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ESC Congress 2003: Can we make a new sinus node? The promises of genetically engineered bio-pacemakers

September 01, 2003

IMPORTANT: This press release accompanies both a presentation and an ESC press conference given at the ESC Congress 2003. Written by the investigator himself/herself, this press release does not necessarily reflect the opinion of the European Society of Cardiology

Heart block is a condition in which the cardiac pacemaker impulse that is normally initiated in the right atrium of the heart cannot reach the ventricles because of disease in the conducting system. Until the 1960s patients afflicted with heart block received the equivalent of a death sentence.

Although some drug therapies were available, their effects were transient and their side-effects problematic. The advent of electronic cardiac pacemakers, wherein a catheter or catheters inserted into the atria and ventricles are attached to a power pack implanted under the skin, provided a life-saving device that now permits patients to survive for years. Variations on this technology have since been adapted to treat other conduction system disorders (e.g. sinoatrial node dysfunction).

Given the drive to continually improve on treatment methods for cardiac disease, recent research has begun to adopt molecular/genetic techniques as a means to provide stable sources of impulse initiation and conduction. Our own effort represents a collaboration among four investigators at two universities: Drs. Peter Brink and Ira Cohen at the State University of New York at Stony Brook, and Drs. Richard Robinson and Michael Rosen at Columbia University.

To understand the nature of the research it is important to understand that the normal pacemaker function of the heart is initiated by the transfer of positive charge into specialized cells by ions moving through channels in the cell's membrane. A key channel of the normal pacemaker has been cloned and is referred to as the HCN (for hyperpolarization-activated, cyclic nucleotide-gated) channel. It has four variants, or isoforms, referred to as HCN1, HCN2, HCN3 and HCN4.

The intent of our experiments has been to use cloned isoforms as well as mutated isoforms of the HCN channel in a variety of gene therapy-based approaches. For example, we have used an adenoviral construct to insert the HCN2 gene into cardiac cells in culture as well as into the intact heart.   
Here we have demonstrated that rat ventricular cells in culture that have incorporated the HCN2 gene beat significantly faster than cells that do not house HCN2. We also have injected the viral construct into localized regions of the atria and the ventricular conducting system of intact canine hearts, and have found a 1000-fold increase in pacemaker current. Moreover, the regions injected have functioned to take over the pacemaker function of the heart when the normal pacemaker impulse is terminated. There still are a number of technological obstacles to overcome, including the use of non-viral approaches, ensuring the long-term function of the pacemaker constructs and optimizing the rate and rhythm characteristics of the cloned pacemakers.

In conclusion, although this work is very much in its infancy, we believe the approaches we are using, as well as those being attempted in other laboratories offer the vista of a new era in pacemaker therapy, in which electronic approaches gradually make way for those which are biological.

Michael R. Rosen, M.D
Columbia University, New York NY
USA

European Society of Cardiology (ESC)