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Keywords

 

Authors

  1. Glenn, Christopher M. MD
  2. Pogwizd, Steven M. MD

Abstract

While cardiac pacemakers are frequently used for the treatment of bradydysrhythmias (from diseases of the cardiac conduction system), their use is still limited by complications that can be life-threatening and expensive. Genetic engineering approaches offer an opportunity to modulate cellular automaticity in a manner that could have significant therapeutic potential. It is well known that ventricular myocytes exhibit a more negative diastolic potential than do pacemaker cells, in large part because of the inward rectifying potassium current IK1(which pacemaker cells lack). Taking advantage of these intrinsic electrophysiological differences, a biological pacemaker has recently been developed by Miake et al (Nature 2002; 419:132-133) using adenoviral gene transfer approaches. By isolating the gene responsible for IK1 (the Kir2.1 gene), mutating it to make it a dysfunctional channel (a dominant-negative), inserting the mutated gene into an adenoviral vector, and delivering the virus to the hearts of guinea pigs, the investigators were able to successfully convert some ventricular myocytes to pacemaker cells. While issues of safety and long-term efficacy need to be further established, the results of these experiments provide proof of principle that gene transfer offers great promise for treatment of electrophysiological disorders including conduction system disease.

 

Cardiac pacemakers are used to treat a variety of disorders of the cardiac conduction system, with sinus node dysfunction being the primary indication 1 (Table 1). In the United States, approximately 1 million people have permanent pacemakers, 2 and the number of pacemaker implantations exceeds 250,000 per year in the United States and 600,000 per year worldwide. Pacemakers are effective in relieving symptoms; however, they are expensive and pose potential health risk associated with their insertion. Complications associated with permanent pacemaker insertion include but are not limited to infection. Retrospective and prospective studies report an incidence of 0.5% to 5% for pacemaker pocket infections and up to 0.5% for septicemia, endocarditis, or both. 3 Additional complications include pneumothorax, thrombosis, erosion, perforation, and lead dislodgement (as well as others listed in Table 2). 4 Such complications could lead to significant morbidity (including increased physical and psychological burdens) and, in rare instances, mortality.

 

Although research continues to develop technologically more advanced mechanical permanent pacemakers, there has been a recent exciting work that has utilized genetic engineering approaches to create a "biological pacemaker" in an experimental model. Miake, Marban, and Nuss from the Johns Hopkins University School of Medicine took advantage of important differences between pacemaker cells and ventricular myocytes in the heart to develop such a biological pacemaker. They used an adenovirus that carried a gene for a specific heart molecule (in this case, a defective cardiac potassium ion (K+) channel). When the heart muscles cells took up the adenovirus and started making the altered ion channel protein, the result was that ventricular muscle cells (myocytes) developed pacemaker-like activity. This work, which has been reported in the journal Nature, 5 provides the first proof of principle that one could use such gene transfer approaches to potentially treat conduction system disease. More research needs to be done to determine the safety and long-term efficacy of this approach. However, the rapid advancements in gene therapy (some of which are in clinical trials) clearly demonstrate that an understanding of these approaches will be important in keeping up with the rapid developments in medicine that will quickly impact on patient management and nursing care.

 

The focus of this review will be on the development of a biological pacemaker. However, to help with fully understanding the significance of such a scientific advancement, we will first review some basic cardiac electrophysiology, starting with a discussion of the structural and functional characteristics of ventricular myocytes, and then compare them to cardiac pacemaker cells (such as in the sinus node). Next, we will discuss gene transfer approaches to modify cardiac proteins in the intact heart. We will conclude with a review of the experimental findings of Miake et al 5 and a discussion of the implications of this work.