Ischaemic preconditioning limits infarct size in the rat heart.

OBJECTIVE: One of the mechanisms by which ischaemic preconditioning is thought to protect against later prolonged ischaemia is via a reduction in ATP utilisation during ischaemia. The ATP "wastage" that occurs during ischaemia is thought to be due to mitochondrial ATPase activity, which may be prevented in ischaemic preconditioning by the binding of a specific inhibitor protein. As the rat is known to have less inhibitor protein than other species, this study was designed to determine whether the rat heart could be ischaemically preconditioned. METHODS: Rats were anaesthetised with pentobarbitone, the chest opened and the hearts ischaemically preconditioned with a 5 min occlusion of the left main coronary artery followed by 10 min reperfusion. The hearts were then subjected to a 45 min occlusion followed by 3 h reperfusion. Control hearts were treated identically but without ischaemic preconditioning. Infarct size was measured using triphenyl tetrazolium and expressed as a percentage of the region at risk, measured with fluorescent particles. RESULTS: Infarct size as a percent of the risk area in the ischaemically preconditioned group (n = 8) was 31.4(SEM 6.1)%, versus 61.0(4.8)% in control hearts (n = 8) (p < 0.005). CONCLUSIONS: These results show that rat hearts can be ischaemically preconditioned and suggest that the protective mechanism involved in this phenomenon is not mediated through the endogenous inhibition of mitochondrial ATPase. An overall reduction in mitochondrial ATP "wastage" may not be the sole mechanism in the protection seen in ischaemic preconditioning.

The effect of preconditioning (ischemic and pharmacological) on myocardial necrosis following coronary artery bypass graft surgery.

OBJECTIVES: Ischemic preconditioning is known to protect the human heart from ischemic injury during coronary artery bypass graft (CABG) surgery but is not practised routinely. Adenosine A1 receptor agonists may confer protection in this setting by mimicking preconditioning. The aim of this study was to compare preconditioning, by ischemia or an adenosine A1 receptor agonist (GR79236X), with an established method of myocardial protection in CABG, namely intermittent cross-clamp fibrillation. METHODS: In this prospective double-blind study, 30 CABG patients were randomised to receive: (a) intermittent cross-clamp fibrillation (control), (b) pharmacological preconditioning (GR79236X), or (c) ischemic preconditioning (two 3-min periods of ischemia, each followed by 2 min of reperfusion). Surgery was performed under standardised conditions by one surgeon (WBP). The primary endpoint was cardiac troponin T release. RESULTS: Mean cardiopulmonary bypass time was 91+/-11.6 (S.D.) min. Mean ischemic time was 33+/-5.5 (S.D.) min with no inter-group difference. Mean troponin T at 72 h was highest in the control group (1.32+/-0.99 (S.D.) microg/l), similar in the GR79236X group (1.22+/-1.22 (S.D.) microg/l; P=0.85) and significantly reduced in the ischemic preconditioning group (0.58+/-0.40 (S.D.) microg/l; P=0.04). CONCLUSIONS: Ischemic preconditioning is superior to the other techniques at limiting myocardial necrosis during CABG. Pharmacological preconditioning may confer some benefit but this was not statistically shown using a specific adenosine A1 agonist (GR79236X).

Coronary artery fistulas presenting with bacterial endocarditis.

Coronary artery fistulas are rare congenital malformations. Two cases presenting with bacterial endocarditis are described. Both were treated successfully by grafting of the coronary artery and ligation of the fistula.

Ischaemic preconditioning reduces troponin T release in patients undergoing coronary artery bypass surgery.

OBJECTIVE: To investigate whether ischaemic preconditioning could reduce myocardial injury, as manifest by troponin T release, in patients undergoing elective coronary artery bypass surgery. DESIGN: Randomised controlled trial. SETTING: Cardiothoracic unit of a tertiary care centre. PATIENTS: Patients with three vessel coronary artery disease and stable angina admitted for first time elective coronary artery bypass surgery were invited to take part in the study; 33 patients were randomised into control or preconditioning groups. INTERVENTION: Patients in the preconditioning group were exposed to two additional three minute periods of myocardial ischaemia at the beginning of the revascularisation operation, before the ischaemic period used for the first coronary artery bypass graft distal anastomosis. MAIN OUTCOME MEASURE: Serum troponin T concentration at 72 hours after cardiopulmonary bypass. RESULTS: The troponin T assays were performed by blinded observers at a different hospital. All patients had undetectable serum troponin T (< 0.1 microgram/l) before cardiopulmonary bypass, and troponin T was raised postoperatively in all patients. At 72 hours, serum troponin T was lower (P = 0.05) in the preconditioned group (median 0.3 microgram/l) than in the control group (median 1.4 micrograms/l). CONCLUSIONS: The direct application of a preconditioning stimulus in clinical practice has been shown, for the first time, to protect patients against irreversible myocyte injury.

Low energy level internal defibrillation during cardiopulmonary bypass.

Low energy level internal direct current shocks were used to defibrillate the hearts of 168 patients during procedures performed on cardiopulmonary bypass. In all cases, the core temperature was greater than 32 degrees C and care was taken to correct hypokalaemia and acid-base balance prior to defibrillation. In 78 patients (46%), defibrillation required 2 joules or less, and in 139 (82.7%) cases, defibrillation was effected with 4 joules or less. Only 4 patients required more than 10 joules to defibrillate the heart. This study shows that it is possible to defibrillate hearts during cardiopulmonary bypass with energy levels well below the 20-30 joule shocks commonly used.

Preconditioning the human heart during aorto-coronary bypass surgery.

UNLABELLED: Ischaemic preconditioning, with brief periods of ischaemia separated by reperfusion, increases myocardial resistance to infarction. In addition, preconditioning leads to preservation of myocardial adenosine triphosphate (ATP) during ischaemia. We propose that ischaemic preconditioning may share fundamental similarities with intermittent aortic cross-clamping utilised during aorto-coronary bypass surgery. The aim of this study was to test the hypothesis that controlled aortic cross-clamping is a form of preconditioning using conservation of ATP as the end point. Patients randomised to the preconditioned group (preconditioned, n = 10 patients), received a preconditioning stimulus of two 3-min periods of cross-clamping separated by 2 min of reperfusion prior to an ischaemic insult of 10 min ischaemia and ventricular fibrillation. In the control group (control, n = 10 patients) hearts received 10 min cross-clamping with fibrillation without prior preconditioning. Myocardial ATP, creatine phosphate (CP), and lactate were determined from biopsy specimens taken at the onset of cardiopulmonary bypass (A), at the end of preconditioning (B), and at the end of 10 min of ischaemic insult (C). RESULTS: expressed as mean +/- SE (mumol/g dry weight). Preconditioning resulted in a significant depletion of the myocardial ATP content (preconditioned, B: 11.7 +/- 0.9 vs A: 19.8 +/- 1.4; P < 0.01). Furthermore 10 min of ischaemia resulted in a significant depletion of ATP in the control patients (control, C: 7.2 +/- 0.3 vs B: 19.5 +/- 1.2; P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Ischaemic preconditioning and cardiac surgery.

OBJECTIVE: This review discusses the phenomenon of ischaemic preconditioning and its potential application to cardiac surgery. The biology of ischaemic preconditioning is explained and the more limited evidence suggesting that the human heart can be preconditioned is discussed. METHODS AND RESULTS: It is now accepted that the heart is capable of short-term rapid adaptation in response to brief ischaemia so that during a subsequent, more severe ischaemic insult myocardial necrosis is delayed-ischaemic preconditioning. The infarct-delaying properties of ischaemic preconditioning have been observed in all species studied. Five minutes of ischaemia is enough to initiate preconditioning and the protective period lasts for 1-2 h. Laboratory experiments have demonstrated that the stimulation of adenosine receptors initiates preconditioning and the intracellular signal transduction mechanisms involve protein kinase C and ATP-dependent potassium channels, although there may be some differences between species. An analysis of studies on myocardial infarction in humans has revealed that some patients reporting angina in the days before infarction have a better outcome and this may be due to the ischaemia causing preconditioning. More direct evidence has come from an investigation of patients undergoing percutaneous transluminal angioplasty in whom the ST-segment changes induced by balloon inflation were more marked during the first inflation than the second. In patients undergoing coronary artery bypass grafting the decline in ATP content during the first 10 min of ischaemia was reduced in patients subjected to a brief preconditioning protocol. CONCLUSIONS: Preconditioning is a powerful and reproducible method of protecting the myocardium from irreversible ischaemic injury. There is now evidence indicating that the human heart can be preconditioned. However, more trials are necessary in patients undergoing cardiac surgery before the role of preconditioning as a means of myocardial protection can be assessed.

The incidence of significant pericardial effusion and tamponade following major aortic root surgery.

OBJECTIVE: To examine the hypothesis that the incidence of significant pericardial effusion following aortic root surgery is higher than anticipated after cardiac surgery. DESIGN: A retrospective data analysis. SETTING: A tertiary referral centre for cardiothoracic surgery. SUBJECTS: All patients undergoing aortic root surgery either with or without aortic valve replacement between January 1991 and July 1993. RESULTS: Three patients developed late cardiac tamponade (7-10 days post-operatively) and a further three developed clinically significant pericardial effusions as a result of post-pericardiotomy syndrome. The 31.6% (95% confidence limit: 12.5-56%) incidence of significant pericardial effusions following aortic root surgery is therefore significantly higher than anticipated after cardiac surgery (0.8-6). CONCLUSION: These data support the hypothesis that the incidence of significant pericardial effusion following aortic root surgery is higher than anticipated after cardiac surgery. We recommend that echocardiography is routinely performed during the post-operative period in these patients to exclude significant pericardial effusions.

Experience with circulatory arrest and hypothermia to facilitate thoracic aortic surgery.

A total of 12 patients underwent surgical repair for thoracic aortic dissections with a technique which included cardiopulmonary bypass, profound hypothermia, high-dose thiopentone and circulatory arrest. Seven of nine early postoperative survivors made a complete recovery on clinical criteria. There were three perioperative deaths and there was one late postoperative death from chronic renal disease. There were no deaths among those operated on electively. Neuropsychological testing may help to define the consequences of circulatory arrest on higher function.

Early to midterm results with the radial artery in coronary artery bypass grafting following autotransplantation without pharmacological manipulation.

BACKGROUND: In our unit when the radial artery is used as a conduit for myocardial revascularization routine, postoperative calcium-channel blockade is not practised. To preserve the radial artery, it is freed from the surrounding structures together with its venae commitantes and then left, in situ, in circulation, until needed for grafting. We evaluated the early to midterm patency of the radial artery using this strategy in our patients. METHODS: We analysed prospectively collected data on 690 consecutive patients who had isolated primary coronary artery bypass grafting performed between June 1999 and February 2003 with at least one conduit being a radial artery. RESULTS: Radial arteries were used for 851 of 2150 distal anastomoses (39.6%). Median follow-up was 399 days (range 20-1323) and was 99.9% complete. Early mortality was 2.0% (14). Late mortality was 3.0% (21), 12 late deaths were not cardiac related. Nine patients (1.4%) had angiography on clinical grounds a mean of 238 days (range 0-511) postoperatively. Six coronary artery territories were inadequately supplied by their radial artery grafts. Kaplan-Meier event-free survival was 94% and 90% at 1 and 3 years, respectively. CONCLUSIONS: The results of coronary artery bypass grafting using the radial artery in our institution compare favourably with those of other contemporary workers. It is safe to leave the radial artery in situ in the circulation until it is required for grafting. The absence of postoperative pharmacological manipulation of the radial artery does not appear to affect early or midterm outcome.

Time relationships in the diagnosis and treatment of left-atrial myxoma.

The records of 40 patients, 28 females and 12 males with a median age of 49 years (range 13-80 years), undergoing excision of left-atrial myxoma at 3 London hospitals during a 21-year period were reviewed. The urgency of treatment is discussed, and the interval between the onset of symptoms and diagnosis (median 38 weeks), and also between diagnosis and surgery (< 48 hours) is considered.

Raised international normalised ratio (INR): is it a cause or an effect of late cardiac tamponade?

Two cases of late cardiac tamponade after valve replacement surgery are reported: both patients were treated with oral anticoagulants (warfarin) after operation. An erratic response in the international normalised ratio (INR) was found before the diagnosis of late tamponade. It is suggested that this response of the INR may be an early indicator of late cardiac tamponade rather than a cause.

The influence of the time period between preconditioning ischemia and prolonged ischemia on myocardial protection.

Ischemic preconditioning with brief periods of ischemia followed by reperfusion protects the myocardium against a subsequent prolonged ischemic insult. Reperfusion may influence the protection given by ischemic preconditioning by washing out metabolites that are accumulated during the preconditioning ischemia. This study was designed to define the duration of reperfusion necessary to provide such protection. Hearts of anesthetized rats were preconditioned by occlusion of the left coronary artery for 5 minutes. This was followed by reperfusion for either 1 minute (n = 6) or 30 seconds (n = 6). The hearts were then subjected to a sustained occlusion of the left coronary artery for 45 minutes followed by reperfusion for 3 hours. Control (n = 11) hearts were subjected only to occlusion of the left coronary artery for 45 minutes followed by reperfusion for 3 hours. Infarct size was measured using tetrazolium and expressed as a percentage of the region at risk. After reperfusion for 1 minute there was a significant reduction in the size of the infarct (32.3 +/- 4.1%), expressed as a percentage of the zone at risk, when compared to controls (61.9 +/- 3.5%) (p < 0.01). However, the protection received by preconditioning was lost when reperfusion was limited to 30 seconds (infarct size 63.4 +/- 3.2%). The results show that the minimum period of reperfusion required to give protection after preconditioning ischemia lies between 30 seconds and 1 minute.

Preconditioning the human myocardium.

Ischaemic preconditioning (short periods of ischaemia with intermittent reperfusion) has been shown paradoxically to protect the myocardium from a subsequent longer ischaemic insult. The protection associated with preconditioning is one of the most powerful mechanisms of protection known and has been shown in every animal species investigated. However, there is no direct evidence that ischaemic preconditioning occurs in the human heart. We studied whether it was possible to precondition the human heart in a setting of coronary artery bypass surgery. The measurement of adenosine triphosphate in biopsy specimens was used as our endpoint. We believe that our results are the first to show that it may be possible to precondition and protect the human myocardium with short controlled periods of intermittent ischaemia and reperfusion.

Open lung biopsy for investigation of acute respiratory episodes in patients with HIV infection and AIDS.

BACKGROUND: Open lung biopsy (OLB) is rarely necessary for investigation of HIV positive patients with acute respiratory episodes because of the high yield from fibreoptic bronchoscopy with bronchoalveolar lavage (BAL). METHODS: A retrospective review of OLB in HIV positive patients admitted to a specialist inpatient unit with acute respiratory symptoms was carried out in order to define clinical indications, diagnostic yield, impact on management, complications and outcome. RESULTS: OLB was performed in 23 patients; 21 had undergone one or more bronchoscopies with BAL (5 also had negative results from transbronchial biopsy). Indications for OLB were: Group A, 15 patients thought clinically to have pneumocystis pneumonia but not responding to treatment; Group B, 4 patients with focal chest radiographic abnormalities; Group C, 4 patients with diffuse radiographic abnormalities and miscellaneous conditions. Preoperative PaO2 (on air) ranged from 4.4 to 14.5 (mean = 9.5) kPa. The results of OLB were in Group A 5 patients had non specific interstitial pneumonitis (NIP), 1 also had Kaposi's sarcoma, 4 had pneumocystis pneumonia (1 also had bronchiolitis obliterans organising pneumonia [BOOP]), 3 had Kaposi's sarcoma and 1 had BOOP and emphysema, 1 had pulmonary infarction and no infection and 1 had normal lung tissue. In Group B diagnoses were NIP, B cell lymphoma, occult alveolar haemorrhage and Pseudomonas aeruginosa pneumonia with BOOP; In Group C 2 patients had NIP and 2 had pneumocystis pneumonia (1 also had cytomegalovirus pneumonitis). All patients survived surgery and none required mechanical ventilation. OLB results significantly affected management; in Group A inappropriate treatment was discontinued in 11 patients found not to have pneumocystis pneumonia, and alternative therapy was begun in the 4 with pneumocystis and in Groups B and C 6 patients began specific therapy; unnecessary therapy was avoided in one and antimicrobial treatment was modified in one. CONCLUSIONS: Open lung biopsy in HIV positive patients with focal and diffuse radiographic abnormalities has a high diagnostic yield and low morbidity. This investigation should be considered in those with acute respiratory episodes and negative results from bronchoscopic investigations or who have contra-indications to this procedure.

Ischaemic preconditioning in a model of global ischaemia: infarct size limitation, but no reduction of stunning.

It is well known that ischaemic preconditioning delays infarct size during regional ischaemic insults. However, the extent of this protective effect against different ischaemia periods has not been established, and any reduction in stunning has been difficult to demonstrate with regional models. In this study we have investigated ischaemic preconditioning in a buffer-perfused isolated rabbit heart model with a global ischaemic insult, and measured both infarct volume and functional recovery. Experiments were performed with three ischaemia time periods of 15, 20 and 30 min at 37 degrees C. Infarct volume (expressed as a percentage of left ventricular volume) was measured by tetrazolium staining after 2 hours reperfusion, and left ventricular developed pressure with an intraventricular balloon. Hearts preconditioned with 5 min ischaemia and 10 min reperfusion were compared with a control group. In this model, preconditioning resulted in a 57% reduction in infarct volume compared with control hearts (P = 0.02) subjected to 20 min of global ischaemia, but the degree of this infarct delaying effect was dependent on the ischaemia time and was only 37% (P = 0.02) and 11% (N.S.) with a 30 min and 15 min ischaemic challenge respectively. Recovery of post-ischaemic left ventricular developed pressure as a percentage of the pre-ischaemic value correlated very well with infarct volume in control r = -0.82 (P < 0.001) and preconditioned r = -0.78 (P < 0.001) groups, and the slope of the regression lines was similar for both groups. These results demonstrate that the degree of protection produced by preconditioning is not uniform but varies with the length of the ishaemic insult. By measuring both infarct volume and functional recovery we have been able to confirm that any post-ischaemic improvement in global left ventricular function produced by preconditioning is secondary to reduced infarction, and hence that preconditioning does not attenuate stunning.

Recurrent left atrial myxoma.

Based on statistics from the UK, the incidence of myxoma is about 1:1,000,000/year. Three recent cases of recurrent myxoma are reported, one where excision was probably incomplete, one where tumour implantation may have occurred and one where a mesenchymal sarcoma was misinterpreted histologically. The relative importance of these three factors in recurrence of cardiac tumours after surgical excision is discussed.

Comparison of the protective effects of a highly selective ATP-sensitive potassium channel opener and ischemic preconditioning in isolated human atrial muscle.

The ATP-sensitive K+ channel (K[ATP] channel) has been implicated in the mechanism of ischemic preconditioning. We compared the protective effects of ischemic preconditioning and a highly selective K(ATP) channel opener, BMS 180448, in human myocardium. BMS 180448 was either used alone or in combination with the K(ATP) channel blocker glibenclamide. Human atrial trabeculae derived from the right atrial appendage were suspended in an organ bath, superfused with oxygenated Tyrode's solution at 37degrees C, and paced at 1 Hz. Experimental groups (n = 6 in each) were as follows: (1) control (C)--90 minutes hypoxic substrate-free perfusion at 3 Hz (simulated ischemia), followed by 120 minutes of reoxygenation with substrate at 1 Hz (reperfusion); (2) preconditioning (PC)--3 minutes simulated ischemia, 7 minutes reperfusion, followed by 90 minutes simulated ischemia and 120 minutes reperfusion; (3) BMS 180448 (BMS)--exposure to the drug for 5 minutes prior to 90 minutes simulated ischemia and 120 minutes reperfusion; (4) BMS 180448 + glibenclamide (BMS + G)--glibenclamide exposure for 10 minutes, and BMS for 5 minutes prior to 90 minutes simulated ischemia and 120 minutes reperfusion. Force of contraction prior to the commencement of the protocol was assigned the arbitrary value of 100%. Percentage recovery of contractile function at 120 minutes reperfusion was used as the endpoint. BMS (59.2 +/- 8.6%) and preconditioning (50.5 +/- 3.6% ) produced a similar degree of recovery of function at the end of 120 minutes of reperfusion; this was significantly different from the untreated control group (20.8 +/- 3.5%, p < 0.05, ANOVA). When glibenclamide was added prior to BMS, protection was lost (20.5 +/- 2.7%). In this human atrial preparation, a highly selective K(ATP) channel opener mimicked the protective effect of ischemic preconditioning. This protective effect of BMS was abolished by glibenclamide. These findings confirm that the mechanism of ischemic preconditioning in human muscle may be mediated via opening of the K(ATP) channel.