Targeting pathological leak of ryanodine receptors: preclinical progress and the potential impact on treatments for cardiac arrhythmias and heart failure

ABSTRACT

Introduction: Type-2 ryanodine receptor (RyR2) located on the sarcoplasmic reticulum initiate systolic Ca²⁺ transients within cardiomyocytes. Proper functioning of RyR2 is therefore crucial to the timing and force generated by cardiomyocytes within a healthy heart. Improper intracellular Ca²⁺ handing secondary to RyR2 dysfunction is associated with a variety of cardiac pathologies including catecholaminergic polymorphic ventricular tachycardia (CPVT), atrial fibrillation (AF), and heart failure (HF). Thus, RyR2 and its associated accessory proteins provide promising drug targets to scientists developing therapeutics for a variety of cardiac pathologies.

Areas covered: In this article, we review the role of RyR2 in a variety of cardiac pathologies. We performed a literature search utilizing PubMed and MEDLINE as well as reviewed registries of trials from clinicaltrials.gov from 2010 to 2019 for novel therapeutic approaches that address the cellular mechanisms underlying CPVT, AF, and HF by specifically targeting defective RyR2 channels.

Expert opinion: The negative impact of cardiac dysfunction on human health and medical economics are major motivating factors for establishing new and effective therapeutic approaches. Focusing on directly impacting the molecular mechanisms underlying defective Ca²⁺ handling by RyR2 in HF and arrhythmia has great potential to be translated into novel and innovative therapies.

KEYWORDS:

• Arrhythmia
• atrial fibrillation
• calcium handing
• catecholaminergic polymorphic ventricular tachycardia
• heart failure
• ryanodine receptor

Article Highlights

• The type-2 ryanodine receptor plays a key role in excitation-contraction coupling in cardiomyocytes

• Inherited mutations or acquired defects in RyR2 and its regulatory subunits promote diastolic Ca²⁺ leak from the sarcoplasmic reticulum

• Pathogenic SR Ca²⁺ leak can promote 1) delayed afterdepolarizations resulting in arrhythmias and 2) depletion of the SR Ca²⁺ content leading to impaired contractility associated with heart failure

• Several FDA approved anti-arrhythmic drugs including flecainide, propafenone and dantrolene suppress pathogenic, diastolic RyR2 openings associated with heart disease but they also inhibit other ion channels

• Various new RyR2-modulating drugs are in preclinical development, and normalize RyR2 channel activity via distinct molecular mechanisms.

This box summarizes key points contained in the article.

Declaration of interest

XHT Wehrens is a founding partner of Elex Biotech, a start-up company that developed drug molecules that target RyRs for the treatment of cardiac arrhythmia disorders. 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 relationships or otherwise to disclose.

Additional information

Funding

The authors are supported by NIH grants 1T32 HL139430-01A1 (TA Word), and R01-HL089598, R01-HL091947, R01-HL117641 (XHT Wehrens).