Jun Yoshioka

Intracellular Sodium Accumulation During Ischemia as the Substrate for Reperfusion Injury

To elucidate the role of intracellular Na+ kinetics during ischemia and reperfusion in postischemic contractile dysfunction, intracellular Na+ concentration ([Na+]i) was measured in isolated perfused rat hearts using 23Na nuclear magnetic resonance spectroscopy. The extension of the ischemic period from 9 minutes to 15, 21, and 27 minutes (at 37 degrees C) increased [Na+]i at the end of ischemia from 270.0+/-10.4% of preischemic level (mean+/-SE, n=5) to 348.4+/-12.0% (n=5), 491.0+/-34.0% (n=7), and 505.3+/-12.1% (n=5), respectively, whereas the recovery of developed pressure worsened with the prolongation of the ischemic period (95.1+/-4.2%, 84.3+/-1. 2%, 52.8+/-13.7%, and 16.9+/-6.4% of preischemic level). The kinetics of [Na+]i recovery during reperfusion was analyzed by the fitting of a monoexponential function. When the hearts were reperfused with low-[Ca]o (0.15 mmol/L) solution, the time constants of the recovery (tau) after 15-minute (8.07+/-0.85 minutes, n=5) and 21-minute ischemia (6.44+/-0.90, n=5) were significantly extended, with better functional recovery (98.5+/-1.4% for 15-minute [P<0.05]; 98.0+/-1.0% for 21-minute [P<0.05]) compared with standard reperfusion ([Ca]o=2.0 mmol/L, tau=3.58+/-0.28 minutes for 15-minute [P<0.0001]; tau=3.02+/-0.20 for 21-minute [P<0.0001]). A selective inhibitor of Na+/Ca2+ exchanger also decelerated the [Na+]i recovery, which suggests that the recovery reflects the Na+/Ca2+ exchange activity. In contrast, high-[Ca]o reperfusion (5 mmol/L) accelerated the [Na+]i recovery after 9-minute ischemia (tau=2.48+/-0.11 minute, n=5 [P<0.0001]) and 15-minute ischemia (tau=2.10+/-0.07, n=6 [P<0. 05]), but functional recovery deteriorated only in the hearts with 15-minute ischemia (29.8+/-9.4% [P<0.05]). [Na+]i recovery after 27-minute ischemia was incomplete and decelerated by low-[Ca]o reperfusion, with limited improvement of functional recovery (42. 5+/-7.9%, n=5 [P<0.05]). These results indicate that intracellular Na+ accumulation during ischemia is the substrate for reperfusion injury and that the [Na+]i kinetics during reperfusion, which is coupled with Ca2+ influx, also determines the degree of injury.

Exercise-induced stunning continues for at least one hour : Evaluation with quantitative gated single-photon emission tomography

Abstract. To elucidate the after-effect of exercise on left ventricular (LV) function, end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (LVEF) were evaluated at 1xa0h after exercise and at rest by technetium-99m tetrofosmin gated myocardial single-photon emission tomography (SPET) using an automated program in 53 subjects. The subjects were grouped as follows: normal scan (nxa0=xa016), ischaemia (nxa0=xa019) and infarction (nxa0=xa018), based on the interpretation of perfusion images. Postexercise LVEF did not differ from resting LVEF in the groups with normal scan and infarction. In patients with ischaemia, postexercise EDV (90±17xa0ml, mean ±SD) and ESV (44±15xa0ml) were significantly higher than EDV (84±15xa0ml, Pxa0=xa00.001) and ESV (36±14xa0ml, P<0.0005) at rest. LVEF was significantly depressed 1xa0h after exercise (53%±9% vs 58%±9%, P<0.0001). In ischaemic patients with depressed postexercise LVEF, LVEF difference between rest and postexercise showed a significant correlation with the sum of defect scores, which were reversible from exercise to rest perfusion images (rxa0=xa00.92, P<0.0001). These results indicate that exercise-induced LV dysfunction (myocardial stunning) continues for at least 1xa0h in ischaemic patients and that the extent of LVEF depression is determined by the severity of ischaemia.

Myocardial viability assessment with gated SPECT TC-99m tetrofosmin % wall thickening: Comparison with F-18 FDG-PET

Object: This study was designed to assess the value of gated SPECT Tc-99m-tetrofosmin (TF) wall thickening (WT) in addition to TF exercise (Ex)/rest myocardial SPECT, in comparison with F-18 fluorodeoxyglucose (FDG)-PET.Methods: The study population consisted of 33 patients with old myocardial infarction (27 men and 6 women; mean age, 62±8 years old). All patients underwent Ex/rest TF SPECT and glucose loading FDG-PET. Polar map images of Ex/rest TF were generated exercise-rest perfusion scintigraphy. LV segments with less than 70% of the maximum TF activity on the exercise image were defined as stress-induced defects. Among these, the segments whose TF activity increased by 10% from exercise to rest images or exceeded 70% of the maximum uptake were defined as reversible (viable) defects. The remaining defects on the rest image were irreversible (non-viable) defect segments, and were considered for viability study on the basis of %WT. %WT was calculated according to the standard method: {(counts ES—counts ED)/counts ED}×100. A viable segment on gated SPECT was defined as a segment whose %WT exceeded the lower limit of the normal value (mean-SD). PET viability was defined as FDG uptake exceeding 50% of the maximum count.Results: Among the 792 segments evaluated in the 33 patients studied, there were 689 PET viable segments. Of the 689 segments analyzed, 198 (29%) were identified as having defects on Ex images. Among these defects, 55 (8%) were reversible or partially reversible, as evidenced by rest images, and 143 (21%) were irreversible. Of the irreversible segments on Ex/rest images, 106 (15%) demonstrated no apparent WT by gated TF SPECT, whereas 37 (6%) segments with irreversible defects did have apparent WT. Overall, the sensitivity of Ex/rest TF perfusion imaging was 79%. Sensitivity was improved from 79% to 85% by combining %WT and perfusion data, but specificity was reduced from 70% to 56%.Conclusion: %WT evaluated from gated TF imaging enhanced myocardial viability assessment in comparison with FDG-PET.

Characteristics of myocardial18F-fluorodeoxyglucose positron emission computed tomography in dilated cardiomyopathy and ischemic cardiomyopathy

Myocardial18F-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) has been used to assess myocardial ischemia and viability, but few studies have conducted on FDG-PET for dilated cardiomyopathy (DCM). We investigated myocardial FDG uptake in patients with DCM in comparison with ischemic cardiomyopathy (ICM). Twenty-four patients with heart failure were included in this study. Fourteen of them were diagnosed as DCM and the other 10 were ICM. All of them underwent myocardial FDG-PET at fasting and after glucose loading the same day. FDG uptake was quantified by the ratio of the counts at the heart to those at the liver (H/L ratio). Left ventricular (LV) function was measured by echocardiography. We classified FDG distribution patterns in the myocardium in the fasting state into 3 types (faint uptake, regional uptake and diffuse uptake). In DCM patients, 5 had faint uptake, 7 had regional uptake, and the other 2 had diffuse uptake. On the other hand, all ICM patient had regional uptake (p<0.05). In DCM, there were no significant relationships between the patterns and LV functions. On the other hand, there were close correlation between the H/L ratio after glucose loading and the left ventricular ejection fraction (r=0.680, p<0.01). The changes in PET images caused by glucose loading were classified into 2 types (non-reversing and reversing patterns). DCM significantly showed a non-reversing pattern (86%, 12 of 14 patients) whereas ICM showed mainly a reversing pattern (70%, 7 of 10 patients; p<0.05) In conclusion, myocardial FDG uptake after glucose loading may indicate a myocardial viable mass although FDG uptake at fasting was not evidently related to LV function. The change in the pattern of the FDG image from fasting to glucose loading may be useful in differentiating DCM from ICM.

Clinical value of lung uptake of iodine-123 metaiodobenzylguanidine (MIBG), a myocardial sympathetic nerve imaging agent, in patients with chronic heart failure

This study investigated the clinical value of I-123 MIBG pulmonary accumulation and washout in patients with chronic heart failure (CHF). Nineteen patients with CHF and 15 normal volunteers (NL) were included. The uptake ratio of heart to mediastinum (H/M), that of lung fields to mediastinum (L/M), and washout rate (WR) of the heart and lung fields were calculated in anterior planar images and compared with results of echocardiography and cardiac catheterization. In the CHF group, the lung uptake in delayed images increased and lung WR was decreased suggesting pulmonary endothelial lesions. Furthermore, there was a negative correlation between right and left lung WR and pulmonary arterial diastolic pressure (PA(d)) and pulmonary arterial systolic pressure (PA(s)) in the CHF group. Since the WR of MIBG reflected PA, it may be used as an index of severity of cardiac dysfunction.

Assessment of left ventricular function by gated myocardial perfusion and gated blood-pool SPECT: Can we use the same reference database?

The purpose of this study was to compare left ventricular (LV) volume and ejection fraction (LVEF) measurements obtained with electrocardiographic gated single-photon emission computed tomographic (SPECT) myocardial perfusion imaging (GS-MPI) with those obtained with gated SPECT cardiac blood-pool imaging (GS-pool). Fifteen patients underwent GS-MPI with technetium-99m-tetrofosmin and GS-pool with technetium-99m-erythrocyte, within a mean interval of 8±3 days. Eight patients had suspected dilated cardiomyopathy and seven patients had angiographically significant coronary artery disease. End-diastolic volume (EDV), end-systolic volume (ESV) and LVEF measurements were estimated from GS-MPI images by means of Cedars-Sinai automatic quantitative program and from GS-pool images by the threshold technique. Mean differences between GS-MPI and GS-pool in EDV, ESV and LVEF measurements were −2.8±10.5 ml [95% confidence interval (CI): −8.6±3.0ml], 2.6±7.3 ml (CI: −1.4∼6.6 ml) and −2.3±5.1% (CI: −5.1∼0.6%), respectively. No significant difference in the mean differences from 0 was found for EDV, ESV or LVEF measurements. Bland-Altman plots revealed no trend over the measured LV volumes and LVEF. For all parameters, regression lines approximated lines of identity. The excellent agreement between GS-MPI and GS-pool measurements suggests that, for estimation of LV volumes and LVEF, these two techniques may be used interchangeably and measurements by one method can serve as a reference for the other.

Troglitazone enhances glucose uptake induced by alpha-adrenoceptor stimulation via phosphatidylinositol 3-kinase in rat heart.

1. Thiazolidinedione‐derived agents have been reported to act as insulin sensitizers by augmenting insulin‐dependent stimulation of phosphatidylinositol 3‐kinase (PI3K) activity in a specific manner. It has been suggested that α‐adrenoceptor stimulation mediates glucose uptake through PI3K in the heart.

Type IV phosphodiesterase inhibitor suppresses insulin-dependent myocardial glucose uptake.

1. Phosphodiesterase (PDE) IV has been localized at cardiomyocytes and the coronary vasculature and modulates cAMP, but the effect of PDE IV on myocardial glucose uptake has not been demonstrated.

Detection of coronary artery disease by iodine-123-labeled iodophenyl-9-methyl pentadecanoic acid SPECT: comparison with thallium-201 and iodine-123 BMIPP SPECT.

To evaluate the ability to detect coronary artery disease (CAD) with a new iodine-123 labeled branched fatty acid analog, iodophenyl-9-methyl pentadecanoic acid (9MPA), we performed 9MPA, iodine-123 BMIPP and thallium-201 SPECT in patients with CAD. Twenty-four patients (11 with effort angina and 13 with myocardial infarction) were studied. In all patients, 9MPA SPECT was obtained at 15 min after injection. Twenty-three patients underwent stress-redistribution201Tl SPECT and 9 patients also underwent BMIPP myocardial fatty acid imaging. The regional uptakes of 9MPA, BMIPP and201Tl were scored semiquantitatively and the segmental agreements were compared among them. In the segment-to-segment comparison, 9MPA showed reduced activity in comparison to stress-redistribution201Tl imaging. The defect score of 9MPA was significantly greater than that of redistribution201Tl images (p<0.001). In addition, segmental 9MPA uptake was lower than BMIPP and its defect score was significantly greater than that of BMIPP (p<0.05). When coronary angiography was used as the criterion, 9MPA showed higher sensitivity and lower specificity than stress-redistribution201Tl (p<0.01). In conclusion, fatty acid metabolic imaging with 9MPA is a sensitive but nonspecific detector of CAD.

Fluorine-18 FDG myocardial positron emission tomographic findings before and after pituitary adenoma resection in a patient with acromegalic cardiomyopathy.

Because of persistently elevated growth hormone levels, acromegaly gives rise to various changes in organs mediated by insulin-like growth factor-I. In the heart, it causes myocardial hypertrophy, and, with time, heart failure. The authors performed pituitary adenomectomy in a patient with acromegalic cardiomyopathy who had heart failure; after operation, the blood growth hormone levels decreased to within the normal range and there was a marked improvement in left ventricular function by gated blood pool scintigraphy. Pre- and postoperative fluorine-18 fluorodeoxyglucose (FDG) myocardial positron emission tomography showed increased accumulation of FDG in the myocardium before surgery, but accumulation within the normal range after operation. Myocardial glucose metabolism changed when the long-term effects of growth hormone and insulin-like growth factor-I were eliminated, and this appears to be accurately reflected by FDG positron emission tomography.