Related Experiment Videos
Ca++ sensitizers impair cardiac relaxation in failing human myocardium
R J Hajjar1, U Schmidt, P Helm
1Boston University School of Medicine, Evans Department of Medicine, MA, USA.
Abstract:
The present study was aimed at investigating the effect of two Ca++ sensitizers, EMD 57033 (without significant phosphodiesterase inhibition) and ORG 30029 (with phosphodiesterase inhibition), in myocardium from nonfailing and failing human hearts. In nonfailing myocardium both EMD 57033 and ORG 30029 increased force of contraction by 280 +/- 27% and 94 +/- 13%, respectively (n = 6); the time to 80% relaxation (t80%) by 278 +/- 45% and 155 +/- 21%; and diastolic force by 28 +/- 8% and 12 +/- 3%, respectively. In trabeculae from failing myocardium, the increase in active force was similar to that in nonfailing trabeculae (EMD, 305 +/- 30%; ORG, 88 +/- 12% (n = 6)). However, the increase in t80% (EMD, 378 +/- 56%; ORG, 230 +/- 26%) and diastolic force (65 +/- 12%; 24 +/- 5%) was more pronounced in failing myocardium. EMD had no effect on the peak of the [Ca++]i transient; however, it prolonged the time course of the [Ca++]i transient in both nonfailing and failing myocardial fibers. ORG increased the peak of the Ca++ transient and prolonged the time course in preparations from both nonfailing and failing hearts. Both EMD and ORG shifted the [Ca++]-force relationship toward lower [Ca++] (EMD > ORG). The Ca++ sensitizers EMD 57033 and ORG 30029 increased active force development in nonfailing and failing human myocardium, but both impaired relaxation in failing myocardium to a greater extent than in nonfailing human myocardium in a concentration-dependent fashion.
Insights
Two calcium sensitizers, EMD 57033 and ORG 30029, enhanced force in human heart muscle. However, both impaired relaxation in failing hearts more than non-failing ones.
Area of Science:
- Cardiology
- Pharmacology
- Physiology
Background:
- Heart failure is a complex condition affecting myocardial contractility and relaxation.
- Calcium sensitizers are a class of drugs investigated for their potential to improve cardiac function.
Purpose of the Study:
- To investigate the effects of two distinct calcium sensitizers, EMD 57033 and ORG 30029, on human nonfailing and failing myocardium.
- To compare the impact of these agents on force development, relaxation, and intracellular calcium handling.
Main Methods:
- Human myocardial trabeculae from nonfailing and failing hearts were used.
- Force development and relaxation parameters were measured in the presence of increasing concentrations of EMD 57033 and ORG 30029.
- Intracellular calcium transients and calcium-force relationships were analyzed.
Main Results:
- Both EMD 57033 and ORG 30029 increased active force in both nonfailing and failing myocardium.
- Relaxation and diastolic force were more significantly impaired in failing myocardium compared to nonfailing myocardium.
- EMD 57033 prolonged the calcium transient, while ORG 30029 increased its peak and prolonged its duration.
- Both agents shifted the calcium-force relationship to lower calcium concentrations.
Conclusions:
- EMD 57033 and ORG 30029 enhance active force in human myocardium, with potential therapeutic implications for heart failure.
- However, impaired relaxation in failing hearts is a significant concern that requires careful consideration for these agents.
- The distinct effects on calcium handling suggest different mechanisms of action and potential for differential clinical utility.