Masanobu Chida

Effects of chronic right ventricular pressure overload on myocardial glucose and free fatty acid metabolism in the conscious rat

OBJECTIVE The aim was to investigate the effects of chronic right ventricular pressure overload on myocardial glucose and free fatty acid metabolism in the right ventricular free wall, ventricular septum, and left ventricular free wall. METHODS Using a glucose analogue, 14C-2-deoxyglucose (14C-DG), and a fatty acid analogue, 14C-beta methylheptadecanoic acid (14C-BMHDA), quantitative autoradiography was performed in conscious rats with 4 week pulmonary artery constriction. RESULTS In rats with chronic pulmonary artery constriction, right ventricular peak systolic pressure and right ventricular weight to body weight ratio increased by 88% and 127%, respectively, compared with sham operated rats (P < 0.01 for each). In the right ventricular free wall, 14C-DG deposition increased but 14C-BMHDA accumulation did not differ in the chronic pulmonary artery constricted rats compared with sham operated rats [212(SEM 27), n = 6 v 101(15) nCi.g-1, n = 4, P < 0.01, and 406(40), n = 6, v 333(48) nCi.g-1, n = 4, NS, respectively]. In sham operated rats, 14C-DG and 14C-BMHDA deposition did not differ between the ventricular septum and the left ventricular free wall. In contrast, 14C-DG and 14C-BMHDA accumulations were lower in the ventricular septum compared with the left ventricular free wall wall in chronic pulmonary artery constricted rats. Myocardial blood flow assessed by 14C-iodoantipyrine was homogeneously distributed throughout both ventricles. CONCLUSIONS Chronic right ventricular pressure overload increases myocardial glucose uptake and/or its phosphorylation in the right ventricular free wall, and alters the regional profiles of substrate use in the ventricular septum and left ventricular free wall despite the homogeneous blood flow distribution. The results of the acute right ventricular pressure overload study, in which only right ventricular 14C-BMHDA deposition was increased compared with controls, suggest that the findings obtained from chronic pulmonary artery constricted rats cannot be explained by increased right ventricular pressure alone.

Long-Term Right Ventricular Volume Overload Increases Myocardial Fluorodeoxyglucose Uptake in the Interventricular Septum in Patients With Atrial Septal Defect

BACKGROUND Several studies have shown that long-term right ventricular (RV) overload in animal models alters myocardial energy substrate metabolism. However, whether long-term RV volume overload alters this metabolism in the human is unclear. METHODS AND RESULTS We performed positron emission tomography with [(18)F]fluorodeoxyglucose (FDG) and single-photon emission tomography (SPECT) with [(201)Tl]TlCl (Tl) and [(123)I]15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) in 11 patients with atrial septal defect (ASD) and 11 control subjects. In the FDG study, we calculated myocardial metabolic rate of glucose (MMR) in interventricular septum (IVS) and left ventricular (LV) free wall. MMR was significantly increased in IVS compared with LV free wall in the ASD patients (420+/-35 versus 333+/-32 mol x kg(-1) x min(-1); P<0.05) but not in the control group (347+/-27 versus 357+/-25 mol x kg(-1) x min(-1)). In both ASD and control groups, SPECT count was not significantly different between IVS and LV free wall in Tl (ASD, 160+/-11 versus 177+/-12; control, 141+/-12 versus 157+/-14 counts per 15 minutes) and BMIPP studies (ASD, 203+/-14 versus 212+/-18; control, 162+/-16 versus 176+/-16 counts per 15 minutes). MMR in the IVS/LV free wall ratio in the ASD group significantly correlated with indices related to RV volume overload. CONCLUSIONS Given the assumption that long-term RV volume overload did not affect the lumped constant, the present study suggests that, unlike myocardial perfusion or fatty acid analogue uptake, myocardial glucose utilization in IVS relative to LV free wall is increased in relation to long-term RV volume overload in patients with ASD.

Regional and temporal profiles of phorbol 12,13-dibutyrate binding after myocardial infarction in rats: effects of captopril treatment.

Phosphoinositide turnover and protein kinase C (PKC) mediate the signaling of angiotensin II, which plays a pivotal role in ventricular remodeling after myocardial infarction (MI). To determine whether PKC is activated after MI, rat hearts after MI were subjected to in vitro quantitative autoradiography with [3H]phorbol 12,13-dibutyrate (PDBu), which is highly selective for PKC. [3H]PDBu binding in the infarcted area increased significantly compared with the non-infarcted region 7 and 21 days after MI, but not 1 and 3 days and 10 months after MI. [3H]PDBu binding in the noninfarcted area was similar to that in the sham-operated rats. Immunohistochemical analysis revealed that abundant macrophages (7 days after MI), fibroblasts, and myofibroblasts (7 and 21 days after MI) occupied the infarcted region. To investigate whether myocardial [3H]PDBu binding is affected by captopril, hearts were subjected to in vitro autoradiography with [3H]PDBu after 1- or 3-week captopril treatment or no treatment. Captopril treatment significantly suppressed [3H]PDBu binding in the infarcted area 3 weeks after MI, but not 1 week after MI nor in the noninfarcted areas. These results suggest that PKC is upregulated during the healing and fibrogenic process after MI and that captopril treatment suppresses the upregulation in the infarcted area.

Heterogeneous fatty acid uptake early after reperfusion in rat hearts

We determined whether spatial distributions of substrate uptake are heterogeneous within the area at risk during reperfusion. Quantitative autoradiography with imaging plates and two long-lived radioisotopes was applied to 15 open-chest, anesthetized rats subjected to 30 min of coronary artery ligation and 30 min of reperfusion. Regions showing increased beta-methyl-[1-14C]heptadecanoic acid ([14C]BMHDA) uptake (166 +/- 17% of that in the nonischemic area) appeared at the lateral borders and subepicardial layer within the area at risk, and 2-deoxy-D-[1-3H]glucose ([3H]DG) uptake was 103 +/- 24% in these regions. Regions with decreased [14C]BMHDA uptake (28 +/- 11%) occupied the midmyocardial layer except at the lateral borders within the area at risk, and [3H]DG uptake was 62 +/- 18% in these regions. The percentage interregional coefficients of variation (index of heterogeneity) in [14C]BMHDA uptake, [3H]DG uptake, and blood flow were higher in the area at risk than in the nonischemic area (76 +/- 23 vs. 21 +/- 7%, 39 +/- 10 vs. 21 +/- 7%, and 49 +/- 19 vs. 14 +/- 4%, respectively). Heterogeneous distributions of substrate uptake may explain the conflicting results concerning substrate metabolism during reperfusion.We determined whether spatial distributions of substrate uptake are heterogeneous within the area at risk during reperfusion. Quantitative autoradiography with imaging plates and two long-lived radioisotopes was applied to 15 open-chest, anesthetized rats subjected to 30 min of coronary artery ligation and 30 min of reperfusion. Regions showing increased β-methyl-[1-14C]heptadecanoic acid ([14C]BMHDA) uptake (166 ± 17% of that in the nonischemic area) appeared at the lateral borders and subepicardial layer within the area at risk, and 2-deoxy-d-[1-3H]glucose ([3H]DG) uptake was 103 ± 24% in these regions. Regions with decreased [14C]BMHDA uptake (28 ± 11%) occupied the midmyocardial layer except at the lateral borders within the area at risk, and [3H]DG uptake was 62 ± 18% in these regions. The percentage interregional coefficientsof variation (index of heterogeneity) in [14C]BMHDA uptake, [3H]DG uptake, and blood flow were higher in the area at risk than in the nonischemic area (76 ± 23 vs. 21 ± 7%, 39 ± 10 vs. 21 ± 7%, and 49 ± 19 vs. 14 ± 4%, respectively). Heterogeneous distributions of substrate uptake may explain the conflicting results concerning substrate metabolism during reperfusion.

Effect of angiotensin converting enzyme inhibition on myocardial phosphoinositide metabolism visualised with 1-[1-11C]-butyryl-2-palmitoyl-rac-glycerol in myocardial infarction in the rat

Abstract. We recently reported that myocardial phosphoinositide (PI) metabolism can be visualised by 1-[1-11C]-butyryl-2-palmitoyl-rac-glycerol (11C-DAG) in rats with myocardial infarction (MI). Angiotensin II, the receptors for which are expressed predominantly in infarcted areas with active fibrogenesis rather than in non-infarcted regions, is involved in the upstream signalling systems of PI metabolism and plays an important role in the process of left ventricular (LV) remodelling after MI. We therefore hypothesised that the distribution of 11C-DAG after MI may be affected by the inhibition of angiotensin converting enzyme, which is one of the most important factors in the development of LV remodelling after MI. Rats were injected with 11C-DAG after 3 or 10weeks of treatment with captopril or no treatment following coronary artery ligation, and quantitative autoradiography was performed. Cells occupying the infarcted region were identified by immunohistochemistry. Compared with untreated rats, treatment with captopril for 3 weeks after MI elicited a reduction in the 11C-DAG uptake in the infarcted region (P<0.05) but not in the non-infarcted region, and was associated with a 22% decrease in the heart weight/body weight ratio. The thallium-201 distribution in the infarcted area was similarly low in the rats with and rats without the 3-week captopril treatment after MI. Abundant macrophages and myofibroblasts occupied the infarcted area in both rats with and rats without the captopril treatment for 3 weeks after MI. The 11C-DAG radioactivity in the infarcted region in the untreated rats was lower 10 weeks after MI than 3 weeks after MI (P<0.01). This finding was in agreement with the results of immunohistochemistry demonstrating that the number and size of macrophages and myofibroblasts were remarkably reduced in rats 10 weeks after MI compared with 3 weeks after MI. Captopril treatment for 10 weeks after MI did not decrease the 11C-DAG radioactivity in the infarcted area further. These data suggest that 11C-DAG is useful for visually detecting regions with activated PI metabolism after MI, and that captopril reduces PI metabolism in the infarcted region in the relatively early phase of MI, which might contribute to the attenuation of ventricular remodelling.

[18F] labeled diacylglycerol analogue as a potential agent to trace myocardial phosphoinositide metabolism.

Phosphoinositide metabolism plays an important role in cardiac pathophysiology. To investigate whether [18F]diacylglycerol could be used to trace myocardial phosphoinositide metabolism, lipids were extracted from rat myocardium after the injection. 1-[8-[18F]fluorooctanoyl]-2-palmitoylglycerol and 1-[8-[18F]fluoropalmitoyl]-2-palmitoylglycerol were predominantly metabolized to phosphatidylethanolamine and triacylglycerol, respectively. The radioactivity incorporated into phosphoinositide metabolism was 51, 44, 32, and 30% 3, 5, 10, and 30 minutes after the injection of 1-[4-[18F]fluorobutyryl]-2-palmitoylglycerol, respectively. 1-[4-[18F]fluorobutyryl]-2-palmitoylglycerol might be a potential tracer to evaluate myocardial phosphoinositide metabolism early after the injection.