Hiroyuki Miyakoda

Catecholamines, Renin-Angiotensin-Aldosterone System, and Atrial Natriuretic Peptide at Rest and During Submaximal Exercise in Patients With Congestive Heart Failure

The aim of this study was to determine the responses of plasma catecholamines, renin-angiotensin-aldosterone (RAA) activity, and plasma atrial natriuretic peptide (ANP) to exercise in patients with congestive heart failure (CHF). Cardiac and neurohormonal responses were assessed during submaximal treadmill exercise testing in 23 patients with CHF (New York Heart Association classes I-III) and 13 control subjects (without CHF). Plasma norepinephrine, epinephrine, renin activity (PRA), angiotensin II (ATII), aldosterone, and ANP were measured at rest and immediately after exercise. Exercise duration was shorter in patients with CHF (control, 10.4 +/- 0.9 minute; CHF, 6.2 +/- 0.7 minute; P < 0.01). Heart rate and blood pressure responses were similar except for the smaller peak heart rate (control, 145 +/- 5 beats per minute; CHF, 129 +/- 4 beats per minute; P < 0.05) and higher systolic blood pressure at recovery stage (control, 122 +/- 4 mm Hg; CHF, 142 +/- 4 mm Hg; P < 0.01) in patients with CHF. At rest, plasma norepinephrine levels were insignificantly higher in patients with CHF (control, 110 +/- 10 pg/mL; CHF, 170 +/- 26 pg/mL; P = 0.09), and ANP levels (control, 40 +/- 5 pg/mL; CHF, 94 +/- 17 pg/mL; P < 0.05) and PRA levels (control, 0.77 +/- 0.11 ng/mL/hr; CHF, 4.33 +/- 1.25 ng/mL/hr; P < 0.05) were significantly higher. There were no differences in peak norepinephrine, epinephrine, or ANP between the two groups. Angiotensin II and aldosterone levels were similar between the two groups, although, in patients with CHF, there was a trend toward higher levels of ATII while at rest (control, 12.4 +/- 1.4 pg/mL; CHF, 20.3 +/- 3.3 pg/mL; P = 0.08) and at peak (control, 20.5 +/- 1.8 pg/mL; CHF, 41.0 +/- 9.4 pg/mL; P = 0.10). Peak values of PRA, ATII, and aldosterone positively correlated with respective resting values of PRA (r = 0.88 ng/mL/hr, P < 0.01), ATII (r = 0.63 pg/mL, P < 0.01), and aldosterone (r = 0.99, P < 0.01). Peak norepinephrine and peak ANP also positively correlated with respective resting values of norepinephrine (r = 0.58 pg/mL, P < 0.05) and ANP (r = 0.94, P < 0.01). Analysis of these results showed that patients with CHF had significantly higher levels of PRA and ANP at rest, and a trend toward augmentation in RAA system activity during exercise with less exercise workload. Basal level of neurohormones seemed to be an important determinant for the degree of exercise-induced neurohormonal activation in patients with CHF.

Responses of plasma norepinephrine and renin-angiotensin-aldosterone system to dynamic exercise in patients with congestive heart failure

BACKGROUND Neurohormonal activation is present and neurohormonal responses to dynamic exercise are altered in congestive heart failure (CHF). Responses of plasma norepinephrine in various degrees of heart failure have been investigated, but the responses of the renin-angiotensin-aldosterone system have not been studied in relation to the severity of CHF. The aim of this study was to determine if the responses of the renin-angiotensin-aldosterone system to exercise are augmented according to the severity of CHF. METHODS AND RESULTS Ventilatory and neurohormonal responses were assessed in 38 patients with CHF (New York Heart Association class: I, 13 patients; II, 14 patients; III, 11 patients) and 11 normal subjects during symptom-limited cardiopulmonary exercise testing. Plasma norepinephrine, renin activity, angiotensin II, and aldosterone were measured at rest and at peak exercise. The increments in neurohormones were divided by peak oxygen consumption, and these ratios (norepinephrine exercise ratio, plasma renin activity-exercise ratio, angiotensin II-exercise ratio, aldosterone-exercise ratio) were compared among groups. Peak oxygen consumption and anaerobic threshold decreased progressively with the severity of CHF. Neurohormonal profiles at rest showed that plasma norepinephrine levels were significantly higher, and the renin-angiotensin-aldosterone system was augmented only in patients with class III CHF. Neurohormones increased during exercise both in patients with CHF and in normal subjects, but patients with class III CHF had significantly higher plasma renin activity (10.11 +/- 2.32 ng/mL/h), angiotensin II (73.9 +/- 14.2 pg/mL), and aldosterone (265.2 +/- 61.1 pg/mL) than did normal subjects. Plasma renin activity-exercise ratio, angiotensin II-exercise ratio, and aldosterone-exercise ratio in patients with class III CHF were significantly higher compared to normal subjects. This augmentation of the renin-angiotensin-aldosterone system was not observed in class I or II patients. Peak plasma norepinephrine levels were not different among normal subjects and subgroups of CHF patients, but the norepinephrine-exercise ratio was significantly higher in classes II and III CHF compared to normal subjects. CONCLUSIONS These data suggest that neurohormonal excitation during exercise increases along with the severity of CHF when normalized for peak exercise level.

Response of sympathetic nervous system activity to exercise in patients with congestive heart failure.

Abstract. To investigate the serial sympathetic nervous system response to exercise, plasma norepinephrine (NE) and epinephrine (E) concentrations were measured at rest, during each stage of treadmill exercise, and immediately and 5 minutes after exercise in 68 congestive heart failure (CHF) patients (NYHA functional class I 24, II 25, III 19) and 30 normal subjects. Circulatory responses of NYHA class II patients increased at early stages of exercise. Systolic blood pressure and double product at peak exercise were significantly lower in NYHA class III patients. Plasma NE response of NYHA class I patients was similar to that of normal subjects. However, plasma NE at rest, and during and after exercise were significantly higher in NYHA classes II and III patients than in normal subjects and NYHA class I patients (peak NE (pg ml‐1); Normals: 547±37, I: 535±53, II: 867±87, III: 1033±157). There was no significant difference in plasma E levels among the four groups. NE response to exercise was augmented according to the severity of heart failure, which suggested compensatory activation of sympathetic nervous system activity. Circulatory responses were reduced in NYHA class III patients despite the exaggerated compensatory activation of the sympathetic nervous system. Blunted circulatory responses to increased NE concentration in NYHA class III patients might relate to a decreased cardiac responsiveness to sympathetic activity in severe CHF patients.

Responses of catecholamines, renin-angiotensin system, and atrial natriuretic peptide to exercise in untrained men and women.

1. Plasma norepinephrine (NE), epinephrine (E), renin activity (PRA), angiotensin II (ATII), aldosterone (ALD), and atrial natriuretic peptide (ANP) were measured in 20 male and 15 female subjects during submaximal treadmill test. 2. Exercise duration was not different between the two groups (male vs. female: 13.4 +/- 0.8 min vs. 11.6 +/- 0.7 min, ns). Female subjects had higher heart rate during exercise, while systolic blood pressure at peak exercise was higher in male subjects. 3. Plasma NE, E, ANP, and ATII responses were comparable between male and female subjects, but PRA both at rest and during exercise and ALD at rest were significantly higher in male subjects. 4. Cardiac responses to submaximal exercise were different between male and female subjects, but neurohormonal responses were comparable between the two groups except for the high PRA at rest and during exercise and high plasma ALD at rest in male subjects.

Effects of Spironolactone on Exercise Capacity and Neurohormonal Factors in Patients with Heart Failure Treated with Loop Diuretics and Angiotensin-Converting Enzyme Inhibitor

1. Treatment with spironolactone is reported to be useful when combined with loop diuretics and an angiotensin-converting enzyme (ACE) inhibitor in severe congestive heart failure (CHF). However, the effects of the addition of spironolactone on exercise capacity and neurohormonal variables have not been demonstrated. This study determined the effects of additive spironolactone on exercise capacity and neurohormonal factors in patients with mild CHF. 2. Oxygen uptake (VO2), plasma norepinephrine (NE), renin activity (PRA), angiotensin II (AII), aldosterone (ALD), and atrial natriuretic peptide (ANP) were measured at rest and after peak exercise in nine patients with CHF (six idiopathic and three ischemic cardiomyopathy; New York Heart Association (NYHA) classes II and III) who were already taking furosemide (mean 29 +/- 5 mg/day) and enalapril (mean 4.7 +/- 0.8 mg/day). Studies were repeated after 16 weeks of treatment with additive single daily dose of 25 mg of spironolactone. In four of nine patients, the exercise test was repeated after a 4-weeks washout of spironolactone. 3. Treatment with spironolactone caused natriuresis, decreased cardiothoracic ratio in chest X-ray (before vs. after treatment: 53.7 +/- 1.2 vs. 50.7 +/- 1.4%, P < 0.01), and improved NYHA functional class. Peak VO2 (17.1 +/- 1.6 vs. 17.5 +/- 2.2 ml/min/kg, NS) and heart rate and blood pressure responses to exercise were not altered. Resting NE (215 +/- 41 vs. 492 +/- 85 pg/ml, P < 0.01) and resting PRA (8.2 +/- 2.3 vs. 16.2 +/- 4.1 ng/ml/hr, P < 0.01) as well as peak NE (1618 +/- 313 vs. 2712 +/- 374 pg/ml, P < 0.01) and peak PRA (12.8 +/- 3.2 vs. 28.1 +/- 11.8 ng/ml/hr, P = 0.17) were augmented after additive spironolactone. ALD and AII were insignificantly increased, and ANP was insignificantly decreased at peak exercise after spironolactone treatment. Spironolactone washout was associated with a trend of the neurohormones to return toward pretreatment values. 4. In conclusion, chronic additive treatment with spironolactone was associated with neurohormonal activation both at rest and during exercise without changing the exercise capacity of patients with mild CHF who were already on loop diuretics and ACE inhibitor therapy.

Sympathetic nervous system response to dynamic exercise in complete AV block patients treated with AV synchronous pacing with fixed AV delay or with auto-AV delay.

IGAWA, O., ET AL.: Sympathetic Nervous System Response to Dynamic Exercise in Complete AV Block Patients Treated with AV Synchronous Pacing with Fixed AV Delay or with Auto‐AV Delay. To investigate the sympathetic nervous system (SNS) responses and circulatory responses to exercise in eight patients (five male and three female) with complete atrioventricular block (CAVB) treated with atrio‐ventricular (AV) synchronous pacing, a symptom‐limited, multistaged treadmill stress test was performed, and plasma norepinephrine (NE) and circulatory parameters were measured at rest, at peak exercise, and in the recovery period. The eight patients were tested using the fixed AV interval (150 or 156 msec). Their exercise tolerance was generally poor. In all measured points, plasma NE levels were significantly higher in the eight study patients than those in the 12 normal subjects (eight male and four female). Systolic blood pressure (SBP) of CAVB patients elevated significantly after exercise compared to that at peak exercise. Heart rate (HR) responses of CAVB patients were characterized by their poor increase at peak exercise. These results suggest that some latent cardiac dysfunction continues in the CAVB patients however satisfactorily the AV synchronous pacing might perform. AV synchronous pacing with three different kinds of auto‐atrioventricular delay (auto‐AVD) was applied to three of the eight patients. In each AVD mode, a treadmill stress test was performed repeatedly according to the same protocol. Plasma NE concentrations under the condition with fixed AVD at peak exercise increased compared to those under the other two conditions with auto‐AVD. These findings suggest that AV synchronous pacing with auto‐AVD WQS better than that with fixed AVD during exercise. Plasma NE response to exercise seems to be a useful indicator for evaluating the condition of patients treated with DDD pacemakers and their adaptation for cardiac function.

Effects of a new angiotensin-converting enzyme inhibitor, alacepril, on changes in neurohormonal factors and arterial baroreflex sensitivity in patients with congestive heart failure

AbstractObjective: Patients with heart failure have abnormal neurohormonal regulation during orthostatic stress, and abnormal arterial baroreflex function. This study investigated the effects of alacepril, a new angiotensin-converting enzyme inhibitor with sulfhydryls, on changes in neurohormonal factors during tilt and on the arterial baroreflex control of heart rate. Methods: Plasma concentrations of noradrenaline, adrenaline, renin activity, angiotensin II, and atrial natriuretic peptide were measured at supine rest and after 30° head-up tilt with measurements of central venous pressure and cardiac dimensions in seven patients with congestive heart failure (65 years, ejection fraction = 34%). Arterial baroreflex control of heart rate was assessed by phenylephrine bolus. The arterial baroreflex test was re-examined 3 h after oral alacepril (37.5 mg). The tilt and arterial baroreflex tests were repeated 12 weeks after alacepril treatment (50 mg␣·␣day−1). Results: Heart rate, blood pressure, and neurohormonal factors did not differ before and after chronic alacepril, except for a trend toward an increase in renin activity (2.0 vs 4.9 ng · ml−1· h−1). Head-up tilt decreased central venous pressure (−2.5 mmHg) with a decrease in cardiac dimensions in the pre-alacepril phase. These changes were accompanied by increases in noradrenaline, adrenaline, and angiotensin II and a decrease in atrial natriuretic peptide. After chronic alacepril, the increase in noradrenaline during head-up tilt tended to be smaller (84 vs 30 pg · ml−1), with similar changes in central venous pressure (−3.4 mmHg) and cardiac dimensions. Both acute (3.6 vs 4.8 ms · mmHg−1) and chronic (3.6 vs 6.7 ms · mmHg−1) alacepril treatment was associated with a trend towards an increase in the arterial baroreflex control of heart rate. Conclusion: These results suggest that treatment with alacepril may cause a reduction of sympathetic activation during orthostatic stress and may enhance arterial baroreflex function in patients with mild to moderate heart failure.

AUGMENTED EXERCISE PLASMA NORADRENALINE WITH IMPAIRED CHRONOTROPIC RESPONSIVENESS IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY

1. There is controversy regarding plasma catecholamine levels in patients with hypertrophic cardiomyopathy (HCM) and few data exist on serial plasma catecholamine measurements during exercise. The present study determined whether cardiovascular and plasma catecholamine responses to exercise were altered in patients with HCM.

Responses of Plasma Catecholamines, Renin-Angiotensin-Aldosterone System, and Atrial Natriuretic Peptide to Exercise in Patients with Essential Hypertension

Neurohormonal responses to exercise have not been studied fully in patients with essential hypertension (HT). This study determined if neurohormonal responses to exercise are altered between three subgroups of HT categorized by basal plasma renin activity (PRA). Plasma norepinephrine, epinephrine, atrial natriuretic peptide (ANP), PRA, angiotensin II (AII), and aldosterone were measured at rest and after submaximal treadmill exercise in 39 patients with essential HT (WHO classes I-II) and 13 controls. Patients with HT were divided into three subgroups based on the PRA level [low-renin (< 0.5) HT (n = 14), normal-renin (0.5-2.0) HT (n = 13), and high-renin (> 2.0) HT (n = 12)]. Patients with HT had higher blood pressure during exercise compared to controls, but blood pressure responses were similar among low-, normal-, and high-renin HT. Neurohormonal factors were comparable between all hypertensives and controls, except for higher plasma AII at rest in patients with HT. When neurohormones were compared among three subgroups of HT, plasma norepinephrine and epinephrine responses were similar. Patients with high-renin HT had higher PRA and AII, and lower ANP levels at rest and after exercise. In all hypertensives, negative correlations were observed between resting PRA and resting ANP (r = -0.41, p < 0.01), as well as peak PRA and peak ANP (r = -0.33, p < 0.05). Thus, neurohormonal responses to exercise varied with similar cardiac responses among subgroups of essential HT stratified according to renin levels. Patients with high-renin HT had augmented renin-angiotensin system activity with a decrease in ANP levels both at rest and after exercise. A reciprocal relationship between renin-angiotensin system activity and ANP was observed both at rest and after exercise in HT.

Renal Hypouricemia with Both Drug-Insensitive Secretion and Defective Reabsorption of Urate: A Novel Type of Renal Hypouricemia

Renal handling of urate in the hypouricemic patient with increase in both urate clearance (Cur) and Cur/creatinine clearance (Ccr) and normal urinary excretion of urate was studied according to the pharmacological evaluation. In the present case there was no response of urate excretion to either pyrazinamide or probenecid. Both furosemide and prednisolone could not alter Cur and Cur/Ccr. Administration of inosine could have increased Cur, which was greater than Ccr. These results suggest that the present case had the defect of both pre- and postsecretory reabsorption of urate, accompanied by the existence of drug-insensitive secretion of urate, which is different from hitherto known types of renal hypouricemia, i.e. a novel type of renal hypouricemia.