Beat to beat Ca2+-dependent regulation of pacemaker cell rate and rhythm

起搏细胞速率和节律的逐搏 Ca2 依赖性调节

基本信息

批准号：
10913120
负责人：
Edward Lakatta
金额：
$ 41.66万
依托单位：
NATIONAL INSTITUTE ON AGING
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

项目摘要

Failure of generation of automaticity and conduction of electrical activity within the heart becomes progressively more common as we age and is associated with a variety of cardiovascular and non-cardiovascular diseases. A major barrier to progress in the pacemaker field is a dearth of research in human hearts although the mouse has a resting heart rate of around 750 beats per minute while human resting heart rate is around 75. LCS Scientists built a team who are on call 24 hours/day, 7 days/week to respond with a regular supply of fresh human hearts from brain-dead donors. Similar to animals, a Ca2+ clock couples to a membrane clock to drive normal automaticity in single isolated human cardiac pacemaker cells. Clock uncoupling in human pacemaker cells as a putative mechanism of sinus node arrest, the endgame of human heart. These discoveries not only generalize the coupled-clock system paradigm from mice to humans but also led us to view clock coupling as a novel therapeutic target to develop a biological pacemaker. This cell-based therapy has a potential to reduce the necessity of conventional electrical pacemaker device implantation, which costs $24B annually in the USA alone. Recently we discovered a long-range power law correlation between periodicity of cardiac pacemaker cell clocks, heart rate and body mass: from mice to humans. Specifically, integrated local Ca2+ releases of Ca2+ clock during action potential (AP) ignition in single SAN cells, isolated from diverse species (ranged from mouse to humans) not only scales linearly to the diverse range of AP cycles across species in these cells, but also to EKG RR intervals in vivo, and furthermore scales allometrically to the broad range of body masses across species. Such power law behavior is a manifestation of trans-species, self-ordered criticality of pacemaker cell molecular functions that regulate HR In other terms, in designing appropriate hear rates to match body masses and energy requirements of different species from mouse to humans, nature did not re-invent the wheels but differentially scaled the gear kinetics that determine the rate at which the wheels spin.

随着年龄的增长，心脏内电活动的自动生成和传导失败变得越来越常见，并且与多种心血管和非心血管疾病相关。起搏器领域取得进展的一个主要障碍是缺乏对人类心脏的研究，尽管小鼠的静息心率约为每分钟 750 次，而人类的静息心率约为 75 次。LCS 科学家建立了一个 24 小时待命的团队每周 7 天、每天数小时，定期供应来自脑死亡捐献者的新鲜人类心脏。与动物类似，Ca2+时钟与膜时钟耦合，驱动单个分离的人类心脏起搏细胞的正常自动性。人类起搏细胞中的时钟解偶联是窦房结停搏（人类心脏的最后阶段）的假定机制。这些发现不仅将耦合时钟系统范式从小鼠推广到人类，而且使我们将时钟耦合视为开发生物起搏器的新治疗目标。这种基于细胞的疗法有可能减少传统电子起搏器植入的必要性，仅在美国每年的费用就高达 24B 美元。最近我们发现心脏起搏细胞的周期性之间存在长程幂律相关性时钟、心率和体重：从老鼠到人类。具体来说，整合局部 Ca2+ 在单个 SAN 细胞的动作电位 (AP) 点火过程中释放 Ca2+ 时钟，与不同的物种（从小鼠到人类）不仅线性地缩放到不同的范围 AP 在这些细胞中跨物种循环，而且还与体内 EKG RR 间隔相关，此外异速生长地适应不同物种的广泛体重范围。这种幂律行为是调节 HR 的起搏细胞分子功能的跨物种、自序临界性的表现换句话说，在设计适当的心率以匹配从老鼠到人类的不同物种的体重和能量需求时，大自然并没有重新发明轮子，而是对决定轮子旋转速度的齿轮动力学进行了差异化调整。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

cAMP-Dependent Signaling Restores AP Firing in Dormant SA Node Cells via Enhancement of Surface Membrane Currents and Calcium Coupling.

DOI：
10.3389/fphys.2021.596832
发表时间：
2021
期刊：
Frontiers in physiology
影响因子：
4
作者：
Tsutsui K;Florio MC;Yang A;Wirth AN;Yang D;Kim MS;Ziman BD;Bychkov R;Monfredi OJ;Maltsev VA;Lakatta EG
通讯作者：
Lakatta EG

Potential effects of intrinsic heart pacemaker cell mechanisms on dysrhythmic cardiac action potential firing.

内在心脏起搏器细胞机制对心律失常心脏动作电位放电的潜在影响。