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

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 p p 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 max), 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.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31461/1/0000383.pd

Left ventricular-arterial coupling relations in the normal human heart

This investigation was undertaken to assess left ventricular-arterial coupling relations in the normal human heart under varying loading conditions and inotropic states and thereby to establish whether the working point of the normal human heart is at optimal output or mechanical efficiency under basal hemodynamic conditions. In 22 patients with an atypical chest pain syndrome who had normal coronary arteriograms, left ventricular (LV) pressures, volumes, ejection fractions, and masses at cardiac catheterization, we acquired radionuclide angiograms in duplicate simultaneously with micromanometer LV pressures. These values were derived under control conditions and during methoxamine and nitroprusside infusions with heart rate held constant by right atrial pacing. Seven other patients underwent the same protocol but, in addition, we acquired these parameters during a steady-state, intravenous infusion of dobutamine (5 [mu]g/kg/min). The interaction of LV chamber elastance (Ees) and effective arterial elastance (Ea) revealed that the normal human heart was operating at an Ees/Ea ratio of 1.62, a stroke work of 76 +/- 31 gm-m, and a mechanical efficiency (stroke work to pressure-volume area ratio [SW/PVA]) of 0.65 +/- 0.10. With an increase in LV load, the Ees/Ea ratio approached 1 (p p p es/Ea ratio increased to slightly above 2.0 (p p p es/Ea, LV stroke work, and SW/PVA over a similar range of LV loading conditions, but enhanced inotropy improved the energy transfer from the left ventricle to the arterial system at comparable Ees/Ea ratios without affecting mechanical efficiency. In conclusion, these data indicate that the normal human heart operates at neither optimal output nor efficiency. The working point, however, more closely approximates maximal mechanical efficiency than maximal LV output, but the normal human heart operates over a narrow range of LV SW values.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30783/1/0000436.pd

Beneficial hemodynamic effects of intravenous and oral diltiazem in severe congestive heart failure

Concern persists about the potential negative inotropic effects of calcium channel blockers in patients with severely depressed myocardial function. Therefore, intravenous diltiazem (100 to 200 ltg/kg per min infusion) was administered for 40 minutes followed by oral diltiazem (90 to 120 mg/8 hours) for 24 hours to patients with advanced congestive heart failure (New York Heart Association class III to IV, mean ejection fraction 26 ± 4 [SD]). Intravenous diltiazem (eight patients) increased cardiac index 20% (2.05 ± 0.8 to 2.47 ± 0.8 liters/min per MZ, p < 0.01), stroke volume index 50% (22 ± 9 to 33 ± 12 MI/M2, p < 0.001) and stroke work index 27% (19 ± 10 to 24 ± 10 g-m/MZ, p < 0.05); while reducing heart rate 23% (97 ± 18 to 75 ± 11 beats/min, p < 0.01), mean arterial pressure 18% (95 ± 13 to 78 ± 7 mm Hg) and pulmonary wedge pressure 34% (29 ± 9 to 19 ± 7 mm Hg), without altering maximal first derivative of left ventricular pressure (dP/dtmax). Oral diltiazem (seven patients) produced equivalent hemodynamic effects. Transient junctional arrhythmias were observed in three of eight patients with intravenous diltiazem and one of seven patients with oral diltiazem.It is concluded that intravenous and short-term oral diltiazem improve left ventricular performance and reduce myocardial oxygen demand by heart rate and afterload reduction without significantly depressing contractile function in severe congestive heart failure. Caution should be exercised to avoid potential adverse, druginduced electrophysiologic effects in such patients

Accurate estimates of absolute left ventricular volumes from equilibrium radionuclide angiographic count data using a simple geometric attenuation correction

To simplify and clarify the methods of obtaining attenuation-corrected equilibrium radionuclide angiographic estimates of absolute left ventricular volumes, 27 patients who also had biplane contrast cineangiography were evaluated. Background-corrected left ventricular end-diastolic and end-systolic counts were obtained by semiautomated variable and hand-drawn regions of interest and were normalized to cardiac cycles processed, frame rate and blood sample counts. Blood sample counts were acquired on (d°) and at a distance (d′) from the collimator. A simple geometric attenuation correction was performed to obtain absolute left ventricular volume estimates.Using blood sample counts obtained at d° or d′, the attentuation.corrected radionuclide left ventricular end-diastolic volume estimates using both region of interest selection methods correlated with the cineangiographic end-diastolic volumes (r = 0.95 to 0.96). However, both mean radionuclide semiautomated variable left ventricular end-diastolic volumes (179 ± 100 [± 1 standard deviation] and 185 ± 102 ml, p < 0.001) were smaller than the average cineangiographic end-diastolic volume (217 ± 102 ml), and both mean hand-drawn left ventricular end-diastolic volumes (212 ± 104 and 220 ± 106 ml) did not differ from the average cineangiographic end-diastolic volume. Using the blood sample counts obtained at d° or d′, the attenuation-corrected radionuclide left ventricular end-systolic volume estimates using both region of interest selection methods correlated with the cineangiographic end-systolic volumes (r = 0.96 to 0.98). Also, using blood sample counts at d°, the mean radionuclide semiautomated variable left ventricular end-systolic volume (116 ± 98 ml, p < 0.05) was less than the average cineangiographic end-systolic volume (128 ± 98 ml), and the other radionuclide end-systolic volumes did not differ from the average cineangiographic end-systolic volume.Therefore, it is concluded that: 1) a simple geometric attenuation-correction of radionuclide left ventricular end-diastolic and end-systolic count data provides accurate estimates of biplane cineangiographic end-diastolic and end-systolic volumes; and 2) the hand-drawn region of interest selection method, unlike the semiautomated variable method that underestimates end-diastolic and end-systolic volumes, provides more accurate estimates of biplane cineangiographic left ventricular volumes irrespective of the distance blood sample counts are acquired from the collimator

Accurate estimates of absolute left ventricular volumes from equilibrium radionuclide angiographic count data using a simple geometric attenuation correction

To simplify and clarify the methods of obtaining attenuation-corrected equilibrium radionuclide angiographic estimates of absolute left ventricular volumes, 27 patients who also had biplane contrast cineangiography were evaluated. Background-corrected left ventricular end-diastolic and end-systolic counts were obtained by semiautomated variable and hand-drawn regions of interest and were normalized to cardiac cycles processed, frame rate and blood sample counts. Blood sample counts were acquired on (d°) and at a distance (d′) from the collimator. A simple geometric attenuation correction was performed to obtain absolute left ventricular volume estimates.Using blood sample counts obtained at d° or d′, the attentuation.corrected radionuclide left ventricular end-diastolic volume estimates using both region of interest selection methods correlated with the cineangiographic end-diastolic volumes (r = 0.95 to 0.96). However, both mean radionuclide semiautomated variable left ventricular end-diastolic volumes (179 ± 100 [± 1 standard deviation] and 185 ± 102 ml, p < 0.001) were smaller than the average cineangiographic end-diastolic volume (217 ± 102 ml), and both mean hand-drawn left ventricular end-diastolic volumes (212 ± 104 and 220 ± 106 ml) did not differ from the average cineangiographic end-diastolic volume. Using the blood sample counts obtained at d° or d′, the attenuation-corrected radionuclide left ventricular end-systolic volume estimates using both region of interest selection methods correlated with the cineangiographic end-systolic volumes (r = 0.96 to 0.98). Also, using blood sample counts at d°, the mean radionuclide semiautomated variable left ventricular end-systolic volume (116 ± 98 ml, p < 0.05) was less than the average cineangiographic end-systolic volume (128 ± 98 ml), and the other radionuclide end-systolic volumes did not differ from the average cineangiographic end-systolic volume.Therefore, it is concluded that: 1) a simple geometric attenuation-correction of radionuclide left ventricular end-diastolic and end-systolic count data provides accurate estimates of biplane cineangiographic end-diastolic and end-systolic volumes; and 2) the hand-drawn region of interest selection method, unlike the semiautomated variable method that underestimates end-diastolic and end-systolic volumes, provides more accurate estimates of biplane cineangiographic left ventricular volumes irrespective of the distance blood sample counts are acquired from the collimator

Mechanisms for an abnormal radionuclide left ventricular ejection fraction response to exercise in patients with chronic, severe aortic regurgitation

To clarify the mechanisms for an abnormal radionuclide left ventricular (LV) ejection fraction response to exercise in patients with chronic, severe aortic regurgitation (AR), we studied seven control patients and 21 patients with AR. We used exercise radionuclide angiography and catheterization of the right and left sides of the heart to obtain a calculation of LV chamber elastance. The control and AR groups had similar heart rates, systolic blood pressure responses to exercise and exercise durations. In both patient groups, LV end-diastolic volume did not change with exercise. In contrast to the decrease in LV end-systolic volume (p p r = 0.79, p r = 0.88, p &lt; 0.02). These data demonstrate that in patients with AR, the radionuclide LV ejection fraction at peak exercise is principally determined by the cumulative effects of chronic, severe AR on LV systolic chamber performance, and the change in radionuclide LV ejection fraction from rest to peak exercise is principally established by peripheral vascular responses.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30237/1/0000631.pd

Evaluation of left ventricular ejection fraction as a measure of pump performance in patients with chronic mitral regurgitation

Left ventricular (LV) ejection fraction may not adequately detect a reduction in LV systolic performance resulting from chronic mitral regurgitation (MR), due to ventricular unloading into the low-impedance left atrium. To determine whether LV ejection fraction sufficiently gauges myocardial function in MR, nine patients were studied using micromanometer-measured LV pressures and biplane cineventriculography before and 1 year after mitral valve surgery. Six control patients were also studied. LV ejection fraction was normal in MR patients, despite an increase in LV end-systolic volume index. LV end-systolic pressure-volume and stress-volume ratios in MR patients were lower than in controls ( P < 0.05 and P < 0.01), suggesting that LV systolic performance fell. One year after mitral valve surgery, LV ejection fraction decreased ( P < 0.05) even though LV end-systolic volume index ( P < 0.05), pressure-volume ( P < 0.05), and stress-volume ratios ( P < 0.01) all improved. Thus, LV ejection fraction inadequately reflected LV systolic function in MR patients before and after mitral valve surgery. Cathet. Cardiovasc. Intervent. 49:290–296, 2000. © 2000 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35248/1/14_ftp.pd

Radionuclide determination of the relationship between left ventricular contractile state and ejection fraction

To determine whether the relationship between various measures of left ventricular (LV) contractile state and ejection fraction (EF) is linear in man, we studied 30 patients during right atrial pacing over a range of loading conditions. With the use of micromanometer LV pressures and radionuclide LV volumes, pressure-volume (P-V) loops were generated for each loading condition. Then isochronal, instantaneous P-V data points were obtained by linear regression analysis to attain the maximum slope (Emax) of these time-varying isochrones. Other measures of LV end systole were also used to calculate end-systolic P-V relations in a similar fashion, and indirect P-V relations were obtained from the linear regression analysis of brachial artery peak pressure vs minimum LV volume data points. When the slopes of these LV contractile measures were compared to the radionuclide LV EFs, the linear correlation coefficients ranged from 0.53 to 0.67. After natural log transformation of the LV contractile state and EF data, the correlation coefficients for the polynomial curve fits ranged from 0.80 to 0.88. When the correlation coefficients for the polynomial curve fits of the natural log transformed data were compared to those for the linear regression analyses of the raw data, significant improvements were evident (p &lt; 0.05). Thus the relationship between various measures of LV contractile state and EF obtained with radionuclide angiography is best approximated by a complex, curvilinear relationship that is due, in part, to the wide range of LV contractile states within the relatively narrow normal range of LV ejection fractions.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/27169/1/0000166.pd

Assessment of myocardial oxidative metabolism in aortic valve disease using positron emission tomography with C-11 acetate

C-11 acetate has recently been introduced as a tracer of myocardial oxidative metabolism with the use of positron emission tomography. To evaluate this approach in the pressure- or volume-loaded heart, C-11 acetate clearance rate constants were determined in 22 patients with chronic aortic valve disease and in nine normal subjects. Global myocardial C-11 clearance was significantly higher in patients with predominant aortic stenosis (n = 11) or aortic regurgitation (n = 11) than in normal subjects (0.069 +/- 0.017 min-1 and 0.072 +/- 0.010 min-1 compared with 0.050 +/- 0.004 min-1, p r = 0.73, P = 0.0001) for all studies. However, analysis of patient subgroups demonstrated that this correlation held only for aortic stenosis (r = 0.79, p r = 0.89, p &lt; 0.005) but not in patients with aortic regurgitation. Normalization of C-11 acetate clearance rate constants for gradient-corrected rate-pressure product were significantly lower in patients with loaded ventricles, particularly in the presence of a low ejection fraction, compared to normal subjects. Possible mechanisms include myocardial adaptation through hypertrophy or depressed contractility, which would both tend to reduce oxygen consumption under any given load. Serial comparison of C-11 acetate kinetics and noninvasive indexes of oxygen demand may provide assessment of disease progression in pathologic ventricular loading.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/30196/1/0000584.pd