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.

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.

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.

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.

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.

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.

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.

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.

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.

The metabolic syndrome and cardiovascular disease - an ongoing tsunami.

The metabolic syndrome represents a cluster of closely connected premorbid risk factors or diseases with visceral obesity type 2 diabetes, hypertension and low HLD/hypertriglyceridemia as established traits affecting about 20% in the adult European populations. This syndrome develops on a complex soil with overnutrition, low physical activity and psychosocial stress. Common comorbidities are fatty liver, sleep apnoe and endothelial dysfunction with cardiovascular complications, nephropathy and type 2 diabetes as "end-stage" diseases. Thus, a rational diagnostic is needed to elucidate the complex cluster of diseases as basis for an integrated therapy. There is a clear priority for life style intervention, however, most diseases of the metabolic syndrome need medical treatment. Medical treatment of single traits has to take into account possible pleiotropic or adverse effects on the other traits. This paper presents the pros and cons of major drug intervention for type 2 diabetes, hypertension, dyslipidemia and hypercoagulation in the context with the metabolic syndrome.

Influence of peritoneal dialysis solution on measurements of fluid status by bioimpedance spectroscopy.

PURPOSE AND METHODS: The accurate estimation of volume status is a central problem in dialysis patients. Recently, a bioimpedance spectroscopy (BIS) device (BCM Body Composition Monitor FMC, Germany) has attained growing interest in this regard. By processing the raw data for extracellular water (ECW) and intracellular water (ICW) by means of a validated body composition model, this device allows a quantification of the individual fluid overload (FO) compared to a representative healthy population. In this study, we addressed the issue whether the presence of peritoneal dialysate has an impact on measurements of FO by BIS in PD patients. RESULTS: Forty-two BIS measurements using the BCM device were performed both in the absence (D-) and presence (D+) of peritoneal dialysate in 17 stable PD patients. Data for ECW, ICW and FO (D+; D-) were analyzed by paired t test and linear regression. Mean FO was 0.99 ± 1.17 L in D- and 0.94 ± 1.27 in D+ (p = n.s. paired t test). Linear regression demonstrated an excellent degree of conformity between FO (D-) and FO (D+) (r (2) = 0.93). CONCLUSION: The presence of peritoneal fluid in PD patients has a negligible influence on measurements of FO by BIS. The BIS measurements can be therefore conveniently and reliably done without emptying the peritoneal cavity; this may facilitate the use of BIS in this particular group of patients.

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.

Conversion of IGT to type 2 diabetes mellitus is associated with incident cases of hypertension: a post-hoc analysis of the STOP-NIDDM trial.

BACKGROUND: Type 2 diabetes mellitus and hypertension are closely associated and contribute together to microvascular and macrovascular end-organ damage. Prevalence of hypertension is increased even in the prediabetic state. However, there is little information available about the relationship between incidence of hypertension and a deterioration of glucose tolerance from impaired glucose tolerance (IGT) to diabetes. METHODS: To clarify these issues we analysed data from the Stop non insulin dependent diabetes mellitus (STOP-NIDDM) trial - a prospective interventional study for the prevention of type 2 diabetes in people with prediabetes using the alpha-glucosidase inhibitor acarbose. Hypertension was already present at study entry in 702 (51.3%) of 1368 patients who were eligible for intention-to-treat analysis. RESULTS: A total of 96 out of the 666 normotensive individuals at baseline developed hypertension during the 3.3-year follow-up. The strongest risk factors for time to development of hypertension were abdominal obesity at baseline [hazard ratio 1.91, 95% confidence interval (CI) 1.19-3.05, P < 0.01] and worsening of glucose tolerance (hazard ratio 1.54, 95% CI 1.02-2.32, P < 0.05), whereas acarbose treatment reduced the risk of hypertension (hazard ratio 0.59, 95% CI 0.39-0.90, P < 0.05). CONCLUSION: A significant relationship was found between the development of type 2 diabetes and hypertension in patients with IGT, and treatment with acarbose, which primarily improved postprandial hyperglycaemia, reduced the incidence of hypertension as well as diabetes. This suggests that the two entities shared 'common soil'.

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.