Superior myocardial protection with nicorandil cardioplegia.

OBJECTIVE: The ATP-sensitive potassium channel (K(ATP)) activator nicorandil used as cardioplegic agent may protect the left ventricle during cardiac arrest. Nicorandil in cold blood was compared with standard hyperkalemic blood and crystalloid cardioplegia. METHODS: Twenty-one pigs were randomly assigned to three groups: (1) cold hyperkalemic crystalloid (n=7); (2) cold hyperkalemic blood (n=7); and (3) nicorandil as cardioplegia in cold blood (n=7). Left ventricular mechanical performance, pressure-volume area (PVA) and myocardial oxygen consumption (MVO(2)) were measured before and at 1 and at 2 h after 60 min of cold global ischemia on cardiopulmonary bypass using intraventricular pressure-volume conductance catheters, coronary flow probes and O(2)-content difference. RESULTS: The slope (M(w)) of the stroke work end-diastolic volume relationship, the preload recriutable stroke work relationship, was unchanged after ischemia in the nicorandil group, but was reduced to averaged 62.5% (standard deviation 14) of baseline values in both hyperkalemic perfusions (P<0.05). The slope of the MVO(2)-PVA relationship was unchanged after nicorandil cardioplegia while the slope after hyperkalemic blood and crystalloid cardioplegia increased with 33% (P<0.02) and 52% (P<0.02) of baseline values, respectively. CONCLUSIONS: Nicorandil as sole cardioplegic agent in cold blood given intermittently preserves left ventricular contractility and myocardial energetics significantly better than traditional forms of cardioplegia after cardiac arrest.

Preserved myocardial energetics in acute ischemic left ventricular failure -- studies in an experimental pig model.

OBJECTIVE: We hypothesised that acute ischemic left ventricular failure is characterised by depressed systolic and diastolic function combined with inefficiency in oxygen to mechanical work energy transfer. METHODS: Eight anaesthetised pigs (32+/-3 kg) were employed in an in vivo open chest model. Intraventricular combined pressure and conductance catheters were used to generate continuous left ventricular pressure-volume relations. Myocardial oxygen consumption (MVO(2)) was determined from coronary flow and coronary arteriovenous oxygen difference. After baseline measurements, ischemia was induced by repeated left coronary injections of 50 microm polystyrene microspheres until stroke volume was reduced by 30%. Haemodynamic and biochemical measurements were repeated 30, 90 and 150 min after microembolisation. RESULTS: Coronary embolisation induced a significant reduction in stroke work (2749+/-504-1473+/-449 mmHg ml, P<0.05) at 30 min compared to baseline. Post-embolic contractility was reduced measured by the slope of the preload recruitable stroke work index (66.2+/-12.8-50.0+/-5.8 mmHg, P<0.05) and the slope of the curvilinearly fitted end-systolic pressure-volume relation in V(0) (7.1+/-2.2-4.9+/-2.2 mmHg/ml, P<0.05). The dP/dt(min) decreased (2076+/-291-1468+/-266 mmHg/s, P<0.05), but there was no significant change in diastolic stiffness or Tau. Following the 30 min measurements, there were only small changes in most indices. We found no change in myocardial oxygen consumption for basal metabolic processes or excitation-contraction coupling (unloaded MVO(2)), and there were no changes in conversion of oxygen to total mechanical work (MVO(2)-PVA slope). However, decreased mechanical efficiency (SW/MVO(2)) paralleled an increased ratio of arterial elastance to ventricular elastance. CONCLUSIONS: Coronary microembolisation in pigs induce a stable ischemic left ventricular failure characterised by reduced contractility and minimally impaired diastolic function. In this acute ischemic left ventricular failure, the main contributor to all over cardiovascular inefficiency is increased ratio of arterial- to ventricular elastance, a setting that impairs mechanical efficiency. However, efficiency of oxygen to total mechanical work transfer in the myocardium is unaltered. The mechanism behind this finding is elusive and warrants further investigation.

Postischemic mechanoenergetic inefficiency is related to contractile dysfunction and not altered metabolism.

Mechanoenergetic inefficiency in postischemic nonnecrotic myocardium may partly be explained by an increased fatty acid (FA) oxidation rate. In the present study, left ventricular (LV) postischemic energy transfer was characterized in 10 intact anesthetized pigs. The LV was stunned by 11 brief left main coronary artery occlusions/reperfusions (20-min accumulated ischemia). Seven pigs served as time controls. The relationship between myocardial oxygen consumption (MVO(2)) and LV pressure-volume area (PVA) was assessed. [(14)C]glucose and [(3)H]oleate markers were used to discriminate between glucose and FA consumption. In stunned hearts, severe postischemic dysfunction was observed, and contractile efficiency was reduced (increased MVO(2)-PVA slope, P = 0.001). Unloaded (nonmechanical) MVO(2) was not affected by ischemia. We observed only a small transient increase in FA preference and conclude that the contribution from increased FA utilization to postischemic mechanoenergetic inefficiency is insignificant. Disrupted postischemic chemical-to-mechanical energy transfer in vivo is, therefore, related to inefficient energy utilization in the contractile apparatus.

N-acetylcysteine increases cerebral perfusion pressure in pigs with fulminant hepatic failure.

OBJECTIVE: Intravenous administration of N-acetylcysteine beyond 15 hrs reduces mortality rates in patients suffering from paracetamol-induced fulminant hepatic failure, although the mechanism of the therapeutic benefit remains unclear. We hypothesized increased survival to be caused by improved hemodynamic performance. The main objective for the study was to explore the effect of N-acetylcysteine on hemodynamics, oxygen transport, and regional blood flow in pigs with fulminant hepatic failure. DESIGN: Prospective, randomized, controlled trial. SETTING: Surgical research laboratory in a university hospital. SUBJECTS: Female Norwegian Landrace pigs. INTERVENTIONS: Fulminant hepatic failure was induced by a total liver devascularization procedure. Five hours later, the pigs were allocated to N-acetylcysteine treatment (150 mg.kg-1 in 100 mL of 0.9% saline over 15 mins, followed by 50 mg.kg-1 in 500 mL of 0.9% saline over a period of 4 hrs) or placebo. MEASUREMENTS AND MAIN RESULTS: Mean arterial pressure stabilized in the N-acetylcysteine group and increased slightly during the last 2 hrs (pGT =.009). Thus, mean arterial pressure was significantly higher compared with placebo after 3 hrs (p =.01). Cerebral perfusion pressure was significantly higher during the last 2 hrs in the N-acetylcysteine group (pGT =.033). Common carotid artery flow also increased and was maintained at a higher level compared with placebo (pG =.027). Systemic vascular resistance index initially decreased but then gradually increased (pGT <.001). Cardiac index increased after 15 mins of N-acetylcysteine infusion, causing a significant interaction (pGT =.038), but did not differ after 3 hrs. No significant differences in hindleg and mesentery hemodynamics were found. A short-lived increase in oxygen delivery caused by a temporary increase in cardiac index was observed but without any corresponding increase in oxygen consumption. CONCLUSIONS: Intravenous N-acetylcysteine infusion increases cerebral perfusion pressure in pigs with fulminant hepatic failure. Earlier reported effects on oxygen transport and uptake could not be confirmed.

Cardiac dysfunction and inefficiency after substrate-enriched warm blood cardioplegia.

OBJECTIVE: The study assessed the outcome after prolonged warm continuous antegrade blood cardioplegia (WCBC) with substrate enrichment, in terms of mechanical performance and mechanoenergetic efficiency. METHODS: WCBC was given for 3 h to three groups of pigs on cardiopulmonary bypass; WCBC alone (n=7), WCBC+glucose and insulin (+GIK, n=7) and WCBC+L-glutamine (+GLN, n=7). Cardiac systolic and diastolic function, pressure-volume area (PVA) and myocardial oxygen consumption (MVO(2)) were assessed before, and twice after WCBC using pressure-conductance catheter, coronary flow-probes and O(2)-content difference. RESULTS: In the WCBC, +GIK and +GLN groups respectively, the following parameters decreased after WCBC compared to baseline: left ventricular developed pressure by 26, 19 and 25% (P<0.001); dP/dt(max) by 36, 37 and 34% (P<0.001); preload recruitable stroke work by 35, 41 and 28% (P<0.001); mechanoenergetic efficiency (PVA/MVO(2)) by 44, 41 and 22% (P<0.001). End-diastolic stiffness increased early after WCBC in the WCBC and +GLN groups, while it was unchanged in the +GIK group (P=0.032). CONCLUSION: Despite continuous aerobic conditions and additional substrates, post-WCBC cardiac contractile function and mechanoenergetic efficiency was severely depressed. The results demonstrate the hazards of sustained normothermic hyperkalemic perfusion.

Renal elimination of protein S-100beta in pigs with acute encephalopathy.

BACKGROUND: Protein S-100beta is an established biochemical marker for cerebral injury in serum. For the further interpretation and possible use of S-100beta serum measurements in acute hepatic encephalopathy, renal elimination of S-100beta was measured in pigs with elevated S-100beta levels due to hepatic encephalopathy. METHODS: Eighteen female Norwegian Landrace pigs were randomly allocated to either hepatic devascularization (n=13) or sham operation (n=5). Repeated samples from the common carotid artery, right renal vein, and urine were simultaneously drawn for S-100beta analysis, using the Sangtec100 Liamat immunoassay. RESULTS: In hepatic devascularized pigs, arterial serum levels of S-100beta increased from 0.96+/-0.04 microg/L (mean +/- SEM) at t = 0h to 1.74+/-0.11 microg/L (mean +/- SEM) at t = 5 h. Urinary excretion increased simultaneously from 8.48+/-3.66 ng/h (mean +/- SEM) to 20.4+/-9.54 ng/h (mean +/- SEM), while renal arterial-venous fluxes for both kidneys increased from 1022+/-404 ng/h (mean +/- SEM) to 2444+/-590 ng/h (mean +/- SEM). CONCLUSIONS: Increased arterial S-100beta levels in pigs with acute hepatic encephalopathy are not a result of decreased renal elimination. The large difference between the renal arterial venous S-100beta concentrations and the urinary excretion of S-100beta indicate that renal metabolism is the major route of elimination.

New aspects of myocardial oxygen consumption. Invited review.

This paper gives an overview of mainly new aspects of myocardial oxygen consumption. Experimental models have quantified energy consumption in mechanical work, excitation-contraction coupling and metabolic processes. However, there are still contradictory observations between hemodynamic, thermodynamic and subcellular models and further knowledge of subcellular energy consumption is anticipated. The energy cost of contractility-enhancing drugs has been investigated in various experimental and clinical studies, and the calcium sensitizers have been proven to be the most mechanoenergetically efficient. An "oxygen-wasting" effect in post-ischemic hearts was observed some 15 years ago. The mechanism for this inefficiency has been thoroughly investigated, and seems to be caused by an inefficient excitation-contraction coupling and/or inefficiency in the contractile apparatus. The mechanoenergetic efficiency in heart failure needs further investigation.

Myocardial metabolism and efficiency after warm continuous blood cardioplegia.

BACKGROUND: Warm continuous blood cardioplegia (WCBCP) has been recommended during prolonged cardiac arrest to minimize functional deterioration. Myocardial metabolism and efficiency after this cardioplegic modality are not well described. METHODS: Substrate oxidation, blood flow, and myocardial function were measured before, during, and after 3 hours of WCBCP in 7 pigs. RESULTS: Free fatty acid and glucose oxidation decreased by 60% +/- 3.8% and 94% +/- 1.2%, respectively, during cardioplegia (both p < 0.05) and increased to 62% +/- 28% and 122% +/- 62% of baseline during the early recovery phase (p < 0.05 for glucose). One hour after WCBCP oxidation rates were similar to baseline. The transient postcardioplegic increase in substrate oxidation was associated with a 43% +/- 23% elevation of oxygen consumption (MVO2) compared with baseline and a 62% +/- 18% increase in myocardial blood flow. Cardiac output and mean arterial pressure did not change significantly after WCBCP, although myocardial function (stroke work, left ventricular end-systolic pressure, end-diastolic pressure, contractility, and efficiency) was depressed (p < 0.05). End-diastolic pressure and contractility improved from early to late phase of recovery, whereas the other indicators of ventricular function remained depressed. CONCLUSIONS: Myocardial substrate oxidation was preserved after 3 hours of WCBCP, although ventricular function was moderately impaired. Thus, WCBCP with a seemingly normal substrate and oxygen supply was associated with a reduced cardiac efficiency.

Protein S-100beta: a biochemical marker for increased intracranial pressure in pigs with acute hepatic failure.

BACKGROUND: Acute hepatic failure (AHF) may cause encephalopathy. Intracranial pressure (ICP) is frequently monitored to guide therapy, but such monitoring may cause intracerebral haemorrhagic complications. We hypothesize that determination of serum levels of S-100beta, a protein synthesized in astroglial cells, will provide useful clinical information on the presence and extent of intracranial hypertension in AHF. METHODS: Continuous intraparenchymatous ICP monitoring and serial S-100beta measurements in serum were performed in 11 Norwegian Landrace pigs with surgically induced AHF and in 4 sham-operated controls. RESULTS: ICP increased hour by hour in the devascularized pigs in parallel with increased serum levels of protein S-100beta. In the sham-operated controls S-100beta was not detectable at any time point. CONCLUSIONS: Serum levels of S-100beta are increased early in experimental AHF. Determination of protein S-100beta may provide useful information on the presence and extent of intracranial hypertension in AHF.

Myocardial substrate metabolism influences left ventricular energetics in vivo.

The myocardial oxygen consumption (MVO(2)) to left ventricular pressure-volume area (PVA) relationship is assumed unaltered by substrates, despite varying phosphate-to-oxygen ratios and possible excess MVO(2) associated with fatty acid consumption. The validity of this assumption was tested in vivo. Left ventricular volumes and pressures were assessed with a combined conductance-pressure catheter in eight anesthetized pigs. MVO(2) was calculated from coronary flow and arterial-coronary sinus O(2) differences. Metabolism was altered by glucose-insulin-potassium (GIK) or Intralipid-heparin (IH) infusions in random order and monitored with [(14)C]glucose and [(3)H]oleate tracers. Profound shifts in glucose and fatty acid oxidation were observed. Contractility, coronary flow, and slope of the MVO(2)-PVA relationship were unchanged during GIK and IH infusions. MVO(2) at zero PVA (unloaded MVO(2)) was 0.16 +/- 0.13 J x beat(-1) x 100 g(-1) higher during IH compared with GIK infusion (P = 0.001), a 48% increase. The study demonstrates a marked energetic advantage of glucose oxidation in the myocardium, profoundly affecting the MVO(2)-PVA relationship. This may in part explain the "oxygen-wasting" effect of lipid-enhancing interventions such as adrenergic drugs and ischemia.

Oxygen-wasting effect of inotropy in the "virtual work model".

In the "virtual work model," left ventricular total mechanical energy (TME) is linearly related to myocardial oxygen consumption (MVO2). This relationship (MVO2-TME) is supposedly independent of inotropic stimulation, vascular loading, and heart rate variations. We reexamined the effect of inotropic stimulation (dopamine) on the metabolic to mechanical energy transfer in nine open-chest anesthetized pigs. Left ventricular mechanical energy was calculated using TME (mean ejection pressure x end-diastolic volume + stroke work), TMEW (end-diastolic volume reduced by unstressed ventricular volume), and the pressure-volume area (PVA). A highly linear relationship between MVO2 and mechanical energy was found for all three indexes during control and dopamine runs (r = 0.87-0.99). The slopes were unaltered by dopamine. y-Axis intercepts were (control vs. dopamine) as follows (in J. beat-1. 100 mg-1; means +/- SD): TME, 0.36 +/- 0.12 vs. 0.61 +/- 0.30 (P < 0.02); TMEW, 0.43 +/- 0.16 vs. 0.72 +/- 0.32 (P < 0.02); and PVA, 0.34 +/- 0.13 vs. 0.60 +/- 0.30 (P < 0.02). We conclude that the virtual work model is dependent on inotropic stimulation and that new insight into myocardial chemomechanical coupling is not added by this concept.

Substrate preference of isolated perfused rat hearts during hypothermia and rewarming.

Fatty acid and glucose oxidation rates were measured in isolated rat hearts undergoing hypothermia and rewarming. The hearts were perfused in the Langendorff mode with Krebs-Henseleit bicarbonate buffer containing 11.1 mM glucose plus 0.6 mM albumin-bound oleic acid as energy substrates. The hearts were stabilized at 37 degrees C and thereafter cooled progressively to 15 degrees C over a period of 60 min. The hearts were kept at this temperature for 10 min and then rewarmed to 37 degrees C during the next 30 min. Control hearts were perfused at 37 degrees C throughout the whole perfusion period. Trace amounts of [14C]glucose or [14C]oleic acid were included in the perfusate, and the rate of substrate oxidation was determined on the basis of the radioactive CO2 production. In normothermic hearts steady state oxidation rates of glucose and oleate were found to be 0.17 +/- 0.01 and 0.51 +/- 0.07 mumol min-1 g-1 dry wt, respectively (mean +/- SEM). In response to hypothermia (15 degrees C) glucose oxidation was reduced by 76% (from 0.17 +/- 0.01 to 0.04 +/- 0.01 mumol min-1 g-1 dry wt) and oleate oxidation by 47% (from 0.51 +/- 0.07 to 0.27 +/- 0.02 mumol min-1 g-1 dry wt). Upon rewarming glucose and fatty acid oxidation rates returned to essentially the same values (0.12 +/- 0.02 and 0.45 +/- 0.04 mumol min-1 g-1 dry wt) as those observed under steady state normothermic conditions. The molar ratio between glucose and fatty acid oxidation was, however, significantly (P < 0.05) lower in hypothermic than in normothermic hearts.(ABSTRACT TRUNCATED AT 250 WORDS)