141 research outputs found
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Grand Rounds: Asbestos-Related Pericarditis in a Boiler Operator
Context: Occupational and environmental exposures to asbestos remain a public health problem even in developed countries. Because of the long latency in asbestos-related pathology, past asbestos exposure continues to contribute to incident disease. Asbestos most commonly produces pulmonary pathology, with asbestos-related pleural disease as the most common manifestation. Although the pleurae and pericardium share certain histologic characteristics, asbestos-related pericarditis is rarely reported. Case presentation: We present a 59-year-old man who worked around boilers for almost 30 years and was eventually determined to have calcific, constrictive pericarditis. He initially presented with an infectious exacerbation of chronic bronchitis. Chest radiographs demonstrated pleural and pericardial calcifications. Further evaluation with cardiac catheterization showed a hemodynamic picture consistent with constrictive pericarditis. A high-resolution computerized tomography scan of the chest demonstrated dense calcification in the pericardium, right pleural thickening and nodularity, right pleural plaque without calcification, and density in the right middle lobe. Pulmonary function testing showed mild obstruction and borderline low diffusing capacity. Discussion: Based on the patient’s occupational history, the presence of pleural pathology consistent with asbestos, previous evidence that asbestos can affect the pericardium, and absence of other likely explanations, we concluded that his pericarditis was asbestos-related. Relevance to clinical practice: Similar to pleural thickening and plaque formation, asbestos may cause progressive fibrosis of the pericardium
Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial
Aims Thiazolidinediones are insulin sensitizers, and are associated with fluid retention and increased risk of heart failure (HF) in people with type 2 diabetes. We assessed fatal and non-fatal HF events and their outcome, and identified HF predictors in the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes) trial population. Methods and results In a multicentre, open-label study, we randomized 4447 people with type 2 diabetes on metformin or sulfonylurea monotherapy with a mean HbA(1c) of 7.9% to add-on rosiglitazone (n = 2220) or to a combination of metformin and sulfonylurea (n = 2227) and followed them over 5.5 years on average. Heart failure hospitalizations and deaths were adjudicated by a Clinical Endpoint Committee using pre-specified criteria. Independent predictors of HF events were identified out of a group of 30 pre-specified clinical, demographic, and biological variables. In the rosiglitazone group, the risk of HF death or hospitalization was doubled: HR = 2.10 (95% CI, 1.35-3.27): the excess HF event rate was 2.6 (1.1-4.1) per 1000 person-years. An excess in HF deaths was observed (10 vs. two), including four HF deaths as first HF events. By contrast, there was no increase in cardiovascular mortality or hospitalization (HR = 0.99, 95% Cl, 0.85-1.16) or in cardiovascular deaths (60 vs. 71). Independent predictors of HF were rosiglitazone assignment, age, urinary albumin : creatinine ratio, body mass index, and systolic blood pressure at baseline. A history of previous cardiovascular disease was not predictive of HF. Duration of HF hospitalization and rate of HF re-hospitalization were similar in the two groups. Conclusion These findings confirm the increased risk of HF events in people treated with rosiglitazone and support the recommendation that this agent should not continue to be used in people developing symptomatic HF while using the medication. Close follow-up for the risk of HF should be offered to elderly people, people with markedly increased body mass index, people with microalbuminuria/proteinuria, and people with increased systolic blood pressur
Peroxisome Proliferator-Activated Receptor-Gamma Agonists Suppress Tissue Factor Overexpression in Rat Balloon Injury Model with Paclitaxel Infusion
The role and underlying mechanisms of rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, on myocardial infarction are poorly understood. We investigated the effects of this PPAR-γ agonist on the expression of tissue factor (TF), a primary molecule for thrombosis, and elucidated its underlying mechanisms. The PPAR-γ agonist inhibited TF expression in response to TNF-α in human umbilical vein endothelial cells, human monocytic leukemia cell line, and human umbilical arterial smooth muscle cells. The overexpression of TF was mediated by increased phosphorylation of mitogen-activated protein kinase (MAPK), which was blocked by the PPAR-γ agonist. The effective MAPK differed depending on each cell type. Luciferase and ChIP assays showed that transcription factor, activator protein-1 (AP-1), was a pivotal target of the PPAR-γ agonist to lower TF transcription. Intriguingly, two main drugs for drug-eluting stent, paclitaxel or rapamycin, significantly exaggerated thrombin-induced TF expression, which was also effectively blocked by the PPAR-γ agonist in all cell types. This PPAR-γ agonist did not impair TF pathway inhibitor (TFPI) in three cell types. In rat balloon injury model (Sprague-Dawley rats, n = 10/group) with continuous paclitaxel infusion, the PPAR-γ agonist attenuated TF expression by 70±5% (n = 4; P<0.0001) in injured vasculature. Taken together, rosiglitazone reduced TF expression in three critical cell types involved in vascular thrombus formation via MAPK and AP-1 inhibitions. Also, this PPAR-γ agonist reversed the paclitaxel-induced aggravation of TF expression, which suggests a possibility that the benefits might outweigh its risks in a group of patients with paclitaxel-eluting stent implanted
Evaluation of in-stent restenosis in the APPROACH trial (assessment on the prevention of progression by Rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history)
To determine (1) the medium-term effect of rosiglitazone and glipizide on intra-stent neointima hyperplasia, (2) restenosis pattern as assessed by intra-vascular ultrasound (IVUS) and quantitative coronary angiography (QCA) in patients with T2DM and coronary artery disease. A total of 462 patients with T2DM were randomized to rosiglitazone or glipizide for up to 18 months in the APPROACH trial, and had evaluable baseline and follow-up IVUS examinations. There was no significant difference in the size of plaque behind stent between the rosiglitazone and glipizide groups at 18 months among those treated with a bare metal stent (−5.6 mm3 vs. 1.9 mm3; P = 0.61) or with a drug-eluting stent (12.1 mm3 vs. 5.5 mm3; P = 0.09). Similarly, there was no significant difference in percentage intimal hyperplasia volume between the rosiglitazone and glipizide groups at 18 months among those treated with a bare metal stent (24.1% vs. 19.8%; P = 0.38) or with a drug-eluting stent (9.8% vs. 8.3%; P = 0.57). QCA data (intra-stent late loss, intra-stent diameter stenosis or binary restenosis) were not different between the rosiglitazone and glipizide groups. This study suggests that both rosiglitazone and glipizide have a similar effect on neointimal growth at medium term follow-up, a finding that warrants investigation in dedicated randomized trials
Chemical Proteomics-Based Analysis of Off-target Binding Profiles for Rosiglitazone and Pioglitazone: Clues for Assessing Potential for Cardiotoxicity
Drugs exert desired and undesired effects based on their binding interactions with protein target(s) and off-target(s), providing evidence for drug efficacy and toxicity. Pioglitazone and rosiglitazone possess a common functional core, glitazone, which is considered a privileged scaffold upon which to build a drug selective for a given target—in this case, PPARγ. Herein, we report a retrospective analysis of two variants of the glitazone scaffold, pioglitazone and rosiglitazone, in an effort to identify off-target binding events in the rat heart to explain recently reported cardiovascular risk associated with these drugs. Our results suggest that glitazone has affinity for dehydrogenases, consistent with known binding preferences for related rhodanine cores. Both drugs bound ion channels and modulators, with implications in congestive heart failure, arrhythmia, and peripheral edema. Additional proteins involved in glucose homeostasis, synaptic transduction, and mitochondrial energy production were detected and potentially contribute to drug efficacy and cardiotoxicity
EphA2-receptor deficiency exacerbates myocardial infarction and reduces survival in hyperglycemic mice
Background
We have previously shown that EphrinA1/EphA expression profile changes in response to myocardial infarction (MI), exogenous EphrinA1-Fc administration following MI positively influences wound healing, and that deletion of the EphA2 Receptor (EphA2-R) exacerbates injury and remodeling. To determine whether or not ephrinA1-Fc would be of therapeutic value in the hyperglycemic infarcted heart, it is critical to evaluate how ephrinA1/EphA signaling changes in the hyperglycemic myocardium in response to MI.
Methods
Streptozotocin (STZ)-induced hyperglycemia in wild type (WT) and EphA2-receptor mutant (EphA2-R-M) mice was initiated by an intraperitoneal injection of STZ (150 mg/kg) 10 days before surgery. MI was induced by permanent ligation of the left anterior descending coronary artery and analyses were performed at 4 days post-MI. ANOVAs with Student-Newman Keuls multiple comparison post-hoc analysis illustrated which groups were significantly different, with significance of at least p < 0.05.
Results
Both WT and EphA2-R-M mice responded adversely to STZ, but only hyperglycemic EphA2-R-M mice had lower ejection fraction (EF) and fractional shortening (FS). At 4 days post-MI, we observed greater post-MI mortality in EphA2-R-M mice compared with WT and this was greater still in the EphA2-R-M hyperglycemic mice. Although infarct size was greater in hyperglycemic WT mice vs normoglycemic mice, there was no difference between hyperglycemic EphA2-R-M mice and normoglycemic EphA2-R-M mice. The hypertrophic response that normally occurs in viable myocardium remote to the infarct was noticeably absent in epicardial cardiomyocytes and cardiac dysfunction worsened in hyperglycemic EphA2-R-M hearts post-MI. The characteristic interstitial fibrotic response in the compensating myocardium remote to the infarct also did not occur in hyperglycemic EphA2-R-M mouse hearts to the same extent as that observed in the hyperglycemic WT mouse hearts. Differences in neutrophil and pan-leukocyte infiltration and serum cytokines implicate EphA2-R in modulation of injury and the differences in ephrinA1 and EphA6-R expression in governing this are discussed.
Conclusions
We conclude that EphA2-mutant mice are more prone to hyperglycemia-induced increased injury, decreased survival, and worsened LV remodeling due to impaired wound healing
Transcriptome Alteration in the Diabetic Heart by Rosiglitazone: Implications for Cardiovascular Mortality
BACKGROUND: Recently, the type 2 diabetes medication, rosiglitazone, has come under scrutiny for possibly increasing the risk of cardiac disease and death. To investigate the effects of rosiglitazone on the diabetic heart, we performed cardiac transcriptional profiling and imaging studies of a murine model of type 2 diabetes, the C57BL/KLS-lepr(db)/lepr(db) (db/db) mouse. METHODS AND FINDINGS: We compared cardiac gene expression profiles from three groups: untreated db/db mice, db/db mice after rosiglitazone treatment, and non-diabetic db/+ mice. Prior to sacrifice, we also performed cardiac magnetic resonance (CMR) and echocardiography. As expected, overall the db/db gene expression signature was markedly different from control, but to our surprise was not significantly reversed with rosiglitazone. In particular, we have uncovered a number of rosiglitazone modulated genes and pathways that may play a role in the pathophysiology of the increase in cardiac mortality as seen in several recent meta-analyses. Specifically, the cumulative upregulation of (1) a matrix metalloproteinase gene that has previously been implicated in plaque rupture, (2) potassium channel genes involved in membrane potential maintenance and action potential generation, and (3) sphingolipid and ceramide metabolism-related genes, together give cause for concern over rosiglitazone's safety. Lastly, in vivo imaging studies revealed minimal differences between rosiglitazone-treated and untreated db/db mouse hearts, indicating that rosiglitazone's effects on gene expression in the heart do not immediately turn into detectable gross functional changes. CONCLUSIONS: This study maps the genomic expression patterns in the hearts of the db/db murine model of diabetes and illustrates the impact of rosiglitazone on these patterns. The db/db gene expression signature was markedly different from control, and was not reversed with rosiglitazone. A smaller number of unique and interesting changes in gene expression were noted with rosiglitazone treatment. Further study of these genes and molecular pathways will provide important insights into the cardiac decompensation associated with both diabetes and rosiglitazone treatment
Prognostic value of CT coronary angiography in diabetic and non-diabetic subjects with suspected CAD: importance of presenting symptoms
AIM:
To assess the prognostic relevance of 64-slice computed tomography coronary angiography (CT-CA) and symptoms in diabetics and non-diabetics referred for cardiac evaluation.
METHODS:
We followed 210 patients with diabetes type 2 (DM) and 203 non-diabetic patients referred for CT-CA for ruling out coronary artery disease (CAD). Patients were without known history of CAD and were divided into four categories on the basis of symptoms at presentation (none, atypical angina, typical angina and dyspnoea). Clinical end points were major cardiac events (MACE): cardiac-related death, non-fatal myocardial infarction, unstable angina and cardiac revascularizations. Cox proportional hazard models, with and without adjustment for risk factors and multiplicative interaction term (obstructive CAD
7 DM), were developed to predict outcome.
RESULTS:
DM patients with dyspnoea or who were asymptomatic showed a higher prevalence of obstructive CAD than non-diabetics (p\u2009 64\u20090.01). At mean follow-up of 20.4 months, DM patients had worse cardiac event-free survival in comparison with non-DM patients (90% vs. 81%, p\u2009=\u20090.02). In multivariate analysis, CT-CA evidence of obstructive CAD (in DM patients: HR: 6.4; 95% CI: 2.3-17.5; p\u2009100 in non-DM patients (HR: 5.6; 95% CI: 1.4-21.5; p\u2009=\u20090.01). In Cox regression analysis of the overall population, interaction term obstructive CAD
7 DM resulted in non-significance.
CONCLUSIONS:
Among DM patients, dyspnoea carried a high event risk with a MACE rate four times higher. CT-CA findings were strongly predictive of outcome and proved valuable for further risk stratification
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