R. J C Hall

Absolute blood flow and oxygenconsumption in stunned myocardiumin patients with coronary artery disease

OBJECTIVES In patients with coronary artery disease (CAD), we sought to demonstrate normal myocardial blood flow (MBF) and myocardial oxygen consumption (MMRO(2)) to post-ischemic myocardium that exhibited reversible dysfunction and the relation between the severity of the dysfunction and the preceding ischemia. BACKGROUND In animal models of stunning, MBF and MMRO(2) are normal or near normal, and the severity of stunning is related to the degree of the preceding ischemia. METHODS Myocardial blood flow and MMRO(2) were measured using positron emission tomography and oxygen 15-labelled water (H(2)(15)O) and oxygen 15-labelled oxygen ((15)O(2)), respectively, in 14 patients with CAD and normal left ventricular (LV) function. Global ejection fraction and regional LV systolic function (SF) were measured using quantitative echocardiography during and after dobutamine-induced ischemia. RESULTS Ejection fraction and SF were reduced 30 min after dobutamine (both: p < 0.01) but recovered by 120 min. Myocardial blood flow (ml/min per g) to regions with reversible LV dysfunction was normal at baseline and during dysfunction (0.88 [0.82 to 0.99] and 1.09 [0.75 to 1.37], respectively, p = NS) as was MMRO(2) (ml/min per 100 g) (16.64 [10.16 to 16.18] and 11.68 [8.43 to 15.30] respectively, p = NS). Left ventricular dysfunction was related to stenosis severity and peak MBF. Regions were divided into those subtended by a stenosis of <50%, 50% to 80% and >80% luminal diameter. Systolic function 30 min after dobutamine was 93.9% (83.4% to 104.4%) (p = NS), 85.4% (80.0% to 90.9%) and 67.4% (56.2% to 78.7%) (both: p < 0.001), respectively. Peak MBF was 2.0 (1.71 to 2.31), 1.75 (1.65 to 1.85) (p = 0.01 compared with <50%) and 1.47 (1.33 to 1.60) (p = 0.03 compared with 50% to 80% and p = 0.002 compared with <50%), respectively. CONCLUSIONS In patients with CAD, dobutamine produces prolonged, but reversible, LV dysfunction when MBF is normal, confirming stunning. This stunning is related to the severity of the coronary stenosis and the reduction in peak MBF. Myocardial oxygen consumption to stunned myocardium is normal.

Immunocytochemical evidence for inducible nitric oxide synthase and cyclooxygenase-2 expression with nitrotyrosine formation in human hibernating myocardium.

Abstract.Background: Myocardial hibernation may result from repetitive episodes of transient ischaemia leading to prolonged dysfunction. Inducible nitric oxide synthase (iNOS) expression has been demonstrated in animals following brief, non-lethal ischaemia-reperfusion injury. We therefore, hypothesised that in human hibernating myocardium: 1) iNOS would be present; 2) the reaction of nitric oxide and superoxide would form the strong oxidant peroxynitrite; 3) that this process would be accompanied by the expression of cyclooxygenase-2 (Cox-2) which interacts with NOS and whose products could further affect myocardial function. Method and results: In sixteen patients with coronary artery disease (CAD), left ventricular biopsies were obtained from chronically dysfunctional segments subtended by a stenotic artery (> 75 %) and shown to be viable by 18F-fluorodeoxyglucose positron emission tomography. Comparison was made with myocardial biopsies (n = 8) from normally contracting myocardium in patients undergoing coronary surgery, from unused transplant donors and at post-mortem. Regional wall motion score improved in all patients 6 months post-revascularisation (from 2.7 ± 0.7 to 1.5 ± 0.5; p < 0.001), confirming hibernation. Immunocytochemistry localized reactivity to iNOS, Cox-2 and nitrotyrosine (a marker of peroxynitrite formation) to cardiomyocytes from hibernating segments. No difference in reactivity to endothelial NOS was seen between hibernating and control cardiomyocytes. Conclusion: Cox-2 and iNOS are co-expressed in hibernating myocardium with nitrotyrosine suggesting nitric oxide production and peroxynitrite formation. We propose that this is secondary to ischaemia-reperfusion and that the products of these enzymes may have consequences for myocardial contractile function and survival.

Prolonged left ventricular dysfunction occurs in patients with coronary artery disease after both dobutamine and exercise induced myocardial ischaemia

OBJECTIVE To determine whether pharmacological stress leads to prolonged but reversible left ventricular dysfunction in patients with coronary artery disease, similar to that seen after exercise. DESIGN A randomised crossover study of recovery time of systolic and diastolic left ventricular function after exercise and dobutamine induced ischaemia. SUBJECTS 10 patients with stable angina, angiographically proven coronary artery disease, and normal left ventricular function. INTERVENTIONS Treadmill exercise and dobutamine stress were performed on different days. Quantitative assessment of systolic and diastolic left ventricular function was performed using transthoracic echocardiography at baseline and at regular intervals after each test. RESULTS Both forms of stress led to prolonged but reversible systolic and diastolic dysfunction. There was no difference in the maximum double product (p = 0.53) or ST depression (p = 0.63) with either form of stress. After exercise, ejection fraction was reduced at 15 and 30 minutes compared with baseline (mean (SEM), −5.6 (1.5)%, p < 0.05; and −6.1 (2.2)%, p < 0.01), and at 30 and 45 minutes after dobutamine (−10.8 (1.8)% and −5.5 (1.8)%, both p < 0.01). Regional analysis showed a reduction in the worst affected segment 15 and 30 minutes after exercise (−27.9 (7.2)% and −28.6 (5.7)%, both p < 0.01), and at 30 minutes after dobutamine (−32 (5.3)%, p < 0.01). The isovolumic relaxation period was prolonged 45 minutes after each form of stress (p < 0.05). CONCLUSIONS In patients with coronary artery disease, dobutamine induced ischaemia results in prolonged reversible left ventricular dysfunction, presumed to be myocardial stunning, similar to that seen after exercise. Dobutamine induced ischaemia could therefore be used to study the pathophysiology of this phenomenon further in patients with coronary artery disease.

Repetitive myocardial stunning in pigs is associated with the increased expression of inducible and constitutive nitric oxide synthases

OBJECTIVES Nitric oxide (NO) has complex effects on myocardial function particularly following ischaemia-reperfusion. The goal of this study was to examine the result of repetitive myocardial stunning on myocardial NO release and expression of inducible (iNOS) and constitutive (eNOS) NO synthases. METHODS AND RESULTS Propofol anaesthetised pigs underwent ten, 2-min episodes of circumflex artery occlusion (n = 6) or acted as sham operated controls (n = 4). Measurements of segment shortening demonstrated a fall in function in the ischaemic territory to 52.5 +/- 7.3% (mean +/- S.E.M.) of baseline shortening 30 min after the stunning stimulus, recovering to 92 +/- 8.7% 5.5 h later. Function remained stable in sham controls. The change in venous-arterial [NO] between baseline and 6 h reperfusion was found to be significantly different between the two groups (0.2 +/- 0.7 in stunned vs. -4.3 +/- 1.6 microM in shams; P < 0.02). Western blotting and band optical density used to compare tissue from stunned territory (S), non-stunned territory (IC) and sham control animals (SC) demonstrated this was associated with an increase in the expression of both iNOS (S: 93 +/- 13.4, IC: 37 +/- 2.4 and SC: 25 +/- 4 [arbitrary units], P < 0.01 and P = 0.031) and eNOS (S: 104 +/- 7.4, IC; 62.5 +/- 7.4 and SC; 75.7 +/- 0.6, P < 0.03 and P < 0.01) in stunned myocardium. Immunocytochemistry localised iNOS reactivity to vascular smooth muscle cells and cardiomyocytes in stunned tissue and eNOS reactivity to endothelial cells. CONCLUSION Recovery from repetitive myocardial stunning is associated with the increased expression of both iNOS and eNOS and would be compatible with a protective role for both these enzymes. This finding has possible relevance for both the late window of ischaemic preconditioning and myocardial hibernation.

Endocarditis: problems—patients being treated for endocarditis and not doing well

Most patients with infective endocarditis respond to appropriate antibiotic treatment within 72 hours, with a definitive loss of fever and improvement in general well being. Patients who show such prompt improvement will usually do well, but those who remain febrile and septic despite optimal antibiotics usually need surgery.1Late recurrence of fever is frequently the result of antibiotic sensitivity or an infected central line, and is less often caused by the development of bacterial resistance, infection by multiple organisms or a second infection by fungus or staphylococcus. Lack of success in treating endocarditis frequently comes from failure to observe recognised guidelines,2 3 and from lack of a team approach involving both the clinical microbiologist and the cardiac surgeon from an early stage. ### Microbiological issues From the outset the clinical microbiologist needs to be involved closely. The treatment regimen needs to be matched to both the clinical and microbiological circumstances. When there is a continuing clinical problem, despite appropriate initial treatment, then the microbiologist must be consulted again. ### Infection elsewhere The possibility of infection occurring elsewhere—intracardiac or extracardiac—must be the first thought of the clinician faced with this situation. #### Line infection A common cause of recurrence of fever is the central line. This should be removed and the tip sent for culture. Often the culture is sterile but the fever resolves rapidly after removal of the line. Recolonisation of the infected valve by staphylococcus or fungus derived from the line is rare but can occur. It is usually caused by poor sterile technique and line care. Such additional infection is a serious problem. It needs appropriate antibiotic treatment and frequently requires urgent surgery. #### Paravalvar/intracardiac abscess The patient not doing well despite being infected by an antibiotic sensitive organism probably has a paravalvar abscess until proved otherwise. This must be sought vigorously and usually requires surgery to effect …

Evidence that stunning can be cumulative in man.

Myocardial stunning and hibernation are two entities that have become increasingly recognised as clinically important causes of reversible left ventricular (LV) dysfunction. Their occurrence is important as resting myocardial dysfunction, which was once thought to be irreversible, may recover if ischaemia is lessened or abolished. Recent evidence has suggested that cumulative stunning can occur in man and may in fact be responsible for the phenomenon of hibernation. In this chapter we will review the evidence supporting the occurrence of cumulative stunning in man.

34 Comparison of PCI vs CABG in insulin treated and non-insulin treated diabetic patients in the cardia trial

Aims The CARDia trial randomised diabetic patients to coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) and concluded that PCI is a potentially safe and feasible alternative to CABG in selected patients with diabetes mellitus (DM) and multivessel coronary artery disease. The impact of insulin treatment on clinical outcomes after revascularisation is unclear. The present study is a sub group analysis of the CARDia trial comparing the cardiovascular outcomes at 12 months following revascularisation between the insulin treated (IT) and non-insulin treated (NIT) group. Methods 508 patients with an established diagnosis of DM and de novo coronary artery disease were identified and randomised to CABG or PCI. Of those, 316 patients were treated with oral antidiabetic medication and the rest were treated with additional subcutaneous insulin injections. Demographics, clinical presentation, history, haemodynamic parameters, anti diabetic therapy, concomitant medications, duration of DM and HBA1C were documented. Death, stroke and myocardial infarction were classified as the primary outcome events. The secondary outcome events included death, MI, Stroke, repeat revascularisation and TIMI major bleed. The clinical results of patients in the IT and NIT groups were compared. Results There were 192 patients in the IT group (37.8%). Asian patients constituted one fifth of the total population with a slightly higher representation (24.5% vs 21.6%) in the NIT. The clinical severity of dyspnoea, heart rate, systolic and diastolic BP, body mass index, risk factors for coronary artery disease appeared similar in the IT and NIT groups, but more patients in the IT group had a prior MI (30.7% vs 19.6%, p=0.004) and duration of diabetes was longer in the IT group (14 vs 6 yrs, p<0.001). For the comparison of CABG vs PCI for the primary outcome events the HR and 95% CI in the IT and NIT groups respectively were 1.66 (0.76 to 3.76) and 1.01 (0.51 to 2.01). For death, MI, stroke, repeat revascularisation they were 2.47 (1.18 to 5.20) in the IT and 1.41 (0.71 to 2.57) in the NIT group. The results suggest that IT patients may have a worse outcome with PCI compared to CABG, whereas no difference was found for NIT patients. Conclusion Our data suggest that insulin treatment is a marker for higher risk for PCI when compared with CABG. Treatment with insulin rather than diabetic status alone should be considered when choosing the mode of revascularisation.