Molecular Cardiovascular Medicine

Published on 07/02/2015 by admin

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Chapter 5 Molecular Cardiovascular Medicine

Marcel E. Durieux, MD, PhD, J. Paul Mounsey, MD

In the past decades we have witnessed what may well be termed a revolution in the biomedical sciences, as molecular methodologies have suddenly become more evident on the clinical scene. Molecular biology originated in the 1950s, its birth most commonly identified with the description of the structure of deoxyribonucleic acid (DNA) by Watson and Crick.¹

Not generally appreciated was the rapidity with which molecular biology would advance. Now, five decades since the discovery of the structure of DNA, the human genome has been sequenced completely. Techniques for manipulating nucleic acids have been simplified enormously, and for many routine procedures kits are now available. The development of the polymerase chain reaction (PCR), a technique of remarkable simplicity and flexibility, has dramatically increased the speed with which many molecular biology procedures can be performed.

Cardiovascular medicine has been a major beneficiary of these advances. Not only have the electrophysiologic and pump functions of the heart been placed on a firm molecular footing, but for a number of disease states the pathophysiology has been determined, allowing progress in therapeutic development. Importantly, there is no indication that the pace of progress in molecular biology has slowed. If anything, the opposite is the case, and more dramatic advances may be expected in the years to come. Thus, techniques such as gene therapy may become available as therapeutic options in cardiac disease.

In this chapter, the most important aspects of molecular cardiovascular medicine are surveyed, with specific emphasis on medical issues relevant to the anesthesiologist. The myocyte membrane signaling proteins are of primary importance in this respect, and the two major classes—membrane channels and membrane receptors—are discussed. Simply stated, the channels form the machinery behind the cardiac rhythm, whereas the receptors are involved in regulation of cardiac function.

MACHINERY BEHIND THE CARDIAC RHYTHM: ION CHANNELS

The cardiac action potential results from the flow of ions through ion channels, which are the membrane-bound proteins that form the structural basis of cardiac electrical excitability. In response to changes in electrical potential across the cell membrane, ion channels open to allow the passive flux of ions into or out of the cell along their electrochemical gradients. Ion flux results in a flow of current, which displaces the cell membrane potential toward the potential at which the electrochemical gradient for the ion is zero, called the equilibrium potential (E) for the ion. Depolarization of the cell could, in principle, result from an inward cation current or an outward anion current; for repolarization the reverse is true. In excitable cells, action potentials are mainly caused by the flow of cation currents. Membrane depolarization results principally from the flow of Na⁺ down its electrochemical gradient (E_Na is around +50 mV), whereas repolarization results from the outward flux of K⁺ down its electrochemical gradient (E_K is around −90 mV). Opening and closing of multiple ion channels of a single type result in an individual ionic current. The integrated activity of many different ionic currents, each activated over precisely regulated potential ranges and at different times in the cardiac cycle, results in the cardiac action potential (Box 5-1).

BOX 5-1 Properties of Ion Channels

• Ion selectivity

• Rectification (passing current more easily in one direction than the other)

• Gating (mechanism for opening and closing the channel):

• Activation (opening)

• Inactivation (closing)

Phase 0: The Rapid Upstroke of the Cardiac Action Potential

The rapid upstroke of the cardiac action potential (phase 0) is caused by the flow of a large inward Na⁺ current (I_Na) (Box 5-2). I_Na is activated by depolarization of the sarcolemma to a threshold potential of −65 to −70 mV. I_Na activation, and hence the action potential, is an all-or-nothing response. Subthreshold depolarizations have only local effects on the membrane. After the threshold for activation of fast Na⁺ channels is exceeded, Na⁺ channels open (i.e., I_Na activates) and Na⁺ ions enter the cell down their electrochemical gradient. This results in displacement of the membrane potential toward the equilibrium potential for Na⁺ ions, around +50 mV. I_Na activation is transient, lasting at most 1 to 2 ms because, simultaneous with activation, a second, slightly slower conformational change in the channel molecule occurs (inactivation), which closes the ion pore in the face of continued membrane depolarization. The channel cannot open again until it has recovered from inactivation (i.e., regained its resting conformation), a process that requires repolarization to the resting potential for a defined period of time. The channels cycle through three states: resting (and available for activation), open, and inactivated. While the channel is inactivated, it is absolutely refractory to repeated stimulation.

BOX 5-2 Cardiac Action Potential

• Phase 0 (rapid upstroke): primarily Na⁺ channel opening

• Phase 1 (early rapid repolarization): inactivation of Na⁺ current, opening of K⁺ channels

• Phase 2 (plateau phase): balance between K⁺ currents and Ca²⁺ currents

• Phase 3 (final rapid repolarizations): activation of Ca²⁺ channels

• Phase 4 (diastolic depolarization): balance between Na⁺ and K⁺ currents

Phase 1: Early Rapid Repolarization

The early rapid repolarization phase of the action potential, which follows immediately after phase 0, results both from rapid inactivation of the majority of the Na⁺ current and from activation of a transient outward current (I_TO), carried mainly by K⁺ ions.

Phases 2 and 3: The Plateau Phase and Final Rapid Repolarization

The action potential plateau and final rapid repolarization are mediated by a balance between the slow inward current and outward, predominantly K⁺, currents. During the plateau phase, membrane conductance to all ions falls and very little current flows. Phase 3, regenerative rapid repolarization, results from time-dependent inactivation of L-type Ca²⁺ current and increasing outward current through delayed rectifier K⁺ channels. The net membrane current becomes outward and the cell repolarizes.

Phase 4: Diastolic Depolarization and I_f

Phase 4 diastolic depolarization, or normal automaticity, is a normal feature of cardiac cells in the sinus and atrioventricular (AV) nodes, but subsidiary pacemaker activity is also observed in the His-Purkinje system and in some specialized atrial and ventricular myocardial cells. Pacemaker discharge from the sinus node normally predominates because the rate of diastolic depolarization in the sinoatrial (SA) node is faster than in other pacemaker tissues. Pacemaker activity results from a slow net gain of positive charge, which depolarizes the cell from its maximal diastolic potential to threshold.

Molecular Biology of Ion Channels

The preceding sections have focused on the electrical events that underlie cardiac electrical excitability and on the identification of cardiac ionic currents on the basis of their biophysical properties. Subsequent sections examine the molecular physiology of these electrical phenomena. The first step in understanding the molecular physiology of cardiac electrical excitability is to identify the ion channel proteins responsible for the ionic currents.

Ion Channel Pore and Selectivity Filter

The presence of four homologous domains in voltage-gated Na⁺ and Ca²⁺ channels suggests that basic ion channel architecture consists of a transmembrane pore surrounded by the four homologous domains arranged symmetrically (Fig. 5-1).

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