Diastolic dysfunction is a significant risk factor for the development and progression of atrial fibrillation. Flecainide (Flec) and Amiodarone (AM) are frequently used in patients with atrial fibrillation but their impact on diastolic function has not been evaluated yet. We tested the effect of Flec and AM on systolic and diastolic performance in isolated muscle strips from failing human and nonfailing rabbit myocardium. Isolated ventricular trabeculae contracted isometrically at 1 Hz, Ca2+ 2.5 mmol/L, 37°C. Flec (0.01 – 100 μmol/L, dissolved in water) showed a concentration dependent negative inotropic effect in human myocardium (13 ± 2 vs. 3 ± 0.5 mN/mm
2
at base vs. 100 μmol/L; p< 0.05). This was associated with a significant prolongation of the relaxation time RT95 and an increase of diastolic tension (Dias) by 35 ± 9 % (at 100 μmol/L; p< 0.05). Water alone had no effect. Calcium transients measured by Aequorin technique declined proportionally to developed force after Flec. In contrast, AM (0.01 – 100 μmol/L, dissolved in 2% benzyl alcohol and 10% polsorbate) showed identical negative inotropic effects to solvent alone (maximally by 16 ± 8 %), and neither AM nor its solvent affected diastolic tension or relaxation times. Flec (3 μmol/L) resulted in a significant impairment of the Force frequency relationship (FFR) at 0.5–3.0 Hz in human myocardium. This was related to a decline in systolic force and a rise in Dias at high frequencies (at 3 Hz by 32 ± 12 % in control and 87 ± 25 % after Flec, p < 0.05 vs. control). In nonfailing rabbit myocardium (1.0–5.0 Hz) Dias decreased by 11 ± 10 % (n.s.) in control but raised by 65 ± 25 % after Flec, p < 0.05). AM (100 μmol/L) had no significant effect on FFR, whereas its solvent tended to impair the FFR by a decline in systolic performance.
Conclusion: Flec exerts calcium dependent negative inotropic effects in human myocardium and significantly impairs diastolic function. The latter is observable not only in human failing myocardium with preexisting diastolic dysfunction but also in nonfailing animal myocardium. In contrast AM shows no compound specific negative inotropic effect and no change in diastolic function. In patients treated with Flec attention should be turned to the potential of the drug to deteriorate diastolic function.
Insulin Causes [Ca
2+
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-Dependent and [Ca
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i
-Independent Positive Inotropic Effects in Failing Human Myocardium
