For the treatment of acute congestive heart failure, several vasodilators have been used to reduce left ventricular (LV) preload and afterload, both of which are substantially increased and thus cause pulmonary congestion or low cardiac output or both in heart failure.
Flosequinan is a unique arteriovenous vasodilator that also exerts positive inotropic and chronotropic actions (3,8-10,25). Flosequinan has been shown to improve hemodynamics in patients with heart failure by increasing cardiac output, by reducing right atrial and left ventricular filling pressures, and by decreasing pulmonary and systemic vascular resistances (4,7). Although the mode of action of flosequinan is still not entirely clear, it has been demonstrated that flosequinan inhibits the endothelin-1-induced changes in inositol 1,4,5-triphosphate (IP3) and particulate protein kinase C activity in aorta (15) and nonselectively inhibits cardiac phosphodiesterases (11).
In the hemodynamic analysis of the vasodilating action of various vasodilators, aortic impedance is quite useful to assess quantitatively not only steady but also pulsatile components of LV afterload in beating hearts. In congestive heart failure, it has been demonstrated that not only vascular resistance but also arterial wave reflection (17) and characteristic impedance (6) are significantly increased, leading to additional LV afterload. However, little information is available as to the effect of the vasodilator, flosequinan, on the pulsatile components of LV afterload in heart failure.
In this study, we focused on the effect of flosequinan on cardiac function and aortic impedance in the experimental model of heart failure and demonstrated that flosequinan improved LV-pump function by the mechanism of increasing LV contractility and also reducing both steady and pulsatile components of LV afterload.
MATERIALS AND METHODS
Seven mongrel dogs weighing 12-18 kg were anesthetized with morphine, 5 mg, s.c., followed by the administration of α-chloralose, 100 mg/kg, i.v. After endotracheal intubation was established, the animals were ventilated with a Harvard respirator. A left thoracotomy was performed at the fifth intercostal space with the dog on its right side. The pericardium was excised and was used to support the heart in a pericardial cradle. The sinus node was crushed, and the left atrial appendage was electronically paced (pacing rate, 100). An electromagnetic flowmeter probe (model FR-100T or MF-27; Nihon Koden, Tokyo, Japan) was placed around the proximal ascending aorta after removing the fat pad. We selected the size of the probe to minimize the constriction of the ascending aorta. Calibration was carried out by a steady flow of saline, and sufficient linearity was obtained up to 5 L/min. The frequency response of this system was 3 dB down at 30 Hz. At this setting, the phase lag was linear with frequency. Zero shift of the probes was not detected throughout the experiment. The stroke volume was recorded by electronic beat-to-beat integration. The LV and the ascending aortic pressures were measured by a high-fidelity 7F micromanometer-tipped catheter (Millar, Houston, TX, U.S.A.) inserted from the left carotid artery and from the femoral artery, respectively. The tip of the micromanometer for measuring aortic pressure was placed just distal to the flow probe so as not to interfere the aortic-flow signal. Before insertion, both micromanometer-tipped catheters were calibrated at 37°C by using a mercury manometer. Zero shift of the pressure transducers was checked by simultaneous recording of fluid-filled transducer (Gould Statham P23Db, Oxnard, CA, U.S.A.), in which the zero reference point was taken at the level of the right atrium. Aortic pressure was measured with a low-pass filter with a 100-Hz cut-off frequency, and an aortic-flow signal was recorded with a low-pass filter with a 25-Hz cut-off frequency.
For measurement of the external LV short axis, a pair of crystals (3 MHz), 8 mm in diameter, was sutured to the epicardium of the anterior and posterior walls perpendicular to the long axis of the LV, midway between the apex and the base of the heart. A second pair of crystals (5 MHz), 2 mm in diameter, was implanted at opposing sites across the myocardium of the LV anterior free wall, on the equatorial plane of the short axis, to measure the wall thickness.
After control recording, carbon powder, 25-50 μm in diameter, which had been dissolved with low-molecular-weight dextran (1 mg/ml), was infused at a rate of 0.6 mg/kg into left coronary artery via left main trunks to produce acute cardiac failure. Forty minutes after the infusion, LV-pump function was severely impaired. After being stabilized, solvent (dimethylsulfoxide; DMSO) was first administered. Then flosequinan was infused cumulatively, from 0.3 mg/kg to 0.9 mg/kg. Hemodynamic measurements were obtained 2 min after the administration of each dose and just before increasing the dose of flosequinan.
Blood samples were taken at each stage of the study, and plasma noradrenaline and atrial natriuretic peptide (ANP) were measured.
All data were recorded at the end of an expiration on an multichannel recorder (Electronics for Medicine VR12, White Plains, NY, U.S.A.) digitized at intervals of 2 ms with an online analog-to-digital converter and stored. To obtain data for analysis, we used the average of 10 consecutive cardiac cycles. Aortic pressure and flow signals were transformed to a Fourier series, and aortic input impedance was computed as a function of frequency. Characteristic impedance (Zc) was estimated by averaging impedance moduli between 2 and 12 Hz. Total systemic resistance (TSR) was determined as input resistance (the modulus of the impedance at 0 Hz). Arterial wave reflection was evaluated by the modulus of the first harmonic of aortic-impedance spectra (Z1). Reflection coefficient (RC) was also calculated by the following equation: Equation (1)
The internal LV short axis was calculated by subtracting the wall thickness from the external LV short axis, as described by Rankin et al. (21). The LV wall stress (WSt) was calculated by using the following equation (23): Equation (2)
where LVP is the LV pressure, SAD is the internal LV short axis, and WTh is the wall thickness. End diastole was defined by the peak of the R wave on the electrocardiogram. End systole was defined by the timing of dicrotic notch on the aortic pressure.
Data are expressed as mean ± SD except for aortic-impedance spectra, in which data are expressed as mean ± SEM. Paired t tests were used to compare the hemodynamic data between the control condition and cardiac failure. One-way analysis of variance was used to compare the changes in hemodynamics during the infusion of flosequinan in acute cardiac failure. When a significant trend was identified by the F test, Scheffés post hoc test was used to compare the data. A p value <0.05 was accepted as statistically significant.
Hemodynamic parameters and aortic impedance
Hemodynamic parameters in cardiac failure are summarized in Table 1 As compared with control condition, LV peak +dP/dt, mean Vcf, percentage wall thickness, and cardiac output were all decreased in cardiac failure, associated with an increase in LV end-diastolic pressure and a prolongation of time constant of LV pressure decay (τ). There was no significant change in these hemodynamics after the infusion of the solvent, DMSO (not shown). After the infusion of flosequinan, these parameters for systolic function were all increased in a dose-dependent manner, accompanied by a decrease in LV enddiastolic pressure and a shortening of τ. The LV end-systolic wall stress, which was increased in cardiac failure, was decreased after flosequinan.
The hemodynamic parameters of LV afterload are summarized in Table 2. After the infusion of flosequinan, not only total systemic resistance (as a steady component of afterload) but also characteristic impedance (as a pulsatile component of afterload) were decreased. Arterial wave reflection was reduced after flosequinan, as evidenced by a decrease in reflection coefficient and the modulus of the first harmonic of impedance spectra (Z1). Figure 1 shows the average of aortic-impedance spectra for each stage of the study. During the infusion of flosequinan, the impedance modulus at low frequencies decreased. The zero intercept of the phase was shifted slightly toward lower frequencies after flosequinan.
Change in humoral factors after administration of flosequinan
Figure 2 shows the change in the concentration of plasma noradrenaline and ANP at each stage of the study. Plasma noradrenaline level increased significantly in cardiac failure, and further tended to increase after the administration of flosequinan. However, plasma ANP level increased in cardiac failure, followed by a decrease after flosequinan. The plasma ANP level was significantly correlated with LV end-diastolic pressure during the infusion of flosequinan (r = 0.42, p = 0.039).
The major findings of this study are that flosequinan exerted both positive inotropic and lusitropic actions in cardiac failure and that flosequinan substantially decreased not only systemic vascular resistance but also pulsatile components of LV afterload, characteristic impedance and arterial-wave reflection, leading to an improvement of LV systolic pump function.
Effect of flosequinan on aortic impedance
Although several reports already showed that flosequinan possesses positive inotropic and balanced vasodilating effects as well (3,8-10,25), none of the prior studies focused on the effect of flosequinan on pulsatile component of LV afterload, which significantly influence the LV systolic function in beating hearts. In human heart failure, it was demonstrated that arterial-wave reflection was increased and returned early during systole, as opposed to the LV ejection, and that nitroprusside, a balanced vasodilator, reduced the arterial-wave reflection in association with the improvement of LV-pump function (12,16,17). In experimental heart failure, Eaton et al. (6) found a significant increase in characteristic impedance at the early developmental stage of heart failure. In previous reports, we demonstrated that the acute increase in characteristic impedance led to a reduction in regional LV wall motion at the apical region and a decrease in cardiac output (14,26). Taken together with these findings, the pulsatile components (i.e., arterial-wave reflection and characteristic impedance) might greatly influence LV systolic function as LV afterload in cardiac failure. Therefore the reduction in the pulsatile components of LV afterload by flosequinan might contribute to the improvement of LV systolic function in cardiac failure.
Positive inotropic and lusitropic effects of flosequinan
Consistent with the prior reports (8-10), we observed that flosequinan increased LV contractility, as evidenced by a significant increase in peak +dP/dt in association with a decrease in LV end-diastolic pressure. Although the underlying mechanism by which flosequinan exerts positive inotropism is still unclear, reflex sympathetic stimulation (13) or phosphodiesterase inhibition (11) have been proposed. Recently Miao et al. (18) showed that flosequinan produces a positive inotropic effect by reduction of Na+/Ca2+ exchange in mammalian myocardium. In addition to the improvement of LV systolic function, we observed that the time constant of LV pressure decay was significantly shortened without any change in blood pressure after the infusion of flosequinan, indicating a positive lusitropic effect of flosequinan. This enhancement of active LV relaxation might contribute to an improvement of pulmonary congestion in heart failure.
Effect of flosequinan on humoral parameters
The increase in plasma noradrenaline level after flosequinan might be due to reflex sympathetic autonomic stimulation as a response to the decrease in blood pressure. In contrast, consistent with prior reports (2,5,22), plasma ANP level decreased in a dose-dependent manner after flosequinan, probably reflecting the reduction in wall stress of the atrium due to vasodilatation. Indeed, the plasma ANP level was significantly correlated with LV end-diastolic pressure during the infusion of flosequinan (r = 0.42; p = 0.039).
In the clinical settings, dobutamine or dopamine or both are frequently used for the treatment of acute heart failure. Binkley et al. (1) reported that in patients with heart failure, significant reduction in characteristic impedance, wave reflection, and low-frequency impedance were noted with dobutamine and were not seen with dopamine. Therefore the hemodynamic effects of flosequinan seem to be comparable with those of dobutamine. However, Schneeweiss et al. (24) reported that flosequinan showed additive acute hemodynamic improvement (i.e., decrease in pulmonary capillary wedge pressure, increase in cardiac output) in patients with heart failure, complicating acute myocardial infarction, which is resistant to conventional therapy including dobutamine. This. additive hemodynamic beneficial effect of flosequinan might be due to the different pharmacologic action from that of dobutamine.
Clinically, long-term administration of flosequinan is not advisable because a higher incidence of the adverse events was already reported (19,20). However, this drug might still be useful for the treatment of acute heart failure on the basis of our finding that flosequinan indeed has positive inotropic and also lusitropic effects, and, furthermore, effectively decreases both steady and pulsatile components of LV afterload.
1. Binkley PF, Van Fossen DB, Haas GJ, Leier CV. Increased ventricular contractility is not sufficient for effective positive inotropic intervention. Am J Physiol
2. Cavero PG, De MT, Kwasman M, Lau D, Liu M, Chatterjee K. Flosequinan, a new vasodilator
: systemic and coronary hemodynamics and neuroendocrine effects in congestive heart failure. J Am Coll Cardiol
3. Corin WJ, Monrad ES, Strom JA, Giustino S, Sonnenblick ES, LeJemtel T. Flosequinan: a vasodilator
with positive inotropic activity. Am Heart J
4. Cowley AJ, Wynne RD, Stainer K, Fullwood L, Rowley JM, Hampton JR. Flosequinan in heart failure: acute haemodynamic and longer term symptomatic effects. BMJ
5. Dakak N, Makhoul N, Merdler A, et al. Haemodynamic and neurohumoral effects of flosequinan in severe heart failure: similarities and differences compared with intravenous nitroglycerin therapy. Eur Heart J
6. Eaton GM, Cody RJ, Binkley PF. Increased aortic impedance precedes peripheral vasoconstriction at the early stage of ventricular failure in the paced canine model. Circulation
7. Elborn JS, Stanford CF, Nicholls DP. Effect of flosequinan on exercise capacity and symptoms in severe heart failure. Br Heart J
8. Falotico R, Haertlein BJ, Lakas WC, Salata JJ, Tobia AJ. Positive inotropic and hemodynamic properties of flosequinan, a new vasodilator
, and a sulfone metabolite. J Cardiovasc Pharmacol
9. Greenberg S, Touhey B. Positive inotropy contributes to the hemodynamic mechanism of action of flosequinan (BTS 49465) in the intact dog. J Cardiovasc Pharmacol
10. Greenberg S, Touhey B, Paul J. Effect of flosequinan (BTS 49465) on myocardial oxygen consumption. Am Heart J
11. Gristwood RW, Beleta J, Bou J, et al. Studies on the cardiac actions of flosequinan in vitro. Br J Pharmacol
12. Ikram H, Foy SG, Low CJ, et al. Hemodynamic comparison of dopexamine and nitroprusside at high and low doses in patients with coronary artery disease and impaired left ventricular function. J Cardiovasc Pharmacol
13. Isnard R, Lechat P, Pousset F, et al. Hemodynamic and neurohormonal effects of flosequinan in patients with heart failure. Fundam Clin Pharmacol
14. Kohno M, Matsuzaki M, Ozaki M, et al. Influence of acute increase in aortic impedance on left ventricular regional wall motion during early ejection period. IEEE Eng Med Biology Society 10th Annual International Conference 1988, p. 249-51.
15. Lang D, Lewis MJ. The effects of flosequinan on endothelin-1-induced changes in inositol 1,4,5-trisphosphate levels and protein kinase C activity in rat aorta. Eur J Pharmacol
16. Laskey WK, Kussmaul WG. Arterial wave reflection in heart failure. Circulation
17. Merillon JP, Fontenier G, Lerallut JF, et al. Input impedance in heart failure: comparison with normal subjects and its changes during vasodilator
therapy. Eur Heart J
18. Miao L, Perreault CL, Travers KE, Morgan JP. Mechanisms of positive inotropic action of flosequinan, hydralazine, and milrinone on mammalian myocardium. Eur J Pharmacol
19. Packer M, Narahara KA, Elkayam U, et al. Double-blind, placebo-controlled study of the efficacy of flosequinan in patients with chronic heart failure: principal investigators of the REFLECT Study. J Am Coll Cardiol
20. Packer M. Beta-blockade in the management of chronic heart failure: another step in the conceptual evolution of a neurohormonal model of the disease. Eur Heart J
21. Rankin JS, McHale PA, Arentzen CE, Ling D, Greenfield JC Jr, Anderson RW. The three-dimensional dynamic geometry of the left ventricle in the conscious dog. Circ Res
22. Riegger GA, Kahles H, Wagner A, Kromer EP, Elsner D, Kochsiek K. Exercise capacity, hemodynamic, and neurohumoral changes following acute and chronic administration of flosequinan in chronic congestive heart failure. Cardiovasc Drugs Ther
23. Ross J Jr, Sonnenblick EH, Covell JW. The architecture of the heart in systole and diastole: technique of rapid fixation and analysis of left ventricular geometry. Circ Res
24. Schneeweiss A, Wynne RD, Marmor A. The effect of flosequinan in patients with acute-onset heart failure complicating acute myocardial infarction. Jpn Heart J
25. Sim MF, Yates DB, Parkinson R, Cooling MJ. Cardiovascular effects of the novel arteriovenous dilator agent, flosequinan in conscious dogs and cats. Br J Pharmacol
26. Yano M, Kohno M, Konishi M, et al. Effect of aortic impedance on preload-afterload mismatch in canine hearts in situ. Basic Res Cardiol