Hitoshi Ishihara

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.

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.

Phenotypic variation of familial hypertrophic cardiomyopathy caused by the Phe110→Ile mutation in cardiac troponin T

Mutation of the cardiac troponin T (cTnT) gene is a genetic determinant of familial hypertrophic cardiomyopathy (HCM). A Japanese family of 14 individuals, including 6 with HCM, was subjected to genetic and clinical assessment. Five exons of the cTnT gene were sequenced in all family members. A heterozygous or homozygous T340→A (Phe110→Ile) mutation in exon 9 of the cTnT gene was detected in 11 subjects. Morphological and functional evaluation of the left and right ventricles by echocardiography revealed that 4 of 9 individuals heterozygous for the mutant allele exhibited HCM with moderate cardiac hypertrophy. Cardiac hypertrophy and other clinical features in the 2 subjects homozygous for the mutation were more severe than were those in heterozygous individuals with HCM. Thus, the clinical features of HCM due to the Phe110→Ile mutation in the cTnT gene appear to be modified by a gene dosage effect.

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.

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.

Biphasic relaxation-frequency relations in patients with effort angina pectoris: a new marker of myocardial demand ischemia.

BACKGROUND Relaxation-frequency relations (RFR) during demand ischemia have not been fully examined in patients with effort angina pectoris (AP). We sought to clarify the effects of pacing and exercise on RFR in patients with AP. METHODS We recorded left ventricular (LV) pressures during rapid atrial pacing and symptom-limited supine bicycle exercise. RFR were analyzed in 24 patients with AP and 10 controls. RESULTS LV pressure half-time (T(1/2)) in controls was gradually shortened with an increase in heart rate (HR) during pacing (-19% +/- 6% at peak HR). The changes in T(1/2) during pacing were biphasic with initial shortening (-12% +/- 5% at the critical HR) followed by prolongation (-3% +/- 7% at peak HR) in all patients with AP. The critical HR, at which T(1/2) was minimum, preceded the HR at 0.1-mV ST-segment depression, and finally chest pain occurred. The critical HR was correlated negatively with the severity of ischemia as assessed by thallium-201 scintigraphy. T(1/2) was remarkably shortened during exercise in controls (-41% +/- 10% at peak exercise). In patients with AP, 2 distinct patterns of RFR were observed during exercise. T(1/2) was shortened progressively (-37% +/- 8% at peak exercise) in 15 patients, whereas RFR remained biphasic (-21% +/- 10% at the critical HR and -11% +/- 11% at peak exercise) in the other 9 patients. Coronary angiography and exercise scintigraphy suggested more severe ischemia in patients with biphasic RFR during exercise. CONCLUSIONS Impaired RFR might be the most sensitive parameter of pacing-induced ischemia. The critical HR was closely related with severity of ischemia. Adverse effects of ischemia on LV relaxation may be alleviated by exercise.

Effects of Various Inotropic Agents on the Relation Between Ventriculoarterial Coupling and Myocardial Energetics in Patients with Idiopathic Dilated Cardiomyopathy

Idiopathic dilated cardiomyopathy (DCM) is one of the fatal heart diseases which severely compromises cardiac performance. Various aspects of this disease have been analyzed and reported (1–7) including the pathophysiology, hemodynamics, and mortality, but many problems remain unresolved. One problem is that this disease is extremely resistant to therapy and no cardiotonic agent has been reported to decrease its mortality (8–11).