Myocardial contractility is modulated via different basic physiologic mechanisms: First, an increase in preload extends sarcomere length, which results in augmented contractile strength of the heart (Frank-Starling law; 1-6). Second, the sympathetic nervous system subsequent to the release of catecholamines activates α- and β-adrenoceptors, which regulate myocardial performance (7,8). Third, increasing heart rate over a physiologic range leads to a frequency-dependent increase in myocardial contractility (positive force-frequency relation of the heart; heart-rate inotropism; 9-11). Each of these mechanisms, which are crucial for the normal, physiologic regulation of myocardial function, is attenuated in the failing human heart. In congestive heart failure, increased preload is less effective in modulating intrinsic contractility, which is obvious from the rightward and downward shift of the left ventricular working curve (12,13). Hemodynamic response to catecholamines is substantially diminished because of downregulation of β-adrenoceptors and overexpression of inhibitory G proteins in the failing human heart (14,15). Concerning heart-rate inotropism, clinical and experimental investigations recently demonstrated an inverse relation between heart rate and inotropic state in patients with congestive heart failure: increasing heart rate exerts pronounced positive inotropic effects in nonfailing human myocardium, but frequency potentiation of contractility is absent or even inverse in failing human hearts (16-20). Pharmacologic reduction in heart rate with agents lacking negative inotropic properties might therefore exert beneficial effects on hemodynamics in patients with congestive heart failure. Reducing heart rate with long-term administration of β-adrenoceptor blockers has proved to be a beneficial therapeutic approach in patients with congestive heart failure (21-23). However, β-adrenoceptor blockers reduce both heart rate and inotropic state. Tedisamil dihydrochloride is a novel potassium channel-blocking agent with bradycardic activity (24-26). Chemically, the compound is a bispidine derivative that selectively depresses heart rate via direct action on the sinus node, thereby improving the oxygen demand/supply ratio, without impairing either ventricular pump function or contractility to a clinically relevant degree (24-28). Accordingly, this study was designed to investigate the hemodynamic response to tedisamil of patients with congestive heart failure. We hypothesized that tedisamil would reduce heart rate and thereby improve hemodynamic parameters of failing hearts with inverse force-frequency relation.
Right heart catheterization with hemodynamic measurements was performed in nine in-hospital patients with mild to moderate heart failure due to dilated cardiomyopathy. Coronary heart disease was excluded in all patients by coronary angiography, and patients were included if angiocardiographic left ventricular ejection fraction was <40% and if valvular heart disease and a history of arterial hypertension could be excluded. All patients were in New York Heart Association functional class II or III; mean left ventricular ejection fraction was 26 ± 4%. Patients also were excluded if left ventricular function was severely impaired (LVEF <20%), if congestive heart failure was stage NYHA IV, or if bradycardia <60 beats/min was present. The group consisted of eight men and one woman. Mean age was 51 ± 4 years, ranging from 32 to 67 years. Previous medication of the patients included digoxin (n = 6), digitoxin (n = 1), captopril (n = 3), enalapril (n = 1), perindopril (n = 3), cilazapril (n = 1), furosemide (n = 2), xipamide (n = 5), potassium chloride (n = 2), isosorbide mononitrate (n = 1), isosorbide dinitrate (n = 1), sotalol (n = 1), glibenclamide (n = 1), heparin (n = 3), phenprocoumon (n = 3), levothyroxine (n = 1), famotidine (n = 1), allopurinol (n = 1), diazepam (n = 1), acetylcysteine (n = 1), and flunisolide (n = 1). All patients were in sinus rhythm and had given written informed consent before participation in the study.
The protocol of this open, baseline controlled study was reviewed and approved by the Ethical Committee of the Albert-Ludwigs-University of Freiburg. Cardiac catheterization was performed in the fasting state; any cardioactive medication except digitalis and diuretics had to be withheld for a washout period of at least five half-lives (for β-adrenoceptor blockers, seven half-lives, respectively). A 7F flow-directed balloon-tipped thermodilution catheter was advanced via the right transjugular approach into the pulmonary artery. Patients were continuously monitored for heart rate, ECG, and noninvasive blood pressure. After a resting period of 4 h, hemodynamic measurements were performed, and heart rate was determined. After a stabilization period of 30 min, baseline measurements were repeated, and a first intravenous dose of tedisamil (0.3 mg/kg BW) was administered over a 10-min period. Heart rate and blood pressure were measured and recorded at that time, and hemodynamic assessments were repeated. If heart rate did not decrease >20% compared with baseline, a repetition dose of tedisamil (0.2 mg/kg BW) was infused after a 5-min pause over a period of 10 min, and heart rate was again recorded. An increase of blood pressure >20% or QT prolongation >20% compared with baseline prohibited a further repetition dose. Hemodynamic measurements and determination of heart rate were repeated thereafter and again 1, 2, 4, and 6 h after infusion. Blood samples for determination of neurohormonal plasma levels [atrial natriuretic factor (ANF), vasopressin, and renin] were taken at time points −30, 10, and 20 min, 1, 2, 4, and 6 h after infusion.
Heart rate and hemodynamic variables
Heart rate was continuously monitored. At the time points of hemodynamic measurements, a 12-lead ECG was recorded for determination of heart rhythm and conduction and repolarization times. QTc was calculated automatically according to Bazett's formula. Blood pressure was measured noninvasively by using the oscillatory method. Systolic and diastolic pulmonary artery pressure, mean pulmonary capillary wedge pressure, and mean right atrial pressure were measured through fluid-filled catheters connected to pressure transducers. Cardiac output was measured in triplicate by using the thermodilution technique. Mean blood pressure, stroke volume index, systemic vascular resistance, and pulmonary vascular resistance were calculated by using standard formulas.
Blood and urine samples for laboratory assessments were drawn before application of tedisamil and 24 h after infusion. The analysis included hemoglobin, hematocrit, red cell count, differential white cell count, platelets, glucose, creatinine, total protein, total bilirubin, alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), γ-glutamyl transpeptidase, alkaline phosphatase, lactate dehydrogenase, creatinine phosphokinase, total cholesterol, triglycerides, sodium, potassium, and urine glucose, protein, hemoglobin, and nitrate.
Data are expressed as mean ± one standard error of the mean. Comparison of the baseline data (time point −30 min) with the values at time points 10 and 20 min, and 1, 2, 4, and 6 h was performed by using analysis of variance for repeated measurements followed by Bonferroni t tests.
All patients received an initial dose of 0.3 mg/kg tedisamil, and seven (78%) patients received a repetitive dose of 0.2 mg/kg tedisamil. Mean heart rate at baseline was 84 ± 6 beats/min. Administration of tedisamil reduced heart rate significantly by 13% to 73 ± 4 beats/min at time point 20 min (Table 1). Four hours after infusion, heart rate had returned to baseline values (Fig. 1). Cardiac index under resting conditions was 2.7 ± 0.2 L/min/m2, which did not change significantly after tedisamil infusion. There was a tendency to a transient slight decrease of cardiac index only immediately after the drug infusion. Thereafter, cardiac index returned to baseline levels within 4 h. Stroke volume index remained unchanged over the entire study period. Mean blood pressure was 98 ± 5 mm Hg at baseline; administration of tedisamil resulted in a significant increase to 104 ± 6 mm Hg at time point 10 min, and blood pressure remained elevated throughout the whole observation period. Even after 6 h, there was still a significant elevation of mean blood pressure compared with baseline. Pulmonary artery pressures showed similar changes: systolic pulmonary artery pressure demonstrated only a slight increase, which did not reach significance, whereas diastolic pulmonary pressure increased significantly from 13 ± 3 to 18 ± 4 mm Hg at time point 20 min and remained elevated over the whole study period. This elevation was statistically significant at each time point. The increase in systemic pressure was associated with a pronounced increase in systemic vascular resistance from 1,619 ± 145 to 2,079 ± 198 dyn·s·cm−5 at time point 20 min, which was constant over the whole time course (Fig. 2). Similarly, pulmonary vascular resistance increased significantly from 161 ± 19 to 228 ± 31 dyn·s·cm−5 at time point 10 min (Fig. 3).
During the treatment phase, ECG changes were observed with significant QT and QTc prolongation, which peaked at 20 min (QT) and at 10 min (QTc) after start of tedisamil infusion, respectively (Table 2). For QT, the maximal difference from baseline was 63 ms mean (range, −28 to 100 ms) and for QTc, mean 48 ms (range, −34 to 105 ms). QRS duration and AV conduction remained unchanged. One patient experienced ventricular tachycardia immediately after the end of the first tedisamil injection, which degenerated to ventricular flutter and made immediate cardioversion necessary. The patient recovered without sequelae and was discontinued from the study. This patient showed QTc prolongation of 455 ms at baseline, which further increased to 469 ms before the arrhythmia occurred.
Neurohormonal and laboratory results
The measurement of neurohormone plasma levels showed a tendency to an increase in ANF levels from 213 ± 57 to 289 ± 104 mg/L at time point 10 min, which did not reach statistical significance (Table 3). Renin and vasopressin levels tended to decrease at time point 10 min, but this trend still was not significant. Pre- to poststudy comparisons revealed no clinically relevant changes of the laboratory safety parameters.
This study shows that intravenous administration of tedisamil results in a significant reduction in heart rate in patients with congestive heart failure. This was associated with increases in mean blood pressure and systemic vascular resistance, as well as increases in pulmonary artery pressures and pulmonary vascular resistance. Furthermore, infusion of tedisamil resulted in prolongation of QT and QTc intervals in the ECG recordings.
Tedisamil dihydrochloride was developed mainly as an antianginal drug for the treatment of patients with coronary heart disease and exercise-induced stable angina (28-31). Tedisamil selectively reduces heart rate via direct action on the sinus node (32,33), which leads to a reduction in myocardial oxygen consumption. In comparison with conventional β-adrenoceptor-blocking agents, tedisamil does not exhibit either clinically significant negative inotropic or bronchoconstrictive properties (27,29). Besides its antiischemic potential, which was proven in a number of experimental and clinical studies (27-29,31), tedisamil demonstrates class III antiarrhythmic effects with prolongation of action-potential duration and repolarization, which are explained by potassium channel blockade (26,32).
In this study, we investigated tedisamil under the hypothesis that tedisamil-induced reduction in heart rate would improve hemodynamic parameters in patients with heart failure, because it was recently shown that cardiac index decreases with higher heart rates in those patients (20). Although administration of tedisamil resulted in a considerable heart-rate reduction, this was not associated with an improvement of hemodynamics. In contrast, cardiac index tended to decrease under treatment with tedisamil. The lack of hemodynamic improvement after tedisamil-induced reduction in heart rate may be related to increased afterload of the left and right ventricle. The increase in systemic and pulmonary vascular resistance occurred within 10 min after administration of tedisamil and persisted >2 h. One may even speculate that increase of systemic blood pressure may have in part contributed to the observed heart-rate reduction by increasing baroreceptor sympathetic inhibition.
The basic mechanism underlying the reduction in heart rate, as well as the increase in systemic and pulmonary vascular resistance, can be explained by the pharmacologic mode of action of tedisamil. Preclinical electrophysiologic and functional studies demonstrated that the predominant cardiac action of tedisamil is the suppression of the outward-directed potassium currents Ito and IK, which prolongs repolarization, thereby producing QT prolongation and bradycardia (32,34). It is hypothesized that the increase in vascular tone is related to increased calcium influx in vascular myocytes due to inhibition of distinct calcium-sensitive and adenosine triphosphate (ATP)-sensitive potassium channels (35). Indirect evidence for this hypothesis exists from documented vasorelaxant properties of potassium channel openers (35,36).
It should be noted that in one patient, ventricular tachycardia occurred shortly after infusion of tedisamil and that this patient exhibited a further increase of a QT prolongation under tedisamil treatment, which may indicate that tedisamil promoted the arrhythmia. Proarrhythmic effects with the occurrence of ventricular tachycardia (e.g., torsade de pointes) are not uncommon with most class III antiarrhythmic agents (37,38).
Our data were obtained in patients with congestive heart failure due to dilated cardiomyopathy after intravenous administration of tedisamil. It should therefore be mentioned that oral or intravenous administration of tedisamil in patients with ischemic heart disease and normal left ventricular function has proven to be both an effective and safe approach to the treatment of stable angina with clear reduction of ST-segment depressions and the time to onset of angina during exercise testing in comparison with placebo (28,29). In several studies in patients with ischemic heart disease, no proarrhythmic activity of tedisamil could be observed (27-29). It may therefore be concluded that the pharmacologic profile of tedisamil is different in patients with congestive heart failure and activated neurohormonal system from that of patients with coronary heart disease and exercise-induced angina. Further investigations are mandatory to elucidate the underlying mechanisms. However, because of increases in afterload, tedisamil so far does not appear to be suitable for patients with congestive heart failure due to dilated cardiomyopathy.
Acknowledgment: This work was supported by Solvay Pharmaceuticals GmbH, Hannover, FRG.
1. Gordon AM, Huxley AF, Julian FJ. The variation in isometric tension with sarcomere length in vertebrate muscle fibers. J Physiol (Lond)
2. Allen DG, Kentish JC. The cellular basis of the length-tension relation in cardiac muscle. J Mol Cell Cardiol
3. Hibbered MG, Jewell BR. Calcium- and length-dependent force production in rat ventricular muscle. J Physiol (Lond)
4. Frank O. Zur Dynamik des Herzmuskels. J Biol
1895;32:470-7. Translation from German: Chapman CP, Wasserman EB. On the dynamics of cardiac muscle. Am Heart J
5. Starling EH. Linacre lecture on the law of the heart.
London, England: Longmanns, 1918.
6. Holubarsch C, Ruf T, Goldstein D, et al. Existence of the Frank-Starling mechanism in the failing human heart: investigations on the organ, tissue, and sarcomere level. Circulation
7. Fleming JW, Wisler PL, Watanabe AM. Signal transduction by G-protein in cardiac tissues. Circulation
8. Hasenfuss G, Mulieri LA, Leavitt BJ, Alpert NR. Influence of isoproterenol on contractile function, excitation-contraction coupling, and energy turnover of isolated nonfailing human myocardium. J Mol Cell Cardiol
9. Bowditch HP. Über die Eigenthümlichkeiten der Reizbarkeit, welche die Muskelfasern des Herzens zeigen. Ber Sachs Ges (Akad) Wiss
10. Blinks JR, Koch-Weser J. Analysis of the effects of change in rate and rhythm upon myocardial contractility. J Pharmacol Exp Ther
11. Allen DG, Blinks JR. Calcium-transients in aequorin-injected frog cardiac muscle. Nature
12. Weber KT, Janicki JS. The heart as a muscle-pump system and the concept of heart failure. Am Heart J
13. Grossman W, Braunwald E, Mann T, McLaurin LP, Green LH. Contractile state of the left ventricle in man as evaluated from end-systolic pressure-volume relation. Circulation
14. Bristow MR, Ginsburg R, Minobe W, et al. Decreased catecholamine sensitivity and β-adrenergic-receptor density in failing human hearts. N Engl J Med
15. Böhm M, Gierschik P, Erdmann E. Quantification of Giα
-proteins in the failing and nonfailing human myocardium. Basic Res Cardiol
16. Mulieri LA, Hasenfuss G, Leavitt B, Allen PD, Alpert NR. Altered myocardial force-frequency relation in human heart failure. Circulation
17. Pieske B, Hasenfuss G, Holubarsch CH, Schwinger R, Böhm M, Just H. Alterations of the force-frequency relationship in the failing human heart depend on the underlying cardiac disease. Basic Res Cardiol
18. Feldman MD, Gwathmey JK, Phillips P, Schoen F, Morgan JP. Reversal of the force-frequency relationship in working myocardium from patients with end-stage heart failure. J Appl Cardiol
19. Phillips PJ, Gwathmey JK, Feldman MD, Schoen FI, Grossman W, Morgan JP. Post-extrasystolic potentiation and the force-frequency relationship: differential augmentation of myocardial contractility in working myocardium from patients with end-stage heart failure. J Mol Cell Cardiol
20. Hasenfuss G, Holubarsch Ch, Hermann HP, Astheimer K, Pieske B, Just H. Influence of the force-frequency relationship on hemodynamics
and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy. Eur Heart J
21. Jessup M. Beta-adrenergic blockade in congestive heart failure: answering the old questions. J Am Coll Cardiol
22. Engelmeier RS, O'Connell JB, Walsh R, et al. Improvements in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomized, placebo-controlled trial. Circulation
23. Packer M, Colucci WS, Sackner-Bernstein JD, et al. Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure: the PRECISE Trial. Circulation
24. Kuehl UG, Buschmann G. Cardiovascular profile of KC 8857 in comparison with other cardioactive agents. J Mol Cell Cardiol
25. Buschmann G, Kuehl UG, Varchim G, Ziegler G. In vitro and in vivo bradycardic activities of KC 8857. Naunyn Schmiedebergs Arch Pharmacol
26. Nemeth M, Virag L, Hala O, Varro A, Kovacs G, Thormaehlen D, Papp JG. The cellular electrophysiological effects of tedisamil in human atrial and ventricular fibers. Cardiovasc Res
27. Thormann J, Mitrovic V, Riedel H, et al. Tedisamil (KC 8857) is a new specific bradycardic drug: does it also influence myocardial contractility? Analysis by the conductance (volume) technique in coronary artery disease. Am Heart J
28. Mitrovic V, Oehm E, Liebrich A, Thormann J, Schlepper M. Hemodynamic and antiischemic effects of tedisamil in humans. Cardiovasc Drug Ther
29. Mitrovic V, Oehm E, Strasser R, Schlepper M. Hemodynamic, antiischemic and neurohumoral effects of the new potassium channel blocking agent tedisamil in patients with coronary artery disease. Z Kardiol
30. Kobinger W. Specific bradycardic agents: a new approach to therapy in angina pectoris. Prog Pharmacol
31. Grohs JG, Fischer G, Raberger G. Cardiac and hemodynamic effects of the selective bradycardic agent KC 8857 during exercise-induced myocardial ischemia. Eur J Pharmacol
32. Oexle B, Weirich J, Antoni H. Electrophysiological profile of KC 8857, a new bradycardic agent. J Mol Cell Cardiol
33. Ohler A, Ravens U. Effects of E-4031, almokalant and tedisamil on postrest action potential duration of human papillary muscles. J Pharmacol Exp Ther
34. Dukes ID, Cleemann L, Morad M. Tedisamil blocks the transient and delayed rectifier K+
-currents in mammalian cardiac and glial cells. J Pharmacol Exp Ther
35. Escande D, Henry P. Potassium channels as pharmacological targets in cardiovascular medicine. Eur Heart J
36. Anderson KE. Clinical pharmacology of potassium channel openers. Pharmacol Toxicol
37. Hohnloser SH. Proarrhythmia with class III antiarrhythmic drugs: types, risks and management. Am J Cardiol
38. Waldo AL, Camm AJ, deRuyter H, et al. Effect of d-sotalol on mortality in patients with left ventricular dysfunction after recent and remote myocardial infarction: the SWORD Investigators. Lancet