Katsuya Hata

Superoxide Generation in Directional Coronary Atherectomy Specimens of Patients With Angina Pectoris: Important Role of NAD(P)H Oxidase

Objective—NADH/NADPH oxidase is an important source of reactive oxygen species (ROS) in the vasculature. Recently, we demonstrated that p22phox, an essential component of this oxidase, was expressed in human coronary arteries and that its expression was enhanced with the progression of atherosclerosis. The present study was undertaken to investigate its functional importance in the pathogenesis of coronary artery disease. For this aim, the expression of p22phox, the distribution of oxidized low density lipoprotein (LDL), and the generation of ROS in directional coronary atherectomy (DCA) specimens were examined. Methods and Results—DCA specimens were obtained from patients with stable or unstable angina pectoris. The distribution of p22phox and of oxidized LDL was examined by immunohistochemistry. The generation of superoxide in DCA specimens was assessed by the dihydroethidium method and lucigenin-enhanced chemiluminescence. ROS were closely associated with the distribution of p22phox and oxidized LDL. Not only inflammatory cells but also smooth muscle cells and fibroblasts generated ROS. There was a correlation between ROS and the expression of p22phox or oxidized LDL. The generation of ROS was significantly higher in unstable angina pectoris compared with stable angina pectoris. Conclusions—ROS generated by p22phox-based NADH/NADPH oxidase likely mediate the oxidative modification of LDL and might play a major role in pathogenesis of atherosclerotic coronary artery disease.

Single-beat estimation of the slope of the end-systolic pressure-volume relation in the human left ventricle.

This study assessed a new method of estimating the slope (Ees) of the end-systolic pressurevolume relation (ESPVR) from a single beat of the human heart. Left ventricular pressure was recorded with a high-fidelity micromanometer in patients with heart disease during left ventriculography. Peak isovolumic pressure at the end-disastolic volume was estimated by a curve-fitting technique from an isovolumic left ventricular pressure curve. The ESPVR line was drawn from the estimated peak isovolumic pressure-volume point tangential to the left upper corner of the pressure-volume loop. The slope of this estimated ESPVR line from single-beat analysis was compared with the slope of the ESPVR line obtained from three pressure-volume loops in 16 patients given angiotensin II or nitroglycerin infusion. The estimated Ees was 5.0 ± 2.2 mm Hg/m1/m2, and the conventional Ees was 4.9 ± 2.7 mm Hg/mlm2. The estimated Ees showed a positive correlation with the conventional Ees (r = 0.91, p < 0.001, SEE= 1.2 mm Hg/ml/m2). In the other 13 patients, after dobutamine infusion (5, μg/kg/min i.v.) the estimated Ees increased significantly from 5.6 ± 1.4 to 7.4 ± 2.0 mm Hg/ml/m2 (p < 0.01). Thus, the estimated Ees approximated the conventional Ees and was sensitive to a positive inotropic intervention. We conclude that this single-beat analysis method facilitates assessment of the beat-by-beat ESPVR of the human heart.

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.

Prevalence, predictors, and prognosis of reversal of maladaptive remodeling with intensive medical therapy in idiopathic dilated cardiomyopathy

Some recent trials have shown that angiotensin-converting enzyme (ACE) inhibitors and/or beta blockers can improve left ventricular (LV) function and decrease LV mass in patients with idiopathic dilated cardiomyopathy (IDC). We assessed the prevalence and predictors of patients with IDC that showed marked reverse remodeling (a decrease in LV end-diastolic dimension > or = 5 mm to a final LV end-diastolic dimension < or = 55 mm and an increase in percent LV fractional shortening > or = 5% to a final percent fractional shortening of > or = 25% and a decrease in LV mass > or = 10%) after 2 years of intensive therapy with ACE inhibitors and/or beta blockers. In 78 patients with IDC (mean age 51 +/- 14 years), the clinical, echocardiographic, hemodynamic, laboratory, and endomyocardial biopsy data were evaluated at diagnosis and serial echocardiography was performed for 2 years. After 2 years of therapy, 20 of 78 patients (26%) showed marked reverse remodeling. Multivariate analysis revealed that higher systolic blood pressure (135 +/- 17 vs 120 +/- 16 mm Hg, p <0.001) and lower pulmonary arterial wedge pressure (7 +/- 3 vs 12 +/- 8 mm Hg, p <0.01) at diagnosis were independent predictors of reverse remodeling. Then, we further analyzed the prognosis of these patients for a mean of 50 +/- 32 months; 5-year survival (p <0.02) and event-free rates (p = 0.001) were better in patients with reverse remodeling than in patients without reverse remodeling.

Nitric Oxide Spares Myocardial Oxygen Consumption Through Attenuation of Contractile Response to β-Adrenergic Stimulation in Patients With Idiopathic Dilated Cardiomyopathy

BACKGROUNDnThe results of recent studies suggest that NO synthase may increase in the failing myocardium and that NO modulates the myocardial contractile response to beta-adrenergic stimulation. However, there are few data regarding the physiological role of NO in patients with heart failure. The aim of the present study was to address the role of NO in left ventricular (LV) contractile response to beta-adrenergic stimulation and corresponding oxygen expenditure in human heart failure.nnnMETHODS AND RESULTSnWe studied 15 patients with heart failure due to idiopathic dilated cardiomyopathy (mean ejection fraction 0.33). We examined LV contractility (E(max), the slope of end-systolic pressure-volume relation), LV external work (EW), myocardial oxygen consumption (MVO(2)), and mechanical efficiency (measured as EW/MVO(2)) with the use of conductance and coronary sinus thermodilution catheters before and during dobutamine (DOB) infusion via a peripheral vein (4. 8+/-0.3 microg. kg(-1). min(-1) IV). Heart rate was kept constant with atrial pacing. We carried out a similar protocol during the intracoronary infusion of the NO synthase inhibitor N(G)-monomethyl-L-arginine (L-NMMA; 200 micromol). DOB increased E(max), EW, and MVO(2) (by 77+/-17%, 39+/-5%, and 21+/-5%, respectively), leading to an increase in mechanical efficiency (25.4+/-3.1% to 29.6+/-4.1%). L-NMMA alone did not significantly change these variables. Although the concurrent infusion of DOB with L-NMMA increased E(max), EW, and MVO(2) (by 140+/-21%, 64+/-9%, and 35+/-5%, respectively) more than DOB alone, mechanical efficiency did not increase further (24.3+/-3.3% to 29.5+/-4.5%) because EW and MVO(2) increased in parallel. Conclusions-These data suggest that in patients with idiopathic dilated cardiomyopathy, endogenous NO spares MVO(2) through attenuation of LV contractile response to beta-adrenergic stimulation while maintaining LV energy-converting efficiency.

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

OBJECTIVESnThe 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.nnnBACKGROUNDnRecent 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.nnnMETHODSnWith 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.nnnRESULTSnThe 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).nnnCONCLUSIONSnThe 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.

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

BACKGROUNDnThe 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.nnnMETHODS AND RESULTSnIn 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.nnnCONCLUSIONSnThe 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.

Mechanoenergetic effects of pimobendan in canine left ventricles. Comparison with dobutamine.

BackgroundWe hypothesized that the effect of pimobendan (UD-CG 115 BS) to increase calcium sensitivity of contractile protein might result in less myocardial oxygen consumption (Vo2) in comparison with dobutamine when they enhance ventricular contractility to the same extent. To examine this hypothesis, we compared the effects of pimobendan and dobutamine on left ventricular contractility and energetics using the frameworks of Emax (contractility index) and the relation between Vo2 and PVA (systolic pressure-volume area, a measure of left ventricular total mechanical energy) Methods and ResultsWe measured Vo2, Emax, PVA, and force-time integral (FVI) in excised, cross-circulated, nonfailing dog hearts. The slope of the Vo2-PVA relation reciprocally indicates the efficiency from PVA-dependent Vo2 to the total mechanical energy (contractile efficiency). The Vo2 intercept of the Vo2-PVA relation, i.e., PVA-independent Vo2, reflects energy utilization for excitationcontraction coupling. The ratio of FTI to PVA-dependent Vo2 can be called contractile economy. Both drugs comparably enhanced Emax. Although the contractile economy was greater by 14±19% (p<0.05>) for pimobendan than for dobutamine, the contractile efficiency was similar between the two drugs. Oxygen cost of contractility, defined as the slope of the relation between the PVA-independent Vo2 and Emax, was the same between the two drugs. Other mechanoenergetic effects of both drugs were similar except for a greater coronary vasodilating effect of pimobendan ConclusionsPimobendan has almost the same mechanoenergetic effects as dobutamine but slightly greater contractile economy and coronary vasodilation. The calcium-sensitizing effect of pimobendan did not save the oxygen cost of contractility.

Systolic pressure-volume area (PVA) as the energy of contraction in Starling's law of the heart

SummaryWe have theoretically proposed “systolic pressure-volume area” (PVA) as a measure of total mechanical energy generated by ventricular contraction. We then experimentally showed that PVA closely correlates with left ventricular oxygen consumption (Vo2) regardless of ventricular loading conditions in a stable contractile state. Although Starlings law of the heart has been generally considered to describe the relation between ventricular preload as the input and the “energy of contraction” as the output, the energy of cardiac contraction has been variously identified with cardiac output, external work, contractile element work, tension-time index, etc., by different investigators. However, none of these variables has been unanimously accepted as the total mechanical energy of contraction because they do not consistently correlate withVo2 which represents the total energy utilization for contraction. Considering the nature of PVA which has been revealed over the last decade, we now confidently propose that PVA is the most likely expression of the total mechanical energy of contraction that has been pursued for many years as the energy of contraction in Starlings law of the heart.

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

OBJECTIVESnThe 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.nnnBACKGROUNDnUnlike 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.nnnMETHODSnThe 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.nnnRESULTSnBoth 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).nnnCONCLUSIONSnThese 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.