Biological Pacemakers – A Review

Slow heart rates, due to sinus node disease or atrioventricular conduction block, are a significant problem for many patients. Currently, these patients are treated with electronic pacemakers, which provide effective therapy, but are also associated with many problems. Use of biological pacemakers is an attractive solution to these problems. Approaches for the creation of such pacemakers include either the injection of cells that have pacemaker activity (cell-based approach) or modification of cells in the heart to induce pacemaker activity by delivering genes (gene-based approach). This article reviews the progress in the development of biological pacemakers

Genetically engineered cardiac pacemaker: stem cells transfected with HCN2 gene and myocytes - a model

Artificial biological pacemakers were developed and tested in canine ventricles. Next steps will require obtaining oscillations sensitive to external regulations, and robust with respect to long term drifts of expression levels of pacemaker currents and gap junctions. We introduce mathematical models intended to be used in parallel with the experiments. The models describe human mesenchymal stem cells ({\it hMSC}) transfected with HCN2 genes and connected to myocytes. They are intended to mimic experiments with oscillation induction in a cell pair, in cell culture and in the cardiac tissue. We give examples of oscillations in a cell pair, in a 1 dim cell culture, and oscillation dependence on number of pacemaker channels per cell and number of gap junctions. The models permit to mimic experiments with levels of gene expressions not achieved yet, and to predict if the work to achieve this levels will significantly increase the quality of oscillations. This give arguments for selecting the directions of the experimental work

Gene Therapy in Cardiac Arrhythmias

Gene therapy has progressed from a dream to a bedside reality in quite a few human diseases. From its first application in adenosine deaminase deficiency, through the years, its application has evolved to vascular angiogenesis and cardiac arrhythmias. Gene based biological pacemakers using viral vectors or mesenchymal cells tested in animal models hold much promise. Induction of pacemaker activity within the left bundle branch can provide stable heart rates. Genetic modification of the AV node mimicking beta blockade can be therapeutic in the management of atrial fibrillation. G protein overexpression to modify the AV node also is experimental. Modification and expression of potassium channel genes altering the delayed rectifier potassium currents may permit better management of congenital long QT syndromes. Arrhythmias in a failing heart are due to abnormal calcium cycling. Potential targets for genetic modulation include the sarcoplasmic reticulum calcium pump, calsequestrin and sodium calcium exchanger.Lastly the ethical concerns need to be addressed

Bistability: Requirements on Cell-Volume, Protein Diffusion, and Thermodynamics

Bistability is considered wide-spread among bacteria and eukaryotic cells, useful e.g. for enzyme induction, bet hedging, and epigenetic switching. However, this phenomenon has mostly been described with deterministic dynamic or well-mixed stochastic models. Here, we map known biological bistable systems onto the well-characterized biochemical Schloegl model, using analytical calculations and stochastic spatio-temporal simulations. In addition to network architecture and strong thermodynamic driving away from equilibrium, we show that bistability requires fine-tuning towards small cell volumes (or compartments) and fast protein diffusion (well mixing). Bistability is thus fragile and hence may be restricted to small bacteria and eukaryotic nuclei, with switching triggered by volume changes during the cell cycle. For large volumes, single cells generally loose their ability for bistable switching and instead undergo a first-order phase transition.Comment: 23 pages, 8 figure

A rat model of complete atrioventricular block recapitulates clinical indices of bradycardia and provides a platform to test disease-modifying therapies

Complete atrioventricular block (CAVB) is a life-threatening arrhythmia. A small animal model of chronic CAVB that properly reflects clinical indices of bradycardia would accelerate the understanding of disease progression and pathophysiology, and the development of therapeutic strategies. We sought to develop a surgical model of CAVB in adult rats, which could recapitulate structural remodeling and arrhythmogenicity expected in chronic CAVB. Upon right thoracotomy, we delivered electrosurgical energy subepicardially via a thin needle into the atrioventricular node (AVN) region of adult rats to create complete AV block. The chronic CAVB animals developed dilated and hypertrophied ventricles with preserved systolic functions due to compensatory hemodynamic remodeling. Ventricular tachyarrhythmias, which are difficult to induce in the healthy rodent heart, could be induced upon programmed electrical stimulation in chronic CAVB rats and worsened when combined with β-adrenergic stimulation. Focal somatic gene transfer of TBX18 to the left ventricular apex in the CAVB rats resulted in ectopic ventricular beats within days, achieving a de novo ventricular rate faster than the slow atrioventricular (AV) junctional escape rhythm observed in control CAVB animals. The model offers new opportunities to test therapeutic approaches to treat chronic and severe CAVB which have previously only been testable in large animal models.ope