Acute Kidney Injury in Patients Undergoing Both Right and Left Heart Catheterization with Coronary Angiography Vs Right Heart Catheterization Only.

BACKGROUND: Recent studies have challenged the reported causal association between acute kidney injury and iodinated contrast administration, ascribing some cases to changes in renal function that are independent of contrast administration. METHODS: We studied 1779 consecutive patients undergoing right heart catheterization (RHC) at a Veterans Administration Medical Center. We compared the incidence of acute kidney injury and of nephropathy at 3 months in veterans undergoing right and left heart catheterization and coronary angiography (R&LHC) to the incidence of acute kidney injury and of nephropathy at 3 months in patients undergoing RHC only. RESULTS: The incidence of acute kidney injury at 3 days was 47 (9.7%) in the R&LHC group and 58 (9.6%) in the RHC group (P = .99). The incidence of nephropathy at 3 months was 115 (17%) in the L&RHC group and 141 (19.2%) in the RHC group (P = 0.31). In a propensity score-paired analysis of 782 patients and after adjustment for baseline characteristics, the odds ratio for acute kidney injury at 3 days among patients undergoing R&LHC was 1.25 (95% confidence interval, 0.65-2.42; P = .50), and the odds ratio for nephropathy at 3 months was 0.69 (95% confidence interval, 0.46-1.04; P = .08). CONCLUSION: The incidence of changes in creatinine consistent with acute kidney injury at 3 days and of nephropathy at 3 months was not significantly different in patients undergoing R&LHC compared with patients undergoing RHC only. This supports the thesis that not all changes in creatinine after procedures involving administration of contrast are caused by the contrast.

Polyphenols Targeting MAP Kinase Signaling Pathway in Neurological Diseases: Understanding Molecular Mechanisms and Therapeutic Targets.

Polyphenols are a class of secondary metabolic products found in plants that have been extensively studied for how well they regulate biological processes, such as the proliferation of cells, autophagy, and apoptosis. The mitogen-activated protein kinase (MAPK)-mediated signaling cascade is currently identified as a crucial pro-inflammatory pathway that plays a significant role in the development of neuroinflammation. This process has been shown to contribute to the pathogenesis of several neurological conditions, such as Alzheimer's disease (AD), Parkinson's disease (PD), CNS damage, and cerebral ischemia. Getting enough polyphenols through eating habits has resulted in mitigating the effects of oxidative stress (OS) and lowering the susceptibility to associated neurodegenerative disorders, including but not limited to multiple sclerosis (MS), AD, stroke, and PD. Polyphenols possess significant promise in dealing with the root cause of neurological conditions by modulating multiple therapeutic targets simultaneously, thereby attenuating their complicated physiology. Several polyphenolic substances have demonstrated beneficial results in various studies and are presently undergoing clinical investigation to treat neurological diseases (NDs). The objective of this review is to provide a comprehensive summary of the different aspects of the MAPK pathway involved in neurological conditions, along with an appraisal of the progress made in using polyphenols to regulate the MAPK signaling system to facilitate the management of NDs.

Cardiac Effects of Phosphodiesterase-5 Inhibitors: Efficacy and Safety.

The coexistence of cardiovascular disease and erectile dysfunction is widespread, possibly owing to underlying endothelial dysfunction in both diseases. Millions of patients with cardiovascular disease are prescribed phosphodiesterase-5 (PDE5) inhibitors for the management of erectile dysfunction. Although the role of PDE5 inhibitors in erectile dysfunction therapy is well established, their effects on the cardiovascular system are unclear. Preclinical studies investigating the effect of PDE5 inhibitors on ischemia-reperfusion injury, pressure overload-induced hypertrophy, and chemotoxicity suggested a possible clinical role for each of these medications; however, attempts to translate these findings to the bedside have resulted in mixed outcomes. In this review, we explore the biologic preclinical effects of PDE5 inhibitors in mediating cardioprotection. We then examine clinical trials investigating PDE5 inhibition in patients with heart failure, coronary artery disease, and ventricular arrhythmias and discuss why the studies likely have yet to show positive results and efficacy with PDE5 inhibition despite no safety concerns.

Exploring the Immune-Boosting Functions of Vitamins and Minerals as Nutritional Food Bioactive Compounds: A Comprehensive Review.

Food components have long been recognized to play a fundamental role in the growth and development of the human body, conferring protective functionalities against foreign matter that can be severe public health problems. Micronutrients such as vitamins and minerals are essential to the human body, and individuals must meet their daily requirements through dietary sources. Micronutrients act as immunomodulators and protect the host immune response, thus preventing immune evasion by pathogenic organisms. Several experimental investigations have been undertaken to appraise the immunomodulatory functions of vitamins and minerals. Based on these experimental findings, this review describes the immune-boosting functionalities of micronutrients and the mechanisms of action through which these functions are mediated. Deficiencies of vitamins and minerals in plasma concentrations can lead to a reduction in the performance of the immune system functioning, representing a key contributor to unfavorable immunological states. This review provides a descriptive overview of the characteristics of the immune system and the utilization of micronutrients (vitamins and minerals) in preventative strategies designed to reduce morbidity and mortality among patients suffering from immune invasions or autoimmune disorders.

Radial Artery Access Complications: Prevention, Diagnosis and Management.

The transradial approach for cardiac catheterization, coronary angiography, and percutaneous intervention is associated with a lower risk of access site-related complications compared to the transfemoral approach. However, with increasing utilization of transradial access for not only coronary procedures but also peripheral vascular procedures, healthcare personnel are more likely to encounter radial access site complications, which can be associated with morbidity and mortality. There is significant heterogeneity in the reporting of incidence, manifestations, and management of radial access site complications, at least partly due to vague presentation and under-diagnosis. Therefore, physicians performing procedures via transradial access should be aware of possible complications and remain vigilant to prevent their occurrence. Intraprocedural complications of transradial access procedures, which include spasm, catheter kinking, and arterial dissection or perforation, may lead to patient discomfort, increased procedure time, and a higher rate of access site cross over. Post-procedural complications such as radial artery occlusion, hematoma, pseudoaneurysm, arteriovenous fistula, or nerve injury could lead to patient discomfort and limb dysfunction. When radial access site complications occur, comprehensive evaluation and prompt treatment is necessary to reduce long-term consequences. In this report, we review the incidence, clinical factors, and management strategies for radial access site complications associated with cardiac catheterization.

Novel oral anticoagulants in the treatment of radial artery occlusion.

Transradial access of the vascular system for coronary angiography and percutaneous coronary intervention has become the primary approach in several cardiac catheterization laboratories across the world. The paradigm shift from transfemoral access has been driven by improved outcomes in patients undergoing these cardiac procedures by transradial access. Radial artery occlusion is the most common vascular complication of transradial coronary procedures. Only a few studies have reported on the optimal treatment of radial artery occlusion, with ulnar artery compression and anticoagulation, especially with low-molecular-weight heparin, having shown the best results. In this case series, four patients who were found to have evidence of post-cardiac catheterization radial artery occlusion on ultrasound imaging were treated with a 30-day course of apixaban. Three of the four patients showed complete resolution of radial artery occlusion with addition of apixaban to current standard therapeutic strategies. This case series shows that treatment with novel oral anticoagulants can be an alternative and more convenient option compared to subcutaneous injection of low-molecular heparin for anticoagulation in patients with post-coronary angiography radial artery occlusion.

Angiotensin-Converting Enzyme Inhibitors and Contrast-Associated Acute Kidney Injury After Coronary Angiography and Intervention.

Contrast-associated acute kidney injury has multiple definitions, but is generally described as worsening renal function after administration of iodinated contrast media. It is associated with high in-hospital mortality and poor long-term survival. Furthermore, patients undergoing coronary angiography commonly have comorbidities such as hypertension or congestive heart failure, which are often treated with renin-angiotensin-aldosterone system-blocking agents such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. Trials assessing the effects of these renin-angiotensin-aldosterone system-blocking agents on the subsequent development of contrast-associated acute kidney injury have shown conflicting data, suggesting both beneficial and harmful effects. Therefore, there are no clear guidelines on whether clinicians should discontinue renin-angiotensin-aldosterone system-blocking agents peri-procedurally. In this article, we review the data from trials assessing the effects of peri-procedural renin-angiotensin system-blocking agent use in patients undergoing coronary and peripheral angiography and intervention. Future studies will likely focus on the extent of damage or potential benefit of these agents on renal function, cardiac function, as well as morbidity and mortality. Currently, there is insufficient evidence to recommend discontinuation of angiotensin-converting enzyme inhibitors prior to coronary angiography.

Type 2 diabetes mellitus and cardiovascular disease: focus on the effect of antihyperglycemic treatments on cardiovascular outcomes.

Introduction: Type 2 diabetes mellitus and cardiovascular disease contribute to significant morbidity, mortality, and health-care resource expenditure. The pathophysiological and clinical associations between diabetes and cardiovascular disease have been the subject of multiple studies, most recently culminating in large trials of several new antiglycemic agents being found to confer additional cardiovascular risk reduction. Understanding the potential cardiovascular benefits of antiglycemic medications offers the unique opportunity to reduce the morbidity and mortality presented by both diseases at once.Areas covered: The literature search was comprised of a Pubmed search querying 'cardiovascular outcomes' and 'diabetes'. This article reviews the pathophysiology of cardiovascular complications in type 2 diabetes and the cardiovascular outcome trials related to newer antiglycemic medications.Expert opinion: The treatment of patients with type 2 diabetes mellitus and cardiovascular disease is rapidly advancing. In particular, the sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists have demonstrated cardiovascular benefit by reducing major adverse cardiovascular events and cardiovascular mortality. Future directions of the treatment of type 2 diabetes and cardiovascular disease will focus on targeting and preventing diabetic cardiomyopathy and further defining the role of SGLT2 inhibitors and of GLP-1 receptor agonists in additional patient populations.

Cardiac Transplantation for Refractory Catecholaminergic Polymorphic Ventricular Tachycardia.

We present a patient with catecholaminergic polymorphic ventricular tachycardia who failed maximal antiarrhythmic drug therapy and bilateral sympathetic denervation, who presented with syncope and recurrent ventricular tachycardia for 11 min refractory to 21 shocks. She underwent cardiac transplantation as curative treatment for refractory ventricular arrhythmias in catecholaminergic polymorphic ventricular tachycardia. (Level of Difficulty: Advanced.).

Vancomycin-Induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome Masquerading as Elusive Sepsis.

We present a unique case of vancomycin-induced drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome masquerading as elusive endocarditis. A 37-year-old female actively using intravenous drugs presented with worsening right upper extremity pain, fever, and chills. Workup revealed methicillin-resistant staphylococcus aureus (MRSA) bacteremia and multiple right-sided septic pulmonary emboli. Echocardiogram was negative for vegetation. Vancomycin was initiated for bacteremia management suspected secondary to right upper extremity abscesses. However, despite resolution of abscesses, fevers persisted, raising suspicion for endocarditis not detected by echocardiogram. On hospital day 25, the patient began showing signs of DRESS syndrome, ultimately manifesting as transaminitis, eosinophilia, and a diffuse, maculopapular rash. Vancomycin was switched to Linezolid and she improved on high dose steroids. The persistent fevers throughout this hospital course were thought to be an elusive endocarditis before DRESS syndrome fully manifested. Although Vancomycin-induced DRESS is uncommon, this case highlights the importance of identifying early signs of significant adverse effects.

Racial Variation in the Complexity of Coronary Artery Disease in Patients with Acute ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Racial variations in presentation of patients with ST-segment elevation myocardial infarction (STEMI) have been suggested. METHODS: This was a retrospective analysis of a tertiary center from 2012 to 2016. We included patients presenting with acute STEMI who received primary percutaneous coronary intervention (PCI). The main outcome was racial variation in the complexity of coronary artery disease assessed by SYNTAX score. We also reported predictors of higher SYNTAX scores in the study population. RESULTS: Our final analysis included 260 patients: 201 Whites (77.3%), 24 African Americans-AA (9.2%), 19 Hispanics (7.3%) and 15 were of other ethnicities (5.8%). The mean SYNTAX score was 13.8 ±â€¯7.7. There was no significant difference between Whites, AA, Hispanics and other races in the SYNTAX score (13.8 ±â€¯7.7, 13.4 ±â€¯7.9, 14.5 ±â€¯9 and 13.5 ±â€¯6.6, p = 0.965). Logistic regression analysis identified chronic kidney disease as the only significant predictor of higher SYNTAX score (Coefficient = 3.5, 95%CI:0.41-6.60, p = 0.026), while no significant association was identified between different races and higher SYNTAX score. CONCLUSION: The current study did not identify racial variations in the complexity of coronary artery disease for STEMI patients. Further studies are needed at a larger scale to identify racial variations in STEMI patients.

Retinal fibrosis in diabetic retinopathy.

In response to injury, reparative processes are triggered to restore the damaged tissue; however, such processes are not always successful in rebuilding the original state. The formation of fibrous connective tissue is known as fibrosis, a hallmark of the reparative process. For fibrosis to be successful, delicately balanced cellular events involving cell proliferation, cell migration, and extracellular matrix (ECM) remodeling must occur in a highly orchestrated manner. While successful repair may result in a fibrous scar, this often restores structural stability and functionality to the injured tissue. However, depending on the functionality of the injured tissue, a fibrotic scar can have a devastating effect. For example, in the retina, fibrotic scarring may compromise vision and ultimately lead to blindness. In this review, we discuss some of the retinal fibrotic complications and highlight mechanisms underlying the development of retinal fibrosis in diabetic retinopathy.

Beneficial effects of fenofibric acid on overexpression of extracellular matrix components, COX-2, and impairment of endothelial permeability associated with diabetic retinopathy.

In the Fenofibric Acid (FA) Intervention and Event Lowering in Diabetes (FIELD) study, FA, a lipid-lowering drug, has been shown to significantly reduce macular edema in diabetic patients. In the present study, we investigated whether FA reduces vascular permeability by inhibiting cyclooxygenase-2 (COX-2), a critical mediator of inflammation, and reducing overexpression of fibronectin (FN) and collagen IV (Coll IV), two basement membrane (BM) components upregulated in diabetic retinopathy. Rat retinal endothelial cells (RRECs) were grown in normal (N:5 mM glucose) or high glucose (HG:30 mM glucose) medium with or without FA for 7 days. Total protein isolated from these cells was assessed for FN, Coll IV, COX-2, and zonula occludens-1 (ZO-1), a tight junction protein, using Western blot analysis. In addition, the distribution and localization of ZO-1 was determined by immunofluorescence microscopy, and cell monolayer permeability was studied by in vitro permeability (IVP) assay. RRECs grown in HG medium showed significant increase in FN, Coll IV, and COX-2 expression (179%, 144%, 139% of N respectively), and a decrease in ZO-1 expression (48% of N) compared to those of N cells. Cells grown in HG medium supplemented with FA significantly reduced FN, Coll IV, and COX-2 expression by 47%, 32%, and 34% respectively, with concomitant increase in ZO-1 expression by 42%. In parallel studies, IVP assays showed a significant increase (139% of N) in cell monolayer permeability in RRECs grown in HG medium, which was significantly reduced with FA treatment. Additionally, immunostaining results indicated FA prevents HG-induced downregulation of ZO-1. The findings indicate that the beneficial effect of FA in reducing excess permeability is mediated, at least in part, by downregulating abnormal overexpression of BM components and inflammatory factors and preventing compromised tight junctions associated with diabetic retinopathy.

Hyperhexosemia-Induced Retinal Vascular Pathology in a Novel Primate Model of Diabetic Retinopathy.

The paucity of animal models exhibiting full pathology of diabetic retinopathy (DR) has impeded understanding of the pathogenesis of DR and the development of therapeutic interventions. Here, we investigated whether hyperhexosemic marmosets (Callithrix jacchus) develop characteristic retinal vascular lesions including macular edema (ME), a leading cause of vision loss in DR. Marmosets maintained on 30% galactose (gal)-rich diet for 2 years were monitored for retinal vascular permeability, development of ME, and morphological characteristics including acellular capillaries (AC) and pericyte loss (PL), vessel tortuosity, and capillary basement membrane (BM) thickness. Excess vascular permeability, increased number of AC and PL, vascular BM thickening, and increased vessel tortuosity were observed in the retinas of gal-fed marmosets. Optical coherence tomography (OCT) images revealed significant thickening of the retinal foveal and the juxtafoveal area, and histological analysis showed incipient microaneurysms in retinas of gal-fed marmosets. Findings from this study indicate that hyperhexosemia can trigger retinal vascular changes similar to those seen in human DR including ME and microaneurysms. The striking similarities between the marmoset retina and the human retina, and the exceptionally small size of the monkey, offer significant advantages to this primate model of DR.

Mitochondrial dysfunction and endoplasmic reticulum stress in diabetic retinopathy: mechanistic insights into high glucose-induced retinal cell death.

Hyperglycemia, a prominent characteristic of diabetes, has been implicated in the apoptotic death of vascular and neuronal cells in the retina. In diabetic retinopathy, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and subsequent breakdown of cellular homeostasis play a critical role in retinal cell death. In particular, changes in mitochondrial morphology, mitochondrial membrane potential heterogeneity, oxygen consumption rate and protein misfolding are beginning to be recognized as key players in the demise of retinal vascular cells in diabetes. Some of these key changes contribute to oxidative stress and influence ion transport, impacting overall cellular homeostasis. The primary objective of this review is to provide insight into the mechanisms in which high glucose influences two disparate cellular organelles, mitochondria and ER, in promoting apoptotic demise of retinal vascular and neuronal cells in diabetic retinopathy.

Investigation of the reaction of hexabromocyclododecane with polysulfide and bisulfide in methanol/water solutions.

Reactions of hexabromocyclododecane (HBCD), a widely used brominated flame retardant, with reduced sulfur species (e.g., polysulfide and bisulfide) were investigated in well-defined solutions under anoxic conditions. It is likely that reactions of HBCD with reduced sulfur species such as polysulfides and bisulfide present in anoxic subregions of coastal water bodies and sediments could have a significant impact on the fate of HBCD. The second-order reaction rate constant of HBCD with polysulfides in 80% methanol/20% water at 40°C is 2.2 (±0.3)×10(-2) M(-1) s(-1). The second-order reaction rate constant of HBCD with bisulfide is 8.9 (±2.8)×10(-4) M(-1) s(-1) under the same conditions. The formation of two products was observed with either of the two reduced sulfur species. The experiments also indicate that the γ-isomer of HBCD is reacting significantly faster with reduced sulfur species than the α-isomer.

A long-term siRNA strategy regulates fibronectin overexpression and improves vascular lesions in retinas of diabetic rats.

PURPOSE: A sustained gene modulatory strategy is necessary for regulating abnormal gene expression in diabetic retinopathy, a long-term complication. We investigated the efficacy of a small interference RNA (siRNA) strategy in mediating the long-term downregulatory effect of fibronectin (FN) overexpression in vivo. METHODS: Streptozotocin-induced diabetic rats were intravitreally injected with 3 µM of FN-siRNA at six week intervals over a period of 4.5 months. Retinal FN protein expression, vascular basement membrane (BM) thickness, and retinal vascular cell loss were assessed by western blot, electron microscopy, and retinal trypsin digest, respectively. RESULTS: Retinal FN expression and BM thickness were significantly increased in diabetic rat retinas compared to those in non-diabetic control rats (188±14.2% of control versus 100±7.4% of control, p<0.002; 72.5±5.0 nm versus 51.5±4.8 nm, p<0.001, respectively). FN-siRNA treatment reduced FN overexpression and BM thickening (145±19.9% of control and 56.4±2.8 nm, respectively) and significantly reduced the number of acellular capillaries (35%) and pericyte loss (55%) compared to those of untreated diabetic eyes. CONCLUSIONS: These findings suggest that BM thickening is an important target for preventing vascular cell loss in a diabetic retina, and that the siRNA approach could be useful for long-term gene modulation in diabetic retinopathy.

Fenofibric acid reduces fibronectin and collagen type IV overexpression in human retinal pigment epithelial cells grown in conditions mimicking the diabetic milieu: functional implications in retinal permeability.

PURPOSE: To determine whether fenofibric acid (FA) reduces high glucose (HG)-induced basement membrane component overexpression and hyperpermeability in human retinal pigment epithelial (RPE) cells. METHODS: Retinal pigment epithelial cells (ARPE-19) were cultured for 18 days in normal glucose (5 mM) or HG (25 mM) medium and studied for the effects of FA on fibronectin (FN) and collagen IV (Coll IV) expression. During last 3 days of the experiment, 100 µM FA was added to cells grown in HG medium or in HG medium plus IL-1ß (HG + IL-1ß) to mimic, at least in part, the inflammatory aspect of the diabetic milieu. Real-time RT-PCR was performed to determine FN and Coll IV mRNA levels, whereas protein levels were assessed by Western blot analyses. Cell monolayer morphology and barrier function were analyzed by confocal microscopy using specific antibodies against tight junction proteins, ZO-1, and claudin-1 and by measuring apical-basolateral movements of FITC-dextran, respectively. RESULTS: FN and Coll IV expression were significantly increased in RPE cells grown in HG or HG + IL-1ß medium compared with cells grown in normal medium. When cells grown in HG or HG + IL-1ß medium were treated with FA, significant reductions in FN and Coll IV expression were observed. In addition, exposure to FA decreased excess permeability in a dose-dependent manner in cells grown in HG + IL-1ß medium. This effect was unrelated to changes in tight junction protein content. CONCLUSIONS: Findings from this study suggest that the downregulation of basement membrane components by FA may have a protective effect against outer blood-retinal barrier leakage associated with diabetic retinopathy.

High glucose-induced altered basement membrane composition and structure increases trans-endothelial permeability: implications for diabetic retinopathy.

PURPOSE: The following study was designed to investigate early biosynthetic and ultrastructural changes that alter functional properties of the basement membrane (BM) and affect vascular permeability in diabetic retinopathy. MATERIALS AND METHODS: To determine whether altered matrix synthesis affects cell monolayer permeability, rat retinal endothelial cells (RRECs) were grown for 4 days to confluency in normal (N, 5 mM) or high glucose (HG, 30 mM) medium on transwell inserts and subjected to an in vitro cell monolayer permeability assay. Inserts were cut out and viewed under a transmission electron microscope to assess extracellular matrix (ECM) accumulation and cell morphology. In parallel cell cultures, fibronectin and collagen IV protein expression were determined using Western Blot analysis. RESULTS: Electron microscopic analysis of cells exposed to short-term HG showed no difference in inter-endothelial cell tight junctions (TJs) or in the number of vesicles or coated pits compared to those of normal cells. However, ECM accumulation underlying HG cells was significantly increased compared to that of cells grown in N medium (139 ± 7% of control, p = 0.04), with areas of focal thickening. Western blot analysis showed increased fibronectin and collagen IV expression (152 ± 24% of control, p = 0.01; 146 ± 16% of control, p = 0.02, respectively) in cells grown in HG compared to those grown in N medium. Cell monolayers grown in HG exhibited increased permeability to FITC-dextran compared to cells grown in N medium (134 ± 15% of control, p = 0.02). CONCLUSIONS: High glucose-induced excess ECM accumulation and altered composition underlies structural and functional changes that allow increased permeability. This finding provides evidence for the first time that the thickened vascular basement membrane contributes to the development of excess permeability seen in diabetic retinopathy.