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Decreased inotropic but relatively preserved relaxation response to cyclic adenosine monophosphate-dependent agents
D E Gutstein1, K Flemmal, E Bruce
1Charles A. Dana Research Institute, Boston, Massachusetts, USA.
Insights
In advanced heart failure, cyclic AMP-dependent agents preserve relaxation effects despite diminished inotropic responses. This suggests potential therapeutic benefits for lusitropic effects in heart failure patients.
Area of Science:
- Cardiology
- Molecular Pharmacology
- Biochemistry
Background:
- Elevated cyclic adenosine monophosphate (cAMP) enhances myocardial contractility and relaxation.
- Heart failure impairs the inotropic response to cAMP-dependent drugs.
- This study investigates cAMP-dependent and independent agent responses in failing vs. healthy heart muscle.
Purpose of the Study:
- To compare the inotropic and relaxation effects of cAMP-dependent and independent agents in human heart failure.
- To determine if lusitropic effects are preserved in advanced heart failure.
- To identify potential therapeutic targets for heart failure treatment.
Main Methods:
- Human ventricular trabeculae from heart failure patients and controls were studied.
- Dose-response curves were generated for cAMP-dependent (isoproterenol, phosphodiesterase inhibitors) and independent (acetylstrophanthidin) agents.
- Inotropic and relaxation responses were measured under controlled physiological conditions.
Main Results:
- The cAMP-independent agent acetylstrophanthidin showed similar effects on tension and relaxation in both groups.
- The inotropic effects of cAMP-dependent agents were significantly reduced in myopathic muscle.
- Relaxation effects of cAMP-dependent agents were preserved in myopathic heart muscle compared to controls.
Conclusions:
- Advanced heart failure preserves the lusitropic (relaxation) effects of cAMP-dependent agents.
- Despite attenuated inotropic effects, cAMP-dependent agents may still benefit heart failure patients through their relaxant properties.
- This highlights the potential of targeting lusitropic pathways in heart failure therapy.
Background:
Increased intracellular concentrations of cyclic adenosine monophosphate (AMP) stimulate a positive inotropic and lusitropic response in healthy myocardial tissue. Heart failure results in an attenuated inotropic response to cyclic AMP-dependent agents. This study compares the inotropic versus relaxation response to cyclic AMP-dependent and cyclic AMP-independent agents in myocardium from patients with end-stage heart failure and control patients without heart failure.
Methods And Results:
Fifty-four control and 59 myopathic human ventricular trabeculae, 1 mm or less in diameter were placed in physiologic saline, 2.5 mM Ca2+, and stretched to the length at which maximal isometric force developed at 30 degrees C, 0.33 Hz. Dose-response curves plotted as percentage change from baseline versus concentration of drug were determined for acetylstrophanthidin, isoproterenol, isobutylmethylxanthine, and milrinone. Acetylstrophanthidin, a cyclic AMP-independent agent, showed similar increases in peak tension relative to baseline over the entire dose range tested for both control and myopathic heart muscle; its effect on relaxation of control and failing cardiac muscle was equivalent over the dose range tested. In contrast, the inotropic actions of the cyclic AMP-dependent agents, isoproterenol and the phosphodiesterase inhibitors, were significantly decreased in myopathic muscle compared with control muscle, but effects on relaxation in the control and myopathic groups remained relatively preserved.
Conclusions:
A relatively preserved relaxant effect is associated with the cyclic AMP-dependent agents, despite significant diminution of their inotropic effects. Thus, in advanced heart failure, patients may continue to benefit from the lusitropic effects of the cyclic AMP-dependent agents, even when the inotropic effects of these agents are severely attenuated.