The Myofilament Force-Calcium Relationship as a Target for Positive Inotropic Therapy in Congestive Heart Failure

Abstract

To-date positive inotropic therapy in the treatment of congestive heart failure has resulted in adverse effects on long term survival. These agents increase calcium cycling through beta-adrenergic stimulation or phosphodiesterase inhibition. An alternative method of producing positive inotropy is to increase the myofilament sensitivity to calcium. This can occur at several levels within the myofilament, and has potential benefits with respect to avoiding increased calcium cycling and producing a more favourable energy efficient positive inotropy. A potential adverse effect of increasing calcium sensitivity is slowed relaxation and diastolic dysfunction. We have learnt a considerable amount about the function of specific sites within the myofilament by the use of genetically engineered mouse models, which have shown diverse effects of various myofilament sites on global left ventricular function. Levosimendan is a novel inotropic agent that has several mechanisms of action including calcium sensitization, and is undergoing clinical trials at present. This review article will provide a comprehensive molecular, biophysical and physiological insight into the concepts underlying the myofilament force-calcium relationship and its potential as a target for positive inotropic therapy in heart failure.

Cyclosporine A attenuates mitochondrial permeability transition and improves mitochondrial respiratory function in cardiomyocytes isolated from dogs with heart failure

“…At this time, it is not possible to completely translate the data obtained from isolated cardiomyocytes into action of CsA in situ in failing heart where failing cardiomyocytes are subjected to continuous chronic hypoxia, elevated levels of angiotensin-II , cateholamines, TNFα and calcium overload [14,35,36]. Additional investigations are required to understand the feasibility of use of MPTP blockers in the treatment of heart failure.…”

Advantages of Catheter-Based Adenoviral Delivery of Genes to the Heart for Studies of Cardiac Disease

“…In heart failure, the calcium sensitivity of myofilaments is altered in both human and rodent models (Marston et al, 2008). A potential adverse effect of increasing calcium sensitivity is slowed relaxation and diastolic dysfunction (MacGowan, 2005). If myofilament properties are limiting the relaxation rate and force development in heart failure, the overexpression of SERCA would be competitive and deleterious.…”

Real‐time monitoring of intracellular calcium dynamic mobilization of a single cardiomyocyte in a microfluidic chip pertaining to drug discovery

“…An in vitro method is often used to measure the [Ca 21 ] i response of the drugs on cardiomyocytes [15,39]. IQ, which is an ingredient of the traditional Chinese herb, licorice, has been reported to have antitumor effect on human gastric cancer [40], prostate cancer…”

“…Monitoring [Ca 21 ] i in cardiomyocytes could facilitate the discovery of cardiovascular drugs (e.g., positive inotropic therapy [15]). In addition, with respect to drug biosafety issue, many chemicals (e.g., caffeine [16]) have undesirable side effects on the heart as measured by their effects on the [Ca 21 ] i mobilization.…”