SPTLC3 Is Essential for Complex I Activity and Contributes to Ischemic Cardiomyopathy.

Background: Dysregulated metabolism of bioactive sphingolipids, including ceramides and sphingosine-1-phosphate, has been implicated in cardiovascular disease, although the specific species, disease contexts, and cellular roles are not completely understood. Sphingolipids are produced by the serine palmitoyltransferase enzyme, canonically composed of 2 subunits, SPTLC1 (serine palmitoyltransferase long chain base subunit 1) and SPTLC2 (serine palmitoyltransferase long chain base subunit 2). Noncanonical sphingolipids are produced by a more recently described subunit, SPTLC3 (serine palmitoyltransferase long chain base subunit 3).

Priorities in Cardio-Oncology Basic and Translational Science: GCOS 2023 Symposium Proceedings: State-of-the-Art Review.

Despite improvements in cancer survival, cancer therapy-related cardiovascular toxicity has risen to become a prominent clinical challenge. This has led to the growth of the burgeoning field of cardio-oncology, which aims to advance the cardiovascular health of cancer patients and survivors, through actionable and translatable science. In these Global Cardio-Oncology Symposium 2023 scientific symposium proceedings, we present a focused review on the mechanisms that contribute to common cardiovascular toxicities discussed at this meeting, the ongoing international collaborative efforts to improve patient outcomes, and the bidirectional challenges of translating basic research to clinical care.

Identifying Inflammasome Activation in Human Tissues.

The NACHT, LRR, and PYD domain-containing protein-3 (NLRP3) inflammasome activation is part of a stereotyped cellular response to injury or infection. The NLRP3 inflammasome activation promotes cellular dysfunction and death, leading to local and systemic inflammation, organ dysfunction, and adverse outcome. Immunohistochemistry and immunofluorescence can be used to determine whether the NLRP3 inflammasome components are present in human biopsy or autopsy tissue samples.

Novel Pathophysiological, Diagnostic and Therapeutic Concepts in Acute and Recurrent Pericarditis.

Acute pericarditis is the most frequent pericardial disease characterized by inflammation of the pericardial layers resulting in pain, dyspnea and fatigue. Often limited to an isolated event, up to 30% of patients experience one or more recurrences. There is limited knowledge about the pathophysiology of this disease, possibly due to the limited availability of animal models.

NLRP3-mediated inflammation in cardio-oncology: sterile yet harmful.

Despite significant advances and the continuous development of novel, effective therapies to treat a variety of malignancies, cancer therapy-induced cardiotoxicity has been identified as a prominent cause of morbidity and mortality, closely competing with secondary malignancies. This unfortunate limitation has prompted the inception of the field of cardio-oncology with its purpose to provide the necessary knowledge and key information on mechanisms that support the use of the most efficacious cancer therapy with minimal or no interruption while paying close attention to preventing cardiovascular related morbidity and mortality. Several mechanisms that contribute to cancer therapy-induced cardiotoxicity have been proposed and studied.

Cardiac complications of cancer therapies.

The quest of defeating cancer and improving prognosis in survivors has generated remarkable strides forward in research and have advanced the development of new antineoplastic therapies. These achievements, combined with rapid screening and early detection, have considerably extended the life expectancy of patients surviving multiple types of malignancies. Consequently, chemotherapy-related toxicity in several organ systems, especially the cardiovascular system, has surfaced as one of the leading causes of morbidity and mortality among cancer survivors.

Chronic treatment with serelaxin mitigates adverse remodeling in a murine model of ischemic heart failure and modulates bioactive sphingolipid signaling.

Relaxin is a pleiotropic hormone demonstrated to confer cardioprotection in animal models of myocardial infarction and ischemic heart failure by modulating inflammation, fibrosis and arrhythmogenesis. Several of these pathways in the ischemic myocardium are intricately tied with the downstream signaling of bioactive sphingolipids, which play an active role during post-infarction remodeling. In this current study, we examined the effects of relaxin on sphingosine 1-phosphate (S1P), and the potential benefits of relaxin treatment on cardiac health in a rodent model of ischemic heart failure.

Advances in pharmacotherapy for acute and recurrent pericarditis.

Introduction: Aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are first-line treatments for acute and recurrent pericarditis. Drugs blocking the NACHT, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome/interleukin-1β (IL-1β) axis are beneficial in patients with multiple recurrences.

Areas Covered: In this review, the role of the NLRP3 inflammasome/IL-1β axis in the pathophysiology of pericarditis is discussed.

Assessment of machine perfusion conditions for the donation after circulatory death heart preservation.

Background: Donation after circulatory death (DCD) hearts requires machine perfusion preservation, the conditions of which are not well defined.

Methods: To achieve this, rat hearts were procured following a DCD or control beating-heart donation (CBD) model, and perfused for 60 min with one of three machine perfusion solutions-St. Thomas (ST), University of Wisconsin (UW), or Polyethylene Glycol-20k (PEG)-at one of two temperatures, 4°C or 15°C.

Cardiac Gene Therapy With Relaxin Receptor 1 Overexpression Protects Against Acute Myocardial Infarction.

Relaxin is a pleiotropic hormone shown to confer cardioprotection in several preclinical models of cardiac ischemia-reperfusion injury. In the present study, the effects of up-regulating relaxin family peptide receptor 1 (RXFP1) via adeno-associated virus serotype 9 (AAV9) vectors were investigated in a mouse model of myocardial infarction. AAV9-RXFP1 vectors were generated and injected in adult male CD1 mice.

The interleukin-1 receptor type I promotes the development of aging-associated cardiomyopathy in mice.

Background: Aging is associated with metabolic and structural changes causing heart failure with preserved ejection fraction (HFpEF). Interleukin-1 (IL-1) is a pro-inflammatory cytokine involved in aging-related inflammation.

Objective: We sought to determine whether IL-1 mediates aging-related changes in the heart, as seen in HFpEF.

Refining murine heterotopic heart transplantation: A model to study ischemia and reperfusion injury in donation after circulatory death hearts.

Heart transplantation is a lifesaving procedure, which is limited by the availability of donor hearts. Using hearts from donors after circulatory death, which have sustained global ischemia, requires thorough studies on reliable and reproducible models that developing researchers may not have mastered. By combining the most recent literature and our recommendations based on observations and trials and errors, the methods here detail a sound in vivo heterotopic heart transplantation model for rats in which protective interventions on the ischemic heart can be studied, and thus allowing the scientific community to advance organ preservation research.

Preservation of Contractile Reserve and Diastolic Function by Inhibiting the NLRP3 Inflammasome with OLT1177 (Dapansutrile) in a Mouse Model of Severe Ischemic Cardiomyopathy Due to Non-Reperfused Anterior Wall Myocardial Infarction.

Interleukin-1β (IL-1β), a product of the NLRP3 inflammasome, modulates cardiac contractility and diastolic function. We proposed that OLT1177 (dapansutrile), a novel NLRP3 inhibitor, could preserve contractile reserve and diastolic function after myocardial infarction (MI). We used an experimental murine model of severe ischemic cardiomyopathy through the ligation of the left coronary artery without reperfusion, and after 7 days randomly assigned mice showing large anterior MI (>4 akinetic segments), increased left ventricular (LV) dimensions ([LVEDD] > 4.

Mitigation of Radiation-Induced Lung and Heart Injuries in Mice by Oral Sepiapterin after Irradiation.

After radiation exposure, endothelium-dependent vasorelaxation is impaired due to impaired nitric oxide production. Endothelial dysfunction is characterized by uncoupled endothelial nitric oxide synthase activity, oxidation of the reduced cofactor tetrahydrobiopterin to dihydrobiopterin as one well recognized mechanism. Oral treatment with sepiapterin, a tetrahydrobiopterin precursor, decreased infiltrating inflammatory cells and cytokine levels in mice with colitis.

The Role of NLRP3 Inflammasome in Pericarditis: Potential for Therapeutic Approaches.

Human samples of patients with chronic pericarditis and appropriate control subjects were stained for the inflammasome components. A mouse model of pericarditis was developed through the intrapericardial injection of zymosan A. Different inflammasome blockers were tested in the mouse model.

Targeting tumor-derived NLRP3 reduces melanoma progression by limiting MDSCs expansion.

Interleukin-1β (IL-1β)-mediated inflammation suppresses antitumor immunity, leading to the generation of a tumor-permissive environment, tumor growth, and progression. Here, we demonstrate that nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in melanoma is linked to IL-1β production, inflammation, and immunosuppression. Analysis of cancer genome datasets (TCGA and GTEx) revealed greater NLRP3 and IL-1β expression in cutaneous melanoma samples ( = 469) compared to normal skin ( = 324), with a highly significant correlation between NLRP3 and IL-1β ( < 0.

An update on the pathophysiology of acute and recurrent pericarditis.

Introduction: Pericarditis is an inflammatory disease of the pericardium. Progress has been done in recent years in the understanding of its pathophysiology. In particular, preclinical and clinical studies have contributed to increasing our knowledge on the role of interleukin (IL)-1 and NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome.

Inflammasome formation in the lungs of patients with fatal COVID-19.

Objective: The orf8b protein of the coronavirus SARS-CoV, analogous to SARS-CoV-2, triggers the NLRP3 inflammasome in macrophages in vitro. Deregulated inflammasome-mediated release of interleukin-1 family cytokines is important in hyper-inflammatory syndromes, like happens in SARS-CoV-2-mediated cytokine release syndrome. We propose that an intense inflammasome formation characterizes the lungs of patients with fatal COVID-19 disease due to pneumonia and acute respiratory distress syndrome (ARDS).

Clinical Presentation and Outcomes of Acute Pericarditis in a Large Urban Hospital in the United States of America.

Background: Acute pericarditis is the most common presentation of pericardial diseases. Although generally benign, complications such as constrictive pericarditis, cardiac tamponade, and recurrence can occur.

Research Question: What are the clinical factors associated with adverse outcomes in acute pericarditis?

Study Design And Methods: We used an informatics-based search engine to search for International Classification of Diseases codes related to pericardial disease between January 1, 2009 and November 14, 2018 and then extracted clinical information, including only patients meeting the European Society of Cardiology criteria for acute pericarditis.

Remote Ischemic Pre-Conditioning Attenuates Adverse Cardiac Remodeling and Mortality Following Doxorubicin Administration in Mice.

Objectives: Because of its multifaceted cardioprotective effects, remote ischemic pre-conditioning (RIPC) was examined as a strategy to attenuate doxorubicin (DOX) cardiotoxicity.

Background: The use of DOX is limited by dose-dependent cardiotoxicity and heart failure. Oxidative stress, mitochondrial dysfunction, inflammation, and autophagy modulation have been proposed as mediators of DOX cardiotoxicity.

Author Correction: The Transcriptomic Signature Of Disease Development And Progression Of Nonalcoholic Fatty Liver Disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Hydrogen Sulfide Therapy Suppresses Cofilin-2 and Attenuates Ischemic Heart Failure in a Mouse Model of Myocardial Infarction.

Aims: Hydrogen sulfide (HS) protects against ischemic and inflammatory injury following myocardial ischemia via induction of microRNA (miR)-21. We sought to determine whether HS attenuates ischemic heart failure with reduced ejection fraction (HFrEF) and interrogate the role of cofilin-2, a target of miR-21, in this protective process.

Methods And Results: Adult male mice underwent myocardial infarction (MI) by coronary artery ligation after baseline echocardiography.

B7-33, a Functionally Selective Relaxin Receptor 1 Agonist, Attenuates Myocardial Infarction-Related Adverse Cardiac Remodeling in Mice.

Background Human relaxin-2 is a peptide hormone capable of pleiotropic effects in several organ systems. Its recombinant formulation (serelaxin) has been demonstrated to reduce infarct size and prevent excessive scar formation in animal models of cardiac ischemia-reperfusion injury. B7-33, a synthetically designed peptide analogous to B-chain of relaxin-2, invokes signaling at relaxin family peptide receptor 1 (cognate receptor for relaxin-2) by preferentially phosphorylating the mitogen-activated protein kinase extracellular signal-regulated kinase 1/2.

Determinants of Cardiorespiratory Fitness Following Thoracic Radiotherapy in Lung or Breast Cancer Survivors.

We measured peak oxygen consumption (VO) in previous recipients of thoracic radiotherapy and assessed the determinants of cardiorespiratory fitness with an emphasis on cardiac and pulmonary function. Cancer survivors who have received thoracic radiotherapy with incidental cardiac involvement often experience impaired cardiorespiratory fitness, as measured by reduced peak VO, a marker of impaired cardiovascular reserve. We enrolled 25 subjects 1.