Myocardial Lactate Consumption Research Articles

Abstract 13: Myocardial Metabolic And Electrolyte Derangements Linked To PEA Rearrest

Background: Cardiac rearrest after return of spontaneous circulation (ROSC) is a significant barrier to successful resuscitation, making it a high priority for emergency care research. Regardless of initial arrest rhythm, rearrest is commonly due to pulseless electrical activity (PEA). However, mechanisms underlying PEA rearrest are poorly understood. Previously, myocardial contractile function during ischemia-reperfusion has been tied to alterations in extracellular sodium (Na+) and calcium (Ca2+) concentrations. Objective: To determine physiological predictors and explore potential mechanisms underlying susceptibility to PEA rearrest. Methods: Acute myocardial infarction (AMI) induced by left anterior descending artery (LAD) occlusion was followed by 8 min of VF, then pigs were resuscitated (defibrillation, CPR, epinephrine) to ROSC and the LAD was reperfused. Pigs were instrumented to measure metabolic variables from arterial and coronary sinus venous blood gases, electrolytes, and hemodynamics. Subjects that had PEA rearrest (n=7) were compared to those that did not rearrest (n=4). Results: Hemodynamic and primary arrest characteristics were similar between PEA and no rearrest groups, including ischemia duration, time to ROSC, CPR events, and epinephrine administration. At ROSC, hemodynamic and metabolic variables including pH, myocardial lactate consumption, myocardial arterial/venous oxygen difference were also similar between groups. Importantly, post-ROSC myocardial lactate consumption was significantly increased in the PEA group (3.9 vs. 0.5 mmol, p<0.03) as was coronary sinus Na+ (147 vs. 135 mEq/L, p<.03); however, coronary sinus Ca2+ was significantly reduced (1.9 vs. 2.3 mEq/L, p<.01 ). Taken together, these data suggest that metabolic substrate depletion may promote local electrolyte shifts contributing to mechanical dysfunction underlying PEA. Conclusion: PEA rearrest was associated with increased myocardial lactate consumption and derangements in cardiac Na+ and Ca2+ in a translational model with well controlled arrest characteristics. Improved understanding of mechanisms underlying post-ROSC electrolyte shifts may identify novel mechanisms and therapeutic approaches to prevent and treat PEA.

Coronary microvascular dysfunction results in impaired coronary flow reserve and altered oxygen balance in a swine model of INOCA with multiple risk factors

Abstract Introduction Comorbidities of ischemic heart disease, including diabetes mellitus (DM), hypercholesterolemia and chronic kidney disease (CKD), are associated with coronary microvascular dysfunction (CMD) and may contribute to myocardial “Ischemia and No Obstructive Coronary Artery disease” (INOCA). Purpose We studied myocardial perfusion and oxygen delivery using a novel swine model with multiple comorbidities. Methods DM (streptozotocin), HFD (high fat diet) and CKD (renal embolization), were induced in 12 female swine (DM+HFD+CKD), while 12 healthy female swine on a normal diet served as controls (CON). After 6 months, in the absence of coronary atherosclerosis, myocardial perfusion and function were studied at rest and during treadmill exercise. Results DM+HFD+CKD animals showed hyperglycemia, hypercholesterolemia and impaired kidney function. During exercise, DM+HFD+CKD demonstrated impaired myocardial blood flow and oxygen delivery, necessitating higher myocardial oxygen extraction (despite reduced capillary density), resulting in lower coronary venous oxygen levels, (Fig. 1). These perturbations were associated with lower myocardial efficiency, requiring higher oxygen consumption for a given level of myocardial work (Fig. 1), lower myocardial lactate consumption, stroke volume and LVdP/dtmax, suggestive of myocardial ischemia and dysfunction. Furthermore DM+HFD+CKD showed a reduction in adenosine-recruitable coronary flow reserve (2.69±0.26 vs 3.64±0.2 in CON, p<0.05), which was exclusively the result of an increase in basal coronary blood flow, while maximal coronary flow per gram of myocardium was maintained. The latter was consistent with the unchanged arteriolar wall/lumen ratio, arteriolar density and peri-arteriolar collagen content. eNOS blockade indicated loss of NO bioavailability in DM+HFD+CKD swine in vivo (Fig. 1), which was supported by blunted endothelium-dependent vasodilation to bradykinin in isolated small arteries. These findings suggest that changes in coronary microvascular function rather than structure contributed to the perturbations in myocardial oxygen delivery. Conclusion Common comorbidities result in CMD and impaired NO bioavailability rather than structural alterations in the microvasculature in swine, in the absence of appreciable atherosclerosis. These alterations are severe enough to produce perturbations in myocardial oxygen balance and coronary metabolism and function, particularly during exercise, resembling key features of INOCA. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): This study was supported by grants from the European Commission FP7-Health-2010 grant MEDIA-261409, the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation [CVON2014-11 (RECONNECT)].

Perturbations in myocardial perfusion and oxygen balance in swine with multiple risk factors: a novel model of ischemia and no obstructive coronary artery disease

Comorbidities of ischemic heart disease, including diabetes mellitus (DM), hypercholesterolemia (HC) and chronic kidney disease (CKD), are associated with coronary microvascular dysfunction (CMD). Increasing evidence suggests that CMD may contribute to myocardial ‘Ischemia and No Obstructive Coronary Artery disease’ (INOCA). In the present study, we tested the hypothesis that CMD results in perturbations in myocardial perfusion and oxygen delivery using a novel swine model with multiple comorbidities. DM (streptozotocin), HC (high-fat diet) and CKD (renal embolization) were induced in 10 female swine (DM + HC + CKD), while 12 healthy female swine on a normal diet served as controls (Normal). After 5 months, at a time when coronary atherosclerosis was still negligible, myocardial perfusion, metabolism, and function were studied at rest and during treadmill exercise. DM + HC + CKD animals showed hyperglycemia, hypercholesterolemia, and impaired kidney function. During exercise, DM + HC + CKD swine demonstrated perturbations in myocardial blood flow and oxygen delivery, necessitating a higher myocardial oxygen extraction—achieved despite reduced capillary density—resulting in lower coronary venous oxygen levels. Moreover, myocardial efficiency was lower, requiring higher oxygen consumption for a given level of myocardial work. These perturbations in myocardial oxygen balance were associated with lower myocardial lactate consumption, stroke volume, and LVdP/dtmax, suggestive of myocardial ischemia and dysfunction. Further analyses showed a reduction in adenosine-recruitable coronary flow reserve, but this was exclusively the result of an increase in basal coronary blood flow, while maximal coronary flow per gram of myocardium was maintained; the latter was consistent with the unchanged arteriolar wall/lumen ratio, arteriolar density and peri-arteriolar collagen content. However, isolated small arteries displayed selective blunting of endothelium-dependent vasodilation in response to bradykinin in DM + HC + CKD swine, suggesting that changes in coronary microvascular function rather than in structure contributed to the perturbations in myocardial oxygen delivery. In conclusion, common comorbidities in swine result in CMD, in the absence of appreciable atherosclerosis, which is severe enough to produce perturbations in myocardial oxygen balance, particularly during exercise, resembling key features of INOCA.

Alterations in Myocardial Oxygen Balance, Anaerobic Metabolism and Diastolic Dysfunction in Exercising Swine with Multiple Comorbidities

IntroductionMultiple comorbidities, including diabetes mellitus (DM), hypercholesterolemia and chronic kidney disease (CKD) are associated with diastolic dysfunction. These risk factors also cause coronary microvascular dysfunction leading to impaired myocardial perfusion and ischemia with non‐obstructive coronary artery disease (INOCA). Recently a link has been proposed between INOCA and HFpEF. We investigated the detrimental effects of DM, CKD and high fat diet (HFD) on myocardial function and perfusion.HypothesisProlonged exposure to multiple comorbidities in swine leads to diastolic dysfunction, associated with impaired myocardial perfusion and anaerobic metabolism.MethodsDM (streptozotocin 3×50mg/kg i.v.) and CKD (renal embolization) were induced in 7 female swine fed a high fat diet (DM+HFD+CKD), while 10 female healthy swine on normal diet served as controls (CON). After 6 months, myocardial perfusion and oxygen balance were studied at rest and during treadmill exercise. At sacrifice PV‐loop measurements and histology were performed.ResultsDM+HFD+CKD animals showed hyperglycemia (glucose: 19.2±1.5 vs 7.5±0.6 mmol/L), renal dysfunction (glomerular filtration rate: 132±14 vs 197±10 ml/min) and hypercholesterolemia (total cholesterol: 8.28±0.86 vs 1.65±0.06 mmol/l, all P<0.05). DM+HFD+CKD had an increased EDPVR (0.14±0.02 vs 0.09±0.01 mmHg/mL) with preserved ejection fraction, a lower cardiac index compared to CON at similar levels of exercise (fig A). Left ventricular myocardial capillary density was decreased (1229±59 vs 1502±86 #/mm2) and collagen content was increased (9.6±1.9 vs 5.0±0.6 %). Their myocardium required more oxygen for similar levels of cardiac work, suggesting cardiac inefficiency (fig B). Furthermore, they showed a lower myocardial oxygen delivery (fig C), forcing the myocardium to increase its oxygen extraction (fig D) leading to lower coronary venous oxygen saturation (fig E) both at rest and during exercise. This was accompanied by a decrease in myocardial lactate consumption at the same lactate supply as in CON (fig F), suggestive of anaerobic metabolism. Importantly, DM+HFD+CKD showed no coronary atherosclerosis.ConclusionMultiple co‐morbidities in swine result in severe perturbations in myocardial oxygen balance and anaerobic metabolism in the absence of significant atherosclerosis, indicating severe coronary microvascular dysfunction co‐occurring with diastolic dysfunction.Support or Funding InformationThis study was supported by grants from the European Commission FP7‐Health‐2010 grant MEDIA‐261409, the Netherlands CardioVascular Research Initiative: an initiative with support of the Dutch Heart Foundation [CVON2012‐08 (PHAEDRA), CVON2014‐11 (RECONNECT)]. Cardiac index (CI) of DM+HFD+CKD was lower than in CON swine (A). Myocardium of DM+HFD+CKD swine shows increased oxygen consumption (MVO2) for the same level of cardiac work (B), has a lower myocardial oxygen delivery (MDO2, C) and a higher oxygen extraction (MEO2, D), which results in lower coronary venous oxygen saturation (cv SaO2, E). Lower myocardial lactate consumption (MVlactate) at a given level of myocardial lactate delivery (MDlactate, F). *p<0.05 DM+HFD+CKD versus CONimageCardiac index (CI) of DM+HFD+CKD was lower than in CON swine (A). Myocardium of DM+HFD+CKD swine shows increased oxygen consumption (MVO2) for the same level of cardiac work (B), has a lower myocardial oxygen delivery (MDO2, C) and a higher oxygen extraction (MEO2, D), which results in lower coronary venous oxygen saturation (cv SaO2, E). Lower myocardial lactate consumption (MVlactate) at a given level of myocardial lactate delivery (MDlactate, F). *p<0.05 DM+HFD+CKD versus CONThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

High-dose erythropoietin during cardiac resuscitation lessens postresuscitation myocardial stunning in swine

We investigated the metabolic and functional myocardial effects of erythropoietin (EPO) administered during resuscitation from cardiac arrest using an open-chest pig model of ventricular fibrillation and resuscitation by extracorporeal circulation, after having reported in rats a reversal of postresuscitation myocardial dysfunction associated with activation of mitochondrial protective pathways. Ventricular fibrillation was induced in 16 male domestic pigs and left untreated for 8 minutes, after which extracorporeal circulation was started and maintained for 10 additional minutes, adjusting the extracorporeal flow to provide a coronary perfusion pressure of 10 mmHg. Defibrillation was accomplished and the extracorporeal flow was adjusted to secure a mean aortic pressure of 40 mmHg or greater during spontaneous circulation for up to 120 minutes. Pigs were randomized 1:1 to receive EPO (1200 U/kg) or 0.9% NaCl before starting extracorporeal circulation. Severe postresuscitation myocardial dysfunction developed in both groups. However, recovery of myocardial function-comparing baseline with 120 minutes postresuscitation-was better in pigs treated with EPO than NaCl, as shown for left ventricular ejection fraction (from 45 ± 8% to 36 ± 9% in EPO, not significant; and from 46 ± 8% to 26 ± 8% in NaCl, P < 0.001) and for peak systolic pressure/end-systolic volume (from 2.7 ± 0.8 mmHg/mL to 2.4 ± 0.7 mmHg/mL in EPO, not significant; and from 3.0 ± 1.1 mmHg/mL to 1.8 ± 0.6 mmHg/mL, P < 0.001 in NaCl). The EPO effect was associated with significantly higher myocardial O2 consumption (12 ± 6 mL/min/unit of tissue vs 6 ± 2 mL/min/unit of tissue, P < 0.017) without effects on myocardial lactate consumption. Thus, EPO administered during resuscitation from ventricular fibrillation lessened postresuscitation myocardial stunning-an effect that could be useful clinically to help promote postresuscitation hemodynamic stability.

Depletion of lactate by dichloroacetate reduces cardiac efficiency after hemorrhagic shock.

We have demonstrated previously that dichloroacetate (DCA) treatment in rodents ameliorates, via activation of the pyruvate dehydrogenase complex, the cardiovascular depression observed after hemorrhagic shock. To explore the mechanism of this effect, we administered DCA in a large animal model of hemorrhagic shock. Mongrel hounds were anesthetized with 1.5% isoflurane and were measured for hemodynamics, myocardial contractility, and myocardial substrate utilization. They were hemorrhaged to a mean arterial pressure of 35 mm Hg for 90 min or until arterial lactate levels reached 7.0 mM (1137 +/- 47 mL or 49 +/- 2% total blood volume). Animals were chosen at random to receive DCA dissolved in water or an equal volume of saline at the onset of resuscitation. Two-thirds of the shed blood volume was returned immediately after giving an equivalent volume of saline. Two hours after the onset of resuscitation, mean arterial pressure was not different between DCA and control groups (79 +/- 3 vs. 82 +/- 3 mm Hg, respectively). Arterial lactate levels were significantly reduced by DCA (0.5 +/- 0.06 vs. 2.0 +/- 0.2 mM). However, DCA treatment was associated with a decreased stroke volume index (0.56 +/- 0.06 vs. 0.82 +/- 0.08 mL/kg/beat) and a decreased myocardial efficiency (19 vs. 41 L x mm Hg/mL/100 g tissue). During resuscitation by DCA, myocardial lactate consumption was reduced (21.4 +/- 3.7 vs. 70.7 +/- 16.3 micromole/min/100 g tissue) despite a three-fold increase in myocardial pyruvate dehydrogenase activity, while free fatty acid levels actually began to rise. Although increased lactate oxidation should be beneficial during resuscitation, we propose that DCA treatment led to a deprivation of myocardial lactate supply, which reduced net myocardial lactate oxidation, thus compromising myocardial function during resuscitation from hemorrhagic shock.

Regulation of Myocardial Blood Flow by Oxygen Consumption Is Maintained in the Failing Heart During Exercise

The hemodynamic abnormalities and neurohumoral activation that accompany congestive heart failure (CHF) might be expected to impair the increase in coronary blood flow that occurs during exercise. This study was performed to determine the effects of CHF on myocardial oxygen consumption and coronary blood flow during exercise. Coronary blood flow was measured in chronically instrumented dogs at rest, during 2 stages of graded treadmill exercise under control conditions (n=10), and after the development of CHF produced by 3 weeks of rapid ventricular pacing (n=9). In the normal dogs, coronary blood flow increased during exercise in proportion to the increase in the heart rate x the left ventricular systolic blood pressure product (RPP). After the development of CHF, resting myocardial blood flow was 25% lower than normal (P<0.05). Myocardial blood flow increased during the first stage of exercise, but then failed to increase further during the second stage of exercise despite an additional increase in the RPP. Myocardial oxygen consumption during exercise was significantly lower in animals with CHF and paralleled coronary flow. Despite the lower values for coronary blood flow in animals with CHF, there was no evidence for myocardial ischemia. Thus, even during the second level of exercise when coronary flow failed to increase, myocardial lactate consumption continued and coronary venous pH did not fall. In addition, the failure of coronary flow to increase as the exercise level was increased from stage 1 to stage 2 was not associated with a further increase in myocardial oxygen extraction. Thus, cardiac failure was associated with decreased myocardial oxygen consumption and failure of oxygen consumption to increase with an increase in the level of exercise. This abnormality did not appear to result from inadequate oxygen availability, but more likely represented a reduction of myocardial oxygen usage with a secondary decrease in metabolic coronary vasodilation.

Myocardial anaerobic metabolism occurs at a critical coronary venous PO2 in pigs.

We tested the hypothesis that the onset of myocardial anaerobic metabolism is fundamentally different from the whole body and other organs, where the onset of anaerobic metabolism occurs at a critical oxygen extraction ratio--not at a critical venous PO2. We measured oxygen saturation and PO2 of arterial and coronary venous blood at the onset of global myocardial anaerobic metabolism during progressive hypoxic hypoxia (n = 7) compared with carbon monoxide hypoxia (n = 7), which left-shifted the oxygen-hemoglobin dissociation curve. The onset of global myocardial anaerobic metabolism was defined by decreased myocardial lactate consumption and left ventricular contractility. Coronary venous PO2 was no different during hypoxic hypoxia and carbon monoxide hypoxia at equivalent arterial oxygen saturations, particularly at the onset of myocardial anaerobic metabolism (PO2 17.0 +/- 1.7 torr versus 15.9 +/- 2.2 torr, p = NS). However, the myocardial oxygen extraction ratio was significantly greater during hypoxic hypoxia than during carbon monoxide hypoxia at the onset of myocardial anaerobic metabolism (0.88 +/- 0.02 versus 0.65 +/- 0.04, p < 0.01). Thus, in contrast to the whole body where the onset of anaerobic metabolism occurs at a critical oxygen extraction ratio, the onset of myocardial anaerobic metabolism occurs at a critical coronary venous PO2.

Myocardial oxygen extraction ratio is decreased during endotoxemia in pigs.

Why the myocardial oxygen extraction ratio (ERm) is decreased during septic shock in humans is unknown. Therefore, we calculated ERm in 15 anesthetized pigs by measuring arterial and coronary venous oxygen content. We measured myocardial lactate flux, myocardial contractility, and global myocardial blood flow and its distribution. After baseline measurements, animals received either saline (n = 6) or 50 micrograms/kg of endotoxin (n = 9). Measurements were repeated for 4 h. After endotoxin, ERm decreased from 67 +/- 12% at baseline to 36 +/- 10% (P < 0.01) at 1 h and 54 +/- 10% (P < 0.05) at 4 h, associated with an increased myocardial blood flow that was heterogeneous. Neither myocardial oxygen nor lactate consumption decreased in the endotoxin group, and changes in left ventricular contractility were not correlated with changes in ERm. We conclude that the decrease in ERm after endotoxin infusion is due to both increased blood flow and mismatching between myocardial oxygen delivery and demand. Impaired myocardial oxygen extraction capacity during sepsis did not cause global myocardial tissue hypoxia.

Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate

Objectives. The purpose of this study was to determine whether sodium dichloroacetate improves hemodynmic performance and mechanical efficiency in congestive heart failure.Background. Congestive heart failure is associated with impaired hemodynamic performance and reduced mechanical efficiency. Dichloroacetate stimulates pyruvate dehydrogenase activity by inhibition of pyruvate dehydrogenase kinase, which results in inhibition of free fatty acid metabolism and stimulation of high respiratory quotient glucose and lactate consumption by the heart. Facilitation of glucose and lactate consumption with dichloroacetate should improve mechanical efficiency of the failing ventricle.Methods. Ten patients with New York Heart Association functional class III to IV congestive heart failure were studied. Dichloroacetate (50 mg/kg body weight) was administered intravenously for 30 min, with measurements of hemodynamic variables, coronary sinus blood flow and blood gas, glucose and lactate levels for 2 h. The same patients were also given dobutamine (5 to 12.5 mg/kg per min) for comparison.Results. Therapeutic levels of dichloroacetate were achieved (100 to 160 μg/liter of plasma). Myocardial consumption of lactate was stimulated from 29% to 37.4%. Forward stroke volumes increased (+5.3 ml/beat, p < 0.02), as did left ventricular stroke work (+1.8 g-m/m2per beat, p < 0.02) and left ventricular minute work (from 1.38 to 1.55 kg-m/m2per min, p < 0.01). Myocardial oxygen consumption decreased (from 19.3 to 16.3 ml/min, p = 0.06) as left ventricular minute work increased. Left ventricular mechanical efficiency thus improved from 15.2% to 20.6% (p = 0.03).Dobutamine administration resulted in the opposite trend with respect to myocardial lactate extraction (from 34% to 15.3%, p < 0.02). Stroke volume increased (+7.4 ml/beat, p = NS vs. dichloroacetate), as did left ventricular minute work (from 1.29 to 1,59 g-m/m2per min, p < 0.01 vs. dichloroacetate) and myocardial oxygen consumption (from 18.6 to 21.0 ml/min, p = 0.06 vs. dichloroacetate). Left ventricular mechanical efficiency did not change with dobutamine administration (from 16.4% to 15.8%, p = NS).Conclusions. Dichloroacetate administration stimulates myocardial lactate consumption and improves left ventricular mechanical efficiency. Forward stroke volume and left ventricular minute work increase significantly, with a simultaneous reduction in myocardial oxygen consumption. Dobutamine administration results in similar hemodynamic improvements but with no change in left ventricular mechanical efficiency and with opposite effects on lactate metabolism. The opposing metabolic actions, yet similar hemodynamic responses, of dichloroacetate and dobutamine suggest that these agents may be complementary in the treatment of congestive heart failure.

Myocardial energetics and blood flow in acute rapid ventricular pacing.

The mechanism whereby chronic rapid ventricular pacing induces severe heart failure is unclear, but the phenomenon is associated with a reduction in left ventricular ATP levels. Accordingly, the current study was undertaken to evaluate the acute effects of rapid ventricular pacing on hemodynamics, left ventricular adenine nucleotide levels, myocardial blood flow, and oxygen consumption. Anesthetized dogs (n = 7) were studied in sinus rhythm and during 30 min of pacing at 250 beats/min. Pacing caused a significant (means +/- SD, all p < 0.001) decrease in cardiac output (3.0 +/- 0.6 to 2.0 +/- 0.6 L/min) and peak left ventricular systolic pressure (133 +/- 14 to 82 +/- 10 mmHg (1 mmHg = 133.3 Pa)) and an increase in pulmonary wedge pressure (10 +/- 2 to 18 +/- 3 mmHg). Following pacing, the peak first derivative of left ventricular pressure and the relaxation time constant, tau, remained unchanged compared with baseline values. Myocardial blood flow and oxygen consumption both increased by 70% with pacing. The transmural distribution of myocardial blood flow and myocardial lactate consumption remained unchanged. There was no change in left ventricular ATP or ADP levels with the observed increase in myocardial oxygen consumption. Therefore, the hemodynamic deterioration associated with acute rapid ventricular pacing, in contrast to that of chronic pacing, is not associated with perturbed myocardial energetics.

The link between acute haemodynamic adrenergic beta-blockade and long-term effects in patients with heart failure. A study on diastolic function, heart rate and myocardial metabolism following intravenous metoprolol.

The present study was performed to find possible mechanisms linking the early effects of beta-blockade with the observed long-term effects in patients with heart failure. In 57 patients with heart failure, 13 +/- 3.1 mg of metoprolol was given intravenously. The patients were investigated by invasive haemodynamics (n = 34), including collection of myocardial metabolic data during atrial pacing stress (n = 16), by radionuclide angiography during physiological atrial pacing (n = 13), and by a bedside evaluation (n = 10). Diastolic function, measured by early peak filling rate, followed changes in heart rate, but was similar when heart rate was held constant by atrial pacing before and after beta-blockade. Following beta-blockade and slower heart rates, diastolic filling volumes were redistributed to late diastole. Metoprolol induced a parallel decrease in coronary sinus flow and myocardial oxygen consumption. Myocardial oxygen consumption following beta-blockade decreased both during spontaneous rhythm (25 +/- 15 to 16 +/- 8.8 ml min-1; P = 0.006), and during atrial pacing stress (30 +/- 13 to 23 +/- 11 ml.min-1; P = 0.004). Cardiac index decreased owing to reduction of heart rate (2.3 +/- 1.0 to 1.9 +/- 0.64 l.min-1.m2; P = 0.0003), while left ventricular filling pressure was unchanged. Ejection fraction and ventricular volumes were unaltered following atrial pacing or beta-blockade. There was a reflex increase in noradrenaline concentration after beta-blockade injection (0.96 +/- 0.66 to 1.20 +/- 0.91 nmol.l-1; P = 0.002), whereas myocardial noradrenaline overflow was unchanged. There was a trend towards an increase in myocardial lactate consumption after beta-blockade administration during atrial pacing stress. It is suggested that the surprisingly good tolerability seen after acute administration of beta-blockers to patients with severe heart failure may be explained by prolongation of the diastolic filling phase, which outweighs the negative inotropic effects. The reduced myocardial metabolic demand may allow the failing myocardium to recover and explain the excellent long-term effect on heart function following beta-blockade treatment.

L-Propionylcarnitine Does Not Affect Myocardial Metabolic or Functional Response to Chronotropic and Inotropic Stimulation After Repetitive Ischemia in Anesthetized Pigs

In postischemic myocardium, fatty acid oxidation may be deficient owing to depletion of carnitine and citric acid cycle intermediates and fatty acylCoA-induced inhibition of adenine nucleotide translocase. During postischemic stress, the impairment of the fatty acid oxidation may become more apparent. We therefore investigated in open-chest anesthetized pigs the effect of L-propionylcarnitine [100 mg/kg per day orally (p.o.) for 3 days and 50 mg/kg intravenously (i.v.) 2 h before the first occlusion; n = 13] on myocardial function and metabolism of postischemic (two cycles of 10-min occlusion each followed by 30-min reperfusion) myocardium under resting conditions and during chronotropic and inotropic stimulation with dobutamine. Myocardial levels of free carnitine were higher after pretreatment (5.7 +/- 1.4 vs. 4.0 +/- 1.3 mumol/g protein, p < 0.05). The ischemia-reperfusion-induced decreases in free carnitine were similar for both the untreated and treated animals, but in the latter free carnitine was not different from the baseline levels in the control animals. In untreated animals (n = 15), regional systolic segment shortening (SS) was 18.5 +/- 5.5% (means +/- SD) at baseline, but was reduced to 5.1 +/- 5.5% (p < 0.05) at the end of the second reperfusion period. Myocardial ATP levels had decreased by 30% (p < 0.05) in the presence of a maintained energy charge, while myocardial oxygen and lactate consumption had decreased to 61% and 9% of baseline, respectively. During subsequent i.v. infusion of dobutamine (2 micrograms/kg/min), SS and myocardial oxygen consumption per beat increased to 75 and 65% of baseline, respectively, whereas lactate consumption per beat increased to only 25% of baseline. Decreases in myocardial ATP and oxygen and lactate consumption were not different between treated and untreated animals. L-Propionylcarnitine-treated animals displayed slightly better postischemic recovery of systolic SS than did control animals; to 39 and 28% (p = 0.056) of baseline, respectively, probably owing to a reduction in arterial blood pressure (BP), because L-propionylcarnitine prevented the increase in systemic vascular resistance produced by ischemia-reperfusion. L-Propionylcarnitine did not affect myocardial metabolic and contractile functional responses to chronotropic and inotropic stimulation. In a model of repetitive myocardial ischemia, L-propionylcarnitine prevents systemic vasoconstriction in response to ischemia and reperfusion and, probably as a result of the lower afterload, slightly ameliorates postischemic hypofunction, but loss of carnitine apparently does not play a role in myocardial hypofunction after brief repetitive ischemia and reperfusion in pigs.

Decreased regional lactate production and output due to intracoronary continuous infusion of esmolol during acute coronary occlusion in dogs

This study was designed to test the hypothesis that intracoronary administration of esmolol can confer metabolic protection during coronary constriction or occlusion, without affecting hemodynamic parameters, in a canine model. Seventeen anesthetized open-chest dogs underwent direct cannulation of the left anterior descending coronary artery (LADa), its companion vein (LADv), and the distal circumflex vein (CFXv). LADa flow was measured with an electromagnetic flowmeter. Using a micrometer-driven snare around the LADa, flow was reduced by 50%, 75%, and 100% for 15 minutes, with 1 hour of normal flow before each constriction. In 7 dogs (group 1) chosen randomly, esmolol, 15 to 20 μg/kg/min, was infused continuously into the LADa; the rate was adjusted to maintain baseline hemodynamic values. The second group (10 dogs) was not treated with esmolol. Heart rate (HR), electrocardiogram (ECG), LADa flow, LV dP/dt, and aorta (Ao), pulmonary artery (PA), LADa, and left ventricular (LV) pressures were recorded continuously. Cardiac output (CO) (thermodilution) was measured and blood was sampled from all catheters before and after constrictions for analysis of glucose, lactate, sodium, potassium, and blood gases. Flow and pressure in the LADa in both groups decreased similarly during each corresponding constriction. Systolic LV pressure, LV dP/dt, and LV stroke work index were affected in both groups only during 100% constriction. HR, Ao, and PA pressures, and total and peripheral pulmonary resistances were affected similarly in both groups during each constriction. Myocardial lactate extraction and consumption were less negative (negative = net production and output) in the LAD perfusion bed during corresponding constrictions with esmolol than without it. Electrolyte and glucose concentrations and extraction and arteriovenous oxygen content differences in the ischemic and nonischemic areas during constriction were affected similarly in both groups. The ratio of oxygen delivery to oxygen consumption in the ischemic zone was higher with esmolol than without it before constriction (75% and 100%) and during constriction (50%). This study indicates that the intracoronary use of esmolol during moderate-to-severe coronary hypoperfusion can protect ischemic myocardium.

Haemodynamics of induced atrial fibrillation: A comparative assessment with sinus rhythm, atrial and ventricular pacing

The haemodynamics and myocardial lactate consumption during induced atrial fibrillation (AF) were studied in 10 patients with paroxysmal AF. Their mean age (+/- SD) was 61 +/- 5 years and none had clinical evidence of ischaemic or rheumatic heart disease. Compared with sinus rhythm, the onset of AF was associated with a reduction in systolic blood pressure (152 +/- 13 mmHg) in AF vs 169 +/- 23 mmHg in sinus rhythm, P less than 0.01). There was no consistent change in cardiac output at the onset of AF compared with sinus rhythm, but the cardiac output was lower compared with regular atrial pacing at rates similar to those of induced AF (3.85 +/- 0.76 vs 4.38 +/- 0.89 l min-1, P less than 0.02). Compared with sinus rhythm or rate-matched atrial pacing, AF was associated with an elevated pulmonary arterial pressure (24.2 +/- 5.6 mmHg in AF vs 17.9 +/- 14.4 mmHg in sinus rhythm, P less than 0.01) and pulmonary arterial wedge pressure (18.6 +/- 5.6 vs 9.7 +/- 3.9 mmHg, P less than 0.01). The haemodynamic changes during AF were similar to those seen during regular ventricular pacing at an equivalent rate, although the latter was associated with a lower systolic blood pressure (152 +/- 13 mmHg in AF vs 136 +/- 25 mmHg in ventricular pacing, P less than 0.05) and higher right atrial pressure (8.2 +/- 4.4 vs 11.5 +/- 7.5 mmHg respectively, P less than 0.05), presumably due to the deleterious effects of cannon 'a' waves.(ABSTRACT TRUNCATED AT 250 WORDS)

Angina due to coronary microvascular disease in hypertensive patients without left ventricular hypertrophy.

When angina occurs in patients with hypertension, it is usually attributed to coronary artery disease or left ventricular hypertrophy. To determine the contribution of coronary microvascular abnormalities to angina in patients with hypertension, we evaluated hypertensive patients without coronary artery disease or left ventricular hypertrophy by measuring the coronary responses to rapid atrial pacing before and after administration of ergonovine. We compared 12 hypertensive patients who had pacing-induced angina with 13 normotensive subjects without such angina. The two groups had similar coronary flow (in the great cardiac vein) at rest; however, pacing increased coronary flow less in hypertensive patients with angina than in normotensive subjects (48 vs. 83 percent; P = 0.05). In the hypertensive patients with angina, pacing after ergonovine increased coronary flow by only 32 percent (as compared with 48 percent before ergonovine; P less than 0.05) and decreased coronary resistance by 15 percent (as compared with 28 percent before ergonovine; P less than 0.05), indicating the presence of ergonovine-induced vasoconstriction. In normotensive subjects, in contrast, cardiac pacing after ergonovine increased coronary flow by 112 percent (P less than 0.001), and its effect on coronary resistance was not different from that of pacing before ergonovine. The hypertensive patients with angina had a significant increase in myocardial oxygen extraction during pacing after ergonovine and less of an increase in myocardial lactate consumption - a response consistent with the presence of myocardial ischemia. Thus, angina in hypertensive patients without epicardial coronary disease may be caused by myocardial ischemia, which appears to be due to an abnormally elevated resistance of the coronary microvasculature.

Beta 2-mediated changes in central haemodynamics, coronary circulation and myocardial metabolism in canine.

The combined effect of terbutaline on systemic and coronary circulation was investigated in dogs to clarify its influence on myocardial oxygen supply and lactate balance. The dogs were anaesthetized and the chest opened. Coronary sinus blood flow and cardiac output were monitored by thermodilution, aortic pressure was measured by tip-transducer and heart rate by RR-interval on ECG, coronary sinus blood were analyzed for lactate, oxygen and carbon dioxide. Terbutaline caused a substantial systemic vasodilation and an increased heart rate, the total external cardiac work increased to a minor degree. Terbutaline increased arterial lactate concentration. Coronary vascular resistance was reduced after terbutaline. Even if myocardial perfusion pressure was reduced and an increased external cardiac work was present, no signs of myocardial distress was observed in lactate metabolism or coronary sinus oxygen content. In fact a tendency to increased myocardial aerobic metabolism was observed, as myocardial lactate consumption increased after terbutaline. Terbutaline seems to be a coronary vasodilator in dogs. However, the demand for oxygen secondary to both an increase in cardiac work and aerobic metabolism can be hazardous to the potentially ischaemic myocardium.

Effects of atrial natriuretic factor on coronary hemodynamics and myocardial energetics in patients with heart failure

Synthetic analogues of atrial natriuretic factor (ANF) have been developed for potential use as therapeutic agents in the treatment of congestive heart failure and hypertension. We studied the effects of 14 intravenous infusions of synthetic ANF (anaritide, human ANF 102–126) on coronary hemodynamics and myocardial energetics in six patients with heart failure. ANF infusion caused no change in coronary blood flow and a fall in coronary vascular resistance from 1.22 ± 0.22 to 1.08 ± 0.18 mm Hg-min/ml ( p < 0.05). Myocardial oxygen and lactate consumption were unchanged from baseline values. Mean arterial pressure fell from 91 ± 4 to 78 ± 3 mm Hg ( p < 0.01), right atrial pressure fell from 10 ± 1 to 8 ± 1 mm Hg ( p < 0.01), pulmonary capillary wedge pressure fell from 21 ± 3 to 16 ± 2 mm Hg ( p < 0.01), heart rate and cardiac index were unchanged, and systemic vascular resistance fell from 1346 ± 130 to 1087 ± 98 dyne-sec/cm 5 ( p < 0.05). We conclude that infusion of ANF in hemodynamically effective doses in patients with heart failure decreases coronary vascular resistance with no change in coronary blood flow or myocardial oxygen or lactate metabolism.

Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary artery disease

Dichloroacetate (DCA), which activates pyruvate dehydrogenase, has the potential to enhance carbohydrate and lactate utilization in animals, but data from patients with coronary artery disease are lacking. Accordingly, 9 patients (ages 49 to 72 years) with angina and coronary artery disease undergoing catheterization were studied. Systemic and coronary hemodynamic and metabolic measurements were made before and during DCA administration (mean dose 35 mg/kg, intravenously). DCA increased left ventricular (LV) stroke volume from 77 ± 7 to 87 ± 7 ml and decreased systemic vascular resistance from 1,573 ± 199 to 1,319 ± 180 dynes · s · cm −5 (both, p < 0.01). There were no significant changes in heart rate, mean aortic pressure, LV end-diastolic pressure, LV dP/dt max, coronary sinus flow, coronary resistance or myocardial oxygen consumption, but myocardial efficiency index (LV work/myocardial oxygen consumption) improved from 24 to 32% (p < 0.05). Myocardial lactate consumption was maintained (21 ± 8 vs 19 ± 11 × 10 3 mEq/min, p is not significant at p < 0.05 level) at a lower arterial lactate concentration (0.72 ± 0.09 to 0.47 ± 0.08 mEq/liter, p < 0.05). DCA appears to stimulate myocardial lactate utilization at a lower arterial concentration, cause peripheral vasodilation, augment stroke volume and enhance myocardial efficiency in patients with coronary artery disease.

Effect of aortocoronary bypass surgery on coronary circulation and myocardial metabolism during atrial pacing.

Eleven patients with coronary heart disease, in whom at least one of several bypass grafts to the left coronary artery was patent, were selected for the study. The hemodynamics, coronary sinus blood flow, myocardial oxygen consumption, and myocardial lactate metabolism were evaluated at rest and during atrial pacing stress test before and after surgery. There were no significant improvements in the cardiac index, pulmonary arterial end-diastolic pressure, and left ventricular ejection fraction after aortocoronary bypass surgery. However, significant improvement of coronary sinus blood flow, myocardial oxygen consumption, and myocardial lactate extraction and consumption were found during postoperative atrial pacing compared with the preoperative findings. These results suggest that successful bypass grafting may improve myocardial lactate metabolism in ischemic lesions and contribute to the postoperative relief of angina.