New insights into the basics of arrhythmias

Irene Savelieva and John Camm
Irene Savelieva and John Camm

By Irene Savelieva and John Camm

This year Cardiostim included a session “New Insights in Basics of Arrhythmias”, which discussed the novel concepts in arrhythmia mechanisms and their potential implications in the clinical arena. According to Isabelle van Gelder of the University of Groningen, the Netherlands, who spoke about clinical evidence and possible therapies at the session at Cardiostim, better understanding of the mechanisms behind arrhythmias will result in target-specific therapy at an earlier stage, more efficient deterrence of atrial fibrillation (AF) progression, and ultimately, primary prevention of AF.

Assiduous and unrelenting research into specific mechanisms of AF over the past two decades has substantially advanced our knowledge of electrical and structural alterations linked to the arrhythmia and identified new molecular mechanisms. However, multiple gaps exist between experimental evidence and clinical manifestations of AF, and the role of these mechanisms as potential therapeutic targets is not well characterised. Furthermore, while the association of AF with ageing and several clinical conditions, such as hypertension and diabetes, has been firmly established, we only partially understand the mechanisms underlying these relations.

AF is no longer regarded as simply multiple-circuit re-entry but as a sequence of hierarchical and organised mechanisms. The presence in the left atrium of areas with high-frequency driver activity, often arising from afterdepolarisation-induced triggered activity, is an essential component in the initiation of AF. The L-type Ca2+ current is one of the main depolarising currents in the atria. It is down-regulated during AF leading to shortening of the action potential.

During AF, a larger increase in intracellular Na+ relative to Ca2+ may cause the bidirectional Na+/Ca2+-exchanger to work in the reverse mode, bringing Ca2+ into the cell and further shorten the action potential.

Altered Ca2+ handling and Ca2+-sensitive signalling systems, as discussed by Antonio Zaza, the University of Milano-Bicocca, Italy, is a key element in promoting triggered activity either by facilitating delayed afterdepolarisations (DADs) that result from diastolic Ca2+ release, leading to an increase in inward current through the Na+/Ca2+-exchanger, or by causing early after depolarisations due to Ca2+ current reactivation during prolonged action potentials.

It has recently been established that abnormality in the ryanodine receptors (RyR2) or regulatory proteins and enzymes, leading to Ca2+ leak from the sarcoplasmic reticulum and afterdepolarisations, is linked to a specific type of ventricular tachyarrhythmia-catecholaminergic polymorphic ventricular tachycardia-as well as arrhythmogenic activity in pulmonary vein cardiomyocytes. Intrinsic instability of RyR2 receptors is a major determinant of diastolic Ca2+ leak and the susceptibility to DADs leading to triggered activity and AF, but AF per se further promotes abnormal Ca2+ handling, eg, by increasing CaMKII activity secondary to fast atrial rates, or by reducing the expression of accessory proteins (eg, FKBP12.6) involved in the regulation of RyR2 activity.

Cytosolic Ca2+ is a determinant of activity of several currents (such as acetylcholine-regulated potassium current and a recently identified small conductance Ca2+-activated potassium current) that are expressed in the atria and are involved in the pathogenesis of AF. Ca2+ activates calpain I and II proteases and plays a role in structural remodelling (eg, myofilament degeneration and activation of fibroblasts), leading to contractile dysfunction. Agents that oppose Ca2+ leak by modulating RyR2 receptors or the Na+/Ca2+-exchanger are under investigation.

Oxidative stress is a mediator for several cellular signalling systems that promote local and systemic inflammatory responses, fibroblast proliferation, reactive fibrosis and hypertrophy, and gap junctional uncoupling. Oxidative injury causes impairment of vital electron transport in mitochondria leading to increased production of reactive oxygen species, such as superoxide anion, and decreased ATP synthesis, which, in turn, can alter activity of multiple ion channels, Ca2+ handling, and contractile proteins. Understanding the mechanisms by which mitochondrial dysfunction predisposes to arrhythmias may open potential targets for antiarrhythmic therapy-for example, modulating mitochondrial Ca2+ transport, mitochondrial ATP-sensitive K+ current, inner membrane anion channels, and improving the redox status with mitochondria-targeted anti-oxidant peptides. Targeting these pathways has proven effective in experiments (eg, in ischaemia/perfusion ventricular arrhythmias). Several agents targeting inflammation and oxidative injury (eg, antioxidant vitamins, corticosteroids, statins, and polyunsaturated fatty acids) have been investigated, with some success, as novel therapeutic strategies for AF.

Alteration in gap junction physiology is another important constituent of arrhythmogenesis. Remodelling of gap junctions associated with a decrease in the expression and/or redistribution of connexins lead to impaired intercellular communication and reduced conductance between cardiomyocytes and has been linked to ventricular arrhythmias and AF. Gap junction modifiers rotigaptide and GAP-134, developed specifically for AF, have been shown to alleviate metabolic stress-induced changes in conduction, but no their efficacy in humans has not been reported.

Dr Ulrich Schotten of Masstricht University, The Netherlands, recapitulated the existing evidence by describing four positive-feedback loops (involving triggers, electrical, structural, and hemodynamic mechanisms) as the major determinant for atrial remodelling in AF, emphasising the dynamic and diverse nature of this process. Despite the diversity of contributors, the loops are interconnected by mechanisms (nodes) that are part of more than one loop.

Basic research continues to deliver more information and new hypotheses relevant to the development of successful primary and secondary prevention of cardiac arrhythmias.

Both John Camm and Irene Savelina at a Division of Cardiovascular Sciences
St George’s University of London, London, UK.