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.

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.

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.

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.

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.

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.

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.].

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.

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.

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.

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.

Atrioventricular and Sinus Node Dysfunction in Stable COVID-19 Patients.

There are now well-documented cardiac complications of COVID-19 infection which include myocarditis, heart failure, and acute coronary syndrome resulting from coronary artery thrombosis or SARS-CoV-2-related plaque ruptures. There is growing evidence showing that arrhythmias are also one of the major complications. We report two patients with no known history of cardiac conduction disease who presented with COVID-19 symptoms, positive SARS-CoV-2 infection, and developed cardiac conduction abnormalities. Cardiac conduction system disease involving the sino-atrial (SA) node and atrioventricular (AV) node could be a manifestation of SARS-CoV-2 infection.

Polymorphic Ventricular Tachycardia with a Normal QTc Interval in a Patient with COVID-19 and Fever: Case Report.

Arrhythmias or conduction system disease are not the most common manifestation of COVID-19 infection in patients requiring hospital admission. Torsade de pointes typically occurs in bursts of self-limiting episodes with symptoms of dizziness and syncope. However, it may occasionally progress to ventricular fibrillation and sudden death. In this article, we report a case of COVID-19 patient who developed polymorphic ventricular tachycardia with torsade de pointes morphology with normal QTc interval in the setting of fever. An 81-year-old woman was admitted with symptoms of COVID-19. She was treated with hydroxychloroquine, azithromycin, and doxycycline at an outside facility and finished the treatment 5 days prior to admission to our facility. Her course was complicated by atrial fibrillation with rapid ventricular response requiring cardioversion. Later, she developed two episodes of polymorphic ventricular tachycardia with TdP morphology with normal QTc. There was a correlation with fever triggering the ventricular tachycardia. We advocated aggressive fever control given the QTc was normal and stable. Following fever control, the patient remained stable and had no abnormal rhythm. COVID-19 patients are prone to different arrhythmias including life-threatening ventricular arrhythmias with normal left ventricular systolic function and normal QTc, and they should be monitored for fever and electrolyte abnormality during their hospital stay.

Arrhythmia in COVID-19.

The current outbreak of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) also known as coronavirus disease 2019 (COVID-19) has quickly progressed to a global pandemic. There are well-documented cardiac complications of COVID-19 in patients with and without prior cardiovascular disease. The cardiac complications include myocarditis, heart failure, and acute coronary syndrome resulting from coronary artery thrombosis or SARS-CoV-2-related plaque ruptures. There is growing evidence showing that arrhythmias are also one of the major complications. Myocardial inflammation caused by viral infection leads to electrophysiological and structural remodeling as a possible mechanism for arrhythmia. This could also be the mechanism through which SARS-CoV-2 leads to different arrhythmias. In this review article, we discuss arrhythmia manifestations in COVID-19.