Junichiro Hayano

Accuracy of assessment of cardiac vagal tone by heart rate variability in normal subjects

The correlations of 11 indexes of heart rate variability were examined with pharmacologically determined cardiac vagal tone in 15 normal subjects at supine rest. After sympathetic influences by intravenous propranolol were eliminated, RR interval variability was measured for 10 minutes under controlled respiration (0.25 Hz), and cardiac vagal tone was determined as the decrease in mean RR interval following complete vagal blockade with atropine. Time domain indexes (standard deviation, coefficient of variance and mean successive difference) correlated strongly with vagal tone (r = 0.87, 0.81 and 0.92, respectively; p less than 0.001 for all). The same was true for frequency domain indexes for the high-frequency (0.25 Hz) component calculated both by autoregressive spectrum analysis (square root of power and coefficient of component variance) and by fast Fourier transform (mean amplitude) (r = 0.91, 0.85 and 0.86, respectively; p less than 0.0001 for all). However, frequency domain indexes for the low-frequency spectral component (0.03 to 0.15 Hz) correlated less strongly (r = 0.69, 0.55 and 0.70, respectively), and the fraction of power [power/(total power greater than 0.03 Hz)] of both components showed no correlation. Principal component analysis showed that the first 6 indexes with strong correlations contained solely the first principal component closely related to vagal tone, whereas the remaining 5 indexes also contained the second component unrelated to vagal tone. These results indicate that most of the time and frequency domain analyses in use provides an accurate and common measure of cardiac vagal tone at rest.

Decreased magnitude of heart rate spectral components in coronary artery disease. Its relation to angiographic severity.

We analyzed the spectral components of RR interval variability under controlled respiration (15 breaths/min) in 56 patients (age range, 35-73 years) referred for coronary angiography; 14 patients had multivessel disease (group M), 21 had one-vessel disease (group S), and 21 had nonsignificant disease or normal coronary artery (group N). There were 43 healthy controls (age range, 36-71 years) (group C). The patients had no clinical evidence of heart failure, hypertension, diabetes mellitus, or acute stage of infarction and had taken no medication for 3 days. The autoregressive power spectral density of RR interval variability contains two major components, respiratory sinus arrhythmia (RSA) (0.25 Hz) and Mayer wave-like sinus arrhythmia (MWSA) (0.04-0.15 Hz), which have magnitudes that are quantitative markers of cardiac vagal activity and sympathetic activity with vagal modulation, respectively. We represented the magnitudes by the coefficient of component variance (CCV), which provided the amplitude relative to the mean RR interval. The age- and sex-adjusted mean of CCVRSA significantly decreased with advancing angiographic severity (1.64 +/- 0.09%, 1.66 +/- 0.12%, 1.22 +/- 0.13%, and 0.81 +/- 0.16% for groups C, N, S, and M, respectively) (p = 0.0001). The CCVRSA was unrelated to left ventricular function, previous myocardial infarction, or stenosis of any specific artery including the sinoatrial and atrioventricular node arteries. The CCVMWSA decreased only in group M (p = 0.0462). These results indicate that coronary artery disease is associated with vagal dominant impairment in autonomic cardiac function and that reduction in the vagal cardiac function correlates with the angiographic severity.

Short- and long-term effects of cigarette smoking on heart rate variability.

The short- and long-term effects of cigarette smoking on autonomic cardiac regulation were investigated by power spectral analysis of heart rate variability under controlled respiration (15/min). The short-term effects were examined in 9 smokers without evidence of cardiopulmonary disorders after an overnight abstinence from smoking. The heart rate spectral component reflecting the respiratory sinus arrhythmia (0.25 Hz), a quantitative index of vagal cardiac control, decreased 3 minutes after smoking 1 cigarette (p = 0.0061) and the component reflecting Mayer wave sinus arrhythmia (0.04 to 0.15 Hz), which includes sympathetically mediated activity, increased after 10 to 17 minutes (p = 0.0124). The long-term effects were examined in 81 normal subjects comprising 25 nonsmokers, 31 moderate (1 to 24 cigarettes/day) smokers and 25 heavy (greater than 25 cigarettes/day) smokers after an overnight abstinence. Although the magnitude of the Mayer wave component was unaffected by the smoking status, the respiratory component in the supine position was smaller in the young (less than or equal to 30 years) heavy smokers than in the young nonsmokers or moderate smokers (p = 0.0078). Also, postural changes in the components, a decrease in the respiratory component and an increase in the Mayer wave component with standing, were observed in the nonsmokers but not in the heavy smokers. These results suggest that smoking causes an acute and transient decrease in vagal cardiac control, and that heavy smoking causes long-term reduction in vagal cardiac control in young people and blunted postural responses in autonomic cardiac regulation.

‘Non‐hypotensive’ hypovolaemia reduces ascending aortic dimensions in humans.

1. The notion that small, ‘non‐hypotensive’ reductions of effective blood volume alter neither arterial pressure nor arterial baroreceptor activity is pervasive in the experimental literature. We tested two hypotheses: (a) that minute arterial pressure and cardiac autonomic outflow changes during hypovolaemia induced by lower body suction in humans are masked by alterations in breathing, and (b) that evidence for arterial baroreflex engagement might be obtained from measurements of thoracic aorta dimensions. 2. In two studies, responses to graded lower body suction at 0 (control), 5, 10, 15, 20 and 40 mmHg were examined in twelve and ten healthy young men, respectively. In the first, arterial pressure (photoplethysmograph), R‐R interval, and respiratory sinus arrhythmia amplitude (complex demodulation) were measured during uncontrolled and controlled breathing (constant breathing frequency and tidal volume). In the second, cross‐sectional areas of the ascending thoracic aorta were calculated from nuclear magnetic resonance images. 3. Lower body suction with controlled breathing resulted in an increased arterial pulse pressure at mild levels (5‐20 mmHg; ANOVA, P < 0.05) and a decreased arterial pulse pressure at moderate levels (40 mmHg; ANOVA, P < 0.05). Both R‐R intervals and respiratory sinus arrhythmia were negatively related to lower body suction level, whether group averages (general linear regression, r > 0.92) or individual subjects (orthogonal polynomials, 12 of 12 subjects) were assessed. 4. Aortic pulse area decreased progressively and significantly during mild lower body suction, with 47% of the total decline occurring by 5 mmHg. 5. These results suggest that small reductions of effective blood volume reduce aortic baroreceptive areas and trigger haemodynamic adjustments which are so efficient that alterations in arterial pressure escape detection by conventional means.

Severity of coronary atherosclerosis correlates with the respiratory component of heart rate variability

Decreased vagal activity is frequently observed in coronary artery disease, but the mechanism of this association is unknown. We investigated cardiac autonomic function by relating heart rate spectral components to clinical and angiographic findings in 80 patients who were undergoing coronary angiography. The age- and sex-adjusted magnitude of the respiratory spectral component, which is an index of cardiac vagal tone, showed a significant negative correlation with the extent of coronary atheromatosis (r = -0.43, p less than 0.0001) and a less significant negative correlation with the severity of coronary stenosis (r = -0.30, p = 0.0070). These relationships were independent of previous myocardial infarction and of left ventricular function. Stepwise regression analysis showed that the respiratory spectral component contributed to atheromatosis independently of established coronary risk factors (partial R2 = 9.4%, p = 0.002), but not to stenosis. Our results support the hypothesis that decreased cardiac vagal activity is associated with an increased risk of coronary atherosclerosis.

Hypothesis: respiratory sinus arrhythmia is an intrinsic resting function of cardiopulmonary system

A hypothesis is presented that explains the physiological reasons why the magnitude of respiratory sinus arrhythmia (RSA) appears to correlate with cardiac vagal tone. The hypothesis is that RSA is an intrinsic resting function of the cardiopulmonary system. Although RSA is mediated by respiratory modulation of cardiac vagal outflow and its magnitude is used as an index of cardiac vagal activity, RSA itself reflects cardiorespiratory interaction. RSA is universally observed among vertebrates throughout the evolution, suggesting that it may bear an intrinsic physiological role. Recent studies have shown that RSA improves pulmonary gas exchange efficiency by matching alveolar ventilation and capillary perfusion throughout respiration cycle. This suggests that in resting animals and humans, RSA could save cardiac and respiratory energy by suppressing unnecessary heartbeats during expiration and ineffective ventilation during waning phases of perfusion. Furthermore, evidence is accumulating for possible dissociation between the magnitude of RSA and vagal control of heart rate, suggesting separated and independent regulations for respiratory modulation of cardiac vagal outflow from those for cardiac vagal tone. By our hypothesis, the apparent associations between RSA and cardiac vagal tone are explained as indirect consequences; i.e., whenever the cardiac vagal tone changes in response to the resting level of the cardiopulmonary system, RSA appears to change parallel to it. Our hypothesis seems more consistent with both physiological and clinical evidence about RSA than that presuming RSA is an index of cardiac vagal activity.

Clinical usefulness of carotid arterial wave intensity in assessing left ventricular systolic and early diastolic performance

Wave intensity (WI) is a novel hemodynamic index, which is defined as (dP/dt)·(dU/dt) at any site of the circulation, where dP/dt and dU/dt are the derivatives of blood pressure and velocity with respect to time, respectively. However, the pathophysiological meanings of this index have not been fully elucidated in the clinical setting. Accordingly, we investigated this issue in 64 patients who underwent invasive evaluation of left ventricular (LV) function. WI was obtained at the right carotid artery using a color Doppler system for blood velocity measurement combined with an echo-tracking method for detecting vessel diameter changes. The vessel diameter changes were automatically converted to pressure waveforms by calibrating its peak and minimum values by systolic and diastolic brachial blood pressures. The WI of the patients showed two sharp positive peaks. The first peak was found at the very early phase of LV ejection, while the second peak was observed near end-ejection. The magnitude of the first peak of WI significantly correlated with the maximum rate of LV pressure rise (LV max. dP/dt) (r = 0.74, P ≪ 0.001). The amplitude of the second peak of WI significantly correlated with the time constant of LV relaxation (r = −0.77, P ≪ 0.001). The amplitude of the second peak was significantly greater in patients with the inertia force of late systolic aortic flow than in those without the inertia force (3 080 ± 1 741 vs 1 890 ± 1 291 mmHg m s−3, P ≪ 0.01). These findings demonstrate that the magnitude of the first peak of WI reflects LV contractile performance, and the amplitude of the second peak of WI is determined by LV behavior during the period from late systole to isovolumic relaxation. WI is a noninvasively obtained, clinically useful parameter for the evaluation of LV systolic and early diastolic performance at the same time.

Difference in human cardiovascular response between upright and supine recovery from upright cycle exercise

Abstract Cardiovascular responses were examined in seven healthy male subjects during 10 min of recovery in the upright or supine position following 5 min of upright cycle exercise at 80% peak oxygen uptake. An initial rapid decrease in heart rate (fc) during the early phase of recovery followed by much slower decrease was observed for both the upright and supine positions. The average fc at the 10th min of recovery was significantly lower (P < 0.05) in the supine position than in the upright position, while they were both significantly greater than the corresponding pre-exercise levels (each P < 0.05). Accordingly, the amplitude of the high frequency (HF) component of R-R interval variability (by spectrum analysis) in both positions was reduced with a decrease in mean R-R interval, the relationship being expressed by a regression line – mean R-R interval = 0.006 × HF amplitude + 0.570 (r = 0.905, n = 28, P < 0.001). These results would suggest that the slower reduction in fc following the initial rapid reduction in both positions is partly attributable to a retardation in the restoration of the activity of the cardiac parasympathetic nervous system. Post-exercise upright stroke volume (SV, by impedance cardiography) decreased gradually to just below the pre-exercise level, whereas post-exercise supine SV increased markedly to a level similar to that at rest before exercise. The resultant cardiac output (Q˙c) and the total peripheral vascular resistance (TPR) in the upright and supine positions returned gradually to their respective pre-exercise levels in the corresponding positions. At the 10th min of recovery, both average SV and Q˙c were significantly greater (each P < 0.005) in the supine than in the upright position, while average TPR was significantly lower (P < 0.05) in the supine than in the upright position. In contrast, immediately after exercise, mean blood pressure dropped markedly in both the supine and upright positions, and their levels at the 10th min of recovery were similar. Therefore we concluded that arterial blood pressure is maintained relatively constant through various compensatory mechanisms associated with fc, SV, Q˙c, and TPR during rest and recovery in different body positions.

Effect of Slowed Respiration on Cardiac Parasympathetic Response to Threat

The present study was designed to examine the effect of voluntarily slowed respiration on the cardiac parasympathetic response to a threat:the anticipation of an electric shock. Thirty healthy college students were randomly assigned to the slow, fast, and nonpaced breathing groups (10 subjects each). Subjects in the slow and fast paced breathing groups regulated their breathing rate to 8 and 30 cpm, respectively, and those in the nonpaced breathing group breathed spontaneously. Immediately after the period of paced or nonpaced breathing for 5 minutes, the subjects were exposed for 2 minutes to the anticipation of an electric shock during breathing paced at 15 cpm. The amplitude of the high frequency (HF) component of the heart rate variability, an index of cardiac parasympathetic tone, significantly decreased during the threat in the fast and nonpaced breathing groups, whereas it was unchanged in the slow paced breathing group. No significant difference was observed among the three groups in the amplitude of respiration during the threat. Results suggest that a slowed respiration decreases the cardiac parasympathetic withdrawal response to the threat. This study provides a rationale for the therapeutic uses of the slowed respiration maneuver in attenuating the cardiac autonomic responses in patients with anxiety disorder.

Circadian rhythms of atrioventricular conduction properties in chronic atrial fibrillation with and without heart failure.

OBJECTIVES We examined the circadian variations in atrioventricular (AV) conduction properties during atrial fibrillation (AF) by a technique based on the Lorenz plot of successive ventricular response (VR) intervals and analyzed their relations with clinical features. BACKGROUND The VR interval in chronic AF shows circadian variation, which is attenuated in patients with an increased risk of death. Although the VR interval is determined by the dynamic processes in the AV node randomly stimulated by rapid atrial activity, the circadian variations of the AV conduction properties related to this mechanism are unknown. METHODS In 48 patients with chronic AF, Lorenz plots were generated on overlapping sequential segments of 512 VR intervals in 24-h ambulatory electrocardiograms. For each scatter plot, the 1.0-s intercept of the lower envelope (LE1.0) of the plot and the degree of scatter above the envelope (root mean square difference from the envelope [scattering index]) were measured for estimating AV node refractoriness and concealed AV conduction, respectively. RESULTS In all patients, a significant circadian rhythm was observed for the average VR interval, LE1.0 and scattering index, with an acrophase occurring at night. The mesor, amplitude and acrophase of LE1.0 and the scattering index closely and independently correlated with the corresponding rhythm variables of the average VR interval (partial r2 0.98, 0.86 and 0.68 for LE1.0 and 0.98, 0.92 and 0.92 for scattering index). The amplitudes of these measures were lower in patients with congestive heart failure (CHF) even after adjustment for the effects of age, duration of AF, medications, left atrial diameter and blood pressure (p < 0.01 for all). CONCLUSIONS These results suggest that 1) both AV node refractoriness and the degree of concealed AV conduction during AF may show a circadian rhythm; 2) the circadian rhythms of these properties may independently contribute to the circadian variation of the VR interval; and 3) these circadian rhythms may be attenuated in patients with CHF.