Nitric oxide spares myocardial oxygen consumption through attenuation of contractile response to beta-adrenergic stimulation in patients with idiopathic dilated cardiomyopathy

BACKGROUND: The results of recent studies suggest that nitric oxide (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 contractile response to beta-adrenergic stimulation and corresponding oxygen expenditure in human heart failure. METHODS AND RESULTS: We studied 15 patients with heart failure due to idiopathic dilated cardiomyopathy (mean ejection fraction 0.33). We examined left ventricular contractility (Emax, the slope of end-systolic pressure-volume relation), left ventricular external work (EW), myocardial oxygen consumption (MVO2), and mechanical efficiency (measured as EW/MVO2) with the use of conductance and coronary sinus thermodilution catheters before and during dobutamine (DOB) infusion via a peripheral vein (4.8 +/- 0.3 micrograms.kg-1.min-1 i.v.). Heart rate was kept constant with atrial pacing. We carried out a similar protocol during the intracoronary infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 200 mumol). DOB increased Emax, EW, and MVO2 (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 Emax, EW, and MVO2 (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 MVO2 increased in parallel. CONCLUSIONS: These data suggest that in patients with idiopathic dilated cardiomyopathy, endogenous NO spares MVO2 through attenuation of left ventricular contractile response to beta-adrenergic stimulation while maintaining left ventricular energy-converting efficiency.     

Nitric oxide spares myocardial oxygen consumption through attenuation of contractile response to beta-adrenergic stimulation in patients with idiopathic dilated cardiomyopathy

BACKGROUND: The 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. METHODS AND RESULTS: We 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.     

Relation between maximum time-varying elastance pressure-volume areas and myocardial oxygen consumption in dogs

To establish whether pressure-volume areas (PVAs) calculated using the maximum time-varying elastance (Emax) have a relation with myocardial oxygen consumption (MVO2) that improves on other indexes of myocardial oxygen demand, we studied nine dogs of either sex weighing 19-39 kg, which were instrumented with a micromanometer left ventricular (LV) catheter and a Wilton-Webster coronary sinus flow catheter and had red blood cells tagged with technetium-99m for radionuclide angiography. Hemodynamics, coronary sinus flow determinations, and radionuclide angiograms were obtained under control conditions and during three to five steady-state loading conditions (mean +/- SD, 5.6 +/- 0.7). Isochronal pressure-volume data points from each pressure-volume loop were subjected to linear regression analysis to calculate Emax. The Emax relations, diastolic curves, and systolic portions of each pressure-volume loop were used to obtain calibrated PVAs. The Emax PVA (mm Hg.ml.beat-1.100 g-1) and MVO2 (ml O2.beat-1.100 g-1) values correlated in each animal (r = 0.77 to 0.99). Their slopes averaged (3.48 +/- 1.68) x 10(-5) ml O2.mm Hg-1.ml-1, and their y-axis intercepts averaged 0.07 +/- 0.04 ml O2.beat-1.100 g-1. When the MVO2 relations were compared with Emax PVA, LV systolic pressure-rate product, LV stroke work, and a modification of the LV pressure-work index, the Emax PVA, LV systolic pressure-rate product, and LV pressure-work index had similar relations with MVO2, whereas LV stroke work was a weaker index of MVO2 (p less than 0.05 versus Emax PVA). This occurred because the Emax PVA:MVO2 slopes and y-axis intercepts differed in each dog, which was due to differences in basal LV contractility. The Emax PVA:MVO2 slopes correlated with Emax (r = 0.73, p less than 0.05), and the y-axis intercepts were also weakly related to Emax (r = 0.48, p = 0.19). We conclude that the Emax PVAs calculated using data acquisition techniques that are clinically applicable have relations with MVO2 that in general do not improve on other indexes of myocardial oxygen demand in this animal preparation.     

Nitric oxide synthase inhibition impairs myocardial efficiency and ventriculo-arterial matching in acute ischemic heart failure

BACKGROUND AND AIMS: The effect of nitric oxide (NO) manipulation in acute heart failure has not been sufficiently investigated. Therefore, we assessed the impact of NO-synthase (NOS) inhibition on left ventricular (LV) function and energetics as well as overall hemodynamics, in a porcine model of acute ischemic LV failure. METHODS: Acute heart failure was induced by left coronary artery microembolization in fourteen anesthetized pigs. LV pressure-volume relationships and mechanical work (PVA) were assessed 30 min after stable heart failure, using pressure-conductance catheters. Myocardial oxygen consumption (MVO(2)) was determined from coronary flow and coronary arteriovenous oxygen difference. Microembolization led to a significant decrease in cardiac output, arterial pressure and LV systolic and diastolic performance. Animals were then randomized to a control group (n=7) or to receive 15 mg/kg N(omega)-Nitro-L-arginine-metyl ester (n=7), an inhibitor of NO synthase (NOS). RESULTS: Measurements 15 min later revealed that NOS inhibited animals had significantly reduced cardiac output (1.53+/-0.45 vs. 2.13+/-0.49 l/min, P=0.003) and stroke work (1054+/-461 vs. 1296+/-348 mmHg ml, P=0.03), and also displayed a significant increase in the slope of the MVO(2)-PVA relationship (2.57+/-0.53 vs. 1.92+/-0.15, P=0.008), i.e. an inefficient chemomechanical coupling. NOS inhibition did not alter contractility, diastolic function or arterial pressure, but afterload was significantly increased compared to controls (arterial elastance 6.03+/-1.48 vs. 2.74+/-0.34 mmHg/ml, P=0.009). CONCLUSION: Inhibition of NOS in experimental acute heart failure increased afterload without altering left ventricular systolic and diastolic function. Consequently, cardiac output was reduced. Furthermore, mechanoenergetic efficiency was severely impaired. NOS inhibition in acute heart failure and cardiogenic shock warrants further investigations.     

Beneficial effects of heart rate reduction on cardiac mechanics and energetics in patients with left ventricular dysfunction

It has been shown recently that the force-frequency relationship is blunted in experimental heart failure models. Furthermore, tachycardia is thought to have adverse effects on the diseased heart for several reasons, one of which is an increase in myocardial oxygen consumption. Inversely, the oxygen-saving effects of bradycardia may be beneficial for the treatment of heart failure. The aim of this study was to elucidate how heart rate (HR) modulates cardiac mechanics and energetics in patients with left ventricular (LV) dysfunction. LV pressure-volume data and myocardial oxygen consumption (MVO2) was assessed using conductance and coronary sinus thermodilution catheters in 14 patients with moderate LV dysfunction (mean ejection fraction 34%) under 3 conditions: (a) basal, (b) HR increased by 20% using atrial pacing, and (c) HR decreased by 16% using a specific bradycardic agent, zatebradine (7.5 mg p.o.). Atrial pacing decreased external work (EW) (from 0.39 to 0.31 J beat(-1) m(-2), p<0.05) at a comparable MVO2 per beat with a marginal increase in LV contractility index (Ees) (from 2.34 to 2.76 mm Hg ml(-1) m(-2), p = 0.08), resulting in a decrease in mechanical efficiency (EW/MVO2) (from 25.9 to 22.1%, p<0.05). In contrast, zatebradine did not decrease Ees (from 2.34 to 2.24 mm Hg ml(-1) m(-2), NS), but increased EW (from 0.39 to 0.42 J beat(-1) m(-2), p<0.05 vs. basal level) without a change in MVO2 per beat, resulting in improved mechanical efficiency (from 25.9 to 29.7%, p<0.05 vs. basal level). These results suggest that mild bradycardia is energetically advantageous and does not decrease myocardial contractility and performance, whereas pacing-induced tachycardia worsens cardiac mechanics and energetics in patients with LV dysfunction. Thus, the oxygen-saving effect of bradycardia may be beneficial for the treatment of heart failure.     

Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart

Inhibition of xanthine oxidase (XO) in failing hearts improves cardiac efficiency by an unknown mechanism. We hypothesized that this energetic effect is due to reduced oxidative stress and critically depends on nitric oxide synthase (NOS) activity, reflecting a balance between generation of nitric oxide (NO) and reactive oxygen species. In dogs with pacing-induced heart failure (HF), ascorbate (1000 mg) mimicked the beneficial energetic effects of allopurinol, increasing both contractility and efficiency, suggesting an antioxidant mechanism. Allopurinol had no additive effect beyond that of ascorbate. Crosstalk between XO and NOS signaling was assessed. NOS inhibition with N(G)-monomethyl-L-arginine (L-NMMA; 20 mg/kg) had no effect on basal contractility or efficiency in HF, but prevented the +26.2+/-3.5% and +66.5+/-17% enhancements of contractility and efficiency, respectively, observed with allopurinol alone. Similarly, improvements in contractility and energetics due to ascorbate were also inhibited by L-NMMA. Because of the observed NOS-XO crosstalk, we predicted that in normal hearts NOS inhibition would uncover a depression of energetics caused by XO activity. In normal conscious dogs, L-NMMA increased myocardial oxygen consumption (MVO2) while lowering left ventricular external work, reducing efficiency by 31.1+/-3.8% (P<0.005). Lowered efficiency was reversed by XO inhibition (allopurinol, 200 mg) or by ascorbate without affecting cardiac load or systemic hemodynamics. Single-cell immunofluorescence detected XO protein in cardiac myocytes that was enhanced in HF, consistent with autocrine signaling. These data show that both NOS and XO signaling systems participate in the regulation of myocardial mechanical efficiency and that upregulation of XO relative to NOS contributes to mechanoenergetic uncoupling in heart failure.     

Short-term treatment with ranolazine improves mechanical efficiency in dogs with chronic heart failure

The present study assesses whether ranolazine increases left ventricular (LV) function without an increase in myocardial oxygen consumption (MVO2) and thus improves LV mechanical efficiency in dogs with heart failure (HF). Ranolazine did not change MVO2 and LV mechanical efficiency increased (22.4+/-2.8% to 30.9+/-3.4% (P<0.05). In contrast, dobutamine significantly increased MVO2 and did not improve mechanical efficiency. Thus, short-term treatment with ranolazine improved LV function without an increase in MO2, resulting in an increased myocardial mechanical efficiency in dogs with HF.     

Cardiac nitric oxide production due to angiotensin-converting enzyme inhibition decreases beta-adrenergic myocardial contractility in patients with dilated cardiomyopathy

OBJECTIVES: This study tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitors attenuate beta-adrenergic contractility in patients with idiopathic dilated cardiomyopathy (DCM) through nitric oxide (NO) myocardial signaling. BACKGROUND: The ACE inhibitors increase bradykinin, an agonist of NO synthase (NOS). Nitric oxide inhibits beta-adrenergic myocardial contractility in patients with heart failure. METHODS: The study patients were given the angiotensin-1 (AT-1) receptor antagonist losartan for one week. The hemodynamic responses to intravenous dobutamine were determined before and during intracoronary infusion of enalaprilat (0.2 mg/min) with and without the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 5 mg/min). RESULTS: In patients with DCM (n = 8), dobutamine increased the peak rate of rise of left ventricular pressure (+dP/dt) by 49 +/- 8% (p < 0.001) and ventricular elastance (Ecs) by 53 +/- 16% (p < 0.03). Co-infusion with enalaprilat decreased +dP/dt to 26 +/- 12% and Ecs to -2 +/- 17% above baseline (p < 0.05), and this anti-adrenergic effect was reversed by L-NMMA co-infusion (p < 0.05 vs. enalaprilat). In addition, intracoronary enalaprilat reduced left ventricular end-diastolic pressure (LVEDP), but not left ventricular end-diastolic volume, consistent with increased left ventricular distensibility. Infusion with L-NMMA before enalaprilat in patients with DCM (n = 5) prevented the reduction in +dP/dt, Ecs and LVEDP. In patients with normal left ventricular function (n = 5), enalaprilat did not inhibit contractility or reduce LVEDP during dobutamine infusion. CONCLUSIONS: Enalaprilat attenuates beta-adrenergic contractility and enhances left ventricular distensibility in patients with DCM, but not in subjects with normal left ventricular function. This response is NO modulated and occurs in the presence of angiotensin receptor blockade. These findings may have important clinical and pharmacologic implications for the use of ACE inhibitors, AT-1 receptor antagonists and their combination in the treatment of heart failure.     

Energy conversion efficiency in human left ventricle.

BACKGROUND. Left ventricular mechanical efficiency is one of the most important measures of left ventricular pump performance. Several clinical studies, however, have shown that mechanical efficiency does not fall substantially as the heart fails. To clarify the insensitivity of mechanical efficiency to the change in pump performance, we analyzed human left ventricular mechanical efficiency, applying the concept of left ventricular systolic pressure-volume area (PVA). METHODS AND RESULTS. PVA correlates linearly with myocardial oxygen consumption per beat (MVO2): MVO2 = a.PVA+b, and represents the total mechanical energy of contraction. We determined MVO2-PVA relation and external work in 11 patients with different contractile states. We also calculated the energy transfer from MVO2 to PVA (PVA/MVO2 efficiency), that from PVA to external work (work efficiency), and mechanical efficiency (external work/MVO2). Left ventricular pressure-volume loops were constructed by plotting the instantaneous left ventricular pressure against the left ventricular volume at baseline and during pressure loading. The contractile properties of the ventricle were defined by the slope of the end-systolic pressure-volume relation (Ees). Pressure elevation raised external work by 41.4%, PVA by 71.2%, and MVO2 by 54.5%. These changes were associated with a decrease in work efficiency and an increase in PVA/MVO2 efficiency. The opposite directional changes in these two efficiencies rendered the mechanical efficiency constant. The slope, a, of the relation between MVO2 and PVA was relatively constant (2.46 +/- 0.33) over the range of 0.8-8.8 mm Hg/ml of Ees, but the oxygen axis intercept, b, tended to decrease with the reduction in Ees. PVA/MVO2 efficiency correlated inversely (r = -0.66, p less than 0.05) with Ees, whereas work efficiency correlated linearly with Ees (r = 0.91, p less than 0.01). CONCLUSIONS. Mechanical efficiency is not appreciably affected by changes in loading and inotropic conditions as long as the left ventricular contractility is not severely depressed.     

Evaluation of left ventricular mechanical energy efficiency and ventriculo-arterial coupling in humans using the conductance catheter technique

To evaluate left ventricular mechanical energy efficiency and ventriculo-arterial coupling in humans, left ventricular pressure-volume relations were determined using the conductance catheter technique in 20 patients undergoing cardiac catheterization. The results were as follows: 1. A convex, curvilinear relationship was observed between end-systolic pressure-volume relations (Emax) and left ventricular ejection fraction (EF), as shown in the equation of EF = 28.5 x log (Emax) + 39.6 (r = 0.67, p less than 0.01, n = 20); EF remained nearly constant in the range of Emax greater than or equal to 4 mmHg/ml/m2, whereas, EF decreased markedly under the Emax of 4 mmHg/ml/m2. 2. A convex, curvilinear relationship was observed between Emax and mechanical energy efficiency (EW/PVA), as shown in the equation of EW/PVA = 30.5 x log (Emax) + 54.8 (r = 0.83, p less than 0.01, n = 16). 3. A concave, curvilinear relationship was observed between Emax and ventriculo-arterial coupling (Ea/Emax), as shown in the equation of Ea/Emax = -0.8 x (Emax)0.5 + 2.6 (r = -0.85, p less than 0.01, n = 16). Accordingly, EW/PVA was markedly decreased with changes in Emax in the range less than 4 mmHg/ml/m2, although it remained slightly increased above 4 mmHg/ml/m2. Ea/Emax was maintained constant (p less than 0.5) in the range of Emax above 4 mmHg/ml/m2 but was abruptly decreased when Emax was reduced below 4 mmHg/ml/m2. These results indicate that depressed left ventricle attempts to work effectively at the risk of mechanical energy efficiency and with suitable matching by aortic property. Application of pressure-volume relationships provides a new framework for evaluation and treatment of the failing heart.     

Exhaled nitric oxide does not provide a marker of vascular endothelial function in healthy humans.

In the lung, nitric oxide synthase (NOS) has been found in both alveolar epithelial and vascular endothelial cells. Nitric oxide (NO) in the exhaled air stemming from the lower respiratory tract has been claimed to represent a marker of the vascular endothelial NO production. Experimental evidence for this concept, however, is lacking. We compared, in eight healthy volunteers, effects on exhaled NO of epithelial NOS inhibition by N (G)-monomethyl-L-arginine (L-NMMA) inhalation (6 mg/kg over 15 min) with those of endothelial NOS inhibition by L-NMMA infusion (25 microgram/kg/min for 30 min). We also measured blood pressure, heart rate, and L-NMMA plasma concentration. The major new findings were that L-NMMA inhalation which did not have any detectable effect on hemodynamics and L-NMMA plasma concentration, decreased the pulmonary exhaled NO by almost 40%. In contrast, L-NMMA infusion that inhibited endothelial NOS, as evidenced by an increase in blood pressure and a decrease in heart rate, had only a barely detectable effect on exhaled NO (-11 +/- 4% from baseline). Pulmonary exhaled NO is mostly of epithelial rather than endothelial origin, and does not provide a marker for vascular endothelial NO production and/or endothelial function in healthy humans.     

Cardiovascular and adenylate cyclase stimulating effects of colforsin daropate, a water-soluble forskolin derivative, compared with those of isoproterenol, dopamine and dobutamine.

Colforsin daropate is a recently developed water-soluble derivative of forskolin that directly stimulates adenylate cyclase, unlike the catecholamines. The chronotropic, inotropic and coronary vasodilator actions of colforsin daropate were compared with those of isoproterenol, dopamine and dobutamine, using canine isolated, blood-perfused heart preparations. The stimulating effect of each drug on adenylate cyclase activity was also assessed. Colforsin daropate, as well as each of the catecholamines, exerted positive chronotropic, inotropic and coronary vasodilator actions. The order of selectivity for the cardiovascular variables of colforsin daropate was coronary vasodilation > positive inotropy > positive chronotropy; whereas that of isoproterenol, dopamine and dobutamine was positive inotropy > coronary vasodilation > positive chronotropy. Thus, a marked characteristic of colforsin daropate is its potent coronary vasodilator action. On the other hand, each drug significantly increased the adenylate cyclase activity in a dose-related manner: colforsin daropate > isoproterenol > dopamine = dobutamine. These results suggest that colforsin daropate may be preferable in the treatment of severe heart failure where the coronary blood flow is reduced and beta-adrenoceptor-dependent signal transduction pathway is down-regulated.     

Role of nitric oxide in regulation of coronary blood flow in response to increased metabolic demand in dogs with pacing-induced heart failure

The role of endothelium-derived nitric oxide (NO) in the metabolic control of coronary blood flow (CBF) in heart failure (HF) is poorly understood, so the present study investigated the effects of inhibitors of NO synthesis on the response of CBF to changes in myocardial oxygen consumption (MVO2) in dogs with HF produced by rapid ventricular pacing and in control dogs. The CBF, MVO2, and other hemodynamic parameters were measured in anesthetized animals. Before infusion of Nomega-nitro-L-arginine methyl ester (L-NAME), the increases in CBF and MVO2 during pacing tachycardia were not significantly different between the control and HF dogs. Intracoronary infusion of L-NAME did not alter the responses of CBF or MVO2 to pacing tachycardia in the control dogs, but in the HF dogs, it reduced the CBF response to pacing tachycardia without altering the tachycardia-induced changes in MVO2. Intracoronary infusion of L-arginine reversed the effect of L-NAME. These results suggest that in HF dogs NO contributes to the regulation of CBF in response to an increased metabolic demand.     

Comparison between the effects of 2-3 butanedione monoxime (BDM) and calcium chloride on myocardial oxygen consumption.

The agent 2,3-butanedione monoxime (BDM) has been reported to reduce the sensitivity of myofilament force development to calcium ions, without affecting the calcium transient in myocardium. One would predict, therefore, that BDM should reduce the contractile state of the heart without reducing the amount of oxygen that is consumed to fuel the process of excitation-contraction coupling. The purpose of the present experiment was to test this hypothesis using isovolumically contracting, isolated, blood perfused canine hearts during beta-blockade induced by continuous intra-coronary infusion of propranolol (1 mg/h). Contractile state was increased in seven hearts by CaCl2 infusion. Subsequently, while the CaCl2 infusion was continued at the highest rate, contractile state was reduced by BDM infusion. At each contractile state, we measured the left-ventricular end-systolic pressure-volume relation (ESPVR), the relation between myocardial oxygen consumption and its mechanical correlate, pressure-volume area (MVO2 vs PVA), and the duration of the LV pressure waveform. Contractile state was quantified by interpolated developed pressure at a reference ventricular volume of 25 ml (P25). BDM infusion (0.5-7 mM) caused a dose-dependent reduction in contractile state (50% reduction in P25 at 2.4 +/- 0.3 mM), and a dose-independent increase in coronary blood flow. Furthermore, BDM significantly reduced the duration of the pressure waveform up to 40% at the highest rate of BDM infusion compared to the pressure waveform duration measured at maximum CaCl2 infusion. We observed a direct relationship between MVO2 of the mechanically unloaded heart and contractility; this relation was unaffected by BDM infusion (P > 0.3). The slope of the MVO2-PVA relation decreased with increases in contractile state, but this decrease was unaffected by BDM (P > or = 0.4). We conclude that in the isolated canine heart, BDM does not act energetically as expected for a myofibrillar calcium desensitizing agent.     

A sodium channel enhancer, LY341311, increases myocardial contractile performance without increasing heart rate in conscious normal dogs: a comparison with dobutamine

BACKGROUND: Catecholamines and many inotropic agents increase cardiac contractility but also cause excessive myocardial O2 consumption (MVO2). We determined if the novel Na+ channel enhancer LY341311, which increases myocardial contractility independent of beta receptors, can produce significant cardiac inotropic effects compared with dobutamine but at lower oxygen cost in conscious dogs. METHODS AND RESULTS: Mongrel dogs were chronically instrumented for measurement of arterial pressure, left ventricular (LV) pressure and internal diameter, coronary blood flow, and arterial and coronary sinus O2 content. Both LY341311 and dobutamine produced dose-dependent increases in LV dP/dt, dP/dt/40, fractional shortening, and cardiac stroke work and minute work estimated from the LV pressure-diameter loop. The major difference between LY341311 and dobutamine was an opposing effect on heart rate with LY341311 slightly reducing it but dobutamine markedly increasing it. LY341311 caused a significantly smaller increase in MVO2 than dobutamine (P <.05) and produced similar cardiac inotropic effects, yielding a higher cardiac mechanical efficiency than dobutamine. However, after pacing to match heart rate with dobutamine LY341311 increased MVO2 markedly, approaching the same level as with dobutamine. CONCLUSIONS: The novel Na+ channel enhancer LY341311 caused significant increases in myocardial contractility and contractile performance without increasing heart rate. It had a beneficial energetic effect on the heart with significantly less O2 cost and improved cardiac mechanical efficiency.     

Effect of coronary hyperemia on Emax and oxygen consumption in blood-perfused rabbit hearts. Energetic consequences of Gregg's phenomenon.

To assess the relation between increases in contractile function and oxygen consumption (VO2) during increased coronary flow (Gregg's phenomenon), we measured the end-systolic pressure-volume relation and the relation between VO2 and left ventricular systolic pressure-volume area (PVA, a measure of total mechanical energy output) in blood-perfused, isovolumically contracting rabbit hearts during control and intracoronary adenosine infusion. During adenosine infusion at a constant perfusion pressure (93 +/- 11 mm Hg), coronary flow increased by 99 +/- 76% (p less than 0.01), and the slope of the end-systolic pressure-volume relation, Emax (ventricular contractility index), increased by 18 +/- 15% (p less than 0.01). When compared at the same left ventricular volume, PVA increased by 20 +/- 14% (p less than 0.01) and VO2 by 19 +/- 15% (p less than 0.01) with adenosine. The VO2-PVA relation was linear under each condition (both median r = 0.98). With increased coronary flow, the VO2-intercept of the VO2-PVA relation (unloaded VO2) increased by 22 +/- 18% (p less than 0.01) without a change in the slope; that is, a parallel upward shift was observed, indicating that the contractile efficiency (energy conversion efficiency of the contractile machinery) remained constant. These increases in Emax and unloaded VO2 were not eliminated by beta-adrenergic blockade with propranolol. We conclude that increased coronary flow with adenosine at a constant perfusion pressure augments both Emax and the nonmechanical energetic cost for excitation-contraction coupling and basal metabolism via nonadrenergic mechanisms, without changing contractile efficiency.     

Effects of fluorocarbons with and without oxygen supplementation on cardiac hemodynamics and energetics

Because of uncertainty about the mechanism by which fluorocarbons ameliorate myocardial ischemia, the effects of a fluorocarbon emulsion, perfluorodecalin and perfluorotripropylamine (Fluosol-DA 20% TM) with and without 100% O2 inhalation, on cardiac hemodynamics and energetics were studied in the anesthetized dog. Left ventricular (LV) intramural partial pressure of oxygen (PmO2) was measured by mass spectrometry before and after intravenous infusion of Fluosol-DA 20% (40 ml/kg), and was compared with measurements made in another group of dogs receiving the volume expander dextran (36 ml/kg). Both groups of dogs were then ventilated with 100% O2 and repeat measurements were performed. In the 11 animals receiving fluorocarbons, there were increases in left atrial pressure, LV myocardial blood flow, and LV myocardial O2 consumption (MVO2) compatible with volume expansion. After 100% O2, LV MVO2 decreased to control values, while PmO2 increased to 127 +/- 48 mm Hg (p less than 0.001). There were no significant changes in heart rate, arterial pressure or first derivative of LV pressure (dP/dt) during the study. In 10 dogs treated with dextran there was no change in heart rate or dP/dt, but arterial and left atrial pressures were higher after dextran infusion and remained elevated after 100% O2 inhalation. LV MVO2 increased with volume expansion, and remained increased after 100% O2. PmO2 (66 +/- 18 mm Hg) after 100% O2 was lower (p less than 0.02) than in the fluorocarbon-treated dogs after O2 inhalation.(ABSTRACT TRUNCATED AT 250 WORDS)     

The Role of Nitric Oxide in the Failing Heart

Nitric oxide (NO) has effects on contractility, energetics and gene expression of failing myocardium. Initial studies on isolated cardiomyocytes showed NO to reduce systolic shortening but intracoronary infusions of NO-donors or of NO synthase (NOS) inhibitors failed to elicit changes in baseline LV contractility indices such as LVdP/dt(max). Intracoronary infusions of NO-donors or of substance P, which releases NO from the coronary endothelium, however demonstrated NO to induce a downward displacement of the left ventricular (LV) diastolic pressure-volume relation, consistent with increased LV diastolic distensibility. In end-stage failing myocardium, the increased oxygen consumption is related to reduced NO production and in isolated cardiomyocytes, NO blunts the norepinephrine-induced expression of the fetal gene programme thereby preserving myocardial calcium homeostasis.In dilated cardiomyopathy, changed endomyocardial NOS gene expression has been reported. Because of lower endomyocardial NOS gene expression in patients with higher functional class and lower LV stroke work, increased endomyocardial NOS gene expression seems to be beneficial rather than detrimental for the failing heart. A beneficial effect of increased NOS gene expression could result from NO's ability to increase LV diastolic distensibility, to augment LV preload reserve, to reduce myocardial oxygen consumption and to prevent downregulation of calcium ATPase. Upregulated endomyocardial NOS gene expression has also been reported in athlete's heart and could therefore play a role in physiological LV remodeling. Reduced endomyocardial NO content because of decreased NO or increased superoxide production could lower LV diastolic distensibility and contribute to diastolic heart failure. In many conditions such as aging, hypertension, diabetes or posttransplantation, the increased incidence of diastolic heart failure is indeed paralleled by reduced endothelium-dependent vasodilation.     

Alterations in left ventricular mechanics, energetics, and contractile reserve in experimental heart failure.

The contributions of changes in primary systolic and diastolic properties, limitations of contractile reserve, and alterations in energy efficiency to the left ventricular dysfunction seen with chronic pacing tachycardia were investigated. Seven dogs (heart failure group) were ventricularly paced at 250 beats per minute for 26.3 +/- 2.9 days and compared with a separate control group (n = 8). STudies were performed with isolated, metabolically supported hearts coupled to a computer-controlled loading system. Pressure-volume relations and myocardial oxygen consumption (MVO2) were measured to assess chamber systolic and diastolic properties and efficiency (relation between MVO2 and pressure-volume area [PVA]). Systolic function was reduced in failure hearts versus controls as assessed by the slope of the end-systolic pressure-volume relation (1.29 +/- 0.94 versus 2.71 +/- 0.98 mm Hg/ml, p less than 0.01) and lowered end-systolic stiffness at a matched stress (956.1 +/- 123.5 versus 1,401.7 +/- 431.7 g/cm2, p less than 0.05). Diastolic chamber and myocardial stiffness were unaltered in failure hearts, but the unstressed diastolic-arrested volume was significantly larger (33.3 +/- 3.9 versus 21.9 +/- 7.6 ml, p less than 0.01). Inotropic response to increased heart rate and exogenous beta-adrenergic stimulation (dobutamine HCl) was significantly impaired in failure compared with control hearts. Most interestingly, failure hearts had a lowered slope of the MVO2-PVA relation (2.1 +/- 1.1 versus 2.9 +/- 1.4 ml O2.mm Hg-1.ml-1.100 g left ventricle-1, p less than 0.001), indicating increased efficiency of chemomechanical energy conversion. The y intercept of the MVO2-PVA relation, which reflects oxygen costs of basal metabolism and excitation-contraction coupling, was unchanged in the two groups despite decreased contractility of the heart failure hearts. These results demonstrate reduced chamber and myocardial contractility, dilatation without alteration of passive myocardial properties, impaired contractile reserve, and novel alterations in cardiac efficiency in this model of heart failure.