Comparative cohort study of post-acute COVID-19 infection with a nested, randomized controlled trial of ivabradine for those with postural orthostatic tachycardia syndrome (the COVIVA study)
BackgroundSignificant clinical similarities have been observed between the recently described “Long-Haul” COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, genera...
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2025-07-01
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| author | David Saunders Thomas B. Arnold Thomas B. Arnold Thomas B. Arnold Jason M. Lavender Jason M. Lavender Jason M. Lavender Daoqin Bi Daoqin Bi Daoqin Bi Karl Alcover Lydia D. Hellwig Lydia D. Hellwig Lydia D. Hellwig Sahar T. Leazer Sahar T. Leazer Sahar T. Leazer Roshila Mohammed Roshila Mohammed Roshila Mohammed Bethelhem Markos Bethelhem Markos Bethelhem Markos Kanchana Perera Kanchana Perera Kanchana Perera Dutchabong Shaw Dutchabong Shaw Priscilla Kobi Priscilla Kobi Martin Evans Autumn Mains Autumn Mains Autumn Mains Marian Tanofsky-Kraff Marian Tanofsky-Kraff Emilie Goguet Emilie Goguet Edward Mitre Kathleen P. Pratt Clifton L. Dalgard Clifton L. Dalgard Mark C. Haigney Mark C. Haigney |
| author_facet | David Saunders Thomas B. Arnold Thomas B. Arnold Thomas B. Arnold Jason M. Lavender Jason M. Lavender Jason M. Lavender Daoqin Bi Daoqin Bi Daoqin Bi Karl Alcover Lydia D. Hellwig Lydia D. Hellwig Lydia D. Hellwig Sahar T. Leazer Sahar T. Leazer Sahar T. Leazer Roshila Mohammed Roshila Mohammed Roshila Mohammed Bethelhem Markos Bethelhem Markos Bethelhem Markos Kanchana Perera Kanchana Perera Kanchana Perera Dutchabong Shaw Dutchabong Shaw Priscilla Kobi Priscilla Kobi Martin Evans Autumn Mains Autumn Mains Autumn Mains Marian Tanofsky-Kraff Marian Tanofsky-Kraff Emilie Goguet Emilie Goguet Edward Mitre Kathleen P. Pratt Clifton L. Dalgard Clifton L. Dalgard Mark C. Haigney Mark C. Haigney |
| author_sort | David Saunders |
| collection | DOAJ |
| description | BackgroundSignificant clinical similarities have been observed between the recently described “Long-Haul” COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, “brain-fog,” and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms.Methods/designA detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction. A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction. Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights.DiscussionOptimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT05481177. |
| format | Article |
| id | doaj-art-b2b3131b7dc14dfd9cf6fa683cf449b4 |
| institution | Kabale University |
| issn | 1664-2295 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Neurology |
| spelling | doaj-art-b2b3131b7dc14dfd9cf6fa683cf449b42025-08-20T03:28:38ZengFrontiers Media S.A.Frontiers in Neurology1664-22952025-07-011610.3389/fneur.2025.15506361550636Comparative cohort study of post-acute COVID-19 infection with a nested, randomized controlled trial of ivabradine for those with postural orthostatic tachycardia syndrome (the COVIVA study)David Saunders0Thomas B. Arnold1Thomas B. Arnold2Thomas B. Arnold3Jason M. Lavender4Jason M. Lavender5Jason M. Lavender6Daoqin Bi7Daoqin Bi8Daoqin Bi9Karl Alcover10Lydia D. Hellwig11Lydia D. Hellwig12Lydia D. Hellwig13Sahar T. Leazer14Sahar T. Leazer15Sahar T. Leazer16Roshila Mohammed17Roshila Mohammed18Roshila Mohammed19Bethelhem Markos20Bethelhem Markos21Bethelhem Markos22Kanchana Perera23Kanchana Perera24Kanchana Perera25Dutchabong Shaw26Dutchabong Shaw27Priscilla Kobi28Priscilla Kobi29Martin Evans30Autumn Mains31Autumn Mains32Autumn Mains33Marian Tanofsky-Kraff34Marian Tanofsky-Kraff35Emilie Goguet36Emilie Goguet37Edward Mitre38Kathleen P. Pratt39Clifton L. Dalgard40Clifton L. Dalgard41Mark C. Haigney42Mark C. Haigney43Uniformed Services University School of Medicine, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesThe Metis Foundation, San Antonio, TX, United StatesMilitary Cardiovascular Outcomes Research, Uniformed Services University, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesThe Metis Foundation, San Antonio, TX, United StatesMilitary Cardiovascular Outcomes Research, Uniformed Services University, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesMilitary Cardiovascular Outcomes Research, Uniformed Services University, Bethesda, MD, United StatesHenry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesHenry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United StatesCenter for Military Precision Health, Uniformed Services University, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesThe Metis Foundation, San Antonio, TX, United StatesMilitary Cardiovascular Outcomes Research, Uniformed Services University, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesThe Metis Foundation, San Antonio, TX, United StatesMilitary Cardiovascular Outcomes Research, Uniformed Services University, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesThe Metis Foundation, San Antonio, TX, United StatesMilitary Cardiovascular Outcomes Research, Uniformed Services University, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesThe Metis Foundation, San Antonio, TX, United StatesMilitary Cardiovascular Outcomes Research, Uniformed Services University, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesHenry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesHenry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United StatesWalter Reed Army Institute of Research, Silver Spring, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesThe Metis Foundation, San Antonio, TX, United StatesMilitary Cardiovascular Outcomes Research, Uniformed Services University, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesMilitary Cardiovascular Outcomes Research, Uniformed Services University, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesHenry M Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesCenter for Military Precision Health, Uniformed Services University, Bethesda, MD, United StatesUniformed Services University School of Medicine, Bethesda, MD, United StatesMilitary Cardiovascular Outcomes Research, Uniformed Services University, Bethesda, MD, United StatesBackgroundSignificant clinical similarities have been observed between the recently described “Long-Haul” COVID-19 (LHC) syndrome, Postural Orthostatic Tachycardia Syndrome (POTS) and Inappropriate Sinus Tachycardia (IST). Shared symptoms include light-headedness, palpitations, tremulousness, generalized weakness, blurred vision, chest pain, dyspnea, “brain-fog,” and fatigue. Ivabradine is a selective sinoatrial node blocker FDA-approved for management of tachycardia associated with stable angina and heart failure not fully managed by beta blockers. In our study we aim to identify risk factors underlying LHC, as well as the effectiveness of ivabradine in controlling heart rate dysregulations and POTS/IST related symptoms.Methods/designA detailed prospective phenotypic evaluation combined with multi-omic analysis of 200 LHC volunteers will be conducted to identify risk factors for autonomic dysfunction. A comparator group of 50 volunteers with documented COVID-19 but without LHC will be enrolled to better understand the risk factors for LHC and autonomic dysfunction. Those in the cohort who meet diagnostic criteria for POTS or IST will be included in a nested prospective, randomized, placebo-controlled trial to assess the impact of ivabradine on symptoms and heart rate, assessed non-invasively based on physiologic response and ambulatory electrocardiogram. Additionally, studies on catecholamine production, mast cell and basophil degranulation, inflammatory biomarkers, and indicators of metabolic dysfunction will be measured to potentially provide molecular classification and mechanistic insights.DiscussionOptimal therapies for dysautonomia, particularly associated with LHC, have yet to be defined. In the present study, ivabradine, one of numerous proposed interventions, will be systematically evaluated for therapeutic potential in LHC-associated POTS and IST. Additionally, this study will further refine the characteristics of the LHC-associated POTS/IST phenotype, genotype and transcriptional profile, including immunologic and multi-omic analysis of persistent immune activation and dysregulation. The study will also explore and identify potential endotheliopathy and abnormalities of the clotting cascade.Clinical trial registrationhttps://clinicaltrials.gov/, identifier NCT05481177.https://www.frontiersin.org/articles/10.3389/fneur.2025.1550636/fullsevere acute respiratory syndrome coronavirus 2long-haul COVID-19postural orthostatic tachycardia syndromeivabradine (Procoralan)clinical trial |
| spellingShingle | David Saunders Thomas B. Arnold Thomas B. Arnold Thomas B. Arnold Jason M. Lavender Jason M. Lavender Jason M. Lavender Daoqin Bi Daoqin Bi Daoqin Bi Karl Alcover Lydia D. Hellwig Lydia D. Hellwig Lydia D. Hellwig Sahar T. Leazer Sahar T. Leazer Sahar T. Leazer Roshila Mohammed Roshila Mohammed Roshila Mohammed Bethelhem Markos Bethelhem Markos Bethelhem Markos Kanchana Perera Kanchana Perera Kanchana Perera Dutchabong Shaw Dutchabong Shaw Priscilla Kobi Priscilla Kobi Martin Evans Autumn Mains Autumn Mains Autumn Mains Marian Tanofsky-Kraff Marian Tanofsky-Kraff Emilie Goguet Emilie Goguet Edward Mitre Kathleen P. Pratt Clifton L. Dalgard Clifton L. Dalgard Mark C. Haigney Mark C. Haigney Comparative cohort study of post-acute COVID-19 infection with a nested, randomized controlled trial of ivabradine for those with postural orthostatic tachycardia syndrome (the COVIVA study) Frontiers in Neurology severe acute respiratory syndrome coronavirus 2 long-haul COVID-19 postural orthostatic tachycardia syndrome ivabradine (Procoralan) clinical trial |
| title | Comparative cohort study of post-acute COVID-19 infection with a nested, randomized controlled trial of ivabradine for those with postural orthostatic tachycardia syndrome (the COVIVA study) |
| title_full | Comparative cohort study of post-acute COVID-19 infection with a nested, randomized controlled trial of ivabradine for those with postural orthostatic tachycardia syndrome (the COVIVA study) |
| title_fullStr | Comparative cohort study of post-acute COVID-19 infection with a nested, randomized controlled trial of ivabradine for those with postural orthostatic tachycardia syndrome (the COVIVA study) |
| title_full_unstemmed | Comparative cohort study of post-acute COVID-19 infection with a nested, randomized controlled trial of ivabradine for those with postural orthostatic tachycardia syndrome (the COVIVA study) |
| title_short | Comparative cohort study of post-acute COVID-19 infection with a nested, randomized controlled trial of ivabradine for those with postural orthostatic tachycardia syndrome (the COVIVA study) |
| title_sort | comparative cohort study of post acute covid 19 infection with a nested randomized controlled trial of ivabradine for those with postural orthostatic tachycardia syndrome the coviva study |
| topic | severe acute respiratory syndrome coronavirus 2 long-haul COVID-19 postural orthostatic tachycardia syndrome ivabradine (Procoralan) clinical trial |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2025.1550636/full |
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