Insights into cardiac conduction system formation provided by HCN4 expression

Abstract

Specialized myocytes of the cardiac conduction system (CCS) are essential to coordinate sequential contraction of cardiac atria and ventricles. Anomalies of the CCS can result in lethal cardiac arrhythmias, including sick sinus syndrome, and atrial or ventricular fibrillation. To develop future therapies and regenerative medicine aimed at cardiac arrhythmias, it is important to understand formation and function of distinct components of the CCS. Essential to this understanding is the development of CCS specific markers. In this review, we briefly summarize available mouse models of CCS markers, and focus on those involving the hyperpolarization cation-selective nucleotide gated cation channel, HCN4, which selectively marks all components of the specialized CCS in adult heart. Recent studies have revealed, however, that HCN4 expression during development is highly dynamic in cardiac precursors. These studies have offered insights into the contributions of the first and second heart field to myocyte and conduction system lineages, and suggested the timing of allocation of specific conduction system precursors during development. Altogether, they have highlighted the utility of HCN4 as a cell surface marker for distinct components of the CCS at distinct stages of development, which can be utilized to facilitate purification and characterization of CCS precursors in mouse and human model systems and pave the way for regenerative therapies.

Comprehensive Analysis and Co-Expression Network of mRNAs and lncRNAs in Pressure Overload-Induced Heart Failure

“…Besides, lncRNA NONRATT027756 was predicted to trans-regulate HCN4 by means of miRNA sequestration. Hyperpolarization activated cyclic nucleotide gated potassium channel 4 (HCN4) shows slow kinetics of activation and inactivation, and is necessary in cardiac pacemaking and conduction processes (Liang et al, 2015;Verkerk and Wilders, 2015). Abnormalities of HCN4 may result in a variety of arrhythmias, such as atrial fibrillation, sick sinus syndrome (DiFrancesco, 2015;Ishikawa et al, 2017).…”

Pathology and Function of Conduction Tissue in Fabry Disease Cardiomyopathy

“…In this study, we report the histological examination of CT in 13 patients with FDCM, identified by Monckeberg and Aschoff morphological criteria and positive immunostaining for the molecular marker HCN4. 11 The relatively high prevalence of CT inclusion in endomiocardial biopsy specimens (17% of 74 subjects with FDCM) may be due to the biventricular approach with withdrawal of 8 to 10 fragments per patient. In addition, CT was mostly found in biopsies from the LV, a common site of investigation in our laboratory for patients with cardiomyopathies 12 allowing an easier approach of the interventricular septum where CT branches are expected to be more represented in comparison with cardiac apex, as well as RV and LV free wall.…”

Transcriptome analysis of mouse and human sinoatrial node cells reveals a conserved genetic program

“…This current may contribute to the diastolic depolarization phase of SAN cell action potentials (DiFrancesco, 2006;Verkerk et al, 2009), and is carried by the hyperpolarization-activated cyclicnucleotide gated (Hcn) gene family, of which Hcn4 is the most predominant isoform found in the SAN (Marionneau et al, 2005;Moosmang et al, 2001;Stieber et al, 2003). Owing to its virtual absence in the WM and its abundance in the SAN area, Hcn4 has become a potent marker for the mature SAN, although its expression in the mouse and human embryonic hearts, and during pathophysiological conditions, is much broader (Liang et al, 2015a;Mommersteeg et al, 2007;Nattel et al, 2008;Sizarov et al, 2011). Mutations in HCN4 in humans are associated with bradycardia (den Hoed et al, 2013;Milano et al, 2014;Verkerk and Wilders, 2015).…”