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European Journal of Heart Failure 2007 9(11):1086-1094; doi:10.1016/j.ejheart.2007.08.004
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© 2007 European Society of Cardiology

Mechanistic insight into the functional and toxic effects of Strophanthidin in the failing human myocardium

Dirk von Lewinskia,b, Egbert Bispinga,b, Andreas Elgnera, Jens Kockskämpera,b and Burkert Pieskeb,*

a Abteilung Kardiologie und Pneumologie, Georg-August-Universität Göttingen Robert-Koch-Str. 40, 37075 Göttingen, Germany
b Abteilung Kardiologie, Medizinische Universität Graz Auenbruggerplatz 15, 8036 Graz, Austria

* Corresponding author. Tel.: +43 385 2544; fax: +43 385 3733. E-mail address: burkert.pieske{at}meduni-graz.at


  Abstract

Background: Cardiac glycosides are characterized by a narrow therapeutic range with Ca2+-overload and arrhythmias occurring at higher concentrations. Data on cardiac glycosides in isolated failing human myocardium are scarce and the frequency-dependent actions and toxicity of Strophanthidin have not yet been characterized.

Aims: To determine inotropic responses and toxicity of Strophanthidin in failing human myocardium.

Methods and results: Experiments were performed in trabeculae from 64 end-stage failing hearts. Developed force, and intracellular [Ca2+]i and [Na+]i were recorded with Strophanthidin (0.01 to 1 µmol/L; 37°C, 1 Hz) and compared to interventions with distinct mechanisms of action (elevated [Ca2+]o, Isoproterenol, and EMD57033). The effects of Strophanthidin on force–frequency behaviour were also assessed.

Strophanthidin exerted concentration-dependent positive inotropic effects. These were paralleled by increases in intracellular [Na+] as well as increasing [Ca2+]i-transients and SR-Ca2+-load. At high concentrations (>0.5 µmol/L), Strophanthidin caused afterglimmers and aftercontractions, with declining developed force despite further increasing [Ca2+]i-transients. The force–frequency-relationship and diastolic function at higher pacing rates was worsened by Strophanthidin in a concentration-dependent manner.

Conclusions: Strophanthidin toxicity was dependent on concentration, calcium load, beating rate and β-adrenergic receptor activation. Our data support the view that low doses, heart rate control and additional β-adrenergic receptor blockade are essential in the use of cardiac glycosides in heart failure.

Key Words: Cardiac glycosides • Human myocardium • Calcium • Contractile function • Arrhythmias

Received June 13, 2007; Accepted August 22, 2007


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