Related Experiment Videos
Calcium sensitising agents in heart failure
1Columbia Presbyterian Medical Center, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA.
Insights
Calcium sensitizing agents offer positive inotropic effects for congestive heart failure (CHF) but require further study. Long-term safety and efficacy of these agents, which often inhibit phosphodiesterase type III, remain uncertain.
Area of Science:
- Cardiology
- Pharmacology
Background:
- Congestive heart failure (CHF) is characterized by reduced cardiac output.
- Positive inotropic agents are explored for CHF treatment.
- Previous trials showed increased mortality risk with some positive inotropic drugs.
Purpose of the Study:
- To review calcium sensitizing agents as potential therapies for CHF.
- To evaluate their mechanism of action and clinical trial outcomes.
Main Methods:
- Review of existing literature on calcium sensitizing agents.
- Analysis of their effects on cardiac tissue and animal models.
- Examination of clinical trial data for agents like pimobendan.
Main Results:
- Five calcium sensitizing agents demonstrated positive inotropic action in preclinical studies.
- Pimobendan showed improved exercise tolerance in early trials but a trend towards increased mortality.
- Many agents also inhibit phosphodiesterase type III, raising safety concerns.
Conclusions:
- Calcium sensitizing agents have shown promise in preclinical and early clinical CHF studies.
- Long-term safety and efficacy, particularly regarding mortality, require large-scale survival trials.
- The role of these agents in CHF treatment is not yet defined.
Abstract:
Congestive heart failure (CHF) is a common cardiovascular disorder that is characterised, in part, by a decreased cardiac output reserve. Accordingly, there is ongoing interest in the role of positive inotropic agents (e.g. adrenergic agonists and phosphodiesterase type III inhibitors, which mediate their cardiovascular effects via a cyclic adenosine monophosphate-dependent mechanism) in the treatment of CHF. However, enthusiasm for positive inotropic therapy in CHF has been dampened by the results of clinical trials, which have shown that these drugs are associated with an increased risk of mortality. Calcium sensitising agents are a heterogeneous group of positive inotropic agents that mediate their cardiovascular actions (at least in part) by increasing the sensitivity of the contractile elements to calcium. Increased sensitivity to calcium may be related to changes in calcium binding to troponin C, or to direct effects on the actin-myosin complex. In addition, the inhibition of phosphodiesterase type III may contribute to the positive inotropic action of calcium sensitising agents. Five agents with calcium sensitising properties (pimobendan, levosimendan, MCI-154, EMD-53998 and CGP-48506) have been studied as possible therapies for CHF. All of these agents have demonstrated a positive inotropic action in isolated cardiac tissue and in animal models of CHF. In clinical trials, pimobendan, the most extensively studied of these drugs, was well tolerated and was associated with improved exercise tolerance during the first 6 months of therapy; however, it was also associated with a nonsignificant trend towards increased mortality. Because many of the calcium sensitising agents also inhibit phosphodiesterase type III activity, the long term safety of these agents is uncertain. Large-scale survival trials are required to determine the long term safety and efficacy of these agents before their role in the treatment of CHF can be defined.