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AIM: Compensatory tachycardia can potentially be deleterious in acute heart failure. In this study, we tested a therapeutic strategy of combined inotropic support (dobutamine) and selective heart rate (HR) reduction through administration of ivabradine. METHODS: In an open-chest pig model (n = 12) with left ventricular (LV) post-ischaemia dysfunction, cardiac function was assessed by LV pressure catheter and sonometric crystals. Coronary flow and blood samples from the coronary sinus were used to measure myocardial oxygen consumption (MVO2 ). LV energetics was assessed by comparing MVO2 with cardiac work at a wide range of workloads. RESULTS: In the post-ischaemia heart, dobutamine (5 µg kg(-1)  min(-1) ) increased cardiac output (CO) by increasing HR from 102 ± 21 to 131 ± 16 bpm (beats per min; P < 0.05). Adding ivabradine (0.5 mg kg(-1) ) slowed HR back to 100 ± 9 bpm and increased stroke volume from 30 ± 5 to 36 ± 5 mL (P < 0.05) by prolonging diastolic filling time and increasing end-diastolic dimensions. Adding ivabradine had no adverse effects on CO, mean arterial pressure and cardiac efficiency. Similar findings on efficiency and LV function were also seen using an ex vivo working mouse heart protocol. CONCLUSIONS: A combined infusion of dobutamine and ivabradine had a neutral effect on post-ischaemia LV efficiency and increased left ventricular output without an increase in HR.

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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.

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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.

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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.

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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.

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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.

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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.

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OBJECTIVES: To evaluate non-invasive indexes measuring systolic and diastolic ventricular function. Eleven coronary artery bypass grafting (CABG) patients were investigated in order to assess the ability of preoperative ejection fraction (EF) and end diastolic pressure (EDP) to predict left ventricular function determined non-invasively at surgery. DESIGN: End-systolic elastance (Ees) was assessed perioperatively using transoesophageal echocardiographic area estimation and arterial pressure monitoring during preload variations (caval balloon). Diastolic function was evaluated using three different echo/Doppler indexes. RESULTS: EF correlated positively to Ees (r = 0.69, p = 0.03). No correlations were found between EDP and the perioperative diastolic indexes. Ees fell from pre-bypass to post-bypass (from 9.0 +/- 2.7 to 4.7 +/- 1.7 mmHg/cm2, mean +/- SD, p < 0.001), but no alterations in diastolic parameters occurred. CONCLUSIONS: A positive correlation was found between preoperative EF and Ees at surgery. The semi-invasive Ees detected a systolic "stunning" after cardiopulmonary bypass and is promising as a surveillance tool for left ventricular perioperative function and treatment. No correlations between preoperative EDP and non-invasive diastolic indexes were found, and assessment of perioperative diastolic function needs further refinement.

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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.

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Osteogenesis imperfecta is an hereditary defect in the synthesis of collagen fibres. The disease can cause cardiac defects, such as aortic and mitral incompetence. Surgical repair of these defects is complicated by tissue friability and bleeding problems. We describe a case where an incompetent aortic valve was successfully replaced by a mechanical prosthesis.

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We report on a resection of a myxoma arising from the septal leaflet of the tricuspid valve in a 62 year-old female. A tricuspid valvuloplasty was performed. At follow-up 27 months after surgery echo cardiography showed a normal tricuspid valve without any evidence of insufficiency.

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A bronchopleural fistula after pneumonectomy is a serious complication, and successful healing is a therapeutic challenge. Increasing evidence indicates that closing of the fistula combined with wrapping the bronchus with omentum (omentoplasty) can secure permanent healing in the majority of cases. The omentum is highly vascularized, and has angiogenetic and anti-inflammatory properties. We describe two patients with bronchopleural fistulas after surgery for lung cancer. The fistulas were diagnosed respectively one and fifteen months after operation. Both were treated successfully with antibiotics, surgical debridement, secondary closure and wrapping of the fistulas with omentum transposed from the abdomen with its attachment to the right gastroepiploic artery preserved.

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At the University Clinic Tromsø 27 and 16 patients with aortic dissection of Stanford type A and B have been admitted during the last eight years. The treatment strategy has been immediate surgery for type A and a conservative strategy consisting of blood pressure reduction and observation for type B. Nine (33%) of the patients with type A dissections were diagnosed either too late for surgery or at autopsy. Two were deemed too ill for operative treatment. One patient with a chronic type A dissection has been followed up without surgery. The remaining 15 were operated on. Four of these (26%) died within 30 days. Apart from a temporary hemiparesis, no sequelae related to the surgical treatment were observed in the remaining 11 patients. Six of the 16 patients with type B dissections were operated on because of organ ischemia or rupture/threatening rupture. Two died within 30 days. One patient had a prolonged postoperative course owing to multiple organ failure and muscle necrosis. Two of the ten patients with type B dissections who were followed up without surgery died during the observation period. These observations indicate a need for a more aggressive approach to the diagnosis and follow-up of aortic dissections.

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Freeman et al. (1993) have recently introduced a new index measuring isovolumic relaxation in the in situ left ventricle. This index, called the R-average, shows less variability than the traditionally used monoexponential time constant (tau), and could therefore represent an alternative measure of isovolumic relaxation during different physiological or pathophysiological interventions. However, the R-average represents the average pressure fall during isovolumic relaxation (isovolumic pressure fall divided by the isovolumic time period), and is therefore highly influenced by the end-systolic pressure level. The present study was done in order to assess whether small increments in loading conditions would alter the R-average without changes in the isovolumic relaxation period or the monoexponential pressure decay tau. We used a right heart bypass porcine model, and end-systolic pressure was altered between 92 and 140 mmHg by pre-loading (servo-pump) or after-loading (phenylephrine) in spontaneously beating and paced hearts. During loading, we found a significant increase in the R-average and a close correlation (r = 0.72 - 0.99) between R-average and en-systolic pressure. However, no alterations were found in the duration of the isovolumic relaxation time period or monoexponential pressure decay (tau) during these loading conditions. In our view, the R-average indicates the systolic loading level for the ventricle, but does not necessarily reflect alterations in the process of active relaxation.

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The induction of heat shock proteins in the myocardium has been suggested as a possible intervention to allow for enhanced cardioprotection. We have postulated that a brief period of retrograde hyperthermic perfusion would be sufficient to induce Hsp 70 mRNA and protein accumulation. To investigate this hypothesis, rat hearts (n = 45) were perfused at 37 degrees C for 30 min, then perfused for 15 min at 42 degrees C, and allowed to recover at 37 degrees C for 120 min. Control hearts (n = 23) were perfused at 37 degrees C continuously. Northern analysis indicated that in hearts treated with a brief period of retrograde hyperthermic perfusion Hsp 70 mRNA levels were increased 2.85 +/- 0.02-fold (P < 0.01) by 10 min, 4.88 +/- 0.94-fold (P < 0.01) by 15 min, 9.19 +/- 0.62-fold (P < 0.001) by 30 min, 9.4 +/- 0.52-fold (P < 0.001) by 60 min, 9.45 +/- 0.57-fold (P < 0.001) by 90 min and 9.66 +/- 0.99-fold (P < 0.001) by 120 min of normothermic recovery as compared to control hearts. Western analysis revealed that the heat inducible Hsp 72 kDa protein was increased 2.37 +/- 0.45-fold (P < 0.01) at 60 min, 2.53 +/- 0.25-fold (P < 0.01) at 90 min, and 2.7 +/- 0.6&-fold (P < 0.01) at 120 min when compared to control hearts. Our results indicate that the induction of the heat shock protein Hsp 70 can be rapidly achieved through retrograde hyperthermic perfusion of the myocardium.

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The surgical mortality among 22 patients treated for thoracic or thoracoabdominal aneurysm was compared with the mortality in 47 patients managed without surgery. Surgical mortality ( < 30 days) was low (1/13) in ascending aortic aneurysm, but higher (3/8) in aneurysm of the descending or thoracoabdominal aorta (including both acute and elective operations). Of the 20 non-surgically managed patients in the latter group, 15 died after a mean of 1.1 year. The only patient operated on for aortic arch aneurysm died of cerebral ischaemia 2 days postoperatively. Most of the 19 non-operated patients with aneurysm of the arch or total aorta (mean age 76 years) were never considered for surgical treatment. The analysis supports aggressive management of patients with aneurysm of the ascending, descending or thoracoabdominal aorta. Many of our patients with aneurysm of the arch or involving most of the aorta were old and had other, concomitant diseases, and in such cases an aggressive treatment strategy does not seem justified.

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BACKGROUND: Both heat-shock protein (HSP) 70 and its mRNA are induced in the ischemic myocardium. The inductor stimuli are, however, not known. Stretch and ischemic metabolic alterations are the two most likely HSP70 inductors. METHODS AND RESULTS: To assess whether anaerobic metabolism induces HSP70 mRNA expression, 61 rat hearts were perfused with Krebs-Henseleit buffer (37 degrees C) in a modified Langendorff apparatus built for rapid switching between pressure-controlled and flow-controlled perfusions. Each heart was initially perfused for 30 minutes at a constant perfusion pressure of 65 mm Hg. Subsequently, separate hearts were perfused at a constant flow of 8, 6, 4, 2, 1, 0.5, or 0 mL/min for 30 minutes using a nonpulsatile pump (n = 5, each perfusion level). Hemodynamic measurements demonstrated a linear correlation between coronary flow and both perfusion pressure and developed pressure (r = .94 and r = .89, respectively; P < .0001 for both comparisons). Diastolic pressure at the end of the perfusions increased only in globally ischemic hearts (34 +/- 3 mm Hg at 0 mL/min versus 5 +/- 1 mm Hg at 8 mL/min; mean +/- SEM, P < .05). The highest lactate release during the 30-minute constant-flow period was observed at a flow level of 4 mL/min (177 +/- 1 versus 71 +/- 8 mumol at 8 mL/min). Creatine kinase release was detected at 2 mL/min (28 +/- 8 mU/mL after 25 minutes of constant flow versus < 8 mU/mL at 4 mL/min). The highest flow level showing cessation of mechanical activity despite pacing of the hearts was at 2 mL/min (2 of 5 hearts). An increased level of HSP70 mRNA expression was found only at 4 mL/min (10-fold increase). Blocking lactate production by substituting glucose with 2-deoxyglucose in the perfusion buffer reduced the HSP70 mRNA level by 44% at 4 mL/min. No increase of HSP/70 was detected (Western blots) at any flow level. CONCLUSIONS: These results indicate that anaerobic metabolism is a strong stimulus for HSP70 transcription and that cessation of anaerobic metabolism in severe ischemia is associated with a shutdown of HSP70 mRNA expression.

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Although hypothermia is regarded as providing protection of the myocardium during cardiac operations, rapid cooling of the myocardium in the nonarrested state may have detrimental effects on the function of the myocardial cell membrane as a permeability barrier. We therefore measured total cellular calcium in isolated working rat hearts, receiving either glucose (11.1 mmol/L) or glucose plus palmitate (1.2 mmol/L), before, during, and after a 40-minute hypothermic arrest (10 degrees C, Langendorff perfusion). In both groups a rise in total cellular calcium, measured by 45Ca2+ technique, was observed during hypothermia, followed by a decline on rewarming. However, the rise in total cellular calcium during hypothermia was significantly (p < 0.05) higher in hearts perfused with palmitate (from 1.0 +/- 0.2 to 3.5 +/- 0.2 nmol/mg dry weight) compared with that in glucose-perfused hearts (from 1.1 +/- 0.13 to 2.6 +/- 0.2 nmol/mg dry weight). Palmitate-perfused, but not glucose-perfused, hearts showed arrhythmias and delayed pressure development 1 to 2 minutes after rewarming. In addition cardiac output of these hearts was significantly lower (p < 0.025) than that of glucose-perfused hearts 5 to 10 minutes after rewarming. These data show that hypothermia per se causes a net calcium uptake in isolated rat hearts and that this effect is aggravated by high concentrations of fatty acids. Thus the impaired recovery of myocardial function in palmitate-perfused hearts can possibly be related to a distorted calcium handling.

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A phospholipase C specific for choline and ethanolamine acyl and plasmalogen glycerophospholipids (PC-PLC) has been described in myocardial tissue. In the present study we investigated whether an endogenous PC-PLC is activated in hypoxic, substrate-free incubations of rat ventricular myocytes. The phosphatidylcholine pool of the myocytes was prelabelled with [14C]choline during a 4-h preincubation (pulse) period. The myocytes were subsequently washed and incubated for another 2 h (chase period) in normoxic, hypoxic, or hypoxic buffer supplemented with PC-PLC from Bacillus cereus. We hypothesized that an increase in the total (intracellular plus extracellular) content of [14C]phosphocholine (one of the products resulting from PC-PLC action on phosphatidylcholine) throughout the chase period would indicate PC-PLC activity. Instead, an apparent decrease was observed for this parameter in all myocyte groups (17-29%), even in the one exposed to exogenous PC-PLC. However, 60 min after the start of the chase period, the level of total [14C]phosphocholine was higher in hypoxic (p = 0.022) and hypoxic + PC-PLC exposed (p = 0.013) myocytes compared with normoxic controls. The total content of [14C]choline increased significantly (p < 0.017) in all myocyte groups during the incubation period (98-153%) as a result of an increment of this metabolite in the buffer. Furthermore, the values measured in hypoxic and hypoxic + PC-PLC exposed myocytes during the first hour of the chase period were significantly (p < 0.017) higher than the corresponding values in normoxic myocytes. The present results do not allow firm conclusions regarding endogenous PC-PLC activation in energy-depleted rat cardiac myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

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