Effects of low-dose flosequinan on left ventricular systolic and diastolic chamber performance

Abstract

Flosequinan (manoplax) is a new vasodilating agent for the treatment of congestive heart failure. Although it may have several mechanisms of action, whether it has effects on left ventricular inotropic or luisotropic events in hemodynamically relevant low doses when added to standard therapy for congestive heart failure is unknown. Ten patients with dilated congestive cardiomyopathy who were receiving standard therapy for heart failure were studied. A bipolar right atrial pacing catheter was used to maintain a constant heart rate. A 7F thermodilution catheter was used to measure right heart pressures and obtain cardiac outputs. An 8F micromanometer catheter was used to measure left ventricular and ascending aortic pressures. Gated equilibrium radionuclide angiography was performed both before and during a steady-state infusion of flosequinan. The average flosequinan infusion rate was 2.03 +/- 0.85 mg/min, and the total administered dose averaged 84 +/- 35 mg. The hemodynamic data documented substantial systemic vasodilation manifest by a reduction in right atrial pressure (p = 0.01), mean pulmonary artery pressure (p < 0.0001), pulmonary capillary wedge pressure (p < 0.0001), and left ventricular end-diastolic pressure (p < 0.0001). These hemodynamic changes were associated with increases in cardiac index (p = 0.01) and left ventricular ejection fraction (p = 0.02) and reductions in mean aortic pressure (p = 0.02), systemic vascular resistance (p = 0.01), and left ventricular volumes (p < 0.05). There was, however, no significant effect on left ventricular contractile function measured by end-systolic pressure-volume relationship (Emax), Emax corrected for the change in left ventricular volume, or preload recruitable stroke work (Msw). In contrast, there was an improvement in isovolumic relaxation manifest by an increase in maximum rate of fall of left ventricular pressure standardized for left ventricular end-systolic pressure [(-)dP/dtmin/Pes]; p = 0.02), an acceleration in the rate of isovolumic relaxation (p = 0.01), and an improvement in left ventricular chamber stiffness (p = 0.02). These data indicate that when flosequinan, a new therapeutic agent for the treatment of congestive heart failure, is administered in hemodynamically relevant low doses to patients with dilated congestive cardiomyopathy who were receiving standard therapy for heart failure, left ventricular pump function and diastolic function is further improved. There was, however, no significant effect on left ventricular contractility. This study emphasizes that new therapeutic agents like flosequinan, when administered in lower doses to avoid the potential deleterious effects of enhanced inotropy, may be useful additions to standard therapy in patients with congestive heart failure.