Hirofumi Yasue

Localization and mechanism of secretion of B-type natriuretic peptide in comparison with those of A-type natriuretic peptide in normal subjects and patients with heart failure.

B-type or brain natriuretic peptide (BNP) is a novel natriuretic peptide secreted from the heart that forms a peptide family with A-type or atrial natriuretic peptide (ANP), and its plasma level has been shown to be increased in patients with congestive heart failure. This study was designed to examine the sources and mechanisms of the secretion of BNP in comparison with those of ANP in control subjects and in patients with heart failure. Methods and ResultsWe measured the plasma levels of BNP as well as ANP in 16 patients with dilated cardiomyopathy (11 men and 5 women; mean age, 59 years) and 18 control subjects (9 men and 9 women; mean age, 54 years) by sampling blood from the femoral vein, the aortic root, the anterior interventricular vein (AIV), and the coronary sinus using the newly developed immunoradiometric assay systems. In the control subjects, there was no significant difference in the plasma ANP level between the aortic root and the AIV (24.0±5.2 pg/mL versus 32.2±17.0 pg/mL), but there was a highly significant step-up of the level between the AIV and the coronary sinus (32.2±17.0 pg/mL versus 371.4±111.1 pg/mL, P < .001). In contrast, there was a significant step-up of the plasma BNP level between the aortic root and the AIV (8.6±6.4 pg/mL versus 19.0±11.5 pg/mL, P < .01) but not between the AIV and the coronary sinus (19.0±11.5 pg/mL versus 28.8±14.0 pg/mL). On the other hand, in patients with dilated cardiomyopathy, there was a significant step-up in the plasma ANP level between the aortic root and the AIV (280.6±183.7 pg/mL versus 612.3±431.6 pg/mL, P < .01) and between the AIV and the coronary sinus (612.3 ±431.6 pg/mL versus 1229.0±772.7 pg/mL, P < .01). There was a significant step-up in the plasma BNP level between the aortic root and the AIV (268.4±293.2 pg/mL versus 511.6±458.1 pg/mL, P < .01) but not between the AIV and the coronary sinus (511.6±458.1 pg/mL versus 529.7±455.3 pg/mL) in patients with dilated cardiomyopathy. The arteriovenous difference at the AIV of the plasma level of BNP had a significant positive correlation with left ventricular end-systolic volume index (r=0.859, P < .001) and a significant negative correlation with left ventricular ejection fraction (r= −.735, P < .001). ConclusionsWe conclude that (1) BNP is secreted mainly from the left ventricle in normal adult humans as well as in patients with left ventricular dysfunction, whereas ANP is secreted from atria in normal adult humans and also from the left ventricle in patients with left ventricular dysfunction; (2) secretion of BNP as well as ANP from the left ventricle increases in proportion to the severity of the left ventricular dysfunction, suggesting that the secretions of ANP and BNP from the left ventricle are regulated mainly by wall tension of the left ventricle; and (3) the peripheral plasma levels of ANP and BNP reflect the secretion rate of these hormones from the left ventricle and may be used as a marker of the degree of left ventricular dysfunction in patients with left ventricular dysfunction.

Hyperglycemia Rapidly Suppresses Flow-Mediated Endothelium- Dependent Vasodilation of Brachial Artery

OBJECTIVES We examined whether endothelial dysfunction occurs when acute hyperglycemia is induced by oral glucose loading. BACKGROUND Endothelial dysfunction has been shown to occur in patients with diabetes mellitus (DM), and chronic hyperglycemia is implicated as a cause of endothelial dysfunction. However, in many patients with Type 2 DM and in those with impaired glucose tolerance (IGT), fasting blood glucose may be within normal limits, and hyperglycemia occurred only post-prandially. METHODS With ultrasound technique, we measured flow-mediated endothelium-dependent vasodilation during oral glucose tolerance test in 58 subjects: (17 patients with normal glucose tolerance [NGT], 24 with IGT, and 17 with type 2 DM). In addition, we measured the levels of thiobarbituric acid reactive substances (TBARS) and nitrite/nitrate. RESULTS Flow-mediated vasodilation decreased after glucose loading (NGT: 7.53+/-0.40, 4.24+/-0.28 and 6.35+/-0.40, in fasting, at 1- and 2-h, respectively, IGT: 6.50+/-0.48, 1.40+/-0.41** and 4.00+/-0.47*, respectively; DM: 4.77+/-0.37, 1.35+/-0.38** and 1.29+/-0.29%**, respectively; *p < 0.01 vs. fasting, **p < 0.005 vs. fasting). The TBARS concentration increased in parallel with plasma glucose level in each group (NGT: 1.43+/-0.07, 2.03+/-0.12 and 1.80+/-0.12, respectively; IGT: 1.65+/-0.11, 2.46+/-0.12** and 1.94+/-0.08*, respectively; DM: 1.73+/-0.07, 2.34+/-0.08** and 2.47+/-0.09** nmol/ml, respectively; *p < 0.05 vs. fasting, **p < 0.01 vs. fasting). Glucose loading did not change nitrite/nitrate concentration in any of the groups. CONCLUSIONS Hyperglycemia in response to oral glucose loading rapidly suppresses endothelium-dependent vasodilation, probably through increased production of oxygen-derived free radicals. These findings strongly suggest that prolonged and repeated post-prandial hyperglycemia may play an important role in the development and progression of atherosclerosis.

Different secretion patterns of atrial natriuretic peptide and brain natriuretic peptide in patients with congestive heart failure.

BackgroundThe plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are increased in relation to the severity of congestive heart failure (CHF). This study was designed to examine whether the secretion patterns of ANP and BNP vary with underlying cardiac disorders of CHF with different degrees of overload in atria and ventricles. Methods and ResultsWe measured plasma levels ofANP and BNP in the aorta in 20 patients with mitral stenosis (MS) in whom atria are mainly overloaded, 30 patients with dilated cardiomyopathy (DCM) in whom both atria and ventricles are overloaded, and 20 control subjects during cardiac catheterization. Pulmonary capillary wedge pressure (PCWP) was significantly higher in the MS and DCM groups (16.7±4.7 mm Hg and 15.1±7.7 mm Hg, respectively) than in the control group (7.2±+1.1 mm Hg, p<0.01), whereas there was no significant difference between the MS and DCM groups. Left ventricular end-diastolic pressure (LVEDP) was significantly higher in the DCM group than in the MS group (16.4±7.8 mm Hg versus 7.6±2.0 mm Hg, p<0.01), and the level was comparable between the MS and control groups (7.6±2.0 mm Hg versus 6.8 ± 1.2 mm Hg, p=NS). The plasma ANP level was significantly higher in the MS and DCM groups (356+ 169 pg/ml and 331±323 pg/ml, respectively) than in the control group (98±41 pg/ml, p<0.01), whereas there was no significant difference between the MS and DCM groups. The plasma BNP level was significantly higher in the DCM group than in the MS group (333±405 pg/ml versus 147±54 pg/ml, p<0.01), and the level was significantly higher in the MS group than in the control group (147±54 pg/ml versus <10 pg/ml, p<0.01). The plasma levels ofANP and BNP had a highly positive correlation with PCWP in the DCM group (p<0.01). On the other hand, in the MS group, the plasma ANP level had a highly significant correlation with PCWP (p<0.01) but the plasma BNP level did not. ConclusionWe conclude that plasma levels of BNP mainly reflect the degree of ventricular overload and that the secretion patterns of ANP and BNP vary with underlying cardiac disorders of CHF with different degrees of overload in atria and ventricles.

Increased plasma levels of brain natriuretic peptide in patients with acute myocardial infarction.

BackgroundBrain natriuretic peptide is a novel natriuretic peptide that is secreted predominantly from the ventricles, and its plasma levels have been shown to be markedly increased in patients with chronic congestive heart failure. This study was designed to examine the plasma levels of brain natriuretic peptide as well as atrial natriuretic peptide in patients with acute myocardial infarction. Methods and ResultsWe examined the plasma levels of brain natriuretic peptide as well as atrial natriuretic peptide in 50 consecutive patients (36 men and 14 women; mean age, 66 years) with acute myocardial infarction over the time course of 4 weeks. The plasma level of brain natriuretic peptide was significantly increased on admission in patients with acute myocardial infarction compared with controls (92±28 versus 5.2±0.5 pg/mL, p<.01) and reached the peak level of 319±58 pg/mL at 16.4±0.7 hours after admission. Thereafter, the level decreased and then again increased, forming the second peak of 277±66 pg/mL on day 5. The level then decreased gradually but was still much higher in the fourth week than that of controls (149±47 versus 5.2±0.5 pg/mL, p<.001). On the other hand, the plasma atrial natriuretic peptide level already had been increased at the time of admission compared with controls (116±14 versus 39.5±2.6 pg/mL, p<.01) and decreased thereafter, again increasing and making a small peak on day 2 to 3. The time course of the plasma brain natriuretic peptide level could be divided into two patterns: a monophasic pattern with one peak at about 16 hours after admission and a biphasic pattern with two peaks at about 16 hours and 5 days after admission. There were significantly more patients with anterior infarction, congestive heart failure, higher level of maximal creatine kinase-MB isoenzyme, and lower left ventricular ejection fraction in the biphasic group than in the monophasic group. ConclusionWe conclude that the plasma level of brain natriuretic peptide is increased markedly in patients with acute myocardial infarction and may reflect the degree of left ventricular dysfunction in these patients.

Endothelial Nitric Oxide Synthase Gene Is Positively Associated With Essential Hypertension

Essential hypertension has a genetic basis. Accumulating evidence, including findings of elevation of arterial blood pressure in mice lacking the endothelial nitric oxide synthase (eNOS) gene, strongly suggests that alteration in NO metabolism is implicated in hypertension. There are, however, no reports indicating that polymorphism in the eNOS gene is associated with essential hypertension. We have identified a missense variant, Glu298Asp, in exon 7 of the eNOS gene and demonstrated that it is associated with both coronary spastic angina and myocardial infarction. To explore the genetic involvement of the eNOS gene in essential hypertension, we examined the possible association between essential hypertension and several polymorphisms including the Glu298Asp variant, variable number tandem repeats in intron 4 (eNOS4b/4a), and two polymorphisms in introns 18 and 23. We performed a large-scale study of genetic association using two independent populations from Kyoto (n=458; 240 normotensive versus 218 hypertensive subjects) and Kumamoto (n=421; 223 normotensive versus 187 hypertensive subjects), Japan. In both groups, a new coding variant, Glu298Asp, showed a strong association with essential hypertension (Kyoto: odds ratio, 2.3 [95% confidence interval, 1.4 to 3.9]; Kumamoto: odds ratio, 2.4 [95% confidence interval, 1.4 to 4.0]). The allele frequencies of 298Asp in hypertensive subjects were significantly higher than those in normotensive subjects in both groups (Kyoto: 0.103 versus 0.050, P<0.0017; Kumamoto: 0.120 versus 0.058, P<0.0013, respectively). No such disequilibrium between genotypes was significantly associated with any other polymorphisms we examined; the Glu298Asp variant was also not linked to any other polymorphisms. In conclusion, the Glu298Asp missense variant was significantly associated with essential hypertension, which suggests that it is a genetic susceptibility factor for essential hypertension.

Induction of coronary artery spasm by acetylcholine in patients with variant angina: possible role of the parasympathetic nervous system in the pathogenesis of coronary artery spasm.

We injected acetylcholine (ACh), the neurotransmitter of the parasympathetic nervous system, into the coronary arteries of 28 patients with variant angina. Injection of 10 to 80 micrograms ACh into the coronary artery responsible for the attack induced spasm together with chest pain and ST segment elevation or depression on the electrocardiogram in 30 of the 32 arteries of the 25 of the 27 patients. The injection of 20 to 100 micrograms ACh into the coronary artery not responsible for the attack in 18 patients resulted in various degrees of constriction in most of them, but no spasm in any of them. After intravenous injection of 1.0 to 1.5 mg atropine sulfate, the injection of ACh into the coronary artery responsible for the attack did not induce spasm or attack in any of the nine coronary arteries injected in eight patients. We conclude that the intracoronary injection of ACh induces coronary spasm and attack in patients with variant angina and that the activity of the parasympathetic nervous system may play a role in the pathogenesis of coronary spasm. We also conclude that the intracoronary injection of ACh is a useful test for provocation of coronary spasm.

Circadian variation of exercise capacity in patients with Prinzmetal's variant angina: role of exercise-induced coronary arterial spasm.

Thirteen patients with Prinzmetals variant angina performed treadmill exercise tests in the early morning in the afternoon of the same day. The attacks with ST elevation were induced repeatedly in all 13 patients in the early morning, but in only two patients in the afternoon. Propranolol did not suppress the exercise-induced attacks in all 13 patients. Diltiazem suppressed the attacks in all 13 patients phentolamine in eight of the nine patients. Coronary arteriograms demonstrated that spasm occluding completely or almost completely the large coronary artery supplying the area of myocardium showing ST elevation appeared during the attacks disappeared along with the attacks after nitroglycerin administration in all four patients in whom the attacks were induced by arm exercise in the catheterization laboratory. We conclude that there is circadian variation of exercise capacity in patients with Prinzmetals variant angina caused by coronary arterial spasm induced by exercise in the early morning but not in the afternoon.

Rapid Ventricular Induction of Brain Natriuretic Peptide Gene Expression in Experimental Acute Myocardial Infarction

BACKGROUND We have demonstrated that brain natriuretic peptide (BNP) is a cardiac hormone predominantly synthesized in and secreted from the ventricle. We have also reported that, compared with atrial natriuretic peptide (ANP), the plasma concentration of BNP is increased to a greater degree in patients with congestive heart failure and more rapidly in patients with acute myocardial infarction (AMI). METHODS AND RESULTS To investigate ventricular gene expression of BNP in AMI, we analyzed plasma and ventricular BNP concentrations along with ventricular BNP mRNA in rats with AMI produced by coronary artery ligation. The BNP concentration in the left ventricle increased about 2-fold as early as 12 hours postinfarction and 5-fold 1 day postinfarction compared with sham-operated rats, whereas left ventricular ANP concentration remained unchanged within 1 day. The tissue concentration of BNP increased in the noninfarcted region as well as in the infarcted region. The surviving myocytes in and around the necrotic tissues in the infarcted region were intensely stained with the anti-BNP antiserum, indicating augmented production in the remaining myocytes in the infarcts. The BNP concentration in the right ventricle also increased about 10-fold 12 hours postinfarction, whereas the ANP concentration remained unchanged within 12 hours. Northern blot analysis revealed that BNP mRNA expression was augmented 3-fold in the left ventricle as early as 4 hours postinfarction. In contrast, ANP mRNA expression was unchanged. Reflecting the rapid induction of ventricular BNP production, the plasma BNP concentration rose to about 100 pg/mL 12 hours postinfarction (sham-operated rats, < 70 pg/mL). CONCLUSIONS These results demonstrate the rapid induction of ventricular BNP gene expression in rats with AMI compared with ANP and suggest that BNP gene expression in the ventricle is regulated distinctively from ANP gene expression against acute ventricular overload. They also suggest that the BNP gene can be one of the acutely responsive cardiac genes for the ventricular overload and suggest a possible pathophysiological role of BNP distinct from ANP in AMI.

Prinzmetal's variant form of angina as a manifestation of alpha-adrenergic receptor-mediated coronary artery spasm: Documentation by coronary arteriography

In four patients with Prinzmetals variant form of angina, the attack was induced by the combined administration of epinephrine (0.4 to 0.5 mg, given subcutaneously at 7:30 to 8:00 A.M.) and propranolol (40 mg. given orally at 5:00 A.M.). Selective coronary cinearteriography was done before, during, and after the attack with constant monitoring of the ECG and blood pressure. Severe spasm of the right coronary artery occurred at the proximal portion in association with ST-segment elevation in Lead III during the attack and disappeared with the subsidence of the attack in all of them. These results strongly suggest that severe spasm of a large coronary artery mediated by alpha-adrenergic receptors is responsible for the attack of Prinzmetals variant form of angina.

Role of Autonomic Nervous System in the Pathogenesis of Prinzmetal's Variant Form of Angina

In ten patients with Prinzmetals variant form of angina the effects of various drugs were assessed: subcutaneous injection of methacholine (10 mg), atropine (0.7 mg), and epinephrine (0.7 mg); intravenous infusion of isoproterenol (20-25 &mgr;g/min); and in the three of the above patients who were having recurrent spontaneous attacks at the time of the examination, oral administration of atropine (0.6-1.2 mg), propranolol (30-90 mg), and phenoxybenzamine (10 mg in one patient). Masters triple two-step test and selective coronary arteriography were done on all the patients.In the three patients who were having spontaneous attacks at the time of the examination, the administration of methacholine induced the attacks and that of atropine suppressed the attacks. Epinephrine induced the attacks in two patients and propranolol was without effect in suppressing the attacks. Phenoxybenzamine (in one patient) suppressed the attacks. Neither Masters triple two-step test nor isoproterenol infusion precipitated the attacks, though heart rate increased to more than 110 beats/min and 160 beats/min respectively in all the patients. Coronary arteriograms were normal in seven of the ten patients.It is concluded that enhanced activity of the parasympathetic nervous system, which occurs at rest, is involved in the initiation of the attack by stimulating the sympathetic nerve which in turn probably induces coronary arterial spasm by way of activating alpha (vasoconstrictor) receptors present in the large coronary arteries.