Molecular Cardiovascular Medicine

Published on 07/02/2015 by admin

Filed under Anesthesiology

Last modified 07/02/2015

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Chapter 5 Molecular Cardiovascular Medicine

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.


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 (ENa is around +50 mV), whereas repolarization results from the outward flux of K+ down its electrochemical gradient (EK 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).

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 (INa) (Box 5-2). INa is activated by depolarization of the sarcolemma to a threshold potential of −65 to −70 mV. INa 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., INa 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. INa 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.