Edward Barnes

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.

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.

Dobutamine‐induced hyperaemia inversely correlates with coronary artery stenosis severity and highlights dissociation between myocardial blood flow and oxygen consumption

Objectives: To compare the relationship between dobutamine myocardial blood flow (MBF), rate–pressure product (RPP) and stenosis severity in patients with coronary artery disease (CAD). Methods: 27 patients with single-vessel CAD were allocated to three groups based on stenosis severity: group 1, 50–69% (n  =  9); group 2, 70–89% (n  =  9); and group 3, ⩾ 90% (n  =  9). Nine normal volunteers served as controls. Resting and dobutamine MBF were measured by positron emission tomography in the territory subtended by the stenosis (Isc) and remote myocardium (Rem). Mean left ventricular MBF was used for controls. Results: In group 1, mean dobutamine MBF-Isc (2.48 (SD 0.48 ml/min/g)) and dobutamine MBF-Rem (2.70 (0.50) ml/min/g, NS) were comparable. In groups 2 and 3, dobutamine MBF-Isc (1.91 (0.44) and 1.22 (0.21) ml/min/g) was significantly lower than dobutamine MBF-Rem (2.27 (0.28) and 1.98 (0.25) ml/min/g, p < 0.02 and p < 0.005, respectively). An inverse relation between dobutamine MBF and stenosis severity existed both in Isc (r  =  0.79, p < 0.001) and in Rem territories (r  =  0.71, p < 0.001). For any given RPP, dobutamine MBF was greater in controls than in Rem (p < 0.05), which in turn was greater than in Isc (p < 0.05). Conclusion: Dobutamine MBF inversely correlated with stenosis severity and achieved significant flow heterogeneity for coronary stenoses > 70%. Dobutamine MBF and RPP were dissociated in both Isc and Rem segments in patients compared with controls.