Clinical implications of cardiac (123)I-meta-iodobenzylguanidine scintigraphy and cardiac natriuretic peptides in patients with heart disease.

The purpose of this study was to evaluate whether or not cardiac sympathetic nerve activity, using (123)I-meta-iodobenzylguanidine ((123)I-MIBG) imaging, and cardiac natriuretic peptides (atrial and brain, ANP and BNP) were independent predictors of cardiac events, and, if so, which was the stronger predictor. Planar (123)I-MIBG images were obtained from 62 patients with heart disease. Plasma ANP and BNP levels, left ventricular ejection fraction (LVEF) by echocardiography, serum total cholesterol and triglyceride were measured. (123)I-MIBG was assessed as the heart-to-mediastinum (H/M) ratio of the delayed image and the washout rate (WoR) from the early to the delayed image. Patients were followed up for an average of 16.2 months, and 12 of 62 patients had cardiac events. Patients with events had significantly lower LVEF and H/M ratio compared with those without events. They had significantly higher WoR, ANP and BNP. By multivariate Cox proportional hazard analysis, (123)I-MIBG (H/M or WoR), ANP and BNP were independent predictors for cardiac events. Event-free survival using a Kaplan-Meier model, with a threshold value of 2.0 for H/M and 45% for WoR, showed that patients with H/M<2.0 and/or WoR>45% had a significantly poorer prognosis. These results suggest that (123)I-MIBG imaging and cardiac natriuretic peptides are useful tools for the evaluation of patients with heart disease, and that cardiac sympathetic nerve activity is a stronger predictor of cardiac events.

Angiotensin-(1-7) attenuates vasoconstriction evoked by angiotensin II but not by noradrenaline in man.

Angiotensin-(1-7) has been suggested to be a novel vasodilating peptide. We investigated the direct vascular effect of angiotensin-(1-7) in human forearm resistant vessels, particularly with regard to the interaction with angiotensin II, in healthy normotensive men by strain-gauge venous occlusion plethysmography with intra-arterial infusions of peptides. Intra-arterial infusion of angiotensin-(1-7) at 0.1 to 2000 pmol/min did not cause vasodilatation but rather reduced forearm blood flow by approximately 10% at the highest dose. A placebo-controlled study showed that angiotensin-(1-7) at 0.5 to 40 nmol/min caused weak but significant vasoconstriction (P=0.0016 by ANOVA). Angiotensin-(1-7) at 100 pmol/min, but not at 10 pmol/min, significantly shifted the angiotensin II dose-response curve toward the right (mean+/-SD of percent changes in forearm blood flow: -19+/-17%, -33+/-22%, -55+/-12%, -63+/-10%, and -68+/-5% at 5, 10, 25, 50, and 100 pmol/min of angiotensin II, respectively, with saline; 5+/-13%, 0. 9+/-18%, -40+/-16%, -54+/-9%, and -61+/-6% with angiotensin-(1-7), P=0.0021 by ANOVA). Angiotensin-(1-7) did not affect the dose-response curve of noradrenaline [3+/-12%, 5+/-16%, -20+/-22%, -31+/-18%, and -40+/-12% at 25, 50, 100, 300, and 600 pmol/min of noradrenaline, respectively, with saline; -4+/-15%, -2+/-23%, -29+/-22%, -34+/-16%, and -42+/-9% with angiotensin-(1-7)]. Our results suggest that angiotensin-(1-7) antagonizes vasoconstriction by angiotensin II in human resistant vessels and might act as an endogenous angiotensin II antagonist.

[Clinical usefulness of myocardial iodine-123-15-(p-iodophenyl)-3(R,S)-methyl-pentadecanoic acid distribution abnormality in patients with mitochondrial encephalomyopathy based on normal data file in bull's-eye polar map].

Visual interpretation of iodine-123-beta-15-(p-iodophenyl)-3(R,S)-methyl-pentadecanoic acid (123I-BMIPP) myocardial images cannot easily detect mild reduction in tracer uptake. Objective assessment of myocardial 123I-BMIPP maldistributions at rest was attempted using a bull's-eye map and its normal data file for detecting myocardial damage in patients with mitochondrial encephalomyopathy. Six patients, two with Kearns-Sayre syndrome and four with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and 10 normal subjects were studied. Fractional myocardial uptake of 123I-BMIPP was also measured by dynamic static imaging to assess the global myocardial free fatty acid. These data were compared with the cardiothoracic ratio measured by chest radiography and left ventricular ejection fraction assessed by echocardiography. Abnormal cardiothoracic ratio and lower ejection fraction were detected in only one patient with Kearns-Sayre syndrome. Abnormal fractional myocardial uptake was detected in two patients (1.61%, 1.91%), whereas abnormal regional 123I-BMIPP uptake assessed by the bull's-eye map was detected in five patients (83%). All patients showed abnormal uptake in the anterior portion, and one showed progressive atrioventricular conduction abnormality and systolic dysfunction with extended 123I-BMIPP abnormal uptake. The results suggest that assessment based on the normal data file in a bull's-eye polar map is clinically useful for detection of myocardial damage in patients with mitochondrial encephalomyopathy.

Percutaneous transluminal mitral valvuloplasty normalizes baroreflex sensitivity and sympathetic activity in patients with mitral stenosis.

BACKGROUND: In patients with mitral stenosis, reduced cardiac output or altered pulmonary hemodynamics may increase sympathetic nerve activity. However, the magnitude of the increase in sympathetic activity in such patients and the effect of valvuloplasty on this activity are unknown. METHODS AND RESULTS: We microneurographically measured muscle sympathetic nerve activity before and after mitral valvuloplasty in 10 patients (mean+/-SEM age, 48+/-2 years) with mitral stenosis and in 10 healthy volunteers (47+/-4 years); hemodynamic variables were also measured. Baroreflex sensitivity was assessed on the basis of the ratio of the change in heart rate or muscle sympathetic activity to the change in mean arterial pressure during intravenous infusion of sodium nitroprusside or phenylephrine. At baseline, muscle sympathetic activity was significantly higher in the patients with mitral stenosis than in the control subjects (42.1+/-3.2 versus 26.1+/-3.7 bursts/min, P<.05). However, there was no significant difference between the groups in sympathetic activity at 1 week after valvuloplasty. The reduction in sympathetic activity after valvuloplasty was maintained for > or = 6 months and correlated with the increase in cardiac index (r=.74, P<.05). Baroreflex sensitivity was significantly lower in the patients than in the control subjects, but after valvuloplasty there was no significant difference in baroreflex sensitivity between the groups. CONCLUSIONS: Sympathetic activity is increased in patients with mitral stenosis. Mitral valvuloplasty in such patients results in early and long-lasting normalization of sympathetic nerve activity, possibly because of an improvement in arterial baroreflex sensitivity.

[Assessment of auscultatory blood pressure measurements versus intra-arterial pressure in patients with atrial fibrillation].

The accuracy of auscultatory blood pressure (BP) determination was assessed in patients with chronic atrial fibrillation by performing simultaneous auscultatory BP determination on the upper arm and a direct BP determination on the contralateral arm. The subjects were three hospitalized patients, aged from 52 to 75 years. A Teflon catheter was introduced into the radial artery which was connected to a pressure transducer, and a cuff was twisted around the contralateral upper arm in the supine position. Simultaneous recording of directly determined BP and cuff pressure enabled the comparison of direct BP with auscultatory BP. The appearance of the Korotkoff I sound (systolic BP) and V sound (diastolic BP) was marked on the cuff pressure curve. This maneuver was repeated five times in each patient. The method of Bland and Altman was employed to assess the agreement between auscultatory and direct determinations. The auscultatory method estimated BP with differences of -14.3 to +27.3 mmHg in systolic BP and -12.1 to +11.9 mmHg (+/-2SD) in diastolic BP compared with the direct method. The difference in systolic BP between the auscultatory and the direct methods was greater than that in diastolic BP. Thus, there are unacceptable differences in systolic BP between auscultatory and direct methods that can be attributed to BP fluctuations. The auscultatory method in diastolic BP is more accurate than that in systolic BP and may be more useful in the clinical setting.

Effect of doxazosin therapy on glucose tolerance and lipid metabolism in hypertensive patients with impaired glucose tolerance.

The effects of long-term monotherapy with doxazosin, an alpha 1-blocker, or placebo on blood pressure (BP), glucose tolerance, and serum lipid levels were investigated prospectively in 43 hypertensive patients with impaired glucose tolerance. The levels of plasma glucose, serum lipids, fructosamine, and glycated hemoglobin A1c (Hb A1c) were determined before and during long-term (mean treatment period, 6.7 months) therapy with doxazosin (n = 23) or placebo (n = 20). A 75-g oral glucose tolerance test was performed before and during therapy. Significant decreases in both systolic and diastolic BP were maintained during doxazosin therapy; BP did not change in the placebo group. Neither fasting nor post-glucose-load venous plasma glucose levels were altered, and there was no significant change in the insulinogenic index in either group. Glucose intolerance was slightly improved with significant reductions in Hb A1c and fructosamine levels during doxazosin therapy. Serum total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol levels were significantly decreased, and high-density lipoprotein cholesterol levels were significantly increased in patients treated with doxazosin. Moreover, TC, LDL cholesterol, and apolipoprotein B levels were significantly decreased in patients with hypercholesterolemia (TC > or = 5.69 mmol/L). In contrast, there were no significant changes in Hb A1c, fructosamine, and lipid levels in the placebo group. These results suggest that long-term doxazosin therapy may improve glucose and lipid metabolism in hypertensive patients. Doxazosin appears useful as an antihypertensive agent for hypertensive patients with either impaired glucose metabolism or dyslipidemia.

[A case of mitochondrial cardiomyopathy with heart failure, sick sinus syndrome and diabetes mellitus: mitochondrial DNA adenine-to-guanine transition at 3243 of mitochondrial tRNA(LEU)(UUR) gene].

A 42-year-old woman with diabetes mellitus lost consciousness and was transferred to the Yokohama City University Hospital. Blood chemistry findings indicated low blood sugar levels and chest X-ray examination revealed cardiomegaly and bilateral pleural effusions. These clinical abnormalities were corrected by treatment with glucose, diuretics, angiotensin converting enzyme inhibitor and digitalis. Cardiological laboratory examinations were performed after admission. Electrocardiography revealed first degree atrioventricular block and incomplete right bundle branch block. Ultrasonography showed lower grade of ejection fraction and diffuse hypokinesis of the cardiac wall. After admission, sinus arrest suddenly occurred. The diagnosis was sick sinus syndrome. Scintigraphy using iodine-123 betamethyl-p-iodophenyl-pentadecanoic acid showed abnormal mottled defects. Coronary angiography found no significant stenosis of the coronary artery. Electron microscopy showed abnormally shaped mitochondrial accumulations in an endomyocardial biopsy specimen. Mitochondrial DNA amplification by polymerase chain reaction followed by restriction enzyme Apa I digestion revealed adenine-to-guanine transition at 3243 of the mitochondrial tRNA(LEU)(UUR) gene.

Alpha 1-adrenergic receptors in cardiac ventricles of Dahl rats.

This study was designed to examine the effects of sex, age, and a high-salt diet on cardiac alpha 1-adrenoceptors in an animal model of genetic hypertension, the Dahl salt-sensitive rat. Ventricular alpha 1-adrenoceptors were measured by radioligand binding with [3H]prazosin in membrane fractions in Dahl S and R rats of 7, 12, and 15 weeks of age. In both S and R rats, the maximal binding (Bmax) of alpha 1-adrenoceptor binding was greater in male than in female rats. The Bmax decreased with age in both the S and R strains; at 12 weeks of age, Bmax was approximately one-half of that observed at 7 weeks of age in both S and R strains. In the rats fed a high-salt diet, the Bmax tended to be greater in S rats than in R rats at 12 weeks of age and this difference became significant at 15 weeks of age. A significant positive correlation was found between the Bmax and the heart-to-body weight ratio in the Dahl S and R rats. The dissociation constant (Kd) was not different between male S and R rats at each age. These results suggest that the ventricular alpha 1-adrenoceptor may be involved in cardiac hypertrophy in Dahl rats.

Effect of an angiotensin receptor antagonist, TCV-116, on sympathetic nerve activity in patients with essential hypertension.

The effects of an angiotensin II receptor (AT1) antagonist on sympathetic nervous responses to a mental arithmetic task and a cold pressor test were investigated using a placebo-controlled, single-blind design in 8 patients with essential hypertension (53 +/- 3 years). All patients received a placebo for 2 weeks (placebo run-in period), after which the control group (P; n = 4) continued to receive the placebo, while the experimental group (TCV; n = 4) received TCV-116 at 4 mg/day for 4 weeks (treatment period). After basal measurements were carried out, an arithmetic task and a cold pressor test were conducted on the last day of each period. Blood pressure (BP), heart rate (HR) and electrocardiogram (ECG) were continuously monitored. Muscle sympathetic nerve activity (MSNA) was assessed by determining the burst rate of the mean voltage neurogram obtained from the tibial nerve. Sympathovagal balance was also assessed, by determining the area ratio of the low frequency (LF: 0.05-0.15 Hz) to high frequency bands (HF: 0.16-0.5 Hz) of a power spectral analysis of HR variability (maximum entropy method). During the placebo run-in period, there were no significant differences in basal BP, HR, LF/HF or MSNA between the two groups. During the treatment period, basal mean BP in the TCV group was significantly lower (p < 0.05) than that in the P group, but there were no significant differences in basal HR, LF/HF or MSNA between the two groups. Although the arithmetic stress significantly increased BP, HR and LF/HF in both groups, MSNA was not significantly altered in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Depressor effects and pharmacokinetics of single and consecutive doses of delapril in hypertensive patients with normal or impaired renal function.

The antihypertensive effects and pharmacokinetic properties of delapril, an angiotensin-converting enzyme (ACE) inhibitor, were investigated in hypertensive patients with normal renal function (NRF; n = 6) and in those with impaired renal function (IRF; n = 5). A 15-mg oral dose of delapril was given once on the first and last days, and twice daily on the other days. The measurement of blood pressure and sampling were done at 0, 1, 2, 4, 6, 12, and 24 hours postdose on the first and last days of treatment. Plasma and urinary concentrations of delapril and its metabolites were measured by HPLC. ACE activity was suppressed from 1 hour after the first dose to 24 hours after the last dose of delapril in both the NRF and IRF groups. During the consecutive dosing, significant BP falls were observed from 1 hour postdose of delapril to 24 hours in the NRF group and to 6 hours in the IRF group. Peak plasma concentrations of 5-hydroxydelapril diacid and areas under the plasma concentration-time curve (AUC) of both delapril diacid and 5-hydroxydelapril diacid in the IRF group were significantly higher (p less than 0.001 or 0.05) than in the NRF group. No significant increase of pharmacokinetic parameters in repeated dosing was observed in both the NRF and IRF groups. Significant positive correlations (p less than 0.001) were found between the inverse of creatinine clearance and the AUCs of the active diacid metabolites in single and consecutive doses.