Masuki Mori

Comparison of hemodynamic determinants for myocardial oxygen consumption under different contractile states in human ventricle.

BackgroundRecently, several indexes such as tension-time index (TII), tension-time or force-time integral (FfM), rate-pressure product (RPP), pressure-work index (PWI), and systolic pressure-volume area (PVA) have been developed as predictors of myocardial oxygen consumption in experimental and clinical studies. However, it is still unclear whether these indexes are reliable predictors of myocardial oxygen consumption under various contractile states in human hearts. Methods and ResultsWe assessed the relation between TTI, FTI, RPP, PWI, and PVA and myocardial oxygen consumption per beat (&OV0622;O2) in 13 patients with heart disease during volume loading. Left ventricular (LV) volume and pressure were measured simultaneously by the conductance catheter with the tipped micromanometer technique. &OV0622;O2 was calculated from arterial coronary sinus oxygen content difference, and coronary sinus blood flow was measured by the thermodilution method. After z transformation of the correlation coefficients, mean z value for the &OV0622;O2-PVA relation (1.83±0.60) was greater than those for the &OV0622;O2-TII relation (1.22±O.66; p<0.005), &OV0622;O2-FTI] relation (1.18±O.61;p <0.05), &OV0622;O2-RPP relation (0.95±0.65; p<0.05), and &OV0622;O2-PWI relation (1.24±0.58;p<0.05). During dobutamine infusion (5 μ·kg−1·min−1) in five of the 13 patients, &OV0622;O2 also correlated best with PVA (z=1.70±0.89) compared with TII (z=1.43±0.86), FTI (z=1.48±0.95), RPP (z=1.00±0.53), and PWI (z=0.88±0.80). The contractile efficiency (38±14% to 38±20%), the reciprocal of the slope of the &OV0622;O2-PVA relation, remained unchanged, whereas the &OV0622;O2, PVA 0.8 (&OV0622;O2 at PVA=0.8 J per beat/100 g LV) increased from 1.48±1.16 to 2.06±1.13 J per beat/100 g LV (p<0.05). These results show the parallel upward shift of the &OV0622;O2-PVA relation during dobutamine infusion. Because increases in the &OV0622;O2-intercept represent the &OV0622;O2 for the increased excitation-contraction (E-C) coupling associated with the augmented contractile state, the parallelism of the &OV0622;O2-PVA relation could discriminate between &OV0622;O2 for mechanical work (PVA-dependent &OV0622;O2) and &OV0622;O2 for E-C coupling (PVA-independent &OV0622;O2). ConclusionsThe results of the present study indicate that PVA is a reliable and valuable predictor of myocardial oxygen consumption under different contractile states in human hearts. The &OV0622;O2-PVA relation could provide useful information about mechanoenergetics in diseased human hearts.

Comparison of the effects on arterial-ventricular coupling between phosphodiesterase inhibitor and dobutamine in the diseased human heart

OBJECTIVES The aim of this study was to compare the effects of a phosphodiesterase inhibitor and catecholamine on arterial-ventricular coupling and myocardial energetics in the diseases human heart. BACKGROUND Recent experimental studies have indicated that the arterial-ventricular coupling analysis using the time-varying elastance model could discriminate between inotropic and vasoactive effects of the two agents. METHODS With the use of a conductance catheter, left ventricular contractility and arterial afterload were measured from the slope of the end-systolic pressure-volume relation, Emax, and the slope of the end-systolic pressure-stroke volume relation, Ea. Arterial-ventricular coupling was assessed by Ea/Emax before and after administration of a new phosphodiesterase inhibitor, E-1020 (0.3 microgram/kg per min), and a beta 1-stimulant, dobutamine (5 micrograms/kg per min), in 20 patients with heart disease. Left ventricular mechanical efficiency was assessed as the ratio of stroke work to myocardial oxygen consumption per beat measured by the thermodilution method. RESULTS The slope of the end-systolic pressure-volume relation increased comparably with both E-1020 (39%, p < 0.01) and dobutamine (47%, p < 0.01), but Ea/Emax decreased with E-1020 (1.25 to 0.78, -37%, p < 0.01) more than with dobutamine (1.23 to 0.99, -16%, p < 0.05). Although stroke work index increased with both agents, myocardial oxygen consumption remained unchanged with E-1020 but increased with dobutamine (p < 0.05). Consequently, left ventricular mechanical efficiency increased with E-1020 (0.30 to 0.36, p < 0.05) but remained unchanged with dobutamine (0.27 to 0.29, p = NS). CONCLUSIONS The phosphodiesterase inhibitor E-1020 improved arterial-ventricular coupling more than did dobutamine, with a resultant increase in mechanical efficiency. These data were in accordance with the theoretic prediction of the coupling analysis in the diseases human heart.

Alteration in Energetics in Patients With Left Ventricular Dysfunction After Myocardial Infarction Increased Oxygen Cost of Contractility

BACKGROUND Although the use of inotropic agents to treat congestive heart failure (CHF) in patients with coronary artery disease has yielded short-term hemodynamic improvement, long-term mortality has shown less improvement. The loss of cardiac muscle as a result of infarction not only decreases the pumping ability of the heart but also leads to some dramatic changes in myocardial energetics. However, little is known about the mechanoenergetics of the heart in patients with left ventricular (LV) dysfunction after myocardial infarction. METHODS AND RESULTS The present study was designed to compare by means of the Vo2-pressure-volume area relation (PVA, a measure of total mechanical energy) and Emax (LV contractility index), the incremental oxygen cost of contractility measured as nonmechanical energy per unit increment in contractility in patients with various kinds of LV dysfunction. We assessed Emax, Vo2, and PVA using conductance and Webster catheters under control conditions and during different rates of dobutamine infusion (3 and 6 micrograms x kg-1 x min-1) in 30 patients with coronary artery disease. Patients were divided into three groups according to LV ejection fraction (EF): 10 without LV dysfunction (EF>/= 60%), 10 with mild LV dysfunction (40% </= EF < 60%), and 10 with severe LV dysfunction (EF < 40%). Under control conditions, the Vo2-PVA relation was linear in each group. Contractile efficiency, the reciprocal of the slope of this relation, was comparable among the three groups. The oxygen cost of contractility in the severe LV dysfunction group was significantly greater than in the groups without and with mild LV dysfunction (0.022 +/- 0.014 versus 0.005 +/- 0.002 and 0.0012 +/- 0.005 mL O2 x mL x mm Hg-1 per beat, P <.05). CONCLUSIONS These findings suggest that the alteration in mechanoenergetics in patients with severe LV dysfunction after myocardial infarction may result from the increased oxygen cost of excitation-contraction coupling rather than from a reduction in the efficiency of chemomechanical energy transduction.

Negative Chronotropic Effect of β-Blockade Therapy Reduces Myocardial Oxygen Expenditure for Nonmechanical Work

BACKGROUND The negative chronotropic effect of beta-blocking agents is likely to provide hemodynamic and energetic advantages. However, the negative chronotropic effect on cardiac energetics observed on the initiation of beta-blockade therapy has not been fully elucidated. METHODS AND RESULTS In 18 patients with heart failure, left ventricular pressure and volume, external work (EW), myocardial oxygen consumption per beat (total Vo2), mechanical efficiency (EW/total Vo2), and Vo2 for nonmechanical work (total Vo2-2.EW) were measured with the use of conductance catheter and Webster catheter at the following three states: under control conditions and after beta-blockade (0.15 +/- 0.07 mg/kg propranolol IV) with and without atrial pacing to keep the heart rate at control levels. Heart rate decreased after atrial pacing was stopped. EW decreased during beta-blockade with pacing and returned to the control level after pacing was stopped. Total Vo2 did not change during beta-blockade with or without pacing, whereas Vo2 for nonmechanical work increased with pacing and returned to the control level after pacing was stopped. As a result, mechanical efficiency decreased during beta-blockade with pacing and returned to the control level after pacing was stopped. CONCLUSIONS The negative chronotropic effect of a beta-blocking agent may offset the mechanoenergetical deterioration resulting from its negative inotropic effect through a reduction in oxygen expenditure for nonmechanical work. These findings suggest that the negative chronotropic effect is an important aspect of beta-blockade therapy.

Effect of NKH477, a new water-soluble forskolin derivative, on arterial-ventricular coupling and mechanical energy transduction in patients with left ventricular systolic dysfunction: comparison with dobutamine.

We examined the effects of a novel water-soluble forskolin derivative, NKH477 (0.5 microgram/kg/min), on arterial-ventricular (A-V) coupling and mechanical energy transduction from heart to circulatory bed in comparison with those of dobutamine (3 micrograms/kg/min) in 8 patients with left ventricular (LV) systolic dysfunction using a conductance catheter method. A-V coupling was assessed as the ratio of the effective arterial elastance (E(a)) to the slope of the end-systolic pressure-volume relation (ESPVR) (E(max), left ventricular contractility index), and the ratio of mechanical energy transduction was obtained as the fraction of PV area (PVA) comprised of stroke work (SW). E(max) (2.59 mm Hg/ml/m2), E(a)/E(max) (1.62), and SW/PVA (0.58) were impaired in control contractile state. NKH477 increased Emax to the same extent as dobutamine. E(a) decreased with NKH477 but not with dobutamine. As a consequence, the decrease in E(a)/E(max) with NKH477 was greater than that with dobutamine (52 vs. 47%, p < 0.05); the increase in SW/PVA with NKH477 was also greater than that with dobutamine (28 vs. 21%, p < 0.05). These findings suggest that NKH477 may be a superior alternative to dobutamine in A-V coupling and mechanical energy transduction in patients with LV systolic dysfunction.

Oxygen-Saving Effect of a New Cardiotonic Agent, MCI-154, in Diseased Human Hearts

OBJECTIVES The aim of this study was to examine the left ventricular mechanoenergetic effects of a novel Ca2+ sensitizing agent, MCI-154, on diseased human hearts compared with dobutamine. BACKGROUND Unlike conventional cardiotonic agents, a Ca2+ sensitizer that could produce a positive inotropic action by altering the responsiveness of myofilament to Ca2+ could generate force with smaller amounts of Ca2+; thus, it may potentially save energy expenditure. METHODS The left ventricular pressure-volume relation and myocardial oxygen consumption per beat (Vo2) were measured by a conductance (volume) catheter and a Webster catheter. Left ventricular contractility (Emax), systolic pressure-volume area (PVA [index of left ventricular total mechanical energy]) and Vo2 were assessed before and after infusion of MCI-154 or dobut-amine. The PVA-independent Vo2 (Vo2 mainly for excitation-contraction coupling) was assessed as the Vo2 at zero PVA. RESULTS Both agents increased Emax comparably (dobutamine: from 3.55 +/- 1.10 [mean +/- SD] to 5.04 +/- 1.16 mm Hg/ml per m2, p < 0.0001; MCI-154: from 3.36 +/- 1.26 to 5.37 +/- 2.14 mm Hg/ml per m2, p < 0.0001); dobutamine increased total Vo2 (from 0.22 +/- 0.08 to 0.27 +/- 0.09 ml O2, p < 0.05) and PVA-independent Vo2 (from 0.019 +/- 0.019 to 0.091 +/- 0.051 ml O2, p < 0.005); but MCI-154 did not change these variables significantly. Consequently, the oxygen cost of contractility (delta PVA-independent Vo2/delta Emax) was less with MCI-154 than with dobutamine (0.14 +/- 0.18 vs. 1.10 +/- 0.80 J/mm Hg per ml per m2, p < 0.05). CONCLUSIONS These results suggest that the cardiotonic action mediated by MCI-154 could provide an energetic advantage over the conventional cardiotonic action with currently used inotropic agents.

Lusitropic effects of a Ca2+ sensitization with a new cardiotonic agent, MCI-154, on diseased human hearts

OBJECTIVES Recognition of the problems of conventional cardiotonic agents has led to an interest in drugs that produce a positive inotropic action by altering the responsiveness of myofilament to Ca2+ (i.e., Ca2+ sensitizing agents). The importance of the effects of these compounds on left ventricular (LV) systolic function has been emphasized, whereas the effect of them on LV diastolic function is still problematic. To investigate the lusitropic action of a novel Ca2+ sensitizing agent, MCI-154, we compared the effects of MCI-154 on LV relaxation and filling dynamics with those of dobutamine in diseased human hearts. METHODS We assessed the slope of the end-systolic pressure-volume relation (Emax), the time constant of LV pressure decay (Tw) and the maximum rate of LV early filling (dV/dtmax) before and after the infusion of dobutamine (n = 10) or MCI-154 (n = 9). LV volume and pressure were measured by a conductance catheter and a micro-tip catheter pressure transducer. RESULTS When both agents increased Emax comparably, dobutamine decreased Tw from 51 to 37 ms and MCI-154 decreased Tw from 54 to 44 ms. The decrease of Tw with MCI-154 was less than that with dobutamine (17 vs. 29%, P < 0.05). At the same time, dobutamine increased dV/dtmax per end-diastolic volume (dV/dtmax/V) from 2.84 to 3.88 s-1, whereas MCI-154 did not. CONCLUSIONS Diastolic properties were not compromised by MCI-154, though the alteration in them with MCI-154 was less than that with dobutamine when MCI-154 increased LV contractile state to the same extent as dobutamine. The present results suggest that MCI-154 would be an ideal Ca2+ sensitizing agent that enhances force during systole without impairing diastolic function.

Beneficial effects of a Ca 2+ sensitizer, MCI-154, on the myocardial oxygen consumption–cardiac output relation in patients with left ventricular dysfunction after myocardial infarction: Comparison with dobutamine and phosphodiesterase inhibitor

Although conventional inotropic agents such as catecholamines increase myocardial oxygen consumption, a newly developed inotropic agent, a Ca2+ sensitizer, may be able to increase cardiac output with less myocardial oxygen consumption. By using right-side heart catheterization, we assessed the ratio of the increase in myocardial oxygen consumption per unit increase in cardiac output during beta-adrenergic receptor stimulation (dobutamine, n = 15), phosphodiesterase inhibition (E-1020, n = 10), and Ca2+ sensitization (MCI-154, n = 17) in patients with coronary artery disease. Dobutamine increased cardiac output and myocardial oxygen consumption. E-1020 increased cardiac output but did not change myocardial oxygen consumption. MCI-154 increased cardiac output and decreased myocardial oxygen consumption. The oxygen cost of increasing cardiac output with dobutamine and with E-1020 was different from that with dextran infusion (n = 18); in contrast, the oxygen cost with MCI-154 was significantly smaller. Thus a newly developed Ca2+ sensitizer, MCI-154, may be beneficial for the treatment of heart failure.

Serum beta2-microglobulin concentration as a novel marker to distinguish levels of risk in acute heart failure patients

BACKGROUND Recently, serum beta2-microglobulin, an endogenous marker for renal function, has been shown to be an independent predictor of mortality in older adults. However, the prognostic role of beta2-microglobulin in heart failure has not been elucidated. METHODS We prospectively evaluated serum beta2-microglobulin and creatinine concentrations, creatinine-based renal parameters (estimated glomerular filtration rate and creatinine clearance), and echocardiographic data in 131 patients with acute heart failure and creatinine concentrations < or =3.0mg/dL admitted to our hospitals. RESULTS During 2.3+/-1.3 years, 42 patients died of cardiovascular causes and 12 died of noncardiac causes. Cardiovascular events were observed in 63 patients: 53 were readmitted due to worsening heart failure, 5 readmitted for cerebral embolism, and 5 died from sudden cardiac death. According to multivariate stepwise Cox proportional hazard analysis, higher baseline serum beta2-microglobulin concentrations (X(2)=16, p<0.0001), previous congestive heart failure (X(2)=11, p<0.001), presence of chronic obstructive pulmonary disease (X(2)=8, p<0.01), and lower diastolic blood pressure (X(2)=6, p<0.05) were independent predictors of increased cardiovascular events. Also, higher baseline serum beta2-microglobulin (X(2)=20, p<0.0001), lower systolic blood pressure (X(2)=11, p<0.001), higher relative left ventricular wall thickness (X(2)=6, p<0.05), and lower body mass index (X(2)=5, p<0.05) were independent predictors of increased cardiac mortality. The adjusted hazard ratio for cardiovascular events increased with baseline serum beta2-microglobulin above 2.1 mg/L: 2.9 with beta2-microglobulin of 2.2-2.6 mg/L (95%CI 1.2-6.9, p<0.05), 2.9 with beta2-microglobulin of 2.7-3.9 mg/L (95%CI 1.2-7.2, p<0.05), and 4.7 with beta2-microglobulin of > or =4.0 mg/L (95%CI 2.0-11, p<0.001). CONCLUSIONS Higher baseline serum beta2-microglobulin concentration could be a promising risk marker in acute heart failure patients with creatinine < or =3.0 mg/dL.

Effect of Inotropic Agents on Mechanoenergetics in Human Diseased Heart

For the treatment of heart failure, inotropic agents yield short-term hemodynamic improvement. However, inotropic therapy is still an unfilled promise for the treatment of chronic heart failure (1). This may partly result from the fact that inotropic interventions increase myocardial oxygen consumption (VO2). Therefore, the investigation of myocardial energetics in relation to inotropic agents in patients with heart disease has clinical and therapeutic relevance. Recently, the concept of left ventricular (LV) elastance (Emax) and systolic pressure-volume area (PVA) has been proposed by Suga and his colleagues (2,3,4,5). Experimental studies have shown that the relation between VO2 and PVA is linear under a variety of loading conditions. This linear relation has been used to partition VO2 into non-mechanical and mechanical portions. Experimental studies have shown that positive inotropic interventions, which enhance Emax, shift the VO2-PVA relation line upward in a parallel manner. The resultant increase in VO2 intercept of the relation has been considered to be VO2 for non-mechanical work. The relation between Emax and PVA-independent VO2 has been reported to be linear; the slope represents “oxygen cost of contractility” under various inotropic interventions. The aim of this study was to examine the effects of various inotropic agents on human cardiac mechanoenergetics by utilizing the concept of Emax and the VO2-PVA relation. To this end, we compared the effects of the newly developed phosphodiesterase inhibitor E-1020 and a novel Ca++ sensitizing agent, MCI-154, with dobutamine in patients with heart disease.