Michael G. Usher

Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice.

Inappropriate excess of the steroid hormone aldosterone, which is a mineralocorticoid receptor (MR) agonist, is associated with increased inflammation and risk of cardiovascular disease. MR antagonists are cardioprotective and antiinflammatory in vivo, and evidence suggests that they mediate these effects in part by aldosterone-independent mechanisms. Here we have shown that MR on myeloid cells is necessary for efficient classical macrophage activation by proinflammatory cytokines. Macrophages from mice lacking MR in myeloid cells (referred to herein as MyMRKO mice) exhibited a transcription profile of alternative activation. In vitro, MR deficiency synergized with inducers of alternatively activated macrophages (for example, IL-4 and agonists of PPARgamma and the glucocorticoid receptor) to enhance alternative activation. In vivo, MR deficiency in macrophages mimicked the effects of MR antagonists and protected against cardiac hypertrophy, fibrosis, and vascular damage caused by L-NAME/Ang II. Increased blood pressure and heart rates and decreased circadian variation were observed during treatment of MyMRKO mice with L-NAME/Ang II. We conclude that myeloid MR is an important control point in macrophage polarization and that the function of MR on myeloid cells likely represents a conserved ancestral MR function that is integrated in a transcriptional network with PPARgamma and glucocorticoid receptor. Furthermore, myeloid MR is critical for blood pressure control and for hypertrophic and fibrotic responses in the mouse heart and aorta.

Peroxisome Proliferator-Activated Receptor-γ–Mediated Effects in the Vasculature

Peroxisome proliferator-activated receptor (PPAR)-γ is a nuclear receptor and transcription factor in the steroid superfamily. PPAR-γ agonists, the thiazolidinediones, are clinically used to treat type 2 diabetes. In addition to its function in adipogenesis and increasing insulin sensitivity, PPAR-γ also plays critical roles in the vasculature. In vascular endothelial cells, PPAR-γ activation inhibits endothelial inflammation by suppressing inflammatory gene expression and therefore improves endothelial dysfunction. In vascular smooth muscle cells, PPAR-γ activation inhibits proliferation and migration and promotes apoptosis. In macrophages, PPAR-γ activation suppresses inflammation by regulating gene expression and increases cholesterol uptake and efflux. A recurring theme in many cell types is the modulation of the innate immunity system particularly through altering the activity of the nuclear factor &kgr;B. This system is likely to be even more prominent in modulating disease in vascular cells. The effects of PPAR-γ in the vascular cells translate into the beneficial function of this transcription factor in vascular disorders, including hypertension and atherosclerosis. Both human genetic studies and animal studies using transgenic mice have demonstrated the importance of PPAR-γ in these disorders. However, recent clinical studies have raised significant concerns about the cardiovascular side effects of thiazolidinediones, particularly rosiglitazone. Weighing the potential benefit and harm of PPAR-γ activation and exploring the functional mechanisms may provide a balanced view on the clinical use of these compounds and new approaches to the future therapeutics of vascular disorders associated with diabetes.

Ppars: the vasculature, inflammation and hypertension

Purpose of reviewPeroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors activated by nutrient molecules and their derivatives. Their role has been increasingly recognized to be important in hypertension, metabolic disorders and cardiovascular disease, including atherosclerosis. Control of innate inflammatory processes mostly through alteration of monocyte/macrophage phenotype promises to be a unifying paradigm in understanding the pleiotropic effects of PPAR agonists. Recent findingsAlthough PPAR-γ was the first to be described as an anti-inflammatory agent, both PPAR-α and PPAR-δ are now known to have similar effects as well. Inflammation is an important part of the damage caused by hypertensive diseases. PPARs have now been recognized as important determinants of macrophage polarization. Monocyte precursors of classical and alternatively activated macrophages are being defined as important changes in progression of cardiovascular disease associated with metabolic syndrome including hypertension, hyperlipidemia and obesity. SummaryA major unifying role for PPARs in hypertension and its complications through modification of the innate immune system and inflammation is increasingly likely. PPAR agonists may be beneficial, alone or in combination with other drugs that modify the inflammatory response, in treating hypertension, atherosclerosis and metabolic derangements associated with obesity.

PPAR-gamma in the Cardiovascular System.

Peroxisome proliferator-activated receptor-γ (PPAR-γ), an essential transcriptional mediator of adipogenesis, lipid metabolism, insulin sensitivity, and glucose homeostasis, is increasingly recognized as a key player in inflammatory cells and in cardiovascular diseases (CVD) such as hypertension, cardiac hypertrophy, congestive heart failure, and atherosclerosis. PPAR-γ agonists, the thiazolidinediones (TZDs), increase insulin sensitivity, lower blood glucose, decrease circulating free fatty acids and triglycerides, lower blood pressure, reduce inflammatory markers, and reduce atherosclerosis in insulin-resistant patients and animal models. Human genetic studies on PPAR-γ have revealed that functional changes in this nuclear receptor are associated with CVD. Recent controversial clinical studies raise the question of deleterious action of PPAR-γ agonists on the cardiovascular system. These complex interactions of metabolic responsive factors and cardiovascular disease promise to be important areas of focus for the future.

Sex dimorphic actions of rosiglitazone in generalised peroxisome proliferator-activated receptor-γ (PPAR-γ)-deficient mice

Aims/hypothesisThe aim of this study was to determine the dependency on peroxisome proliferator-activated receptor-γ (PPAR-γ) of insulin sensitisation and glucose homeostasis by thiazolidinediones using a global Ppar-γ (also known as Pparg)-knockout mouse model.MethodsGlobal Mox2-Cre-Ppar-γ-knockout (MORE-PGKO) mice were treated with rosiglitazone and analysed for insulin sensitivity and glucose metabolism. Metabolic and hormonal variables were determined. Adipose and other tissues were measured and analysed for gene expression.ResultsRosiglitazone induced regrowth of fat in female but not male MORE-PGKO mice, and only in specific depots. Insulin sensitivity increased but, surprisingly, was not associated with the typical changes in adipokines, plasma NEFA or tissue triacylglycerol. However, increases in alternatively activated macrophage markers, which have been previously associated with metabolic improvement, were observed in the regrown fat. Rosiglitazone improved glucose homeostasis but not insulin sensitivity in male MORE-PGKO mice, with further increase of insulin associated with an apparent expansion of pancreatic islets.Conclusions/interpretationStimulating fat growth by rosiglitazone is sufficient to improve insulin sensitivity in female mice with 95% PPAR-γ deficiency. This increase in insulin sensitivity is not likely to be due to changes typically seen in adipokines or lipids but may involve changes in macrophage polarisation that occur independent of PPAR-γ. In contrast, rosiglitazone improves glucose homeostasis in male mice with similar PPAR-γ deficiency by increasing insulin production independent of changes in adiposity. Further, the insulin-sensitising effect of rosiglitazone is dependent on PPAR-γ in this male lipodystrophic model.

Myeloid mineralocorticoid receptor during experimental ischemic stroke: effects of model and sex.

Background Mineralocorticoid receptor (MR) antagonists have protective effects in the brain during experimental ischemic stroke, and we have previously demonstrated a key role for myeloid MR during stroke pathogenesis. In this study, we explore both model- and sex-specific actions of myeloid MR during ischemic stroke. Methods and Results The MR antagonist eplerenone significantly reduced the infarct size in male (control, 99.5 mm3; eplerenone, 74.2 mm3; n=8 to 12 per group) but not female (control, 84.0 mm3; eplerenone, 83.7 mm3; n=6 to 7 per group) mice after transient (90-minute) middle cerebral artery occlusion. In contrast to MR antagonism, genetic ablation of myeloid MR in female mice significantly reduced infarct size (myeloid MR knockout, 9.4 mm3 [5.4 to 36.6]; control, 66.0 mm3 [50.0 to 81.4]; n=6 per group) after transient middle cerebral artery occlusion. This was accompanied by reductions in inflammatory gene expression and improvement in neurological function. In contrast to ischemia-reperfusion, myeloid MR–knockout mice were not protected from permanent middle cerebral artery occlusion. The infarct size and inflammatory response after permanent occlusion showed no evidence of protection by myeloid MR knockout in photothrombotic and intraluminal filament models of permanent occlusion. Conclusions These studies demonstrate that MR antagonism is protective in male but not female mice during transient middle cerebral artery occlusion, whereas genetic ablation of myeloid MR is protective in both male and female mice. They also highlight important mechanistic differences in the role of myeloid cells in different models of stroke and confirm that specific myeloid phenotypes play key roles in stroke protection.

Interhospital transfer handoff practices among US tertiary care centers: A descriptive survey

BACKGROUND Interhospital transfer is an understudied area within transitions of care. The process by which hospitals accept and transfer patients is not well described. National trends and best practices are unclear. OBJECTIVE To describe the demographics of large transfer centers, to identify common handoff practices, and to describe challenges and notable innovations involving the interhospital transfer handoff process. DESIGN AND PARTICIPANTS A convenience sample of 32 tertiary care centers in the United States was studied. Respondents were typically transfer center directors surveyed by phone. MAIN MEASURES Data regarding transfer center demographics, handoff communication practices, electronic infrastructure, and data sharing were obtained. RESULTS The median number of patients transferred each month per receiving institution was 700 (range, 250-2500); on average, 28% of these patients were transferred to an intensive care unit. Transfer protocols and practices varied by institution. Transfer center coordinators typically had a medical background (78%), and critical care-trained registered nurse was the most prevalent (38%). Common practices included: mandatory recorded 3-way physician-to-physician conversation (84%) and mandatory clinical status updates prior to patient arrival (81%). However, the timeline of clinical status updates was variable. Less frequent transfer practices included: electronic medical record (EMR) cross-talk availability and utilization (23%), real-time transfer center documentation accessibility in the EMR (32%), and referring center clinical documentation available prior to transport (29%). A number of innovative strategies to address challenges involving interhospital handoffs are reported. CONCLUSIONS Interhospital transfer practices vary widely amongst tertiary care centers. Practices that lead to improved patient handoffs and reduced medical errors need additional prospective evaluation. Journal of Hospital Medicine 2016;11:413-417.

PPAR-γin the Cardiovascular System

Peroxisome proliferator-activated receptor-γ (PPAR-γ), an essential transcriptional mediator of adipogenesis, lipid metabolism, insulin sensitivity, and glucose homeostasis, is increasingly recognized as a key player in inflammatory cells and in cardiovascular diseases (CVD) such as hypertension, cardiac hypertrophy, congestive heart failure, and atherosclerosis. PPAR-γ agonists, the thiazolidinediones (TZDs), increase insulin sensitivity, lower blood glucose, decrease circulating free fatty acids and triglycerides, lower blood pressure, reduce inflammatory markers, and reduce atherosclerosis in insulin-resistant patients and animal models. Human genetic studies on PPAR-γ have revealed that functional changes in this nuclear receptor are associated with CVD. Recent controversial clinical studies raise the question of deleterious action of PPAR-γ agonists on the cardiovascular system. These complex interactions of metabolic responsive factors and cardiovascular disease promise to be important areas of focus for the future.

Information handoff and outcomes of critically ill patients transferred between hospitals

PURPOSE Patients transferred between hospitals are at high risk of adverse events and mortality. This study aims to identify which components of the transfer handoff process are important predictors of adverse events and mortality. MATERIALS AND METHODS We conducted a retrospective, observational study of 335 consecutive patient transfers to 3 intensive care units at an academic tertiary referral center. We assessed the relationship between handoff documentation completeness and patient outcomes. The primary outcome was in-hospital mortality. Secondary outcomes included adverse events, duplication of labor, disposition error, and length of stay. RESULTS Transfer documentation was frequently absent with overall completeness of 58.3%. Adverse events occurred in 42% of patients within 24 hours of arrival, with an overall in-hospital mortality of 17.3%. Higher documentation completeness was associated with reduced in-hospital mortality (odds ratio [OR], 0.07; 95% confidence interval [CI], 0.02 to 0.38; P = .002), reduced adverse events (coefficient, -2.08; 95% CI, -2.76 to -1.390; P < .001), and reduced duplication of labor (OR, 0.19; 95% CI, 0.04 to 0.88; P = .033) when controlling for severity of illness. CONCLUSIONS Documentation completeness is associated with improved outcomes and resource utilization in patients transferred between hospitals.

PPAR- in the Cardiovascular System

Peroxisome proliferator-activated receptor-γ (PPAR-γ), an essential transcriptional mediator of adipogenesis, lipid metabolism, insulin sensitivity, and glucose homeostasis, is increasingly recognized as a key player in inflammatory cells and in cardiovascular diseases (CVD) such as hypertension, cardiac hypertrophy, congestive heart failure, and atherosclerosis. PPAR-γ agonists, the thiazolidinediones (TZDs), increase insulin sensitivity, lower blood glucose, decrease circulating free fatty acids and triglycerides, lower blood pressure, reduce inflammatory markers, and reduce atherosclerosis in insulin-resistant patients and animal models. Human genetic studies on PPAR-γ have revealed that functional changes in this nuclear receptor are associated with CVD. Recent controversial clinical studies raise the question of deleterious action of PPAR-γ agonists on the cardiovascular system. These complex interactions of metabolic responsive factors and cardiovascular disease promise to be important areas of focus for the future.