Cardiac conduction diseases: understanding the molecular mechanisms to uncover targets for future treatments

ABSTRACT

Introduction

The cardiac conduction system (CCS) is crucial for maintaining adequate cardiac frequency at rest and modulation during exercise. Furthermore, the atrioventricular node and His-Purkinje system are essential for maintaining atrioventricular and interventricular synchrony and consequently maintaining an adequate cardiac output.

Areas covered

In this review article, we examine the anatomy, physiology, and pathophysiology of the CCS. We then discuss in detail the most common genetic mutations and the molecular mechanisms of cardiac conduction disease (CCD) and provide our perspectives on future research and therapeutic opportunities in this field.

Expert opinion

Significant advancement has been made in understanding the molecular mechanisms of CCD, including the recognition of the heterogeneous signaling at the subcellular levels of sinoatrial node, the involvement of inflammatory and autoimmune mechanisms, and the potential impact of epigenetic regulations on CCD. However, the current treatment of CCD manifested as bradycardia still relies primarily on cardiovascular implantable electronic devices (CIEDs). On the other hand, an I_f specific inhibitor was developed to treat inappropriate sinus tachycardia and sinus tachycardia in heart failure patients with reduced ejection fraction. More work is needed to translate current knowledge into pharmacologic or genetic interventions for the management of CCDs.

KEYWORDS:

• Cardiac conduction disease
• pacemaker
• sinoatrial node
• atrioventricular node
• his-purkinje system

Article highlights

• The microstructure of the conduction system, including the sinoatrial node, atrioventricular node, and the His-Purkinje system, has been characterized using high resolution imaging.

• Sinus node dysfunction may be due to genetic (e.g. mutations affecting ion channels or their associated proteins involved in the ‘M clock’ or the ‘Ca²⁺ clock’) and epigenetic (e.g. non-coding microRNAs) factors, autoimmunity (e.g. Anti-Ro/SSA autoantibodies) or fibrosis.

• Ivabradine, a HCN channel inhibitor, has emerged as an effective treatment for inappropriate sinus tachycardia.

• Atrioventricular block may be due to genetic and epigenetic factors, and autoimmunity.

• Inflammatory cytokines (e.g. TNF-α, IL-1, IL-6 and IL-17) may play a role in certain types of AVN disease.

• Sodium channels and connexins have been linked to His-Purkinje disease.

• Pacemakers remain the mainstay for the treatment of symptomatic bradycardias albeit biological pacemakers show promise. Biventricular pacing and conduction system pacing are effective treatments in patients with left ventricular dyssynchrony due to intra- and infrahisian conduction system disease.

Declaration of interest

MG Chelu received research funding from Impulse Dynamics and Abbott and modest speaking honoraria from Impulse Dynamics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Tingting Li received Heart Rhythm Society Research Fellowship. N Li received funding from National Institute of Health (R01HL136389, R01HL163277, R01HL164838) and American Heart Association (936111). M Chelu received funding from Patient-Centered Outcomes Research Institute (PLACER 2021C3- 24160).