Manipulations and Alterations of the Force-Frequency Response in Isolated Cardiac Muscle

There are three main physiological governing mechanisms for cardiac contractility; the force-frequency response, the length-tension response, and the beta-adrenergic response. One of the major hallmarks of heart failure is a decrease in the force of contraction with increasing frequency. Here we utilize the ex vivo isolated cardiac muscle in an attempt to discuss the physiological role of the force-frequency response in health. We aim to determine the functional attributes of the normal heart by studying alterations in contractility, calcium transient amplitude, and phosphorylation status following changes in frequency, alterations in beta-adrenergic stimulation, and chronic stretch. All experiments were conducted on isolated muscle preparations extracted from the right ventricular free wall of the male New Zealand white rabbit. Our hope is to increase the understanding of the manipulations and alterations that occur in the context of the force-frequency response in health.;We first determined the direct changes in the calcium and force response on a beat-to-beat basis during an instantaneous change in frequency. Because heart failure is rarely a spontaneous event, determining the minute changes in calcium transient amplitude as it relates to force production provides insight into the intricate balance that occurs at every beat. In this study we were able to highlight the dynamic relationship between force and calcium during the process of force stabilization at different frequencies.;In additional studies, we determined the effects of beta-adrenergic stimulation in conjunction to the force-frequency response. This work aimed to combine the force-frequency response with the beta-adrenergic response in a controlled manner. These experiments highlighted a modulation of the force-frequency response during beta-adrenergic stimulation, suggesting an important role for beta-stimulation in immediate contractile alterations which have an inhibitory effect on the response to frequency.;Finally, we determined the time dependent effects of stretch on alterations of the force-frequency response. We show that if a muscle is set to contract at a maintained stretch, there is a significant reversal of the force-frequency response that occurs in conjunction with alterations in the phosphorylation state of key myofilament proteins after 24 hours. Taken together, these results highlight potential modulators of the force-frequency relationship, which could be ideal targets for future work.