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Addleman JS, Lackey NS, Tobin MA, Lara GA, Sinha S, Morse RM, Hajduczok AG, Gharbo RS, Gevirtz RN. Heart Rate Variability Applications in Medical Specialties: A Narrative Review. Appl Psychophysiol Biofeedback 2025:10.1007/s10484-025-09708-y. [PMID: 40293647 DOI: 10.1007/s10484-025-09708-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
HRV is clinically considered to be a surrogate measure of the asymmetrical interplay of the sympathetic and parasympathetic nervous system. While HRV has become an increasingly measured variable through commercially-available wearable devices, HRV is not routinely monitored or utilized in healthcare settings at this time. The purpose of this narrative review is to discuss and evaluate the current research and potential future applications of HRV in several medical specialties, including critical care, cardiology, pulmonology, nephrology, gastroenterology, endocrinology, infectious disease, hematology and oncology, neurology and rehabilitation, sports medicine, surgery and anesthesiology, rheumatology and chronic pain, obstetrics and gynecology, pediatrics, and psychiatry/psychology. A narrative literature review was conducted with search terms including HRV and relevant terminology to the medical specialty in question. While HRV has demonstrated promise for some diagnoses as a non-invasive, easy to use, and cost-effective metric for early disease detection, prognosis and mortality prediction, disease monitoring, and biofeedback therapy, several issues plague the current literature. Substantial heterogeneity exists in the current HRV literature which limits its applicability in clinical practice. However, applications of HRV in psychiatry, critical care, and in specific chronic diseases demonstrate sufficient evidence to warrant clinical application regardless of the surmountable research issues. More data is needed to understand the exact impact of standardizing HRV monitoring and treatment protocols on patient outcomes in each of the clinical contexts discussed in this paper.
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Affiliation(s)
| | - Nicholas S Lackey
- Center for Applied Biobehavioral Sciences (CABS), Alliant International University, San Diego, CA, USA.
| | - Molly A Tobin
- Touro University CA College of Osteopathic Medicine, Vallejo, CA, USA
| | - Grace A Lara
- Touro University CA College of Osteopathic Medicine, Vallejo, CA, USA
| | - Sankalp Sinha
- Touro University CA College of Osteopathic Medicine, Vallejo, CA, USA
| | - Rebecca M Morse
- Touro University CA College of Osteopathic Medicine, Vallejo, CA, USA
| | - Alexander G Hajduczok
- Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, CA, USA
| | - Raouf S Gharbo
- Virginia Commonwealth University School of Medicine Department of Physical Medicine and Rehabilitation, Richmond, VA, USA
| | - Richard N Gevirtz
- Center for Applied Biobehavioral Sciences (CABS), Alliant International University, San Diego, CA, USA
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Garg I, Verma M, Kumar H, Maurya R, Negi T, Jain P. Bioelectronic Therapeutics: A Revolutionary Medical Practice in Health Care. Bioelectricity 2025; 7:2-28. [PMID: 40342937 PMCID: PMC12054615 DOI: 10.1089/bioe.2024.0039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2025] Open
Abstract
The emerging field of bioelectronic therapeutics unfolds great opportunities for treating numerous neurological and inflammatory conditions by utilizing the amalgamation of molecular medicine, neuroscience, engineering, and computing. These innovative treatments leverage advanced technology to precisely identify, design, and regulate electrical signaling patterns in the nervous system, addressing multiple diseases. Modifying neural signaling patterns to produce therapeutic effects at a particular organ may blur the lines between conventional medical practices. These modify the neurological behavior using electrical, magnetic, optical, and ultrasonic pulses through closed-loop systems to optimize neural behavior. The Food and Drug Administration (FDA) has approved numerous invasive and noninvasive bioelectronic devices, in the treatment of various neuronal diseases and non-neuronal diseases. Furthermore, the FDA has approved many devices for clinical studies. The field of bioelectronics encounters challenges in integrating with the health care system, including incomplete understanding of human nervous anatomy, neuronal function, membrane potential, and technological limitations. This review aims to explore bioelectronics therapeutics, their role or action in challenges to growth and their solutions, and the prospects of bioelectronic therapeutics.
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Affiliation(s)
- Ishu Garg
- Sardar Bhagwan Singh University, Dehradun, Uttarakhand, India
| | - Madhu Verma
- ITS College of Pharmacy, Ghaziabad, Uttar Pradesh, India
| | - Harish Kumar
- Sardar Bhagwan Singh University, Dehradun, Uttarakhand, India
| | - Ravi Maurya
- Sardar Bhagwan Singh University, Dehradun, Uttarakhand, India
| | - Tushar Negi
- Sardar Bhagwan Singh University, Dehradun, Uttarakhand, India
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Kumar A, Ashawat MS, Pandit V, Kumar P. Bioelectronic Medicines-A Novel Approach of Therapeutics in Current Epoch. Curr Pharm Des 2025; 31:163-178. [PMID: 39313906 DOI: 10.2174/0113816128326489240827100537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2024] [Accepted: 07/19/2024] [Indexed: 09/25/2024]
Abstract
BACKGROUND Bioelectronic medicines aim to diagnose and treat a wide range of illnesses and ailments, including cancer, rheumatoid arthritis, inflammatory bowel disease, obesity, diabetes, asthma, paralysis, blindness, bleeding, ischemia, organ transplantation, cardiovascular disease, and neurodegenerative diseases. The focus of bioelectronic medicine is on electrical signaling of the nervous system. Understanding the nervous system's regulatory roles and developing technologies that record, activate, or inhibit neural signaling to influence particular biological pathways. OBJECTIVE Bioelectronic medicine is an emerging therapeutic option with the interconnection between molecular medicine, neuroscience, and bioengineering. The creation of nerve stimulating devices that communicate with both the central and peripheral nervous systems has the potential to completely transform how we treat disorders. Although early clinical applications have been largely effective across entire nerves, the ultimate goal is to create implantable, miniature closed-loop systems that can precisely identify and modulate individual nerve fibers to treat a wide range of disorders. METHODOLOGY The data bases such as PubMed, and Clinicaltrial.gov.in were searched for scientific research, review and clinical trials on bioelectronic medicine. CONCLUSION The field of bioelectronic medicine is trending at present. In recent years, researchers have extended the field's applications, undertaken promising clinical trials, and begun delivering therapies to patients, thus creating the groundwork for significant future advancements. Countries and organizations must collaborate across industries and regions to establish an atmosphere and guidelines that foster the advancement of the field and the fulfillment of its prospective advantages.
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Affiliation(s)
- Ajay Kumar
- Department of Pharmaceutics, Laureate Institute of Pharmacy, Kathog, Jwalamukhi, H.P., India
| | - Mahendra Singh Ashawat
- Department of Pharmaceutics, Laureate Institute of Pharmacy, Kathog, Jwalamukhi, H.P., India
| | - Vinay Pandit
- Department of Pharmaceutics, Laureate Institute of Pharmacy, Kathog, Jwalamukhi, H.P., India
| | - Pravin Kumar
- Department of Pharmaceutics, Laureate Institute of Pharmacy, Kathog, Jwalamukhi, H.P., India
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Gülkesen A, Yıldırım Uslu E, Akgöl G, Alkan G, Kobat MA, Gelen MA, Uslu MF. Is the development of arrhythmia predictable in rheumatoid arthritis? Arch Rheumatol 2024; 39:429-435. [PMID: 39507840 PMCID: PMC11537683 DOI: 10.46497/archrheumatol.2024.10590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Accepted: 02/09/2024] [Indexed: 11/08/2024] Open
Abstract
Objectives This study aimed to determine whether there is a difference in the electrocardiography (ECG) measurements of healthy controls and rheumatoid arthritis (RA) patients and to predict whether they can be used to determine the risk of arrhythmia in patients. Patients and methods The prospective study included 50 cardiac asymptomatic RA patients (38 males, 12 females; mean age: 46.8±9.1 years; range, 18 to 60 years) who met the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology RA criteria and 50 healthy volunteers (34 males, 16 females; mean age: 43.4±10.4 years; range, 18 to 60 years) as a control group between June 1, 2022, and August 31, 2022. Disease activity of the patients was calculated with the Disase Activity Score (DAS28). Heart rate, minimum and maximum QT intervals, QT dispersion, minimum and maximum P waves, P wave dispersion (Pd), minimum and maximum Tp-e intervals, Tp-e dispersion, minimum and maximum corrected QT (QTc) intervals, QTc dispersion, and the Tp-e/QTc ratio in ECGs were calculated. Results The mean disease duration of the RA group was 9.09±5.74 years. The mean C-reactive protein level was 9.83±8.29, the mean erythrocyte sedimentation rate was 26.12±16.28 mm/h, and the mean DAS28 was 3.03±0.37. There was a statistically significant increase in the maximum P wave, Pd, maximum QT, QT dispersion, maximum QTc, QTc dispersion, maximum Tp-e, Tp-e dispersion, and Tp-e/QTc dispersion parameters in the RA group compared to the control group, while there was a significant decrease in the minimum P wave, minimum QT, and minimum QTc parameters. Conclusion In our study, the Pd, QTc dispersion, Tp-e dispersion, and Tp-e/QTc dispersion values of our patients, which indicate the risk of atrial and ventricular arrhythmia, were found to be significantly higher. This finding suggests that our patients had an increased risk of cardiac morbidity and mortality. Arrhythmias are the likely source of the increase in sudden cardiac death in RA, and these new indicators measured on ECG can be used as standardized cardiovascular morbidity and mortality indicators in the future.
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Affiliation(s)
- Arif Gülkesen
- Department of Physical Medicine and Rehabilitation, Medicine Faculty of Fırat University, Elazığ, Türkiye
| | - Emine Yıldırım Uslu
- Department of Physical Medicine and Rehabilitation, Fethi Sekin City Hospital, Elazığ, Türkiye
| | - Gürkan Akgöl
- Department of Physical Medicine and Rehabilitation, Medicine Faculty of Fırat University, Elazığ, Türkiye
| | - Gökhan Alkan
- Department of Physical Medicine and Rehabilitation, Medicine Faculty of Fırat University, Elazığ, Türkiye
| | - Mehmet Ali Kobat
- Department of Cardiology, Medicine Faculty of Fırat University, Elazığ, Türkiye
| | - Mehmet Ali Gelen
- Department of Cardiology, Fethi Sekin City Hospital, Elazığ, Türkiye
| | - Muhammed Fuad Uslu
- Department of Internal Medicine, Fethi Sekin City Hospital, Elazığ, Türkiye
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Das S, Ghosh B, Sahoo RN, Nayak AK. Recent Advancements in Bioelectronic Medicine: A Review. Curr Drug Deliv 2024; 21:1445-1459. [PMID: 38173212 DOI: 10.2174/0115672018286832231218112557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 11/17/2023] [Accepted: 12/04/2023] [Indexed: 01/05/2024]
Abstract
Bioelectronic medicine is a multidisciplinary field that combines molecular medicine, neurology, engineering, and computer science to design devices for diagnosing and treating diseases. The advancements in bioelectronic medicine can improve the precision and personalization of illness treatment. Bioelectronic medicine can produce, suppress, and measure electrical activity in excitable tissue. Bioelectronic devices modify specific neural circuits using electrons rather than pharmaceuticals and uses of bioelectronic processes to regulate the biological processes underlining various diseases. This promotes the potential to address the underlying causes of illnesses, reduce adverse effects, and lower costs compared to conventional medication. The current review presents different important aspects of bioelectronic medicines with recent advancements. The area of bioelectronic medicine has a lot of potential for treating diseases, enabling non-invasive therapeutic intervention by regulating brain impulses. Bioelectronic medicine uses electricity to control biological processes, treat illnesses, or regain lost capability. These new classes of medicines are designed by the technological developments in the detection and regulation of electrical signaling methods in the nervous system. Peripheral nervous system regulates a wide range of processes in chronic diseases; it involves implanting small devices onto specific peripheral nerves, which read and regulate the brain signaling patterns to achieve therapeutic effects specific to the signal capacity of a particular organ. The potential for bioelectronic medicine field is vast, as it investigates for treatment of various diseases, including rheumatoid arthritis, diabetes, hypertension, paralysis, chronic illnesses, blindness, etc.
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Affiliation(s)
- Sudipta Das
- Department of Pharmaceutics, Netaji Subhas Chandra Bose Institute of Pharmacy, Chakdaha, Nadia - 741222, West Bengal, India
| | - Baishali Ghosh
- Department of Pharmaceutics, Netaji Subhas Chandra Bose Institute of Pharmacy, Chakdaha, Nadia - 741222, West Bengal, India
| | - Rudra Narayan Sahoo
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, 751003, Odisha, India
| | - Amit Kumar Nayak
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Siksha 'O' Anusandhan (Deemed to be University), Bhubaneswar, 751003, Odisha, India
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Saramet EE, Pomȋrleanu C, Maştaleru A, Oancea A, Cojocaru DC, Russu M, Negru RD, Ancuța C. Autonomic Dysfunction and Cardiovascular Risk in Patients with Rheumatoid Arthritis: Can Heart Rate Variability Analysis Contribute to a Better Evaluation of the Cardiovascular Profile of a Patient? J Clin Med 2023; 12:7736. [PMID: 38137805 PMCID: PMC10743610 DOI: 10.3390/jcm12247736] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/08/2023] [Accepted: 12/15/2023] [Indexed: 12/24/2023] Open
Abstract
(1) Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease of autoimmune etiology. Increased scientific evidence suggests that immune-mediated inflammatory dis-eases are associated with autonomic nervous system (ANS) dysfunction. Studies proved that autonomic imbalance is correlated with RA evolution and may explain augmented cardiovascular pathology and mortality not attributable to classical risk factors. (2) Methods: 75 patients (25 males, 50 females) with RA were submitted to standard ECG recording and 24 h Holter monitoring. Twenty-five healthy patients were used as controls. Both time (SDNN, SDANN, SDANN Index, RRmed, rMSSD, and pNN50) and frequency domain (TP, VLF, HF, LF and LF/HF) heart rate variability (HRV) parameters were obtained. Parameters were compared to controls, and correlations with the QTc-interval and inflammatory status expressed through the C-reactive protein (CRP) were evaluated. (3) Results: In patients with a CRP > 5 mg/L, HRV parameters were lower compared to controls and to patients with a CRP ≤ 5 mg/L. All HRV parameters generated by Holter monitoring are negatively correlated with CRP levels and QTc values. The number of premature ventricular contractions (PVC) recorded is correlated with SDNN, SDANN, and LF/HF values. (4) Conclusions: Our study supports recent data suggesting that in RA there is an autonomic system dysfunction strongly connected with the inflammatory status of the patient. The autonomic dysfunction can contribute to the increased risk of cardiovascular death observed in patients with RA.
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Affiliation(s)
- Elena Esmeralda Saramet
- “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iași, Romania; (E.E.S.); (M.R.)
| | - Cristina Pomȋrleanu
- Department of Medical Specialties II, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (C.P.); (C.A.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania; (A.M.); (A.O.); (D.-C.C.)
| | - Alexandra Maştaleru
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania; (A.M.); (A.O.); (D.-C.C.)
- Department of Medical Specialties I, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Andra Oancea
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania; (A.M.); (A.O.); (D.-C.C.)
- Department of Medical Specialties I, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Doina-Clementina Cojocaru
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania; (A.M.); (A.O.); (D.-C.C.)
- Department of Medical Specialties I, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Mara Russu
- “Grigore T. Popa” University of Medicine and Pharmacy, 16 Universitatii Str., 700115 Iași, Romania; (E.E.S.); (M.R.)
| | - Robert Daniel Negru
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania; (A.M.); (A.O.); (D.-C.C.)
- Department of Medical Specialties I, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania
| | - Codrina Ancuța
- Department of Medical Specialties II, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (C.P.); (C.A.)
- Clinical Rehabilitation Hospital, 700661 Iasi, Romania; (A.M.); (A.O.); (D.-C.C.)
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Adam J, Rupprecht S, Künstler ECS, Hoyer D. Heart rate variability as a marker and predictor of inflammation, nosocomial infection, and sepsis - A systematic review. Auton Neurosci 2023; 249:103116. [PMID: 37651781 DOI: 10.1016/j.autneu.2023.103116] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 07/11/2023] [Accepted: 08/11/2023] [Indexed: 09/02/2023]
Abstract
PURPOSE The autonomic nervous system interacts with the immune system via the inflammatory response. Heart rate variability (HRV), a marker of autonomic activity, is associated with inflammation, and nosocomial infections/sepsis, and has clinical implications for the monitoring of at-risk patients. Due to the vagal tone's influence on anti-inflammatory immune response, this association may predominately be reflected by vagally-mediated HRV indices. However, HRV's predictive significance on inflammation/infection remains unclear. METHODS 843 studies examining the associations/prognostic value of HRV indices on inflammation, and nosocomial infection/sepsis were screened in this systematic review. According to inclusion and exclusion criteria, 68 associative studies and 14 prediction studies were included. RESULTS HRV and pro-inflammatory state were consistently associated in healthy subjects and patient groups. Pro-inflammatory state was related to reduced total power HRV including vagally- and non-vagally-mediated HRV indices. Similar, compared to controls, HRV reductions were observed during nosocomial infections/sepsis. Only limited evidence supports the predictive value of HRV in the development of nosocomial infections/sepsis. Reduced very low frequency power HRV showed the highest predictive value in adults, even with different clinical conditions. In neonates, an increased heart rate characteristic score, combining reduced total power HRV, decreased complexity, and vagally-dominated asymmetry, predicted sepsis. CONCLUSIONS Pro-inflammatory state is related to an overall reduction in HRV rather than a singular reduction in vagally-mediated HRV indices, reflecting the complex autonomic-regulatory changes occurring during inflammation. The potential benefit of using continuous HRV monitoring for detecting nosocomial infection-related states, and the implications for clinical outcome, need further clarification.
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Affiliation(s)
- Josephine Adam
- Department of Neurology, Jena University Hospital, Jena, Germany.
| | - Sven Rupprecht
- Department of Neurology, Jena University Hospital, Jena, Germany; Interdisciplinary Centre for Sleep and Ventilatory Medicine, Jena University Hospital, Jena, Germany
| | - Erika C S Künstler
- Department of Neurology, Jena University Hospital, Jena, Germany; Interdisciplinary Centre for Sleep and Ventilatory Medicine, Jena University Hospital, Jena, Germany
| | - Dirk Hoyer
- Department of Neurology, Jena University Hospital, Jena, Germany
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Erelund S, Södergren A, Wiklund U, Sundström N. Heart rate variability and cardiovascular risk factors in patients with rheumatoid arthritis: A longitudinal study. Auton Neurosci 2023; 249:103119. [PMID: 37703773 DOI: 10.1016/j.autneu.2023.103119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Revised: 08/28/2023] [Accepted: 09/03/2023] [Indexed: 09/15/2023]
Abstract
BACKGROUND It is established that the risk of cardiovascular disease (CVD) is increased in patients with Rheumatoid Arthritis (RA). Heart rate variability (HRV) is a method for evaluating the activity in the cardiac autonomic nervous system. Our aim was to assess the longitudinal development of HRV in patients with RA and compare with healthy controls. Furthermore, we wanted to investigate associations between HRV, inflammatory disease activity and cardiovascular complications in patients with RA over time. METHOD HRV was assessed with frequency-domain analysis at baseline and after five years in 50 patients with early RA, all being younger than 60 years. HRV indices were age-adjusted based on the estimated age-dependency in 100 age and sex matched healthy controls. Additionally, clinical data including serological markers, disease activity, and blood pressure were collected from the patients. Eleven years after inclusion CVD was assessed. RESULTS At baseline, patients with RA presented with lower HRV compared to controls during deep breathing (6 breaths/min), paced normal breathing (12 breaths/min) and after passive tilt to the upright position. No significant change in HRV was observed at the five-year follow-up. A significant negative correlation was found between HRV parameters and systolic blood pressure (SBP) at baseline. A significant positive correlation was found between heart rate and inflammatory markers at baseline but not after five years. Nine patients had developed CVD after 11 years, but no significant association was found with baseline HRV data. CONCLUSION This study showed that patients with RA have autonomic imbalance both at an early stage of the disease and after five years, despite anti-rheumatic medication, but no correlation between HRV and inflammation markers were observed. Reduced HRV was also significantly negatively correlated with increased SBP. Hypertension is a common finding in patients with RA. Thus, significant decline of HRV could be a useful early marker for development of hypertension in patients with RA.
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Affiliation(s)
- Sofia Erelund
- Department of Surgery and Perioperative Sciences, Umeå University, Umeå, Sweden.
| | - Anna Södergren
- Department of Public Health and Clinical Medicine/Rheumatology, Umeå University, Umeå, Sweden
| | - Urban Wiklund
- Department of Radiation Sciences, Radiation Physics, Biomedical Engineering, Umeå University, Umeå, Sweden
| | - Nina Sundström
- Department of Radiation Sciences, Radiation Physics, Biomedical Engineering, Umeå University, Umeå, Sweden
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Pironti G, Gastaldello S, Rassier DE, Lanner JT, Carlström M, Lund LH, Westerblad H, Yamada T, Andersson DC. Citrullination is linked to reduced Ca 2+ sensitivity in hearts of a murine model of rheumatoid arthritis. Acta Physiol (Oxf) 2022; 236:e13869. [PMID: 36002394 PMCID: PMC9788013 DOI: 10.1111/apha.13869] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 08/16/2022] [Accepted: 08/17/2022] [Indexed: 01/29/2023]
Abstract
AIMS Cardiac contractile dysfunction is prevalent in rheumatoid arthritis (RA), with an increased risk for heart failure. A hallmark of RA has increased levels of peptidyl arginine deaminases (PAD) that convert arginine to citrulline leading to ubiquitous citrullination, including in the heart. We aimed to investigate whether PAD-dependent citrullination in the heart was linked to contractile function in a mouse model of RA during the acute inflammatory phase. METHODS We used hearts from the collagen-induced arthritis (CIA) mice, with overt arthritis, and control mice to analyze cardiomyocyte Ca2+ handling and fractional shortening, the force-Ca2+ relationship in isolated myofibrils, the levels of PAD, protein post-translational modifications, and Ca2+ handling protein. Then, we used an in vitro model to investigate the role of TNF-α in the PAD-mediated citrullination of proteins in cardiomyocytes. RESULTS Cardiomyocytes from CIA mice displayed larger Ca2+ transients than controls, whereas cell shortening was similar in the two groups. Myofibrils from CIA hearts required higher [Ca2+ ] to reach 50% of maximum shortening, ie Ca2+ sensitivity was lower. This was associated with increased PAD2 expression and α-actin citrullination. TNF-α increased PAD-mediated citrullination which was blocked by pre-treatment with the PAD inhibitor 2-chloroacetamide. CONCLUSION Using a mouse RA model we found evidence of impaired cardiac contractile function linked to reduced Ca2+ sensitivity, increased expression of PAD2, and citrullination of α-actin, which was triggered by TNF-α. This provides molecular and physiological evidence for acquired cardiomyopathy and a potential mechanism for RA-associated heart failure.
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Affiliation(s)
- Gianluigi Pironti
- Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden,Department of Medicine, Cardiology Research UnitKarolinska InstitutetStockholmSweden
| | - Stefano Gastaldello
- Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden
| | - Dilson E. Rassier
- Department of Kinesiology and Physical EducationMcGill UniversityMontrealCanada
| | - Johanna T. Lanner
- Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden
| | - Mattias Carlström
- Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden
| | - Lars H. Lund
- Department of Medicine, Cardiology Research UnitKarolinska InstitutetStockholmSweden,Heart, Vascular and Neurology Theme, Cardiology UnitKarolinska University HospitalStockholmSweden
| | - Håkan Westerblad
- Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden
| | - Takashi Yamada
- School of Health Sciences, Sapporo Medical UniversitySapporoJapan
| | - Daniel C. Andersson
- Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden,Heart, Vascular and Neurology Theme, Cardiology UnitKarolinska University HospitalStockholmSweden
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Yuniadi Y, Yugo D, Fajri M, Tejo BA, Widowati DR, Hanafy DA, Raharjo SB. ECG characteristics of COVID-19 patient with arrhythmias: Referral hospitals data from Indonesia. J Arrhythm 2022; 38:432-438. [PMID: 35785388 PMCID: PMC9237289 DOI: 10.1002/joa3.12718] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Revised: 03/17/2022] [Accepted: 03/27/2022] [Indexed: 12/12/2022] Open
Abstract
Background Arrhythmia is a significant clinical modifier in COVID-19 patient outcomes. Currently, data on arrhythmia and ECG characteristics in COVID-19 from lower middle-income countries are limited. Methods COVID-19 was confirmed by polymerase chain reaction testing of a nasopharyngeal sample. All clinical records were systematically evaluated to obtain demographic characteristics and medical comorbidities. The ECG was recorded on admission, in-hospital, and at discharge. Results Total documented arrhythmia events account for 22% of patients, comprising 6% of new-onset arrhythmia and 16% of existing arrhythmia. Atrial fibrillation is the most common arrhythmia. The ECG changes were a decrease in heart rate (91 ± 22 vs. 83 ± 20, p < .001) and an increase in the QT interval (354.7 ± 53.70 vs. 371.4 ± 59.48 msec, p < .001) from hospital admission to hospital discharge, respectively. The in-hospital HR of 85 bpm or higher increases the risk of death (OR = 2.69, p = .019). Conclusion The incidence of arrhythmias in COVID-19 patients at COVID-19 referral hospitals in Indonesia is 22%. Atrial fibrillation is the most common arrhythmia in COVID-19 patients. Prolongation of QRS duration from admission to discharge was related to the occurrence of new-onset arrhythmia. The in-hospital HR of 85 bpm or higher increased the risk of death.
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Affiliation(s)
- Yoga Yuniadi
- Department of Cardiology and Vascular Medicine, Faculty of MedicineUniversity of Indonesia, and National Cardiovascular Center Harapan KitaJakartaIndonesia
| | - Dony Yugo
- Department of Cardiology and Vascular Medicine, Faculty of MedicineUniversity of Indonesia, and National Cardiovascular Center Harapan KitaJakartaIndonesia
| | | | | | | | - Dicky Armen Hanafy
- Department of Cardiology and Vascular Medicine, Faculty of MedicineUniversity of Indonesia, and National Cardiovascular Center Harapan KitaJakartaIndonesia
| | - Sunu Budhi Raharjo
- Department of Cardiology and Vascular Medicine, Faculty of MedicineUniversity of Indonesia, and National Cardiovascular Center Harapan KitaJakartaIndonesia
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Saramet EE, Negru RD, Oancea A, Constantin MML, Ancuta C. 24 h Holter ECG Monitoring of Patients with Rheumatoid Arthritis-A Potential Role for a Precise Evaluation of QT Interval Duration and Associated Arrhythmic Complications. Diagnostics (Basel) 2022; 12:diagnostics12030638. [PMID: 35328191 PMCID: PMC8946977 DOI: 10.3390/diagnostics12030638] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/22/2022] [Accepted: 03/01/2022] [Indexed: 02/01/2023] Open
Abstract
Background: Patients with rheumatoid arthritis (RA) have increased systemic inflammatory burden associated with elevated cardiovascular mortality. Prolonged ventricular repolarisation evaluated by QT interval duration is a risk factor for cardiovascular and total mortality. In RA, mortality risk is correlated with dynamics and cumulative incidence of QTc prolongation rather than QTc value. The aim is to evaluate if QT parameters evaluated with 24 h Holter ECG are a better option to complete the cardiovascular profile of RA patients than parameters from short ECG recordings. Materials and methods: A total of 58 patients (22 males, 36 females) with RA were submitted to short ECG recordings at admission and to 24 h Holter ECG. QT interval parameters and ventricular ectopy generated from both types of recordings were analyzed. Results: QTc interval values obtained from Holter ECG were significantly higher than the values from short term ECG and were correlated with severity of inflammatory process. The number of QRS complexes with QTc > 450 ms recorded during 24 h Holter was strongly correlated with the number of ventricular events and severity of the inflammatory process. Conclusions: In patients with RA, the Holter ECG recordings could realize a more precise evaluation of the extent and dynamics of QTc interval duration and of ventricular ectopic events with potential risk of sudden death.
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12
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Armbruster AL, Campbell KB, Kahanda MG, Cuculich PS. The role of inflammation in the pathogenesis and treatment of arrhythmias. Pharmacotherapy 2022; 42:250-262. [PMID: 35098555 DOI: 10.1002/phar.2663] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 11/30/2021] [Accepted: 12/03/2021] [Indexed: 12/20/2022]
Abstract
The pathogenesis of arrhythmias is complex and multifactorial. The role of inflammation in the pathogenesis of both atrial and ventricular arrhythmias (VA) has been explored. However, developing successful pharmacotherapy regimens based on those pathways has proven more of a challenge. This narrative review provides an overview of five common arrhythmias impacted by inflammation, including atrial fibrillation (AF), myocardial infarction, arrhythmogenic cardiomyopathy, cardiac sarcoidosis, and QT prolongation, and the potential role for anti-inflammatory therapy in their management. We identified arrhythmias and arrhythmogenic disease states with the most evidence linking pathogenesis to inflammation and conducted comprehensive searches of United States National Library of Medicine MEDLINE® and PubMed databases. Although a variety of agents have been studied for the management of AF, primarily in an effort to reduce postoperative AF following cardiac surgery, no standard anti-inflammatory agents are used in clinical practice at this time. Although inflammation following myocardial infarction may contribute to the development of VA, there is no clear benefit with the use of anti-inflammatory agents at this time. Similarly, although inflammation is clearly linked to the development of arrhythmias in arrhythmogenic cardiomyopathy, data demonstrating a benefit with anti-inflammatory agents are limited. Cardiac sarcoidosis, an infiltrative disease eliciting an immune response, is primarily treated by immunosuppressive therapy and steroids, despite a lack of primary literature to support such regimens. In this case, anti-inflammatory agents are frequently used in clinical practice. The pathophysiology of arrhythmias is complex, and inflammation likely plays a role in both onset and duration, however, for most arrhythmias the role of pharmacotherapy targeting inflammation remains unclear.
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Affiliation(s)
- Anastasia L Armbruster
- St. Louis College of Pharmacy, University of Health Sciences and Pharmacy in St. Louis, St. Louis, Missouri, USA
| | | | - Milan G Kahanda
- Cardiovascular Division, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
| | - Phillip S Cuculich
- Cardiovascular Division, Department of Internal Medicine, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
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13
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Bellocchi C, Carandina A, Montinaro B, Targetti E, Furlan L, Rodrigues GD, Tobaldini E, Montano N. The Interplay between Autonomic Nervous System and Inflammation across Systemic Autoimmune Diseases. Int J Mol Sci 2022; 23:ijms23052449. [PMID: 35269591 PMCID: PMC8910153 DOI: 10.3390/ijms23052449] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 02/17/2022] [Accepted: 02/18/2022] [Indexed: 12/13/2022] Open
Abstract
The autonomic nervous system (ANS) and the immune system are deeply interrelated. The ANS regulates both innate and adaptive immunity through the sympathetic and parasympathetic branches, and an imbalance in this system can determine an altered inflammatory response as typically observed in chronic conditions such as systemic autoimmune diseases. Rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis all show a dysfunction of the ANS that is mutually related to the increase in inflammation and cardiovascular risk. Moreover, an interaction between ANS and the gut microbiota has direct effects on inflammation homeostasis. Recently vagal stimulation techniques have emerged as an unprecedented possibility to reduce ANS dysfunction, especially in chronic diseases characterized by pain and a decreased quality of life as well as in chronic inflammation.
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Affiliation(s)
- Chiara Bellocchi
- Department of Internal Medicine, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.C.); (B.M.); (E.T.); (L.F.); (E.T.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy;
- Correspondence: (C.B.); (N.M.)
| | - Angelica Carandina
- Department of Internal Medicine, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.C.); (B.M.); (E.T.); (L.F.); (E.T.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy;
| | - Beatrice Montinaro
- Department of Internal Medicine, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.C.); (B.M.); (E.T.); (L.F.); (E.T.)
| | - Elena Targetti
- Department of Internal Medicine, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.C.); (B.M.); (E.T.); (L.F.); (E.T.)
| | - Ludovico Furlan
- Department of Internal Medicine, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.C.); (B.M.); (E.T.); (L.F.); (E.T.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy;
| | - Gabriel Dias Rodrigues
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy;
- Laboratory of Experimental and Applied Exercise Physiology, Department of Physiology and Pharmacology, Fluminense Federal University, Niterói 24210-130, Brazil
| | - Eleonora Tobaldini
- Department of Internal Medicine, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.C.); (B.M.); (E.T.); (L.F.); (E.T.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy;
| | - Nicola Montano
- Department of Internal Medicine, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.C.); (B.M.); (E.T.); (L.F.); (E.T.)
- Department of Clinical Sciences and Community Health, University of Milan, 20122 Milan, Italy;
- Correspondence: (C.B.); (N.M.)
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14
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Saad S, Delouya G, Lambert C, Barkati M, Dariane C, Laskine M, Taussky D. Prevalence and risk factors of QTc prolongation in prostate cancer patients undergoing brachytherapy. Cancer Invest 2022; 40:219-227. [PMID: 35000504 DOI: 10.1080/07357907.2022.2027435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
QTc prolongation is linked to Torsade de Pointes, sudden cardiac death, and overall cardiovascular mortality. 754 prostate cancer patients undergoing brachytherapy were analyzed, prolonged QTc was defined as ≥450ms. A prolonged QTc was more frequent (10.1% vs 5.1%, p = 0.040) in patients with high-risk cancer than in low to intermediate risk patients. The absolute QTc-time was correlated with age (r = 0.125), neutrophil count (r = 0.130) and negatively correlated with the testosterone level (r=-0.205). Treating physicians should be aware of this and monitor the QTc during ADT to possibly decrease cardiac morbidity/mortality in these patients who are more likely to require ADT.
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Affiliation(s)
- Simon Saad
- Department of Radiation Oncology, University of Montreal Health Center, Montreal, Canada
| | - Guila Delouya
- Department of Radiation Oncology, University of Montreal Health Center, Montreal, Canada.,CRCHUM-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Canada
| | - Carole Lambert
- Department of Radiation Oncology, University of Montreal Health Center, Montreal, Canada.,CRCHUM-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Canada
| | - Maroie Barkati
- Department of Radiation Oncology, University of Montreal Health Center, Montreal, Canada.,CRCHUM-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Canada
| | - Charles Dariane
- Department of Urology, University of Montreal Health Center, Montreal, Canada.,Department of Urology, Hôpital européen Georges-Pompidou, Paris University, Paris, France
| | - Mikhael Laskine
- CRCHUM-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Canada.,Department of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Daniel Taussky
- Department of Radiation Oncology, University of Montreal Health Center, Montreal, Canada.,CRCHUM-Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Canada
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15
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Ding J, Liu W, Guan H, Feng Y, Bao Y, Li H, Wang X, Zhou Z, Chen Z. Corrected QT interval in hospitalized patients with coronavirus disease 2019: Focus on drugs therapy. Medicine (Baltimore) 2021; 100:e26538. [PMID: 34260531 PMCID: PMC8284736 DOI: 10.1097/md.0000000000026538] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 06/15/2021] [Indexed: 12/22/2022] Open
Abstract
Corrected QT (QTc) interval prolongation has been associated with poor patient prognosis. In this study, we assessed the effects of different drugs and cardiac injury on QTc interval prolongation in patients with coronavirus disease 2019 (COVID-19).The study cohort consisted of 395 confirmed COVID-19 cases from the Wuhan Union Hospital West Campus. All hospitalized patients were treated with chloroquine/hydroxychloroquine (CQ/HCQ), lopinavir/ritonavir (LPV/r), quinolones, interferon, Arbidol, or Qingfei Paidu decoction (QPD) and received at least 1 electrocardiogram after drug administration.Fifty one (12.9%) patients exhibited QTc prolongation (QTc ≥ 470 ms). QTc interval prolongation was associated with COVID-19 severity and mortality (both P < .001). Administration of CQ/HCQ (odds ratio [OR], 2.759; 95% confidence interval [CI], 1.318-5.775; P = .007), LPV/r (OR, 2.342; 95% CI, 1.152-4.760; P = .019), and quinolones (OR, 2.268; 95% CI, 1.171-4.392; P = .015) increased the risk of QTc prolongation. In contrast, the administration of Arbidol, interferon, or QPD did not increase the risk of QTc prolongation. Notably, patients treated with QPD had a shorter QTc duration than those without QPD treatment (412.10 [384.39-433.77] vs 420.86 [388.19-459.58]; P = .042). The QTc interval was positively correlated with the levels of cardiac biomarkers (creatine kinase-MB fraction [rho = 0.14, P = .016], high-sensitivity troponin I [rho = .22, P < .001], and B-type natriuretic peptide [rho = 0.27, P < .001]).In conclusion, QTc prolongation was associated with COVID-19 severity and mortality. The risk of QTc prolongation was higher in patients receiving CQ/HCQ, LPV/r, and quinolones. QPD had less significant effects on QTc prolongation than other antiviral agents.
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16
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Ingegnoli F, Buoli M, Antonucci F, Coletto LA, Esposito CM, Caporali R. The Link Between Autonomic Nervous System and Rheumatoid Arthritis: From Bench to Bedside. Front Med (Lausanne) 2020; 7:589079. [PMID: 33365319 PMCID: PMC7750536 DOI: 10.3389/fmed.2020.589079] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 10/30/2020] [Indexed: 12/25/2022] Open
Abstract
Neuronal stimulation is an emerging field of research focused on the management and treatment of various diseases through the reestablishment of physiological homeostasis. Electrical vagus nerve stimulation has recently been proposed as a revolutionary therapeutic option for rheumatoid arthritis (RA) in combination with or even as a replacement for conventional and biological drugs. In the past few years, disruption of the autonomic system has been linked to RA onset and activity. Novel research on the link between the autonomic nervous system and the immune system (immune-autonomics) has paved the way for the development of innovative RA management strategies. Clinical evidence supports this approach. Cardiovascular involvement, in terms of reduced baroreflex sensitivity and heart rate variability-derived indices, and mood disorders, common comorbidities in patients with RA, have been linked to autonomic nervous system dysfunction, which in turn is influenced by increased levels of circulating pro-inflammatory cytokines. This narrative review provides an overview of the autonomic nervous system and RA connection, discussing most of the common cardiac and mental health-related RA comorbidities and their potential relationships to systemic and joint inflammation.
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Affiliation(s)
- Francesca Ingegnoli
- Division of Clinical Rheumatology, Gaetano Pini Hospital, Milan, Italy
- Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università degli Studi di Milano, Milan, Italy
| | - Massimiliano Buoli
- Department of Neurosciences and Mental Health, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Flavia Antonucci
- Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Milan, Italy
| | - Lavinia Agra Coletto
- Division of Clinical Rheumatology, Gaetano Pini Hospital, Milan, Italy
- Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università degli Studi di Milano, Milan, Italy
| | - Cecilia Maria Esposito
- Department of Neurosciences and Mental Health, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca'Granda Ospedale Maggiore Policlinico, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Roberto Caporali
- Division of Clinical Rheumatology, Gaetano Pini Hospital, Milan, Italy
- Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università degli Studi di Milano, Milan, Italy
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17
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Psoriatic arthritis is associated with myocardial repolarization dysregulation as assessed by the QTc interval and the Tp-e/QTc ratio. JOURNAL OF SURGERY AND MEDICINE 2020. [DOI: 10.28982/josam.792850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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18
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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.
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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
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19
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Farré N, Mojón D, Llagostera M, Belarte-Tornero LC, Calvo-Fernández A, Vallés E, Negrete A, García-Guimaraes M, Bartolomé Y, Fernández C, García-Duran AB, Marrugat J, Vaquerizo B. Prolonged QT Interval in SARS-CoV-2 Infection: Prevalence and Prognosis. J Clin Med 2020; 9:E2712. [PMID: 32839385 PMCID: PMC7563186 DOI: 10.3390/jcm9092712] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/13/2020] [Accepted: 08/20/2020] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND The prognostic value of a prolonged QT interval in SARS-Cov2 infection is not well known. OBJECTIVE To determine whether the presence of a prolonged QT on admission is an independent factor for mortality in SARS-Cov2 hospitalized patients. METHODS Single-center cohort of 623 consecutive patients with positive polymerase-chain-reaction test (PCR) to SARS Cov2, recruited from 27 February to 7 April 2020. An electrocardiogram was taken on these patients within the first 48 h after diagnosis and before the administration of any medication with a known effect on QT interval. A prolonged QT interval was defined as a corrected QT (QTc) interval >480 milliseconds. Patients were followed up with until 10 May 2020. RESULTS Sixty-one patients (9.8%) had prolonged QTc and only 3.2% had a baseline QTc > 500 milliseconds. Patients with prolonged QTc were older, had more comorbidities, and higher levels of immune-inflammatory markers. There were no episodes of ventricular tachycardia or ventricular fibrillation during hospitalization. All-cause death was higher in patients with prolonged QTc (41.0% vs. 8.7%, p < 0.001, multivariable HR 2.68 (1.58-4.55), p < 0.001). CONCLUSIONS Almost 10% of patients with COVID-19 infection have a prolonged QTc interval on admission. A prolonged QTc was independently associated with a higher mortality even after adjustment for age, comorbidities, and treatment with hydroxychloroquine and azithromycin. An electrocardiogram should be included on admission to identify high-risk SARS-CoV-2 patients.
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Affiliation(s)
- Núria Farré
- Department of Cardiology, Hospital del Mar, 08003 Barcelona, Spain; (D.M.); (M.L.); (L.C.B.-T.); (A.C.-F.); (E.V.); (A.N.); (M.G.-G.); (Y.B.); (C.F.); (A.B.G.-D.); (B.V.)
- Department of Medicine, School of Medicine, Univ Autonoma de Barcelona, 08003 Barcelona, Spain
- Heart Diseases Biomedical Research Group (GREC), IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
| | - Diana Mojón
- Department of Cardiology, Hospital del Mar, 08003 Barcelona, Spain; (D.M.); (M.L.); (L.C.B.-T.); (A.C.-F.); (E.V.); (A.N.); (M.G.-G.); (Y.B.); (C.F.); (A.B.G.-D.); (B.V.)
| | - Marc Llagostera
- Department of Cardiology, Hospital del Mar, 08003 Barcelona, Spain; (D.M.); (M.L.); (L.C.B.-T.); (A.C.-F.); (E.V.); (A.N.); (M.G.-G.); (Y.B.); (C.F.); (A.B.G.-D.); (B.V.)
| | - Laia C. Belarte-Tornero
- Department of Cardiology, Hospital del Mar, 08003 Barcelona, Spain; (D.M.); (M.L.); (L.C.B.-T.); (A.C.-F.); (E.V.); (A.N.); (M.G.-G.); (Y.B.); (C.F.); (A.B.G.-D.); (B.V.)
- Department of Medicine, School of Medicine, Univ Autonoma de Barcelona, 08003 Barcelona, Spain
- Heart Diseases Biomedical Research Group (GREC), IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
| | - Alicia Calvo-Fernández
- Department of Cardiology, Hospital del Mar, 08003 Barcelona, Spain; (D.M.); (M.L.); (L.C.B.-T.); (A.C.-F.); (E.V.); (A.N.); (M.G.-G.); (Y.B.); (C.F.); (A.B.G.-D.); (B.V.)
- Department of Medicine, School of Medicine, Univ Autonoma de Barcelona, 08003 Barcelona, Spain
| | - Ermengol Vallés
- Department of Cardiology, Hospital del Mar, 08003 Barcelona, Spain; (D.M.); (M.L.); (L.C.B.-T.); (A.C.-F.); (E.V.); (A.N.); (M.G.-G.); (Y.B.); (C.F.); (A.B.G.-D.); (B.V.)
- Department of Medicine, School of Medicine, Univ Autonoma de Barcelona, 08003 Barcelona, Spain
- Heart Diseases Biomedical Research Group (GREC), IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
| | - Alejandro Negrete
- Department of Cardiology, Hospital del Mar, 08003 Barcelona, Spain; (D.M.); (M.L.); (L.C.B.-T.); (A.C.-F.); (E.V.); (A.N.); (M.G.-G.); (Y.B.); (C.F.); (A.B.G.-D.); (B.V.)
| | - Marcos García-Guimaraes
- Department of Cardiology, Hospital del Mar, 08003 Barcelona, Spain; (D.M.); (M.L.); (L.C.B.-T.); (A.C.-F.); (E.V.); (A.N.); (M.G.-G.); (Y.B.); (C.F.); (A.B.G.-D.); (B.V.)
| | - Yolanda Bartolomé
- Department of Cardiology, Hospital del Mar, 08003 Barcelona, Spain; (D.M.); (M.L.); (L.C.B.-T.); (A.C.-F.); (E.V.); (A.N.); (M.G.-G.); (Y.B.); (C.F.); (A.B.G.-D.); (B.V.)
| | - Camino Fernández
- Department of Cardiology, Hospital del Mar, 08003 Barcelona, Spain; (D.M.); (M.L.); (L.C.B.-T.); (A.C.-F.); (E.V.); (A.N.); (M.G.-G.); (Y.B.); (C.F.); (A.B.G.-D.); (B.V.)
| | - Ana B. García-Duran
- Department of Cardiology, Hospital del Mar, 08003 Barcelona, Spain; (D.M.); (M.L.); (L.C.B.-T.); (A.C.-F.); (E.V.); (A.N.); (M.G.-G.); (Y.B.); (C.F.); (A.B.G.-D.); (B.V.)
| | - Jaume Marrugat
- REGICOR (Registre Gironí del Cor) Study Group, IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain;
- CIBER (Centro de Investigación Biomédica en Red) of Cardiovascular Diseases (CIBERCV), Instituto de Salud Carlos III (ISCIII), 08003 Barcelona, Spain
| | - Beatriz Vaquerizo
- Department of Cardiology, Hospital del Mar, 08003 Barcelona, Spain; (D.M.); (M.L.); (L.C.B.-T.); (A.C.-F.); (E.V.); (A.N.); (M.G.-G.); (Y.B.); (C.F.); (A.B.G.-D.); (B.V.)
- Department of Medicine, School of Medicine, Univ Autonoma de Barcelona, 08003 Barcelona, Spain
- Heart Diseases Biomedical Research Group (GREC), IMIM (Hospital del Mar Medical Research Institute), 08003 Barcelona, Spain
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20
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Williams DP, Koenig J, Carnevali L, Sgoifo A, Jarczok MN, Sternberg EM, Thayer JF. Heart rate variability and inflammation: A meta-analysis of human studies. Brain Behav Immun 2019; 80:219-226. [PMID: 30872091 DOI: 10.1016/j.bbi.2019.03.009] [Citation(s) in RCA: 221] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 02/23/2019] [Accepted: 03/09/2019] [Indexed: 12/16/2022] Open
Abstract
The inflammatory reflex is known as the body's primary defense against infection and has been implicated in a number of diseases. The magnitude of the inflammatory response is important, as an extreme or insufficient response can be differentially harmful to the individual. Converging evidence suggests that the autonomic nervous system (ANS) regulates the inflammatory reflex. Heart rate variability (HRV) can be separated into components that primarily reflect parasympathetic (PNS) or vagal activity (i.e., indices of vagally mediated HRV) and a combination of both sympathetic (SNS) and PNS influences. Given the physiological relation between the vagus and inflammatory processes, one would expect to find higher HRV, especially indices of vagally-mediated HRV, to be associated with decreased levels of inflammation via the cholinergic anti-inflammatory pathway. However, existing findings here are mixed, such that studies have also shown a positive association between indices of HRV and markers of inflammation. Therefore, the present meta-analysis aimed to synthesize existing studies, estimating the general direction and strength of the relationship between different indices of HRV and inflammatory markers. A systematic search of the literature yielded 2283 studies that were screened for inclusion eligibility (159 studies eligible for inclusion); in sum, 51 studies reported/provided adequate information for inclusion in meta-analyses. Results generally showed negative associations between indices of HRV and markers of inflammation. In this regard, the standard deviation of R-R intervals (SDNN) and power in the high frequency band of HRV (HF-HRV) showed the strongest and most robust associations with inflammatory markers compared to other time- and frequency-domain measures of HRV. Overall, we propose that indices of HRV can be used to index activity of the neurophysiological pathway responsible for adaptively regulating inflammatory processes in humans.
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Affiliation(s)
- DeWayne P Williams
- Department of Psychology, The Ohio State University, Columbus, OH, United States.
| | - Julian Koenig
- Section for Translational Psychobiology in Child and Adolescent Psychiatry, Department of Child and Adolescent Psychiatry, Centre for Psychosocial Medicine, University of Heidelberg, Heidelberg, Germany; University Hospital of Child and Adolescent Psychiatry and Psychotherapy, University of Bern, Bern, Switzerland
| | - Luca Carnevali
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Italy
| | - Andrea Sgoifo
- Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Italy
| | - Marc N Jarczok
- Department for Psychosomatic Medicine and Psychotherapy, University Medical Center Ulm, Germany
| | - Esther M Sternberg
- Center for Integrative Medicine, The University of Arizona, Tucson, AZ, United States
| | - Julian F Thayer
- Department of Psychology, The Ohio State University, Columbus, OH, United States
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21
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Autoimmune and inflammatory K+ channelopathies in cardiac arrhythmias: Clinical evidence and molecular mechanisms. Heart Rhythm 2019; 16:1273-1280. [DOI: 10.1016/j.hrthm.2019.02.017] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Indexed: 12/30/2022]
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Evaluation of ventricular repolarization features with novel electrocardiographic parameters (Tp-e, Tp-e/QT) in patients with psoriasis. Anatol J Cardiol 2019; 18:397-401. [PMID: 29256874 PMCID: PMC6282903 DOI: 10.14744/anatoljcardiol.2017.7901] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Objective: Psoriasis is a chronic inflammatory disorder, which affects around 1%–3% of the human population worldwide. Cardiovascular events are the leading cause of morbidity and mortality in patients with psoriasis. Some studies have reported that psoriasis is related to increased arrhythmias. The Tp-e interval and Tp-e/QT ratio have been accepted as new markers for the assessment of myocardial repolarization and ventricular arrhythmogenesis. The aim of this study was to assess ventricular repolarization in patients with psoriasis using Tp-e interval and Tp-e/QT ratio. Methods: The study population consisted of 74 patients with psoriasis and 74 healthy volunteers. The diagnosis of psoriasis was based on a clinical or histopathological examination of all patients. QT interval, corrected QT (QTc), QT dispersion (QTd), Tp-e interval, corrected Tp-e, and Tp-e/QT ratio were measured from the 12-lead electrocardiogram. These parameters were compared between groups. Results: According to the electrocardiographic parameters, QT and QTc intervals and QTd were significantly higher in patients with psoriasis than in control subjects (p<0.001; p<0.001; p=0.014; respectively). The Tp-e interval, corrected Tp-e, and Tp-e/QT ratio were significantly higher in patients with psoriasis than in control subjects [93±13 milliseconds (ms) vs. 98±14 ms, p=0.040; 104±17 ms vs. 111±17 ms, p=0.008; 0.23±0.03 vs. 0.25±0.03, p<0.001; respectively]. Additionally, the CRP value was an independent predictor of an increased Tp-e/QT ratio (β=0.537, p< 0.001). Conclusion: Our study revealed that ventricular repolarization features were impaired in patients with psoriasis. Therefore, these patients should be more closely screened for ventricular arrhythmias.
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Magodoro IM, Albano AJ, Muthalaly R, Koplan B, North CM, Vořechovská D, Downey J, Kraemer J, Vaglio M, Badilini F, Kakuhire B, Tsai AC, Siedner MJ. Population Prevalence and Correlates of Prolonged QT Interval: Cross-Sectional, Population-Based Study From Rural Uganda. Glob Heart 2019; 14:17-25.e4. [PMID: 30584028 PMCID: PMC6737252 DOI: 10.1016/j.gheart.2018.11.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 11/11/2018] [Accepted: 11/20/2018] [Indexed: 01/19/2023] Open
Abstract
OBJECTIVES We aimed to estimate the prevalence and correlates of QT interval prolongation in rural Uganda. BACKGROUND Major electrocardiographic abnormalities, including prolonged QT interval, have been shown to be independently predictive of adverse cardiovascular events among Western populations. Cardiovascular diseases are on the rise in sub-Saharan Africa with poorly characterized context-specific risk factors. An important question is whether ECG screening might have value in cardiovascular disease risk stratification in SSA. METHODS We conducted a cross-sectional survey in a sample of adults participating in an ongoing whole-population cohort in Mbarara, Uganda, in 2015. Of 1,814 subjects enrolled in the parent whole-population cohort, 856 (47%) participated in the study. Participants completed 12-lead electrocardiography and cardiovascular disease risk factors assessment. We summarized sex-specific, heart rate variation-adjusted QT (QTa) defining prolonged QTa as >460 ms in women and >450 ms in men. We fit linear and logistic regression models to estimate correlates of (continuous) QTa interval length and (dichotomous) prolonged QTa. Models included inverse probability of sampling weights to generate population-level estimates accounting for study nonparticipation. RESULTS We assessed data from 828 participants with electrocardiograms. The weighted population mean age was 38.4 years (95% confidence interval: 36.3-40.4). The weighted population was 50.4% female, 11.5% had elevated blood pressure, and 57.6% had a high-sensitivity C-reactive protein >1 mg/dl. The population mean QTa was 409.1 ms (95% confidence interval: 405.1-413.1), and 10.3% (95% confidence interval: 7.8-13.5) met criteria for prolonged QTa. Women had a higher mean QTa (421.6 ms vs. 396.3 ms; p < 0.001), and a higher proportion of women had a prolonged QTa (14.0% vs. 9.3%; p = 0.122) than did men. In multivariable-adjusted regression models, female sex and hypertension correlated with higher mean QTa and meeting criteria for prolonged QTa, respectively. CONCLUSIONS QT interval prolongation is highly prevalent in rural Uganda and may be more common than in high-income settings. Female sex, age, and high blood pressure correlated with QT interval prolongation. Future work should assess whether genetic predisposition or environmental factors in sub-Saharan African populations contribute to prolonged QT and clarify consequences.
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Affiliation(s)
- Itai M Magodoro
- Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA; University of Cape Town, Cape Town, South Africa.
| | - Alfred J Albano
- Michigan State University School of Medicine, East Lansing, MI, USA
| | - Rahul Muthalaly
- Harvard Medical School, Boston, MA, USA; Arrhythmia Service, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA
| | - Bruce Koplan
- Harvard Medical School, Boston, MA, USA; Arrhythmia Service, Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA
| | - Crystal M North
- Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA
| | | | - Jordan Downey
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - John Kraemer
- Department of Health Systems Administration, Georgetown University, Washington, DC, USA
| | - Martino Vaglio
- Analyzing Medical Parameters for Solutions, LLC, New York, NY, USA
| | - Fabio Badilini
- Analyzing Medical Parameters for Solutions, LLC, New York, NY, USA
| | | | - Alexander C Tsai
- Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA; Analyzing Medical Parameters for Solutions, LLC, New York, NY, USA
| | - Mark J Siedner
- Harvard Medical School, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA; Mbarara University of Science and Technology, Mbarara, Uganda; Africa Health Research Institute, KwaZulu-Natal, South Africa
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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.
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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:
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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.
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Abdolmaleki F, Farahani N, Gheibi Hayat SM, Pirro M, Bianconi V, Barreto GE, Sahebkar A. The Role of Efferocytosis in Autoimmune Diseases. Front Immunol 2018; 9:1645. [PMID: 30083153 PMCID: PMC6064952 DOI: 10.3389/fimmu.2018.01645] [Citation(s) in RCA: 97] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Accepted: 07/04/2018] [Indexed: 12/28/2022] Open
Abstract
Apoptosis happens continuously for millions of cells along with the active removal of apoptotic debris in order to maintain tissue homeostasis. In this respect, efferocytosis, i.e., the process of dead cell clearance, is orchestrated through cell exposure of a set of "find me," "eat me," and "tolerate me" signals facilitating the engulfment of dying cells through phagocytosis by macrophages and dendritic cells. The clearance of dead cells via phagocytes is of utmost importance to maintain the immune system tolerance to self-antigens. Accordingly, this biological activity prevents the release of autoantigens by dead cells, thus potentially suppressing the undesirable autoreactivity of immune cells and the appearance of inflammatory autoimmune disorders as systemic lupus erythematous and rheumatoid arthritis. In the present study, the apoptosis pathways and their immune regulation were reviewed. Moreover, efferocytosis process and its impairment in association with some autoimmune diseases were discussed.
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Affiliation(s)
- Fereshte Abdolmaleki
- Cellular and Molecular Research Center, School of Paramedical Sciences, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Najmeh Farahani
- Department of Genetics and Molecular Biology, Isfahan University of Medical Sciences, Isfahan, Iran
| | | | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - Vanessa Bianconi
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, Perugia, Italy
| | - George E. Barreto
- Departamento de Nutrición y Bioquímica, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
- Instituto de Ciencias Biomédicas, Universidad Autónoma de Chile, Santiago, Chile
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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Jhuo SJ, Hsieh TJ, Tang WH, Tsai WC, Lee KT, Yen HW, Lai WT. The association of the amounts of epicardial fat, P wave duration, and PR interval in electrocardiogram. J Electrocardiol 2018; 51:645-651. [DOI: 10.1016/j.jelectrocard.2018.04.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Revised: 03/18/2018] [Accepted: 04/11/2018] [Indexed: 01/29/2023]
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Cerşit S, Cerşit HP. Impact of cardiac rehabilitation on ventricular repolarization indexes in patients with rheumatid arthritis. J Electrocardiol 2018; 51:787-791. [PMID: 30177313 DOI: 10.1016/j.jelectrocard.2018.06.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 06/03/2018] [Accepted: 06/16/2018] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Abnormalities in ventricular repolarization (VR) parameters have been associated with sudden cardiac death (SCD) in patients with rheumatoid arthritis (RA). The benefits of cardiac rehabilitation (CR) in patients with RA are well recognized. We aimed to assess its impact on VR indexes in patients with RA. METHODS This study included 45 patients with RA (36 female, age 58 ± 5.5 years) and 50 age- and sex-matched otherwise healthy controls. Baseline electrocardiogram (ECG) recordings were used to compare VR parameters such as maximum and minimum QT intervals, and corrected, and dispersion (QTmax, QTmin, cQTmax, cQTmin, QTd, cQTd, respectively), JT and cJT intervals, Tp-e and cTp-e intervals, and Tp-e/QT and Tp-e/cQT ratios in patients with RA and healthy individuals. The effects of 6-week CR in patients with RA were also evaluated by comparing pre- and post-CR ECGs, exercise tolerance test (MET and VO2max) and RA characteristics (C-reactive protein (CRP), Disease Activity Score 28 (DAS28) and Health Assessment Questionnaire(HAQ)). RESULTS In comparison with the healthy individuals, the patients with RA had significantly higher cQTmax and QTmin intervals, QTd, cQTd, Tp-e and cTp-e intervals, and Tp-e/QT and Tp-e/cQT ratios. At the end of CR, all VR indexes (p < 005), except QTd, were significantly decreased as did the results for CRP, DAS28, and HAQ (all p < 0.05), and MET and VO2max (p < 0.05 for both) were significantly increased in patients with RA. CONCLUSIONS CR may provide an improvement in the majority of VR indexes which are related with ventricular arrhythmia and SCD in patients with RA. Changes in ETT parameters and RA characteristics may contribute to improvement of several VR indexes such as cQTd, cJT and Tp-e intervals at the end of CR.
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Affiliation(s)
- Sinan Cerşit
- Koşuyolu Kartal Heart Training and Research Hospital, Department of Cardiology, İstanbul, Turkey.
| | - Hülya Peynirci Cerşit
- Marmara University School of Medicine, Department of Physical Medicine and Rehabilitation, İstanbul, Turkey
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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: 126] [Impact Index Per Article: 18.0] [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.
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Lazzerini PE, Capecchi PL, Galeazzi M, Laghi-Pasini F. Biologic drugs and arrhythmic risk in chronic inflammatory arthritis: the good and the bad. Immunol Res 2018; 65:262-275. [PMID: 27423435 DOI: 10.1007/s12026-016-8833-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Increasing evidence indicates that patients with chronic inflammatory arthritis (CIA), including rheumatoid arthritis and spondyloarthropathies, have an increased risk of arrhythmic events, significantly contributing to the higher cardiovascular disease (CVD) morbidity and mortality observed in these subjects compared to the general population. Although the mechanisms accounting for such an arrhythmogenic substrate are not fully understood, the main role is probably played by chronic systemic inflammation, able to accelerate the development of structural CVD, as well as to directly affect cardiac electrophysiology. In the past decade, biologic therapies have revolutionized the treatment of CIA by highly enhancing the probability to effectively control disease activity and its systemic consequences, including cardiovascular involvement. Accordingly, accumulating data demonstrated that by potently inhibiting systemic inflammation, biologic drugs can reduce CVD progression and ameliorate arrhythmic risk parameters, with a putative beneficial impact on arrhythmia incidence. Nevertheless, a significant number of reports from clinical trials and postmarketing experience suggest that some of these medications, particularly TNF inhibitor monoclonal antibodies and rituximab, may in some circumstances precipitate arrhythmia occurrence, probably by acutely amplifying myocardial electric instability intrinsically associated with these diseases. In this review, we analyze the intricate link between biologic drugs and arrhythmias in CIA in the effort to identify which factors are involved in the fine-tuning of antiarrhythmic/pro-arrhythmic balance, and understand how this knowledge should be translated in the clinical practice to obtain the most favorable benefit-to-risk profile when biologic drugs are used in these patients.
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Affiliation(s)
- Pietro Enea Lazzerini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Policlinico "Le Scotte", Viale Bracci, Siena, Italy.
| | - Pier Leopoldo Capecchi
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Policlinico "Le Scotte", Viale Bracci, Siena, Italy
| | - Mauro Galeazzi
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Policlinico "Le Scotte", Viale Bracci, Siena, Italy
| | - Franco Laghi-Pasini
- Department of Medical Sciences, Surgery and Neurosciences, University of Siena, Policlinico "Le Scotte", Viale Bracci, Siena, Italy
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Provan SA, Olstad DS, Solberg EE, Smedslund G, Dagfinrud H. Evidence of reduced parasympathetic autonomic regulation in inflammatory joint disease: A meta-analyses study. Semin Arthritis Rheum 2017; 48:134-140. [PMID: 29291895 DOI: 10.1016/j.semarthrit.2017.11.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 11/28/2017] [Accepted: 11/30/2017] [Indexed: 02/02/2023]
Abstract
BACKGROUND Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are inflammatory joint disorders (IJD) with increased risk of cardiovascular disease (CVD). Autonomic dysfunction (AD) is a risk factor for CVD, and parasympathetic AD is linked to key features of IJD such as inflammation, physical inactivity and pain. Heart-rate variability (HRV) is a marker of cardiac AD. The study objective was to compare parasympathetic cardiac AD, measured by HRV, between patients with IJD and healthy controls, using meta-analysis methodology, and to examine the impact of inflammation, physical inactivity and pain on HRV in IJD. METHODS Medline, Embase and Amed were searched. Inclusion criteria were adult case-control studies published in English or a Scandinavian language, presenting HRV data in IJD. Two measures of HRV and 3 from the Ewing protocol were selected: square root of mean squared difference of successive R-R intervals (RMSSD), high frequency (HF), Ewing protocol; standing (E-S), breathing (E-B) and Valsalva (E-V). Patients with RA, SpA and healthy controls were compared separately using random-effects meta-analyses of standardized mean differences (SMD). RESULTS In all, 35 papers were eligible for inclusion. For RMSSD the pooled SMD (95% CI) RA vs. controls was -0.90 (-1.35 to -0.44), for SpA vs. controls; -0.34 (-0.73 to 0.06). For HF pooled SMD RA vs. controls was -0.78 (-0.99 to -0.57), for SpA vs. controls; -0.04 (-0.22 to 0.13). All Ewing parameters were significantly lower in cases, except for E-V which was comparable between cases and controls in patients with RA. CONCLUSION Patients with IJD have cardiac parasympathetic AD which is related to inflammation.
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Affiliation(s)
- Sella A Provan
- Department of Rheumatology, Diakonhjemmet Hospital, PB 23 Vindern, 0319 Oslo, Norway.
| | - Daniela Schäfer Olstad
- Department of Rheumatology, National Resource Centre for Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, Norway
| | - Erik E Solberg
- Department of Medicine, Diakonhjemmet Hospital, Oslo, Norway
| | - Geir Smedslund
- Department of Rheumatology, National Resource Centre for Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, Norway
| | - Hanne Dagfinrud
- Department of Rheumatology, National Resource Centre for Rehabilitation in Rheumatology, Diakonhjemmet Hospital, Oslo, Norway
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Masoud S, Lim PB, Kitas GD, Panoulas V. Sudden cardiac death in patients with rheumatoid arthritis. World J Cardiol 2017; 9:562-573. [PMID: 28824786 PMCID: PMC5545140 DOI: 10.4330/wjc.v9.i7.562] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Revised: 03/15/2017] [Accepted: 04/19/2017] [Indexed: 02/06/2023] Open
Abstract
An increased cardiovascular morbidity and mortality, including the risk of sudden cardiac death (SCD), has been shown in patients with rheumatoid arthritis (RA). Abnormalities in autonomic markers such as heart rate variability and ventricular repolarization parameters, such as QTc interval and QT dispersion, have been associated with sudden death in patients with RA. The interplay between these parameters and inflammation that is known to exist with RA is of growing interest. In this article, we review the prevalence and predictors of SCD in patients with RA and describe the potential underlying mechanisms, which may contribute to this. We also review the impact of biologic agents on arrhythmic risk as well as cardiovascular morbidity and mortality.
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Koopman FA, van Maanen MA, Vervoordeldonk MJ, Tak PP. Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis. J Intern Med 2017; 282:64-75. [PMID: 28547815 DOI: 10.1111/joim.12626] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Imbalance in the autonomic nervous system (ANS) has been observed in many established chronic autoimmune diseases, including rheumatoid arthritis (RA), which is a prototypic immune-mediated inflammatory disease (IMID). We recently discovered that autonomic dysfunction precedes and predicts arthritis development in subjects at risk of developing seropositive RA. In addition, RA patients with relatively high vagus nerve tone (higher parasympathetic parameters, measured by heart rate variability) respond better to antirheumatic therapies. Together, these data suggest that the ANS may control inflammation in humans. This notion is supported by experimental studies in animal models of RA. We have found that stimulation of the so-called cholinergic anti-inflammatory pathway by efferent electrical vagus nerve stimulation (VNS) or pharmacological activation of the alpha7 subunit of nicotinic acetylcholine receptors (α7nAChR) improves clinical signs and symptoms of arthritis, reduces cytokine production and protects against progressive joint destruction. Conversely, increased arthritis activity was observed in alpha7nAChR knockout mice. These studies together with previous work in animal models of sepsis and other forms of inflammation provided the rationale for an experimental clinical trial in patients with RA. We could for the first time show that an implantable vagus nerve stimulator inhibits peripheral blood cytokine production in humans. VNS significantly inhibited TNF and IL-6 production and improved RA disease severity, even in some patients with therapy-resistant disease. This work strongly supports further studies using a bioelectronic approach to treat RA and other IMIDs.
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Affiliation(s)
- F A Koopman
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
| | - M A van Maanen
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
| | - M J Vervoordeldonk
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.,Galvani Bioelectronics, Stevenage, UK
| | - P P Tak
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and Immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands.,GlaxoSmithKline, Stevenage, UK.,University of Cambridge, Cambridge, UK.,Ghent University, Ghent, Belgium
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García Bermejo P, de la Cruz Torres B, Naranjo Orellana J, Albornoz Cabello M. Autonomic activity in women during percutaneous needle electrolysis. Eur J Integr Med 2017. [DOI: 10.1016/j.eujim.2017.02.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Turk SA, Heslinga SC, Dekker J, Britsemmer L, van der Lugt V, Lems WF, van Schaardenburg D, Nurmohamed MT. The Relationship Between Cardiac Conduction Times, Cardiovascular Risk Factors, and Inflammation in Patients with Early Arthritis. J Rheumatol 2017; 44:580-586. [DOI: 10.3899/jrheum.161184] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/25/2017] [Indexed: 02/07/2023]
Abstract
Objective.To investigate the prevalence of conduction disorders in patients with early arthritis and the relationship with inflammation and traditional cardiovascular (CV) risk factors.Methods.Patients with rheumatoid arthritis (RA) have a 2-fold higher risk of sudden cardiac death, possibly owing to conduction disorders. This increased risk might already be present at the clinical onset of arthritis. Therefore, we assessed electrocardiography, blood pressure, 28-joint Disease Activity Score (DAS28), lipid profile, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level in 480 patients with early arthritis at baseline and after 1 year.Results.The prevalence of conduction disorders was 12.5%. Conduction times at baseline were not associated with DAS28, ESR, or CRP levels and did not change during antirheumatic treatment. Baseline and the improvement in DAS28 (European League Against Rheumatism response), ESR, and CRP were significantly associated with heart rate, lipid profile, and blood pressure. Elevated total cholesterol and blood pressure were associated with an increased QRS time. The change in heart rate differed 7.3 bpm between patients with the least versus largest DAS improvement.Conclusion.The prevalence of conduction disorders in patients with early arthritis was 12.5%, which is similar to the general population and was not associated with changes in inflammation markers. However, a high cholesterol was associated with a prolonged QRS time. Therefore, the emphasis of CV risk management in arthritis should not be only on treatment of disease activity but also on traditional CV risk factors. The relationship between the improvement in disease activity and heart rate is remarkable because this could imply a 10-year CV mortality risk difference of 24%.
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Aggarwal D, Singla S. Prevalence of Autonomic Neuropathy in Patients of Rheumatoid Arthritis and Its Correlation with Disease Severity. J Clin Diagn Res 2017; 11:OC09-OC13. [PMID: 28571182 DOI: 10.7860/jcdr/2017/24182.9614] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 01/18/2017] [Indexed: 11/24/2022]
Abstract
INTRODUCTION Autonomic Neuropathy (AN), found to be a strong predictor of sudden cardiac death, has been reported variably in patients with Rheumatoid Arthritis (RA). Manifesting as sweating disturbances, gastrointestinal irregularities, bladder or erectile dysfunction, AN can significantly affect a patient's quality of life and alter the course of the disease. AIM This study was undertaken to find out the prevalence and severity of AN in RA patients attending the Rheumatology Clinic at a Tertiary Care Hospital in New Delhi, India and also to investigate its correlation with patient and disease factors such as age, gender, disease severity, duration and serological status. MATERIALS AND METHODS In this cross-sectional study, AN was assessed subjectively by a survey of autonomic symptoms. Cardiac autonomic involvement was assessed by five cardiovascular reflex tests as described by Ewing: Heart Rate (HR) response to deep breathing, standing, and Valsalva and Blood Pressure (BP) response to standing and sustained handgrip. RESULTS A total of 31 RA patients and 31 age and sex matched healthy volunteers were recruited. Upon analysis it was found that the prevalence of cardiac AN was significantly higher in patients (80.65%) as compared to controls (51.61%) (p=0.016). Positive correlation with disease severity was observed with the patient reported questionnaire but not with the objective cardiovascular reflex tests. No significant correlation between grade of AN and patient's age, gender, disease duration or serological status was established. CONCLUSION At the end of the study, it was concluded that the pathological mechanisms responsible for autonomic dysfunction are more active in RA as compared to others.
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Affiliation(s)
| | - Sumeet Singla
- Associate Professor, Department of Medicine, Maulana Azad Medical College, New Delhi, India
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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.
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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.
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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: 14] [Impact Index Per Article: 1.6] [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.
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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
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Osailan A, Metsios GS, Rouse PC, Ntoumanis N, Duda JL, Kitas GD, Veldhuijzen van Zanten JJCS. Factors associated with parasympathetic activation following exercise in patients with rheumatoid arthritis: a cross-sectional study. BMC Cardiovasc Disord 2016; 16:86. [PMID: 27165730 PMCID: PMC4862092 DOI: 10.1186/s12872-016-0264-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Accepted: 04/29/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Patients with rheumatoid arthritis (RA) have an increased risk for cardiovascular disease (CVD) with poor parasympathetic function being implicated as an underlying factor. Factors related to parasympathetic function, commonly assessed by heart rate recovery (HRR) following maximal exercise, are currently not known in RA. We aimed to explore the association between HRR with CVD risk factors, inflammatory markers, and wellbeing in patients with RA. METHODS Ninety-six RA patients (54.4 ± 12.6 years, 68 % women) completed a treadmill exercise test, during which heart rate (HR) was monitored. HRR1 and HRR2 were defined as the absolute change from HR peak to HRR 1 min post HR peak and 2 min post HR peak, respectively. Cardiorespiratory fitness, CVD risk factors, and serological markers of inflammation were measured in all patients. The Framingham Risk Score (FRS) was used as an assessment of global risk for CVD events, and wellbeing was assessed by questionnaires. RESULTS Mean HRR1 and HRR2 were 29.1 ± 13.2 bpm and 46.4 ± 15.3 bpm, respectively. CVD risk factors as well as most inflammatory markers and measures of wellbeing were inversely correlated with HRR1 and HRR2. Multivariate regression analyses revealed that 27.9 % of the variance in HRR1 and 37.9 % of the variance in HRR2 was explained collectively by CVD risk factors, measures of inflammation, and wellbeing (p = 0.009, p = 0.001 respectively), however no individual measure was independently associated with HRR1 or HRR2. CONCLUSION Parasympathetic activation was associated with overall CVD risk, arthritis-related burden and wellbeing in patients with RA. TRIAL REGISTRATION [Exercise, cardiovascular disease and rheumatoid arthritis, ISRCTN04121489 ].
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Affiliation(s)
- Ahmad Osailan
- School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, B15 2TT, UK.
- Department of Rheumatology, Dudley Group NHS Foundation Trust, Dudley, UK.
| | - George S Metsios
- Department of Rheumatology, Dudley Group NHS Foundation Trust, Dudley, UK
- Department of Physical Activity Exercise and Health, University of Wolverhampton, Walsall, West Midlands, UK
| | - Peter C Rouse
- School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, B15 2TT, UK
- Department of Rheumatology, Dudley Group NHS Foundation Trust, Dudley, UK
- Department for Health, University of Bath, Bath, UK
| | - Nikos Ntoumanis
- School of Psychology & Speech Pathology, Curtin University, Perth, Australia
| | - Joan L Duda
- School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - George D Kitas
- School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, B15 2TT, UK
- Department of Rheumatology, Dudley Group NHS Foundation Trust, Dudley, UK
- Department of Physical Activity Exercise and Health, University of Wolverhampton, Walsall, West Midlands, UK
| | - Jet J C S Veldhuijzen van Zanten
- School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, B15 2TT, UK
- Department of Rheumatology, Dudley Group NHS Foundation Trust, Dudley, UK
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Koopman FA, Tang MW, Vermeij J, de Hair MJ, Choi IY, Vervoordeldonk MJ, Gerlag DM, Karemaker JM, Tak PP. Autonomic Dysfunction Precedes Development of Rheumatoid Arthritis: A Prospective Cohort Study. EBioMedicine 2016; 6:231-237. [PMID: 27211565 PMCID: PMC4856742 DOI: 10.1016/j.ebiom.2016.02.029] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 02/02/2016] [Accepted: 02/16/2016] [Indexed: 12/11/2022] Open
Abstract
Background Heart rate variability (HRV) is a validated method to establish autonomic nervous system (ANS) activity. Rheumatoid arthritis (RA) is accompanied by ANS imbalance. We hypothesized that ANS dysfunction may precede the development of RA, which would suggest that it plays a role in its etiopathogenesis. Methods First, we assessed HRV parameters in supine (resting) and upright (active) position in healthy subjects (HS, n = 20), individuals at risk of developing arthritis (AR subjects, n = 50) and RA patients (RA, n = 20). Next, we measured resting heart rate (RHR), a parasympathetic HRV parameter, in an independent prospective cohort of AR subjects (n = 45). We also evaluated expression levels of the parasympathetic nicotinic acetylcholine receptor type 7 (α7nAChR) on circulating monocytes. Findings Both AR subjects (68 beats per minute (bpm), interquartile range (IQR) 68–73) and RA patients (68 bpm, IQR 62–76) had a significantly higher RHR compared to HS (60 bpm, IQR 56–63). RHR was significantly higher at baseline in individuals who subsequently developed arthritis. Expression levels of α7nAChR were lower in AR subjects with RHR ≥ 70 bpm compared to those with RHR < 70 bpm, consistent with reduced activity of the parasympathetic cholinergic anti-inflammatory pathway. Interpretation These data support the notion that autonomic dysfunction precedes the development of RA.
Individuals at risk of developing RA show autonomic dysfunction similar to established RA patients. Autonomic dysfunction is a predictor of development of arthritis in subjects at risk of RA, suggesting a role in its etiopathogenesis. The autonomous nervous system is a neurological control system that acts largely unconsciously and regulates a variety of bodily functions. We found that dysfunction of this system may precede and predict the development of rheumatoid arthritis (RA), a chronic inflammatory disease with great unmet need. These findings provide important insights into the changes in the nervous system contributing to the development of this condition. They also open up the perspective of potential measures aimed at prevention of RA by restoring the balance in the nervous system before arthritis develops, which would have major implications for patients as well as society.
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Affiliation(s)
- F A Koopman
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - M W Tang
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - J Vermeij
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - M J de Hair
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, The Netherlands
| | - I Y Choi
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - M J Vervoordeldonk
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - D M Gerlag
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - J M Karemaker
- Department of Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - P P Tak
- Amsterdam Rheumatology and Immunology Center, Department of Clinical Immunology & Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
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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.
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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
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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.
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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.
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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
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Serum amyloid A as a marker of persistent inflammation and an indicator of cardiovascular and renal involvement in patients with rheumatoid arthritis. Mediators Inflamm 2014; 2014:793628. [PMID: 25525305 PMCID: PMC4265690 DOI: 10.1155/2014/793628] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Revised: 09/24/2014] [Accepted: 11/13/2014] [Indexed: 02/03/2023] Open
Abstract
OBJECTIVES Rheumatoid arthritis (RA) is a systemic, inflammatory disease. Serum amyloid A (SAA) is an acute-phase protein, involved in pathogenesis of atherosclerosis. The aim of the study was to assess serum concentration of SAA in RA patients, with reference to other inflammatory parameters and markers of extra-articular involvement. METHODS The study population consisted of 140 RA patients, low/moderate disease activity (L/MDA) in 98 (70%) patients and high disease activity (HDA) in 42 (30%). Comprehensive clinical and laboratory assessment was performed with evaluation of electrocardiogram and carotid intima-media thickness. RESULTS The mean SAA concentration [327.0 (263.4) mg/L] was increased highly above the normal value, even in patients with L/MDA. Simultaneously, SAA was significantly higher in patients with HDA versus L/MDA. The mean SAA concentration was significantly higher in patients treated with glucocorticoids, was inversely associated with QTc duration, and was markedly higher in patients with atherosclerotic plaques, emphasizing increased CV risk. SAA was significantly higher in patients with increased cystatin-C level. CONCLUSIONS In RA patients, high serum SAA concentration was strongly associated with activity of the disease and risk of CV and renal involvement. Recurrent assessment of SAA may facilitate searching patients with persistent inflammation and risk of extra-articular complications.
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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.
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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
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Balbaloglu O, Ede H, Yolcu S, Ak H, Tanik N, Tekin G. Exercise Profile and Diastolic Functions Measured via Tissue Doppler Imaging of Fibromyalgia Patients. J Clin Med Res 2014; 6:184-9. [PMID: 24734144 PMCID: PMC3985560 DOI: 10.14740/jocmr1799w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2014] [Indexed: 12/19/2022] Open
Abstract
Background Our aim was to evaluate electrocardiographic and echocardiographic properties and exercise response of patients with fibromyalgia (FM). Methods The study included 60 women with primary FM and 30 healthy individuals. Resting electrocardiography, echocardiography and exercise treadmill test were used to compare these two groups. At apical four-chamber window, samples of transmitral diastolic inflow and tissue Doppler imaging of left ventricle lateral wall were obtained. Left ventricle ejection fraction was measured via modified Simpson’s method. Exercise duration, maximal exercise capacity, maximal heart rate (HR) (bpm), maximal HR (%), rate-pressure product at maximal HR (bpm × mmHg), heart rate recovery 1 (bpm), heart rate recovery 2 (bpm) and chronotropic reserve (%) values were calculated. Results Resting HR and QTc values were similar in both groups. Echocardiographic measurements in both groups did not reveal statistically significant difference except left ventricle end-diastolic diameter and left atrial diameter. Parameters related to diastolic function of the left ventricle did not differ significantly in both groups. Also, there was not any significant difference between the groups for E/E’ ratio and chronotropic reserve. Exercise treadmill test results were statistically similar for both groups. Conclusion Patients with FM presented a normal HR response to exercise and those patients had normal diastolic function similar to their healthy controls.
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Affiliation(s)
- Ozlem Balbaloglu
- Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Bozok University, Yozgat, Turkey
| | - Huseyin Ede
- Department of Cardiology, Faculty of Medicine, Bozok University, Yozgat, Turkey
| | - Sadiye Yolcu
- Department of Emergency Medicine, Faculty of Medicine, Bozok University, Yozgat, Turkey
| | - Hakan Ak
- Department of Neurosurgery, Faculty of Medicine, Bozok University, Yozgat, Turkey
| | - Nermin Tanik
- Department of Neurology, Faculty of Medicine, Bozok University, Yozgat, Turkey
| | - Gulacan Tekin
- Department of Cardiology, Faculty of Medicine, Bozok University, Yozgat, Turkey
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