The formation and function of the cardiac conduction system

Weerd, Jan Hendrik van; Christoffels, Vincent M.

doi:10.1242/dev.124883

Cited by 182 publications

(187 citation statements)

References 168 publications

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“…Re-expression of transcription factors such as SHOX2 and TBX18 in postnatal mouse ventricular cardiomyocytes has been used to transform chamber cardiomyocytes into pacemaker cells that possess all the main characteristics of SAN cells 10,12 ; this finding is the basis for a strategy to create biological pacemakers, as discussed below. By the time looping occurs at E9.5, the conduction system activation pattern in the heart tube follows that of the adult heart 9,13 .…”

Section: Cardiac Conduction Systemmentioning

confidence: 94%

“…A series of transcription factors including insulin gene enhancer protein ISL1, short stature homeobox protein 2 (SHOX2), and the T-box transcription factors TBX3 and TBX5 activate the SAN gene programme in the sinus venosus (FIG. 1c), whereas NKX2.5, TBX3, and TBX18 repress the chamber myocyte gene programme in the sinus venosus, the AV canal, and the inner curvature, thereby allowing pacemaking cells to dominate in these regions 9 . Re-expression of transcription factors such as SHOX2 and TBX18 in postnatal mouse ventricular cardiomyocytes has been used to transform chamber cardiomyocytes into pacemaker cells that possess all the main characteristics of SAN cells 10,12 ; this finding is the basis for a strategy to create biological pacemakers, as discussed below.…”

Section: Cardiac Conduction Systemmentioning

confidence: 99%

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Next-generation pacemakers: from small devices to biological pacemakers

2017

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Electrogenesis in the heart begins in the sinoatrial node and proceeds down the conduction system to originate the heartbeat. Conduction system disorders lead to slow heart rates that are insufficient to support the circulation, necessitating implantation of electronic pacemakers. The typical electronic pacemaker consists of a subcutaneous generator and battery module attached to one or more endocardial leads. New leadless pacemakers can be implanted directly into the right ventricular apex, providing single-chamber pacing without a subcutaneous generator. Modern pacemakers are generally reliable, and their programmability provides options for different pacing modes tailored to specific clinical needs. Advances in device technology will probably include alternative energy sources and dual-chamber leadless pacing in the not-too-distant future. Although effective, current electronic devices have limitations related to lead or generator malfunction, lack of autonomic responsiveness, undesirable interactions with strong magnetic fields, and device-related infections. Biological pacemakers, generated by somatic gene transfer, cell fusion, or cell transplantation, provide an alternative to electronic devices. Somatic reprogramming strategies, which involve transfer of genes encoding transcription factors to transform working myocardium into a surrogate sinoatrial node, are furthest along in the translational pipeline. Even as electronic pacemakers become smaller and less invasive, biological pacemakers might expand the therapeutic armamentarium for conduction system disorders.

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Section: Cardiac Conduction Systemmentioning

confidence: 94%

Section: Cardiac Conduction Systemmentioning

confidence: 99%

Next-generation pacemakers: from small devices to biological pacemakers

2017

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“…The findings specifically implicate an origin from cells expressing CSPG4, likely the CCS, which are also known to express desmosome proteins and hence, are expected to be affected in human ACM. 24, 25 Accordingly, deletion of the Dsp gene, specifically in the CSPG4 pos cells, which also tags the CCS in the heart, in addition to the capillary mural and neuroglial cells, leads to spontaneous atrial and ventricular arrhythmias and premature mortality. 22, 23 Notably, these arrhythmias occur in the presence of a normal cardiac function and absence of fibro-adiposis.…”

Section: Discussionmentioning

confidence: 99%

“…22, 23 The CCS, sharing an embryonic origin with cardiac myocytes, also expresses desmosome proteins. 24, 25 CSPG4 is also expressed in the keratinocytes and hair follicle cells, which are known to express DSP 26, 27 . Therefore, CSPG4, along with desmosome proteins, might serve as a shared molecular link between early cardiac arrhythmias and the skin phenotype in the cardiocutaneous syndromes.…”

Section: Introductionmentioning

confidence: 99%

Distinct Cellular Basis for Early Cardiac Arrhythmias, the Cardinal Manifestation of Arrhythmogenic Cardiomyopathy, and the Skin Phenotype of Cardiocutaneous Syndromes

et al. 2017

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Rationale Arrhythmogenic cardiomyopathy (ACM) is caused primarily by mutations in genes encoding desmosome proteins. Ventricular arrhythmias are the cardinal and typically early manifestations, whereas myocardial fibroadiposis is the pathological hallmark. Homozygous DSP (desmoplakin) and JUP (plakoglobin) mutations are responsible for a subset of ACM patients that exhibit cardiac arrhythmias and dysfunction, palmo-planter keratosis, and hair abnormalities (cardiocutaneous syndromes). Objective To determine phenotypic consequences of deletion of Dsp in a subset of cells common to the heart and skin. Methods and Results Expression of chondroitin sulfate proteoglycan 4 (CSPG4) was detected in epidermal keratinocytes and the cardiac conduction system (CCS). CSPG4pos cells constituted ~ 5.6±3.3% of the non-myocyte cells in the mouse heart. Inducible post-natal deletion of Dsp under the transcriptional control of the Cspg4 locus led to ventricular arrhythmias, atrial fibrillation, atrioventricular conduction defects, and death by 4 months of age. Cardiac arrhythmias occurred early and in the absence of cardiac dysfunction and excess cardiac fibro-adipocytes, as in human ACM. The mice exhibited palmo-plantar keratosis and progressive alopecia, leading to alopecia totalis, associated with accelerated proliferation and impaired terminal differentiation of keratinocytes. The phenotype is similar to human cardiocutaneous syndromes caused by homozygous mutations in DSP. Conclusions Deletion of Dsp under the transcriptional regulation of the CSPG4 locus led to lethal cardiac arrhythmias in the absence of cardiac dysfunction or fibroadiposis, palmoplantar keratosis, and alopecia, resembling the human cardiocutaneous syndromes. The findings offer a cellular basis for early cardiac arrhythmias in ACM patients and cardiocutaneous syndromes.

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“…The newly recruited cardiac myocytes at the venous pole are acting as dominant pacemaker [15]. During heart looping, regions at the outer curvature of the heart tube start to proliferate and acquire a chamber-specific gene expression program, which includes high conductance type connexins (Cx40 and Cx43) and the sodium channel SCN5A [16].…”

mentioning

confidence: 99%

Tbx18 and the generation of a biological pacemaker. Are we there yet?

Brand

2016

Journal of Molecular and Cellular Cardiology

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A group of approximately 10,000 cells in the sinoatrial node (SAN), which is located at the entry of the right superior caval vein into the right atrium, is responsible for regular heart beating under different physiological conditions [1]. While the SAN is reliably working for most of our life, in the elderly, sick sinus syndrome (SSS), or sinus node dysfunction (SND) is prevalent [2] and responsible for 30 to 50% of all electronic pacemaker implantations [3]. Moreover, SSS is also often associated with the development of atrial fibrillation [4]

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The formation and function of the cardiac conduction system

Cited by 182 publications

References 168 publications

Next-generation pacemakers: from small devices to biological pacemakers

Next-generation pacemakers: from small devices to biological pacemakers

Distinct Cellular Basis for Early Cardiac Arrhythmias, the Cardinal Manifestation of Arrhythmogenic Cardiomyopathy, and the Skin Phenotype of Cardiocutaneous Syndromes

Tbx18 and the generation of a biological pacemaker. Are we there yet?

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