± 5.2 ml/100 ml, p = 0.004), a numerically increased skin blood flow and reduced soluble P-Selectin plasma level vs aspirin. We did not find significant differences of arterial stiffness or further biomarkers. Neither rivaroxaban nor aspirin influenced VASP phosphorylation of platelets. The number of PMPs increased significantly with both rivaroxaban (365.2 ± 372.1 vs 237.4 ± 157.1 µl-1, p = 0.005) and aspirin (266.0 ± 212.7 vs 201.7 ± 162.7 µl-1, p = 0.021). PMPs of rivaroxaban-treated participants stimulated HUVEC proliferation in vitro compared with aspirin. Rivaroxaban was associated with a higher number of bleeding events. CONCLUSIONS/INTERPRETATION: Our findings indicate that the direct factor Xa inhibitor rivaroxaban improved endothelial function in participants with type 2 diabetes and subclinical inflammation but also increased the risk of bleeding. TRIAL REGISTRATION: ClinicalTrials.gov NCT02164578. FUNDING: The study was supported by a research grant from Bayer Vital AG, Germany.

The metabolic vascular syndrome - guide to an individualized treatment.

In ancient Greek medicine the concept of a distinct syndrome (going together) was used to label 'a group of signs and symptoms' that occur together and 'characterize a particular abnormality and condition'. The (dys)metabolic syndrome is a common cluster of five pre-morbid metabolic-vascular risk factors or diseases associated with increased cardiovascular morbidity, fatty liver disease and risk of cancer. The risk for major complications such as cardiovascular diseases, NASH and some cancers develops along a continuum of risk factors into clinical diseases. Therefore we still include hyperglycemia, visceral obesity, dyslipidemia and hypertension as diagnostic traits in the definition according to the term 'deadly quartet'. From the beginning elevated blood pressure and hyperglycemia were core traits of the metabolic syndrome associated with endothelial dysfunction and increased risk of cardiovascular disease. Thus metabolic and vascular abnormalities are in extricable linked. Therefore it seems reasonable to extend the term to metabolic-vascular syndrome (MVS) to signal the clinical relevance and related risk of multimorbidity. This has important implications for integrated diagnostics and therapeutic approach. According to the definition of a syndrome the rapid global rise in the prevalence of all traits and comorbidities of the MVS is mainly caused by rapid changes in life-style and sociocultural transition resp. with over- and malnutrition, low physical activity and social stress as a common soil.

Hypoglycemia and Cardiovascular Disease: Lessons from Outcome Studies.

Severe hypoglycemia is recognized to be one of the strongest predictors of macrovascular events, adverse clinical outcomes, and mortality in patients with type 2 diabetes. Large clinical trials have reported an increased hazard ratio for all-cause mortality and cardiovascular events in patients with type 2 diabetes and severe hypoglycemia. However, these trials also reported an increased hypoglycemia-associated mortality rate in patients allocated to standard treatment by a factor of 1.5-2 despite a significant 50 % to 70 % lower incidence of hypoglycemia compared to the intensive treatment group. Although the potential for a causal relationship has been demonstrated in mechanistic studies, the evidence from large prospective studies suggest that other pre-existing cardiovascular risk factors in addition to hypoglycemia may be the major link to the final cardiovascular event, and that a low blood glucose level can trigger these events in patients with a high cardiovascular risk.

Calpain inhibition stabilizes the platelet proteome and reactivity in diabetes.

Platelets from patients with diabetes are hyperreactive and demonstrate increased adhesiveness, aggregation, degranulation, and thrombus formation, processes that contribute to the accelerated development of vascular disease. Part of the problem seems to be dysregulated platelet Ca(2+) signaling and the activation of calpains, which are Ca(2+)-activated proteases that result in the limited proteolysis of substrate proteins and subsequent alterations in signaling. In the present study, we report that the activation of µ- and m-calpain in patients with type 2 diabetes has profound effects on the platelet proteome and have identified septin-5 and the integrin-linked kinase (ILK) as novel calpain substrates. The calpain-dependent cleavage of septin-5 disturbed its association with syntaxin-4 and promoted the secretion of α-granule contents, including TGF-ß and CCL5. Calpain was also released by platelets and cleaved CCL5 to generate a variant with enhanced activity. Calpain activation also disrupted the ILK-PINCH-Parvin complex and altered platelet adhesion and spreading. In diabetic mice, calpain inhibition reversed the effects of diabetes on platelet protein cleavage, decreased circulating CCL5 levels, reduced platelet-leukocyte aggregate formation, and improved platelet function. The results of the present study indicate that diabetes-induced platelet dysfunction is mediated largely by calpain activation and suggest that calpain inhibition may be an effective way of preserving platelet function and eventually decelerating atherothrombosis development.

9-Month observational Dia-Vacc study of vaccine type influence on SARS-CoV-2 immunity in dialysis and kidney transplant patients.

BACKGROUND: SARS-CoV-2mRNA vaccination related seroconversion rates are reduced in dialysis and kidney transplant patients. METHODS: We evaluated nine months follow up data in our observational Dia-Vacc study exploring specific cellular (interferon-γ release assay) or/and humoral immune responses after 2x SARS-CoV-2mRNA vaccination in 880 participants including healthy medical personnel (125-MP), dialysis patients (595-DP), kidney transplant recipients (111-KTR), and apheresis patients (49-AP) with positive seroconversion (de novo IgA or IgG antibody positivity by ELISA) after eight weeks. FINDINGS: Nine months after first vaccination, receptor binding domain (RBD) antibodies were still positive in 90 % of MP, 86 % of AP, but only 55 %/48 % of DP/KTR, respectively. Seroconversion remained positive in 100 % of AP and 99·2 % of MP, but 86 %/81 % of DP/KTR, respectively. Compared to MP, DP but not KTR or AP were at risk for a strong RBD decline, while KTR kept lowest RBD values over time. By multivariate analysis, BNT162b2mRNA versus 1273-mRNA vaccine type was an independent risk factor for a strong decline of RBD antibodies. Within the DP group, only time on dialysis was another (inverse) risk factor for the DP group. Compared to humoral immunity, T-cell immunity decline was less prominent. INTERPRETATION: While seroconverted KTR reach lowest RBD values over time, DP are at specific risk for a strong decline of RBD antibodies after successful SARS-CoV-2mRNA vaccination, which also depends on the vaccine type being used. Therefore, booster vaccinations for DP should be considered earlier compared to normal population.

Risk of strong antibody decline in dialysis and transplant patients after SARS-CoV-2mRNA vaccination: Six months data from the observational Dia-Vacc study.

Background: Vulnerable dialysis and kidney transplant patients show impaired seroconversion rates compared to medical personnel eight weeks after SARS-CoV-2mRNA vaccination. Methods: We evaluated six months follow up data in our observational Dia-Vacc study exploring specific cellular (interferon-γ release assay) or/and humoral immune responses after 2x SARS-CoV-2mRNA vaccination in 1205 participants including medical personnel (125 MP), dialysis patients (970 DP) and kidney transplant recipients (110 KTR) with seroconversion (de novo IgA or IgG antibody positivity by ELISA) after eight weeks. Findings: Six months after vaccination, seroconversion remained positive in 98% of MP, but 91%/87% of DP/KTR (p = 0·005), respectively. Receptor binding domain-IgG (RBD-IgG) antibodies were positive in 98% of MP, but only 68%/57% of DP/KTR (p < 0·001), respectively. Compared to MP, DP and KTR were at risk for a strong IgG or RBD-IgG decline (p < 0·001). Within the DP but not KTR group male gender, peritoneal dialysis, short time on dialysis, BNT162b2mRNA vaccine, immunosuppressive drug use and diabetes mellitus were independent risk factors for a strong decline of IgG or RBD antibodies. The percentage of cellular immunity decline was similar in all groups. Interpretation: Both vulnerable DP and KTR groups are at risk for a strong decline for IgG and RBD antibodies. In KTR, antibody titres peak at a markedly lower level and accelerated antibody decline is mixed with a delayed/increasing IgG, RBD-IgG, or cellular immune response in a 16% fraction of patients. In both populations, immune monitoring should be used for early timing of additional booster vaccinations. Funding: This study was funded by the Else Kröner Fresenius Stiftung, Bad Homburg v. d. H., grant number Fördervertrag EKFS 2021_EKSE.27.

Optimized procedures for testing plasma metanephrines in patients on hemodialysis.

Diagnosis of pheochromocytomas and paragangliomas in patients receiving hemodialysis is troublesome. The aim of the study was to establish optimal conditions for blood sampling for mass spectrometric measurements of normetanephrine, metanephrine and 3-methoxytyramine in patients on hemodialysis and specific reference intervals for plasma metanephrines under the most optimal sampling conditions. Blood was sampled before and near the end of dialysis, including different sampling sites in 170 patients on hemodialysis. Plasma normetanephrine concentrations were lower (P < 0.0001) and metanephrine concentrations higher (P < 0.0001) in shunt than in venous blood, with no differences for 3-methoxytyramine. Normetanephrine, metanephrine and 3-methoxytyramine concentrations in shunt and venous blood were lower (P < 0.0001) near the end than before hemodialysis. Upper cut-offs for normetanephrine were 34% lower when the blood was drawn from the shunt and near the end of hemodialysis compared to blood drawn before hemodialysis. This study establishes optimal sampling conditions using blood from the dialysis shunt near the end of hemodialysis with optimal reference intervals for plasma metanephrines for the diagnosis of pheochromocytomas/paragangliomas among patients on hemodialysis.

Humoral and cellular immunity to SARS-CoV-2 vaccination in renal transplant versus dialysis patients: A prospective, multicenter observational study using mRNA-1273 or BNT162b2 mRNA vaccine.

BACKGROUND: Dialysis and kidney transplant patients are vulnerable populations for COVID-19 related disease and mortality. METHODS: We conducted a prospective study exploring the eight week time course of specific cellular (interferon-γ release assay and flow cytometry) or/and humoral immune responses (ELISA) to SARS-CoV-2 boost vaccination in more than 3100 participants including medical personnel, dialysis patients and kidney transplant recipients using mRNA vaccines BNT162b2 or mRNA-1273. RESULTS: SARS-CoV-2-vaccination induced seroconversion efficacy in dialysis patients was similar to medical personnel (> 95%), but markedly impaired in kidney transplant recipients (42%). T-cellular immunity largely mimicked humoral results. Major risk factors of seroconversion failure were immunosuppressive drug number and type (belatacept, MMF-MPA, calcineurin-inhibitors) as well as vaccine type (BNT162b2 mRNA). Seroconversion rates induced by mRNA-1273 compared to BNT162b2 vaccine were 97% to 88% (p < 0.001) in dialysis and 49% to 26% in transplant patients, respectively. Specific IgG directed against the new binding domain of the spike protein (RDB) were significantly higher in dialysis patients vaccinated by mRNA-1273 (95%) compared to BNT162b2 (85%, p < 0.001). Vaccination appeared safe and highly effective demonstrating an almost complete lack of symptomatic COVID-19 disease after boost vaccination as well as ceased disease incidences during third pandemic wave in dialysis patients. CONCLUSION: Dialysis patients exhibit a remarkably high seroconversion rate of 95% after boost vaccination, while humoral response is impaired in the majority of transplant recipients. Immunosuppressive drug number and type as well as vaccine type (BNT162b2) are major determinants of seroconversion failure in both dialysis and transplant patients suggesting immune monitoring and adaption of vaccination protocols.

Platelet sarcoplasmic endoplasmic reticulum Ca2+-ATPase and mu-calpain activity are altered in type 2 diabetes mellitus and restored by rosiglitazone.

BACKGROUND: Platelets from patients with type 2 diabetes mellitus display hyperaggregability and increased thrombogenic potential. METHODS AND RESULTS: In platelets from patients with type 2 diabetes mellitus, we found enhanced tyrosine nitration and inactivation of the sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA-2), elevated platelet [Ca2+]i, and activation of mu-calpain. The tyrosine nitration of SERCA-2 and the activation of mu-calpain in vitro in platelets from healthy volunteers could be evoked in vitro by peroxynitrite. Platelet endothelial cell adhesion molecule-1 was identified as a mu-calpain substrate; its in vitro degradation was stimulated by peroxynitrite and prevented by calpain inhibitors. Calpain activation also was linked to hyperresponsiveness to thrombin and the loss of platelet sensitivity to nitric oxide synthase inhibitors. Platelets from patients with type 2 diabetes mellitus (hemoglobin A1c >6.6%) contained little or no intact platelet endothelial cell adhesion molecule-1, whereas degradation products were detectable. The peroxisome proliferator-activated receptor-gamma agonist rosiglitazone increased SERCA-2 expression in megakaryocytes, and treating patients with type 2 diabetes mellitus with rosiglitazone for 12 weeks increased platelet SERCA-2 expression and Ca2+-ATPase activity, decreased SERCA-2 tyrosine nitration, and normalized platelet [Ca2+]i. Rosiglitazone also reduced mu-calpain activity, normalized platelet endothelial cell adhesion molecule-1 levels, and partially restored platelet sensitivity to nitric oxide synthase inhibition. CONCLUSIONS: These data identify megakaryocytes/platelets as additional cellular targets for peroxisome proliferator-activated receptor-gamma agonists and highlight potential benefits of rosiglitazone therapy in cardiovascular diseases.

Relationship between diurnal blood pressure variation and diurnal blood glucose levels in type 2 diabetic patients.

BACKGROUND: Hypertension and hyperglycemia are established risk factors for progression of microangiopathies and macroangiopathies in type 2 diabetes mellitus. Cardiovascular risk is even more increased in diabetic patients with nocturnal nondipping or postprandial hyperglycemia. We therefore investigated the relationship between diurnal hyperglycemia and diurnal blood pressure (BP) variation in patients. METHODS: One hundred seven hypertensive type 2 diabetic patients received a 24-h ambulatory BP recording. In addition, a diurnal blood glucose profile was assessed under standardized conditions on the same day: before breakfast, 2 h after breakfast, before lunch, 2 h after lunch, before dinner, 2 h after dinner, at 10:00 pm, at midnight, and 3:00 am of the following day. Degrees of fasting and postprandial hyperglycemia were calculated as area under the curve. RESULTS: Nocturnal nondipping occurred in 73% of our patients. Nondippers showed higher postprandial blood glucose excursions than dippers (59.5 +/- 29 v 40.7 +/- 33 mmol h/L), whereas fasting hyperglycemia or glycosylated hemoglobin (HbA(1c)) were not significantly different (56.6 +/- 49 v 54.1 +/- 44 mmol h/L and 8.8% +/- 1.9% v 8.2% +/- 1.8% for nondippers and dippers, respectively). Nocturnal nondipping was associated with a higher urinary protein excretion and lower day/night heart rate ratio. Multivariate analysis revealed postprandial hyperglycemia as an independent predictor for nondipping. CONCLUSIONS: Postprandial rather than fasting hyperglycemia was associated with abnormal diurnal BP variation. These observations might favor treatment regimes targeted on postprandial hyperglycemia, which could restore dipping pattern.

Intra-individual variability and circadian rhythm of vascular endothelial growth factors in subjects with normal glucose tolerance and type 2 diabetes.

Increased levels of systemic vascular endothelial growth factors (VEGFs) in patients with diabetes are associated with increased risk of microvessel disease. On the other hand, low VEGF levels after intravitreal antibody application may be associated with acute cardiovascular complications and treatment failure. Individual levels of systemic VEGF vary in a wide range depending on analytical methods and quality of diabetes control. So far only limited information exists on intraindividual fluctuations over longer periods and circadian rhythms. We analysed the intraindividual variance of VEGF-A, VEGF-C and placental growth factor (PLGF) in CTAD (citrate-theophylline-adenine-dipyridamol) plasma as well as VEGF-A in serum over a period of 6 months in patients with stable controlled type 2 diabetes (10 M, 10 F) and age and sex matched subjects with normal glucose tolerance (NGT). Furthermore, circadian levels of VEGFs were controlled hourly from 7:30 a.m. to 7:30 p.m. under standardized metabolic ward conditions. In addition, the relationship to metabolic, hormonal and inflammatory biomarkers was analyzed. VEGF-A, VEGF-C and PLGF remained stable in plasma and VEGF-A in serum over 6 months in both groups. No circadian change was observed in VEGF-A serum and plasma concentrations. A minor decrease of VEGF-C plasma levels was evident after 5 p.m. in both groups and a significant peak of PLGF concentrations occurred after lunch, which was more pronounced in T2DM. In multivariate analysis, only serum VEGF-A correlated to diabetes duration, whereas VEGF-C only correlated to HbA1c and fasting blood glucose. We did not observe significant intraindividual variances for VEGF-A in serum and VEGF-A, VEGF-C and PLGF in CTAD plasma over a period of 6 months. Taken together, a single morning measurement of systemic VEGF levels after 7:30 am appears to be a reliable parameter for the individual risk associated with abnormal VEGF concentrations in blood. TRIAL REGISTRATION: NCT02325271.

Rosiglitazone improves glomerular hyperfiltration, renal endothelial dysfunction, and microalbuminuria of incipient diabetic nephropathy in patients.

Microalbuminuria, an early feature of diabetic nephropathy, indicates intrarenal endothelial damage. In type 2 diabetes, microalbuminuria is strongly related to insulin resistance. We therefore investigated whether rosiglitazone, an insulin-sensitizing drug that is known to improve endothelial dysfunction, was able to improve intrarenal endothelial dysfunction and microalbuminuria. Nineteen type 2 diabetic patients participated in this double-blind cross-over trial. Nine patients with newly diagnosed disease without microalbuminuria were randomized to a treatment with rosiglitazone or nateglinide, each for 12 weeks. Ten patients with microalbuminuria were randomized to rosiglitazone or placebo, each for 12 weeks in addition to their previous antidiabetic medication. After each treatment, glomerular filtration rate (GFR), renal plasma flow, and filtration fraction were measured before and after blockade of nitric oxide (NO) by intravenous administration of N-monomethyl-L-arginine-acetate (L-NMMA). Ten healthy subjects served as control subjects. Type 2 diabetic patients at baseline showed glomerular hyperfiltration compared with healthy control subjects. Rosiglitazone reduced elevated GFR and filtration fraction toward control primarily in patients with microalbuminuria (GFR: 133.4 +/- 9.8 vs. 119.6 +/- 8.7 ml/min; filtration fraction: 23.2 +/- 1.7 vs. 20.5 +/- 1.6% before and after rosiglitazone, respectively; control subjects: GFR 111.7 +/- 8.6 ml/min, filtration fraction 20.4 +/- 1.5%). Rosiglitazone improved intrarenal NO bioavailability in type 2 diabetes toward control as shown by infusion of L-NMMA. Rosiglitazone reduced albumin excretion in type 2 diabetes with microalbuminuria from 116.5 +/- 31 to 40.4 +/- 12 mg/day. Rosiglitazone ameliorated glomerular hyperfiltration in early type 2 diabetes, improved NO bioavailability, and lessened renal end-organ damage in type 2 diabetes with microalbuminuria.

Hypoglycemia and Cardiovascular Risk: Is There a Major Link?

Severe hypoglycemia is recognized to be one of the strongest predictors of macrovascular events, adverse clinical outcomes, and mortality in patients with type 2 diabetes. However, it is uncertain whether a direct pathophysiological link exists or whether hypoglycemia is primarily a marker of vulnerability to these events. Large clinical trials have reported an increased hazard ratio for all-cause mortality and cardiovascular events in patients with type 2 diabetes and severe hypoglycemia, but such an association has not been demonstrated in prospective trials of people with type 1 diabetes. Several cardiovascular effects occur during hypoglycemia either as a result of low blood glucose levels per se or through activation of the sympathoadrenal response: hemodynamic changes with an increase in cardiac work load and potential attenuation of myocardial perfusion, electrophysiological changes that may be arrhythmogenic, induction of a prothrombotic state, and release of inflammatory markers. Although the potential for a causal relationship has been demonstrated in mechanistic studies, the evidence from large prospective studies that hypoglycemia is a major causal contributor to cardiovascular events is limited to date. Other preexisting cardiovascular risk factors in addition to hypoglycemia may be the major link to the final cardiovascular event, but a low blood glucose level can trigger these events in patients with a high cardiovascular risk.

PPARgamma-agonist rosiglitazone increases number and migratory activity of cultured endothelial progenitor cells.

OBJECTIVE: Endothelial progenitor cells (EPC) are involved in the process of endothelial maintenance and angiogenesis and might be related to endothelial function. EPC function was shown to be impaired in type 2 diabetic patients. Since endothelial dysfunction of type 2 diabetic patients can be ameliorated by treatment with thiazolidinediones we asked whether this treatment might also influence number and function of EPC. METHODS AND RESULTS: We investigated 10 recently diagnosed type 2 diabetic patients and 10 age and sex matched healthy control subjects. After baseline examination of metabolic parameters and EPC, patients received 4 mg rosiglitazone b.i.d. for 12 weeks. We measured EPC number and migratory activity after 3 and 12 weeks of treatment. Migratory activity of EPCs obtained from type 2 diabetic patients at baseline was 40% lower compared to control (P<0.05). There was no significant difference of EPC number between patients (323+/-19) and controls (358+/-25) at baseline. Treatment of patients with rosiglitazone normalized impaired migratory activity of EPC and increased EPC number (464+/-33, P<0.01). In addition treatment improved glycemic control and insulin sensitivity. CONCLUSIONS: Twelve-week treatment with rosiglitazone improved EPC number and migratory activity of type 2 diabetic patients. The latter mechanism may contribute to the recently observed improvement of endothelial function by rosiglitazone in type 2 diabetes.

In type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control.

OBJECTIVE: Insulin resistance is an independent risk factor for arteriosclerosis and cardiovascular mortality. However, the mechanism by which insulin resistance contributes to arteriosclerosis is unknown. Conceivably, endothelial dysfunction could be involved. Therefore, we asked whether therapy for insulin resistance ameliorates any endothelial dysfunction. RESEARCH DESIGN AND METHODS: We performed a double-blind cross-over trial of 12 patients with recently diagnosed type 2 diabetes. They received rosiglitazone 4 mg b.i.d. for 12 weeks and nateglinide 60 mg b.i.d. for the same number of weeks in random order. To assess the degree of endothelial dysfunction, we used venous occlusion plethysmography. We studied vasodilation in response to acetylcholine (ACh) with and without exogenous insulin. The agents were infused into the brachial artery. Furthermore, we determined insulin resistance by euglycemic clamp. RESULTS: Glycemic control was comparable under rosiglitazone and nateglinide. Rosiglitazone ameliorated insulin resistance by 60% compared with nateglinide. ACh response was significantly increased after rosiglitazone treatment (maximum forearm blood flow 12.8 +/- 1.3 vs. 8.8 +/- 1.3 ml/100 ml after rosiglitazone and nateglinide, respectively; P < 0.05) but did not attain the level of healthy control subjects (14.0 +/- 0.7 ml/100 ml). Coinfusion of exogenous insulin increased ACh response further in the rosiglitazone group. N-monomethyl-L-arginine-acetate (L-NMMA), an antagonist of nitric oxide synthase, largely prevented the increased vasodilation after rosiglitazone, regardless of the presence or absence of insulin. Insulin sensitivity and blood flow response were found to be correlated (P < 0.01). CONCLUSIONS: Insulin resistance is a major contributor toward endothelial dysfunction in type 2 diabetes. Both endothelial dysfunction and insulin resistance are amenable to treatment by rosiglitazone.

Risk of and risk factors for hypoglycemia and associated arrhythmias in patients with type 2 diabetes and cardiovascular disease: a cohort study under real-world conditions.

AIMS: Severe hypoglycemia is one of the strongest predictors of adverse clinical outcomes in patients with type 2 diabetes. Our study addressed the question whether there is a relationship between hypoglycemic events (HE) and severe cardiac arrhythmias in type 2 diabetic patients with established clinical risk factors under real-world conditions. METHODS: We included 94 patients with type 2 diabetes and documented cardiovascular disease, in which interstitial glucose values and Holter ECG were recorded for 5 days in parallel. Patients received a stable treatment with insulin and/or sulfonylurea and were instructed to record symptoms of hypoglycemia or arrhythmias. RESULTS: Continuous glucose monitoring revealed 54 HE (interstitial glucose <3.1 mmol/l) in a total of 26 patients. Patients perceived only 39 % of HE during the day and 11 % of HE during the night. Patients with HE had a significantly higher number of severe ventricular arrhythmias [ventricular tachycardia (VT) 32.8 ± 60 vs. 0.9 ± 4.2, p = 0.019], and multivariate regression analysis revealed the duration of severe HE and TSH level as independent predictors of the occurrence of a VT. CONCLUSIONS: In conclusion, our study suggests that hypoglycemia might be able to trigger at least under certain circumstances, such as low TSH, ventricular arrhythmias under real-world conditions. The large number of unrecognized HE and VT in vulnerable patients treated with insulin or sulfonylurea should encourage the practitioner to focus on stable glucose control and to search for silent HE.

Endothelial dysfunction in young patients with long-term rheumatoid arthritis and low disease activity.

OBJECTIVE: Cardiovascular mortality is excessive in patients with rheumatoid arthritis (RA). It has been proposed that the chronic inflammatory state of RA contributes to accelerated atherosclerosis. The aim of this study was to determine whether endothelial dysfunction, an early sign of arteriosclerosis, is present in young, long-term RA patients receiving standard methotrexate (MTX) therapy. Furthermore, we tested whether etanercept (ENC), a TNF-alpha receptor blocker, resulted in improved endothelial function compared to MTX in the same patients. METHODS: We studied eight RA patients twice: (1) on MTX and (2) after MTX washout and receiving ENC. Eight healthy volunteers matching for age, gender, height, weight and conventional cardiovascular risk factors served as control (C). All participants received intrabrachial infusions of increasing doses of acetylcholine (ACh, endothelium-dependent vasodilator) and glyceryl-trinitrate (GTN, endothelium-independent vasodilator). Forearm blood flow (FBF) was measured by bilateral venous occlusion plethysmography. RESULTS: Disease activity of RA was comparably low during both MTX and ENC (DAS 28 3.9+/-0.3 and 3.5+/-0.3). FBF in response to ACh was reduced in RA compared to C (P<0.01). Switching from MTX to ENC failed to improve vascular responsiveness to ACh. GTN comparably increased FBF in all groups. CONCLUSIONS: Our study for the first time demonstrates that long-term RA is associated with manifested endothelial dysfunction. Switching from MTX to ENC in stable RA patients has no beneficial effect on endothelial function.

Increased total number but impaired migratory activity and adhesion of endothelial progenitor cells in patients on long-term hemodialysis.

BACKGROUND: Endothelial progenitor cells (EPCs), derived from bone marrow, contribute to vessel repair and neovascularization. Because uremia is a state of endothelial dysfunction associated with high cardiovascular mortality, as well as a state of reduced hematopoiesis, we studied the number and function of EPCs in patients on long-term hemodialysis (HD) therapy. METHODS: We counted the number of EPCs in 20 HD patients and 16 healthy volunteers. To assess EPC function, we measured migratory activity, adhesion to matrix proteins, and adhesion to endothelial cells. Furthermore, we measured blood levels of vascular endothelial growth factor (VEGF) and granulocyte-macrophage colony-stimulating factor, factors known to influence EPC kinetics. Circulating precursor cells (CD34+ , CD34+ /CD133+ , CD34+ /KDR+ cells) were counted by means of flow cytometric analysis. RESULTS: The number of EPCs in HD patients was significantly elevated compared with controls (459.7 +/- 92 versus 364.8 +/- 77.4 EPC/high-power field). However, migratory activity was markedly decreased in HD patients (47.5 +/- 27.7 versus 84.7 +/- 3.2 EPC/high-power field). EPCs of HD patients showed impaired adhesion to extracellular matrix and endothelial cells. VEGF blood levels in HD patients were 2-fold greater compared with controls. The number of circulating CD34+ and CD34+ /133+ cells was reduced in HD patients. There were no differences in total numbers of CD34+ /KDR+ cells. CONCLUSION: This study shows an elevated number, but pronounced functional impairment, of EPCs in patients on long-term HD therapy. The latter may result in limited endothelial repair, which, in turn, may contribute to endothelial dysfunction in this particular group of patients.

Relationship between hypoglycemic episodes and ventricular arrhythmias in patients with type 2 diabetes and cardiovascular diseases: silent hypoglycemias and silent arrhythmias.

OBJECTIVE: In patients with type 2 diabetes and cardiovascular diseases (CVDs), intensive treatment with insulin and/or sulfonylurea (SU) may be associated with excessive increased risk of hypoglycemic episodes. To evaluate the risk of critical arrhythmias related to glycemic variability, we carried out an observational study in type 2 diabetes patients with CVD. RESEARCH DESIGN AND METHODS: Thirty patients with type 2 diabetes and documented CVD who had been treated with insulin and/or SU underwent 5 days of monitoring with a continuous glucose measurement system along with parallel electrocardiogram recording for monitoring of ventricular arrhythmias. Twelve age-matched patients with documented CVD who received treatment with metformin and/or dipeptidyl peptidase-4 inhibitor served as the control group. Patients were receiving stable treatment, and were instructed to notice symptoms of arrhythmias and hypoglycemia, respectively. RESULTS: We observed a high incidence of asymptomatic severe episodes of hypoglycemia (<3.1 mmol/L) in patients receiving treatment with insulin and/or SU, whereas severe hypoglycemia did not develop in any of the control subjects. Patients with severe hypoglycemia (n = 12) had a higher number of severe ventricular arrhythmias (patients with versus without severe hypoglycemia, respectively: ventricular couplets 41.7 ± 81.8 vs. 5.5 ± 16.7; ventricular tachycardia 1.0 ± 1.9 vs. 0.1 ± 0.3). No direct correlation could be found among different variables of glucose profile, corrected QT interval, and ventricular arrhythmias. CONCLUSIONS: Our results suggest that severe episodes of hypoglycemia are associated with an increased risk of severe ventricular arrhythmias.