Search

Abnormalities in energy metabolism may play an important role in the development of hypertensive heart failure. However, the transition from compensated hypertrophy to heart failure is not fully understood in terms of energy metabolism. In Dahl salt-sensitive (DS) and salt-resistant (DR) rats, myocardial fatty acid and glucose uptake values were determined using [sup.131]I- or [sup.125]I-labeled 9-methylpentadecanoic acid ([sup.131]I- or [sup.125]I-9MPA), and [[sup.14]C]deoxyglucose ([[sup.14]C]DG), fatty acid [beta]-oxidation was identified using thin-layer chromatography, and insulin-stimulated glucose-uptake was observed using a euglycemic hyperinsulinemic glucose clamp. Six-week-old rats were fed a diet that contained 8% NaCl, which resulted in development of compensated hypertrophy in DS rats at 12 wk of age and ultimately led to heart failure by 18 wk of age. Uptake of [[sup.14]C]DG increased markedly with age in the DS rats, whereas [sup.131]I-9MPA uptake was marginally but significantly increased only in animals aged 12 wk. The ratio of [sup.125]I-9MPA [beta]-oxidation metabolites to total uptake in the DS rats was significantly lower (P < 0.05) at 12 (37%) and 18 (34%) wk compared with at 6 (45%) wk. Insulin increased [[sup.14]C]DG uptake more than twofold in the DS rats at 6 wk, although this increase was markedly attenuated at 12 and 18 wk (11 and 8%, respectively). Our data suggest that in a hypertrophied heart before heart failure, fatty acid oxidation is impaired and the capacity to increase glucose uptake during insulin stimulation is markedly reduced. These changes in both glucose and fatty acid metabolism that occur in association with myocardial hypertrophy may have a pathogenic role in the subsequent development of heart failure. cardiac; failure; deoxyglucose; methylpentadecanoic acid; [beta]-oxidation; insulin

Background: Cardiac (123)I-metaiodobenzylguanidine (MIBG) imaging is widely used to assess cardiac sympathetic neuronal function. However, physiologic significance of impaired cardiac MIBG uptake is not fully elucidated. The purpose of the present study was to determine influences of abnormal cardiac sympathetic neuronal function on heart rate variability (HRV) and ventricular repolarization process.Methods: Twenty-nine patients with prior myocardial infarction were divided into two groups by a heart-to-mediastinum ratio (H/M) of MIBG scintigraphy. Ten patients with globally decreased MIBG uptake (group I: H/M < 1.5), 19 patients with partially decreased MIBG uptake (group II: H/M >or= 1.5), and 17 control subjects with normal MIBG uptake (group III) were studied. Holter recording and a standard 12-lead electrocardiography were used for evaluation of HRV, QT-RR relation, and QT dispersion.Results: Low, high, and total frequency components decreased in groups I and II, as compared to that of group III. The reduction of these frequency domain measures was more severe in group I than in group II, but the differences did not reach statistical significance. Circadian variation of frequency domain measures disappeared in group I. The slope of QT-RR relation was significantly greater in group I than in groups II and III. QT dispersion was also greater in group I (64 +/- 25 msec) than in group II (43 +/- 19 msec) and group III (28 +/- 9 msec).Conclusion: These results suggest that patients with sympathetic neuronal dysfunction inferred from globally impaired cardiac MIBG uptake have an altered modulation of ventricular repolarization process as well as decreased HRV. [ABSTRACT FROM AUTHOR]

In patients routinely treated with metoprolol, influences of CYP2D6 genotype on the response of heart rate to isoproterenol (IP) were studied at its peak and trough concentrations and were compared with those of bisoprolol. In 72 patients treated with metoprolol or bisoprolol, CYP2D6 genotype (ie, CYP2D6*1, *2, *4, *5, *10, and *14) was determined. No patients except one who was heterozygous for CYP2D6*5 carried the null alleles of CYP2D6. The homozygote frequency for CYP2D6*10 was relatively high (19.4%) and these patients had greater peak and trough plasma concentrations of metoprolol than the other patients. Isoproterenol-induced percentage increases in heart rate were 58% and 38% less at the low and high rate of isoproterenol infusion (0.02 and 0.04 microg/kg/min), respectively, in patients homozygous for CYP2D6*10 than in the other patients at the trough, but not at the peak concentrations. In contrast, CYP2D6 genotype did not affect plasma concentrations of bisoprolol and the extent of its beta-adrenergic inhibition. Thus, in patients routinely treated with metoprolol, CYP2D6 genotype significantly affects circadian variations of beta-adrenergic inhibition induced by metoprolol. In contrast, bisoprolol has a relatively constant beta-adrenergic inhibition independent of CYP2D6 genotype.

Unlabelled: Cardiac sympathetic neuronal function is closely coupled with beta-adrenoceptors and adrenergic signaling. However, the recovery process of sympathetic neuronal function and beta-adrenoceptors after reperfusion following transient ischemia is not fully understood. Accordingly, this study was performed to investigate serial changes in sympathetic neuronal function and beta-adrenoceptors after transient myocardial ischemia., Methods: The left coronary artery of male Wister rats was ligated for 15 min followed by reperfusion. A dual-tracer method of (131)I-metaiodobenzylguanidine ((131)I-MIBG) and (125)I-iodocyanopindolol ((125)I-ICYP) was used to assess cardiac sympathetic neuronal function and beta-adrenoceptor density on days 1, 3, 7, 14, and 28 after reperfusion. Myocardial norepinephrine (NE) content in ischemic regions (IR) and in remote regions (RR) and hemodynamic indices were determined. Using a membrane preparation of the rat heart after reperfusion, the maximum specific binding (B(max)) of beta-adrenoceptors was compared with (125)I-ICYP accumulation., Results: The maximum value of the rate of change in left ventricular (LV) pressure (dP/dt(max)) tended to decrease on day 1 after reperfusion but recovered thereafter. Myocardial NE content was significantly reduced in IR compared with RR on day 1 (272 +/- 49 vs. 487 +/- 93 ng/g, P < 0.01), and the decrease became more severe on day 14 (36 +/- 19 vs. 489 +/- 132 ng/g, P < 0.01) and day 28 (37 +/- 14 vs. 455 +/- 216 ng/g, P < 0.01). Decrease in the IR-to-RR uptake ratio of (131)I-MIBG was modest on day 1 (0.64 +/- 0.12) and became more severe on days 7 and 14 (0.38 +/- 0.12 and 0.35 +/- 0.13, respectively). This reduction was partially restored on day 28 (0.50 +/- 0.18). In contrast, the IR-to-RR uptake ratio of (125)I-ICYP was severely decreased until day 3 (0.60 +/- 0.13 on day 1 and 0.54 +/- 0.19 on day 3) and recovered thereafter. On day 3, B(max) was significantly lower in IR than in RR (83 +/- 17 vs. 100 +/- 12 fmol/mg, P < 0.05), but the dissociation constant did not differ between the 2 regions., Conclusion: The recovery course of cardiac (131)I-MIBG uptake after reperfusion following transient ischemia is quite different from that of (125)I-ICYP. Simultaneous scintigraphic portrayal of beta-adrenoceptors together with (131)I-MIBG would provide useful information regarding adrenergic system signaling in patients with coronary artery disease.