Current Pharmaceutical Design - Volume 21, Issue 8, 2015

Adenosine is a ubiquitous, endogenous purine involved in a variety of physiological and pathophysiological regulatory mechanisms. Adenosine has been proposed as an endogenous antiarrhythmic substance to prevent hypoxia/ischemia-induced arrhythmias. Adenosine (and its precursor, ATP) has been used in the therapy of various cardiac arrhythmias over the past six decades. Its primary indication is treatment of paroxysmal supraventricular tachycardia, but it can be effective in other forms of supraventricular and ventricular arrhythmias, like sinus node reentry based tachycardia, triggered atrial tachycardia, atrioventricular nodal reentry tachycardia, or ventricular tachycardia based on a cAMP-mediated triggered activity. The main advantage is the rapid onset and the short half life (1- 10 sec). Adenosine exerts its antiarrhythmic actions by activation of A1 adenosine receptors located in the sinoatrial and atrioventricular nodes, as well as in activated ventricular myocardium. However, adenosine can also elicit A2A, A2B and A3; adenosine receptor-mediated global side reactions (flushing, dyspnea, chest discomfort), but it may display also proarrhythmic actions mediated by primarily A1 adenosine receptors (e.g. bradyarrhythmia or atrial fibrillation). To avoid the non-specific global adverse reactions, A1 adenosine receptor- selective full agonists (tecadenoson, selodenoson, trabodenoson) have been developed, which agents are currently under clinical trial. During long-term administration with orthosteric agonists, adenosine receptors can be internalized and desensitized. To avoid desensitization, proarrhythmic actions, or global adverse reactions, partial A1 adenosine receptor agonists, like CVT-2759, were developed. In addition, the pharmacologically “silent” site- and event specific adenosinergic drugs, such as adenosine regulating agents and allosteric modulators, might provide attractive opportunity to increase the effectiveness of beneficial actions of adenosine and avoid the adverse reactions.

Cardiac arrhythmias are a major cause of morbidity and mortality in the industrialized world. Among their treatment regimens one can find the calcium channel antagonists (CCAs), the class IV agents. In the cardiovascular system L- and T-type calcium channels are found on vascular smooth muscle cells and cardiac myocytes with well defined physiological roles. Inhibition of calcium channels by CCAs has widely been used in clinical practice for several decades. Cardiovascular disorders are one of the many fields of medicine in which CCAs are used for various reasons and conditions. The three main indications of them are hypertension, angina and various cardiac arrhythmias. The most important classes of CCAs are dihydropyridines, phenylalkylamines and benzothiazepines but some newer compounds do not fall into any of these major classes. Dihydropyridines are not used in the antiarrhythmic therapy but are good vasodilators and antianginal agents. In contrast, phenylalkylamines and benzothiazepines exert cardiac actions in vivo and therefore these are one choice of antiarrhythmic drugs. This review focuses on phenylalkylamines, benzothiazepines and on new drugs with potential antiarrhythmic action in the heart as well as the mechanisms how calcium channels antagonism can lead to an antiarrhythmic action.

Heart failure (HF) is a clinical syndrome characterized by significant impairment of cardiac ventricular function. Atrial fibrillation (AF) is the most commonly observed sustained arrhythmia in clinical practice. Both HF and AF are associated with increased morbidity and mortality and their prevalence increases with age. Approximately 50% of patients with moderate HF die due to ventricular fibrillation that leads to sudden cardiac death. Patients with AF exhibit increased mortality due to HF and stroke. HF and AF often co-exist, and the development of the other condition further deteriorates prognosis. Both chronic HF and AF lead to structural and electrophysiological changes in the heart called remodeling, modifying therapeutic targets including those for antiarrhythmic intervention. Current pharmacological treatment of arrhythmias has major limitations due to low efficacy and serious adverse effects. In this review, the main aspects of electrical remodeling in HF and AF are discussed along with possible novel targets identified for future pharmacological antiarrhythmic therapy.

Stimulation of β-adrenergic receptors in the heart is the most effective endogenous way to increase the mechanical performance of cardiac tissues to meet the requirements of a fight-or-flight situation or stress. On the other hand, sustained activation of cardiac β-receptors initiates maladaptive remodeling of the myocardium leading to cardiomyopathies and heart failure. Since both acute and chronic stimulation of β-adrenoceptors are arrhythmogenic, the application of β-receptor blockers exerts effective antiarrhytmic actions at both short and long time scale. Compared to other classes of antiarrhythmic agents, β-blockers are the class of antiarrhythmics that was shown to decrease mortality in postinfarct patients. Chemical, physiological, and pharmacological properties of the β-adrenoceptor related signaling, the role of β-1, β-2, and β-3 receptor subtypes, consequences of acute and long term β-adrenergic stimulation and the underlying proarrhythmic mechanisms, including the changes in cardiac ion currents and Ca2+ handling, are reviewed in this paper together with the clinical relevance of cardioprotective β-blocking therapy.

The short-term beat-to-beat variability of cardiac action potential duration (SBVR) occurs as a random alteration of the ventricular repolarization duration. SBVR has been suggested to be more predictive of the development of lethal arrhythmias than the action potential prolongation or QT prolongation of ECG alone. The mechanism underlying SBVR is not completely understood but it is known that SBVR depends on stochastic ion channel gating, intracellular calcium handling and intercellular coupling. Coupling of single cardiomyocytes significantly decreases the beat-to-beat changes in action potential duration (APD) due to the electrotonic current flow between neighboring cells. The magnitude of this electrotonic current depends on the intercellular gap junction resistance. Reduced gap junction resistance causes greater electrotonic current flow between cells, and reduces SBVR. Myocardial ischaemia (MI) is known to affect gap junction channel protein expression and function. MI increases gap junction resistance that leads to slow conduction, APD and refractory period dispersion, and an increase in SBVR. Ultimately, development of reentry arrhythmias and fibrillation are associated post-MI. Antiarrhythmic drugs have proarrhythmic side effects requiring alternative approaches. A novel idea is to target gap junction channels. Specifically, the use of gap junction channel enhancers and inhibitors may help to reveal the precise role of gap junctions in the development of arrhythmias. Since cell-to-cell coupling is represented in SBVR, this parameter can be used to monitor the degree of coupling of myocardium.

Cardiac arrhythmias are electrical phenomena; thus, sarcolemmal ion channels have long been considered as targets of antiarrhythmic therapy. The contribution of abnormal intracellular Ca2+ handling to digitalis-induced arrhythmogenesis is an old concept; however, the role of abnormal Ca2+ handling as a common cause of arrhythmia, i.e. relevant to all arrhythmogenic mechanisms, has been fully recognized in more recent times. Stability of the intracellular Ca2+ store (sarcoplasmic reticulum, SR) is crucial to physiological Ca2+ handling; when it is compromised, Ca2+ may be released independently from excitation and lead to secondary perturbation of membrane potential. Ca2+ store stability depends on the interplay between sarcolemmal and SR “effectors” (ion channels and transports), which are mutually linked by Ca2+-mediated feed-back control. While instrumental to cell homeostasis, such control makes any attempt to modulate SR stability dauntingly complex. This review discusses current knowledge on the factors leading to SR instability, the mechanisms by which SR instability translates into arrhythmias and which interventions may be best suited to prevent SR instability. Although still at an initial stage of development, such interventions might represent the future of antiarrhythmic drug therapy.

Driven by the limitations of the traditional antiarrhythmic pharmacology, current antiarrhythmic research is trying to identify new avenues for the development of specific and safe antiarrhythmic drugs. One of the most promising approaches in this field is the amelioration of the abnormal events in cellular Ca2+ handling originating from the dysfunction of ryanodine receptor Ca2+ release complex (RyR), which is an inevitable key factor in the pathology of myocardial dysfunction, remodeling and arrhythmogenesis. Accordingly, both in experimental and clinical situations, inhibition of abnormal activity of RyR, regardless of being the primary cause or a consequence during the pathogenesis appears to exert beneficial effect on disease outcome, including a marked antiarrhythmic defense. Considerable amount of our knowledge in this field originates from studies using dantrolene, a human drug with RyR stabilizing effect. Our review summarizes the cardiovascular pharmacology of dantrolene and the results of its use in experimental models of cardiac diseases, which emphasize a promising perspective for the possible antiarrhythmic application of RyR inhibition in the future.

The cardiac late sodium current (INa) has been in the focus of research in the recent decade. The first reports on the sustained component of voltage activated sodium current date back to the seventies, but early studies interpreted this tiny current as a product of a few channels that fail to inactivate, having neither physiologic nor pathologic implications. Recently, the cardiac INa has emerged as a potentially major arrhythmogenic mechanism in various heart diseases, attracting the attention of clinicians and researchers. Research activity on INa has exponentially increased since Ranolazine, an FDA-approved antianginal drug was shown to successfully suppress cardiac arrhythmias by inhibiting INa. This review aims to summarize and discuss a series of papers focusing on the cardiac late sodium current and its regulation under physiological and pathological conditions. We will discuss critical evidences implicating INa as a potential target for treating myocardial dysfunction and cardiac arrhythmias.

Ischemia and heart failure-related cardiac arrhythmias, both atrial (e.g., atrial fibrillation) and ventricular (e.g., malignant tachyarrhythmias) represent a leading cause of morbidity and mortality worldwide. Despite the progress made in the last decade in understanding their pathophysiological mechanisms there is still an unmet need for safer and more efficacious pharmacological treatment, especially when considering the drawbacks and complications of implantable devices. Cardiac ATP-sensitive potassium channels located in the sarcolemmal membrane (sarcKATP) and the inner mitochondrial membrane (mitoKATP) have emerged as crucial controllers of several key cellular functions. In the past three decades a tremendous amount of research led to their structural and functional characterization unveiling both a protective role in cardiac adaptive responses to metabolic stress and a seemingly paradoxical role in promoting as well as protecting against atrial and ventricular arrhythmias. On the other hand, several KATP inhibitors have emerged as potential ischemia selective antiarrhythmic drugs. In this respect, cardioselective, chamber specific and combined sarcKATP and mitoKATP modulators currently represent a promising field for drug development.