The force-frequency relationship: insights from mathematical modeling.

The force-frequency relationship has intrigued researchers since its discovery by Bowditch in 1871. Many attempts have been made to construct mathematical descriptions of this phenomenon, beginning with the simple formulation of Koch-Wesser and Blinks in 1963 to the most sophisticated ones of today. This property of cardiac muscle is amplified by β-adrenergic stimulation, and, in a coordinated way, the neurohumoral state alters both frequency (acting on the sinoatrial node) as well as force generation (modifying ventricular myocytes). This synchronized tuning is needed to meet new metabolic demands. Cardiac modelers have already linked mechanical and electrical activity in their formulations and showed how those activities feedback on each other. However, now it is necessary to include neurological control to have a complete description of heart performance, especially when changes in frequency are involved. Study of arrhythmias (or antiarrhythmic drugs) based on mathematical models should incorporate this effect to make useful predictions or point out potential pharmaceutical targets.