|
1
|
Bahrami P, Aromolaran KA, Aromolaran AS. Proarrhythmic Lipid Inflammatory Mediators: Mechanisms in Obesity Arrhythmias. J Cell Physiol 2025; 240:e70012. [PMID: 39943721 PMCID: PMC11822244 DOI: 10.1002/jcp.70012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2024] [Revised: 01/27/2025] [Accepted: 02/03/2025] [Indexed: 02/16/2025]
Abstract
The prevalence of obesity and associated metabolic disorders such as diabetes is rapidly increasing; therefore, concerns regarding their cardiovascular consequences, including cardiac arrhythmias, are rising. As obesity progresses, the excessively produced lipids accumulate in unconventional areas such as the epicardial adipose tissue (EAT) around the myocardium. Metabolic alterations in obesity contribute to the transformation of these ectopic fat deposits into arrhythmogenic substrates. However, despite advances in therapeutic approaches, particularly in lowering EAT volume and thickness through sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, obese and diabetic patients still suffer from fatal arrhythmias that may lead to sudden cardiac death. Therefore, an investigation into how unappreciated underlying pathways such as lipid mediators contribute to the transformation of adipose tissues into proinflammatory and arrhythmogenic substrates is of significance. Leukotriene B4 (LTB4) is an eicosanoid derived from arachidonic acid and acts as a lipid mediator. LTB4 has recently been identified to be associated with cardiac ion channel modulations and arrhythmogenic conditions in diabetes. LTB4 increases circulatory free fatty acids (FFAs) and has been associated with adipocyte hypertrophy. LTB4 also interferes with insulin signaling pathways, instigating insulin resistance (IR). In addition, LTB4, as a potent chemoattractant, contributes to the mobilization of circulatory immune cells such as monocytes and promotes inflammatory macrophage polarization and macrophage dysfunction. Thus, this review provides a comprehensive overview of LTB4's underlying pathways in obesity; illustrates how these pathways might lead to alterations in cardiac ion channels, currents, and cardiac arrhythmias; and shows how they might pose a therapeutic target for metabolic-associated arrhythmias.
Collapse
Affiliation(s)
- Pegah Bahrami
- Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI)University of Utah School of MedicineSalt Lake CityUtahUSA
| | - Kelly A. Aromolaran
- Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI)University of Utah School of MedicineSalt Lake CityUtahUSA
| | - Ademuyiwa S. Aromolaran
- Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI)University of Utah School of MedicineSalt Lake CityUtahUSA
- Division of Cardiothoracic Surgery, Department of Surgery, Nutrition & Integrative Physiology, Biochemistry & Molecular Medicine ProgramUniversity of Utah School of MedicineSalt Lake CityUtahUSA
| |
Collapse
|
|
2
|
Aromolaran KA, Corbin A, Aromolaran AS. Obesity Arrhythmias: Role of IL-6 Trans-Signaling. Int J Mol Sci 2024; 25:8407. [PMID: 39125976 PMCID: PMC11313575 DOI: 10.3390/ijms25158407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 07/24/2024] [Accepted: 07/29/2024] [Indexed: 08/12/2024] Open
Abstract
Obesity is a chronic disease that is rapidly increasing in prevalence and affects more than 600 million adults worldwide, and this figure is estimated to increase by at least double by 2030. In the United States, more than one-third of the adult population is either overweight or obese. The global obesity epidemic is a major risk factor for the development of life-threatening arrhythmias occurring in patients with long QT, particularly in conditions where multiple heart-rate-corrected QT-interval-prolonging mechanisms are simultaneously present. In obesity, excess dietary fat in adipose tissue stimulates the release of immunomodulatory cytokines such as interleukin (IL)-6, leading to a state of chronic inflammation in patients. Over the last decade, increasing evidence has been found to support IL-6 signaling as a powerful predictor of the severity of heart diseases and increased risk for ventricular arrhythmias. IL-6's pro-inflammatory effects are mediated via trans-signaling and may represent a novel arrhythmogenic risk factor in obese hearts. The first selective inhibitor of IL-6 trans-signaling, olamkicept, has shown encouraging results in phase II clinical studies for inflammatory bowel disease. Nevertheless, the connection between IL-6 trans-signaling and obesity-linked ventricular arrhythmias remains unexplored. Therefore, understanding how IL-6 trans-signaling elicits a cellular pro-arrhythmic phenotype and its use as an anti-arrhythmic target in a model of obesity remain unmet clinical needs.
Collapse
Affiliation(s)
- Kelly A. Aromolaran
- Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, Salt Lake City, UT 84112, USA; (K.A.A.); (A.C.)
| | - Andrea Corbin
- Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, Salt Lake City, UT 84112, USA; (K.A.A.); (A.C.)
- Department of Biomedical Engineering, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
| | - Ademuyiwa S. Aromolaran
- Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, Salt Lake City, UT 84112, USA; (K.A.A.); (A.C.)
- Department of Biomedical Engineering, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
- Department of Surgery, Division of Cardiothoracic Surgery, Nutrition & Integrative Physiology, Biochemistry & Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
| |
Collapse
|
|
3
|
Corbin A, Aromolaran KA, Aromolaran AS. STAT4 Mediates IL-6 Trans-Signaling Arrhythmias in High Fat Diet Guinea Pig Heart. Int J Mol Sci 2024; 25:7813. [PMID: 39063055 PMCID: PMC11277091 DOI: 10.3390/ijms25147813] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/15/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
Obesity is a major risk factor for the development of life-threatening malignant ventricular tachyarrhythmias (VT) and sudden cardiac death (SCD). Risks may be highest for patients with high levels of the proinflammatory cytokine interleukin (IL)-6. We used our guinea pig model of high-fat diet (HFD)-induced arrhythmias that exhibit a heightened proinflammatory-like pathology, which is also observed in human obesity arrhythmias, as well as immunofluorescence and confocal microscopy approaches to evaluate the pathological IL-6 trans-signaling function and explore the underlying mechanisms. Using blind-stick and electrocardiogram (ECG) techniques, we tested the hypothesis that heightened IL-6 trans-signaling would exhibit increased ventricular arrhythmia/SCD incidence and underlying arrhythmia substrates. Remarkably, compared to low-fat diet (LFD)-fed controls, HFD promoted phosphorylation of the IL-6 signal transducer and activator of transcription 4 (STAT4), leading to its activation and enhanced nuclear translocation of pSTAT4/STAT4 compared to LFD controls and pSTAT3/STAT3 nuclear expression. Overactivation of IL-6 trans-signaling in guinea pigs prolonged the QT interval, which resulted in greater susceptibility to arrhythmias/SCD with isoproterenol challenge, as also observed with the downstream Janus kinase (JAK) 2 activator. These findings may have potentially profound implications for more effective arrhythmia therapy in the vulnerable obese patient population.
Collapse
Affiliation(s)
- Andrea Corbin
- Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, Salt Lake City, UT 84132, USA; (A.C.); (K.A.A.)
- Department of Biomedical Engineering, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
| | - Kelly A. Aromolaran
- Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, Salt Lake City, UT 84132, USA; (A.C.); (K.A.A.)
| | - Ademuyiwa S. Aromolaran
- Nora Eccles Harrison Cardiovascular Research and Training Institute (CVRTI), University of Utah School of Medicine, Salt Lake City, UT 84132, USA; (A.C.); (K.A.A.)
- Department of Biomedical Engineering, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
- Department of Surgery, Division of Cardiothoracic Surgery, Nutrition & Integrative Physiology, Biochemistry & Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT 84132, USA
| |
Collapse
|
|
4
|
Murphy MB, Yang Z, Subati T, Farber-Eger E, Kim K, Blackwell DJ, Fleming MR, Stark JM, Van Amburg JC, Woodall KK, Van Beusecum JP, Agrawal V, Smart CD, Pitzer A, Atkinson JB, Fogo AB, Bastarache JA, Kirabo A, Wells QS, Madhur MS, Barnett JV, Murray KT. LNK/SH2B3 loss of function increases susceptibility to murine and human atrial fibrillation. Cardiovasc Res 2024; 120:899-913. [PMID: 38377486 PMCID: PMC11218690 DOI: 10.1093/cvr/cvae036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 08/31/2023] [Accepted: 10/07/2023] [Indexed: 02/22/2024] Open
Abstract
AIMS The lymphocyte adaptor protein (LNK) is a negative regulator of cytokine and growth factor signalling. The rs3184504 variant in SH2B3 reduces LNK function and is linked to cardiovascular, inflammatory, and haematologic disorders, including stroke. In mice, deletion of Lnk causes inflammation and oxidative stress. We hypothesized that Lnk-/- mice are susceptible to atrial fibrillation (AF) and that rs3184504 is associated with AF and AF-related stroke in humans. During inflammation, reactive lipid dicarbonyls are the major components of oxidative injury, and we further hypothesized that these mediators are critical drivers of the AF substrate in Lnk-/- mice. METHODS AND RESULTS Lnk-/- or wild-type (WT) mice were treated with vehicle or 2-hydroxybenzylamine (2-HOBA), a dicarbonyl scavenger, for 3 months. Compared with WT, Lnk-/- mice displayed increased AF duration that was prevented by 2-HOBA. In the Lnk-/- atria, action potentials were prolonged with reduced transient outward K+ current, increased late Na+ current, and reduced peak Na+ current, pro-arrhythmic effects that were inhibited by 2-HOBA. Mitochondrial dysfunction, especially for Complex I, was evident in Lnk-/- atria, while scavenging lipid dicarbonyls prevented this abnormality. Tumour necrosis factor-α (TNF-α) and interleukin-1 beta (IL-1β) were elevated in Lnk-/- plasma and atrial tissue, respectively, both of which caused electrical and bioenergetic remodelling in vitro. Inhibition of soluble TNF-α prevented electrical remodelling and AF susceptibility, while IL-1β inhibition improved mitochondrial respiration but had no effect on AF susceptibility. In a large database of genotyped patients, rs3184504 was associated with AF, as well as AF-related stroke. CONCLUSION These findings identify a novel role for LNK in the pathophysiology of AF in both experimental mice and humans. Moreover, reactive lipid dicarbonyls are critical to the inflammatory AF substrate in Lnk-/- mice and mediate the pro-arrhythmic effects of pro-inflammatory cytokines, primarily through electrical remodelling.
Collapse
MESH Headings
- Animals
- Female
- Humans
- Male
- Action Potentials/drug effects
- Adaptor Proteins, Signal Transducing/genetics
- Adaptor Proteins, Signal Transducing/metabolism
- Atrial Fibrillation/metabolism
- Atrial Fibrillation/physiopathology
- Atrial Fibrillation/genetics
- Benzylamines/pharmacology
- Disease Models, Animal
- Genetic Predisposition to Disease
- Heart Rate/drug effects
- Inflammation Mediators/metabolism
- Interleukin-1beta/metabolism
- Interleukin-1beta/genetics
- Intracellular Signaling Peptides and Proteins/genetics
- Intracellular Signaling Peptides and Proteins/metabolism
- Mice, Inbred C57BL
- Mice, Knockout
- Mitochondria, Heart/metabolism
- Mitochondria, Heart/pathology
- Mitochondria, Heart/drug effects
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/drug effects
- Myocytes, Cardiac/pathology
- Oxidative Stress/drug effects
- Phenotype
- Signal Transduction
- Tumor Necrosis Factor-alpha/metabolism
- Tumor Necrosis Factor-alpha/genetics
Collapse
Affiliation(s)
- Matthew B Murphy
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Zhenjiang Yang
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Tuerdi Subati
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Eric Farber-Eger
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
| | - Kyungsoo Kim
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Daniel J Blackwell
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Matthew R Fleming
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
| | - Joshua M Stark
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Joseph C Van Amburg
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Kaylen K Woodall
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Justin P Van Beusecum
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Vineet Agrawal
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
| | - Charles D Smart
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Ashley Pitzer
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - James B Atkinson
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, 1161 21 Avenue South, Nashville, TN 37232, USA
| | - Agnes B Fogo
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, 1161 21 Avenue South, Nashville, TN 37232, USA
| | - Julie A Bastarache
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
| | - Annet Kirabo
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Quinn S Wells
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
- Department of Biomedical Informatics, Vanderbilt University School of Medicine, 2525 West End Avenue, Nashville, TN 37203, USA
| | - Meena S Madhur
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Joey V Barnett
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| | - Katherine T Murray
- Department of Medicine, Division of Clinical Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, 559 PRB, Nashville, TN 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, 2220 Pierce Avenue, Nashville, TN 37232, USA
| |
Collapse
|
|
5
|
Załęska-Kocięcka M, Wojdyńska Z, Kalisz M, Litwiniuk A, Mączewski M, Leszek P, Paterek A. Epicardial fat and ventricular arrhythmias. Heart Rhythm 2024; 21:206-212. [PMID: 37972673 DOI: 10.1016/j.hrthm.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 11/03/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023]
Abstract
The arrhythmogenic role of epicardial adipose tissue (EAT) in atrial arrhythmias is well established, but its effect on ventricular arrhythmias has been significantly less investigated. Since ventricular arrhythmias are thought to cause 75%-80% of cases of sudden cardiac death, this is not a trivial issue. We provide an overview of clinical data as well as experimental and molecular data linking EAT to ventricular arrhythmias, attempting to dissect possible mechanisms and indicate future directions of research and possible clinical implications. However, despite a wealth of data indicating the role of epicardial and intramyocardial fat in the induction and propagation of ventricular arrhythmias, unfortunately there is currently no direct evidence that indeed EAT triggers arrhythmia or can be a target for antiarrhythmic strategies.
Collapse
Affiliation(s)
- Marta Załęska-Kocięcka
- Heart Failure and Transplantology Department, Mechanical Circulatory Support and Transplant Department, National Institute of Cardiology, Warsaw, Poland
| | - Zuzanna Wojdyńska
- Heart Failure and Transplantology Department, Mechanical Circulatory Support and Transplant Department, National Institute of Cardiology, Warsaw, Poland
| | - Małgorzata Kalisz
- Department of Clinical Neuroendocrinology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Anna Litwiniuk
- Department of Clinical Neuroendocrinology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Michał Mączewski
- Department of Clinical Physiology, Centre of Postgraduate Medical Education, Warsaw, Poland
| | - Przemysław Leszek
- Heart Failure and Transplantology Department, Mechanical Circulatory Support and Transplant Department, National Institute of Cardiology, Warsaw, Poland
| | - Aleksandra Paterek
- Department of Clinical Physiology, Centre of Postgraduate Medical Education, Warsaw, Poland.
| |
Collapse
|
|
6
|
Wu WW, Choe M, Johannesen L, Vicente J, Bende G, Stockbridge NL, Strauss DG, Garnett C. ICH S7B In Vitro Assays Do Not Address Mechanisms of QT C Prolongation for Peptides and Proteins - Data in Support of Not Needing Dedicated QT C Studies. Clin Pharmacol Ther 2023; 114:1332-1341. [PMID: 37702218 DOI: 10.1002/cpt.3047] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 08/29/2023] [Indexed: 09/14/2023]
Abstract
Current cardiac safety testing focuses on detecting drug-induced QTC prolongation as a surrogate for risk of Torsade de Pointes. The nonclinical strategy, described in International Conference on Harmonization (ICH) S7B, includes in vitro assessment of hERG block or ventricular repolarization delay and in vivo QT prolongation. Several studies have reported predictive values of ICH S7B results for clinical QTC outcomes for small molecules; none has examined peptides and proteins other than monoclonal antibodies. To address this knowledge gap, information for peptides and proteins submitted to the US Food and Drug Administration (FDA) was collected. Results of hERG assays, ventricular repolarization assays, and in vivo QT assessment were compared with clinical QTC study outcomes. The results show that 14% clinical QTC studies for approved and investigational products failed to exclude 10-ms QTC prolongation. Clinical QTC prolongation for these molecules lacked concentration-dependence which is expected for hERG block-mediated mechanism or QTC prolongation could not be excluded due to characterization in the clinical study. The hERG and ventricular repolarization assays do not identify clinical QTC prolongation potential for peptides and proteins. Lack of alignment between hERG and ventricular repolarization assay results and clinical QTC outcomes suggests that the mechanisms of QTC prolongation by some peptides and proteins are unrelated to direct cardiac ion channel block. Similar to large targeted proteins and monoclonal antibodies, peptides and proteins regardless of size have a low likelihood of direct cardiac ion channel interactions. This characteristic supports waiving the requirement for thorough QT assessment for products comprised of naturally occurring amino acids unless proarrhythmia potential is suggested by nonclinical or clinical data.
Collapse
Affiliation(s)
- Wendy W Wu
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Moran Choe
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
- Division of Hematology, Oncology, Toxicology, Office of Oncologic Diseases, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Lars Johannesen
- Division of Cardiology and Nephrology, Office of Cardiology, Hematology, Endocrinology and Nephrology, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Jose Vicente
- Division of Cardiology and Nephrology, Office of Cardiology, Hematology, Endocrinology and Nephrology, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Girish Bende
- Division of Cardiometabolic and Endocrine Pharmacology, Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
- Takeda Pharmaceutical Company Limited, Cambridge, Massachusetts, USA
| | - Norman L Stockbridge
- Division of Cardiology and Nephrology, Office of Cardiology, Hematology, Endocrinology and Nephrology, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - David G Strauss
- Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| | - Christine Garnett
- Division of Cardiology and Nephrology, Office of Cardiology, Hematology, Endocrinology and Nephrology, Office of New Drugs, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland, USA
| |
Collapse
|
|
7
|
Liu Y, Zhang D, Yin D. Pathophysiological Effects of Various Interleukins on Primary Cell Types in Common Heart Disease. Int J Mol Sci 2023; 24:ijms24076497. [PMID: 37047468 PMCID: PMC10095356 DOI: 10.3390/ijms24076497] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/22/2023] [Accepted: 03/25/2023] [Indexed: 03/31/2023] Open
Abstract
Myocardial infarction (MI), heart failure, cardiomyopathy, myocarditis, and myocardial ischemia-reperfusion injury (I/R) are the most common heart diseases, yet there is currently no effective therapy due to their complex pathogenesis. Cardiomyocytes (CMs), fibroblasts (FBs), endothelial cells (ECs), and immune cells are the primary cell types involved in heart disorders, and, thus, targeting a specific cell type for the treatment of heart disease may be more effective. The same interleukin may have various effects on different kinds of cell types in heart disease, yet the exact role of interleukins and their pathophysiological pathways on primary cell types remain largely unexplored. This review will focus on the pathophysiological effects of various interleukins including the IL-1 family (IL-1, IL-18, IL-33, IL-37), IL-2, IL-4, the IL-6 family (IL-6 and IL-11), IL-8, IL-10, IL-17 on primary cell types in common heart disease, which may contribute to the more precise and effective treatment of heart disease.
Collapse
Affiliation(s)
- Yong Liu
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan 430062, China
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, Hubei University, Wuhan 430062, China
| | - Donghui Zhang
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan 430062, China
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, Hubei University, Wuhan 430062, China
- Correspondence: (D.Z.); (D.Y.)
| | - Dan Yin
- State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan 430062, China
- Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-Throughput Drug Screening Technology, Hubei University, Wuhan 430062, China
- Correspondence: (D.Z.); (D.Y.)
| |
Collapse
|
|
8
|
Giannotta G, Murrone A, Giannotta N. COVID-19 mRNA Vaccines: The Molecular Basis of Some Adverse Events. Vaccines (Basel) 2023; 11:747. [PMID: 37112659 PMCID: PMC10145134 DOI: 10.3390/vaccines11040747] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Revised: 03/21/2023] [Accepted: 03/22/2023] [Indexed: 03/30/2023] Open
Abstract
Each injection of any known vaccine results in a strong expression of pro-inflammatory cytokines. This is the result of the innate immune system activation, without which no adaptive response to the injection of vaccines is possible. Unfortunately, the degree of inflammation produced by COVID-19 mRNA vaccines is variable, probably depending on genetic background and previous immune experiences, which through epigenetic modifications could have made the innate immune system of each individual tolerant or reactive to subsequent immune stimulations.We hypothesize that we can move from a limited pro-inflammatory condition to conditions of increasing expression of pro-inflammatory cytokines that can culminate in multisystem hyperinflammatory syndromes following COVID-19 mRNA vaccines (MIS-V). We have graphically represented this idea in a hypothetical inflammatory pyramid (IP) and we have correlated the time factor to the degree of inflammation produced after the injection of vaccines. Furthermore, we have placed the clinical manifestations within this hypothetical IP, correlating them to the degree of inflammation produced. Surprisingly, excluding the possible presence of an early MIS-V, the time factor and the complexity of clinical manifestations are correlated to the increasing degree of inflammation: symptoms, heart disease and syndromes (MIS-V).
Collapse
Affiliation(s)
| | - Antonio Murrone
- Oncologia Territoriale, Hospice Cure Palliative ASUFC, 33030 Udine, Italy;
| | - Nicola Giannotta
- Medical and Surgery Sciences, Faculty of Medicine, Magna Græcia University, 88100 Catanzaro, Italy;
| |
Collapse
|
|
9
|
Fir(e)ing the Rhythm. JACC Basic Transl Sci 2023. [DOI: 10.1016/j.jacbts.2022.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/17/2023]
|
|
10
|
Liu M, Lin W, Song T, Zhao H, Ma J, Zhao Y, Yu P, Yan Z. Influenza vaccination is associated with a decreased risk of atrial fibrillation: A systematic review and meta-analysis. Front Cardiovasc Med 2022; 9:970533. [PMID: 36337907 PMCID: PMC9630361 DOI: 10.3389/fcvm.2022.970533] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 09/29/2022] [Indexed: 11/18/2022] Open
Abstract
Background Evidence from longitudinal studies has shown that influenza infection is linked to an increased risk of arrhythmia. Therefore, we aimed to assess the role of influenza vaccination in arrhythmia prevention. Materials and methods The PubMed, Embase, and Cochrane Library databases were searched to identify studies that investigated the potential effects of the influenza vaccine on arrhythmia risk published until October 25th, 2021. The study was registered with PROSPERO (CRD42022300815). Results One RCT with 2,532 patients and six observational studies with 3,167,445 patients were included. One RCT demonstrated a non-significant benefit of the influenza vaccine against arrhythmias [odds ratio (OR) = 0.43, 95% confidence interval (CI): 0.11–1.64; P = 0.20] in patients after myocardial infarction or those with high-risk stable coronary heart disease. A meta-analysis based on observational studies showed that vaccination was associated with a significantly lower risk of arrhythmia (OR: 0.82, 95% CI: 0.70–0.97; P = 0.02; I2 = 76%). Additionally, subgroup analysis showed a decreased risk of atrial fibrillation (AF) (OR: 0.94, 95% CI: 0.90–0.98; P = 0.006; I2 = 0%) and a non-significant but positive trend concerning ventricular arrhythmias (VAs) (OR: 0.68, 95% CI: 0.42–1.11; P = 0.12; I2 = 85%) after influenza vaccination. Conclusion Based on the current evidence, influenza vaccination may be associated with a reduced risk of arrhythmia, especially AF. Influenza vaccination may be an effective tool for the prevention of arrhythmias. The effect of influenza vaccination on the risk of VAs and arrhythmias in patients at low risk for cardiovascular diseases should be further studied. Systematic review registration [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42022300815].
Collapse
Affiliation(s)
- Menglu Liu
- Department of Cardiology, Seventh People’s Hospital of Zhengzhou, Zhengzhou, China
| | - Weichun Lin
- Department of Gastroenterology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Tiangang Song
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Huilei Zhao
- Department of Anesthesiology, The Third Hospital of Nanchang, Nanchang, China
| | - Jianyong Ma
- Department of Pharmacology and Systems Physiology, College of Medicine, University of Cincinnati, Cincinnati, OH, United States
| | - Yujie Zhao
- Department of Cardiology, Seventh People’s Hospital of Zhengzhou, Zhengzhou, China
- *Correspondence: Yujie Zhao,
| | - Peng Yu
- Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Peng Yu,
| | - Zhiwei Yan
- Department of Sports Rehabilitation, College of Human Kinesiology, Shenyang Sport University, Shenyang, China
- Zhiwei Yan,
| |
Collapse
|
|
11
|
Patel KHK, Li X, Xu X, Sun L, Ardissino M, Punjabi PP, Purkayastha S, Peters NS, Ware JS, Ng FS. Increasing Adiposity Is Associated With QTc Interval Prolongation and Increased Ventricular Arrhythmic Risk in the Context of Metabolic Dysfunction: Results From the UK Biobank. Front Cardiovasc Med 2022; 9:939156. [PMID: 35845082 PMCID: PMC9277510 DOI: 10.3389/fcvm.2022.939156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Accepted: 05/31/2022] [Indexed: 11/13/2022] Open
Abstract
Background Small-scale studies have linked obesity (Ob) and metabolic ill-health with proarrhythmic repolarisation abnormalities. Whether these are observed at a population scale, modulated by individuals' genetics, and confer higher risks of ventricular arrhythmias (VA) are not known. Methods and Results Firstly, using the UK Biobank, the association between adiposity and QTc interval was assessed in participants with a resting 12-lead ECG (n = 23,683), and a polygenic risk score (PRS) was developed to investigate any modulatory effect of genetics. Participants were also categorised into four phenotypes according to the presence (+) or absence (-) of Ob, and if they were metabolically unhealthy (MU+) or not (MU-). QTc was positively associated with body mass index (BMI), body fat (BF), waist:hip ratio (WHR), and hip and waist girths. Individuals' genetics had no significant modulatory effect on QTc-prolonging effects of increasing adiposity. QTc interval was comparably longer in those with metabolic perturbation without obesity (Ob-MU+) and obesity alone (Ob+MU-) compared with individuals with neither (Ob-MU-), and their co-existence (Ob+MU+) had an additive effect on QTc interval. Secondly, for 502,536 participants in the UK Biobank, odds ratios (ORs) for VA were computed for the four clinical phenotypes above using their past medical records. Referenced to Ob-MU-, ORs for VA in Ob-MU+ men and women were 5.96 (95% CI: 4.70-7.55) and 5.10 (95% CI: 3.34-7.80), respectively. ORs for Ob+MU+ were 6.99 (95% CI: 5.72-8.54) and 3.56 (95% CI: 2.66-4.77) in men and women, respectively. Conclusion Adiposity and metabolic perturbation increase QTc to a similar degree, and their co-existence exerts an additive effect. These effects are not modulated by individuals' genetics. Metabolic ill-health is associated with a higher OR for VA than obesity.
Collapse
Affiliation(s)
| | - Xinyang Li
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Xiao Xu
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Lin Sun
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Maddalena Ardissino
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | | | | | - Nicholas S. Peters
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - James S. Ware
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Fu Siong Ng
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| |
Collapse
|
|
12
|
Hegazy H, Folke F, Coronel R, Torp-Pedersen C, Gislason GH, Eroglu TE. Risk of out-of-hospital cardiac arrest in patients with rheumatoid arthritis: a nationwide study. Open Heart 2022; 9:openhrt-2022-001987. [PMID: 35649573 PMCID: PMC9161077 DOI: 10.1136/openhrt-2022-001987] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 04/26/2022] [Indexed: 11/30/2022] Open
Abstract
Aim Inflammatory cytokines in patients with rheumatoid arthritis (RA) directly affect cardiac electrophysiology by inhibiting cardiac potassium currents, leading to delay of cardiac repolarisation and QT-prolongation. This may result in lethal arrhythmias. We studied whether RA increases the rate of out-of-hospital cardiac arrest (OHCA) in the general population. Methods We conducted a nested case–control in a cohort of individuals between 1 June 2001 and 31 December 2015. Cases were OHCA patients from presumed cardiac causes, and were matched with non-OHCA-controls based on age, sex and OHCA date. Cox-regression with time-dependent covariates was conducted to assess the association between RA and OHCA by calculating the HR and 95% CI. Stratified analyses were performed according to sex and presence of cardiovascular diseases. Also, the association between OHCA and use of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with RA was studied. Results We included 35 195 OHCA cases of whom 512 (1.45%) had RA, and 351 950 non-OHCA controls of whom 3867 (1.10%) had RA. We found that RA was associated with increased rate of OHCA after adjustment for cardiovascular comorbidities and use of QT-prolonging drugs (HR: 1.22, 95% CI: 1.11 to 1.34). Stratification by sex revealed that increased OHCA rate occurred in women (HR: 1.32, 95% CI: 1.16 to 1.50) but not in men (HR: 1.12, 95% CI: 0.97 to 1.28; P value interaction=0.046). OHCA rate of RA was not further increased in patients with cardiovascular disease. Finally, in patients with RA, use of NSAIDs was not associated with OHCA. Conclusion In the general population, RA is associated with increased rate of OHCA in women but not in men.
Collapse
Affiliation(s)
- Hatem Hegazy
- Department of Cardiology, Copenhagen University Hospital, Kobenhavn, Denmark
| | | | - Ruben Coronel
- Department of Experimental and Clinical Cardiology, Amsterdam UMC Location AMC, Amsterdam, Netherlands
| | - Christian Torp-Pedersen
- Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark.,Department of Cardiology, Nordsjællands Hospital, Hillerod, Denmark
| | | | - Talip E Eroglu
- Department of Cardiology, Copenhagen University Hospital, Kobenhavn, Denmark
| |
Collapse
|
|
13
|
Patel KHK, Hwang T, Se Liebers C, Ng FS. Epicardial adipose tissue as a mediator of cardiac arrhythmias. Am J Physiol Heart Circ Physiol 2022; 322:H129-H144. [PMID: 34890279 PMCID: PMC8742735 DOI: 10.1152/ajpheart.00565.2021] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Obesity is associated with higher risks of cardiac arrhythmias. Although this may be partly explained by concurrent cardiometabolic ill-health, growing evidence suggests that increasing adiposity independently confers risk for arrhythmias. Among fat depots, epicardial adipose tissue (EAT) exhibits a proinflammatory secretome and, given the lack of fascial separation, has been implicated as a transducer of inflammation to the underlying myocardium. The present review explores the mechanisms underpinning adverse electrophysiological remodeling as a consequence of EAT accumulation and the consequent inflammation. We first describe the physiological and pathophysiological function of EAT and its unique secretome and subsequently discuss the evidence for ionic channel and connexin expression modulation as well as fibrotic remodeling induced by cytokines and free fatty acids that are secreted by EAT. Finally, we highlight how weight reduction and regression of EAT volume may cause reverse remodeling to ameliorate arrhythmic risk.
Collapse
Affiliation(s)
| | - Taesoon Hwang
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Curtis Se Liebers
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| | - Fu Siong Ng
- National Heart and Lung Institute, Imperial College London, London, United Kingdom
| |
Collapse
|
|
14
|
Macrophage-Dependent Interleukin-6-Production and Inhibition of IK Contributes to Acquired QT Prolongation in Lipotoxic Guinea Pig Heart. Int J Mol Sci 2021; 22:ijms222011249. [PMID: 34681909 PMCID: PMC8537919 DOI: 10.3390/ijms222011249] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/08/2021] [Accepted: 10/16/2021] [Indexed: 11/17/2022] Open
Abstract
In the heart, the delayed rectifier K current, IK, composed of the rapid (IKr) and slow (IKs) components contributes prominently to normal cardiac repolarization. In lipotoxicity, chronic elevation of pro-inflammatory cytokines may remodel IK, elevating the risk for ventricular arrythmias and sudden cardiac death. We investigated whether and how the pro-inflammatory interleukin-6 altered IK in the heart, using electrophysiology to evaluate changes in IK in adult guinea pig ventricular myocytes. We found that palmitic acid (a potent inducer of lipotoxicity), induced a rapid (~24 h) and significant increase in IL-6 in RAW264.7 cells. PA-diet fed guinea pigs displayed a severely prolonged QT interval when compared to low-fat diet fed controls. Exposure to isoproterenol induced torsade de pointes, and ventricular fibrillation in lipotoxic guinea pigs. Pre-exposure to IL-6 with the soluble IL-6 receptor produced a profound depression of IKr and IKs densities, prolonged action potential duration, and impaired mitochondrial ATP production. Only with the inhibition of IKr did a proarrhythmic phenotype of IKs depression emerge, manifested as a further prolongation of action potential duration and QT interval. Our data offer unique mechanistic insights with implications for pathological QT interval in patients and vulnerability to fatal arrhythmias.
Collapse
|
|
15
|
Wu L, Woudstra L, Dam TA, Germans T, van Rossum AC, Niessen HWM, Krijnen PAJ. Electrocardiographic changes are strongly correlated with the extent of cardiac inflammation in mice with Coxsackievirus B3-induced viral myocarditis. Cardiovasc Pathol 2021; 54:107367. [PMID: 34245872 DOI: 10.1016/j.carpath.2021.107367] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 06/11/2021] [Accepted: 06/30/2021] [Indexed: 01/08/2023] Open
Abstract
OBJECTIVE Viral myocarditis (VM) can induce changes in myocardial electrical conduction and arrhythmia. However, their relationship with myocarditis-associated arrhythmic substrates in the heart such as inflammation and fibrosis is relatively unknown. This we have analyzed in the present study. METHODS C3H mice were infected with 1×105 plaque-forming units Coxsackievirus B3 (CVB3, n=68) and were compared with uninfected control mice (n=10). Electrocardiograms (ECGs) were recorded in all conscious mice shortly before sacrifice and included heart rate; P-R interval; QRS duration; QTc interval and R-peak amplitude of lead II and aVF. Mice were sacrificed at 4, 7, 10, 21, 35 or 49 days post-infection. Cardiac lesion size, calcification, fibrosis and cellular infiltration of CD45+ lymphocytes, MAC3+ macrophages, Ly6G+ neutrophils and mast cells were quantitatively determined in cross-sections of the ventricles. Putative relations between ECG changes and lesion size and/or cardiac inflammation were then analyzed. RESULTS Significant transient reductions in QRS duration and R-peak amplitude occurred between 4 and 14 days post-infection and returned to baseline values thereafter. The magnitude of these ECG changes strongly correlated to the extent of lymphocyte (days 7 and 14), macrophage (days 7 and 10) and neutrophil (days 7) infiltration. The ECG changes did not significantly correlate with lesion size and fibrosis. CONCLUSION VM induces transient changes in myocardial electrical conduction that are strongly related to cellular inflammation of the heart. These data show that even in mild VM, with relatively little cardiac damage, the inflammatory infiltrate can form an important arrhythmogenic substrate.
Collapse
Affiliation(s)
- Linghe Wu
- Department of Pathology, Amsterdam University Medical Centers, location VUmc and AMC, Amsterdam, The Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands.
| | - Linde Woudstra
- Department of Pathology, Amsterdam University Medical Centers, location VUmc and AMC, Amsterdam, The Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Tariq A Dam
- Department of Pathology, Amsterdam University Medical Centers, location VUmc and AMC, Amsterdam, The Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| | - Tjeerd Germans
- Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands; Department of Cardiology, Amsterdam UMC, location VU Medical Center, Amsterdam, The Netherlands
| | - Albert C van Rossum
- Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands; Department of Cardiology, Amsterdam UMC, location VU Medical Center, Amsterdam, The Netherlands
| | - Hans W M Niessen
- Department of Pathology, Amsterdam University Medical Centers, location VUmc and AMC, Amsterdam, The Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands; Department of Cardiac Surgery, Amsterdam UMC, location VU Medical Center, Amsterdam, The Netherlands
| | - Paul A J Krijnen
- Department of Pathology, Amsterdam University Medical Centers, location VUmc and AMC, Amsterdam, The Netherlands; Amsterdam Cardiovascular Sciences, Amsterdam, The Netherlands
| |
Collapse
|
|
16
|
Qiu H, Li HW, Zhang SH, Zhou XG, Li WP. Torsades de pointes episode in a woman with high-grade fever and inflammatory activation: A case report. World J Clin Cases 2021; 9:2899-2907. [PMID: 33969075 PMCID: PMC8058677 DOI: 10.12998/wjcc.v9.i12.2899] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 02/07/2021] [Accepted: 02/24/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND QT interval prolongation can induce torsades de pointes (TdP), a potentially fatal ventricular arrhythmia. Recently, an increasing number of non-cardiac drugs have been found to cause QT prolongation and/or TdP onset. Moreover, recent findings have demonstrated the key roles of systemic inflammatory activation and fever in promoting long-QT syndrome (LQTS) and TdP development.
CASE SUMMARY A 30-year-old woman was admitted with a moderate to high-grade episodic fever for two weeks. The patient was administered with multiple antibiotics after hospitalization but still had repeating fever and markedly elevated C-reactive protein. Once after a high fever, the patient suddenly lost consciousness, and electrocardiogram (ECG) showed transient TdP onset after frequent premature ventricular contraction. The patient recovered sinus rhythm and consciousness spontaneously, and post-TdP ECG revealed a prolonged QTc interval of 560 ms. The patient’s clinical manifestations and unresponsiveness to the antibiotics led to the final diagnosis of adult-onset Still’s disease (AOSD). There was no evidence of cardiac involvement. After the AOSD diagnosis, discontinuation of antibiotics and immediate initiation of intravenous dexamethasone administration resulted in the normal temperature and QTc interval. The genetic analysis identified that the patient and her father had heterozygous mutations in KCNH2 (c.1370C>T) and AKAP9 (c.7725A>C). During the 2-year follow-up period, the patient had no recurrence of any arrhythmia and maintained normal QTc interval.
CONCLUSION This case study highlights the risk of systemic inflammatory activation and antibiotic-induced TdP/LQTS onset. Genetic analysis should be considered to identify individuals at high risk of developing TdP.
Collapse
Affiliation(s)
- Hui Qiu
- Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Hong-Wei Li
- Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Shu-Hong Zhang
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Xiao-Ge Zhou
- Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| | - Wei-Ping Li
- Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China
| |
Collapse
|
|
17
|
Campana C, Dariolli R, Boutjdir M, Sobie EA. Inflammation as a Risk Factor in Cardiotoxicity: An Important Consideration for Screening During Drug Development. Front Pharmacol 2021; 12:598549. [PMID: 33953668 PMCID: PMC8091045 DOI: 10.3389/fphar.2021.598549] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 03/31/2021] [Indexed: 01/08/2023] Open
Abstract
Numerous commonly prescribed drugs, including antiarrhythmics, antihistamines, and antibiotics, carry a proarrhythmic risk and may induce dangerous arrhythmias, including the potentially fatal Torsades de Pointes. For this reason, cardiotoxicity testing has become essential in drug development and a required step in the approval of any medication for use in humans. Blockade of the hERG K+ channel and the consequent prolongation of the QT interval on the ECG have been considered the gold standard to predict the arrhythmogenic risk of drugs. In recent years, however, preclinical safety pharmacology has begun to adopt a more integrative approach that incorporates mathematical modeling and considers the effects of drugs on multiple ion channels. Despite these advances, early stage drug screening research only evaluates QT prolongation in experimental and computational models that represent healthy individuals. We suggest here that integrating disease modeling with cardiotoxicity testing can improve drug risk stratification by predicting how disease processes and additional comorbidities may influence the risks posed by specific drugs. In particular, chronic systemic inflammation, a condition associated with many diseases, affects heart function and can exacerbate medications’ cardiotoxic effects. We discuss emerging research implicating the role of inflammation in cardiac electrophysiology, and we offer a perspective on how in silico modeling of inflammation may lead to improved evaluation of the proarrhythmic risk of drugs at their early stage of development.
Collapse
Affiliation(s)
- Chiara Campana
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Rafael Dariolli
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Mohamed Boutjdir
- Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn, NY, United States.,Department of Medicine, Cell Biology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, NY, United States.,Department of Medicine, New York University School of Medicine, New York, NY, United States
| | - Eric A Sobie
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| |
Collapse
|
|
18
|
Neurological Disorders and Risk of Arrhythmia. Int J Mol Sci 2020; 22:ijms22010188. [PMID: 33375447 PMCID: PMC7795827 DOI: 10.3390/ijms22010188] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/19/2020] [Accepted: 12/24/2020] [Indexed: 01/08/2023] Open
Abstract
Neurological disorders including depression, anxiety, post-traumatic stress disorder (PTSD), schizophrenia, autism and epilepsy are associated with an increased incidence of cardiovascular disorders and susceptibility to heart failure. The underlying molecular mechanisms that link neurological disorders and adverse cardiac function are poorly understood. Further, a lack of progress is likely due to a paucity of studies that investigate the relationship between neurological disorders and cardiac electrical activity in health and disease. Therefore, there is an important need to understand the spatiotemporal behavior of neurocardiac mechanisms. This can be advanced through the identification and validation of neurological and cardiac signaling pathways that may be adversely regulated. In this review we highlight how dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, autonomic nervous system (ANS) activity and inflammation, predispose to psychiatric disorders and cardiac dysfunction. Moreover, antipsychotic and antidepressant medications increase the risk for adverse cardiac events, mostly through the block of the human ether-a-go-go-related gene (hERG), which plays a critical role in cardiac repolarization. Therefore, understanding how neurological disorders lead to adverse cardiac ion channel remodeling is likely to have significant implications for the development of effective therapeutic interventions and helps improve the rational development of targeted therapeutics with significant clinical implications.
Collapse
|
|
19
|
Chen M, Li X, Wang S, Yu L, Tang J, Zhou S. The Role of Cardiac Macrophage and Cytokines on Ventricular Arrhythmias. Front Physiol 2020; 11:1113. [PMID: 33071805 PMCID: PMC7540080 DOI: 10.3389/fphys.2020.01113] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Accepted: 08/11/2020] [Indexed: 12/13/2022] Open
Abstract
In the heart, cardiac macrophages have widespread biological functions, including roles in antigen presentation, phagocytosis, and immunoregulation, through the formation of diverse cytokines and growth factors; thus, these cells play an active role in tissue repair after heart injury. Recent clinical studies have indicated that macrophages or elevated inflammatory cytokines secreted by macrophages are closely related to ventricular arrhythmias (VAs). This review describes the role of macrophages and macrophage-secreted inflammatory cytokines in ventricular arrhythmogenesis.
Collapse
Affiliation(s)
- Mingxian Chen
- The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xuping Li
- The Second Xiangya Hospital, Central South University, Changsha, China
| | - Songyun Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lilei Yu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Jianjun Tang
- The Second Xiangya Hospital, Central South University, Changsha, China
| | - Shenghua Zhou
- The Second Xiangya Hospital, Central South University, Changsha, China
| |
Collapse
|
|
20
|
Patel KHK, Jones TN, Sattler S, Mason JC, Ng FS. Proarrhythmic electrophysiological and structural remodeling in rheumatoid arthritis. Am J Physiol Heart Circ Physiol 2020; 319:H1008-H1020. [PMID: 32946265 DOI: 10.1152/ajpheart.00401.2020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Chronic inflammatory disorders, including rheumatoid arthritis (RA), are associated with a twofold increase in the incidence of sudden cardiac death (SCD) compared with the healthy population. Although this is partly explained by an increased prevalence of coronary artery disease, growing evidence suggests that ischemia alone cannot completely account for the increased risk. The present review explores the mechanisms of cardiac electrophysiological remodeling in response to chronic inflammation in RA. In particular, it focuses on the roles of nonischemic structural remodeling, altered cardiac ionic currents, and autonomic nervous system dysfunction in ventricular arrhythmogenesis and SCD. It also explores whether common genetic elements predispose to both RA and SCD. Finally, it evaluates the potential dual effects of disease-modifying therapy in both diminishing and promoting the risk of ventricular arrhythmias and SCD.
Collapse
Affiliation(s)
| | | | - Susanne Sattler
- National Heart and Lung Institute, Imperial College London, United Kingdom
| | - Justin C Mason
- National Heart and Lung Institute, Imperial College London, United Kingdom
| | - Fu Siong Ng
- National Heart and Lung Institute, Imperial College London, United Kingdom
| |
Collapse
|
|
21
|
Viscido A, Capannolo A, Petroni R, Stefanelli G, Zerboni G, De Martinis M, Necozione S, Penco M, Frieri G, Latella G, Romano S. Association between Corrected QT Interval and C-Reactive Protein in Patients with Inflammatory Bowel Diseases. ACTA ACUST UNITED AC 2020; 56:medicina56080382. [PMID: 32751480 PMCID: PMC7466199 DOI: 10.3390/medicina56080382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 07/27/2020] [Accepted: 07/28/2020] [Indexed: 11/21/2022]
Abstract
Background and objectives: Electrocardiograph abnormalities (i.e., QT interval prolongation) have been described in inflammatory bowel diseases (IBD). We aimed to measure the QT interval in a cohort of patients with IBD and to analyze its relationship with clinical and inflammatory activity. Materials and Methods: We performed a cross-sectional study that included 38 IBD outpatients and 38 “age- and sex-matched” healthy controls. Nine patients had active IBD, and 29 were in clinical remission. Among the latter, 10 patients had sustained (lasting >1 year) and 19 had short-term remission (≤1 year). Corrected QT (QTc) interval was measured on standard 12-lead electrocardiograph. A systematic review of the literature on studies investigating the QT interval in patients with IBD was also performed. Results: QTc interval values were similar between IBD patients and healthy controls (417.58 ± 22.05 ms vs. 409.13 ± 19.61 ms, respectively; p: 0.479). Patients with active IBD had significantly higher QTc values (435.11 ± 27.31 ms) than both controls (409.13 ± 19.61 ms) and patients in remission (412.14 ± 17.33 ms) (p: 0.031). Post hoc analysis showed that the difference in QTc values between active IBD and remission was attributable to the group of patients with sustained remission (p < 0.05). Lastly, a significant correlation between QTc interval and C-reactive protein (CRP) values was observed (Spearman test: r = 0.563; p: 0.0005). Conclusions: Our study demonstrates an association between QTc duration and both clinical and inflammatory activity in patients with IBD. The higher the CRP value, the longer is the QTc duration. For practical purposes, all patients with active IBD should undergo a standard ECG. Prescription of drugs able to modify the QT interval should be avoided in patients with active IBD. The systematic review of the literature indicated that this is the first published study demonstrating an association between the QTc duration and CRP values in patients with IBD.
Collapse
Affiliation(s)
- Angelo Viscido
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (A.C.); (G.S.); (G.F.); (G.L.)
- Correspondence: ; Tel.: +39-086-243-4746
| | - Annalisa Capannolo
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (A.C.); (G.S.); (G.F.); (G.L.)
| | - Renata Petroni
- Cardiology Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (R.P.); (M.P.); (S.R.)
- Di Lorenzo Clinic, Avezzano, 67100 L’Aquila, Italy
| | - Gianpiero Stefanelli
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (A.C.); (G.S.); (G.F.); (G.L.)
| | | | - Massimo De Martinis
- Clinical Immunology Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy;
| | - Stefano Necozione
- Statistics Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy;
| | - Maria Penco
- Cardiology Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (R.P.); (M.P.); (S.R.)
| | - Giuseppe Frieri
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (A.C.); (G.S.); (G.F.); (G.L.)
| | - Giovanni Latella
- Gastroenterology Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (A.C.); (G.S.); (G.F.); (G.L.)
| | - Silvio Romano
- Cardiology Unit, Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy; (R.P.); (M.P.); (S.R.)
| |
Collapse
|
|
22
|
Abe M, Rastelli DD, Gomez AC, Cingolani E, Lee Y, Soni PR, Fishbein MC, Lehman TJA, Shimada K, Crother TR, Chen S, Noval Rivas M, Arditi M. IL-1-dependent electrophysiological changes and cardiac neural remodeling in a mouse model of Kawasaki disease vasculitis. Clin Exp Immunol 2020; 199:303-313. [PMID: 31758701 PMCID: PMC7008220 DOI: 10.1111/cei.13401] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/08/2019] [Indexed: 02/06/2023] Open
Abstract
Kawasaki disease (KD) is the leading cause of acquired heart disease in children. In addition to coronary artery abnormalities, aneurysms and myocarditis, acute KD is also associated with echocardiogram (ECG) abnormalities in 40-80% of patients. Here, we show that these ECG changes are recapitulated in the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model. LCWE-injected mice developed elevated heart rate and decreased R wave amplitude, with significant differences in prolonged ventricular repolarization. LCWE-injected mice developed cardiac ganglion inflammation, that may affect the impulse-conducting system in the myocardium. Furthermore, serum nerve growth factor (NGF) was significantly elevated in LCWE-injected mice, similar to children with KD vasculitis, associated with increased neural remodeling of the myocardium. ECG abnormalities were prevented by blocking interleukin (IL)-1 signaling with anakinra, and the increase in serum NGF and cardiac neural remodeling were similarly blocked in Il1r1-/- mice and in wild-type mice treated with anakinra. Thus, similar to clinical KD, the LCWE-induced KD vasculitis mouse model also exhibits electrophysiological abnormalities and cardiac neuronal remodeling, and these changes can be prevented by blocking IL-1 signaling. These data support the acceleration of anti-IL-1 therapy trials to benefit KD patients.
Collapse
Affiliation(s)
- M. Abe
- Divisions of Infectious Diseases and ImmunologyDepartments of Biomedical Sciences and PediatricsCedars‐Sinai Medical CenterLos AngelesCAUSA
| | - D. D. Rastelli
- Divisions of Infectious Diseases and ImmunologyDepartments of Biomedical Sciences and PediatricsCedars‐Sinai Medical CenterLos AngelesCAUSA
- Division of Gastroenterology and NutritionBoston Children’s HospitalBostonMAUSA
| | - A. C. Gomez
- Divisions of Infectious Diseases and ImmunologyDepartments of Biomedical Sciences and PediatricsCedars‐Sinai Medical CenterLos AngelesCAUSA
| | - E. Cingolani
- Cedars‐Sinai Medical CenterCedars‐Sinai Smidt Heart InstituteLos AngelesCAUSA
| | - Y. Lee
- Divisions of Infectious Diseases and ImmunologyDepartments of Biomedical Sciences and PediatricsCedars‐Sinai Medical CenterLos AngelesCAUSA
| | - P. R. Soni
- Divisions of Infectious Diseases and ImmunologyDepartments of Biomedical Sciences and PediatricsCedars‐Sinai Medical CenterLos AngelesCAUSA
| | - M. C. Fishbein
- Department of PathologyDavid Geffen School of MedicineUCLALos AngelesCAUSA
| | - T. J. A. Lehman
- Division of RheumatologyDepartment of PediatricsWeill Cornell Medical SchoolNew YorkNYUSA
| | - K. Shimada
- Divisions of Infectious Diseases and ImmunologyDepartments of Biomedical Sciences and PediatricsCedars‐Sinai Medical CenterLos AngelesCAUSA
- Department of PediatricsDavid Geffen School of MedicineUCLALos AngelesCAUSA
| | - T. R. Crother
- Divisions of Infectious Diseases and ImmunologyDepartments of Biomedical Sciences and PediatricsCedars‐Sinai Medical CenterLos AngelesCAUSA
- Department of PediatricsDavid Geffen School of MedicineUCLALos AngelesCAUSA
| | - S. Chen
- Divisions of Infectious Diseases and ImmunologyDepartments of Biomedical Sciences and PediatricsCedars‐Sinai Medical CenterLos AngelesCAUSA
- Department of PediatricsDavid Geffen School of MedicineUCLALos AngelesCAUSA
| | - M. Noval Rivas
- Divisions of Infectious Diseases and ImmunologyDepartments of Biomedical Sciences and PediatricsCedars‐Sinai Medical CenterLos AngelesCAUSA
- Department of PediatricsDavid Geffen School of MedicineUCLALos AngelesCAUSA
| | - M. Arditi
- Divisions of Infectious Diseases and ImmunologyDepartments of Biomedical Sciences and PediatricsCedars‐Sinai Medical CenterLos AngelesCAUSA
- Cedars‐Sinai Medical CenterCedars‐Sinai Smidt Heart InstituteLos AngelesCAUSA
- Department of PediatricsDavid Geffen School of MedicineUCLALos AngelesCAUSA
| |
Collapse
|
|
23
|
Aromolaran AS, Srivastava U, Alí A, Chahine M, Lazaro D, El-Sherif N, Capecchi PL, Laghi-Pasini F, Lazzerini PE, Boutjdir M. Interleukin-6 inhibition of hERG underlies risk for acquired long QT in cardiac and systemic inflammation. PLoS One 2018; 13:e0208321. [PMID: 30521586 PMCID: PMC6283635 DOI: 10.1371/journal.pone.0208321] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 11/15/2018] [Indexed: 12/19/2022] Open
Abstract
Increased proinflammatory interleukin-6 (IL-6) levels are associated with acquired long QT-syndrome (LQTS) in patients with systemic inflammation, leading to higher risks for life-threatening polymorphic ventricular tachycardia such as Torsades de Pointes. However, the functional and molecular mechanisms of this association are not known. In most cases of acquired LQTS, the target ion channel is the human ether-á-go-go-related gene (hERG) encoding the rapid component of the delayed rectifier K current, IKr, which plays a critical role in cardiac repolarization. Here, we tested the hypothesis that IL-6 may cause QT prolongation by suppressing IKr. Electrophysiological and biochemical assays were used to assess the impact of IL-6 on the functional expression of IKr in HEK293 cells and adult guinea-pig ventricular myocytes (AGPVM). In HEK293 cells, IL-6 alone or in combination with the soluble IL-6 receptor (IL-6R), produced a significant depression of IKr peak and tail current densities. Block of IL-6R or Janus kinase (JAK) reversed the inhibitory effects of IL-6 on IKr. In AGPVM, IL-6 prolonged action potential duration (APD) which was further prolonged in the presence of IL-6R. Similar to heterologous cells, IL-6 reduced endogenous guinea pig ERG channel mRNA and protein expression. The data are first to demonstrate that IL-6 inhibition of IKr and the resulting prolongation of APD is mediated via IL-6R and JAK pathway activation and forms the basis for the observed clinical QT interval prolongation. These novel findings may guide the development of targeted anti-arrhythmic therapeutic interventions in patients with LQTS and inflammatory disorders.
Collapse
Affiliation(s)
- Ademuyiwa S. Aromolaran
- Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn, New York, United States of America
- Department of Cell Biology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
| | - Ujala Srivastava
- Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn, New York, United States of America
- Department of Cell Biology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
| | - Alessandra Alí
- Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy
| | - Mohamed Chahine
- Centre de Recherche, Institut Universitaire en Santé Mentale de Québec, Department of Medicine, Université Laval, Quebec City, Quebec, Canada
| | - Deana Lazaro
- Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn, New York, United States of America
| | - Nabil El-Sherif
- Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn, New York, United States of America
| | - Pier Leopoldo Capecchi
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Franco Laghi-Pasini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Pietro Enea Lazzerini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Siena, Italy
| | - Mohamed Boutjdir
- Cardiovascular Research Program, VA New York Harbor Healthcare System, Brooklyn, New York, United States of America
- Department of Cell Biology and Pharmacology, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
- Departments of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York, United States of America
- Department of Medicine, New York University School of Medicine, New York, United States of America
- * E-mail:
| |
Collapse
|
|
24
|
ADLAN AHMEDM. Inflammation and Heart Rate–corrected QT Interval: Evidence for a Potentially Reversible Cause of Sudden Death in Patients with Rheumatoid Arthritis? J Rheumatol 2018; 45:1609-1610. [DOI: 10.3899/jrheum.180921] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
|
|
25
|
Lazzerini PE, Capecchi PL, El‐Sherif N, Laghi‐Pasini F, Boutjdir M. Emerging Arrhythmic Risk of Autoimmune and Inflammatory Cardiac Channelopathies. J Am Heart Assoc 2018; 7:e010595. [PMID: 30571503 PMCID: PMC6404431 DOI: 10.1161/jaha.118.010595] [Citation(s) in RCA: 78] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
| | | | - Nabil El‐Sherif
- Veterans Affairs New York Harbor Healthcare SystemState University of New York Downstate Medical CenterNew YorkNY
| | - Franco Laghi‐Pasini
- Department of Medical Sciences, Surgery and NeurosciencesUniversity of SienaItaly
| | - Mohamed Boutjdir
- Veterans Affairs New York Harbor Healthcare SystemState University of New York Downstate Medical CenterNew YorkNY
- New York University School of MedicineNew YorkNY
| |
Collapse
|
|
26
|
Kouvas N, Kontogiannis C, Georgiopoulos G, Spartalis M, Tsilimigras DI, Spartalis E, Kapelouzou A, Kosmopoulos M, Chatzidou S. The complex crosstalk between inflammatory cytokines and ventricular arrhythmias. Cytokine 2018; 111:171-177. [PMID: 30172113 DOI: 10.1016/j.cyto.2018.08.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 08/07/2018] [Accepted: 08/08/2018] [Indexed: 12/23/2022]
Abstract
The network of cytokines consists one of the most extensively studied signaling systems of human body. Cytokines appear to modulate pathogenesis and progress of many different diseases in the human body, particularly in regards to cardiovascular system. However, their effects on the electrical system of the heart has been neglected. Over the past decade, attemps to understand this relationship led to the uncovering of the direct and indirect effects of cytokines on action potential propagation and cell depolarization. This relationship has been depicted in clinical practice as serum levels of cytokines are increasingly associated with prevalence of ventricular arrhythmias either isolated or secondary to either a heart condition or a systemic auto-immune disease. Thus, they present an appealing potential as a biomarker for prediction of arrhythmia generation, as well as the ourtcome of electrophysiological interventions.
Collapse
Affiliation(s)
- N Kouvas
- Department of Clinical Therapeutics, "Alexandra" Hospital, University of Athens, Athens, Greece
| | - C Kontogiannis
- Department of Clinical Therapeutics, "Alexandra" Hospital, University of Athens, Athens, Greece
| | - G Georgiopoulos
- Department of Clinical Therapeutics, "Alexandra" Hospital, University of Athens, Athens, Greece
| | - M Spartalis
- Department of Electrophysiology and Pacing, Onassis Cardiac Surgery Center, Greece
| | - D I Tsilimigras
- Department of Clinical Therapeutics, "Alexandra" Hospital, University of Athens, Athens, Greece
| | - E Spartalis
- Laboratory of Experimental Surgery and Surgical Research, National and Kapodistrian University of Athens, Medical School, Greece
| | - A Kapelouzou
- Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - M Kosmopoulos
- Department of Clinical Therapeutics, "Alexandra" Hospital, University of Athens, Athens, Greece.
| | - S Chatzidou
- Department of Clinical Therapeutics, "Alexandra" Hospital, University of Athens, Athens, Greece
| |
Collapse
|
|
27
|
Kobayashi H, Kobayashi Y, Yokoe I, Kitamura N, Nishiwaki A, Takei M, Giles JT. Heart Rate–corrected QT Interval Duration in Rheumatoid Arthritis and Its Reduction with Treatment with the Interleukin 6 Inhibitor Tocilizumab. J Rheumatol 2018; 45:1620-1627. [DOI: 10.3899/jrheum.180065] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/28/2018] [Indexed: 01/08/2023]
Abstract
Objective.Individuals with rheumatoid arthritis (RA) are at a heightened risk of sudden cardiac death, an outcome increased in those with prolongation of the corrected electrocardiographic QT interval (QTc). We compared QTc between patients with RA and demographically matched controls and studied the change in QTc after treatment with the interleukin 6 inhibitor tocilizumab (TCZ).Methods.Standard 12-lead electrocardiograms were obtained and QTc was measured in patients with RA at baseline and after 24 weeks of TCZ treatment, then compared with non-RA controls who were frequency-matched on age and sex. Indicators of the baseline QTc and predictors of change in QTc were studied using multivariable linear regression.Results.A total of 94 RA and 42 non-RA controls were studied. The average baseline QTc was 10 ms longer in the RA group vs controls (422 vs 412 ms, respectively; p < 0.001) and decreased to an average of 406 ms with treatment (p < 0.001). Baseline QTc was significantly and independently higher among those with anticyclic citrullinated peptide antibodies seropositivity, higher swollen joint counts, and higher levels of C-reactive protein (CRP) and matrix metalloproteinase 3. Each log unit decrease in CRP with treatment was associated with an average reduction in QTc of 2.9 ms (p = 0.002) after adjusting for age and baseline QTc. Clinical response measures were not associated with the change in QTc.Conclusion.The marked normalization of QTc observed with TCZ treatment, and its close parallel with CRP reduction, support the premise that systemic inflammation contributes to cardiac repolarization abnormalities in RA that may be amenable to treatment.
Collapse
|
|
28
|
Flygt J, Ruscher K, Norberg A, Mir A, Gram H, Clausen F, Marklund N. Neutralization of Interleukin-1β following Diffuse Traumatic Brain Injury in the Mouse Attenuates the Loss of Mature Oligodendrocytes. J Neurotrauma 2018; 35:2837-2849. [PMID: 29690837 PMCID: PMC6247990 DOI: 10.1089/neu.2018.5660] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Traumatic brain injury (TBI) commonly results in injury to the components of the white matter tracts, causing post-injury cognitive deficits. The myelin-producing oligodendrocytes (OLs) are vulnerable to TBI, although may potentially be replaced by proliferating oligodendrocyte progenitor cells (OPCs). The cytokine interleukin-1β (IL-1β) is a key mediator of the complex inflammatory response, and when neutralized in experimental TBI, behavioral outcome was improved. To evaluate the role of IL-1β on oligodendrocyte cell death and OPC proliferation, 116 adult male mice subjected to sham injury or the central fluid percussion injury (cFPI) model of traumatic axonal injury, were analyzed at two, seven, and 14 days post-injury. At 30 min post-injury, mice were randomly administered an IL-1β neutralizing or a control antibody. OPC proliferation (5-ethynyl 2'- deoxyuridine (EdU)/Olig2 co-labeling) and mature oligodendrocyte cell loss was evaluated in injured white matter tracts. Microglia/macrophages immunohistochemistry and ramification using Sholl analysis were also evaluated. Neutralizing IL-1β resulted in attenuated cell death, indicated by cleaved caspase-3 expression, and attenuated loss of mature OLs from two to seven days post-injury in brain-injured animals. IL-1β neutralization also attenuated the early, two day post-injury increase of microglia/macrophage immunoreactivity and altered their ramification. The proliferation of OPCs in brain-injured animals was not altered, however. Our data suggest that IL-1β is involved in the TBI-induced loss of OLs and early microglia/macrophage activation, although not the OPC proliferation. Attenuated oligodendrocyte cell loss may contribute to the improved behavioral outcome observed by IL-1β neutralization in this mouse model of diffuse TBI.
Collapse
Affiliation(s)
- Johanna Flygt
- 1 Department of Neuroscience, Section of Neurosurgery, Uppsala University , Uppsala, Sweden
| | - Karsten Ruscher
- 2 Novartis Institutes of Biomedical Research , Basel, Switzerland
| | - Amanda Norberg
- 1 Department of Neuroscience, Section of Neurosurgery, Uppsala University , Uppsala, Sweden
| | - Anis Mir
- 3 Lund University, Skane University Hospital , Department of Clinical Sciences Lund, Neurosurgery, Lund, Sweden
| | - Hermann Gram
- 3 Lund University, Skane University Hospital , Department of Clinical Sciences Lund, Neurosurgery, Lund, Sweden
| | - Fredrik Clausen
- 1 Department of Neuroscience, Section of Neurosurgery, Uppsala University , Uppsala, Sweden
| | - Niklas Marklund
- 1 Department of Neuroscience, Section of Neurosurgery, Uppsala University , Uppsala, Sweden .,3 Lund University, Skane University Hospital , Department of Clinical Sciences Lund, Neurosurgery, Lund, Sweden
| |
Collapse
|
|
29
|
Lazzerini PE, Capecchi PL, Laghi-Pasini F. Systemic inflammation and arrhythmic risk: lessons from rheumatoid arthritis. Eur Heart J 2018; 38:1717-1727. [PMID: 27252448 DOI: 10.1093/eurheartj/ehw208] [Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 05/04/2016] [Indexed: 12/19/2022] Open
Abstract
Rheumatoid arthritis (RA) is a chronic immuno-mediated disease primarily affecting the joints, characterized by persistent high-grade systemic inflammation. Cardiovascular morbidity and mortality are significantly increased in RA, with >50% of premature deaths attributable to cardiovascular disease. In particular, RA patients were twice as likely to experience sudden cardiac death compared with non-RA subjects, pointing to an increased propensity to develop malignant ventricular arrhythmias. Indeed, ventricular repolarization (QT interval) abnormalities and cardiovascular autonomic nervous system dysfunction, representing two well-recognized risk factors for life-threatening ventricular arrhythmias in the general population, are commonly observed in RA. Moreover, large population-based studies seem to indicate that also the prevalence of atrial fibrillation is significantly higher in RA subjects than in the general population, thus suggesting that these patients are characterized by an abnormal diffuse myocardial electrical instability. Although the underlying mechanisms accounting for the pro-arrhythmogenic substrate in RA are probably intricate, the leading role seems to be played by chronic systemic inflammatory activation, able to promote arrhythmias both indirectly, by accelerating the development of ischaemic heart disease and congestive heart failure, and directly, by affecting cardiac electrophysiology. In this integrated mechanistic view, lowering the inflammatory burden through an increasingly tight control of disease activity may represent the most effective intervention to reduce arrhythmic risk in these patients. Intriguingly, these considerations could be more generally applicable to all the diseases characterized by chronic systemic inflammation, and could help elucidate the link between low-grade chronic inflammation and arrhythmic risk in the general population.
Collapse
|
|
30
|
Szekely Y, Arbel Y. A Review of Interleukin-1 in Heart Disease: Where Do We Stand Today? Cardiol Ther 2018; 7:25-44. [PMID: 29417406 PMCID: PMC5986669 DOI: 10.1007/s40119-018-0104-3] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2017] [Indexed: 12/16/2022] Open
Abstract
Cardiovascular diseases are the leading cause of death worldwide. Research in the last two decades has emphasized the inflammatory process as a key component in the pathogenesis of many of them. The Interleukin-1 family is a pivotal element of inflammation and has been well studied as a therapeutic target in various inflammatory states. Recent trials have explored the effect of Interleukin-1 blockade in cardiovascular diseases and initial evidence of the relevance of such treatment in this field of medicine accumulate. This review will describe the role of Interleukin-1 in heart diseases and the potential therapeutic effect of its blockade in such diseases.
Collapse
Affiliation(s)
- Yishay Szekely
- Department of Cardiology, Tel Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Yaron Arbel
- Department of Cardiology, Tel Aviv Sourasky Medical Center Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
|
31
|
Ogunmodede J, Kolo P, Katibi I, Omotoso A. The Use of First Line Highly Active Anti-Retroviral Therapy (HAART) is Not Associated with Qtc Prolongation in HIV Patients. Ethiop J Health Sci 2017; 27:613-620. [PMID: 29487470 PMCID: PMC5811940 DOI: 10.4314/ejhs.v27i6.6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 05/26/2017] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND HAART has improved survival of HIV patients. Its contribution to the development of new cardiovascular abnormalities has generated much interest. This study aimed at determining the prevalence of QTc prolongation among HIV patients and determining the influence if any of the use of HAART on the QTc and on the risk of having QTc prolongation. MATERIALS AND METHODS One hundred and fifty HIV positive subjects comprising 76 HIV positive subjects on HAART (Group A), 74 who were HAART- naïve (Group B), and 150 age and sex-matched healthy controls (Group C) were studied. All subjects had electrocardiography, and QTc duration was calculated. RESULTS Mean QTc was significantly different among the three groups (P <0.001), highest in Group B > Group A > Group C. Frequency of QTc prolongation was highest in Group B (32%)>, Group A (17.3%)> Group C (4.7%) (P<0.001). Mean QTc was significantly longer among patients with CD4 count <200 cells/mm3 than among those with >200 cells/mm3 0.445 ± 0.03secs vs 0.421 ± 0.03secs (P<0.001). QTc prolongation was commoner among individuals with CD4 count <200 cells/mm3 50% vs 20.5% (P<0.001). On binary logistic regression, none of the HAART medications used by our patients was predictive of the occurrence of QTc prolongation. CONCLUSION The QTc is longer, and QTc prolongation occurs more frequently in HAART-naïve HIV patients than patients on HAART and healthy controls. None of the HAART medications used by our patients was predictive of the development of QTc prolongation.
Collapse
Affiliation(s)
| | - Philip Kolo
- Department of Medicine, University of Ilorin, Ilorin, Nigeria
| | - Ibraheem Katibi
- Department of Medicine, University of Ilorin, Ilorin, Nigeria
| | - Ayodele Omotoso
- Department of Medicine, University of Ilorin, Ilorin, Nigeria
| |
Collapse
|
|
32
|
Abstract
Myocardial injury, mechanical stress, neurohormonal activation, inflammation, and/or aging all lead to cardiac remodeling, which is responsible for cardiac dysfunction and arrhythmogenesis. Of the key histological components of cardiac remodeling, fibrosis either in the form of interstitial, patchy, or dense scars, constitutes a key histological substrate of arrhythmias. Here we discuss current research findings focusing on the role of fibrosis, in arrhythmogenesis. Numerous studies have convincingly shown that patchy or interstitial fibrosis interferes with myocardial electrophysiology by slowing down action potential propagation, initiating reentry, promoting after-depolarizations, and increasing ectopic automaticity. Meanwhile, there has been increasing appreciation of direct involvement of myofibroblasts, the activated form of fibroblasts, in arrhythmogenesis. Myofibroblasts undergo phenotypic changes with expression of gap-junctions and ion channels thereby forming direct electrical coupling with cardiomyocytes, which potentially results in profound disturbances of electrophysiology. There is strong evidence that systemic and regional inflammatory processes contribute to fibrogenesis (i.e., structural remodeling) and dysfunction of ion channels and Ca2+ homeostasis (i.e., electrical remodeling). Recognizing the pivotal role of fibrosis in the arrhythmogenesis has promoted clinical research on characterizing fibrosis by means of cardiac imaging or fibrosis biomarkers for clinical stratification of patients at higher risk of lethal arrhythmia, as well as preclinical research on the development of antifibrotic therapies. At the end of this review, we discuss remaining key questions in this area and propose new research approaches. © 2017 American Physiological Society. Compr Physiol 7:1009-1049, 2017.
Collapse
Affiliation(s)
- My-Nhan Nguyen
- Baker Heart and Diabetes Institute, Melbourne, Australia.,Central Clinical School, Monash University, Melbourne, Australia
| | - Helen Kiriazis
- Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Xiao-Ming Gao
- Baker Heart and Diabetes Institute, Melbourne, Australia.,Central Clinical School, Monash University, Melbourne, Australia
| | - Xiao-Jun Du
- Baker Heart and Diabetes Institute, Melbourne, Australia.,Central Clinical School, Monash University, Melbourne, Australia
| |
Collapse
|
|
33
|
Lazzerini PE, Laghi-Pasini F, Bertolozzi I, Morozzi G, Lorenzini S, Simpatico A, Selvi E, Bacarelli MR, Finizola F, Vanni F, Lazaro D, Aromolaran A, El Sherif N, Boutjdir M, Capecchi PL. Systemic inflammation as a novel QT-prolonging risk factor in patients with torsades de pointes. Heart 2017; 103:1821-1829. [DOI: 10.1136/heartjnl-2016-311079] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 03/29/2017] [Accepted: 04/10/2017] [Indexed: 02/06/2023] Open
|
|
34
|
Lin TT, Sung YL, Wu CE, Zhang H, Liu YB, Lin SF. Proarrhythmic risk and determinants of cardiac autonomic dysfunction in collagen-induced arthritis rats. BMC Musculoskelet Disord 2016; 17:491. [PMID: 27894284 PMCID: PMC5127040 DOI: 10.1186/s12891-016-1347-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 11/21/2016] [Indexed: 12/22/2022] Open
Abstract
Backgrounds Patients with rheumatoid arthritis (RA) have increased risk of sudden cardiac death (SCD), which is two-fold higher than general population. The driving cause of SCD was considered due to lift-threatening arrhythmia where systemic inflammation acts as the pathophysiological basis linking RA to autonomicdysfunction. Methods To assess the sympathetic over-activity of “inflammatory reflex”, we measured heart rate variability (HRV) in a rat collagen-induced arthritis (CIA) model, whose arthritis is induced in Lewis rats by intradermal injection of emulsion of type II collagen. Single-lead electrocardiogram (ECG) was recorded for 30 min every two days. Time and frequency-domain parameters, detrended fluctuation analysis (DFA), deceleration (DC) and acceleration capacity (AC) were analyzed. Results Compared with 9 control rats, many of HRV parameters of 9 CIA rats revealed significant different. At the beginning of arthritis, LF/HF was significant higher than controls (1st week: 2.41 ± 0.7 vs. 1.76 ± 0.6, p < 0.05; 2nd week: 2.24 ± 0.5 vs. 1.58 ± 0.5, p < 0.05) indicating intensive inflammatory reflex at the initial phase of inflammation but no significant difference was observed in the following recover phase. The similar trend of DFA parameters was noted. However, the DC appeared progressive lower despite of no significant increase of the LF/HF compared with controls since 4th week. Conclusions We observed sympathetic over-activation of inflammatory reflex during early stage of arthritis in CIA rats. The ongoing decline of DC indicated advanced cardiac autonomic dysfunction regardless of remission of acute arthritis. Electronic supplementary material The online version of this article (doi:10.1186/s12891-016-1347-6) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Ting-Tse Lin
- Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
| | - Yen-Ling Sung
- Institute of Biomedical Engineering, National Chiao-Tung University, 1001 Ta-Hsueh Road, Hsinchu, 300, Taiwan
| | - Chih-En Wu
- Institute of Biomedical Engineering, National Chiao-Tung University, 1001 Ta-Hsueh Road, Hsinchu, 300, Taiwan
| | - Hong Zhang
- Department of Electrical Engineering, Xi'an Jiaotong University, Xi'an, Shaanxi, China
| | - Yen-Bin Liu
- Department of Internal Medicine, National Taiwan University Hospital Hsin-Chu Branch, Hsinchu, Taiwan
| | - Shien-Fong Lin
- Institute of Biomedical Engineering, National Chiao-Tung University, 1001 Ta-Hsueh Road, Hsinchu, 300, Taiwan.
| |
Collapse
|
|
35
|
Monnerat G, Alarcón ML, Vasconcellos LR, Hochman-Mendez C, Brasil G, Bassani RA, Casis O, Malan D, Travassos LH, Sepúlveda M, Burgos JI, Vila-Petroff M, Dutra FF, Bozza MT, Paiva CN, Carvalho AB, Bonomo A, Fleischmann BK, de Carvalho ACC, Medei E. Macrophage-dependent IL-1β production induces cardiac arrhythmias in diabetic mice. Nat Commun 2016; 7:13344. [PMID: 27882934 PMCID: PMC5123037 DOI: 10.1038/ncomms13344] [Citation(s) in RCA: 209] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 09/24/2016] [Indexed: 02/08/2023] Open
Abstract
Diabetes mellitus (DM) encompasses a multitude of secondary disorders, including heart disease. One of the most frequent and potentially life threatening disorders of DM-induced heart disease is ventricular tachycardia (VT). Here we show that toll-like receptor 2 (TLR2) and NLRP3 inflammasome activation in cardiac macrophages mediate the production of IL-1β in DM mice. IL-1β causes prolongation of the action potential duration, induces a decrease in potassium current and an increase in calcium sparks in cardiomyocytes, which are changes that underlie arrhythmia propensity. IL-1β-induced spontaneous contractile events are associated with CaMKII oxidation and phosphorylation. We further show that DM-induced arrhythmias can be successfully treated by inhibiting the IL-1β axis with either IL-1 receptor antagonist or by inhibiting the NLRP3 inflammasome. Our results establish IL-1β as an inflammatory connection between metabolic dysfunction and arrhythmias in DM.
Collapse
MESH Headings
- Action Potentials
- Animals
- Antirheumatic Agents/pharmacology
- Arrhythmias, Cardiac/etiology
- Arrhythmias, Cardiac/immunology
- Arrhythmias, Cardiac/metabolism
- Calcium/metabolism
- Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism
- Caspase 1/metabolism
- Diabetes Mellitus, Experimental/complications
- Diabetes Mellitus, Experimental/immunology
- Diabetes Mellitus, Experimental/metabolism
- Inflammasomes/antagonists & inhibitors
- Interleukin 1 Receptor Antagonist Protein/pharmacology
- Interleukin-1beta/genetics
- Interleukin-1beta/immunology
- Interleukin-1beta/metabolism
- Macrophages/immunology
- Mice
- Mice, Transgenic
- Myocardial Contraction
- Myocytes, Cardiac/immunology
- Myocytes, Cardiac/metabolism
- NLR Family, Pyrin Domain-Containing 3 Protein/antagonists & inhibitors
- NLR Family, Pyrin Domain-Containing 3 Protein/genetics
- NLR Family, Pyrin Domain-Containing 3 Protein/immunology
- Potassium/metabolism
- Receptors, Interleukin-1/antagonists & inhibitors
- Receptors, Interleukin-1/genetics
- Receptors, Interleukin-1/immunology
- Tachycardia, Ventricular/etiology
- Tachycardia, Ventricular/immunology
- Tachycardia, Ventricular/metabolism
- Toll-Like Receptor 2/genetics
- Toll-Like Receptor 2/immunology
Collapse
Affiliation(s)
- Gustavo Monnerat
- Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Micaela L. Alarcón
- Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Luiz R. Vasconcellos
- LIRS-Laboratory of Immunoreceptors and Signaling, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Camila Hochman-Mendez
- Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Guilherme Brasil
- Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Rosana A. Bassani
- Center for Biomedical Engineering, University of Campinas, Campinas 13.083-970, Brazil
| | - Oscar Casis
- Departamento de Fisiología, Facultad de Farmacia, Universidad del País Vasco UPV/EHU, 01006 Vitoria, Spain
| | - Daniela Malan
- Institute of Physiology I, Life and Brain Center, University of Bonn, Bonn D-53127, Germany
| | - Leonardo H. Travassos
- LIRS-Laboratory of Immunoreceptors and Signaling, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Marisa Sepúlveda
- Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata 1900, Argentina
| | - Juan Ignacio Burgos
- Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata 1900, Argentina
| | - Martin Vila-Petroff
- Centro de Investigaciones Cardiovasculares, Conicet La Plata, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata 1900, Argentina
| | - Fabiano F. Dutra
- Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Marcelo T. Bozza
- Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Claudia N. Paiva
- Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Adriana Bastos Carvalho
- Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
| | - Adriana Bonomo
- Instituto de Microbiologia, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- FIOCANCER/ VPPLR/FIOCRUZ, FIOCRUZ-Manguinhos, Rio de Janeiro 21040-360, Brazil
| | - Bernd K. Fleischmann
- Institute of Physiology I, Life and Brain Center, University of Bonn, Bonn D-53127, Germany
| | - Antonio Carlos Campos de Carvalho
- Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- National Center for Structural Biology and Bioimaging—CENABIO/UFRJ, Rio de Janeiro 21941-902, Brazil
| | - Emiliano Medei
- Institute of Biophysics Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro 21941-902, Brazil
- National Center for Structural Biology and Bioimaging—CENABIO/UFRJ, Rio de Janeiro 21941-902, Brazil
| |
Collapse
|
|
36
|
Lazzerini PE, Capecchi PL, Bertolozzi I, Morozzi G, Lorenzini S, Simpatico A, Selvi E, Bacarelli MR, Acampa M, Lazaro D, El-Sherif N, Boutjdir M, Laghi-Pasini F. Marked QTc Prolongation and Torsades de pointes in Patients with Chronic Inflammatory Arthritis. Front Cardiovasc Med 2016; 3:31. [PMID: 27703966 PMCID: PMC5029147 DOI: 10.3389/fcvm.2016.00031] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Accepted: 09/05/2016] [Indexed: 01/08/2023] Open
Abstract
Mounting evidence indicates that in chronic inflammatory arthritis (CIA), QTc prolongation is frequent and correlates with systemic inflammatory activation. Notably, basic studies demonstrated that inflammatory cytokines induce profound changes in potassium and calcium channels resulting in a prolonging effect on cardiomyocyte action potential duration, thus on the QT interval on the electrocardiogram. Moreover, it has been demonstrated that in rheumatoid arthritis (RA) patients, the risk of sudden cardiac death is significantly increased when compared to non-RA subjects. Conversely, to date no data are available about torsades de pointes (TdP) prevalence in CIA, and the few cases reported considered CIA only an incidental concomitant disease, not contributing factor to TdP development. We report three patients with active CIA developing marked QTc prolongation, in two cases complicated with TdP degenerating to cardiac arrest. In these patients, a blood sample was obtained within 24 h from TdP/marked QTc prolongation occurrence, and levels of IL-6, TNFα, and IL-1 were evaluated. In all three cases, IL-6 was markedly elevated, ~10 to 100 times more than reference values. Moreover, one patient also showed high circulating levels of TNFα and IL-1. In conclusion, active CIA may represent a currently overlooked QT-prolonging risk factor, potentially contributing in the presence of other “classical” risk factors to TdP occurrence. In particular, a relevant role may be played by elevated circulating IL-6 levels via direct electrophysiological effects on the heart. This fact should be carefully kept in mind, particularly when recognizable risk factors are already present and/or the addition of QT-prolonging drugs is required.
Collapse
Affiliation(s)
- Pietro Enea Lazzerini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena , Siena , Italy
| | - Pier Leopoldo Capecchi
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena , Siena , Italy
| | - Iacopo Bertolozzi
- Cardiology Intensive Therapy Unit, Department of Internal Medicine, Hospital of Carrara , Carrara , Italy
| | - Gabriella Morozzi
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena , Siena , Italy
| | - Sauro Lorenzini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena , Siena , Italy
| | - Antonella Simpatico
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena , Siena , Italy
| | - Enrico Selvi
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena , Siena , Italy
| | - Maria Romana Bacarelli
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena , Siena , Italy
| | - Maurizio Acampa
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena , Siena , Italy
| | - Deana Lazaro
- VA New York Harbor Healthcare System, SUNY Downstate Medical Center , New York, NY , USA
| | - Nabil El-Sherif
- VA New York Harbor Healthcare System, SUNY Downstate Medical Center , New York, NY , USA
| | - Mohamed Boutjdir
- VA New York Harbor Healthcare System, SUNY Downstate Medical Center, New York, NY, USA; NYU School of Medicine, New York, NY, USA
| | - Franco Laghi-Pasini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena , Siena , Italy
| |
Collapse
|
|
37
|
Kazanski V, Mitrokhin VM, Mladenov MI, Kamkin AG. Cytokine Effects on Mechano-Induced Electrical Activity in Atrial Myocardium. Immunol Invest 2016; 46:22-37. [PMID: 27617892 DOI: 10.1080/08820139.2016.1208220] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
The role of cytokines as regulators of stretch-related mechanisms is of special importance since mechano-sensitivity plays an important role in a wide variety of biological processes. Here, we elucidate the influence of cytokine application on mechano-sensitivity and mechano-transduction. The atrial myocardial stretch induces production of interleukin (IL)-2, IL-6, IL-13, IL-17A, and IL-18 with exception of tumor necrosis factor α (TNF-α), IL-1β, and vascular endothelial growth factor B (VEGF-B). Positive ionotropic effect was specific for VEGF-B, negative ionotropic effects were specific for TNF-α, IL-1β, IL-2, IL-6, IL-13, IL-17A and IL-18, while IL-1α doesn't show direct ionotropic effect. The IL-2, IL-6, IL-17A, IL-18, and VEGF-B cause elongation of the APD, in comparison with the reduced APD caused by the IL-13. The TNF-α, IL-1β, and IL-18 influences L-type Ca2+ channels, IL-2 has an inhibitory effect on the fast Na+ channels while IL-17A and VEGF-B were specific for Kir channels. With exception of the IL-1α, IL-2, and VEGF-B, all analyzed cytokines include nitric oxide dependent signaling with resultant combined effects on mechano-gated and Ca2+ channels. The relationships between these pathways and the time-dependence of their activation are of important considerations in the evaluation of cytokine-induced electrical abnormality, specific for cardiac dysfunctions. In general, the discussion presented in this review covers research devoted to counterbalance between different cytokines in the regulation of stretch-induced effects in rat atrial myocardium. ABBREVIATIONS APs: action potentials; APD25: action potential durations to 25% of re-polarization; APD50: action potential durations to 50% of repolarization; APD90: action potential durations to 90% of repolarization; MGCs: mechanically gated channels.
Collapse
Affiliation(s)
- V Kazanski
- a Department of Fundamental and Applied Physiology , Russian National Research Medical University , Moscow , Russia
| | - V M Mitrokhin
- a Department of Fundamental and Applied Physiology , Russian National Research Medical University , Moscow , Russia
| | - M I Mladenov
- a Department of Fundamental and Applied Physiology , Russian National Research Medical University , Moscow , Russia.,b Faculty of Natural Sciences and Mathematics, Institute of Biology , "Ss. Cyril and Methodius" University , Skopje , Macedonia
| | - A G Kamkin
- a Department of Fundamental and Applied Physiology , Russian National Research Medical University , Moscow , Russia
| |
Collapse
|
|
38
|
Wasson S, Reddy HK, Dohrmann ML. Current Perspectives of Electrical Remodeling and Its Therapeutic Implications. J Cardiovasc Pharmacol Ther 2016; 9:129-44. [PMID: 15309249 DOI: 10.1177/107424840400900208] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Electrical remodeling involves alterations in the electrophysiologic milieu of myocardium in various disease states, such as ventricular hypertrophy, heart failure, atrial tachyarrhythmias, myocardial ischemia, and infarction that are associated with cardiac arrhythmias. Although research in this area dates back to early part of the 19th century, we still lack the exact knowledge of ionic remodeling, the role of various genes and channel proteins, and their relevance for the newer antiarrhythmic therapies. Structural remodeling may also have an impact on the electrical remodeling process, although differences in both structural and electrical remodeling are associated with different disease states. Various electrophysiologic, cellular, and structural alterations, including anisotropic conduction, increased intracellular calcium levels, and gap junction remodeling predispose to increased dispersion of action potential duration and refractoriness. This constitutes a favorable substrate for early and late afterdepolarizations and reentrant arrhythmias. Studying the role of ionic remodeling in the initiation and propagation of cardiac arrhythmias has significant relevance for developing newer antiarrhythmic therapies, for identifying patients at risk of developing fatal arrhythmias, and for implementing effective preventive measures. Further research is required to understand the specific effects of individual ion channel remodeling, to understand the signal transduction mechanisms, and to address whether detrimental effects of electrical remodeling can be altered.
Collapse
Affiliation(s)
- Sanjeev Wasson
- Division of Cardiology, University of Missouri Hospital, Columbia, Missouri 65212, USA
| | | | | |
Collapse
|
|
39
|
The crossroads of inflammation, fibrosis, and arrhythmia following myocardial infarction. J Mol Cell Cardiol 2015; 91:114-22. [PMID: 26739214 DOI: 10.1016/j.yjmcc.2015.12.024] [Citation(s) in RCA: 174] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 12/23/2015] [Accepted: 12/26/2015] [Indexed: 01/08/2023]
Abstract
Optimal healing of damaged tissue following myocardial infarction (MI) requires a coordinated cellular response that can be divided into three phases: inflammatory, proliferative/reparative, and maturation. The inflammatory phase, characterized by rapid influx of cytokines, chemokines, and immune cells, is critical to the removal of damaged tissue. The onset of the proliferative/reparative phase is marked by increased proliferation of myofibroblasts and secretion of collagen to replace dead tissue. Lastly, crosslinking of collagen fibers and apoptosis of immune cells marks the maturation phase. Excessive inflammation or fibrosis has been linked to increased incidence of arrhythmia and other MI-related pathologies. This review describes the roles of inflammation and fibrosis in arrhythmogenesis and prospective therapies for anti-arrhythmic treatment.
Collapse
|
|
40
|
Mitrokhin V, Mladenov M, Kamkin A. IL-1 provokes electrical abnormalities in rat atrial myocardium. Int Immunopharmacol 2015; 28:780-4. [DOI: 10.1016/j.intimp.2015.08.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 08/04/2015] [Accepted: 08/04/2015] [Indexed: 12/14/2022]
|
|
41
|
Lazzerini PE, Capecchi PL, Laghi-Pasini F. Long QT Syndrome: An Emerging Role for Inflammation and Immunity. Front Cardiovasc Med 2015; 2:26. [PMID: 26798623 PMCID: PMC4712633 DOI: 10.3389/fcvm.2015.00026] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 05/08/2015] [Indexed: 01/07/2023] Open
Abstract
The long QT syndrome (LQTS), classified as congenital or acquired, is a multi-factorial disorder of myocardial repolarization predisposing to life-threatening ventricular arrhythmias, particularly torsades de pointes. In the latest years, inflammation and immunity have been increasingly recognized as novel factors crucially involved in modulating ventricular repolarization. In the present paper, we critically review the available information on this topic, also analyzing putative mechanisms and potential interplays with the other etiologic factors, either acquired or inherited. Accumulating data indicate inflammatory activation as a potential cause of acquired LQTS. The putative underlying mechanisms are complex but essentially cytokine-mediated, including both direct actions on cardiomyocyte ion channels expression and function, and indirect effects resulting from an increased central nervous system sympathetic drive on the heart. Autoimmunity represents another recently arising cause of acquired LQTS. Indeed, increasing evidence demonstrates that autoantibodies may affect myocardial electric properties by directly cross-reacting with the cardiomyocyte and interfering with specific ion currents as a result of molecular mimicry mechanisms. Intriguingly, recent data suggest that inflammation and immunity may be also involved in modulating the clinical expression of congenital forms of LQTS, possibly triggering or enhancing electrical instability in patients who already are genetically predisposed to arrhythmias. In this view, targeting immuno-inflammatory pathways may in the future represent an attractive therapeutic approach in a number of LQTS patients, thus opening new exciting avenues in antiarrhythmic therapy.
Collapse
Affiliation(s)
- Pietro Enea Lazzerini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena , Siena , Italy
| | - Pier Leopoldo Capecchi
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena , Siena , Italy
| | - Franco Laghi-Pasini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena , Siena , Italy
| |
Collapse
|
|
42
|
Lazzerini PE, Acampa M, Capecchi PL, Fineschi I, Selvi E, Moscadelli V, Zimbone S, Gentile D, Galeazzi M, Laghi-Pasini F. Antiarrhythmic potential of anticytokine therapy in rheumatoid arthritis: tocilizumab reduces corrected QT interval by controlling systemic inflammation. Arthritis Care Res (Hoboken) 2015; 67:332-9. [PMID: 25186226 DOI: 10.1002/acr.22455] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2014] [Accepted: 08/26/2014] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Patients with rheumatoid arthritis (RA) are twice as likely to experience sudden cardiac death compared with individuals without RA. Although the underlying mechanisms of this have not been clarified, evidence points to the effects of systemic inflammation on ventricular repolarization. Accordingly, prolongation of the corrected QT (QTc) interval is more frequent in patients with RA compared with individuals without RA also correlating with C-reactive protein (CRP) and predicting all-cause mortality. Tocilizumab (TCZ) is an anti-interleukin-6 receptor antibody that potently inhibits inflammatory activation in RA, with rapid normalization of acute-phase reactant levels, including the CRP level. Therefore, we hypothesized that TCZ may normalize the QTc interval by dampening systemic inflammation, thus reducing the risk of arrhythmia in patients with RA. METHODS Seventeen consecutive patients with active RA who were scheduled to receive TCZ once every 4 weeks underwent a clinical examination, electrocardiography, and blood sampling just before the first injection with TCZ and again after 3 months and 6 months of treatment. RESULTS At baseline, 76% of patients displayed prolongation of the QTc interval (mean ± SD 452.3 ± 35.8 msec). TCZ treatment was associated with a rapid and significant reduction of the QTc interval to mean values <440 msec (up to 428.1 ± 34.3 msec). Throughout the study, QTc interval shortening correlated with decreases in both the CRP level, and more strongly, with circulating tumor necrosis factor α level. CONCLUSION These data provide further evidence of the close link between the degree of systemic inflammation and QTc interval duration in RA and also suggest an anti-arrhythmic potential for TCZ treatment, which may have a beneficial impact on the mortality of these patients.
Collapse
|
|
43
|
Adlan AM, Panoulas VF, Smith JP, Fisher JP, Kitas GD. Association between corrected QT interval and inflammatory cytokines in rheumatoid arthritis. J Rheumatol 2015; 42:421-8. [PMID: 25593223 DOI: 10.3899/jrheum.140861] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Corrected QT (QTc) interval predicts all-cause and cardiovascular mortality and may contribute to the increased mortality risk in rheumatoid arthritis (RA). Animal experiments have shown that proinflammatory cytokines [tumor necrosis factor (TNF)-α and interleukin 1 (IL-1)] can prolong cardiomyocyte action potential. We sought to determine whether elevations in circulating inflammatory cytokines were independently associated with QTc prolongation in patients with RA. METHODS One hundred twelve patients [median age 62 (interquartile range 17) yrs; 80 women (71%)] from a well-characterized RA cohort underwent baseline 12-lead electrocardiograms for QT interval measurement and contemporary blood sampling to assess concentrations of inflammatory markers including C-reactive protein (CRP), TNF-α, and interleukins (IL-1α, IL-1β, IL-6, IL-10). QTc was calculated using the Bazett (QTBAZ = QT ÷ √RR) and Framingham Heart Study (QTFHS = QT + 0.154 × [1 - RR]) heart rate correction formulas. RESULTS Inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10) were positively correlated with QTBAZ (Spearman rank correlation coefficient rho = 0.199, 0.210, 0.222, 0.333; all p < 0.05). In multivariable regression analysis, these associations were all confounded by age except IL-10, where higher tertile groups were independently and positively associated with QTBAZ (β = 0.202, p = 0.023) and QTFHS (β = 0.223, p = 0.009) when compared to the lower tertile. CRP (per unit increase) was independently associated with QTBAZ (β = 0.278, p = 0.001), but not QTFHS. CONCLUSION To our knowledge, ours is the first study demonstrating a contemporary link between inflammatory cytokines and QT interval in humans. Our results suggest that a lower inflammatory burden may protect against QTc prolongation in patients with RA. However, further studies are required to confirm the effects of pro- and antiinflammatory cytokines on QTc interval.
Collapse
Affiliation(s)
- Ahmed M Adlan
- From the College of Life and Environmental Sciences, University of Birmingham, Birmingham; Imperial College London, National Heart and Lung Institute, South Kensington Campus, London; and the Department of Rheumatology, Dudley Group of Hospitals National Health Service (NHS) Trust, Russells Hall Hospital, Dudley, UK.A.M. Adlan, MBBS, MRCP, College of Environmental Sciences; J.P. Fisher, BSc (Hons), PhD, College of Life and Environmental Sciences, University of Birmingham; V.F. Panoulas, MD, PhD, Imperial College London, National Heart and Lung Institute, Department of Rheumatology, Dudley Group of Hospitals NHS Trust; J.P. Smith, BSc (Hons), MSc; G.D. Kitas, MD, PhD, FRCP, Department of Rheumatology, Dudley Group of Hospitals NHS Trust.
| | - Vasileios F Panoulas
- From the College of Life and Environmental Sciences, University of Birmingham, Birmingham; Imperial College London, National Heart and Lung Institute, South Kensington Campus, London; and the Department of Rheumatology, Dudley Group of Hospitals National Health Service (NHS) Trust, Russells Hall Hospital, Dudley, UK.A.M. Adlan, MBBS, MRCP, College of Environmental Sciences; J.P. Fisher, BSc (Hons), PhD, College of Life and Environmental Sciences, University of Birmingham; V.F. Panoulas, MD, PhD, Imperial College London, National Heart and Lung Institute, Department of Rheumatology, Dudley Group of Hospitals NHS Trust; J.P. Smith, BSc (Hons), MSc; G.D. Kitas, MD, PhD, FRCP, Department of Rheumatology, Dudley Group of Hospitals NHS Trust
| | - Jacqueline P Smith
- From the College of Life and Environmental Sciences, University of Birmingham, Birmingham; Imperial College London, National Heart and Lung Institute, South Kensington Campus, London; and the Department of Rheumatology, Dudley Group of Hospitals National Health Service (NHS) Trust, Russells Hall Hospital, Dudley, UK.A.M. Adlan, MBBS, MRCP, College of Environmental Sciences; J.P. Fisher, BSc (Hons), PhD, College of Life and Environmental Sciences, University of Birmingham; V.F. Panoulas, MD, PhD, Imperial College London, National Heart and Lung Institute, Department of Rheumatology, Dudley Group of Hospitals NHS Trust; J.P. Smith, BSc (Hons), MSc; G.D. Kitas, MD, PhD, FRCP, Department of Rheumatology, Dudley Group of Hospitals NHS Trust
| | - James P Fisher
- From the College of Life and Environmental Sciences, University of Birmingham, Birmingham; Imperial College London, National Heart and Lung Institute, South Kensington Campus, London; and the Department of Rheumatology, Dudley Group of Hospitals National Health Service (NHS) Trust, Russells Hall Hospital, Dudley, UK.A.M. Adlan, MBBS, MRCP, College of Environmental Sciences; J.P. Fisher, BSc (Hons), PhD, College of Life and Environmental Sciences, University of Birmingham; V.F. Panoulas, MD, PhD, Imperial College London, National Heart and Lung Institute, Department of Rheumatology, Dudley Group of Hospitals NHS Trust; J.P. Smith, BSc (Hons), MSc; G.D. Kitas, MD, PhD, FRCP, Department of Rheumatology, Dudley Group of Hospitals NHS Trust
| | - George D Kitas
- From the College of Life and Environmental Sciences, University of Birmingham, Birmingham; Imperial College London, National Heart and Lung Institute, South Kensington Campus, London; and the Department of Rheumatology, Dudley Group of Hospitals National Health Service (NHS) Trust, Russells Hall Hospital, Dudley, UK.A.M. Adlan, MBBS, MRCP, College of Environmental Sciences; J.P. Fisher, BSc (Hons), PhD, College of Life and Environmental Sciences, University of Birmingham; V.F. Panoulas, MD, PhD, Imperial College London, National Heart and Lung Institute, Department of Rheumatology, Dudley Group of Hospitals NHS Trust; J.P. Smith, BSc (Hons), MSc; G.D. Kitas, MD, PhD, FRCP, Department of Rheumatology, Dudley Group of Hospitals NHS Trust
| |
Collapse
|
|
44
|
Lazzerini PE, Capecchi PL, Acampa M, Galeazzi M, Laghi-Pasini F. Arrhythmic risk in rheumatoid arthritis: the driving role of systemic inflammation. Autoimmun Rev 2014; 13:936-44. [PMID: 24874445 DOI: 10.1016/j.autrev.2014.05.007] [Citation(s) in RCA: 70] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2014] [Accepted: 05/20/2014] [Indexed: 01/08/2023]
Abstract
When compared to the general population, patients with rheumatoid arthritis (RA) have an overall standard mortality ratio of approximately two, with more than 50% of premature deaths attributable to cardiovascular disease (CVD). Moreover, RA patients were twice as likely to experience sudden cardiac death (SCD) compared with non-RA subjects, as a putative consequence of an increased incidence of malignant arrhythmias. Accordingly, mounting data indicate that in patients affected with RA the risk of developing rhythm disturbances, particularly tachyarrhythmias, is high. Although a number of papers reviewing the problem of cardiovascular involvement in RA are currently available, the main focus is on the mechanisms of accelerated atherosclerosis and related ischemic consequences in the clinical setting. On the contrary, only little consideration has been specifically given to the arrhythmic risk so far. In the light of this concern, in the present paper we reviewed the topic with the aim to put together the apparently fragmentary existing information, with particular attention to the putative role of chronic systemic inflammation characterizing the disease. In fact, although the underlying mechanisms accounting the arrhythmogenic substrate in RA are probably intricate, the leading role seems to be played by inflammatory activation, able to promote arrhythmias either indirectly, by accelerating the development of structural CVD, and directly by affecting cardiac electrophysiology. In this view, lowering inflammatory burden through an increasingly tight control of disease activity may represent the most effective intervention to reduce arrhythmic risk and prevent life-threatening complications in these patients.
Collapse
Affiliation(s)
- Pietro Enea Lazzerini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Italy.
| | | | | | - Mauro Galeazzi
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Italy
| | - Franco Laghi-Pasini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Italy
| |
Collapse
|
|
45
|
Ventricular K+ currents are reduced in mice with elevated levels of serum TNFalpha. J Mol Cell Cardiol 2009; 47:238-46. [PMID: 19281815 DOI: 10.1016/j.yjmcc.2009.02.025] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2009] [Revised: 02/25/2009] [Accepted: 02/26/2009] [Indexed: 01/08/2023]
Abstract
In the present study mice were treated with tumor necrosis factor alpha (TNFalpha) for 6 weeks to determine if chronic TNFalpha treatment could produce serum levels of TNFalpha similar to what has been observed in disease states (heart failure, HIV) and to determine if these levels of TNFalpha alter ventricular K(+) currents. Mice chronically treated with TNFalpha and sham treated mice were utilized for experiments. Serum levels were measured with a Searchlight protein array. Patch-clamp techniques, real-time PCR and Western blot analysis were used to study K(+) current densities and K(+) channel expression. Results showed that serum concentrations of TNFalpha were significantly higher in TNFalpha treated mice compared to controls (control: 9.5+/-1.5 pg/ml, TNFalpha: 27.4+/-5.0 pg/ml; p<0.05) and comparable to serum TNFalpha levels observed in heart failure and HIV models. In ventricular myocytes from TNFalpha treated mice the outward K(+) currents I(to) and I(Kur) were significantly reduced (at +30 mV: I(to): control: 45.0+/-2.9 pA/pF, TNFalpha: 34.5+/-2.9 pA/pF; p<0.05; I(Kur): control 34.1+/-2.7 pA/pF, TNFalpha: 25.0+/-2.2 pA/pF; p<0.05). Expression studies revealed that ventricular mRNA and protein expression for the channels underlying I(to) and I(Kur) did not differ between the two groups. However, the recovery from inactivation for I(Kur) was significantly longer in TNFalpha treated mice. Overall, this study shows that pathologically relevant levels of serum TNFalpha modulate K(+) currents in mouse ventricle. These findings could help to explain the role of TNFalpha in the pathogenesis of cardiac arrhythmia.
Collapse
|
|
46
|
Jiménez-Candil J, González IC, González Matas JM, Albarrán C, Pabón P, Moríñigo JL, Ledesma C, Martín F, Diego M, Martín-Luengo C. Short- and long-term prognostic value of the corrected QT interval in the non–ST-elevation acute coronary syndrome. J Electrocardiol 2007; 40:180-7. [PMID: 17254595 DOI: 10.1016/j.jelectrocard.2006.10.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2006] [Accepted: 10/09/2006] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND PURPOSE Myocardial ischemia prolongs the QTc interval. Very little data exists about its prognostic implications in the non-ST-elevation acute coronary syndromes (NST-ACS). METHODS This is and observational and prospective study in which we evaluated the prognostic implications of the QTc obtained at admission (AQTc) in the short- and long-term of the NST-ACS. The median of the follow-up was 17 months. RESULTS AQTc correlated adequately with the incidence of adverse events in the short- and long-term (P < .001), with the best cut-off point in 450 milliseconds. Patients with AQTc > or =450 presented higher frequency of in-hospital death: 8.8% vs 1.2%; P = .001, and MACE (death, recurrent ischemia, or urgent coronary revascularization): 72% vs 25%; P < .001. In a Cox regression analysis, we found 3 independent predictors of cardiovascular death after discharge: AQTc > or =450 (14.7% vs 2.1%; P < .0001), age >65 years and left ventricular ejection fraction <40%. Coronary revascularization reduced the risk of posthospitalary cardiovascular death in AQTc > or =450 milliseconds (5% vs 24%; P < .0001) but had no significant effect in AQTc<450 milliseconds. CONCLUSION These findings provide a new evidence supporting the prognostic value of the AQTc in predicting unfavorable events in the short- and long-term of the NST-ACS.
Collapse
|
|
47
|
Delfino RJ, Sioutas C, Malik S. Potential role of ultrafine particles in associations between airborne particle mass and cardiovascular health. ENVIRONMENTAL HEALTH PERSPECTIVES 2005; 113:934-46. [PMID: 16079061 PMCID: PMC1280331 DOI: 10.1289/ehp.7938] [Citation(s) in RCA: 451] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/03/2023]
Abstract
Numerous epidemiologic time-series studies have shown generally consistent associations of cardiovascular hospital admissions and mortality with outdoor air pollution, particularly mass concentrations of particulate matter (PM) < or = 2.5 or < or = 10 microm in diameter (PM2.5, PM10). Panel studies with repeated measures have supported the time-series results showing associations between PM and risk of cardiac ischemia and arrhythmias, increased blood pressure, decreased heart rate variability, and increased circulating markers of inflammation and thrombosis. The causal components driving the PM associations remain to be identified. Epidemiologic data using pollutant gases and particle characteristics such as particle number concentration and elemental carbon have provided indirect evidence that products of fossil fuel combustion are important. Ultrafine particles < 0.1 microm (UFPs) dominate particle number concentrations and surface area and are therefore capable of carrying large concentrations of adsorbed or condensed toxic air pollutants. It is likely that redox-active components in UFPs from fossil fuel combustion reach cardiovascular target sites. High UFP exposures may lead to systemic inflammation through oxidative stress responses to reactive oxygen species and thereby promote the progression of atherosclerosis and precipitate acute cardiovascular responses ranging from increased blood pressure to myocardial infarction. The next steps in epidemiologic research are to identify more clearly the putative PM casual components and size fractions linked to their sources. To advance this, we discuss in a companion article (Sioutas C, Delfino RJ, Singh M. 2005. Environ Health Perspect 113:947-955) the need for and methods of UFP exposure assessment.
Collapse
Affiliation(s)
- Ralph J Delfino
- Epidemiology Division, Department of Medicine, University of California, Irvine, Irvine, California 92697-7550, USA.
| | | | | |
Collapse
|
|
48
|
|
|
49
|
Kumar A, Krieger A, Symeoneides S, Kumar A, Parrillo JE. Myocardial dysfunction in septic shock: Part II. Role of cytokines and nitric oxide. J Cardiothorac Vasc Anesth 2001; 15:485-511. [PMID: 11505357 DOI: 10.1053/jcan.2001.25003] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Affiliation(s)
- A Kumar
- Division of Cardiovascular Diseases and Critical Care Medicine, Department of Medicine, Rush-Presbyterian-St. Luke's Medical Center, Chicago, IL 60612, USA
| | | | | | | | | |
Collapse
|
|
50
|
Pecherskaya A, Solem M. IGF1 activates PKC alpha-dependent protein synthesis in adult rat cardiomyocytes. MOLECULAR CELL BIOLOGY RESEARCH COMMUNICATIONS : MCBRC 2000; 4:166-71. [PMID: 11281731 DOI: 10.1006/mcbr.2001.0274] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Acute exposure to interleukin 1 beta (IL1beta) or insulin-like growth factor 1 (IGF1) promoted the translocation of PKC alpha from the cytosol to the membrane of adult rat cardiomyocytes. Western analysis demonstrated that membranal localization of PKC alpha was increased from 23% in the control to 49% after exposure to IGF1, and it was increased to 42% after exposure to IL1beta. Activation of Erk1/Erk2 by IGF1 and IL1beta was studied using a phosphorylation-specific antibody. IGF1-induced activation of p44/p42 MAP kinase was blocked by preincubation with the PKC inhibitors, bisindolylmaleimide and Gö6976, as well as the tyrosine kinase inhibitor, genistein. IGF1 increased the rate of protein synthesis, indicated by the increase in L-[(14)C(U)] phenylalanine incorporation over time, and this effect was inhibited by Gö6976.
Collapse
Affiliation(s)
- A Pecherskaya
- Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University, JAH 260, 1020 Locust Street, Philadelphia, Pennsylvania, 19107, USA
| | | |
Collapse
|