Changes In MVO2 Research Articles

Serial measurements of myocardial efficiency in patients with aortic valve stenosis: pathophysiological insights and prognostic information

Abstract Background In patients with aortic valve stenosis (AS), the pathophysiological abnormalities involved in the transition to symptomatic heart failure are unclear. During progression of chronic heart failure, the coupling between myocardial stroke work and myocardial oxygen consumption, i.e. myocardial external efficiency (MEE), deteriorates. However, in AS patients it is unknown whether changes in MEE over time are involved in disease progression and whether MEE has prognostic information. Purpose In patients with AS, we 1) investigated changes in MEE over time and 2) studied if MEE was associated with long-term prognosis. Methods In a prospective design, we studied 10 healthy controls and 38 patients with moderate-severe, asymptomatic AS (aortic valve area 0.5±0.1 cm2/m2, mean gradient 31±12 mmHg) and left ventricular ejection fraction ≥50%. The patient group was evaluated by serial 11C-acetate positron emission tomography, cardiovascular magnetic resonance imaging and echocardiography with a median follow-up period of 2.8 years. Furthermore, we conducted an extended follow-up of patients for a median of 5.2 years to detect clinical events (defined as symptoms due to AS, aortic valve replacement, hospitalization due to heart failure or cardiovascular death) and related them to MEE changes. Results During follow-up AS patients mean aortic valve pressure gradients increased by 13 mmHg (9 to 17; p<0.001) (mean (95% confidence interval)) and aortic valve opening area declined by −0.15 cm2 (−0.20 to −0.09; p<0.001). Global longitudinal strain worsened by 2.6% (1.8 to 3.5; p<0.001) and N-terminal pro-B-type natriuretic peptide increased by 162 ng/L (28 to 296; p=0.02) whereas left ventricular ejection fraction and cardiac index did not change significantly. MEE increased during follow-up by 4.3% (1.9 to 6.8; p=0.001) from 25.2% (24.0 to 26.5) to 29.5% (27.3 to 31.8) and was higher compared to healthy volunteers 19.9% (18.1 to 21.8; p<0.001). The changes in MEE were positively correlated to changes in end-diastolic volume (r=0.58, p=0.005) and wall stress (r=0.54, p=0.01). There were no changes in MVO2 0.0 mL/min/100g (−0.8 to 0.8; p=0.98) during follow-up. As compared to event-free patients, patients who experienced a clinical event during long-term follow-up (n=24, 63%) had higher baseline MEE 26.5% (24.3 to 28.6) vs 23.8% (22.6 to 25.1) (p=0.04) and did not increase MEE during follow-up 1.9% (−1.8 to 5.6; p=0.28) vs 5.9% (2.6 to 9.2; p=0.002). Conclusion In asymptomatic AS patients, MEE increased over time in tandem with increasing transvalvular gradients and wall stress. Thus, the myocardium displayed an inherent capacity to improve the coupling between oxidative metabolism and contractile function in response to pressure overload. High baseline MEE and blunted MEE increase predicted a poor prognosis. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Lundbeck FoundationArvid Nilssons Foundation

β2-adrenergic stress evaluation of coronary endothelial-dependent vasodilator function in mice using (11)C-acetate micro-PET imaging of myocardial blood flow and oxidative metabolism.

BackgroundEndothelial dysfunction is associated with vascular risk factors such as dyslipidemia, hypertension, and diabetes, leading to coronary atherosclerosis. Sympathetic stress using cold-pressor testing (CPT) has been used to measure coronary endothelial function in humans with positron emission tomography (PET) myocardial blood flow (MBF) imaging, but is not practical in small animal models. This study characterized coronary vasomotor function in mice with [11C]acetate micro-PET measurements of nitric-oxide-mediated endothelial flow reserve (EFRNOM) (adrenergic-stress/rest MBF) and myocardial oxygen consumption (MVO2) using salbutamol β2-adrenergic-activation.Methods[11C]acetate PET MBF was performed at rest + salbutamol (SB 0.2, 1.0 μg/kg/min) and norepinephrine (NE 3.2 μg/kg/min) stress to measure an index of MBF response. β-adrenergic specificity of NE was evaluated by pretreatment with α-adrenergic-antagonist phentolamine (PHE), and β2-selectivity was assessed using SB.ResultsAdjusting for changes in heart rate × systolic blood pressure product (RPP), the same stress/rest MBF ratio of 1.4 was measured using low-dose SB and NE in normal mice (equivalent to human CPT response). The MBF response was correlated with changes in MVO2 (p = 0.02). Nitric oxide synthase (NOS)-inhibited mice (Ng-nitro-L-arginine methyl ester (L-NAME) pretreatment and endothelial nitric oxide synthase (eNOS) knockout) were used to assess the EFRNOM, in which the low-dose SB- and NE-stress MBF responses were completely blocked (p = 0.02). With high-dose SB-stress, the MBF ratio was reduced by 0.4 following NOS inhibition (p = 0.03).ConclusionsLow-dose salbutamol β2-adrenergic-stress [11C]acetate micro-PET imaging can be used to measure coronary-specific EFRNOM in mice and may be suitable for assessment of endothelial dysfunction in small animal models of disease and evaluation of new therapies.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-014-0068-9) contains supplementary material, which is available to authorized users.

Adipose-derived regenerative cells in patients with ischemic cardiomyopathy: The PRECISE Trial

Adipose-derived regenerative cells (ADRCs) can be isolated from liposuction aspirates and prepared as fresh cells for immediate administration in cell therapy. We performed the first randomized, placebo-controlled, double-blind trial to examine the safety and feasibility of the transendocardial injections of ADRCs in no-option patients with ischemic cardiomyopathy. Procedural, postoperative, and follow-up safety end points were monitored up to 36 months. After baseline measurements, efficacy was assessed by echocardiography and single-photon emission computed tomography (6, 12, and 18 months), metabolic equivalents and maximal oxygen consumption (MVO2) (6 and 18 months), and cardiac magnetic resonance imaging (6 months). We enrolled 21 ADRC-treated and 6 control patients. Liposuction was well tolerated, ADRCs were successfully prepared, and transendocardial injections were feasible in all patients. No malignant arrhythmias were seen. Adverse events were similar between groups. Metabolic equivalents and MVO2 values were preserved over time in ADRC-treated patients but declined significantly in the control group. The difference in the change in MVO2 from baseline to 6 and 18 months was significantly better in ADRC-treated patients compared with controls. The ADRC-treated patients showed significant improvements in total left ventricular mass by magnetic resonance imaging and wall motion score index. Single-photon emission computed tomography results suggested a reduction in inducible ischemia in ADRC-treated patients up to 18 months. Isolation and transendocardial injection of autologous ADRCs in no-option patients were safe and feasible. Our results suggest that ADRCs may preserve ventricular function, myocardial perfusion, and exercise capacity in these patients.

Negative inotropic action of propofol is enhanced in the acute ischemic myocardium of dogs

We investigated the effects of propofol on contractility and oxygen balance in acute ischemic myocardium and compared them with those of normal myocardium using a coronary microembolization model in dogs. In open-chest dogs, the left anterior descending coronary artery (LAD) was perfused through an extracorporeal bypass from the carotid artery. Regional myocardial contractility and myocardial oxygen balance were evaluated along with segment shortening (%SS), regional myocardial oxygen consumption (MVO2), and lactate extraction ratio (LER) of the area perfused by the LAD. Acute ischemia was produced by repeated injection of microspheres into the LAD-perfused area until %SS decreased by 50% of baseline. In normal myocardium, intracoronary infusion of propofol at doses of 1.2 and 2.4 mg x kg(-1) x h(-1) caused slight decreases in %SS to 83% +/- 8% and 80% +/- 10%, respectively. In ischemic myocardium, propofol caused greater decreases in %SS (59% +/- 18% and 35% +/- 20%, respectively). The changes in MVO2 after propofol infusion generally paralleled the changes in %SS, but LER was not changed in either ischemic or normal myocardium. Propofol causes a greater decrease in the contractility of acute ischemic myocardium as compared with normal myocardium in which myocardial oxygen imbalance is not involved as a mechanism.

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.

Potential Deleterious Effect of ß-Adrenergic Stimulation During Warm-Blood Cardioplegia in Rabbit Hearts

We hypothesized that beta-adrenergic stimulation with isoproterenol during continuous normothermic cardioplegic arrest would enhance the regenerative and regulatory function of the myocardium, resulting in improved cardiac function. We studied isolated rabbit hearts paced at approximately 200 beats per minute (bpm) and perfused by a support rabbit. We measured ventricular pressure over a range of ventricular volumes to determine maximal elastance (Emax) at baseline and 20 and 45 min after discontinuation of cardioplegia. Myocardial oxygen consumption (MVO2) measurements were performed simultaneously and during cardioplegic arrest. Hearts were prospectively randomized to receive either isoproterenol at 0.1 M or control in blinded fashion for 10 min during a 1-h continuous warm-blood cardioplegic arrest. Compared to control hearts, isoproterenol-treated hearts had trends toward longer time to first spontaneous heartbeat (control 141 +/- 43 vs. isoproterenol 200 +/- 74 s, p = .07), and longer time to capture of atrial pacing (control 214 +/- 52 vs. isoproterenol 288 +/- 91 s, p = .06). There was no difference observed in the MVO2 between isoproterenol-treated and control groups of hearts. MVO2 decreased during cardioplegia (p < .01), but there was no significant change in MVO2 during isoproterenol infusion during cardioplegic arrest. There was a significant reduction in Emax compared to baseline 20 min after discontinuation of cardioplegic arrest in both groups (control 7.3 +/- 1.7 mm Hg/microL vs. 9.0 +/- 1.7 mm Hg/microL, p = .02, isoproterenol-treated 6.8 +/- 2.8 mm Hg/microL vs. 8.2 +/- 2.6 mm Hg/microL, p = .01, respectively), with recovery of Emax by 45 min in control hearts only. We conclude that exposure of hearts to isoproterenol during warm cardioplegic arrest has a deleterious effect that may be mediated through mechanisms independent of increased myocardial oxygen consumption.

A critical appraisal of the rate pressure product as index of myocardial oxygen consumption for the study of metabolic coronary flow regulation

For the assessment of metabolic coronary vasodilatation, changes in systolic rate pressure product (RPP) are frequently used to estimate the pacing- or exercise induced changes in myocardial oxygen consumption (MVO2). The present study was designed to test whether this is justified in patients with coronary artery disease. To study the relation between RPP and changes in MVO2 under different conditions, we used data from 21 patients who participated in two previous studies investigating the effect of nitroglycerin (NTG) and anaesthesia on metabolic coronary flow regulation. At control, during administration of NTG 1 μg/kg/min (n=11), and during anaesthesia (n=10), coronary sinus blood flow, MVO2 and RPP were measured at sinus rhythm and during atrial pacing (30 bpm above sinus rate) and the relation between the percentage increase in RPP (Δ%RPP) and MVO2 (Δ%MVO2) was analysed, using standard linear regression analysis. Although a significant relation between Δ%MVO2 and Δ%RPP was found at control and during anaesthesia, prediction intervals were very wide and only 40% and 60% of the variation in Δ%MVO2, respectively, could be explained by the variation in Δ%RPP. During administration of NTG 1 μg/kg/min no significant relation was found between Δ%MVO2 and Δ%RPP. Thus, for the study of metabolic coronary flow regulation, pacing induced changes in MVO2 cannot be predicted accurately from changes in RPP.

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.

Proinflammatory cytokines depress cardiac efficiency by a nitric oxide-dependent mechanism.

Proinflammatory cytokines (interleukin-1beta, tumor necrosis factor-alpha, and interferon-gamma; Cytomix) depress myocardial contractile work partially by stimulating expression of inducible nitric oxide (NO) synthase (iNOS). Because NO and peroxynitrite inhibit myocardial O2 consumption (MVO2), we examined whether this mechanism contributes to reduced cardiac work. In control isolated working rat hearts, cardiac work was stable for 60 min, followed by a decline from 60 to 120 min, without change in MVO2. Cardiac efficiency (work/MVO2) was therefore reduced from 60 to 120 min. Cytomix shortened the onset (within 20-40 min) and enhanced the depression in cardiac work and efficiency and inhibited MVO2 after 80 min. Mercaptoethylguanidine (MEG), an iNOS inhibitor and peroxynitrite scavenger, or the glucocorticoid dexamethasone (Dex) abolished the effects of Cytomix. iNOS expression was increased 10-fold by Cytomix and abolished by Dex but not MEG. That cytokine-induced depression in cardiac work precedes the reduction in MVO2 suggests, at least in the early response, that NO and/or peroxynitrite may not impair heart function by inhibiting mitochondrial respiration but reduce the heart's ability to utilize ATP for contractile work.

Two-year experience with rate-modulated pacing controlled by mixed venous oxygen saturation.

Mixed venous oxy-hemoglobin saturation (MVO2) is a physiological variable with several features that might be desirable as a control parameter for rate adaptive pacing. Despite these desirable characteristics, the long-term reliability of the MVO2 sensor in vivo is uncertain. We, therefore, designed a study to prospectively evaluate the long-term performance of a permanently implanted MVO2 saturation sensor in patients requiring VVIR pacing. Under an FDA approved feasibility study, eight patients were implanted with a VVIR pulse generator and a right ventricular pacing lead incorporating an MVO2 sensor. In order to accurately assess long-term stability of the sensor, patients underwent submaximal treadmill exercise using the Chronotropic Assessment Exercise Protocol (CAEP) at 2 weeks, 6 weeks, and 3, 6, 9, 12, 18, and 24 months following pacemaker implantation. Paired maximal exercise testing using the CAEP was also performed with the pacing system programmed to the VVI and VVIR modes in randomized sequence with measurement of expired gas exchange after 6 weeks and 12 months of follow-up. During maximal treadmill exercise the peak exercise heart rate (132 +/- 9 vs 71.5 +/- 5 beats/min, P < 0.00001) and maximal rate of oxygen consumption (1,704 +/- 633 vs 1382 +/- 407 mL/min, P = 0.01) were significantly greater in the VVIR than in the VVI pacing mode. Similarly, the duration of exercise was greater in the VVIR than the VVI pacing mode (8.9 +/- 3.6 min vs 7.6 +/- 3.7 min, P = 0.04). The resting MVO2 and the MVO2 at peak exercise were similar in the VVI and VVIR pacing modes (P = NS). However, the MVO2 at each comparable treadmill exercise stage was significantly higher in the VVIR mode than in the VVI mode (CAEP stage 1 (P = 0.005), stage 2 (P = 0.04), stage 3 (P = 0.008), and stage 4 (P = 0.04). The correlation between MVO2 and oxygen consumption (VO2) was excellent (r = -0.93). Telemetry of the reflectance of red and infrared light and MVO2 in the right ventricle during identical exercise workloads revealed no significant change over the first 12 months of follow-up (ANOVA, P = NS). The chronotropic response to exercise remained proportional to VO2 in all patients over the first 12 months of follow-up. The time course of change in MVO2 during maximal exercise was significantly faster than for VO2. At the 18- and 24-month follow-up exercise tests, a significant deterioration of the sensor signal with attenuation of chronotropic response was noted for 4 of the 8 subjects with replacement of the pacing system required in one patient because of lack of appropriate rate modulation. Rate modulated VVIR pacing controlled by right ventricular MVO2 provides a chronotropic response that is highly correlated with VO2. This parameter responds rapidly to changes in workload with kinetics that are more rapid than those of VO2. Appropriate rate modulation provides a higher MVO2 at identical workloads than does VVI pacing. Although the MVO2 sensor remains stable and accurate over the first year following implantation, significant deterioration of the signal occurs by 18-24 months in many patients.

Transients in myocardial O2 consumption after abrupt changes in perfusion pressure in goats.

The dynamic oxygen content differences were analyzed in the present study. The left main coronary artery of the anesthetized, open-chest goat was perfused at constant pressure (Pp). Pp(t), arterial flow [Qa(t)], and the arteriovenous oxygen content difference [a-vO2(t)] were averaged per beat. The a-vO2 signal was corrected for mixing processes in the capillaries and transport time from capillaries to the venous measuring site [a-vO2(t)]. A change in Pp of 20 mmHg induced a temporary change in MVO2, referred to as the dynamic Gregg effect. With an increase in Pp, the maximal change of myocardial oxygen consumption [MVO2(t) = Qa(t).a-vO2(t)] was 15.0 +/- 3.6% (means +/- SE) during control and 31.3 +/- 2.3% with glibenclamide. With a decrease in Pp these changes were 16.3 +/- 2.9 and 21.0 +/- 1.1%. During control, the half-time for the rate of return of the MVO2 response was 4.2 +/- 0.8 s for an increase and 4.0 +/- 1.0 s for a decrease in Pp. With glibenclamide these values were 16.9 +/- 2.2 and 22.6 +/- 2.0 s. This study confirms that during steady state the Pp-induced MVO2 (steady-state Gregg effect) is diminished by autoregulation. However, it is concluded that during transients following abrupt changes in Pp, large changes in MVO2 occur depending on the rate of regulation (dynamic Gregg effect).

Functional and energetic effects of the inotropic agents EMD-57033 and BAPTA on the isolated rat heart

This investigation studied the functional and energetic effects of the novel positive inotropic agent EMD-57033 and the negative inotropic agent 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) in the paced Langendorff-perfused rat heart. EMD-57033 is a calcium-sensitizing agent that has previously been shown to increase contractility without affecting calcium transients. Its effects were compared with that of dobutamine, which increases contractility by increasing calcium transient amplitude. EMD-57033 (2 microM) and dobutamine (0.2 microM) induced a 40% increase in developed pressure. Myocardial oxygen consumption (MVO2) increased significantly with dobutamine. However, there was no significant change in MVO2 with EMD-57033. There was no change in phosphate metabolite concentrations as detected by 31P-nuclear magnetic resonance with either agent. Lactate production and basal metabolism were unaffected by either agent. Thus EMD-57033 increased contractility in a more energetically economical manner than did dobutamine. Contractility was decreased with BAPTA, an intracellular calcium chelator that decreases contractility by binding free calcium. The metabolic effects of BAPTA (2.2 microM) were compared with those of verapamil (10 nM), an agent which decreases calcium fluxes. Both agents decreased developed pressure 60%. MVO2 decreased 14% with BAPTA and 50% with verapamil. Neither agent altered the concentrations of phosphate metabolites, lactate production, or basal metabolism. Thus BAPTA lowered contractility in a less energetically economical manner than verapamil. These data suggest that in rat hearts, inotropic agents with different effects on calcium handling have different effects on energetics.

Evaluation of Left Ventricular Mechanical Efficiency in the Human Heart by Echocardiography

It has been proved that ventricular systolic wall stress and myocardial mass are two major determinants of myocardial oxygen consumption (MVO2) in the intact human heart. The product of stress and mass, which we named the stress‐mass‐index (SMI), has the correct unit for work (cm X dyns/cm = dyns x cm), and is very similar to the pressure‐volume work of the heart. To examine whether SMI might be used as a predictor of MVO2, left ventricular mean systolic wall stress (Mσc,Mσm), left ventricular wall mass (Mm), and stroke work (SW) were measured by echocardiography in normal and diseased human hearts. The area bounded by the end‐diastolic and end‐systolic pressure‐volume lines, and the systolic segment of the pressure‐volume loop (PVA) were also measured in each subject. It has been proved repeatedly in the past that PVA correlates significantly with MVO2. Our results showed that there was a close correlation between PVA and SMI in every group (r − 0.76‐0.91, P &lt; 0.001 all), which proved indirectly that SMI may reflect MVO2. On this basis, left ventricular efficiency (Eff) was estimated as SW/SMI × 100%. Effin 30 patients with essential hypertension (17.1%± 1.6%) was normal compared to the control subjects (19.9%± 2.4%). However, Eff of 22 hypertensive patients with mild left ventricular dysfunction (13.3%± 2.1%), 33 coronary artery heart disease patients (10.8%± 1.8%), and 11 chronic congestive heart failure patients (6.6%± 2.1%) was significantly decreased compared to the control. These changes in Eff were in agreement with clinical findings and left ventricular ejection fractions (EF). For the first time, we have measured Eff noninvasively; the results are very close to those evaluated invasively in human hearts by others. This reflects the fact that it is possible to calculate Eff noninvasively. We conclude that the product of left ventricular systolic wall stress could reflect the change in MVO2 at rest. SW/SMI may be a useful method in evaluating Eff and ventricular function.

Effects of contrast media on coronary hemodynamics and myocardial metabolism.

This study was designed to compare the effects of ionic contrast medium (CM), Renografin-76 (R76), and nonionic CM, Omnipaque-350 (OM350), on coronary hemodynamics and myocardial metabolism. In 10 open-chest, atrial-paced dogs, 4 mL of R76 and OM350 were injected into the left anterior descending coronary artery. Coronary blood flow (CBF), myocardial oxygen consumption (MVO2), lactate extraction (LE), left ventricular (LV) dp/dt, and aortic systolic pressure (AOP) were measured. The maximal CBF changes caused by OM350 and R76 were 23.7 +/- 3.3 mL/minute and 18.3 +/- 3.3 mL/minute (NS), respectively. OM350 produced an increase in LV dp/dt by 378 +/- 85 mm Hg/second, which was different from -244 +/- 65 mm Hg/second by R76 (P < .05). The changes in MVO2 and LE after OM350 injection were 2.6 +/- 0.6 mL/minute and 10.2 +/- 5 microM/minute, respectively; those were different from -0.1 +/- 0.4 mL/minute, and -7.7 +/- 5.1 microM/minute after R76 injection (P < .05). Although both agents increased CBF, they appeared to act by different mechanisms. That a direct coronary vasodilator effect is the main action of R76 on coronary vascular response is suggested by decreasing myocardial contractility and oxygen consumption. However, OM350, by enhancing both parameters, may augment CBF at least in part by autoregulation.

Coronary perfusion related changes in myocardial contractile force and systolic ventricular stiffness

The mechanism by which changes in coronary perfusion alter myocardial oxygen consumption (MVO2; Gregg phenomenon) is controversial. This study examined the effect of coronary perfusion on myocardial contractile force and systolic ventricular stiffness in the intact, ejecting heart. During selective perfusion of the left anterior descending coronary artery, coronary blood flow was changed with or without concurrent changes in coronary perfusion pressure in 19 alpha chloralose anaesthetised dogs. Regional myocardial segment length (end diastolic length; end systolic length) and developed force were measured with piezoelectric crystals and with a miniature force transducer, respectively. MVO2 was calculated from coronary flow and arteriovenous O2 difference. The slope of the force-length curve during ejection period (delta F/delta SL) was used as an index of systolic myocardial stiffness. When coronary perfusion pressure was varied from 60 to 180 mm Hg (protocol 1, n = 11), maximum developed force (Fmax), delta F/delta SL, and MVO2 increased with perfusion pressure while end diastolic length, segmental shortening, and other haemodynamic variables stayed constant. When coronary blood flow was increased at constant perfusion pressure by infusion of either a low dose or a high dose adenosine (protocol 2, n = 8), Fmax, delta F/delta SL, and MVO2 increased while end diastolic length, segmental shortening, and other haemodynamic variables stayed constant. MVO2 and delta F/delta SL increased more steeply with flow in protocol 1. (1) Increased coronary blood flow enhances myocardial contractile force, systolic ventricular stiffness, and MVO2 in the intact, ejecting heart. (2) Coronary blood flow induced changes in myocardial contractile force and systolic ventricular stiffness, but not end diastolic length, are probably responsible for coronary blood flow related changes in MVO2.

Endotoxin induces metabolic dysregulation of vascular tone

The goals of this study were to determine 1) if endotoxin alters vascular responsiveness to metabolic stimuli and 2) if the decompensatory loss of skeletal muscle vascular tone that occurs during endotoxemia is induced by increased muscle metabolism. Vascularly isolated and denervated canine gracilis muscles were perfused in situ at a constant flow. In the first set of experiments, gracilis muscle O2 extraction (MVO2) and perfusion pressure were continuously measured during direct electrical stimulation of the muscle mass. Endotoxemia was induced by a 30-min intravenous infusion of Escherichia coli endotoxin (2 mg/kg), and the stimulations were repeated 60 min postendotoxemia. Compared with the nonendotoxic control, the endotoxemic muscle stimulation resulted in a decreased MVO2, and the vascular response (dilation) was potentiated. In the second set of experiments, the MVO2 of the experimental muscle (GMe) was lowered by cooling the temperature of the blood perfusing the muscle to 22-24 degrees C while maintaining the temperature of the contralateral control muscle (GMc) at 34-35 degrees C. After the administration of endotoxin, arterial pressure fell and the GMc showed a progressive increase in MVO2 and loss of vascular tone (decompensation). Coincidently, the GMe showed no significant change in MVO2 and did not vasodilate. The major findings of this study are 1) endotoxin induces the vasculature to become more reactive to metabolic vasodilation, and 2) the decompensatory vasodilation typically observed during endotoxemia can be abolished if MVO2 (i.e., metabolism) is kept low by cooling the muscle. The data suggest that endotoxemia increases vascular sensitivity to vasodilatory metabolites, which allows local mechanisms to dominate extrinsic nonneural forces and control vascular tone, thus inducing vasodilation.

Direct effects of propofol on myocardial contractility in in situ canine hearts.

The pronounced decrease in arterial blood pressure evident during anesthetic induction with propofol has raised the possibility that propofol has a direct negative inotropic effect. Previous attempts to evaluate this mechanism in vivo have been inconclusive because of confounding variables associated with intravenous administration of propofol. Accordingly, in the current study, steady-state changes in myocardial contractility and related hemodynamic parameters were assessed during intracoronary infusions of propofol in seven open-chest dogs anesthetized with fentanyl and midazolam. The left anterior descending coronary artery (LAD) was cannulated and perfused at controlled pressure (100 mmHg) with normal arterial blood. In LAD-perfused myocardium, contractility was evaluated from measurements of percent segmental shortening (%SS) obtained with ultrasonic crystals. Coronary blood flow in LAD was measured electromagnetically and used to calculate myocardial oxygen consumption (MVO2; Fick principle) and coronary propofol concentration. Propofol was infused into the LAD at 150, 300, 600, and 1,200 micrograms/min (P-150, P-300, P-600, P-1,200). These infusion rates yielded calculated blood concentrations of 7 +/- 1, 15 +/- 1, 26 +/- 2, and 50 +/- 5 micrograms.ml-1, respectively. The calculated blood concentrations at P-150 were in the clinical range, whereas those at P-300, P-600, and P-1,200 were supratherapeutic. P-150 had no effect on %SS, whereas higher infusion rates caused decreases in %SS. Changes in MVO2 by propofol generally paralleled changes in %SS. At P-150 and P-300, coronary blood flow was proportional to MVO2, whereas at P-600 and P-1,200, coronary blood flow was in excess of the prevailing MVO2, resulting in increased coronary venous oxygen tension.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative assessment of prolonged metabolic abnormalities in reperfused canine myocardium.

Prolonged metabolic abnormalities have been demonstrated previously in postischemic myocardium, including relative increases in glucose uptake and abnormal fatty acid kinetics. However, quantitative metabolic information is limited, and the time course of changes in MVO2 in postischemic myocardium is unknown. To address these issues, chronically instrumented dogs were studied serially over 1 month after transient left anterior descending coronary artery (LAD) occlusion, using positron emission tomography. Dynamic imaging protocols were used in conjunction with tracer kinetic models to quantify blood flow and metabolic rates. Myocardial sectors were defined as normal, predominantly reversibly injured, and infarct-containing, based on occlusion blood flow images and postmortem histochemistry. Myocardial blood flow and metabolism were homogeneous at baseline. During LAD occlusion for 3 hours, myocardial blood flow in reversibly injured and infarct-containing sectors (determined with 13NH3) was decreased to 46% and 23%, respectively, of blood flow in normal tissue. MVO2, determined with [1-11C]acetate, was decreased less than myocardial blood flow, consistent with increased oxygen extraction in the ischemic tissue. After reperfusion, blood flow normalized rapidly in reversibly injured tissue but remained depressed in infarct-containing sectors. Regional myocardial function, assessed by two-dimensional echocardiography, was severely depressed during occlusion and did not improve significantly until 1 week after reperfusion. MVO2 remained depressed after reperfusion in both reversibly injured and infarct-containing sectors, did not improve from occlusion levels until 1 week after reperfusion, and remained significantly depressed 1 month after reperfusion even in reversibly injured sectors; [1-11C]palmitate kinetics were also abnormal in postischemic tissue. As reported previously, glucose metabolic rates were increased relative to baseline in normal but not in postischemic tissue 3 hours after reperfusion. Subsequently, glucose metabolism tended to be higher in postischemic relative to normal myocardium. The results demonstrate decreased oxidative metabolism in postischemic tissue, with concomitant abnormalities in palmitate kinetics and glucose metabolism. Oxidative metabolism and regional function demonstrated a parallel recovery with time.

Changes in oxygen-haemoglobin affinity and myocardial function during extracorporeal perfusion in immature pigs

An alteration in oxygen-haemoglobin affinity, as indicated by the partial pressure of oxygen at 50% haemoglobin saturation (P50), may theoretically affect oxygen delivery to the myocardium and, thus, alter myocardial tissue PO2 and possibly myocardial function. We studied the effect of changes in P50 on heart function, metabolism, and coronary sinus PO2 in 10 anaesthetized immature domestic pigs. To facilitate exchange transfusions and control of preload (left ventricular end diastolic pressure, LVEDP), afterload (mean arterial pressure), cardiac output, and heart rate, the animals were placed on right heart bypass. Stroke work (SW), myocardial oxygen consumption (MVO 2), coronary blood flow (CBF), arterial-coronary sinus O2 content difference (CaO2 -CcsO2), and P50 were measured with a control blood prime and after an exchange transfusion with blood having either a low (Group I) or high (Group II) affinity for oxygen. Results (Mean ± SEM, Control versus Test): P50 (mmHg) at 37°C and pH 7.4 increased in Group 1 (35.5 ± 0.7 versus 40.1 ± 1.2, p &lt;0.01) and decreased in Group II (34.7 ± 1.3 versus 26.3 ± 0.5, P &lt;0.001). At 8mmHg LVEDP, SW (gram·metres, g.m) remained constant in Group I (12.2 ± 1.1 versus 11.7 ± 0.8 g·m), but decreased (p &lt;0.05) in Group II (11.7 ± 0.9 versus 8.6 ± 0.61 g.m). In addition, Starling curves relating SW to LVEDP between 4 and 18mmHg were uniformly depressed in Group II but not Group I. No significant change in MVO2 occurred in either group. Group II demonstrated decreased CaO2- CcsO2 (9.3 ± 0.8 versus 6.0 ± 0.3ml O2/dl, p &lt;0.05) and increased CBF (121.6 ± 16.5 versus 188.9 ± 16.9ml/min/1 00gm, p &lt;0.01). PcsO2 increased significantly in Group I (26.6 ± 4.2 versus 36.1 ± 2.7, P &lt;0.02) but not Group II. In conclusion, a decrease in P50 appeared to decrease myocardial function despite a lack of change in PcsO2 or MVO2. A decrease in P50 also led to an increase in CBF. An increase in P50 did not alter function, but did increase coronary sinus and, presumably, tissue PO2.

Effects of inspiratory loading on left ventricular myocardial blood flow and metabolism

With airways obstruction, mean pleural pressure decreases. It has been postulated that associated increases in left ventricular afterload increase myocardial O2 demand (MvO2) and coronary blood flow (CBF). We tested this hypothesis in 12 anesthetized mixed-breed dogs. Through a median sternotomy, dogs were instrumented for the measurement of mean arterial pressure, cardiac output, and left anterior descending CBF. A catheter placed in the coronary sinus allowed sampling of left ventricular venous blood. MvO2 was calculated as CBF x (arteriovenous content difference), and coronary resistance was calculated as (mean arterial pressure)/CBF. After closure of the thoracotomy, animals were studied before and during inspiratory threshold loading (IL) of -20 to -25 cmH2O while breathing 100% O2 before and after bilateral cervical vagotomy. During IL, heart rate fell [approximately 20 beats/min (NS prevagotomy, P less than 0.05 postvagotomy)], arterial PCO2 increased [45 to 66 Torr prevagotomy, 45 to 50 Torr postvagotomy (P less than 0.01)], and arterial O2 content was unchanged. CBF increased with IL:41% prevagotomy (P less than 0.01), 18% postvagotomy (P less than 0.02). However, with IL, MvO2 did not increase significantly either pre- or postvagotomy. Coronary resistance decreased with IL [30% prevagotomy, 24% postvagotomy (P less than 0.01)]. In eight dogs, PCO2 was increased by increasing dead space while the animals were mechanically ventilated and paralyzed. Although there was little change in CBF, heart rate fell by an amount equal to that with IL. We conclude that 1) IL causes coronary vasodilation not related to changes in MvO2, PCO2, or vagal tone; 2) MvO2 does not increase with IL; and 3) decreased heart rate with IL is related to hypercapnia and/or acidosis.