Molecular Mechansims of Arrhythmias in Cardiac Diseases

The mortality rate from heart disease is larger than the next seven causes of death combined, including cancer. In specific, over 400,000 of the nearly 1 million annual deaths due to heart disease are ascribed to sudden cardiac death (SCD) presumably due to ventricular arrhythmias. In recent years, our understanding of the mechanisms responsible for the initiation and maintenance of cardiac arrhythmias has increased considerably. There is mounting evidence that cardiac arrhythmias are in part caused by heterogeneous function of myocytes composing different regions of the heart. This heterogeneous activity of cells means that some cells can support organized contraction while others may be unable to coordinate contraction and allow conduction into neighboring myocytes. While much is known about the individual mechanisms by which myocytes support conduction, a global understanding of how these mechanisms work together remains poorly understood. For example, conduction is primarily facilitated by the opening of sodium channels, which allow myocytes to rapidly depolarize and fire an action potential. The magnitude of that action potential provides a driving force (or source) for the neighboring myocytes, which acts as a sink. If the source is too small compared to the sink of the neighboring myocytes the impulse fails to propagate and conduction blocks. Conduction block is extremely dangerous particularly when multiple routes of conduction exist. If an impulse blocks in one area and is capable of conducting around that area, given enough time and distance, that impulse could reenter the former site of block and set up a reentrant circuit. This effectively means that an area of heart is excited at extremely high rates, and results in inefficient filling and emptying of the ventricles. These reentrant circuits are sometimes referred to as arrhythmias.

We are studying the underlying mechanisms which predispose some areas of ventricular tissue to conduction block, while sparing other areas. In specific, we are studying the molecular distribution and function of proteins responsible for safe conduction; namely the cardiac sodium channel, the delayed rectifier potassium channel, connexins, and the L-type calcium channel.

Our lab studies proteins at the molecular level using patch-clamping and immunohistochemistry. The whole heart effects of protein channel regulation are studied with a state of the art optical mapping system.

Metcalf CS, Poelzing S, Little JG, Bealer SL, Status Epilepticus Induces Cardiac Myofilament Damage and Increased Susceptibility to Arrhythmias in Rat. Am J Physiol Heart Circ Physiol 2009 Oct 9;():

Poelzing S, Are electrophysiologically distinct M-cells a characteristic of the wedge preparation? Heart Rhythm 2009 Apr 10;():

Poelzing S, Smoot AF, Veeraraghavan R, Novel x-ray attenuation mechanism: role of interatomic distance. Med Phys 2008 Oct;35(10):4386-95

Veeraraghavan R, Poelzing S, Mechanisms underlying increased right ventricular conduction sensitivity to flecainide challenge. Cardiovasc Res 2008 Mar 1;77(4):749-56

Poelzing S, Veeraraghavan R, Heterogeneous ventricular chamber response to hypokalemia and inward rectifier potassium channel blockade underlies bifurcated T wave in guinea pig. Am J Physiol Heart Circ Physiol 2007 Jun;292(6):H3043-51

Poelzing S, Forleo C, Samodell M, Dudash L, Sorrentino S, Anaclerio M, Troccoli R, Iacoviello M, Romito R, Guida P, Chahine M, Pitzalis M, Deschenes , SCN5A polymorphism restores trafficking of a Brugada syndrome mutation on a separate gene. Circulation 2006 Aug 1;114(5):368-76

Pajouh M, Wilson LD, Poelzing S, Johnson NJ, Rosenbaum D , I(Ks) blockade reduces dispersion of repolarization in heart failure. Heart Rhythm 2005 Jul;2(7):731-8

Poelzing S, Roth BJ, Rosenbaum D , Optical Measurements Reveal Nature of Intercellular Coupling Across the Ventricular Wall. Am J Physiol Heart Circ Physiol 2005 Apr 29;():

Poelzing S, Dikshteyn M, Rosenbaum D , Transmural conduction is not a two-way street. J Cardiovasc Electrophysiol 2005 Apr;16(4):455

Poelzing S, Rosenbaum D , Cellular mechanisms of Torsade de Pointes. Novartis Found Symp 2005;266():204-17; discussion 217-24

Poelzing S, Rosenbaum D , Nature, significance, and mechanisms of electrical heterogeneities in ventricle. Anat Rec A Discov Mol Cell Evol Biol 2004 Oct;280(2):1010-7

Poelzing S, Rosenbaum D , Altered connexin43 expression produces arrhythmia substrate in heart failure. Am J Physiol Heart Circ Physiol 2004 Oct;287(4):H1762-70

Poelzing S, Akar FG, Baron E, Rosenbaum D , Heterogeneous connexin43 expression produces electrophysiological heterogeneities across ventricular wall. Am J Physiol Heart Circ Physiol 2004 May;286(5):H2001-9