Saunders David, Arnold Thomas B, Lavender Jason M, Bi Daoqin, Alcover Karl, Hellwig Lydia D, Leazer Sahar T, Mohammed Roshila, Markos Bethelhem, Perera Kanchana, Shaw Dutchabong, Kobi Priscilla, Evans Martin, Mains Autumn, Tanofsky-Kraff Marian, Goguet Emilie, Mitre Edward, Pratt Kathleen P, Dalgard Clifton L, Haigney Mark C
Uniformed Services University School of Medicine, Bethesda, MD, United States.
The Metis Foundation, San Antonio, TX, United States.
Front Neurol. 2025 Jul 7;16:1550636. doi: 10.3389/fneur.2025.1550636. eCollection 2025.
BACKGROUND: Significant 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/DESIGN: A 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. DISCUSSION: Optimal 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 REGISTRATION: https://clinicaltrials.gov/, identifier NCT05481177.
背景：最近描述的“长期”新冠综合征（LHC）、体位性心动过速综合征（POTS）和不适当窦性心动过速（IST）之间存在显著的临床相似性。共同症状包括头晕、心悸、震颤、全身无力、视力模糊、胸痛、呼吸困难、“脑雾”和疲劳。伊伐布雷定是一种选择性窦房结阻滞剂，已获美国食品药品监督管理局（FDA）批准，用于治疗与稳定型心绞痛和β受体阻滞剂未能充分控制的心力衰竭相关的心动过速。在我们的研究中，我们旨在确定LHC的潜在风险因素，以及伊伐布雷定在控制心率失调和POTS/IST相关症状方面的有效性。 方法/设计：将对200名LHC志愿者进行详细的前瞻性表型评估，并结合多组学分析，以确定自主神经功能障碍的风险因素。将招募一个由50名有新冠病毒感染记录但无LHC的志愿者组成的对照组，以更好地了解LHC和自主神经功能障碍的风险因素。队列中符合POTS或IST诊断标准的患者将被纳入一项嵌套的前瞻性、随机、安慰剂对照试验，以评估伊伐布雷定对症状和心率的影响，基于生理反应和动态心电图进行非侵入性评估。此外，还将对儿茶酚胺生成、肥大细胞和嗜碱性粒细胞脱颗粒、炎症生物标志物以及代谢功能障碍指标进行研究，以潜在地提供分子分类和机制见解。 讨论：自主神经功能障碍的最佳治疗方法，尤其是与LHC相关的治疗方法，尚未确定。在本研究中，伊伐布雷定作为众多提议的干预措施之一，将被系统评估其在LHC相关的POTS和IST中的治疗潜力。此外，本研究将进一步完善LHC相关的POTS/IST表型、基因型和转录谱的特征，包括对持续免疫激活和失调的免疫及多组学分析。该研究还将探索和确定潜在的内皮病变和凝血级联异常。 临床试验注册：https://clinicaltrials.gov/，标识符NCT05481177。
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