Overview

“…as in every phenomenon the Beginning remains always the most notable moment.”

-Thomas Carlyle, Sartor Resartus

From birth to death the human heart beats about 3 billion times. Once per second, more or less, with such regularity that–the story goes–Galileo used his pulse to time the swinging of cathedral chandeliers leading to his discovery of isochronicity. But far too often and tragically, the heart suddenly loses this rhythmic beating and enters a state of wildly irregular electrical and mechanical activity. This transition from rhythmic beating to arrhythmia is sudden and often occurs without an obvious precipitating cause.

How does an arrhythmia begin? Our Cardiac Signaling Lab is working to understand that “most notable moment.” The central hypothesis in our lab is that many arrhythmias begin when the calcium (Ca²⁺) control system of the heart becomes unstable. But what are the antecedents of the instability?

Every heart beat involves three dynamic systems: the electrical, the Ca²⁺ control, and the contractile systems. In a normal heart beat, electrical depolarization of the cell membrane—the action potential—triggers Ca²⁺ release from intracellular stores. The resulting rise in the cytoplasmic Ca²⁺ concentration ([Ca²⁺]_i) causes the muscle cell to contract ultimately leading to ejection of blood from the heart. Arrows a and b in the figure at right depict this flow of information. However, information flow is not unidirectional. Changes in [Ca²⁺]_i also affect various components of the electrical system notably the L-type Ca²⁺ channels and the sodium-calcium exchanger. This flow of information from the Ca²⁺ control system to the electrical system, indicated by arrow a, occurs during every normal heart beat triggered by the action potential.

Unfortunately for millions of people who suffer from arrhythmias or sudden cardiac death every year, this information flow also occurs when the rise in [Ca²⁺]_i is not triggered by the action potential, that is when Ca²⁺ is spontaneously released from intracellular stores. If the spontaneous Ca²⁺ release disrupts the electrical system to a large enough magnitude and if it occurs in a sufficient number of cells then the normal action potential can be disrupted to such a degree as to generate an arrhythmia that might lead to sudden cardiac death.

Spontaneously Ca²⁺ release can occur when the Ca²⁺ control system becomes unstable. There are many routes to instability but one idea we’re working on is that subtle changes in the spatial distribution of ryanodine receptors, the intracellular Ca²⁺ channel, can trigger this instability. The spatial distribution of ryanodine receptors is governed, in part, by the contractile state of the heart cell. Therefore, the contractile system can affect the stability of the Ca²⁺ control system. This effect of the contractile system on the Ca²⁺ control system is shown by arrow b in the figure. This coupling between the contractile and Ca²⁺ control systems could help explain a longstanding conundrum of how mutations in contractile proteins is connected to a very high incidence of cardiac arrhythmias in people with the genetic disorder called familial hypertrophic cardiomyopathy.

Now, note the continuous circular flow of information between the three systems. Each system has its own dynamical behavior, but when they are coupled their dynamics become entangled and very complex behavior can emerge. To understand this complex dynamic system in health and in disease, we use multidisciplinary approaches. (1) We use mathematical modeling and large-scale (supercomputer) simulations to understand how different systems in the heart—the electrical system, the Ca²⁺ control system, and the contractile system—interact with each other to produce the rhythmic or arrhythmic dynamics seen in the heart cells. (2) We use high-speed 2-dimensional confocal microscopy and fluorescent Ca²⁺ imaging to study the Ca²⁺ dynamics. (3) To measure or control electrical properties we use whole-cell and microelectrode electrophysiological techniques. (4) Contractile dynamics are monitored by measuring sarcomere lengths or video edge detection.