Mechanisms of Sinoatrial Node Dysfunction in Heart Failure With Preserved Ejection Fraction.
Mechanisms of Sinoatrial Node Dysfunction in Heart Failure With Preserved Ejection Fraction.
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DOI：
10.1161/circulationaha.121.054976
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发表时间：
2022-01-04
期刊：
影响因子：
37.8
通讯作者：
Cingolani, Eugenio
中科院分区：
文献类型：
--
作者：
Mesquita, Thassio;Zhang, Rui;Cho, Jae Hyung;Zhang, Rui;Lin, Yen-Nien;Sanchez, Lizbeth;Goldhaber, Joshua, I;Yu, Joseph K.;Liang, Jialiu A.;Liu, Weixin;Trayanova, Natalia A.;Cingolani, Eugenio
在运动和其他应激源期间增加心率（HR）的能力是窦房结（SAN）的关键稳态特征。当生理HR反应迟钝时，变时性功能不全限制了运动能力，这是心力衰竭（HF）和射血分数保留（HFpEF）患者的常见问题。尽管其临床意义，变时性功能不全的机制仍然未知。以高盐饮食喂养的Dahl盐敏感大鼠和高脂和组成型一氧化氮合酶抑制剂（L-NAME，2-hit）喂养的C57 B16小鼠作为HFpEF的模型。建立心肌梗死以诱导HF伴射血分数降低（HFrEF）。以正常饮食喂养或进行假手术的大鼠和小鼠作为各自的对照。通过体内、离体和单细胞电生理学研究对SAN功能和变时性反应进行了全面表征。进行SAN的RNA测序以鉴定转录组学变化。创建了生物病理学详细的人类HFpEF SAN的计算建模。具有表型验证的HFpEF的大鼠表现出与内在SAN功能障碍相关的有限变时性反应，包括受损的β-肾上腺素能反应和SAN内的交替领先起搏器。在2次打击小鼠模型中证实了延长的SAN恢复时间和降低的SAN对异丙肾上腺素的敏感性。腺苷激发暴露了SAN内与结构重塑相关的传导阻滞。HFrEF大鼠也出现变时性功能不全和SAN功能障碍。单细胞研究和转录组学分析揭示了HFpEF相关的“膜时钟”（离子通道）和“Ca 2+时钟”（自发Ca 2+释放事件）的改变。通过对人类SAN功能进行经验约束的定量建模，在计算机中再现了生理损伤。因此，在两种HF模型中均观察到变时性功能不全和SAN功能障碍。我们发现，固有的SAN结构和功能异常的基础HFpEF的变时性反应。
The ability to increase heart rate (HR) during exercise and other stressors is a key homeostatic feature of the sinoatrial node (SAN). When the physiologic HR response is blunted, chronotropic incompetence limits exercise capacity, a common problem in patients with heart failure (HF) and preserved ejection fraction (HFpEF). Despite its clinical relevance, the mechanisms of chronotropic incompetence remain unknown. Dahl salt-sensitive rats fed with a high-salt diet and C57Bl6 mice fed with high fat and an inhibitor of constitutive nitric oxide synthase (L-NAME, 2-hit) were used as models of HFpEF. Myocardial infarction was created to induce HF with reduced ejection fraction (HFrEF). Rats and mice fed with a normal diet or having a sham surgery served as respective controls. A comprehensive characterization of SAN function and chronotropic response was conducted by in vivo, ex vivo, and single-cell electrophysiological studies. RNA sequencing of SAN was performed to identify transcriptomic changes. Computational modeling of biophysically-detailed human HFpEF SAN was created. Rats with phenotypically-verified HFpEF exhibited limited chronotropic response associated with intrinsic SAN dysfunction, including impaired β-adrenergic responsiveness and an alternating leading pacemaker within the SAN. Prolonged SAN recovery time and reduced SAN sensitivity to isoproterenol were confirmed in the 2-hit mouse model. Adenosine challenge unmasked conduction blocks within the SAN, which were associated with structural remodeling. Chronotropic incompetence and SAN dysfunction were also found in HFrEF rats. Single-cell studies and transcriptomic profiling revealed HFpEF-related alterations in both the “membrane clock” (ion channels) and the “Ca2+ clock” (spontaneous Ca2+ release events). The physiological impairments were reproduced in silico by empirically-constrained quantitative modeling of human SAN function. Thus, chronotropic incompetence and SAN dysfunction were seen in both models of HF. We identified that intrinsic abnormalities of SAN structure and function underlie the chronotropic response in HFpEF.
影响因子：
4
作者：
Verkerk AO;van Borren MM;van Ginneken AC;Wilders R
通讯作者：
Wilders R