Design and rationale of a clinical trial to increase cardiomyocyte division in infants with tetralogy of Fallot.
Design and rationale of a clinical trial to increase cardiomyocyte division in infants with tetralogy of Fallot.
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DOI：
10.1016/j.ijcard.2021.07.020
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发表时间：
2021-09-15
影响因子：
3.5
通讯作者：
Kühn B
中科院分区：
文献类型：
--
作者：
El Khoudary SR;Fabio A;Yester JW;Steinhauser ML;Christopher AB;Gyngard F;Adams PS;Morell VO;Viegas M;Da Silva JP;Da Silva LF;Castro-Medina M;McCormick A;Reyes-Múgica M;Barlas M;Liu H;Thomas D;Ammanamanchi N;Sada R;Cuda M;Hartigan E;Groscost DK;Kühn B
法洛四联症伴肺动脉瓣狭窄 (ToF/PS) 患者是紫绀型先天性心脏病 (CHD) 的最常见形式，会出现不良的右心室 (RV) 重塑，导致晚期心力衰竭和心律失常。我们最近证明，过度活跃的 β 肾上腺素受体信号传导会抑制 ToF/PS 婴儿的心肌细胞分裂，这为生命早期使用 β 肾上腺素受体阻滞剂普萘洛尔治疗会增加心肌细胞分裂的假设提供了概念基础。尚无关于 ToF/PS 婴儿中普萘洛尔作为一种可能的新型治疗选择以增加心肌细胞分裂并可能减少不良 RV 重塑的功效的数据。通过一项随机、双盲、安慰剂对照试验，我们将评估 40 名 ToF/PS 婴儿服用普萘洛尔对重新激活心肌细胞增殖以预防不良 RV 重塑的效果。普萘洛尔给药（1 mg/kg po QID）将从 1 个月大时开始，一直持续到手术修复。主要终点是心肌细胞分裂，在给予 15N-胸苷后通过对切除的心肌样本进行多同位素成像质谱 (MIMS) 分析进行量化。第二个终点是右心室心肌和心肌细胞肥大的变化。该试验将是第一项在人体中评估是否可以通过药物来增加心肌细胞增殖的研究。如果成功的话，结果可能会导致 ToF/PS 患者的治疗方式从纯粹的手术方法转变为协同的医疗和手术治疗方法。它将为未来对患有 ToF/PS 和其他类型的伴有右心室高血压的先心病的婴儿进行普萘洛尔给药的多中心随机对照试验提供基础。试验方案已在 ClinicalTrials.gov 上注册 (NCT04713657)。
Patients with Tetralogy of Fallot with pulmonary stenosis (ToF/PS), the most common form of cyanotic congenital heart disease (CHD), develop adverse right ventricular (RV) remodeling, leading to late heart failure and arrhythmia. We recently demonstrated that overactive p-adrenergic receptor signaling inhibits cardiomyocyte division in ToF/PS infants, providing a conceptual basis for the hypothesis that treatment with the P-adrenergic receptor blocker, propranolol, early in life would increase cardiomyocyte division. No data are available in ToF/PS infants on the efficacy of propranolol as a possible novel therapeutic option to increase cardiomyocyte division and potentially reduce adverse RV remodeling. Using a randomized, double-blind, placebo-controlled trial, we will evaluate the effect of propranolol administration on reactivating cardiomyocyte proliferation to prevent adverse RV remodeling in 40 infants with ToF/PS. Propranolol administration (1 mg/kg po QID) will begin at 1 month of age and last until surgical repair. The primary endpoint is cardiomyocyte division, quantified after 15N-thymidine administration with Multi-isotope Imaging Mass Spectrometry (MIMS) analysis of resected myocardial specimens. The secondaty endpoints are changes in RV myocardial and cardiomyocyte hypertrophy. This trial will be the first study in humans to assess whether cardiomyocyte proliferation can be pharmacologically increased. If successful, the results could introduce a paradigm shift in the management of patients with ToF/PS from a purely surgical approach, to synergistic medical and surgical management. It will provide the basis for future multi-center randomized controlled trials of propranolol administration in infants with ToF/PS and other types of CHD with RV hypertension. The trial protocol was registered at clinicaltrials.gov (NCT04713657).
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DOI：
10.1007/978-1-0716-0668-1_15
发表时间：
2021
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Liu H;Bersell K;Kühn B
通讯作者：
Kühn B
影响因子：
64.5
作者：
Bersell, Kevin;Arab, Shima;Kuehn, Bernhard
通讯作者：
Kuehn, Bernhard
影响因子：
8
作者：
Guillermier, Christelle;Fazeli, Pouneh K.;Steinhauser, Matthew L.
通讯作者：
Steinhauser, Matthew L.
影响因子：
11.8
作者：
Han, Lu;Choudhury, Sangita;Kuhn, Bernhard
通讯作者：
Kuhn, Bernhard
DOI：
10.1186/1532-429x-15-51
发表时间：
2013-06-13
期刊：
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance
影响因子：
--
作者：
Fratz S;Chung T;Greil GF;Samyn MM;Taylor AM;Valsangiacomo Buechel ER;Yoo SJ;Powell AJ
通讯作者：
Powell AJ