Cardiovascular Therapeutics - Applications of Biotechnology in Cardiovascular Therapeutics - page 13

Ion Channels and the Cardiovascular System
Ion channels of major interest in the cardiovascular system are those that mediate
Na + , K + , and Cl - transport. They are of critical importance in generating conducting
signals and action potentials which elicit the physiologically essential function of
contractile cardiac and vascular smooth muscle. Paradigms of cardiovascular physi-
ology and pathophysiology can be summarized as follows:
1. From a cellular biochemical point of view, regulation of cardiac work is done by
changing myocardial contractility and calcium fluxes. During heart failure, there
is impaired myocardial contractility and relaxation. Electrophysiological basis
of this is abnormal ionic currents and altered channel function.
2. From a gene expression point of view, regulation of cardiac work is based on
altered synthesis of myocardial proteins. During cardiac failure, there are myo-
cardial alterations and cardiomyopathy of overload. The electrophysiological
basis of this is altered ion channel synthesis and assembly.
Cardiac Rhythm Disturbances due to Ion Channels
Sudden cardiac death is a major cause of mortality in the industrialized world.
These deaths are usually due to cardiac rhythm disturbances as a result of altered
electrophysiology. Persons with diseased hearts are more prone to cardiac rhythm
disturbances than those with healthy hearts. Sudden cardiac death involves an inter-
action between structural derangement of the heart, transient functional distur-
bances, and specific electrophysiological events responsible for fatal arrhythmia.
Various arrhythmias following myocardial infarction involve some form of reentry
mechanism. Atrial and ventricular fibrillation are based on multiple interlacing
wavelets of reentry. Arrhythmias such as torsade de pointes and brief polymorphic
form of ventricular tachycardia seen during acute-phase infarction and in patients
with heart failure appear not to be due to reentry but perhaps are caused by trig-
gered automaticity. Similar electrophysiological disturbances are likely to occur in
global dilated cardiomyopathy and these are more widespread than in regional
damage due to myocardial infarction. In such patients, measures should be directed
at the basic disease. There is no evidence that prophylactic antiarrhythmic therapy
is of benefit in these patients.
Gap Junction and Cardiovascular Disease
Electrical coupling between cardiac muscle cells is mediated by specialized sites of
plasma membrane interaction termed gap junctions. In ischemic heart disease, the
orderly distribution of the gap junctions is lost in the zone border of the myocardial
infarct. There is reduction in the number of connexin 43 gap junctions. These and
other changes in the gap junction reduce conduction velocity and predispose to
arrhythmias.