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.
An Excel file of literature supporting this pathway is available.
M. Whirl-Carrillo, E.M. McDonagh, J. M. Hebert, L. Gong, K. Sangkuhl, C.F. Thorn, R.B. Altman and T.E. Klein. "Pharmacogenomics Knowledge for Personalized Medicine" Clinical Pharmacology & Therapeutics (2012) 92(4): 414-417. Full text
Entities in the Pathway
Drugs/Drug Classes (24)
|Novel rare variants in congenital cardiac arrhythmia genes are frequent in drug-induced torsades de pointes. The pharmacogenomics journal. 2012. Ramirez A H, Shaffer C M, Delaney J T, Sexton D P, Levy S E, Rieder M J, Nickerson D A, George A L, Roden D M.|