Toshiaki Ashihara

Iodine-123 metaiodobenzylguanidine images reflect intense myocardial adrenergic nervous activity in congestive heart failure independent of underlying cause

OBJECTIVES This study was undertaken to assess myocardial adrenergic activity using iodine-123 metaiodobenzylguanidine (MIBG) imaging in patients with heart failure. BACKGROUND In patients with congestive heart failure, adrenergic nerve activity is accelerated. However, whether myocardial adrenergic nerve activity reflects the severity of heart failure and its relation to the underlying cause have not yet been elucidated. METHODS Planar MIBG images were obtained from 96 patients with heart failure and compared with images from 9 age-matched healthy subjects. Groups 1 and 2 included 65 patients with heart failure related to impaired myocardial function and whose left ventricular ejection fraction was < 40% (group 1 = 40 patients with dilated cardiomyopathy; group 2 = 25 patients with ischemic cardiomyopathy). Group 3 included 31 patients with heart failure related to a mechanical abnormality and whose left ventricular ejection fraction was > 40% (mitral regurgitation in 16, aortic regurgitation in 9, aortic and mitral regurgitation in 4, ruptured aneurysm of Valsalva in 2). Myocardial uptake of MIBG was calculated as the heart/mediastinal activity ratio. Storage and release of MIBG were calculated as percent myocardial MIBG washout from 15 min to 4 h after isotope injection. RESULTS The heart/mediastinal activity ratio in the immediate images (15 min) showed a significant decrease only in patients with severe heart failure (groups 1 and 2). The myocardial washout was accelerated in all three heart failure groups. The level of myocardial washout was related to severity of heart failure and correlated well with New York Heart Association functional classification. CONCLUSIONS In severe heart failure associated with cardiomyopathy, norepinephrine uptake is reduced. In addition, myocardial adrenergic nerve activity is accelerated in proportion to severity of heart failure, independent of the underlying cause.

Limited maximal vasodilator capacity of forearm resistance vessels in normotensive young men with a familial predisposition to hypertension.

The study was performed to determine whether there is a structural vascular abnormality in normotensive subjects with hypertensive relatives. We examined maximal vasodilator capacity of forearm resistance vessels in 23 normotensive young men (mean blood pressure 94 ± 0.4 mm Hg, mean ± SE) with hypertensive relatives (age 24 ± 0.1 years) and in 17 normotensive subjects (mean blood pressure 85 ± 0.4 mm Hg) with no family history of hypertension (age 24 ± 0.1 years). Maximal vasodilator capacity was examined by measuring minimal vascular resistance during peak reactive hyperemia after release from 10 minutes of arterial occlusion. Minimal forearm vascular resistance after release from 10 minutes of arterial occlusion was 25% higher (P < 0.02) in subjects with hypertensive relatives (2.0 ± 0.02 units) than that in subjects with no family history (1.5 ± 0.01 units). We confirmed the previous findings that increasing metabolic vasodilator stimulus by performing intermittent handgrip exercise during 10 minutes of arterial occlusion did not augment peak dilation. This suggests that 10 minutes of arterial occlusion produced maximal vasodilation. Forearm vascular responses to ice on the forehead was greater in subjects with hypertensive relatives than those in subjects with no family history. These results suggest that there may be a structural abnormality in the forearm resistance vessels in normotensive subjects with family history of hypertension.

Characteristics of responses to salt loading and deprivation in hypertensive subjects.

The mechanisms by which high salt intake increases vascular resistance in hypertensive humans are not clear. This study examined the possibility that salt loading produces structural changes of the forearm resistance vessels in hypertensive patients. Seventeen patients with essential hypertension were given 7 days of 70 mEq and 345 mEq sodium diet. Patients were arbitrarily divided into two groups based on blood pressure response to salt loading: those whose mean blood pressure increased by more than 10% during high salt diet as compared to those on a low salt diet (salt-responsive patients, n = 8) and those who did not increase by more than 10% (salt-nonresponsive patients, n = 9). To determine whether there were structural vascular changes of the forearm resistance vessels during salt loading, we examined maximal vasodilator capacity of the forearm resistance vessels during low and high salt diets by measuring minimal forearm vascular resistance during peak reactive hyperemia following 10 minutes of arterial occlusion. Salt loading increased forearm vascular resistance (P < 0.01) and decreased maximal vasodilator capacity (P < 0.01) in saltresponsive patients but did not alter them in salt-nonresponsive patients. Forearm vascular responses to ice on the forehead or to intravenous phentolamine (10 mg) were augmented (P < 0.01) during the high salt diet in both groups, but more in salt-responsive patients than in salt-nonresponsive patients (P < 0.01). These results are consistent with the view that, in hypertensive patients who responded to salt loading with a greater rise of blood pressure, salt loading produced structural changes of the forearm resistance vessels and structural vascular changes contributed to the saltinduced increase in forearm vascular resistance.

Myocardial adrenergic nervous activity is intensified in patients with heart failure without left ventricular volume or pressure overload

OBJECTIVES To clarify whether myocardial adrenergic activity is different in patients with heart failure without left ventricular volume or pressure overload, we used iodine-123 metaiodobenzylguanidine (MIBG) imaging to study patients with mitral stenosis. BACKGROUND In patients with heart failure due to cardiomyopathy or to valve diseases with volume or pressure overload, or both, myocardial adrenergic nerve activity is accelerated independent of underlying cause. However, it is not clear whether this change in myocardial adrenergic nerve activity is present in patients without left ventricular volume or pressure overload. METHODS The study patients were 20 men and women with normal left ventricular function and heart failure due to mitral stenosis. Planar MIBG images obtained from these patients were compared with images from nine age-matched healthy subjects (control group). Myocardial uptake of MIBG was calculated as the heart/mediastinal activity ratio. Storage and release of MIBG were calculated as percent myocardial MIBG washout from 15 min to 4 h after isotope injection. All 20 study patients underwent echocardiography, and 16 underwent right heart catheterization. RESULTS The heart/mediastinal activity ratio in the immediate images (15 min) did not show any significant difference between the patient and control groups. Myocardial washout was increased in patients with severe heart failure. The level of myocardial washout correlated with left atrial diameter (r = 0.51, p = 0.02) and mitral valve area calculated with Doppler echocardiography (r = -0.61, p < 0.01) and mitral valve area calculated with cardiac catheterization (r = -0.62, p = 0.02). The closest correlation existed between myocardial washout and cardiac output (r = -0.80, p < 0.01). CONCLUSIONS In heart failure due to mitral stenosis, myocardial adrenergic nerve activity is intensified. A decrease in cardiac output associated with mitral stenosis acts as a potent stimulus for this intensification.

The effects of sublingually administered nitroglycerin on forearm vascular resistance in patients with heart failure and in normal subjects.

This study examined the effects of sublingually administered nitroglycerin on forearm resistance vessels in normal subjects (n = 9) and in patients with congestive heart failure (n = 8). Forearm blood flow was measured with a strain-gauge plethysmograph and forearm vascular resistance was calculated. To assess the magnitude of reflex forearm vasoconstriction triggered by decreased central venous pressure after sublingual nitroglycerin, lower body negative pressure (LBNP) was applied to produce a comparable decrease in central venous pressure to that after nitroglycerin. The change in forearm vascular resistance during LBNP was compared with that after nitroglycerin. In normal subjects, LBNP increased but nitroglycerin did not change forearm vascular resistance. In patients with congestive heart failure neither nitroglycerin nor LBNP changed forearm vascular resistance. The direct vasodilator effect of nitroglycerin on forearm resistance vessels assessed by the difference between the change in forearm vascular resistance produced by nitroglycerin and that during LBNP tended to be less in patients with congestive heart failure than in normal subjects, which might have resulted from decreased vasodilator capacity of resistance vessels in patients with congestive heart failure. Changes in forearm vascular resistance with a cold pressor test were not different between normal subjects and patients with congestive heart failure. These data suggest that in normal subjects, nitroglycerin does not alter forearm vascular resistance because its dilator effect is offset by reflex vasoconstriction. In patients with congestive heart failure, reflex vasoconstriction is impaired but the direct vasodilator effect of nitroglycerin also tends to be reduced, so that as a net effect forearm vascular resistance is not altered.

Digitalis-induced augmentation of cardiopulmonary baroreflex control of forearm vascular resistance.

We sought to determine whether digitalis augments cardiopulmonary baroreflex control of forearm vascular resistance in normal young men. Cardiopulmonary baroreceptor input was reduced with lower body negative pressure (LBNP) at 10 and 20 mm Hg, which decreased central venous pressure but did not alter blood pressure or heart rate. Decreases in forearm blood flow and increases in forearm vascular resistance with LBNP were greater after administration of lanatoside C (Cedilanid) than before, and the slope of the regression line relating changes in central venous pressure and those in forearm vascular resistance was steeper after lanatoside C. Vasoconstrictor responses to the cold pressor test did not differ before and after lanatoside C, which suggested that augmented responses to LBNP after the drug were not caused by a generalized change in reflex control. These results suggest that lanatoside C augments the tonic inhibitory influence of cardiopulmonary baroreceptors in normal men.

Venous responses to salt loading in hypertensive subjects.

It has been previously suggested that salt loading produces structural changes of the arteries in hypertensive patients who respond to salt loading with a greater rise of blood pressure. This study examined the possibility that salt loading alters venous distensibility in hypertensive patients. Twenty-one patients with essential hypertension were placed on a low-sodium diet (70 meq) for 7 days and then were placed on a high-sodium diet (345 meq) for 7 days. Patients were arbitrarily divided into two groups based on the response of their blood pressure to salt loading: (1) those whose mean blood pressure increased by more than 10% while on the high-salt diet as compared with those on the low-salt diet (salt-responsive patients, n = 8) and (2) those whose mean blood pressure did not increase by more than 10% (salt-nonresponsive patients, n = 13). The venous pressure-volume relationship was determined in the forearm with a water-filled plethysmograph when patients were on the low- and high-salt diet. Venous pressure-volume curves were not different between salt-responsive and salt-nonresponsive patients while on the low-salt diet. High-salt intake shifted the curve toward the pressure axis for salt-responsive patients (p less than .05) but not for salt-nonresponsive patients. Phentolamine, 1 mg administered intravenously for 5 min, did not significantly alter venous pressure-volume curves for either group while on the low- or high-salt diet. These results suggest that salt loading decreased venous distensibility in salt-responsive patients, which resulted from nonadrenergic mechanisms: structural changes of the veins could perhaps be included as one of these mechanisms.

Endogenous prostaglandins do not modulate the hindquarters vascular responses to adrenergic stimulation in rats.

The purpose of this study was to examine whether endogenous prostaglandins (PGs) modulate vascular responsiveness to adrenergic stimuli in the hindquarters of stroke-prone Spontaneously Hypertensive Rats (SHR-sp) and Wistar-Kyoto rats (WKY). Previously we have shown that synthesis of endogenous PGs in blood vessels in the rat hindquarters was greater in SHR-sp than in WKY and that high salt diet increased the level of endogenous PGs in SHR-sp but not in WKY. Vascular responses to norepinephrine (NE) and sympathetic nerve stimulation (SNS) were examined before and after indomethacin (IND), 2 mg/kg, administered intravenously. NE was administered intraarterially into the autoperfused hindquarters. Hindquarters vascular responses to these vasoconstrictor stimuli were not altered by IND in SHR-sp and WKY at the different level of endogenous PGs. These results indicate that hindquarters vasoconstriction in response to adrenergic stimuli were not altered by IND even when vascular synthesis of endogenous PGs was augmented. The results suggest that endogenous PGs do not modulate the hindquarters responses to adrenergic stimulation in rats.

Altered control of hindlimb vascular resistance by vagal afferents in spontaneously hypertensive rats. Difference in the early and late stage of hypertension.

The aim of this study was to examine whether control of vascular resistance by vagal afferents is altered in the early as well as late stage of hypertension. We examined the effects of vagotomy on hindlimb vascular resistance as well as on arterial baroreflex control of hindlimb vascular resistance in spontaneously hypertensive rats and Wistar-Kyoto rats, 12 and 35 weeks old. Vagotomy in rats with the intact baroreceptors increased hindlimb vascular resistance in all four groups. Hindlimb vascular responses to graded sympathetic nerve stimulation were closely linear up to 6 Hz in all groups, and the slope of the response was approximately 1.4 times steeper in spontaneously hypertensive than in Wistar-Kyoto rats, in both the young and old groups. The increase in hindlimb vascular resistance after vagotomy normalized by the slope of the response to sympathetic nerve stimulation was greater in young spontaneously hypertensive rats than in young Wistar-Kyoto rats, but was less in old spontaneously hypertensive rats than in old Wistar-Kyoto rats. Vagotomy increased the gain of arterial baroreflex control of hindlimb vascular resistance in young spontaneously hypertensive rats, and in two groups of Wistar-Kyoto rats, but not in old spontaneously hypertensive rats. The percent increase in the gain of arterial baroreflex control of hindlimb vascular resistance after vagotomy tended to be greater in young spontaneously hypertensive than in young Wistar-Kyoto rats, but was less in old spontaneously hypertensive than in old Wistar-Kyoto rats. Central venous pressure and left ventricular enddiastolic pressure were higher in spontaneously hypertensive than in Wistar-Kyoto rats in both young and old groups. Left atrial distensibility assessed by obtaining the atrial pressure-volume relationship was comparable between young spontaneously hypertensive and young Wistar-Kyoto rats, but was less in old spontaneously hypertensive than in old Wistar-Kyoto rats. These results indicate that vagal afferents exert tonic inhibition on control of hindlimb vascular resistance in spontaneously hypertensive as well as in Wistar-Kyoto rats, and that tonic inhibitory influence of afferents on control of hindlimb vascular resistance is altered in spontaneously hypertensive rats, augmented in young, but attenuated in old, spontaneously hypertensive rats, compared with that in age-matched Wistar-Kyoto rats. It is considered that altered control of vascular resistance by vagal afferents in spontaneously hypertensive rats may result from changes in vagal afferent activity.

Effects of trapidil on forearm veins and arteries in man

To understand the mechanisms of antianginal effects of trapidil, we examined the effects of trapidil, 100 mg i.v., on forearm veins and arteries in nine young healthy volunteers and compared the results with those of nitroglycerin, 0.3 mg s.1. At the doses used in the study, which are those in clinical use, trapidil and nitroglycerin increased forearm venous distensibility (p < 0.05 for both) and decreased central venous pressure (CVP; p < 0.01 for both). These results suggest that both drugs dilate veins. Forearm vascular resistance was decreased by trapidil but not by nitroglycerin. To examine the possibility that reflex vasoconstriction triggered by the decrease in CVP counteracted the direct vasodilator effect of the drugs, we studied the relationship between CVP and forearm vascular resistance while altering CVP by lower body negative pressure. Forearm vascular resistance at a comparable level of CVP was less after than before trapidil or nitroglycerin. These results suggest that both trapidil and nitroglycerin dilate forearm arteries in humans. Thus, we conclude that at a clinical dose, trapidil, as well as nitroglycerin, dilates forearm veins and arteries in humans.