Effect of beta-blockade on heart rate variability in patients with coronary artery disease.

OBJECTIVES: This study assessed the effects of beta-blockade on heart rate variability in patients with coronary artery disease and determined whether the effects of metoprolol in a controlled-release formulation and atenolol differ with regard to electrocardiographic measures of cardiac autonomic control. BACKGROUND: Low heart rate variability is common in coronary artery disease and is associated with increased mortality. Beta-adrenergic blocking drugs may increase heart rate variability in healthy subjects, but there is limited knowledge of whether they are able to modify heart rate variability in patients with uncomplicated coronary artery disease. METHODS: In a randomly allocated, double-blind crossover study with three 2-week treatment periods, 200 mg of controlled-release metoprolol once a day, 100 mg of atenolol once a day or placebo once a day were administered in 18 male patients with stable coronary artery disease. The 24-h heart rate variability was measured in both the time and frequency domains. RESULTS: Beta-blockade induced a significant increase in heart rate variability, but no significant differences were found between atenolol and metoprolol. The average 24-h high frequency power increased by 64% after atenolol and by 62% after metoprolol. The root-mean-square successive difference of normal RR intervals increased by 70% after atenolol and by 62% after metoprolol, and the standard deviations of RR intervals increased by 20% and 16%, respectively. Beta-blockade had no significant effects on the amplitude of the circadian rhythm of heart rate variability, although both metoprolol and atenolol blunted the abrupt decrease of high frequency power after arousal. CONCLUSIONS: Beta-blockade by metoprolol and atenolol enhance the heart rate variability in patients with coronary artery disease. This may contribute to the protective effects of beta-blockade in ischemic heart disease.

Arterial baroreflex impairment in patients during acute coronary occlusion.

OBJECTIVES: We tested whether acute coronary occlusion interferes with arterial baroreceptor control of heart rate in humans. BACKGROUND: Subnormal baroreflex sensitivity (BRS) is an important risk indicator for sudden death. Animal research indicates that both chronic myocardial infarction and acute coronary occlusion impair baroreflex modulation of heart rate. METHODS: We measured RR interval prolongation after phenylephrine-induced systolic pressure increases before and during 2-min coronary occlusions in 47 patients (27 men) undergoing clinically indicated single-vessel coronary angioplasty for stenoses in the proximal or midportion of the vessel causing >50% reduction in the arterial diameter, with normal antegrade flow (33 anterior descending, 10 circumflex, 4 right coronary artery). A control group of 11 patients treated for chronic total occlusion of a coronary artery was assessed to evaluate nonspecific changes in baroreflex function during a 2-min balloon inflation in the occluded artery. RESULTS: The BRS decreased from 5.2+/-3.8 (mean+/-SD) to 4.1+/-3.5 ms x mm Hg(-1) (p=0.01) during the coronary occlusion in the 28 patients with preserved arterial baroreceptor control of heart rate-that is, adequate blood pressure responses and correlation coefficients of the slopes both in baseline and during coronary occlusion. The same phenylephrine dose increased systolic pressure less during than before coronary artery occlusion (21+/-21 versus 36+/-16 mm Hg, p < 0.0001), and in 6 patients it failed to prevent systolic pressure reduction during occlusion. Correlation coefficients of the baroreflex regressions decreased from 0.81+/-0.27 to 0.47+/-0.44 (p < 0.0001) during coronary artery occlusion in the 41 patients with adequate systolic pressure rises in both phenylephrine tests, and the association between RR intervals and rising systolic pressures was lost in 13 patients during coronary occlusion. Balloon inflation in a chronic total occlusion of a coronary artery did not cause significant changes in BRS (from 5.3+/-4.0 to 5.2+/-3.7 ms x mm Hg(-1)), correlation coefficient of the slope or phenylephrine-induced pressure rise. CONCLUSIONS: Our study shows that abrupt coronary occlusion impairs baroreflex modulation of vagal and sympathetic nervous outflow in humans.

Heart rate variability and occurrence of ventricular arrhythmias during balloon occlusion of a major coronary artery.

Experimental studies suggest that autonomic mechanisms are important in the genesis of ischemia-induced malignant ventricular arrhythmias, but the role of the autonomic nervous system in human arrhythmogenesis is not well known. To assess whether heart rate variability (HRV) predicts the occurrence of ventricular arrhythmias during acute coronary artery occlusion, we performed continuous electrocardiographic, heart rate, and blood pressure recordings before and during a 2-minute balloon occlusion of a stenotic coronary artery in 252 patients with no baseline ventricular premature complexes (VPCs). The ranges of nonspecific responses in heart rate and blood pressure were determined by analyzing a control group of 19 patients with no ischemia during a 2-minute balloon inflation in a totally occluded coronary artery. Balloon occlusion of a coronary artery was stopped because of complex, i.e., bigeminal or repetitive, VPCs in 14 patients, and solitary (<5) VPCs were observed in an additional 19 patients. During coronary occlusion, HRV increased (p <0.001) and heart rate decreased (p <0.05) in patients with no VPCs, whereas an opposite tendency to reduction in HRV (p = 0.08) was observed in patients with complex VPCs. Complex VPCs were observed in 5 (42%) of the 12 patients with a significant coronary occlusion-induced decrease in HRV, in 7 (3.5%) of 200 patients with no change in HRV, but in none of the 40 patients with a significant increase in HRV (p <0.001). Baseline HRV did not predict the occurrence of VPCs during coronary occlusion. Logistic regression analysis identified the decrease in HRV (p <0.001) to be the only independent predictor of complex VPCs. In conclusion, coronary occlusion-induced increase in HRV seems to protect against occurrence of complex ventricular arrhythmias during the early phase of abrupt coronary occlusion, suggesting that vagal activation may modify the outcome of acute coronary events in patients with coronary artery disease.

Effect of beta blockade on heart rate variability during vessel occlusion at the time of coronary angioplasty.

Beta blockers modify cardiovascular neural regulation, which may contribute to their protective effect against sudden cardiac death. To evaluate the effects of beta blockade on cardiovascular autonomic reactions caused by acute coronary occlusion in humans, heart rate (HR) variability was analyzed in the time and frequency domains immediately before and during balloon occlusion of a coronary artery in 116 patients randomly assigned to either chronic beta-blocker therapy (beta-blocker group) or no beta blockade (control group) during elective 1-vessel coronary angioplasty. Coronary occlusion (mean 112 seconds) caused a significant increase in both the high- and low-frequency components of HR variability in the control group (n = 58), from 2.7 +/- 1.6 to 3.4 +/- 1.7 (logarithmic units, p < 0.001) and from 4.3 +/- 1.3 to 4.8 +/- 1.5 (p < 0.01), respectively, whereas in the beta-blocker group (n = 58), the high-frequency power did not change during occlusion, but the low-frequency power increased from 3.9 +/- 1.4 to 4.4 +/- 1.4 (p = 0.01). Changes in high- and low-frequency components and HR were related to the change in systolic blood pressure during occlusion in the beta-blocker group (r = 0.53, p < 0.001; r = 0.34, p < 0.05; and r = -0.41, p < 0.01, respectively), but not in the control group (r = -0.17, r = -0.14, and r = 0.24, respectively). Thus, beta blockade attenuates the initial vagal activation associated with acute coronary occlusion and seems to maintain baroreflex-mediated cardiovascular control. The maintained integrity of baroreflex regulation and the alleviation of extreme autonomic reactions during beta blockade may modify the clinical outcome of acute coronary occlusion in a beneficial way.

Impaired parasympathetic control of heart rate after myocardial infarction.

We measured the variation in heart rate during deep breathing, a sensitive non-invasive measure of cardiac parasympathetic activity, in 95 patients 3 weeks after myocardial infarction and in 40 asymptomatic healthy controls. The variation in rate was significantly lower (11.6 +/- 6.1 vs 17.6 +/- 7.3 beats/min, P less than 0.001) in patients with myocardial infarction than in controls. Forty-nine patients (52%) and 5 controls (13%) were considered to have diminished (less than or equal to 10 beats/min) variation of rate. The diminution in this variation was not related to the type or location of myocardial infarction, to maximum release of CK-MB or to cardiovascular medication. Our results suggest that impairment of vagal control of heart rate is common after myocardial infarction. The impairment cannot be predicted by any specific feature of the disease.

Effect of coronary arterial occlusion on vagal control of heart rate.

Diminished variation in heart rate as a sign of impaired vagal control is common in coronary arterial disease. To evaluate the effect of short-term myocardial ischaemia induced by coronary arterial occlusion during therapeutic percutaneous transluminal coronary angioplasty we measured the variation in heart rate during controlled deep breathing in 50 patients before and during arterial occlusion. Variation in heart rate diminished from 11.1 +/- 4.5 to 9.5 +/- 5.1 beats/min (P less than 0.01) during occlusion. No change occurred in heart rate, blood pressure or levels of noradrenaline and adrenaline. The attenuation of variation in the heart rate was not significantly associated with the site or duration of arterial occlusion nor concomitant chest pain. Thus, brief coronary arterial occlusion seems to be associated with impairment of the vagal control of heart rate in patients with coronary arterial disease.

Effect of beta-blockade on baroreflex sensitivity and cardiovascular autonomic function tests in patients with coronary artery disease.

We wished to assess the effects of beta-blockade on baroreflex sensitivity and standard tests of integrity of autonomic nervous function in patients with coronary artery disease, and to determine whether the effects of lipophilic (metoprolol) and hydrophilic (atenolol) beta-blockers differ. Beta-blocking drugs increase spontaneous heart rate variability in healthy subjects and in patients with coronary heart disease, but little is known about their effects on baroreflex sensitivity and heart-rate based tests of autonomic integrity. In a randomly allocated double-blind crossover study with three 2-week treatment periods, metoprolol CR 200 mg once a day, or atenolol 100 mg once a day, or placebo once a day, were administered to 18 male patients with stable coronary artery disease. Baroreflex sensitivity was determined from the natural baroreflex challenge of Valsalva strain. Heart rate reactions to standard stimuli were measured. No significant differences were found between the effects of atenolol and metoprolol. Beta-blockade did not significantly affect the baroreflex sensitivity, but it diminished the Valsalva ratio significantly (P < 0.001). The difference between maximum and minimum heart rate during hyperventilation was also significantly lower during beta-blockade. The heart rate response to standing up and the ratio of maximum to minimum heart rate during deep breathing were not influenced by beta-blockade. Discontinuation of beta-blockade seems to be unnecessary for reliable determination of baroreflex sensitivity in patients with coronary artery disease, when the natural pressure challenge of Valsalva strain is sued. Both hydrophilic and lipophilic bet-blockers interfere with certain diagnostic tests of autonomic nervous function.(ABSTRACT TRUNCATED AT 250 WORDS)

Vagal heart rate control after percutaneous transluminal coronary angioplasty.

Impairment of vagal heart rate control is common in coronary artery disease. To evaluate whether percutaneous transluminal coronary angioplasty (PTCA) has any beneficial effect on this impairment we measured heart rate responses to deep breathing and to standing up, standard tests of cardiac parasympathetic activity, in 28 patients before and 4 weeks after successful PTCA. Before PTCA, 10 patients (36%) had an abnormal heart rate response to deep breathing and one patient (4%) an abnormal response to standing up. The heart rate responses did not change significantly from the preoperative values after PTCA. Thus, the relief of critical coronary obstruction by PTCA seems to have no beneficial effect on vagal heart rate control.

Effect of coronary artery bypass grafting on cardiac parasympathetic nervous function.

Low heart rate variability (HRV) is a predictor of a poor outcome after myocardial infarction. To determine whether coronary artery bypass grafting (CABG) has any effect on HRV, the power spectrum components of HRV were measured in 35 patients before, and 1 week after, CABG. Significant attenuation of all spectral components of HRV were found after CABG (P less than 0.001). High frequency (HF) power decreased to one third of the preoperative level, mid-frequency (MF) power to as little as one fifteenth and low frequency (LF) power to one seventh of the preoperative level. No significant restoration in MF or HF powers occurred during the 6-week follow-up period. The results suggest that CABG causes a marked attenuation of HRV. The prognostic significance of this attenuation is not known.

Circadian rhythms of frequency domain measures of heart rate variability in healthy subjects and patients with coronary artery disease. Effects of arousal and upright posture.

BACKGROUND: Altered neural regulation of the cardiovascular system may be an important factor for various manifestations of ischemic heart disease. This research was designed to compare the circadian rhythm of cardiac neural regulation and autonomic responses to arousal and upright posture between patients with uncomplicated coronary artery disease (CAD) and age-matched subjects with no evidence of heart disease. METHODS AND RESULTS: Twenty-four-hour heart rate variability (HRV) in the frequency domain was analyzed in 20 male patients (mean age, 52 +/- 7 years) with angiographic evidence of CAD without prior myocardial infarction and in 20 healthy men (mean age, 51 +/- 8 years) with no clinical, echocardiographic, or exercise ECG evidence of heart disease. None of the 24-hour average frequency-domain components of HRV differed significantly between the two groups. Healthy subjects had a significant circadian rhythm of normalized units of high-frequency (HF) power of HRV with higher values during sleep. Normalized units of low-frequency (LF) power and the LF/HF ratio also showed a significant circadian rhythm in healthy subjects, with higher values during the daytime. No significant circadian rhythms in any of the normalized spectral components of HRV were observed in patients with CAD, and the night-day difference in LF/HF ratio was smaller in the patients with CAD than in the healthy subjects (0.5 +/- 1.4 versus 1.8 +/- 0.7, P < .001). Awakening when in the supine position resulted in a significant increase in the LF/HF ratio (P < .01) in the healthy subjects, but no significant changes in HRV were observed after awakening in patients with CAD. Assumption of upright position resulted in a comparable decrease in the components of HRV between the groups. CONCLUSIONS: The circadian rhythm of cardiac neural regulation is altered in patients with uncomplicated CAD. Reduced autonomic responses to sleep-wake rhythm suggest that the modulation of cardiac autonomic function by stimuli from the central nervous system is impaired in CAD.

Valsalva manoeuvre in the assessment of baroreflex sensitivity in patients with coronary artery disease.

The overshoot rise in arterial pressure after release of Valsalva strain is a natural challenge for baroreflex regulation of heart rate. To assess the feasibility of the Valsalva manoeuvre in the determination of baroreflex sensitivity (BRS), we measured the slope of the linear relationship between the length of the RR interval and preceding systolic blood pressure value during the overshoot phase after the strain and compared this index of BRS to a standard phenylephrine test in 64 subjects, of whom 58 had coronary artery disease. The BRS slopes obtained with the Valsalva manoeuvre showed a good linear correlation with the phenylephrine test (r = 0.77 in the 27 patients with two Valsalva and phenylephrine tests and r = 0.56 in the whole cohort). The correlation coefficients of the BRS slopes were better than in the phenylephrine test (r = 0.89 vs r = 0.85, P < 0.05). The rise in systolic blood pressure in the slope calculation area was higher than with phenylephrine (41 +/- 18 vs 30 +/- 10 mmHg, P < 0.01). The reproducibility of BRS slopes in successive tests was comparable with both methods. These results suggest that non-invasive assessment of BRS using Valsalva strain to induce blood pressure rise is possible in patients with coronary artery disease.

Cross spectral analysis in assessment of baroreflex gain in patients with coronary artery disease.

BACKGROUND: Interest in determination of baroreflex sensitivity in clinical practice is growing because of its prognostic information in patients with heart disease. The purpose of the present study was to assess the feasibility of cross spectral analysis in the determination of baroreflex gain from spontaneous RR interval and systolic pressure fluctuations, and to compare the results to the traditional pharmacological method in patients with coronary artery disease. Methods. We measured the gain and time lag between RR interval and systolic pressure variabilities in the frequency domain, and compared baroreflex indexes obtained by this technique with standard phenylephrine tests in 32 patients with coronary artery disease. Results. Cross spectral analysis by fast Fourier transform techniques yielded acceptable (> 0.5) coherence between systolic pressure and RR interval in the mid- (0.07-0.15 Hz) and in the respiratory-frequency (0.15-0.40 Hz) band fluctuations in 30 patients (94%), with mean coherences of 0.69 and 0.74. The mean phase difference in the mid-frequency hand was greater than in the respiratory-frequency band (-83 vs -23 degrees, P < 0.001), suggesting that the mid-frequency fluctuations of RR intervals followed nearly 2 seconds after pressure changes, while respiratory-frequency fluctuations of RR intervals occurred nearly concomitantly with systolic pressure. The mean baroreflex slope derived from the bolus phenylephrine technique was 6.2 ms/mmHg (range 1.6-16.0), 5 patients had an abnormally low (<3 ms/mmHg) baroreflex sensitivity. Baroreflex gain determined by cross spectral analysis from the mid-frequency band correlated significantly (r = 0.60, P < 0.001, n = 27) with the baroreflex gain determined by the phenylephrine test, while the correlation in the respiratory-frequency band was not significant (r = 0.35, P = 0.09, n = 26). Conclusions. Baroreflex slopes derived from cross spectral techniques provide reliable (but not perfect) information regarding baroreflex gain derived from the clasic phenylephrine technique, even in patients with depressed baroreflex responses. Cross correlation calculation of spontaneous baroreflex slopes should be limited to data in the mid-frequency range, where the slopes are likely to reflect simple baroreflex physiology.