The 10th Baltic Summer School

Basic and Clinical Aspects of Cardiac Arrhythmias

Background

The goal of BSS 2008 is to address the emerging understanding of the molecular mechanisms of cardiac arrhythmias and the therapeutic implications of this. Sudden cardiac death due to acute ventricular tachyarrhythmias remains one of the major causes of death in many countries. Arrhythmias often occur in patients with known underlying heart disease, i.e. ischemic heart disease, but may also occur in previously healthy subjects. In the latter cases, it appears that mutations in ion channels (channelopathies) play an important role. Through intensive research there is now a growing understanding of the causes of potentially lethal tachyarrhythmias, but there still remains the challenge of translating this knowledge into new drugs and treatment modalities for heart patients.

At the cellular level the normal heartbeat depends on the coordinated action of a multitude of interacting molecules: various ion channels, ion transporters, and second messengers. The spread of the action potential from cell to cell, and therefore the propagation of the action potential across the heart, depends on proper intercellular communication provided by gap junctions between the cells, and an ordered tissue structure. Fatal arrhythmias may therefore arise from a multitude of causes with a complex interaction between genetic and environmental factors.

Changes in ion channel function, the so called channelopathies, are now a well known cause of fatal arrhythmias. In some cases, the dysfunction is due to mutations in the gene coding for the channel protein(s). For example, dysfunction of potassium channels may lead to a prolonged action potential resulting in the congenital long QT syndrome, while a decreased activity of the sodium channels may result in Brugada's syndrome. In other cases, the channel dysfunction may arise because of environmental factors. Several chemicals, including many pharmaceuticals, interacts with ion channels resulting in dysfunction. A well known example is the acquired long QT syndrome. Some of the major challenges today are the detection of new mutations that increases the risk for fatal arrhythmias or renders the subject more sensitive to environmental factors, the functional characterization of the mutants, and finally, risk assessment and preventive therapies for individual patients.

Gap junctions provide the substrate for the intercellular coupling of cardiomyocytes, and thus, the substrate for the normal propagation of the cardiac action potential. Disruption and/or heterogeneity in impulse propagation across the myocardium can form the substrate for so called reentry circuits where the action potential travels around a closed path resulting in tachyarrhythmias either in the ventricles (ventricular tachycardia or fibrillation) or the atria (atrial flutter of fibrillation). A common cause of abnormal impulse propagation is ischemic heart disease. Ischemia may, through several mechanisms, impair gap junction function. There has been a rapid increase in our understanding of gap junction regulation in the heart because of the development of new experimental approaches like double cell patch clamping, and rapid methods for measurements of metabolic cell-cell coupling. This has lead to the development of a series of new compounds that affects gap junction coupling, and several of these are currently in clinical trial for the treatment of or prevention of arrhythmias.

Ischemic heart disease is probably the major risk factor for cardiac arrhythmias, and a better understanding of how to prevent and treat ischemia is mandatory for reducing the incidence of sudden cardiac death. One line of research focuses on preventing the damage to the heart which follows reestablishment of blood perfusion, so called reperfusion injury. However, other causes of cardiac disease like hypertension and diabetes, also increases the risk for arrhythmias, and there is an urgent need to better understand, prevent and treat the associated arrhythmias in these diseases. Several new treatment modalities like advanced pacemakers, intracardiac defbrillators, and ablation techniques are being developed in these years. Despite good effects of these, there is still a need for new strategies in the treatment of cardiac arrhythmias.

The BSS workshop and course 2008 focuses on the conceptual issues of cardiac arrhythmias in a series of in-depth lectures, discussions, seminars and round-tables held by international experts in the field. The focus of BLC lies in the transfer of new methods and technologies, which are important for competent and high profiled scientific work in the field (engaging the best laboratories at the participating Universities).