Pathologic vs. protective roles of hypoxia-inducible factor 1 in RPE and photoreceptors in wet vs. dry age-related macular degeneration.

It has previously been reported that antioxidant vitamins can help reduce the risk of vision loss associated with progression to advanced age-related macular degeneration (AMD), a leading cause of visual impairment among the elderly. Nonetheless, how oxidative stress contributes to the development of choroidal neovascularization (CNV) in some AMD patients and geographic atrophy (GA) in others is poorly understood. Here, we provide evidence demonstrating that oxidative stress cooperates with hypoxia to synergistically stimulate the accumulation of hypoxia-inducible factor (HIF)-1α in the retinal pigment epithelium (RPE), resulting in increased expression of the HIF-1-dependent angiogenic mediators that promote CNV. HIF-1 inhibition blocked the expression of these angiogenic mediators and prevented CNV development in an animal model of ocular oxidative stress, demonstrating the pathological role of HIF-1 in response to oxidative stress stimulation in neovascular AMD. While human-induced pluripotent stem cell (hiPSC)-derived RPE monolayers exposed to chemical oxidants resulted in disorganization and disruption of their normal architecture, RPE cells proved remarkably resistant to oxidative stress. Conversely, equivalent doses of chemical oxidants resulted in apoptosis of hiPSC-derived retinal photoreceptors. Pharmacologic inhibition of HIF-1 in the mouse retina enhanced-while HIF-1 augmentation reduced-photoreceptor apoptosis in two mouse models for oxidative stress, consistent with a protective role for HIF-1 in photoreceptors in patients with advanced dry AMD. Collectively, these results suggest that in patients with AMD, increased expression of HIF-1α in RPE exposed to oxidative stress promotes the development of CNV, but inadequate HIF-1α expression in photoreceptors contributes to the development of GA.

Assessing the future risks of subsequent pregnancies in peripartum cardiomyopathy.

Peripartum cardiomyopathy is a myocardial disease process which occurs in young women either in late pregnancy or the early postpartum period. Due to the young age of women effected by this disease, many of these patients elect to pursue a subsequent pregnancy after their initial diagnosis. Currently, echocardiography is used to better elucidate the cardiovascular risks these young patients face when undergoing a subsequent pregnancy; however, the most accurate modality to determine these risks is debatable. In this review, we explore the current literature regarding the use and accuracy of resting transthoracic echocardiography, exercise stress echocardiography, and dobutamine stress echocardiography in risk stratification of a subsequent pregnancy in a patient with peripartum cardiomyopathy.

Atrial fibrillation: the role of hypoxia-inducible factor-1-regulated cytokines.

Atrial fibrillation (AF) is a common arrhythmia that has major morbidity and mortality. Hypoxia plays an important role in AF initiation and maintenance. Hypoxia-inducible factor (HIF), the master regulator of oxygen homeostasis in cells, plays a fundamental role in the regulation of multiple chemokines and cytokines that are involved in different physiological and pathophysiological pathways. HIF is also involved in the pathophysiology of AF induction and propagation mostly through structural remodeling such as fibrosis; however, some of the cytokines discussed have even been implicated in electrical remodeling of the atria. In this article, we highlight the association between HIF and some of its related cytokines with AF. Additionally, we provide an overview of the potential diagnostic benefits of using the mentioned cytokines as AF biomarkers. Research discussed in this review suggests that the expression of these cytokines may correlate with patients who are at an increased risk of developing AF. Furthermore, cytokines that are elevated in patients with AF can assist clinicians in the diagnosis of suspect paroxysmal AF patients. Interestingly, some of the cytokines have been elevated specifically when AF is associated with a hypercoagulable state, suggesting that they could be helpful in the clinician's and patient's decision to begin anticoagulation. Finally, more recent research has demonstrated the promise of targeting these cytokines for the treatment of AF. While still in its early stages, tools such as neutralizing antibodies have proved to be efficacious in targeting the HIF pathway and treating or preventing AF.

Administration of a 20-Hydroxyeicosatetraenoic Acid Synthesis Inhibitor Improves Outcome in a Rat Model of Pediatric Traumatic Brain Injury.

The arachidonic acid pathway metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemia/reperfusion brain injury. Inhibition of 20-HETE formation can protect the developing brain from global ischemia. Here, we examined whether treatment with the 20-HETE synthesis inhibitor N-hydroxy-N-4-butyl-2-methylphenylformamidine (HET0016) can protect the immature brain from traumatic brain injury (TBI). Male rats at postnatal day 9-10 underwent controlled cortical impact followed by intraperitoneal injection with vehicle or HET0016 (1 mg/kg, 5 min and 3 h post-injury). HET0016 decreased the lesion volume by over 50% at 3 days of recovery, and this effect persisted at 30 days as the brain matured. HET0016 decreased peri-lesion gene expression of proinflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin-1ß [IL-1ß]) at 1 day and increased reparative cytokine (IL-4, IL-10) expression at 3 days. It also partially preserved microglial ramified processes, consistent with less activation. HET0016 decreased contralateral hindlimb foot faults and improved outcome on the novel object recognition memory task 30 days after TBI. In cultured BV2 microglia, HET0016 attenuated the lipopolysaccharide-evoked increase in release of TNF-α. Our data show that HET0016 improves acute and long-term histologic and functional outcomes, in association with an attenuated neuroinflammatory response after contusion of an immature rat brain.

Angiopoietin-like 4 is a potent angiogenic factor and a novel therapeutic target for patients with proliferative diabetic retinopathy.

Diabetic eye disease is the most common cause of severe vision loss in the working-age population in the developed world, and proliferative diabetic retinopathy (PDR) is its most vision-threatening sequela. In PDR, retinal ischemia leads to the up-regulation of angiogenic factors that promote neovascularization. Therapies targeting vascular endothelial growth factor (VEGF) delay the development of neovascularization in some, but not all, diabetic patients, implicating additional factor(s) in PDR pathogenesis. Here we demonstrate that the angiogenic potential of aqueous fluid from PDR patients is independent of VEGF concentration, providing an opportunity to evaluate the contribution of other angiogenic factor(s) to PDR development. We identify angiopoietin-like 4 (ANGPTL4) as a potent angiogenic factor whose expression is up-regulated in hypoxic retinal Müller cells in vitro and the ischemic retina in vivo. Expression of ANGPTL4 was increased in the aqueous and vitreous of PDR patients, independent of VEGF levels, correlated with the presence of diabetic eye disease, and localized to areas of retinal neovascularization. Inhibition of ANGPTL4 expression reduced the angiogenic potential of hypoxic Müller cells; this effect was additive with inhibition of VEGF expression. An ANGPTL4 neutralizing antibody inhibited the angiogenic effect of aqueous fluid from PDR patients, including samples from patients with low VEGF levels or receiving anti-VEGF therapy. Collectively, our results suggest that targeting both ANGPTL4 and VEGF may be necessary for effective treatment or prevention of PDR and provide the foundation for studies evaluating aqueous ANGPTL4 as a biomarker to help guide individualized therapy for diabetic eye disease.

Hypoxic retinal Muller cells promote vascular permeability by HIF-1-dependent up-regulation of angiopoietin-like 4.

Vision loss from ischemic retinopathies commonly results from the accumulation of fluid in the inner retina [macular edema (ME)]. Although the precise events that lead to the development of ME remain under debate, growing evidence supports a role for an ischemia-induced hyperpermeability state regulated, in part, by VEGF. Monthly treatment with anti-VEGF therapies is effective for the treatment of ME but results in a major improvement in vision in a minority of patients, underscoring the need to identify additional therapeutic targets. Using the oxygen-induced retinopathy mouse model for ischemic retinopathy, we provide evidence showing that hypoxic Müller cells promote vascular permeability by stabilizing hypoxia-inducible factor-1α (HIF-1α) and secreting angiogenic cytokines. Blocking HIF-1α translation with digoxin inhibits the promotion of endothelial cell permeability in vitro and retinal edema in vivo. Interestingly, Müller cells require HIF--but not VEGF--to promote vascular permeability, suggesting that other HIF-dependent factors may contribute to the development of ME. Using gene expression analysis, we identify angiopoietin-like 4 (ANGPTL4) as a cytokine up-regulated by HIF-1 in hypoxic Müller cells in vitro and the ischemic inner retina in vivo. ANGPTL4 is critical and sufficient to promote vessel permeability by hypoxic Müller cells. Immunohistochemical analysis of retinal tissue from patients with diabetic eye disease shows that HIF-1α and ANGPTL4 localize to ischemic Müller cells. Our results suggest that ANGPTL4 may play an important role in promoting vessel permeability in ischemic retinopathies and could be an important target for the treatment of ME.

KSHV induces aerobic glycolysis and angiogenesis through HIF-1-dependent upregulation of pyruvate kinase 2 in Kaposi's sarcoma.

Kaposi's sarcoma (KS) is a vascular neoplasm caused by infection of endothelial or endothelial precursor cells with the Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8). Research efforts have focused on defining the molecular events explaining how KSHV promotes pathological angiogenesis and KS tumor formation. mTOR/HIF-1 is a fundamental pathway driving these processes through the upregulation of angiogenic and inflammatory proteins, including VEGF, ANGPTL4, and ANGPT2. Interestingly, HIF-1 has also been implicated in the upregulation of metabolic genes associated with aerobic glycolysis and the growth of solid tumors. However, whether HIF-1 plays a role in regulating cell metabolism in KS remains unexplored. Here, we show that the HIF-1 metabolic effector, pyruvate kinase 2 (PKM2), is upregulated upon KSHV infection of endothelial cells and is necessary to maintain aerobic glycolysis in infected cells. We further demonstrate that PKM2 regulates KS angiogenic phenotype by acting as a coactivator of HIF-1 and increasing the levels of HIF-1 angiogenic factors, including VEGF. Indeed, inhibition of PKM2 expression blocked endothelial cell migration and differentiation and the angiogenic potential of KSHV-infected cells. We also investigated whether PKM2 regulates the angiogenic dysregulation induced by the KSHV-encoded G protein-coupled receptor (vGPCR), a viral oncogene that promotes Kaposi's sarcomagenesis through the upregulation of HIF angiogenic factors. Interestingly, we found that PKM2 controls vGPCR-induced VEGF paracrine secretion and vGPCR oncogenesis. Our findings provide a molecular mechanism for how HIF-1 dysregulation fuels both angiogenesis and tumor metabolism in KS and support further investigations on therapeutic approaches targeting HIF-1 and PKM2 for KS treatment.

Serum and tissue endothelin-1 are independent from intima-media thickness of peripheral arteries in patients with chronic kidney disease.

AIM: We aimed to study the relationship of peripheral arteries' atherosclerosis with serum and tissue endothelin-1 in chronic kidney disease patients. METHODS: Ninety patients were enrolled, including 35 patients with chronic kidney disease (case group), 31 patients with coronary artery diseases who were candidates for coronary artery bypass grafting (positive control group), and 24 living kidney donors (negative control group). Intima-media thickness of the common carotid and femoral arteries was determined by ultrasonography. Serum and tissue endothelin-1 were measured by ELISA method. RESULTS: The mean serum and tissue endothelin-1 levels in the donor group were significantly lower than other groups (p < 0.001 for both). The coronary artery bypass grafting group had higher carotid and femoral intima-media thickness than other groups (p < 0.001), and the chronic kidney disease group had higher carotid and femoral intima-media thickness than the donor group (p < 0.001). Regression analysis in all groups did not reveal any correlation between the carotid intima-media thickness/femoral intima-media thickness and the serum/tissue endothelin-1. There was a direct linear correlation between the carotid and femoral intima-media thickness (p < 0.001) in all groups. CONCLUSIONS: Endothelin-1 level and intima-media thickness were higher in the chronic kidney disease patients and coronary artery bypass grafting candidates, without any correlation between endothelin-1 and peripheral arteries' intima-media thickness of both groups. Perhaps endothelin-1 rises and remains high upon endothelial damage and initiation of atherosclerosis.

A rare case of primary adult cardiac rhabdomyosarcoma with lower extremity metastasis.

Primary cardiac tumors are uncommon. Rhabdomyosarcomas are among the rarest type of cardiac sarcomas. Echocardiography, cardiac MRI, and computed tomography scan can help the diagnosis and presurgical management. In this article, we report a rare case of primary cardiac rhabdomyosarcoma originating from the mitral valve with left femoral metastasis in a patient in her 60s. The diagnosis was made using transesophageal echocardiography and cardiac MRI. A metastatic lesion was found in an extended PET scan in one of her clinical follow-ups due to her leg pain. Based on this report, we suggest that extending PET scan to the lower extremities could be helpful in the early diagnosis and treatment of remote metastases of cardiac rhabdomyosarcomas.

HIF-1α accumulation in response to transient hypoglycemia may worsen diabetic eye disease.

Tight glycemic control (TGC), the cornerstone of diabetic management, reduces the incidence and progression of diabetic microvascular disease. However, TGC can also lead to transient episodes of hypoglycemia, which have been associated with adverse outcomes in patients with diabetes. Here, we demonstrate that low glucose levels result in hypoxia-inducible factor (HIF)-1-dependent expression of the glucose transporter, Glut1, in retinal cells. Enhanced nuclear accumulation of HIF-1α was independent of its canonical post-translational stabilization but instead dependent on stimulation of its translation and nuclear localization. In the presence of hypoxia, this physiologic response to low glucose resulted in a marked increase in the secretion of the HIF-dependent vasoactive mediators that promote diabetic retinopathy. Our results provide a molecular explanation for how early glucose control, as well as glycemic variability (i.e., oscillating serum glucose levels), contributes to diabetic eye disease. These observations have important implications for optimizing glucose management in patients with diabetes.

Left Atrial Appendage Closure: What Do We Know?

Atrial fibrillation (AF) is the most common arrhythmia in the United States and the most common cause of embolic cerebrovascular events, with the majority of these thrombi originating in the left atrial appendage. The left atrial appendage (LAA) has separate developmental, ultrastructural, and physiological characteristics from the left atrium. Although LAA anatomy is highly variable, it can be categorized into 4 types: cactus, cauliflower, chicken wing, and windsock. The cauliflower type is associated with higher stroke risk in patients with nonvalvular AF. Although the cornerstone of therapy to prevent embolic strokes from AF has been anticoagulation with thrombin inhibitors, a large group of patients are unable to tolerate anticoagulation due to bleeding. This has led to the development and advancement of multiple surgical and percutaneous LAA closure devices to prevent embolic cerebrovascular accidents without the need for anticoagulation. In this article, we discuss the outcomes of major studies that utilized surgical LAA occlusion and its effectiveness. Furthermore, we summarize nonsurgical methods of LAA closure and future directions regarding LAA closure.

PAI-1 is a vascular cell-specific HIF-2-dependent angiogenic factor that promotes retinal neovascularization in diabetic patients.

For patients with proliferative diabetic retinopathy (PDR) who do not respond adequately to pan-retinal laser photocoagulation (PRP) or anti-vascular endothelial growth factor (VEGF) therapies, we hypothesized that vascular cells within neovascular tissue secrete autocrine/paracrine angiogenic factors that promote disease progression. To identify these factors, we performed multiplex ELISA angiogenesis arrays on aqueous fluid from PDR patients who responded inadequately to anti-VEGF therapy and/or PRP and identified plasminogen activator inhibitor-1 (PAI-1). PAI-1 expression was increased in vitreous biopsies and neovascular tissue from PDR eyes, limited to retinal vascular cells, regulated by the transcription factor hypoxia-inducible factor (HIF)-2α, and necessary and sufficient to stimulate angiogenesis. Using a pharmacologic inhibitor of HIF-2α (PT-2385) or nanoparticle-mediated RNA interference targeting Pai1, we demonstrate that the HIF-2α/PAI-1 axis is necessary for the development of retinal neovascularization in mice. These results suggest that targeting HIF-2α/PAI-1 will be an effective adjunct therapy for the treatment of PDR patients.

Utility of High-frequency Jet Ventilation in Atrial Fibrillation Ablation.

Atrial fibrillation (AF) is the most common clinically significant arrhythmia that causes major morbidity and mortality. Catheter ablation focusing on pulmonary vein isolation is increasingly used for the treatment of symptomatic AF. Advances in ablation technologies and improved imaging and mapping have enhanced treatment efficiency but only modestly improved the efficacy. Another-but less commonly used-technology that can have a favorable impact involves enhancing the catheter-tissue contact by manipulating respiration to promote improved catheter stability and optimal contact. High-frequency jet ventilation (HFJV) is a mode of ventilation that can reduce respiratory movements to almost apneic conditions. In this review article, we aimed to highlight different studies, review the current literature regarding the utility of HFJV in AF ablation, and discuss the safety and efficacy of this approach relative to that of conventional ventilation.

Peripheral Administration of Nitroglycerin in Pulseless Ventricular Tachycardia due to Cocaine-Induced Coronary Vasospasm.

Cocaine use accounts for 40% of the annual drug use related emergency department visits in the United States. Cocaine use is hence recognized as a major health problem. Cocaine blocks the presynaptic reuptake of norepinephrine and dopamine. The resulting increased adrenergic activity leads to vasoconstriction. Additionally, via various mechanisms, cocaine leads to a prothrombotic state and increases myocardial demand. Cocaine can cause coronary vasospasm and is therefore, associated with acute myocardial injury even in the absence of pre-existing atherosclerotic coronary artery disease. Nitroglycerin has a class 1C indication by the ACCF/AHA guidelines for patients with ST-segment elevation or depression that accompanies ischemic chest discomfort in the setting of cocaine use. It has been shown to reverse cocaine-induced coronary vasospasm and chest pain. In this case report, for the first time, we discuss how intravenous administration of high dose nitroglycerin to a patient in pulseless ventricular tachycardia with angiographically confirmed vasospasm induced by cocaine resulted in return of spontaneous circulation.

How transforming growth factor contributes to atrial fibrillation?

Atrial fibrillation (AF) is the most common clinically significant arrhythmia. There are four fundamental pathophysiological mechanisms of AF including: electrical remodeling, structural remodeling, autonomic nervous system changes, and Ca2+ handling abnormalities. The transforming growth factor-ß (TGF-ß) superfamily are cytokines that have the ability to regulate numerous cell functions including proliferation, differentiation, apoptosis, epithelial-mesenchymal transition, and production of extracellular matrix. During the last decade numerous studies have demonstrated that TGF-ß affects the architecture of the heart. TGF-ß1 has been shown to be involved in the development and propagation of atrial fibrillation (AF). Investigators have studied TGF-ß signaling in AF with the aim of discovering potential therapeutic agents. In this review we discuss the role of TGF-ß in atrial fibrillation and specifically its role in atrial structural and electrical remodeling.

Impact of COVID-19 on Heart Failure Hospitalizations.

The Novel Coronavirus Disease 2019 (COVID-19) pandemic has transformed individual lives and societal framework on a global scale, and in no other sector is this more evident than healthcare. Herein, we aim to describe the impact of the current COVID-19 pandemic and its associated restrictions on heart failure (HF) admissions. In this retrospective cohort study, we obtained administrative data for patients with a primary discharge diagnosis of HF (identified by ICD-10 code) with discharge dates ranging from January 2019 to November 2020. The study is comprised of 2 distinct sub-cohorts: HF admissions during the COVID-19 pandemic (case) period from March 2020 to October 2020 and corresponding control period during the previous year (March 2019 to December 2019). Primary outcome analysis involved comparison of total and daily HF admissions and secondary outcomes included hospital Length of Stay (LOS) and 30-day readmissions. The number of total HF admissions and average daily admissions were significantly lower in 2020 compared to 2019 (774 vs. 864; p < 0.001 and 3.17 vs. 3.53 days; p < 0.001), respectively. Average length of stay was significantly higher between March and October 2020 relative to the same months in 2019 (6.05 vs. 5.25 days; p < 0.001). Thirty-day readmission rates were also significantly higher in March-October 2020 compared to the same months in 2019 (20.6% vs. 19.1%; p < 0.001). During the pandemic, both readmission rates and length of stay for HF-related admissions were significantly impacted. The COVID-19 pandemic significantly impacted HF-related admissions as well as associated LOS and 30-day readmissions. High-risk patients should be identified carefully, and timely and appropriate treatment should be provided.

Correction: Hypoxia-inducible factor 1 upregulation of both VEGF and ANGPTL4 is required to promote the angiogenic phenotype in uveal melanoma.

[This corrects the article DOI: 10.18632/oncotarget.6868.].

The role of long noncoding RNAs in atrial fibrillation.

Atrial fibrillation (AF) is a common arrhythmia with serious clinical sequelae, yet little is known about its genetic origins. Recently, the untranscribed 98% of the human genome has been increasingly implicated in important processes such as cardiac organogenesis, physiology, and pathophysiology. Specifically, long noncoding RNAs (lncRNAs) have been shown to interact with the transcriptome in various ways that alter gene expression. Previously, multiple lncRNAs have been identified in disease processes such as heart failure, coronary artery disease, and diabetes. Multiple studies now show lncRNAs are involved in each fundamental mechanism leading to the development of AF, including structural remodeling, electrical remodeling, renin angiotensin system effects, and calcium handling abnormalities. The altered expression of lncRNAs offers genetic targets for the diagnosis and treatment of AF. This article discusses the role of lncRNAs in AF and its pathogenesis.

A Provider's Guide to Vascular Disease, Dyslipidemia, and Glycemic Dysregulation in Chronic Spinal Cord Injury.

Individuals with chronic spinal cord injury (SCI) are predisposed to accelerated atherogenesis, dyslipidemia, and glycemic dysregulation, although not enough is known about the etiologies or clinical consequences of these secondary effects of paralysis. While guidelines for the detection and treatment of cardiometabolic disease in SCI have recently been published, there has been a historical paucity of data-driven approaches to these conditions. This article will describe what is and not known about the cardiovascular disease and glycemic dysregulation that frequently attend SCI. It will conclude with a review of both guideline-driven and informal recommendations addressing the clinical care of people living with SCI.

Wide unroofed coronary sinus and cryptogenic stroke: a case report.

BACKGROUND: Unroofed coronary sinus (UCS) is a rare congenital cardiac anomaly in which there is complete or partial absence of the roof of the coronary sinus (CS) resulting in a communication between the right and left atria. There are four types of UCS described in the literature. While usually asymptomatic and discovered incidentally on imaging, UCS can be the source of a brain abscess or paradoxical embolism. CASE SUMMARY: A 62-year-old gentleman presented to the emergency department with sudden onset of right-sided weakness and subsequent unresponsiveness. His brain computed tomography (CT) was consistent with left-sided stroke. Transthoracic echocardiography was remarkable for a dilated CS and an agitated saline study was suggestive of an UCS. A gated cardiac CT with coronary angiography confirmed a wide communication between the CS and left atrium. Right heart catheterization did not show evidence of left to right shunt. He had no abnormal rhythm on telemetry monitoring throughout his hospital stay. DISCUSSION: Unroofed coronary sinus is the least prevalent form of an atrial septal defect. Unroofed coronary sinus is usually asymptomatic and is diagnosed incidentally in imaging studies, however, it should be suspected in patients with cerebral emboli or evidence of left to right shunt with unexplained arterial desaturation. Transthoracic echocardiography is the most widely used imaging modality for the diagnosis of UCS but is limited in its ability to visualize the posterior cardiac structures such as the CS and pulmonary veins. Gated cardiac CT is a great diagnostic tool for UCS.