Akihiko Igawa

Effects of long-term renal sympathetic denervation on heart failure after myocardial infarction in rats

Abstract The purpose of the present study was to investigate the effects of long-term renal denervation (RD) on heart failure due to myocardial infarction (MI). Wistar rats were anesthetized and the bilateral renal nerves were surgically denervated 2 days before MI was induced by coronary artery ligation. Four weeks later, left ventricular (LV) function and sodium excretion were determined. In MI rats, RD improved the reduced sodium excretion. MI + RD rats revealed lower LV end-diastolic pressure and greater maximum dP/dt as compared with those of MI+ innervation (INN) rats. LV end-diastolic and end-systolic dimensions were significantly smaller and LV fractional shortening was greater in MI + RD rats than in MI + INN rats (20.9% ± 3.2% vs 14.9% ± 3.0%). In rats without MI, RD did not affect either sodium excretion or LV function and dimensions. The present results suggest that the long-term RD reduces LV filling pressure and improves LV function after MI, probably due to a restoration of impaired natriuresis. Increased renal sympathetic nerve activity might contribute to the progression of heart failure after MI.

Vitamin E Deficiency in Variant Angina

BACKGROUND Oxidative modification of LDL has been suggested to increase coronary vasoreactivity to agonists. A deficiency of vitamin E, a major antioxidant, may be related to the occurrence of coronary artery spasm. METHODS AND RESULTS Vitamin E levels were determined with the use of high-performance liquid chromatography in normolipidemic subjects, including 29 patients with active variant angina (group 1), 13 patients with inactive stage of variant angina without anginal attacks during the past 6 months (group 2), 32 patients with a significant (>75%) organic coronary stenosis and stable effort angina (group 3), and 30 patients without coronary artery disease (group 4). Total lipid levels in blood were calculated as total cholesterol plus triglyceride levels. The plasma alpha-tocopherol levels as well as alpha-tocopherol/lipids were significantly lower in group 1 than in groups 2 through 4. Also, the plasma gamma-tocopherol levels were significantly lower in group 1 than in groups 2 through 4. The vitamin E levels were not significantly different between group 1 patients with and those without a significant organic stenosis. In group 1, both alpha- and gamma-tocopherol levels were significantly elevated after a > or = 6-month angina-free period. The alpha-tocopherol levels in the LDL fraction were significantly lower in group 1 than in group 4. Plasma alpha-tocopherol levels were significantly correlated with those in the LDL fractions. In 6 patients of group 1 still having anginal attacks while receiving calcium channel blockers, the addition of vitamin E acetate (300 mg/d) significantly elevated plasma alpha-tocopherol levels and inhibited the occurrence of angina. CONCLUSIONS Plasma vitamin E levels were significantly lower in patients with active variant angina than in subjects without coronary spasm, suggesting an association between vitamin E deficiency and coronary artery spasm.

Soluble E-selectin, ICAM-1 and VCAM-1 levels in systemic and coronary circulation in patients with variant angina

OBJECTIVE The purpose of this study was to assess whether the plasma levels of soluble adhesion molecules including E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are elevated in patients with variant angina and whether they are released in the coronary circulation. METHODS Antecubital venous plasma samples were collected from 33 patients with variant angina, 22 patients with stable effort angina and 20 control subjects. Samples were also collected from the aortic root (AO) and the coronary sinus (CS) in 18 patients with variant angina before and after left coronary spasm induced by intracoronary injection of acetylcholine. The soluble adhesion molecules were assayed by enzyme immunoassay. RESULTS Antecubital venous plasma soluble E-selectin (P < .05), ICAM-1 (P < .01) and VCAM-1 (NS) levels were higher in the variant angina group than in the control group, respectively. The plasma soluble ICAM-1 level was also higher (P < .01) in the variant angina group than in the stable effort angina group. In the variant angina group, both soluble ICAM-1 (P < .05) and VCAM-1 (P < .01) levels were significantly lower in CS than AO at baseline. In contrast, after the spasm the plasma soluble ICAM-1 level was (P < .05) higher in CS than AO and the CS-AO differences of soluble ICAM-1 (P < .05) and VCAM-1 (P < .05) increased as compared with the baseline, respectively. These values were remained unchanged in the stable effort angina group after rapid atrial pacing and in the control group after administration of acetylcholine. CONCLUSIONS Circulating plasma levels of both soluble E-selectin and ICAM-1 were elevated in patients with variant angina, indicating an association of an inflammatory reaction with coronary spasm. Both soluble ICAM-1 and VCAM-1 appeared to be trapped in the coronary circulation at baseline and released into the coronary circulation following coronary spasm and reperfusion in the patients.

Alterations of autonomic nervous activity preceding nocturnal variant angina: Sympathetic augmentation with parasympathetic impairment ☆ ☆☆ ★

BACKGROUND Autonomic nervous discharge has been implicated in the pathogenesis of coronary artery spasm. METHODS Cardiac autonomic nervous activities were evaluated from the power of the low-frequency and the high-frequency spectral components of heart rate variability with Holter monitoring in 18 patients with nocturnal variant angina. Samples during the first 512 seconds of each 10-minute period from 60 minutes before to immediately before an anginal attack occurring during the night or at dawn (2:00 to 7:00 AM) were analyzed by fast Fourier transformation. RESULTS The R-R interval during the 10- to 0-minute period was significantly shorter than those during the other 10-minute periods. The coefficient of variance of the high-frequency component (0.15 to 0.40 Hz) (CVHF) from the 10- to 0-minute period was not significantly different from the other 10-minute periods. However, both the coefficient of variance of the low-frequency component (0.04 to 0.15 Hz) (CVLF) and the ratio of CVLF and CVHF (CVLF/CVHF) were significantly greater during the 10- to 0-minute period than those during the 30- to 20-minute period, respectively. A significant nighttime fluctuation in the spectral components of heart rate variability with a peak in the CVHF and a nadir in both the CVLF and CVLF/CVHF observed in the control group was blunted in the patients during the attack-free periods while they were medicated with calcium entry blockers. CONCLUSION Sympathovagal imbalance, sympathetic activation without parasympathetic augmentation, enhanced in the early morning may play an important role in the genesis of coronary artery spasm in patients with nocturnal variant angina.

Influence of CYP2D6 genotype on metoprolol plasma concentration and beta-adrenergic inhibition during long-term treatment: a comparison with bisoprolol.

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 μg/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 β-adrenergic inhibition. Thus, in patients routinely treated with metoprolol, CYP2D6 genotype significantly affects circadian variations of β-adrenergic inhibition induced by metoprolol. In contrast, bisoprolol has a relatively constant β-adrenergic inhibition independent of CYP2D6 genotype.

Time-varying spectral analysis of heart rate and left ventricular pressure variability during balloon coronary occlusion in humans: A sympathoexcitatory response to myocardial ischemia

OBJECTIVES We assessed time-varying spectral components of heart rate and left ventricular (LV) pressure variability during coronary angioplasty to elucidate dynamic autonomic responses to transient myocardial ischemia. BACKGROUND Sympathoexcitatory reflexes elicited by acute coronary occlusion are rarely addressed in the clinical settings because of a lack of technique to monitor transient changes in sympathetic activation. METHODS RR interval and LV pressure and volume were serially recorded in 14 patients with effort angina during balloon coronary angioplasty. Wavelet analysis was applied for determination of nonstationary spectral components of RR interval and LV peak pressure variability. RESULTS The wavelet analysis revealed that coronary occlusion provoked low-frequency (LF) fluctuations of RR interval (seven patients) and LV peak pressure (six patients) at 0.06 +/- 0.01 Hz, but not in the remaining patients. Following the balloon inflation, the LF component of RR interval began to increase after the onset of myocardial ischemia, peaked at about 80 s, and then declined in the late phase of inflation. Consequently, the ratio of low to high frequency component rose to be significantly greater in the LF augmentation group than in the no LF augmentation group in the middle phase of coronary occlusion. The patients with no LF augmentation had little evidence of myocardial ischemia as reflected by changes in ST segment and LV systolic function during coronary occlusion. CONCLUSIONS The wavelet analysis of RR interval and LV pressure variability clearly showed a dynamic profile of spectral components in response to transient coronary artery occlusion. The resultant regional myocardial ischemia elicited a profound sympathoexcitatory response followed by a gradual suppression. This method provides a useful tool to gain a new insight into the nonstationary autonomic influence on the cardiovascular system.

Consumption of vitamin E in coronary circulation in patients with variant angina

OBJECTIVES The plasma status of vitamin E has been suggested to be linked to the activity of coronary artery spasm. This study was designed to determine whether vitamin E is actually consumed in the coronary circulation in patients with active variant angina having repetitive spasm-induced transient myocardial ischemia and reperfusion. METHODS Blood samples were obtained simultaneously from the aortic root, coronary sinus and right atrium in 12 patients with variant angina due to spasm of the left coronary artery, nine patients with stable effort angina and nine control subjects. Plasma vitamin E (alpha- and gamma-tocopherol) concentrations were determined by use of high-performance liquid chromatography and plasma lipid peroxides were measured as thiobarbituric acid-reactive substances (TBARS). RESULTS At baseline, both plasma alpha- (p < 0.01) and gamma- (p < 0.05) tocopherol levels were significantly lower in the coronary sinus (5.50 +/- 0.50 and 0.55 +/- 0.07 mg/l, mean +/- SEM) than in the aortic root (6.63 +/- 0.57 and 0.63 +/- 0.08 mg/l) and also in the right atrium (6.44 +/- 0.61 and 0.63 +/- 0.09 mg/l) in the variant angina group. The TBARS level was significantly (p < 0.05) higher in the coronary sinus than in the aortic in this group. In contrast, these levels were not significantly different between the samples from the coronary sinus and the aortic root or the right atrium in the control group and also in the stable effort angina group. The coronary sinus-aortic difference in plasma vitamin E levels in the variant angina group was not significantly altered after left coronary artery spasm induced by intracoronary injection of acetylcholine. Also, the plasma vitamin E levels in the aortic root, coronary sinus and right atrium all remained unchanged in the stable effort angina group after pacing-induced angina and in the control group after intracoronary administration of acetylcholine. CONCLUSIONS Transcardiac reduction in plasma vitamin E concentrations concomitant with lipid peroxide formation was demonstrated in patients with active variant angina, suggesting actual consumption of this major endogenous antioxidant. Oxidative stress and vitamin E exhaustion may be involved in the pathogenesis of coronary artery spasm.

Dual-Tracer Assessment of Coupling Between Cardiac Sympathetic Neuronal Function and Downregulation of β-Receptors During Development of Hypertensive Heart Failure of Rats

BACKGROUND Heart failure is associated with activation of the sympathetic nervous system and downregulation of beta-receptors. However, the coupling between cardiac sympathetic neuronal function and the beta-receptor during the development of hypertensive heart failure is not clear. METHODS AND RESULTS We determined cardiac neuronal function and beta-receptors with a dual-tracer method of [131I]metaiodobenzylguanidine (MIBG) and 125I-cyanopindolol (ICYP) in Dahl salt-sensitive (DS) and salt-resistant (DR) rats. The rats were fed an 8% NaCl diet after the age of 6 weeks. Blood pressure was raised to >200 mm Hg at 12 weeks in DS rats and remained elevated until 18 weeks, but only slightly in DR rats. Left ventricular (LV) function of DS rats was preserved at 12 weeks but deteriorated at 18 weeks. Despite a 56% reduction of cardiac norepinephrine (NE) content at 12 weeks in DS rats, neither MIBG nor ICYP uptake in DS rats was different from that of DR rats. At 18 weeks, both MIBG and ICYP uptakes decreased, by 52% and 39%, respectively, in association with 71% reduction of cardiac NE, in DS rats. MIBG uptake of the LV was homogeneous at 6 weeks but was lower in the LV endocardial regions at 18 weeks in DS rats. CONCLUSIONS The present results indicate that cardiac sympathetic neuronal function is relatively preserved at the compensated, hypertrophic stage of DS rats but deteriorates in association with beta-receptor downregulation at the failing stage. The cardiac neuronal dysfunction occurs heterogeneously. A combination of scintigraphic portrayal of beta-receptors with MIBG should provide valuable information regarding sympathetic nerve signaling in living hearts.

Importance of magnesium deficiency in alcohol-induced variant angina

I t is well recognized that alcohol is a precipitating factor of angina1 attacks in patients with variant angina. 1,2 Angina1 attacks in some patients with variant angina are closely related to alcohol ingestion.2 The attacks usually occur several hours after alcohol ingestion. Therefore, it is postulated that angina may be induced by a major metabolite, acetaldehyde, rather than the direct action of alcohol.2 Catecholamines released by acetaldehyde may induce coronary spasm through a-adrenergic receptors that are present in large coronary arteries. However, the precise mechanisms responsible for the occurrence of coronary spasm by the ingestion of alcohol have not been elucidated fully. Recent studies indicated that magnesium (Mg) deficiency may be involved in the pathogenesis of coronary spasm. 3,4 Because urinary Mg excretion is augmented by alcohol drinking,5 Mg deficiency may be responsible for angina1 attacks related to alcohol ingestion. The present study was designed to examine: (1) whether there is Mg deficiency in patients with alcoholinduced variant angina, and (2) whether intravenously administered Mg is effective in suppressing alcohol-induced variant angina. This study comprised 2 separate protocols. Protocol I included 21 patients with variant angina, with or with-

Modulation of left ventricular diastolic distensibility by collateral flow recruitment during balloon coronary occlusion

OBJECTIVES The goals of this study were to elucidate the scaffolding effect of blood-filled coronary vasculature and to determine the functional role of recruited collateral flow in modulating left ventricular (LV) distensibility during balloon coronary occlusion (BCO). BACKGROUND Although LV distensibility is an important factor affecting acute dilation after myocardial infarction, the response of LV diastolic pressure-volume (P-V) relations to coronary occlusion is inconsistent in humans. METHODS Micromanometer and conductance derived LV P-V loops were serially obtained from 16 patients undergoing percutaneous transluminal coronary angioplasty. Coronary collateral flow recruitment was angiographically evaluated by contralateral and ipsilateral contrast injection during BCO. RESULTS In the group with poor collateral flow (grades 0-I; n = 8), BCO resulted in a downward and rightward shift of the diastolic P-V relations, where end-diastolic volume (EDV) increased by 13% (p < 0.05) without appreciable change in end-diastolic pressure (EDP; 18 +/- 6 to 18 +/- 8 mm Hg). In contrast, BCO in the group with good collateral flow (grades II-III; n = 8) shifted the diastolic P-V relations upward to the right with a concomitant increase in minimal pressure (min-P; 6 +/- 4 to 10 +/- 5 mm Hg, p < 0.05), EDP (15 +/- 7 to 21 +/- 9 mm Hg, p < 0.05) and EDV (+/- 10%, p < 0.05). Reactive hyperemia after balloon deflation caused a rapid and parallel upward shift of the diastolic P-V relations with a marked increase in min-P and EDP, especially in the group with poor collateral flow, before any improvement in LV contraction or relaxation abnormalities. CONCLUSIONS Grades of coronary filling, either retrograde or anterograde, abruptly modulate LV distensibility through the rapid scaffolding effect of coronary vascular turgor.