Giulia Sandrone

Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog.

In 57 normal subjects (age 20–60 years), we analyzed the spontaneous beat-to-beat oscillation in R-R interval during control recumbent position, 90° upright tilt, controlled respiration (n = 16) and acute (n = 10) and chronic (n = 12) β-adrenergic receptor blockade. Automatic computer analysis provided the autoregressive power spectral density, as well as the number and relative power of the individual components. The power spectral density of R-R interval variability contained two major components in power, a high frequency at ∼0.25 Hz and a low frequency at ∼0.1 Hz, with a normalized low frequency: high frequency ratio of 3.6 ± 0.7. With tilt, the low-frequency component became largely predominant (90 ± 1%) withalow frequency: high frequency ratio of 21 ± 4. Acute β-adrenergic receptor blockade (0.2 mg/kg IV propranolol) increased variance at rest and markedly blunted the increase in low frequency and low frequency: high frequency ratio induced by tilt. Chronic β-adrenergic receptor blockade (0.6 mg/kg p.o. propranolol, t.i.d.), in addition, reduced low frequency and increased high frequency at rest, while limiting the low frequency: high frequency ratio increase produced by tilt. Controlled respiration produced at rest a marked increase in the high-frequency component, with a reduction of the low-frequency component and of the low frequency: high frequency ratio (0.7 ± 0.1); during tilt, the increase in the low frequency: high frequency ratio (8.3 ± 1.6) was significantly smaller. In seven additional subjects in whom direct high-fidelity arterial pressure was recorded, simultaneous R-R interval and arterial pressure variabilities were examined at rest and during tilt. Also, the power spectral density of arterial pressure variability contained two major components, with a relative low frequency: high frequency ratio at rest of 2.8 ± 0.7, which became 17 ± 5 with tilt. These power spectral density components were numerically similar to those observed in R-R variability. Thus, invasive and noninvasive studies provided similar results. More direct information on the role of cardiac sympathetic nerves on R-R and arterial pressure variabilities was derived from a group of experiments in conscious dogs before and after bilateral stellectomy. Under control conditions, high frequency was predominant and low frequency was very small or absent, owing to a predominant vagal tone. During a 9% decrease in arterial pressure obtained with IV nitroglycerin, there was a marked increase in low frequency, as a result of reflex sympathetic activation. Bilateral stellectomy prevented this low-frequency increase in R-R but not in arterial pressure autospectra, indicating that sympathetic nerves to the heart are instrumental in the genesis of low-frequency oscillations in R-R interval.

Effects of beta blockers (atenolol or metoprolol) on heart rate variability after acute myocardial infarction

This study analyzed, with spectral techniques, the effects of atenolol or metoprolol on RR interval variability in 20 patients 4 weeks after the first uncomplicated myocardial infarction. Beta blocker-induced bradycardia was associated with a significant increase in the average 24-hour values of RR variance (from 13,886 +/- 1,479 to 16,728 +/- 1,891 ms2) and of the normalized power of the high-frequency component (from 22 +/- 1 to 28 +/- 2 normalized units), whereas the low-frequency component was greatly reduced (from 60 +/- 3 to 50 +/- 3 normalized units). When considering day and nighttime separately, the effects of both drugs were more pronounced in the daytime. In addition, a marked attenuation was observed in the circadian variation of the low-frequency component after beta blockade. As a result, the early morning increase of the spectral index of sympathetic modulation was no longer detectable. These results indicate that beta-blocker administration has important effects on RR interval variability and on its spectral components. The observed reduction in signs of sympathetic activation and the increase in vagal tone after beta blockade help to explain the beneficial effects of these drugs after myocardial infarction. However, the potential clinical relevance of the increase in RR variance remains to be established.

Linear and nonlinear dynamics of heart rate variability after acute myocardial infarction with normal and reduced left ventricular ejection fraction

We analyzed heart rate variability (HRV) in 2 groups of patients after acute myocardial infarction with normal and reduced ejection fraction (EF) by considering both the power of the 2 major harmonic components at low and high frequency and 2 indexes of nonlinear dynamics, namely the 1/f slope and the correlation dimension D2. HRV of patients with a reduced EF was characterized by a diminished RR variance as well as a different distribution of the residual power in all frequency ranges, with lower values of the low-frequency component expressed in both absolute and normalized units, and of the low- to high-frequency ratio. In these patients we also observed a steeper slope of the negative regression line between power and frequency in the very low frequency range. The presence of a smaller fractal dimension was suggested by a lower D2. Thus, in patients after acute myocardial infarction with a reduced EF, the reduction in HRV is associated with a different distribution of the residual power in the entire frequency range, which suggests a diminished responsiveness of sinus node to neural modulatory inputs.

Circadian variation of spectral indices of heart rate variability after myocardial infarction

The circadian variations of spectral indices of heart rate variability were analyzed in 20 patients 4 weeks after a first and uncomplicated myocardial infarction (MI) and in 20 control subjects. R-R interval and variance showed a characteristic day-night pattern with a significant reduction of the latter parameter in patients after MI (10,967 +/- 1109 msec2 vs 16,860 +/- 2132 msec2). Control subjects were characterized by a predominance of low-frequency (approximately 0.1 Hz) component during the day and of high-frequency (approximately 0.25 Hz) component during the night, which reflected the expected 24-hour pattern of variation of sympatho-vagal balance. A 24-hour elevation (64 +/- 3 normalized units [nu] vs 56 +/- 2 nu; p less than 0.05) of the low-frequency component and a smaller (23 +/- 2 nu vs 32 +/- 2 nu; p less than 0.05) high-frequency component during the night differentiated patients after MI from subjects. The difference between the two groups was even more evident when the 24-hour sympatho-vagal balance was assessed with the low frequency/high frequency ratio. Thus spectral analysis of heart rate variability indicates that in patients after MI there is an alteration of neural control mechanisms as indicated by the presence of signs of sympathetic activation and by the attenuation of the nocturnal increase in vagal tone.

Heart rate variability in the early hours of an acute myocardial infarction.

The occurrence of an autonomic disturbance early in acute myocardial infarction (AMI) has been reported: signs of sympathetic activation were mainly observed in relation to an anterior localization, whereas signs of vagal overactivity were more frequent in inferior wall AMI. Information is limited in relation to the persistence of these alterations during the early hours of AMI. We studied 33 patients with an AMI within 188 +/- 16 minutes from the onset of symptoms and 1 week after hospital admission. From a 20-minute Holter recording, we computed with autoregressive methodology, time and frequency domain indexes of heart rate variability. At admission, patients with an anterior wall AMI exhibited a smaller RR variance (593 +/- 121 ms2) than did those with an inferior wall AMI (1,122 +/- 191 ms2). In both groups the spectral profile was characterized by a predominant (73 +/- 4 and 61 +/- 4 normalized units) low frequency and by a small (13 +/- 2 and 22 +/- 3 normalized units) high-frequency component, indicating the presence of a sympathetic excitation and of a diminished vagal modulation. Although signs of sympathetic activation were more evident in patients with anterior wall AMI, no evidence of a vagal hyperactivity was observed in patients with inferior wall AMI. In the latter group, we noticed 1 week after the acute event an increase in the low-frequency component, which reached the values observed in patients with anterior wall AMI. Thrombolysis did not affect heart rate variability parameters. Thus, this study suggests the presence of an autonomic disturbance characterized by signs of sympathetic excitation and of a reduced vagal modulation, which was more evident in patients with an anterior localization early after AMI.

Analysis of the pressor sympathetic reflex produced by intracoronary injections of bradykinin in conscious dogs.

The reflex hemodynamic effects of intracoronary bradykinin were tested in 20 conscious instrumented dogs. When the experiments were performed after full recovery from surgery and anesthesia, graded doses (10–300 ng/kg) of bradykinin always produced graded pressor responses, in the absence of any pain reaction. At the maximum pressor response obtained with 100 ng/kg, mean arterial pressure rose 28 ± 3% from 89 ± 4 mm Hg, left ventricular pressure 20 ± 3% from 121 ± 2 mm Hg, heart rate 30 ± 4% from 88 ± 5 beats/min, rate of change of left ventricular pressure 18 ± 3% from 2812 ± 65 mm Hg/sec (P < 0.01). Higher doses of bradykinin did not produce greater responses. The magnitude of the response was similar when the injection was performed in either the left anterior descending (change in mean arterial pressure 29 ± 3%) or circumflex (change in mean arterial pressure 27 ± 2%) coronary artery. The reflex nature of the response was proved by its disappearance after appropriate pharmacological blockades; moreover, after vagotomy, the pressor rise was maintained, the heart rate response was reduced (change in heart rate 10 ± 2%), and the inotropic response was enhanced (rate of change of left ventricular pressure 24 ± 3%). This suggested that the afferent pathway of the pressor reflex was in the sympathetic nerves and that a subordinate vagal depressor reflex was also operative. No pain reaction was obtained even when injecting very large amounts (1000–2000 ng/kg) of bradykinin, which, instead, induced arterial hypotension. Pain reactions (as inferred by agitation and vocalization) were observed in three out of nine dogs studied during the first week after surgery. This reaction was no longer present when the same animals were tested later on, at the time of complete recovery. In five of the nine dogs studied during the first week after surgery, the intracoronary injection of bradykinin produced a depressor (change in mean arterial pressure −31 ± 6%) response, which, however, reverted to a pressor effect (change in mean arterial pressure 22 ± 4%) later, when recovery was complete. In five additional dogs, the pressor response observed after full recovery from surgery was no longer present when the injection of bradykinin was repeated under anesthesia. The present experiments in conscious dogs show that the chemical stimulation of the fully innervated heart with intracoronary bradykinin can initiate pressor reflexes independent of pain and in the presence of intact buffering mechanisms.

Beta-blocking effect of propafenone based on spectral analysis of heart rate variability

RR variability was analyzed in 15 patients with ventricular arrhythmias to evaluate whether the antiarrhythmic action of propafenone is associated with alteration of neural control mechanisms. Before drug administration, spectral analysis of RR variability was characterized by 2 major components at low and high frequency, which are considered to reflect sympathetic and parasympathetic modulation of the heart period. After propafenone (600 to 900 mg/day), there was a marked reduction in RR variance (826 +/- 184 to 412 +/- 77 ms2; p < 0.05), although the mean RR interval was unchanged. The drug significantly reduced the low-frequency component (52 +/- 6 to 28 +/- 4 nu) and augmented the high-frequency component (39 +/- 6 to 55 +/- 5 nu). As a result, the low-/high-frequency ratio (an index of sympathovagal balance) decreased from 2.0 +/- 0.4 to 0.6 +/- 0.1. A positive correlation between serum levels and drug-induced changes in the low-frequency component was also observed. Furthermore, the increase in the low-frequency component induced by tilt (53 +/- 5 to 79 +/- 3 nu) was markedly attenuated after drug administration (27 +/- 5 to 54 +/- 7 nu). Thus, propafenone administration is associated with changes in spectral components that are consistent with a beta-blocking effect of the drug.

Reliability of the measurement of RT variability

The variability of the interval between the R peak and the apex of T wave has a power 2-3 orders of magnitude smaller than that of RR interval variability therefore, adequate recording, pre-processing and detection procedures are required to avoid artefacts. Emphasis is posed on the dramatic differences occurring between different leads, which are explained as artefacts induced by changes in the cardiac electrical axis. A satisfactory compensation appears to be provided by the modulus signal from three orthogonal leads. So, the low frequency (LF) and high frequency (HF) components were clearly recognised in 14 normal (N) subjects and in 12 patients 2 weeks after myocardial infarction (MI). This was confirmed by the cross-spectrum between the RT and the RR series. In N, HF (36.7/spl plusmn/23.1 nu.) was predominant over LF (25.4/spl plusmn/14.5), while in MI the ratio was inverted (LF=37.0/spl plusmn/23.3, HF=25.6/spl plusmn/13.9).<<ETX>>

Model for RT-RR variability interaction assessment

A parametric dynamic model to evaluate the dependence of the ventricular repolarization duration on the heart period and on different not measurable inputs is proposed. Its parameters were identified from the beat-to-beat series of the cardiac cycle duration (RR interval) and ventricular repolarization period (RT period). Indexes relevant to the RT-RR relationship both in time and in frequency domain were extracted and validated in human subjects during experimental conditions known to alter the RT-RR coupling and/or sympatho-vagal balance.

Nothing as it seems

Dr. Tobaldini: An 82-year-old woman was brought by her daughter to the Emergency Department (ED) because she was found on the ground, confused, with right ocular deviation, dysarthria, left hemisoma hyposthenia, attention and executive functions’ deficit. The past medical history was significant for Lewy bodies dementia and systemic hypertension. Her medications included quetiapina, selegina, zolpidem, escitalopram, acetylsalicylic acid, atenolol, enalapril and amlodipina. On admission to ED, the patient was confused and apyretic; blood pressure was 235/135 mmHg, SatO2 97 % in ambient air, heart rate 95 beats/min, respiratory rate 26/min and plasma glucose 101 mg/dl. General physical examination revealed pulmonary bibasilar crackles. Neurological examination showed a left sided inattention, right ocular deviation, left partial vision paralysis, deficiency of the VII left cranial nerve, left hemisoma hyposthenia, positive Babinsky reflex on the left side, deep pain stimulus extinction on the left side; the NIH Stroke Scale (NIHSS) score was 11. Laboratory blood tests, ECG and a chest X-ray study were normal; the first brain CT-scan performed showed a past lacunar ischemia of the left thalamic region but it was negative for acute lesions. In the ED, the patient was treated with captopril and urapidil for blood pressure control; due to the patient’s agitation, iv delorazepam was administered. The patient was admitted to internal medicine service. The patient was sleepy but arousable, the physical examination remained unchanged.