Sci-Fri AM: Imaging - 09: Serial estimation of cross-talk for correction in dual-isotope imaging with dynamic tracers.

The recent radioisotope shortage has led to interest in non-Tc99m-based tracers. We have developed a novel I-123-labelled myocardial perfusion imaging tracer. We compare the I123-tracer to the clinical standard of Tc99m tetrofosmin in vivo in a rat model using a small-animal SPECT/CT camera. SPECT distinguishes different isotopes based on the different energies of the emitted gamma rays and thus allows simultaneous comparison of two tracer distributions in the same animal. Dual-isotope imaging is complicated by cross-talk between the energy windows of the isotopes. Standard energy-window-based correction methods are difficult to employ because of the proximity in energy of Tc99m (140keV) and I123 (159keV). Imaging the second tracer's energy window prior to its injection provides an estimate of the cross-talk. However, this estimate is only accurate if the tracer distribution is static. We use serial imaging prior to the introduction of the second tracer to estimate the dynamics of the first tracer and interpolate the cross-talk images to provide a more accurate correction. We used rat models of myocardial disease (n=3). I123 tracer was injected and imaged for one hour at 20min intervals. The Tc99m tetrofosmin was then injected and 30min later, a dual-isotope image was obtained. The impact of this approach is assessed by comparing the differences in the Tc99m-tetrofosmin image using this method with correction by simple correction for physical decay. The interpolative approach improves the accuracy of the correction by 2%-5% and thereby enhances the comparison of the two tracers.

Potential utility of rubidium 82 PET quantification in patients with 3-vessel coronary artery disease.

BACKGROUND: Standard perfusion imaging may underestimate the extent of disease in 3-vessel coronary atherosclerosis. This study determined whether positron emission tomography quantification of perfusion reserve by use of rubidium 82 net retention defined a greater extent of disease than the standard approach in patients with 3-vessel disease. METHODS AND RESULTS: Rb-82 net retention was quantified as an estimation of absolute perfusion at rest and with dipyridamole stress by use of dynamic positron emission tomography imaging. The percent of abnormal myocardial sectors, as compared with a normal database, for a standard and quantification approach was determined. Twenty-three patients were evaluated. Defect sizes were larger in patients with 3-vessel disease (n = 13) by use of quantification methods: 44% +/- 18% of the myocardial sectors were abnormal by use of the standard approach versus 69% +/- 24% of sectors when measured by quantification of the stress-rest perfusion difference (P =.008). In patients with single-vessel disease (n = 10), defect sizes were smaller with quantification methods. CONCLUSIONS: Quantification of Rb-82 net retention to measure the stress-rest perfusion difference in the myocardium defined a greater extent of disease than the standard approach in this group of patients with triple-vessel disease. More accurate measurement of the extent of coronary artery disease could facilitate better risk stratification and identify more high-risk patients in whom aggressive intervention is required.

Myocardial glucose utilization and optimization of (18)F-FDG PET imaging in patients with non-insulin-dependent diabetes mellitus, coronary artery disease, and left ventricular dysfunction.

UNLABELLED: In patients with non-insulin-dependent diabetes mellitus (NIDDM), FDG PET imaging is often problematic because of poor uptake of FDG. Different protocols have been used; however, these have not been directly compared in patients with NIDDM who have both coronary artery disease (CAD) and severe left ventricular (LV) dysfunction, for which defining viability is most relevant. The aim of this study was to better define the optimal means of FDG PET imaging, assessed by image quality and myocardial glucose utilization rate (rMGU), among 3 imaging protocols in patients with NIDDM, CAD, and severe LV dysfunction. METHODS: Ten patients with NIDDM, CAD, and severe LV dysfunction (mean ejection fraction, 29.8% +/- 7.1%) underwent dynamic FDG PET scanning using 3 different protocols: the standard protocol, consisting of oral glucose loading or a supplemental insulin bolus based on fasting glucose; the niacin protocol, consisting of pretreatment with niacin to lower free fatty acids; and the insulin clamp protocol, consisting of hyperinsulinemic euglycemic clamp. Image quality was satisfactory with at least 1 approach in 8 patients, who formed the primary analysis group. RESULTS: Myocardium-to-blood-pool ratios were significantly higher with the insulin clamp (standard, 1.7 +/- 1.2; niacin, 1.6 +/- 1.0; insulin clamp, 3.4 +/- 2.5 [P < 0.05 vs. standard and niacin]). Values for rMGU were higher with the insulin clamp (standard, 0.11 +/- 0.07 micromol/g/min; niacin, 0.12 +/- 0.11 micromol/g/min; insulin clamping, 0.22 +/- 0.12 micromol/g/min [P = 0.004 vs. standard and 0.07 vs. niacin]). CONCLUSION: The hyperinsulinemic euglycemic clamp yielded the highest FDG PET image quality and the highest rMGU in a comparison with the standard and niacin protocols in this difficult group of patients with NIDDM, CAD, and severe LV dysfunction. The hyperinsulinemic euglycemic clamp may be the preferred method for FDG PET viability imaging in this population. Larger clinical trials are needed to assess whether accuracy is greater with this approach.

Canadian national high blood pressure prevention and control strategy.

Despite major efforts to prevent and control high blood pressure, it is one of the most common and important health problems facing Canadians. To address this issue, Health Canada, in collaboration with the Canadian Coalition for High Blood Pressure Prevention and Control, established an Expert Working Group to prepare a national strategy. The present report outlines a strategy to prevent and control high blood pressure. It is directed at policy makers at the local, provincial, and/or territorial and national levels in both the health and nonhealth sectors. The strategy is based on current research and expertise. A multifaceted, comprehensive approach is proposed because there is no one intervention that will accomplish the goal of improving the health of Canadians through high blood pressure prevention and control. The present report focuses on the general population. It does not address the unique needs of children, pregnant women or aboriginal peoples. Each of these groups needs to be studied in its own right, and, in particular, with the involvement of aboriginal people themselves. An implementation committee has been established to realize this strategy, and the Canadian Hypertension Society is a key stakeholder in this effort. Several initiatives are underway. Strong advocates are necessary to increase public awareness and to support the system changes required for a successful public health approach to reduce the prevalence of hypertension and its complications.

Detection of serial changes in absolute myocardial perfusion with 82Rb PET.

UNLABELLED: Serial changes in myocardial perfusion may represent an important marker of disease progression or regression or the effects of therapy for patients with coronary artery disease (CAD). Quantitative methods have not been developed for the assessment of serial changes in perfusion. The objective of this study was to use receiver operator characteristic (ROC) analysis to determine the sensitivity and specificity of direct paired comparisons (DPCs) to detect changes in absolute myocardial perfusion measured with 82Rb PET. METHODS: Repeated dynamic 82Rb PET scans were obtained on 8 dogs at rest and during hyperemia induced with dobutamine (n = 4) or atrial pacing (n = 4). Radiolabeled microspheres were used to verify perfusion changes. Polar maps of absolute 82Rb retention and associated SD were estimated from the dynamic images. Paired comparisons were then performed using a t test on each of the 532 polar map sectors. Rest-rest and stress-stress differences were used to assess specificity and reproducibility, and stress-rest differences were used to assess sensitivity. RESULTS: 82Rb retention differences of 20% over baseline were detected with 85%-90% sensitivity and specificity, using the optimal DPC probability value and image smoothness. The average 82Rb retention differences correlated well with microspheres (r = 0.74; P = 0.001). Reproducibility of the mean retention values was 4.7% +/- 2.1%. As reproducibility varies, the DPC probability value can be adjusted to maintain specificity. These ROC results are directly applicable to other image modalities that produce measurements with similar SEs (3.7% +/- 0.9%). CONCLUSION: The developed method of DPCs is sensitive and specific for the detection of changes in absolute myocardial perfusion measured with 82Rb PET.

Stress perfusion/metabolism imaging: a pilot study for a potential new approach to the diagnosis of coronary disease in women.

BACKGROUND: The diagnosis of coronary artery disease (CAD) in women continues to be a challenge. F-18 deoxyglucose (FDG) positron emission tomography (PET) has been used for detection of myocardial ischemia at rest. Little has been reported about FDG stress imaging. The aim of this pilot study was to assess stress FDG PET imaging for defining CAD in a group of women referred for chest pain. METHODS: Stress FDG imaging was performed in 19 women (mean age 59 +/- 10 years). All had abnormal stress testing before entering the study. FDG and 2-methoxy-2-methylpropyl isonitrile were injected at peak stress (treadmill n = 8, dipyridamole n = 11) followed by PET and single photon emission computed tomography image acquisitions. Myocardial ischemia was defined by regions that demonstrated both a defect on perfusion imaging and increased FDG uptake relative to uptake in normal perfusion zones. Defect/normal zone FDG ratios were also determined. Coronary angiography was performed on all patients. RESULTS: Average, or mean, body mass index was high at 29.2 +/- 5 kg/m2. Nine of 19 patients had significant CAD. Eight of 9 with CAD had FDG-defined ischemia. Nine of the 10 without CAD had negative FDG images (sensitivity 89%, specificity 90%). The average defect/normal zone FDG ratio was greater in patients with CAD than in those without (2.4 +/- 1.9 vs 0.9 +/- 0.4, P < .05). CONCLUSIONS: Regional FDG uptake in areas of perfusion defects with stress increased in this group with CAD. These pilot data suggest that stress FDG PET may be diagnostically helpful in obese female patients. This novel approach may complement current methods of CAD detection in women and warrants further study.

Establishing an approach for patients with recent coronary occlusion: identification of viable myocardium.

BACKGROUND: Revascularization of occluded coronary arteries after myocardial infarction (MI) may restore flow to viable myocardium and improve ventricular function. The aim of this pilot study was to determine the potential utility of thallium-201 viability imaging for the prediction of recovery of regional ventricular function in patients undergoing revascularization of total or subtotal occlusion of infarct-related arteries (TIMI 0-2 flow) during the convalescent period after MI. METHODS: Twenty-three patients were identified < 6 weeks after MI and underwent Tl-201 viability imaging (rest imaging, n = 16; stress/reinjection imaging, n = 7) and radionuclide angiography. Patients were revascularized with percutaneous transluminal coronary artery in 10, stent in 10, and bypass in 3. Follow-up radionuclide angiography at 3 months was used to assess recovery of regional wall motion. RESULTS: Among 41 abnormal wall motion segments in the infarct territories, the sensitivity, specificity, and accuracy for Tl-201 imaging in the prediction of recovery of regional function were 89% (25/28), 54% (7/13), and 78% (32/41), respectively. When 8 segments supplied by vessels with restenosis to >70% were excluded, specificity improved to 70%. Wall motion scores improved in those with adequate revascularization (1.6+/-1.4 vs 2.7+/-1.6; P < .001) but not in those with restenosis or occlusion (1.8+/-1.0 vs 2.0+/-1.6; P = NS). CONCLUSIONS: In patients with an occluded artery after MI, Tl-201 viability imaging can detect recoverable myocardium with reasonable accuracy and may help select which patients will most benefit from revascularization.

Delay in revascularization is associated with increased mortality rate in patients with severe left ventricular dysfunction and viable myocardium on fluorine 18-fluorodeoxyglucose positron emission tomography imaging.

BACKGROUND: The identification of high-risk patients who require early revascularization has become increasingly important with the present emphasis on reducing health care resources. This is particularly relevant to health care systems with prolonged waiting times for interventions. Myocardial viability imaging with the use of fluorine 18-fluorodeoxyglucose (FDG) PET may help to identify high-risk patients with severe left ventricular dysfunction. The aim of this study was to evaluate the consequences of prolonged waiting time on cardiac outcomes in patients with left ventricular dysfunction directed to revascularization based on FDG PET imaging. METHODS AND RESULTS: Forty-six patients with coronary disease and an ejection fraction of < or = 35% were considered candidates for revascularization based on FDG PET viability imaging. Thirty-five of 46 patients were subsequently accepted for revascularization. Patients were divided into 2 groups based on the median waiting time after PET: an early group (< 35 days; n = 18) and a late group (> or = 35 days; n = 17). Preoperative mortality rates were significantly increased in the late group (4 of 17 [24%] versus 0 of 18 in the early group; P < 0.05). In postoperative follow-up (17 +/- 7 months), cardiac events occurred in 2 of 18 (11%) and 1 of 13 (7.8%) patients in the early and late groups, respectively. Left ventricular ejection fraction increased after early revascularization (24 +/- 7% to 29 +/- 8%, P < 0.001, baseline versus 3 months) but not in the late group (27 +/- 5% to 28 +/- 6%, P = NS). CONCLUSIONS: Preoperative FDG PET can be used to identify a high-risk group of patients who may benefit from early revascularization. A long waiting time for revascularization is associated with a high mortality rate and suggests that early revascularization is desirable after the identification of hibernating viable myocardium.

Comparative efficacy of two angiotensin II receptor antagonists, irbesartan and losartan in mild-to-moderate hypertension. Irbesartan/Losartan Study Investigators.

The primary objectives of this double-blind study were to compare the antihypertensive efficacy and tolerability of irbesartan and losartan, two angiotensin II (AT1 subtype) receptor antagonists with different pharmacokinetic profiles in patients with mild-to-moderate hypertension. Both drugs are approved for once-daily use (although losartan may also be prescribed twice-daily). After a placebo lead-in, 567 patients were randomized (1:1:1:1) to once-daily therapy with placebo, 100 mg losartan, 150 mg irbesartan, or 300 mg irbesartan for 8 weeks. Treatment groups had comparable demographic and baseline characteristics. After 8 weeks of treatment, reductions from baseline in trough seated diastolic blood pressure (SeDBP) and trough seated systolic blood pressure (SeSBP) with 300 mg irbesartan were greater than with 100 mg losartan (P < .01 for both comparisons), by 3.0 and 5.1 mm Hg, respectively; larger reductions were also demonstrated at weeks 1 and 4 (P < .01 and P = .017, respectively, for SeDBP). Throughout the study, the antihypertensive effect of 150 mg irbesartan did not differ significantly from that of 100 mg losartan. All therapies were well tolerated. The 300 mg dose of irbesartan was associated with the lowest incidence of adverse events (AE) and discontinuations because of AE. This study demonstrates that the maximally effective once-daily doses of two different AT1 receptor antagonists may result in clinically significant differences in blood pressure reductions, and therefore highlights the potential importance of the pharmacokinetic and pharmacodynamic differences between these two members of this class.

Nisoldipine CC and lisinopril alone or in combination for treatment of mild to moderate systemic hypertension. Canadian Nisoldipine CC Hypertension Trial Group.

The efficacy and safety of nisoldipine CC and lisinopril were compared in 278 patients with mild to moderate systemic hypertension in a double-blind, placebo run-in trial. Patients were randomized to nisoldipine CC or lisinopril for 8 weeks to achieve a trough sitting diastolic blood pressure (BP) < or = 90 mmHg. Responders were maintained on their optimal dose for a further 8 weeks. Nonresponders were switched to combination therapy and treated for 8 weeks. Twenty-four-hour ambulatory BP monitoring (ABPM) was carried out during placebo and monotherapy. The responder rate of 73.8% with nisoldipine CC after 8 weeks was greater than 56.1% with lisinopril (p = 0.007). The responder rate with combination therapy was 61%. ABPM showed that both nisoldipine CC and lisinopril produced constant blood pressure lowering effects over the 24-hour period and maintained circadian rhythm. Adverse effects were more frequent with nisoldipine CC (headache and peripheral edema) than with lisinopril (cough) monotherapy. Nisoldipine CC monotherapy was at least as effective as lisinopril monotherapy in the management of mild to moderate hypertension. Both agents were well tolerated. Combination therapy with nisoldipine CC and lisinopril was effective and well tolerated in patients with blood pressure not controlled by monotherapy alone.

Differentiation of myocardial ischemia and necrosis by technetium 99m glucaric acid kinetics.

BACKGROUND: Current clinical approaches may not always be helpful in the early differentiation of necrotic tissue from ischemic viable myocardium in patients with acute myocardial infarction. Tc-99m-glucaric acid is a carbohydrate ligand that may permit differentiation of necrosis from ischemia. However, the myocardial kinetics of Tc-99m-glucaric acid have not been well defined early after myocardial injury. The aim of this study was to evaluate the effect of necrosis in comparison to postischemic injury alone on the kinetics of Tc-99m-glucaric acid with the use of an isolated perfused rat heart model. METHODS AND RESULTS: Three groups of hearts were studied: group I: control (n = 6); group II: postischemia (15 minutes of no flow with complete reperfusion, n = 6); and group III: necrosis (90 minutes of no flow to induce necrosis with complete reperfusion, n = 6). Tc-99m-glucaric acid (1.3 +/- 0.6 mCi/L of buffer) was perfused for 30 minutes to evaluate tracer accumulation. Then tracer-free buffer was perfused for 45 minutes to evaluate clearance. The peak accumulation relative to the control group mean was significantly increased (p < 0.01) in group III (necrosis) (254% +/- 75%) compared with control (100% +/- 10%) and compared with postischemia (108% +/- 26%). On kinetic data analysis, the monoexponential clearance rate constant: (kc) was significantly reduced with necrosis (control: kc = 20.2 +/- 14.0 x 10(-4) sec-1; postischemia: kc = 22.3 +/- 15.2 x 10(-4) sec-1; and necrosis: kc = 1.2 +/- 0.3 x 10(-4) sec-1; p < 0.05). A retention fraction was calculated from the activity after 45 minutes of clearance corrected for the peak activity for each group. The necrotic group had significant myocardial retention in comparison to control and postischemia (control: 12% +/- 8%; postischemia: 14% +/- 16%; necrosis: 64% +/- 10%; p < 0.01). CONCLUSIONS: The accumulation and retention of Tc-99m-glucaric acid is markedly increased in the presence of myocardial necrosis in comparison to control and postischemic myocardial injury. In this model, Tc-99m-glucaric acid is capable of defining the presence of necrotic myocardial injury in comparison to postischemic injury alone. This agent may have potential application for the early differentiation of ischemic from necrotic myocardium in acute myocardial infarction.

Comparison of Tc-99m sestamibi perfusion imaging and echocardiography using an arbutamine infusion for the detection of coronary artery disease.

Arbutamine, a synthetic catecholamine, coupled with a closed-loop, computerized delivery system was evaluated in conjunction with technetium-99m sestamibi scintigraphy and echocardiography for the detection of coronary artery disease. Concordance between the imaging methods was 68%, with a similar sensitivity for coronary disease using echocardiography (78%) and technetium-99m sestamibi (76%), although more arbutamine-induced ischemia was noted with perfusion imaging.

F-18-fluorodeoxyglucose PET imaging alters clinical decision making in patients with impaired ventricular function.

The effect of F-18-fluorodeoxyglucose positron emission tomography imaging on decision making in the selection of patients with impaired ventricular function for revascularization was determined in 87 patients. In 57% of patients, positron emission tomography data influenced management decisions, indicating an important effect of myocardial viability determination on difficult therapy decisions in these patients.

Myocardial kinetics of technetium-99m teboroxime in the presence of postischemic injury, necrosis and low flow reperfusion.

OBJECTIVES: This study evaluated technetium-99m (Tc-99m) teboroxime kinetics in postischemic and partially necrotic myocardium with complete and low flow reperfusion using an isolated perfused rat heart model. BACKGROUND: Technetium-99m teboroxime has been proposed for use in the early diagnosis of reperfusion after thrombolysis on the basis of models of myocardial necrosis with complete reperfusion. Clinically, however, reperfusion is frequently incomplete, resulting in a mixture of necrotic, ischemic and postischemic tissue. METHODS: Hearts were classified into five groups: group 1 (n = 8, control); group 2 (n = 7, 30 min of no flow with complete reperfusion); group 3 (n = 12, 60 min of no flow to induce partial necrosis, followed by complete reperfusion); group 4 (n = 8, continuous low flow without flow interruption); and group 5 (n = 9, 60 min of no flow with low flow reperfusion). Buffer containing Tc-99m teboroxime was perfused for 15 min, followed by tracerfree buffer for 35 min, to evaluate uptake and clearance, respectively. RESULTS: Uptake slopes for groups 1 to 5 were (mean +/- SD) 3.0 +/- 0.7, 2.6 +/- 0.8, 2.1 +/- 0.5, 0.8 +/- 0.2 and 0.8 +/- 0.3, respectively (p < or = 0.0005 for groups 1, 2 and 3 vs. groups 4 and 5, and p = 0.003 for group 3 vs. groups 1 and 2). Clearance curves from groups 1 to 3 were best fit by a biexponential function (p < 0.001); those from groups 4 and 5 were monoexponential. In groups 1, 2 and 3, the initial clearance rate constants (ki) (0.9 +/- 0.5 x 10(-3); 1.0 +/- 0.2 x 10(-3); 1.1 +/- 0.5 x 10(-3) s-1, respectively) and the monoexponential rate constants (Kmono) (2.0 +/- 0.3 x 10(-4); 2.2 +/- 0.4 x 10(-4); 2.1 +/- 0.2 x 10(-4) s-1, respectively) were significantly greater than those in groups 4 and 5 (0.9 +/- 0.5 x 10(-4); 1.2 +/- 0.3 x 10(-4) s-1, respectively, p < or = 0.005). CONCLUSIONS: The uptake and initial clearance kinetics of Tc-99m teboroxime depend mainly on myocardial flow in this model. The presence of partial necrosis and postischemic injury has little effect on the initial clearance but leads to some reduction in uptake at normal flow rates. Evaluation of Tc-99m teboroxime kinetics may permit early noninvasive detection of inadequate reperfusion in acute myocardial infarction.

Regression of left ventricular hypertrophy in patients with essential hypertension. Results of 6 month treatment with indapamide.

Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity in hypertensive patients. The effects of diuretics on LVH have raised controversies, but recent studies suggest that diuretics are able to reduce LVH in hypertensive patients, mainly through a reduction in ventricular diameter. The present multicenter open study was designed to test the effects of indapamide, a widely used nonthiazide diuretic, on LVH in patients with essential hypertension. Patients had to have mild-to-moderate essential hypertension (supine diastolic blood pressure [sDBP] 95 to 115 mm Hg) with echocardiographic evidence of LVH (left ventricular mass index [LVMI] > 130 g/m2 for men and > 110 g/m2 for women). After a 2 week placebo run-in period, eligible patients underwent a 6 month treatment with 2.5 mg indapamide daily. All echograms were performed by the same investigator before and after 6 months of indapamide. Clinical and biological acceptability and quality of life (visual analog scale) were also studied. One hundred and thirty patients were included in the study and 112 completed the trial. Indapamide induced a significant reduction i systolic and diastolic blood pressures. Indapamide induced a marked reduction in posterior wall thickness (from 12.1 +/- 2.0 to 11.2 +/- 1.6 mm) and in interventricular wall thickness (from 12.7 +/- 1.7 to 11.8 +/- 1.9 mm; each P < .001) and a slight decrease in left ventricular diameter (P = .049). This resulted in a 13% reduction in LVMI (from 161.9 +/- 37.9 to 140.7 +/- 33.8 g/m2, P < .001). Left ventricular fractional shortening remained unchanged. There was no significant relation between changes in LVMI and changes in systolic, diastolic, or mean blood pressure. No significant adverse clinical or biological effects were reported during the study. The increased score of the visual analog scale indicated that overall well-being was improved (P < .001). Our study indicates that indapamide, in addition to blood pressure control, is able to reduce LVH. This effect was achieved mainly through a reduction in wall thicknesses rather than in internal cavity diameter.