MTWA on the surface ECG is linked to beat-to-beat fluctuations in the action potential duration (APD) of individual cardiac cells or myocytes. Evidence suggests that intracellular calcium cycling is the underlying mechanism for cardiac alternans.

When groups of myocytes alternate out of sync with one another (a phenomenon called "spatially discordant alternans"), the heart becomes prone to a variety of potentially life-threatening ventricular arrhythmias.

MTWA is a rate-dependent phenomenon. In practice, low-level exercise is commonly used to elevate the heart rate for MTWA measurement.