Comparative effects of mibefradil and nifedipine gastrointestinal transport system on autonomic function in patients with mild to moderate essential hypertension.

BACKGROUND: L-type dihydropyridine calcium channel blockers (CCBs) have been implicated in increased cardiovascular events in patients with hypertension, perhaps due to adverse effects on autonomic nervous system (ANS) function. Blockade of T-type calcium channels may limit ANS dysfunction by inhibition of T channel-mediated neuroendocrine effects. OBJECTIVE AND DESIGN: This double-blind, parallel group study compared the effect of nifedipine gastrointestinal transport system (GITS) (L-type CCB) versus mibefradil (T-type CCB) on ANS function in patients with mild-moderate essential hypertension. METHODS: Sixteen patients (10 male, 6 female; age 57.2 +/- 2.3 years), diastolic blood pressure (DBP) < 95 mmHg were randomized to nifedipine 30 mg daily or mibefradil 50 mg daily (2 weeks), then nifedipine 60 mg daily or mibefradil 100 mg daily (4 weeks). Sympathetic nervous system activity (SNSA) was assessed using norepinephrine kinetics. Parasympathetic nervous system activity (PSNA) was assessed from 24 h Holter recordings of heart rate variability (HRV). Non-invasive baroreflex sensitivity (BRS) provided integrated assessment of ANS. RESULTS: Patient groups were well matched at baseline. Achieved DBP was lower in patients treated with mibefradil compared with nifedipine, (83.4 +/- 1.7 versus 95.25 +/- 3.3 mmHg). There were no significant differences in SNSA and BRS between groups, however the root mean square of successive differences and high frequency power (HFP) were increased in mibefradil compared with nifedipine-treated patients [(+ 1.07 +/- 1.6 versus -3.36 +/- 1.2 ms, P < 0.05) and (+ 0.28 +/- 0.1 versus -0.23 +/- 0.1 ms2, P < 0.01), respectively]. Furthermore, Ln HFP/Ln total power was increased from week 0 to week 6 in the mibefradil-treated group, (0.71 +/- 0.02 versus 0.74 +/- 0.03, P = 0.046). CONCLUSION: No differences existed between effect of L- and T-type CCBs on SNSA and BRS. However, T-type CCBs increased PSNA, independent of achieved changes in heart rate.

Reduced dietary fat intake increases parasympathetic activity in healthy premenopausal women.

1. Hypercholesterolaemia has been associated with decreased heart rate variability, a measure of cardiac parasympathetic activity. However, the effect of perturbation of the lipid profile on autonomic function has not been examined systematically. 2. The effects of short-term dietary lipid modification on autonomic function are studied in 25 normotensive, non-smoking, premenopausal women with normal bodyweight. Subjects consumed either a low (L, 25%) or high fat (H, 40%) diet for 2 weeks in an open, randomized, cross-over manner with a 2 week washout. 3. Baroreflex sensitivity was determined by gating beat-to-beat heart period (RR) interval and continuous non-invasive blood pressure recordings. Heart rate variability measures of cardiac parasympathetic nervous system activity were obtained in the time (standard deviation of RR intervals, root mean square of successive differences (rMSSD)) and frequency (high frequency power) domains. All assessments were made at the same timepoint in the menstrual cycle. 4. Both low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol decreased significantly (P < 0.05) with increased dietary fat intake (H, 2.7 +/- 0.1 vs L, 2.2 +/- 0.1; H, 1.3 +/- 0.1 vs L, 1.1 +/- 0.1 mmol/L, respectively) as did mean arterial pressure (H, 78.1 +/- 1.5 vs L, 74.3 +/- 1.5 mmHg). Weight was unchanged by dietary lipid intake (H, 62.6 +/- 8.5 vs L, 62.3 +/- 8.3 kg, P = NS). 5. There was a significant increase in rMSSD (H, 29.6 +/- 3.4 vs L, 38.8 +/- 6.4 msec, P < 0.05) and natural logarithm of high frequency power following low fat diet (H, 4.4 +/- 0.2 vs L, 4.8 +/- 0.3 msec2, P = 0.01). Baroreflex sensitivity also increased following the low fat diet (H, 13.91 +/- 2.2 vs L, 16.9 +/- 3.2 msec/mmHg, P = 0.23). 6. Short-term dietary lipid modification can significantly increase cardiac parasympathetic nervous system activity in healthy premenopausal women. These changes in autonomic status appear to be independent of changes in bodyweight and may be of clinical relevance considering the prognostic implications of heart rate variability in cardiovascular disease.

Low-dose but not high-dose captopril increases parasympathetic activity in patients with heart failure.

Parasympathetic nervous activity (PSNA) is an important determinant of the risk of sudden death and outcome in patients with cardiovascular disease, so the effects of drug therapy on PSNA may be of prognostic importance in patients with chronic heart failure (CHF). The angiotensin-converting enzyme (ACE) inhibitors are the only drugs that are reasonably accepted to improve prognosis in such patients. Accordingly we determined PSNA by heart-rate variability (HRV) analysis in nine patients (four women and five men, aged 73.6 +/- 6 yrs) with heart failure (NYHA Classes II-III) and in sinus rhythm. HRV was determined during 20-40 min supine rest at baseline and then at 2-weekly intervals during incremental dosing of oral captopril, 12.5 mg b.i.d., 25 mg b.i.d., and 50 mg b.i.d. Poincaré plot and conventional time- and frequency-domain measures were used to analyze the data. Low-dose captopril (12.5 mg b.i.d.) resulted in an increase in SD delta RR (16.0 +/- 6.6 to 22.0 +/- 9.1 ms; p < 0.05). We previously validated this as a measure of PSNA. Higher dose captopril (25 mg b.i.d.) also produced an increase in PSNA activity (16.0 +/- 6.6 to 18.7 +/- 7.8 ms), although this failed to reach statistical significance. However, the highest dose of captopril (50 mg b.i.d.) reduced PSNA activity to near-baseline values, as shown by measures of HRV in both the time and frequency domains. These data suggest that only a low dose of captopril augments PSNA in patients with heart failure. Dosing of ACE inhibitors may be important in optimizing their benefit in CHF.

Poincaré plot of heart rate variability allows quantitative display of parasympathetic nervous activity in humans.

1. Time domain summary statistics and frequency domain parameters can be used to measure heart rate variability. More recently, qualitative methods including the Poincaré plot have been used to evaluate heart rate variability. The aim of this study was to validate a novel method of quantitative analysis of the Poincaré plot using conventional statistical techniques. 2. Beat-to-beat heart rate variability was measured over a relatively short period of time (10-20 min) in 12 healthy subjects aged between 20 and 40 years (mean 30 +/- 7 years) during (i) supine rest, (ii) head-up tilt (sympathetic activation, parasympathetic nervous system activity withdrawal), (iii) intravenous infusion of atropine (parasympathetic nervous system activity withdrawal), and (iv) after overnight administration of low-dose transdermal scopolamine (parasympathetic nervous system augmentation). 3. The "width' of the Poincaré plot, as quantified by SD delta R-R (the difference between successive R-R intervals), was determined at rest (median 48.9, quartile range 20 ms) and found to be significantly reduced during tilt (median 19.1, quartile range 13.7 ms, P < 0.01) and atropine administration (median 7.1, quartile range 5.7 ms, P < 0.01) and increased by scopolamine (median 79.3, quartile range 33 ms, P < 0.01). Furthermore, log variance of delta R-R intervals correlated almost perfectly with log high-frequency (0.15-0.4 Hz) power (r = 0.99, P < 0.01). 4. These findings strongly suggest that the "width' of the Poincaré plot is a measure of parasympathetic nervous system activity. The Poincaré plot is therefore a quantitative visual tool which can be applied to the analysis of R-R interval data gathered over relatively short time periods.

Non-invasive assessment of baroreflex sensitivity and relation to measures of heart rate variability in man.

1. We have developed a simple noninvasive method to assess the spontaneous baroreflex (BRS; reflex heart rate response to change in systemic blood pressure) in man. The BRS is impaired in many cardiovascular disorders and is known to be of major prognostic significance; however, the invasive nature of traditional BRS assessment has thus far limited its clinical application. 2. Sixteen healthy subjects (7M, 9F; age 28 +/- 3 years) were studied at baseline and during stepwise i.v. infusion of phenylephrine and bolus i.v. dosing of nitroprusside. Invasive BRS was derived from linear regression of the change in systolic blood pressure (SBP) and RR interval from baseline following these perturbations. Noninvasive BRS was derived from approximately 1500 gated beat-to-beat SBP and RR interval data points acquired by Finapres BP and continuous ECG monitoring. Slopes were derived from linear regression of three consecutive baroreflex-mediated data points (following a phase shift of one RR interval from its accompanying SBP value) and were averaged to determine BRS. Correlations between invasive and noninvasive BRS measures were found to be highly significant (r = 0.78; P = 0.0009; slope = 0.87). 3. Significant correlations between noninvasively determined BRS and heart rate variability derived measures of autonomic activity (24h standard deviation of normal RR intervals, root mean square of successive RR intervals, low frequency and high frequency power) were also observed (r = 0.79-0.83; P = 0.003-0.008). 4. These results support the validity of this noninvasive method of measurement of BRS in man and of parasympathetic contribution to spontaneous baroreflex.

Application of the Poincaré plot to heart rate variability: a new measure of functional status in heart failure.

BACKGROUND: Conventional methods of quantifying heart rate variability using summary statistics have shown that decreased variability is associated with increased mortality in heart failure. However, many patients with heart failure have arrhythmias which make the 'raw' heart rate variability data less suitable for the use of summary statistical measures. AIMS: To examine the clinical potential of a new measure of heart rate variability data, presented by the Poincaré plot pattern, as an adjunct to the summary statistical measures of R-R interval variability. METHODS: We used the Poincaré plot pattern to display beat-to-beat heart rate variability data from a group of 23 patients with heart failure and compared them with data collected from 20 healthy age-matched control subjects. The data, which consists of 2000 consecutive R-R intervals, were gathered over 20-40 minutes while the subjects rested supine in a quiet darkened room. RESULTS: The morphological classification scheme proposed reflected the functional status of patients in heart failure. There was a significant difference (chi-square = 27.5, p < 0.0001) in the different pattern types between patients with NYHA Class I and II compared to patients with NYHA Class II and IV. All healthy subjects displayed a 'cluster' type of pattern characterised by normally distributed data. Sixteen of the 23 patients in heart failure also produced data which were normally distributed but the remaining seven produced data which required careful filtering to make them suitable for analysis using summary statistics, but which could be analysed by the Poincaré plot. CONCLUSIONS: The Poincaré plot pattern is a semi-quantitative tool which can be applied to the analysis of R-R interval data. It has potential advantages in that it allows assessment of data which are grossly non-Gaussian in distribution, and is a simple and easily implemented method which can be used in a clinical setting to augment the standard electrocardiogram to provide 'real time' visualisation of data.