Looking Forward Five Years

looking forward five years

Nine projects, involving current members of the Center, are in planning and/or early operational stages.

1. Remodeling of myocardium based on our understanding of cardiac memory and myocardial infarction (Drs. Rosen, Feinmark, Wit, Steinberg, Boyden). Based on current understanding of the physiological remodeling of myocardium that characterizes cardiac memory and of the pathological remodeling that characterizes myocardial infarction, the Center seeks to: predict the changes in myocardial function that will predispose to the occurrence of ventricular tachycardia and fibrillation, to prevent the evolution of a substrate that will be arrhythmogenic; and to use pacing and/or drugs to alter the arrhythmogenic substrate once it has evolved. This differs importantly from current strategies, which are often inadequate as predictors and do not take the overall cardiac substrate enough into consideration with respect to therapy, focusing, instead, almost entirely on the immediate arrhythmia and its management. This new direction will attack arrhythmias "upstream," i.e., targeting predisposing mechanisms as the optimal method of prevention and treatment.

2. Prevention and treatment of atrial fibrillation in the elderly population (Drs. Boyden, Steinberg, Rosen). These studies focus on an arrhythmia, which afflicts about 5% of the population over age 65 and is a major cause of morbidity and of mortality in association with stroke. Using a chronic model for atrial fibrillation and approaches to early diagnosis of predisposing mechanisms (including those which are hemodynamic, electrophysiological and autonomic), the intent is to identify those changes that can be studied non-invasively and to use these to develop interventions that will prevent evolution of the atrial substrate to a point at which fibrillation develops and then advances to chronicity. This, too, represents an upstream approach to prevention and therapy.

3. Intervention and prevention in the evolution of potassium, sodium and calcium channel abnormalities (Drs. Kass, Marks, Boyden, Wit). These studies bear on a variety of abnormalities that occur congenitally or in the setting of infarction and/or hypertrophy of the heart. They include conditions such as the congenital long QT syndrome, Brugada's syndrome, and arrhythmias induced by cardiac and non-cardiac drugs. The area of commonality is the identification of an abnormality in a specific ion channel, as well as associated abnormalities in calcium handling by cells, all of which are arrhythmogenic. Using transgenic animal technology and molecular interventions, the intent is to develop therapies that will prevent the occurrence of arrhythmias in these settings. The approach is also applicable to myocardial infarction, where the occurrence of lethal arrhythmias in about 25% of the population may have a genetic predisposition.

4. Intervention and prevention in events that predispose to sudden death in the young (Drs. Rosen, Steinberg, Kass). In addition to the congenital long QT syndrome, there is a variety of abnormalities that appear to involve the autonomic nervous system and that predispose to lethal arrhythmias in the young, including a number of highly visible instances in athletes. Using spontaneously occurring models of arrhythmias that evolve in the young and that induce sudden death, the intent is to identify the genetic underpinnings and the myocardial and cellular localization of the arrhythmogenic substrate, and to intervene in a way that will prevent the expression of arrhythmias, while not interfering in the lifestyles of these young individuals.

5. New approaches to treating abnormalities of heart rate (Drs. Robinson and Rosen in collaboration with Dr. Ira Cohen). A variety of conditions including sick sinus syndrome and sinoatrial and atrioventricular block require therapy to regularize the heartbeat. While pacemaker therapy has been highly effective in treating heart block, it requires the implantation of an electrical device and its monitoring for years thereafter. Recent advances in molecular biology have permitted the cloning of the endogenous pacemaker channel in the human heart and Drs. Robinson and Cohen (SUNY Stony Brook) and their associates have been at the forefront in expanding our understanding of the channel isoforms and their function. The overall goal of these studies is to devise a means for gene therapy of abnormalities of heart rate that will permit the generation of new pacemaker cells in the heart, replacing those no longer functioning appropriately.

6. Implementation of normal cardiac electrophysiological function by manipulation of the endogenous protein structures of the heart (Drs. Rosen, Wit, Feinmark, Kass, Steinberg). These studies utilize the principles of cardiac memory to attempt to maintain electrical function in the heart within normal parameters. This work currently focuses on the cyclic AMP response element binding protein (CREB) which is essential to the development of normal memory in the central nervous system. In collaboration with Dr. Lena Sun (Director of Pediatric Anesthesiology) a systematic approach to the identification of the role of CREB in cardiac memory has commenced. This approach will identify changes in molecules that contribute to the maintenance of normal function and the development of pathologic substrates, as well as target molecules for subsequent modulation in a way that will reduce the likelihood of arrhythmias.

7. Development of novel antiarrhythmic drugs that act specifically to alter cell communication in diseased areas of the heart (Drs. Wit, Boyden, Rosen). Abnormal transmission of the electrical signal of the heart from one cell to the next through gap junctions is responsible for some lethal arrhythmias. We will design chemical compounds that can specifically prevent this electrical transmission. Drug design will come from molecular modeling of the gap junctional channels to determine the characteristics of a chemical compound that can bind to these sites to prevent the flow of electrical current. Clues can be obtained from the structure of some experimental chemicals which act on gap junctions but are not suited for therapeutic use. Additionally, structural differences will be sought between gap junctional channels in diseased regions where remodeling has occurred and normal regions to allow for targeting the drug only to the abnormal region and not influencing electrical transmission in normal regions. This represents a novel approach to antiarrhythmic drug development: are not previously used in industry or in the general research community. If successful, there will be applicability to arrhythmias in the setting of myocardial infarction.

8. Development of novel antiarrhythmic drugs to increase intracellular calcium in diseased myocardium (Drs. Wit, Kass, Boyden, Marks). We have shown that increasing intracellular calcium in diseased myocardium can effectively stop some lethal arrhythmias because the calcium prevents intercellular transmission of electrical activity. Here, effective drug design involves targeting a chemical to the L-type calcium channel to prolong its open time, thereby increasing the entrance of calcium into the cell. Such drug design requires specific studies to elucidate the structure and function of the calcium channel in diseased myocardium, which should identify additional targets residing at intracellular sites that control the uptake, storage and release of calcium. Here, as above, there is applicability to the infarcted heart. There may be additional application to various forms of cardiomyopathy, given the positive effect of calcium on cardiac contractility.

9. Acute and long-term changes in the electrical function of the heart after infarction: role of autacoids and cytokines (Drs. Boyden, Feinmark, Steinberg). During and immediately after a heart attack, a series of biological messengers are activated that not only directly affect cardiac cells but recruit white blood cells and induce them to release molecules that act upon cardiac cells. Immediate changes in cell signaling occur and these can cause acute electrical disorders of the heart. Longer lasting effects that require changes in the cell's nucleus must occur as well. Accordingly, using the mouse as a model, we plan to identify the biologically active principles that initiate the acute and the long-term electrical effects of these mediators. This model allows us to take advantage of transgenic technology to assess the role of specific pathways in controlling the function of the heart during a myocardial infarct. In this way, the research will identify novel approaches to therapy that could prevent death in the days immediately after a heart attack.

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