Mismatch between insulin-mediated glucose uptake and blood flow in the heart of patients with Type II diabetes.

AIMS/HYPOTHESIS: We investigated the effect of physiological hyperinsulinaemia on global and regional myocardial blood flow and glucose uptake in five patients with Type II (non-insulin-dependent) diabetes mellitus and seven healthy control subjects. METHODS: Myocardial blood flow was assessed by positron emission tomography with oxygen-15 labelled water (H(2)(15)O) either before or after 1 h of euglycaemic hyperinsulinaemia. Myocardial glucose uptake was assessed by positron emission tomography and fluorine-18 labelled fluorodeoxyglucose ((18)FDG). RESULTS: During hyperinsulinaemia, myocardial blood flow increased from 0.91+/-0.03 to 1.00+/-0.03 ml(.)min(-1.)g(-1) in control subjects ( p<0.005) and from 0.81+/-0.02 to 0.95+/-0.04 ml(.)min(-1.)g(-1) in diabetic patients ( p<0.0005). Corresponding glucose uptakes were 0.56+/-0.01 and 0.36+/-0.02 micro mol(.)min(-1.)g(-1) ( p<0.0001), respectively. During hyperinsulinaemia, the regional distribution of myocardial blood flow and glucose uptake showed higher values in the septum and anterolateral wall (short axis) and in the mid-ventricle (long axis) in control subjects, and insulin action was circumscribed to these regions. In diabetic patients, the regional distribution of glucose uptake was similar; however, insulin-induced increase of myocardial blood flow was mainly directed to the postero-inferior areas (short axis) and to the base (long axis) of the heart, thus cancelling the predominance of the anterior wall observed before insulin administration. CONCLUSION/INTERPRETATION: These results provide evidence that insulin-mediated regulation of global myocardial blood flow is preserved in Type II diabetic patients. In contrast, the regional re-distribution of myocardial blood flow induced by insulin is directed to different target areas when compared with healthy subjects, thereby resulting in a mismatch between blood flow and glucose metabolism.

Heterogeneity of resting and hyperemic myocardial blood flow in healthy humans.

OBJECTIVE: Absolute myocardial blood flow (MBF) is not well-defined in large normal populations, and appears to be heterogeneous in both humans and animals. These factors contribute to the difficulties in defining resting MBF to hibernating myocardium. We therefore assessed absolute baseline and hyperemic MBF in a large population of normal humans. METHODS: MBF was quantified by positron emission tomography with oxygen-15-labeled water at baseline and during hyperemia induced by either adenosine or dipyridamole in 131 men and 38 women, aged 21-86 (mean 46+/-12) years. MBF was corrected for workload using the rate-pressure product (RPP). RESULTS: Uncorrected baseline MBF ranged from 0.590 to 2.050 (mean 0.985+/-0.230) ml/min/g (coefficient of variation=27%), and corrected MBF from 0.736 to 2.428 (mean 1.330+/-0.316) ml/min/g (coefficient of variation=24%). MBF in the inferior region was significantly (P<0.0001) lower than either the anterior or lateral regions. Baseline MBF in females was significantly (P<0.001) higher than in males. CONCLUSIONS: These results confirm the heterogeneity of MBF in normals and highlight the difficulty in establishing the lower limit of normal MBF.

The impact of time to thrombolytic treatment on outcome in patients with acute myocardial infarction. For the CORE investigators (Collaborative Organisation for RheothRx Evaluation).

OBJECTIVES: To examine the impact of time to thrombolytic treatment on multiple acute outcome variables in a single trial of thrombolysis in acute myocardial infarction. DESIGN AND PATIENTS: Mortality and reinfarction rate were measured in 2770 patients with acute myocardial infarction who received thrombolysis within 12 hours in CORE, an international, dose ranging trial of poloxamer 188. Tc-99m sestamibi infarct size and radionuclide angiographic ejection fraction substudies included 1099 and 1074 patients, respectively. RESULTS: Time to thrombolysis, subgrouped by intervals (< 2, 2-4, > or = 4-6, and > or = 6 hours), was significantly associated with infarct size (median 15.0%, 18.5%, 22.0%, 18.5% of left ventricle; p = 0.033), mean (SD) ejection fraction (51.5 (12.0)%, 48. 3 (13.9)%, 48.2 (13.3)%, 48.2 (15.0)%; p = 0.006), 35 day mortality (5.7%, 7.1%, 7.9%, 12.5%; p = 0.0004), six month mortality (7.3%, 8. 6%, 10.4%, 15.5%; p < 0.0001), and 35 day reinfarction rate (6.1%, 3. 2%, 4.0%, 0.9%; p = 0.0001). CONCLUSIONS: In this single large trial, the beneficial effect of time to thrombolysis on infarct size and ejection fraction was restricted to treatment given within two hours of symptom onset, while the effect on mortality was evident over all time intervals. Reinfarction rate was higher in patients treated with earlier thrombolysis.

The effect of collateral flow and myocardial viability on the distribution of technetium-99m sestamibi in a closed-chest model of coronary occlusion and reperfusion.

Myocardial uptake of technetium-99m sestamibi at low coronary flow rates overestimates blood flow, but the relative impact of flow and viability on 99mTc-sestamibi kinetics is unclear. The objective of this study was to determine the effect of myocardial viability and the degree of collateral blood flow on the uptake and retention of 99mTc-sestamibi by examining three animal models of coronary occlusion and reperfusion, each reflecting a different state of viability and collateral blood flow. Three closed-chest animal models were studied: canine (high collateral flow, preserved viability), porcine (low collateral flow, absent viability) and porcine with slowly occlusive coronary stents producing infarction and enhanced collateral blood flow (high collateral flow, absent viability). There were seven dogs, seven pigs and six pigs, respectively, in each animal model. Animals from all three models were subjected to a 40-min total left anterior descending artery (LAD) occlusion followed by 2 h of reperfusion. 99mTc-sestamibi and radiolabelled microspheres were injected during LAD occlusion 10 min prior to reperfusion. Animals were sacrificed after 2 h of reperfusion flow. Ex situ heart slice imaging to determine risk area was followed by viability staining to determine infarct size. Slices were subsequently sectioned into equally sized radial segments and placed in a gamma well counter. Risk area as determined by ex situ 99mTc-sestamibi imaging was not significantly different by model. Pathological infarct size differed significantly by model [canine = 1%+/-1% of the left ventricle (LV); porcine = 13%+/-8% LV; porcine with stent = 14%+/-7% LV; P = 0.002)]. Collateral blood flow by microspheres during occlusion tended to differ among models (overall P = 0.08), with the canine and porcine with stent models having relatively high flow rates compared with the acute porcine model. 99mTc-sestamibi activity correlated with microsphere blood flow in all three models, with r values for individual animals (n = 20) ranging from 0.86 to 0.96 (all P<0.0001). There was a significant difference in the regression line intercepts (P<0.0001) and slopes (P<0.01) among the three models comparing 99mTc-sestamibi uptake with myocardial blood flow. 99mTc-sestamibi uptake overestimated blood flow to a greater extent in the canine model (high flow with viability) than in the porcine model (low flow, absent viability). Despite enhanced collateral flow, there was significantly less overestimation of flow in the porcine stent model (high flow, absent viability). In conclusion, at low flow rates 99mTc-sestamibi activity overestimates myocardial blood flow. This effect is most pronounced in myocardium with significant collateral flow and preserved viability, consistent with over-extraction or redistribution of the tracer. The effect is markedly decreased in non-viable myocardium regardless of blood flow.

Correlation of resting first-pass left ventricular ejection fraction and resting myocardial infarct size.

This study determined the correlation between the extent of the resting perfusion defect by technetium-99m sestamibi tomographic imaging and the first-pass left ventricular (LV) ejection fraction (EF). A total of 1,955 patients underwent technetium-99m sestamibi tomographic imaging with measurement of first-pass resting LVEF. Twenty-five percent of patients had a prior history of myocardial infarction. First-pass LVEF was measured using a peripheral intravenous injection and a multicrystal gamma camera with standard software. Resting tomographic perfusion defect size (infarct size) was quantitated using previously published methods. Mean LVEF for the study group was 0.60 +/- 0.11. Mean LV infarct size was 5 +/- 11%. For the 1,265 patients (65% of the study group) with no measurable perfusion defect, the prevalence of a normal (> or = 0.50) LVEF was 96% (1,212 of 1,265 patients). For patients with a measurable defect (n = 690, 35%), the inverse linear correlation with LVEF was highly significant (r = -0.60, p <0.0001) but with wide confidence limits (SEE = 10 LVEF points), thereby limiting the predictive value in individual patients. Thus, in the absence of known cardiomyopathy, valvular heart disease, or left bundle branch block, patients without a quantifiable resting perfusion defect are highly likely to have a normal resting LVEF and may not require determination of LV function. For patients with resting perfusion defects, LVEF cannot be predicted with confidence and should therefore be measured.

Noninvasive prediction of residual blood flow within the risk area during acute myocardial infarction: a multicenter validation study of patients undergoing direct coronary angioplasty.

BACKGROUND: In a previous study from a single center, radionuclide measures of collateral flow with technetium 99m sestamibi have been shown to be significantly associated with angiographic residual (antegrade and collateral) flow and independent predictors of final infarct size in acute myocardial infarction. This study examined whether the previously described radionuclide measures of blood flow to the infarct zone were reproducible with different laboratories and imaging systems. METHODS AND RESULTS: Residual flow to the infarct zone was assessed by both invasive and noninvasive methods in 77 patients with first-time myocardial infarction (32 anterior, 45 nonanterior). All patients underwent acute coronary angiography before any intervention within 8 hours of the onset of chest pain (4.0 +/- 1.5 hours; range 1.2 to 7.9 hours). 99mTc sestamibi was injected intravenously before reperfusion therapy, and tomographic imaging was performed 1 to 6 hours after injection. A central core laboratory processed the acquired images from three centers, each with a unique camera and computer system. Three previously published methods based on the severity of the acute perfusion defect were used to measure residual flow to the infarct zone (nadir, severity index, area). Antegrade (Thrombolysis in Myocardial Infarction flow) and collateral flow before direct angioplasty were blindly graded on a four-point scale (0 to 3) from the acute angiogram. The simple sum of the two grades was defined as the angiographic flow index, representing residual flow to the jeopardized zone. All three noninvasive measures of residual flow were highly associated with the angiographic flow index in a linear fashion: severity index (p = 0.0006), area (p = 0.003), and nadir (minimum/maximum counts; p = 0.004). This association was independent of the laboratory where the data were acquired. CONCLUSIONS: Despite different laboratories and camera systems, radionuclide measures of residual flow were highly associated with the angiographic flow index before reperfusion therapy. These results suggest that these measures are applicable on a broader scale for the noninvasive determination of collateral and antegrade flow in acute myocardial infarction.

Prevalence of normal resting left ventricular function with normal rest electrocardiograms.

This study examined the prevalence of normal resting left ventricular function in 2,275 patients referred for technetium-99m sestamibi stress imaging. The strongest predictor of normal left ventricular function was a normal electrocardiogram at rest.

Relation of initial infarct size to extent of left ventricular remodeling in the year after acute myocardial infarction.

OBJECTIVES: This study attempted to determine the relation between infarct size after acute myocardial infarction and subsequent left ventricular remodeling using precise clinical measurements. BACKGROUND: Animal studies have demonstrated that the degree of left ventricular remodeling after myocardial infarction is linearly related to infarct size. Clinical studies have not clearly replicated these results because of imprecise measurements and failure to adjust for patency of the infarct-related artery. METHODS: Infarct size was measured from technetium-99m (Tc-99m) sestamibi perfusion images in 14 patients (12 with an anterior, 2 with an inferior infarction) by a threshold method previously described and expressed as percent of the left ventricle (32 +/- 17% left ventricle [mean +/- SD], range 6% to 58%). Absolute end-systolic volume, end-diastolic volume and ejection fraction were determined by electron beam computed tomographic images performed at discharge and at 6 weeks, 6 months and 1 year after myocardial infarction. All patients had documented infarct-related artery patency after reperfusion therapy. RESULTS: At hospital discharge, there was no correlation between infarct size and end-systolic and end-diastolic volumes or ejection fraction. There was significant left ventricular dilation in the study group over the next year. As remodeling progressed, there was closer correlation between infarct size and ejection fraction and end-systolic volume measures (infarct size vs. end-systolic volume, from r = 0.43 at discharge to r = 0.80 at 1 year; infarct size vs. ejection fraction, from r = -0.39 at discharge to r = -0.84 at 1 year). There was a strong inverse correlation between infarct size at discharge and subsequent changes over the next year in end-systolic volume (r = 0.63, p = 0.02) and ejection fraction (r = -0.66, p = 0.01). CONCLUSION: Infarct size as measured by Tc-99m sestamibi at hospital discharge after an index infarction is predictive of subsequent change in left ventricular volume and function in the year after myocardial infarction. Patients with a large infarct demonstrated the greatest degree of dilation in the setting of patency of the infarct-related artery.