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With each heart beat, cardiac myocytes undergo excitation, contraction, relaxation, and repolarization.
Impulses generated by these processes in each cell propagate over the whole heart to generate normal or
abnormal rhythms. The diagram above shows the major physiologic entities involved in the heart beat.
Membrane ionic currents, pumps, and exchangers underlie excitation and repolarization, gap junction
function determines impulse propagation, and contraction and relaxation reflect intracellular calcium cycling
into and out of the sarcoplasmic reticulum.
Each of the physiologic events reflects the expression and function of multiple genes. Ionic currents are
generated by expression of pore-forming proteins ("channels"), termed alpha subunits, along with function-modifying
proteins, termed beta subunits. Some currents require expression of more than one alpha subunit gene. Beta subunits
accomplish a range of tasks, including acting as chaperones or modifying gating. A mouse click over each molecular
entity in the above diagram will reveal the specific underlying genes. In some cases (cytoskeleton, calcium buffering),
the list includes only genes whose dysfunction is linked to an arrhythmia. HUGO gene names are used, with other
widely-used names listed in [].
Drugs are used to suppress abnormalities of cardiac rhythm, and antiarrhythmic (and other) drugs can
occasionally exacerbate arrhythmias. Most available drugs exert these beneficial or adverse effects by
inhibiting one or more of the specific processes shown above. The commonest targets are INa, IKr, ICa-L,
and adrenergic receptors and variation in function or expression of the genes underlying these targets can lead
to variable responses to blocking drugs. Importantly, however, cardiac electrogenesis shown here is a highly
integrated signaling system in which dysfunction of one component can lead to abnormal rhythms or to altered
responses to drugs that target other component(s). One well-described example is reduction of function variants
in the genes underlying IKs increasing the pharmacologic effect of IKr block. Another is the common syndrome of
congestive heart failure usually accompanied by abnormal intracellular calcium cycling; this has many downstream
effects, including altered transcription of ion channel genes, that increase arrhythmia susceptibility with
physiologic stressors or drugs.
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