Hitoshi Ozaki

Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure

OBJECTIVES Vagally mediated heart rate recovery after exercise was assessed in patients with chronic heart failure and in well trained athletes by analyzing the postexercise heart rate decay. BACKGROUND Vagal reactivation is an important cardiac deceleration mechanism after exercise. However, alterations of this mechanism under pathologic conditions have not been characterized because of the lack of a specific index. METHODS To find a vagally mediated component of heart rate recovery, the time constants of the beat-by-beat heart rate decay for the first 30 s (T30) and the first 120 s (T120) after exercise were obtained at six levels of exercise in eight normal volunteers: 1) at maximal exercise, 2) at anaerobic threshold, 3) at anaerobic threshold with propranolol administration, 4) at anaerobic threshold with atropine administration, 5) at anaerobic threshold with concomitant administration of both drugs, and 6) at 50% of anaerobic threshold. To investigate the effects of heart failure and endurance training on vagally mediated heart rate recovery, T30 and T120 at anaerobic threshold were obtained in 20 patients with chronic heart failure and in 9 cross-country skiers. RESULTS In normal volunteers, T30 and T120 were markedly prolonged by atropine administration, indicating that both time constants are mediated by vagal reactivation. Moreover, T30 was almost independent of the exercise intensity and sympathetic blockade, whereas T120 was affected by sympathetic nerve activity and exercise work load. These results indicate that T30 is mediated primarily by vagal reactivation, independent of sympathetic withdrawal, and is significantly smaller in athletes (p < 0.01) and significantly larger in patients with chronic heart failure (p < 0.01) than that in respective age-matched normal control subjects. CONCLUSIONS The T30 value could be a specific index for vagally mediated heart rate recovery. Vagally mediated heart rate recovery after exercise is accelerated in well trained athletes but blunted in patients with chronic heart failure.

Hemodynamic effects of the beta 1-adrenoceptor partial agonist xamoterol in relation to plasma norepinephrine levels during exercise in patients with left ventricular dysfunction.

A new cardioselective beta 1-adrenoceptor partial agonist, xamoterol, has been developed for the treatment of heart failure, especially that associated with ischemic heart disease. To investigate the hemodynamic effect of xamoterol in relation to sympathetic nervous activity, hemodynamic variables and plasma norepinephrine (NE) levels were measured at rest and during three graded bicycle exercise tests before and after a single intravenous dose of 0.15 mg/kg xamoterol in 10 patients with mild-to-moderate left ventricular dysfunction. Plasma NE increased with increasing grade of exercise and a linear correlation between plasma NE and heart rate was observed at four time points (at rest and three exercise levels) before and after xamoterol. After administration of xamoterol, the slope of the regression line of plasma NE-heart rate relation was significantly less steep than that before drug. Predose and postdose regression lines crossed at 440 pg/ml of plasma NE. Similar effects were observed on the plasma NE-cardiac index and plasma NE-systolic blood pressure relations (regression lines crossed at 380 and 530 pg/ml of plasma NE, respectively). Thus, xamoterol had a dual agonist-antagonist effect in relation to plasma NE, and the crossover point lay approximately between 400 pg/ml and 500 pg/ml. This level of plasma NE was achieved at a low exercise level and at a heart rate of about 100 beats/min. These results indicate that xamoterol has intrinsic sympathomimetic activity comparable to relatively low sympathetic activity (400 to 500 pg/ml of plasma NE) and therefore acts as a beta 1-agonist when sympathetic nervous activity is below this level and as an antagonist when sympathetic activity is above this level.

Exercise-induced upward shift of diastolic left ventricular pressure-volume relation in patients with dilated cardiomyopathy. Effects of beta-adrenoceptor blockade.

BackgroundThe effectiveness of β-blocker therapy for dilated cardiomyopathy (DCM) may be attributed to the inhibition of detrimental effects on the failing heart of sympathetic stimulation during exertion. However, the harmful effects of activity as well as the protective effects of (-blockers have not been demonstrated. Diastolic ventricular function is known to be sensitive to transient myocardial metabolic insult. In this study, we investigated the effect of modest exercise with or without (blockade on the diastolic left ventricular pressure-volume (P-V) relation in patients with DCM. Methods and ResultsThe diastolic left ventricular P-V relation was obtained by high-fidelity pressure measurements and digital subtraction left ventriculography at rest and immediately after modest supine bicycle exercise in 12 patients with DCM. The effects of intravenous administration of 0.1 mg/kg propranolol on resting and exercise P-V relations were studied. The end-diastolic and lowest left ventricular pressures were significantly elevated by exercise (20±9 to 32± 13 mm Hg, P<.01, and 12±6 to 21±11 mm Hg, P<.01, respectively) despite insignificant changes in left ventricular volumes. The administration of propranolol did not alter the resting diastolic P-V relation. However, propranolol significantly attenuated the exercise-induced upward shift of the diastolic P-V relation despite a significant increase in end-diastolic volume. The significant upward shift and attenuation by propranolol were also observed even when the left ventricular pressure was corrected by the subtraction of right atrial pressure. ConclusionsThese results indicate that even modest exercise exerts detrimental effects on diastolic left ventricular function of the failing heart through, β-adrenergic stimulation. The clinical effectiveness of (β-blocker therapy in patients with DCM can be attributed in part to the inhibition of detrimental myocardial effects of sympathetic stimulation during daily activity.

The effect of losartan and amlodipine on left ventricular diastolic function and atherosclerosis in Japanese patients with mild-to-moderate hypertension (J-ELAN) study.

This study was a prospective, randomized, open, blinded endpoint study to assess the effects of angiotensin II type 1 receptor blocker, losartan, compared with calcium channel blocker, amlodipine, on left ventricular (LV) diastolic function and atherosclerosis of the carotid artery in Japanese patients with mild-to-moderate hypertension, LV hypertrophy, diastolic dysfunction and preserved systolic function. Fifty-seven patients were randomly assigned to losartan- or amlodipine-based treatment groups and were followed up for 18 months. Blood pressure was similarly reduced by both regimens. Losartan shortened the transmitral E-wave deceleration time, and amlodipine reduced LV mass index; however, there was no significant difference in the percent changes of these indices between the two groups. Mean carotid intima–media thickness (mean IMT) as well as plaque score significantly increased in the amlodipine-based regimen (pre: 1.05±0.26 mm, follow-up: 1.23±0.33 mm, P=0.0015), but not in the losartan-based regimen (pre: 1.08±0.35 mm, follow-up: 1.16±0.52 mm, P=non-significant). The percent increase in mean IMT in the amlodipine-based regimen tended to be large compared with the losartan-based regimen (amlodipine: 19.8±23.7%, losartan: 6.9±23.3%, P=0.06). Under similar reduction of blood pressure, losartan is likely effective in protecting the progression of atherosclerosis of the carotid artery compared with amlodipine. Losartan may improve LV diastolic function, and amlodipine may attenuate LV hypertrophy; however, this study cannot make consecutive remarks about the superiority of either treatment regimen in the effects on cardiac function and geometry. This study has been registered at http://www.umin.ac.jp/ctr/listj/ (identifier C000000319).

Predominantβ-adrenoceptor blocking effect of xamoterol averaged over the day in patients with mild to moderate heart failure: insight into the mechanism of its long-term clinical efficacy

SummaryXamoterol acts as aβ1-adrenoceptor agonist at low sympathetic activity and as an antagonist at high activity. Although its long-term efficacy has been proven in patients with mild to moderate heart failure, it remains unclear which effect, agonism or antagonism, accounts for its long-term activity.To clarify the effect of xamoterol on cardiac sympathetic activity in daily life, 24-h R-R interval histograms were obtained during administration of xamoterol 100 mg b. d. for 1 week to 10 patients with mild to moderate heart failure. Eight normal subjects were also studied as controls. To examine the relation between the effect of xamoterol and sympathetic activity, plasma noradrenaline (NA) levels were measured under 5 graded conditions simulating daily living.Xamoterol administration significantly decreased the standard deviation of the R-R interval, both in patients with heart failure and in normal subjects. The mean R-R interval, however, was increased in patients with heart failure, relative to normal subjects.In both groups, the R-R interval histograms had two peaks, i. e. a short daytime peak and a long night-time peak. Xamoterol decreased the median of the night-time peak without changing the daytime peak in normal subjects. In contrast, it increased the median of the daytime peak without producing a significant change in the nighttime peak in patients with heart failure. Levels of plasma NA were significantly higher in patients than in normal subjects under all conditions.Thus, in normal subjects xamoterol predominantly increased the slower heart rate at night with only a minor effect on the higher heart rate in the daytime, whereas it predominantly attenuated the daytime tachycardia induced by sympathetic stimulation in patients with heart failure.It is concluded that xamoterol tends overall to act as aβ-adrenoceptor antagonist during the day, especially in the daytime in patients with mild to moderate heart failure. Its antagonist rather than its agonist effect may account for the long-term efficacy of xamoterol in patients with mild to moderate heart failure.

Pharmacological effects of concomitant administration of β-adrenoceptor blocker and agonist in normal subjects: characterization by heart rate response to exercise

The effects of a combination regimen of metoprolol and β1-adrenoceptor agonist denopamine on resting and exercise heart rate have been studied in 10 normal volunteers. Maximal ramp upright bicycle exercise was performed three times at 1-week intervals. Two hours before each exercise test, 5 mg metoprolol plus 20 mg denopamine, 5 mg metoprolol plus a denopamine placebo, or two placebos were orally administered in a double-blind fashion.During exercise after placebo administration, heart rate increased in parallel with the exercise intensity. Compared to the placebo values, resting heart rate was significantly decreased by an average of 10 beats · min−1 by 5 mg metoprolol, whereas it was not altered by the combination regimen. During exercise, however, both the combination regimen and metoprolol alone showed a significant negative chronotropic effect, decreasing peak exercise heart rate by an average of 14 and 21 beats · min−1, respectively. Peak oxygen uptake was also significantly decreased by both regimens.We conclude that concomitant administration of 5 mg metoprolol and 20 mg denopamine exerts an effective β-adrenoceptor blocking action during exercise but a minimal effect at rest in normal subjects. The combination regimen appears to have a favourable pharmacological profile for β-adrenoceptor blocker therapy in patients with chronic heart failure.

Clinical Efficacy of Flosequinan in Patients with Mild Chronic Heart Failure: a Double-Blind Placebo-Controlled Study

Flosequinan is a novel vasodilating agent with a mild positive inotropic effect [1]. This drug has been reported to increase exercise capacity in patients with severe heart failure [2–4]. However, its efficacy has not been studied In patients with less severe forms of heart failure. In the present study we investigated the effects of 4-week administration of flosequinan (50 mg daily) on exercise capacity, cardiac function, and subjective symptoms in patients with chronic mild heart failure in a randomized placebo-controlled double-blind clinical trial.