Conversion of Unmodified Stem Cells to Pacemaker Cells by Overexpression of Key Developmental Genes

Karimi, Tahereh; Pan, Zhizhong Z.; Potaman, Vladimir N.; Alt, Eckhard

doi:10.3390/cells12101381

Cited by 4 publications

(1 citation statement)

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“…Given the limited treatment options available, different strategies have been used to develop biological pacemakers that could potentially replace the electronic devices currently used for the treatment of SND and other arrhythmias. For reviews and the most recent progress, please refer to references [288][289][290][291][292] . In line with the focus of this review, it is worth mentioning that many of the approaches used to generate a biological pacemaker involve HCN channels.…”

Section: Hcn Channels In Disease and Therapymentioning

confidence: 99%

Pacemaker Channels and the Chronotropic Response in Health and Disease

Hennis,

Piantoni,

Biel

et al. 2024

Circulation Research

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Loss or dysregulation of the normally precise control of heart rate via the autonomic nervous system plays a critical role during the development and progression of cardiovascular disease—including ischemic heart disease, heart failure, and arrhythmias. While the clinical significance of regulating changes in heart rate, known as the chronotropic effect, is undeniable, the mechanisms controlling these changes remain not fully understood. Heart rate acceleration and deceleration are mediated by increasing or decreasing the spontaneous firing rate of pacemaker cells in the sinoatrial node. During the transition from rest to activity, sympathetic neurons stimulate these cells by activating β-adrenergic receptors and increasing intracellular cyclic adenosine monophosphate. The same signal transduction pathway is targeted by positive chronotropic drugs such as norepinephrine and dobutamine, which are used in the treatment of cardiogenic shock and severe heart failure. The cyclic adenosine monophosphate–sensitive hyperpolarization–activated current (I f ) in pacemaker cells is passed by hyperpolarization-activated cyclic nucleotide-gated cation channels and is critical for generating the autonomous heartbeat. In addition, this current has been suggested to play a central role in the chronotropic effect. Recent studies demonstrate that cyclic adenosine monophosphate–dependent regulation of HCN4 (hyperpolarization-activated cyclic nucleotide-gated cation channel isoform 4) acts to stabilize the heart rate, particularly during rapid rate transitions induced by the autonomic nervous system. The mechanism is based on creating a balance between firing and recently discovered nonfiring pacemaker cells in the sinoatrial node. In this way, hyperpolarization-activated cyclic nucleotide-gated cation channels may protect the heart from sinoatrial node dysfunction, secondary arrhythmia of the atria, and potentially fatal tachyarrhythmia of the ventricles. Here, we review the latest findings on sinoatrial node automaticity and discuss the physiological and pathophysiological role of HCN pacemaker channels in the chronotropic response and beyond.

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