Toshikazu Sobue

Relation between ventriculoarterial coupling and myocardial energetics in patients with idiopathic dilated cardiomyopathy

OBJECTIVES The purpose of this study was to evaluate left ventricular contractility, arterial loading conditions and the way their interaction affects myocardial energetics. BACKGROUND Ventriculoarterial coupling, defined as the ratio of effective arterial elastance to left ventricular end-systolic elastance, is known to reflect the mechanoenergetic performance of the heart. However, relations between the coupling and efficiencies of energy transfer from oxygen consumption to hydraulic energy have not been fully investigated in failing hearts. METHODS Pressure-volume data were measured in 23 patients with idiopathic dilated cardiomyopathy by using a conductance catheter, and myocardial oxygen consumption was obtained simultaneously in 16 patients by a double-thermistor coronary sinus catheter. End-systolic elastance was determined by transient inferior cava occlusion. RESULTS Data are reported as mean value +/- SE. Ventriculoarterial coupling at baseline was 3.24 +/- 0.28. It decreased from 3.12 +/- 0.43 to 1.86 +/- 0.15 (p < 0.05) for the group receiving dobutamine infusion and from 3.16 +/- 0.45 to 1.78 +/- 0.22 (p < 0.01) for the group receiving the oral phosphodiesterase inhibitor MS-857. The ratio of pressure-volume area to myocardial oxygen consumption had a positive correlation with ventriculoarterial coupling. The ratio of external work to pressure-volume area had a hyperbolic correlation with the coupling. The mechanical efficiency defined as the ratio of external work to myocardial oxygen consumption remained within a narrow range (16.4 +/- 1.2%). CONCLUSIONS The degree of ventriculoarterial coupling is far from optimal and the cardiovascular performance is severely depressed mechanically and energetically in patients with idiopathic dilated cardiomyopathy. Although inotropic agents improve the coupling, they have a minimal effect on mechanical efficiency.

Prognostic value of mechanical efficiency in ambulatory patients with idiopathic dilated cardiomyopathy in sinus rhythm

OBJECTIVES The purpose of this study was to determine, by analyzing the pressure-volume relationship, the prognostic value of parameters related to myocardial energetics for predicting mortality in patients with dilated cardiomyopathy (DCM) in sinus rhythm. BACKGROUND The relationship between the myocardial energetics and the prognosis of patients with DCM in sinus rhythm remains unclear. METHODS We followed 114 ambulatory patients with nonischemic DCM in sinus rhythm for a mean period of 5.8 +/- 3.9 years. Over 70% of our patients were in New York Heart Association functional class I and class II. Pressure-volume data were obtained by the conductance method, and myocardial oxygen consumption per beat (VO(2)) measurements were obtained. RESULTS The 3-, 5-, and 10-year cumulative survival rates were 88.6%, 80.0%, and 73.9%, respectively. Of the 114 patients, 47 were selected randomly to assess their myocardial energetics. By univariate analysis, the mechanical efficiency (ME, external work/VO(2)), left ventricular (LV) ejection fraction and the LV end-diastolic pressure were statistically associated with cardiac death. The ME was the strongest predictor of survival in a Cox proportional-hazards analysis (p = 0.011). The best cutoff point of ME identified by the receiver-operating curve was 11%. This value had a sensitivity of 100%, a specificity of 87% and an overall predictive accuracy of 88% to distinguish survivors from nonsurvivors. CONCLUSIONS This study clearly demonstrates that ME is a powerful clinical predictor for cardiac death in patients with mild to moderate heart failure and with sinus rhythm. Whether these conclusions apply to patients with more severe heart failure requires further investigations.

Impaired Force-Frequency Relations in Patients With Hypertensive Left Ventricular Hypertrophy A Possible Physiological Marker of the Transition From Physiological to Pathological Hypertrophy

BACKGROUND The extent to which force-frequency and relaxation-frequency relations (FFR and RFR, respectively) and exercise-induced adrenergic stimulation affect myocardial inotropic and lusitropic reserves has not been established in patients with left ventricular (LV) hypertrophy (LVH). METHODS AND RESULTS We calculated the maximum first derivative of LV pressure (LV dP/dtmax) and the LV pressure half-time (T1/2) during pacing, exercise, and isoproterenol infusion in 17 patients with hypertensive LVH and 9 control subjects to investigate the influence of increases in heart rate (HR) and adrenergic stimulation on inotropic and lusitropic reserves. Group A consisted of 10 LVH patients who showed a progressive increase in the HR-LV dP/dtmax relation. Group B consisted of 7 LVH patients in whom the HR-dP/dtmax relation at physiological pacing rates was biphasic. The LV mass index was larger and the LV ejection fraction was smaller in group B than in group A (244+/-72 g/m2 versus 172+/-22 g/m2 and 55+/-18% versus 72+/-6%, respectively; both P<0.05). The increase in LV dP/dtmax was greater during exercise than pacing alone for similar increases in HR in all groups (P<0.05) (group A, 111+/-22% versus 25+/-14%; group B, 105+/-35% versus 14+/-10%; control, 111+/-24% versus 25+/-12%). T1/2 was shorter (P<0.05) during exercise than with pacing alone in all groups (group A, 41+/-6% versus 11+/-3%; group B, 38+/-9% versus 14+/-4%; control, 44+/-6% versus 12+/-5%). Isoproterenol infusion caused similar increases in LV dP/dtmax and similar decreases in T1/2 in all groups. CONCLUSIONS The FFR was biphasic in patients with severe LVH irrespective of LV function but was preserved in patients with less severe LVH and control subjects. Importantly, the RFR and adrenergic control of both inotropic and lusitropic reserves were well preserved in all LVH patients. A biphasic FFR at physiological pacing rates may be one of the earliest markers of the transition from physiological adaptation to the pathological process in LVH patients.

Influence of left ventricular hypertrophy on left ventricular function during dynamic exercise in the presence or absence of coronary artery disease.

OBJECTIVES We investigated the influence of left ventricular hypertrophy in the presence or absence of coronary artery disease on hemodynamic characteristics during exercise in subjects without previous myocardial infarction. BACKGROUND Left ventricular hypertrophy has been found to increase the vulnerability of the myocardium to the development of ischemia. However, the independent influences of left ventricular hypertrophy and coronary artery disease have not been assessed in humans. METHODS Symptom-limited supine leg exercise tests were performed by 78 patients. They were classified into the following subgroups: no coronary artery disease or left ventricular hypertrophy (group I, n = 30), left ventricular hypertrophy only (group II, n = 12), coronary artery disease only (group III, n = 20) and both left ventricular hypertrophy and coronary artery disease (group IV, n = 16). Mean left ventricular mass index was 105, 158, 109 and 159 g/m2 in groups I to IV, respectively. RESULTS Pulmonary artery wedge pressure increased from 6 +/- 3 (mean +/- SD) mm Hg at rest to 10 +/- 5 mm Hg at peak exercise in group I, from 8 +/- 2 to 18 +/- 8 mm Hg in group II (p < 0.05 vs. group I), from 6 +/- 3 to 23 +/- 6 mm Hg in group III (p < 0.01 vs. group I) and from 8 +/- 4 to 30 +/- 7 mm Hg in group IV (p < 0.01 vs. group I; p < 0.01 vs. group II; p < 0.05 vs. group III). Multiple regression analysis showed that the number of diseased coronary vessels and left ventricular mass index were independent predictors of peak pulmonary artery wedge pressure (F = 59.2 and 19.1, respectively; multiple correlation coefficient r = 0.74, p < 0.0001). CONCLUSIONS Left ventricular hypertrophy and coronary artery disease independently increased left ventricular filling pressure during supine leg exercise. Severe left ventricular dysfunction was induced by exercise when both conditions were present.

Differential effects of dobutamine and a phosphodiesterase inhibitor on early diastolic filling in patients with congestive heart failure

OBJECTIVES This study was designed to compare the influence of beta-adrenergic stimulation (dobutamine) and a selective phosphodiesterase inhibitor (MS-857) on left ventricular diastolic performance and Doppler transmitral flow velocity patterns in patients with congestive heart failure and to elucidate the mechanisms for changes in early diastolic filling induced by each agent. BACKGROUND Both beta-adrenergic agonists and phosphodiesterase inhibitors act through the cyclic adenosine monophosphate pathway. However, it is controversial whether they have similar effects on diastolic performance. No previous studies have investigated the effects of these agents on Doppler-derived measurements of diastolic filling. We hypothesized that they would have different effects on early diastolic filling in patients with congestive heart failure. METHODS Twenty patients with chronic congestive heart failure resulting from idiopathic dilated cardiomyopathy were randomized to receive intravenous infusion of dobutamine (5 micrograms/kg body weight per min, n = 10) or oral administration of MS-857 (15 mg, n = 10). Transmitral flow velocity patterns were obtained with simultaneous recordings of pressure-volume loops using a conductance catheter with a micromanometer tip before and after drug administration. RESULTS Left ventricular filling pressure was reduced by both agents. Dobutamine decreased the time constant of isovolumetric relaxation and increased the difference between pulmonary artery wedge pressure at the peak of the v wave and left ventricular minimal pressure (10 +/- 3 to 12 +/- 4 mm Hg, p < 0.01) and peak early filling velocity (47 +/- 7 to 56 +/- 11 cm/s, p < 0.01). The diastolic pressure-volume relation showed a leftward shift in all patients. In contrast, MS-857 did not affect the time constant but maintained the pressure difference (9 +/- 3 to 8 +/- 3 mm Hg, p = NS) and peak early filling velocity (50 +/- 7 to 49 +/- 12 cm/s, p = NS). The diastolic pressure-volume relation after MS-857 showed a downward shift in most patients. CONCLUSIONS These results indicate that beta-adrenergic stimulation and phosphodiesterase inhibitors have different effects on early diastolic filling through different mechanisms in patients with congestive heart failure.

Impaired response of left ventricular relaxation to exercise-induced adrenergic stimulation in patients with hypertrophic cardiomyopathy.

OBJECTIVES We investigated the effect of adrenergic stimulation on left ventricular relaxation in patients with hypertrophic cardiomyopathy. BACKGROUND Exercise-induced decreases in acceleration of left ventricular relaxation have been observed in patients with hypertrophic cardiomyopathy. However, data on sequential changes in left ventricular relaxation during exercise are limited. METHODS We measured right (fluid filled) and left (high fidelity micromanometer) ventricular pressures during moderate supine ergometer exercise and during rapid right atrial pacing in four groups of patients: 9 with severe hypertrophic cardiomyopathy, 9 with moderate hypertrophic cardiomyopathy, 10 with hypertension and moderate hypertrophy and 5 control subjects. RESULTS There was a curvilinear relation between the time constant of relaxation (tau) and heart rate in all groups during exercise. There was no difference in the slope of this relation between the two hypertrophic cardiomyopathy subgroups. Although the slope of this relation between tau and heart rate was steeper in the hypertensive than the moderate hypertrophic cardiomyopathy group (p < 0.001, analysis of covariance), the decrease in tau during right atrial pacing was similar in both groups. There were no significant differences in plasma levels of catecholamines at rest or at peak exercise among groups or in maximal heart rate during pacing. CONCLUSIONS Pacing-induced changes in tau in hypertrophic cardiomyopathy were similar to those in hypertensive hypertrophy, but remarkable decrease in exercise-induced acceleration of tau were observed only in hypertrophic cardiomyopathy. Our results may indicate a depressed left ventricular relaxation response to exercise-induced adrenergic stimulation in hypertrophic cardiomyopathy.

A novel inotropic vasodilator, OPC-18790, reduces myocardial oxygen consumption and improves mechanical efficiency with congestive heart failure

We analyzed the left ventricular (LV) pressure-volume relation and obtained direct measurements of myocardial oxygen consumption (MVO2) before and after drug administration in 21 patients with New York Heart Association functional class II to III congestive heart failure to compare the mechanoenergetic effects of OPC-18790, a novel inotropic agent, and dobutamine. Pressure-volume data were obtained by the conductance method, and MVO2 measurements were obtained with a double-thermistor coronary sinus catheter before and after administration of OPC-18790 and dobutamine. The LV end-diastolic volume index decreased significantly without an increase in the heart rate after administration of OPC-18790, unlike that after administration of dobutamine. Both drugs significantly increased the LV contractility index (Emax) and caused similar improvements in ventricular-arterial coupling. OPC-18790 significantly reduced MVo2, whereas dobutamine increased MVo2. The ratio of the pressure-volume area to myocardial oxygen consumption (PVA/MVo2) remained unchanged after administration of OPC-18790 and decreased after administration of dobutamine. The ratio of external work to the pressure-volume area (EW/PVA) was similarly increased by both drugs, resulting in an improvement in mechanical efficiency (EW/MVo2) with OPC-18790 (p < 0.05) and in a deterioration with dobutamine (p < 0.05). OPC-18790 had an energetic advantage over dobutamine in spite of its positive inotropic effect. Our findings suggest that OPC-18790 may be useful for the treatment of patients with congestive heart failure.

The discrepancy between echocardiography, cineventriculography and thermodilution. Evaluation of left ventricular volume and ejection fraction.

We have often experienced disagreement in left ventricular end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF) between cineventriculography and echocardiography not performed simultaneously, and unnaturally hyperdynamic left ventricular wall motion. We determined EDV, ESV, stroke volume, and EF (with modified Simpsons rule) in 65 consecutive patients using 2-dimensional echocardiography with a 2.5 MHz, 128-element phased-array transducer within three days of cardiac catheterization and compared our results with those obtained by the thermodilution technique and biplane cineventriculography. Heart rate and stroke volume were significantly different among the three techniques: cineventriculography yielded the highest values. These findings suggest that patients may have been in a hyperadrenergic state caused by anxiety experienced during invasive cineventriculography and thermodilution examinations. Inter- and intraobserver variabilities for echocardiography differed little from the variability in cineventriculography. Although there were good correlations between echocardiographic and cineventriculographic findings for EDV (r=0.67), ESV (r=0.80), and EF (r=0.78) by two independent observers, there was a lack of agreement for EDV, ESV, and EF. Echocardiographic EDV values were significantly lower than cineventriculographic values. When left ventricular function is good, the left ventricle tends to be hyperadrenergic and in a more hyperdynamic state with smaller ESV than echocardiographic values during cineventriculography. When left ventricular function is poor, the left ventricle tends to be influenced by the effect of the contrast medium and stress during the invasive examinations and in a more hypodynamic state with larger ESV than echocardiographic values during cineventriculography. The echocardiography is highly reproducible and may provide information that is not available from cineventriculography and thermodilution. Cineventriculography may provide another manifestation of cardiac reserve. In conclusion, we must take into account each peculiar property of the echocardiography, the cineventriculography, or the thermodilution technique when patients are examined with cardiac conditions by different methods at different days.

Effect of antianginal agents on the relationship between rate-pressure product and myocardial oxygen uptake

To evaluate the effects of antianginal agents on the correlation between rate-pressure product and myocardial oxygen uptake, multistage supine leg exercise tests were performed by 21 patients with stable effort-induced angina pectoris before and after administration of antianginal drugs (a calcium channel blocker of the dihydropyridine class [10 mg of nisoldipine orally] in 11 patients and a beta-blocker [0.2 mg/kg of propranolol intravenously] in 10 patients). The rate-pressure product was closely correlated with myocardial oxygen uptake before and after administration of each drug. However, the slope of the regression line of rate-pressure product (X) and myocardial oxygen uptake (Y) became significantly steeper after the calcium channel blocker administration, and the Y-intercept was significantly increased by administration of the beta-blocker. Myocardial oxygen uptake was increased after administration of the calcium channel blocker and the beta-blocker compared with control values at corresponding rate-pressure product. These observations should be considered when the rate-pressure product is used to predict myocardial oxygen uptake in patients with angina pectoris who are receiving antianginal drugs.

Effect of dobutamine and OPC-18790 on diastolic chamber stiffness in patients with idiopathic dilated cardiomyopathy.

We investigated the acute effects of the positive inotropic agents (dobutamine and a novel phosphodiesterase inhibitor OPC-18790) on left ventricular diastolic chamber stiffness in patients with idiopathic dilated cardiomyopathy (DCM). We obtained pressure-volume (PV) data before and after drug administration in 17 patients with DCM by using a conductance catheter with a micromanometer tip. Patients were randomly assigned to receive intravenous infusions of dobutamine (2.5-7.5 micrograms/kg body weight per min, n = 8) or OPC-18790 (5-10 micrograms/kg body weight per min, n = 9). The dynamic diastolic chamber stiffness constant was calculated from a steady-state beat. The passive diastolic chamber stiffness constant was determined from the end-diastolic PV relation determined during transient inferior vena caval occlusion. Dobutamine and OPC-18790 similarly improved left ventricular end-systolic elastance (Ees) and left ventricular isovolumic relaxation time constants. The dynamic diastolic chamber stiffness constant decreased significantly in both the dobutamine (0.0934 +/- 0.0271 to 0.0685 +/- 0.0248; p < 0.01) and OPC-18790 (0.0843 +/- 0.0477 to 0.0569 +/- 0.0246; p < 0.05) groups. The passive diastolic chamber stiffness constant decreased significantly in the OPC-18790-treated group (0.0211 +/- 0.0114 to 0.0144 +/- 0.0117; p < 0.005) but not in the dobutamine-treated group (0.0197 +/- 0.0130 to 0.010186 +/- 0.0102; p > 0.05). Thus both dobutamine and OPC-18790 reduced the dynamic diastolic chamber stiffness constant, but only OPC-18790 reduced the passive diastolic chamber stiffness constant. OPC-18790 had a favorable effect on diastolic function in patients with DCM, compared with that of dobutamine. The passive diastolic chamber stiffness obtained from the end-diastolic PV relations represents more likely passive chamber properties than the dynamic diastolic chamber stiffness obtained from traditional single-beat analysis.