Complement and contact system activation in acute congestive heart failure patients.

Recent experimental data indicate a pathogenic role of complement activation in congestive heart failure (CHF). The aim of this study was to evaluate contact and complement systems activation in patients hospitalized for an acute episode of CHF. Forty-two of 80 consecutive patients admitted at our hospital with confirmed diagnosis of acute CHF were enrolled. They underwent blood sampling within 24 h from admission (T0) and at clinical stability (T1). Patients were stratified for ejection fraction (EF) based on echocardiographic test. We measured plasma levels of C3, C4, sC5b-9 and cleaved high molecular weight kininogen (contact activation marker). At T1, C3 levels increased significantly compared to T0 (97 ± 2 versus 104 ± 3% of total pooled plasma, P < 0·01). Classifying patients according to EF, only patients with preserved EF presented a significant increase of C3 from T0 to T1 (99 ± 3 versus 108 ± 4%, P = 0·03). When the sample was stratified according to clinical outcome, C3 (98 ± 3 versus 104 ± 4%, P = 0·03) and sC5b-9 levels (204 ± 10 versus 230 ± 11 ng/ml, P = 0·03) were increased in patients who had positive outcome after hospitalization. CHF patients with preserved EF and positive outcome after hospitalization showed higher levels of sC5b-9 in the T1 period compared with T0 (211 ± 14 versus 243 ± 14 ng/ml, P = 0·04). Our results suggest that the complement system reacts differently if CHF occurs with preserved or reduced EF. This finding is interesting if we consider the difference in epidemiology, pathogenesis and possible therapeutic approaches of these two clinical entities.

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.

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.

Spectral analysis of short term R-Tapex interval variability during sinus rhythm and fixed atrial rate.

Analysis of heart rate variability has been proven useful in stratifying post myocardial patients at risk and in evaluating autonomic dysfunction. Recently augmented inter-lead variability of the QT interval has been associated with increased mortality as a result of arrhythmia and proposed as a marker of dispersion of ventricular repolarization. As the duration of the QT interval is largely dependent upon the length of the preceding cardiac cycle it is tempting to analyse whether neural mechanisms might also directly exert additional modulation. Using autoregressive algorithms we therefore analysed RR and R-Tapex interval variabilities in 15 normal subjects during sinus rhythm and in six patients with a fixed atrial rate. In controls mean R-Tapex interval and variance measured on the vector magnitude were, respectively, 245 +/- 6 ms and 5.1 +/- 0.7 ms2. Spectral analysis of R-Tapex indicated the presence of two spectral components which corresponded to the low and high frequency components of heart rate variability. In R-Tapex variability, high frequency (44 +/- 4 nu) was predominant over low frequency (29 +/- 4 nu). During controlled respiration, a manoeuvre associated with enhanced vagal modulation of sinus node, there was a further increase in high frequency (58 +/- 4 nu) whereas during tilt the low frequency component of R-Tapex variability became predominant (57 +/- 6 nu). In patients with a fixed atrial rate, variance was extremely low (3 +/- 0.9 ms2) and only a respiration-related high frequency component was recognizable in spectral analysis of RR and R-Tapex variabilities. This component was likely to depend upon mechanically induced changes in cardiac vector orientation. These data indicate that during sinus rhythm short-term R-Tapex interval variability is characterized by the same rhythmical components present in RR variability. However, the presence of a very low variance and of only a high frequency component in patients in whom the physiological variability of sinus node is abolished by atrial pacing. suggests that neural modulatory mechanisms do not exert a direct effect on the length of the R-Tapex 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.

Evidence of functional alterations in sympathetic activity after myocardial infarction.

To assess whether the presence of areas of efferent sympathetic denervation might contribute to alterations in sympathetic and vagal neural regulatory activities observed after myocardial infarction, we attempted to correlate the changes in the spectral components of RR variability with the I-123 MIBG and Thallium-201 uptake defects. Ten patients with first and uncomplicated myocardial infarction were studied. Thallium-201 and I-123 MIBG scintigraphy as well as spectral analysis of heart rate variability were performed 7 days, 4, 12 and 30 months after the acute event. Regional abnormalities in I-123 MIBG uptake were more extensive than the perfusion defects indicated by Thallium-201 images and remained constant throughout the entire period of observation. In the early post-infarction period, spectral analysis of RR variability was characterized by a predominant LF (74 +/- 6 nu) and a smaller HF (16 +/- 3 nu) component indicating a sympathetic predominance. Thereafter, we observed a progressive reduction in LF and a gradual increase in HF which were consistent with a normalization of sympatho-vagal balance. These data indicate that after a myocardial infarction, the presence and persistence of areas of sympathetic functional denervation do not seem to play a major role in determining the changes in sympathetic and vagal neural regulatory activities directed to the heart.

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.

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.

Autonomic nervous system adaptations to short-term exercise training.

Signs of sympathetic hyperactivity and low parasympathetic activity have been found during the acute and recovery phases of myocardial infarction and have been associated with an increased risk of cardiac mortality. Beneficial effects of physical training have been recently reported in post-myocardial infarction patients. We tested the hypothesis that physical training would be effective in improving the autonomic balance by studying 22 patients with a first and recent myocardial infarction who were randomly assigned to enter or not enter a 4-week in-hospital physical training program. Spectral indices of heart rate variability were analyzed at rest and during 70 degrees head-up tilt before and after the index training, not training period. As expected, physical training induced a significant increase in exercise duration (13.7 +/- 0.8 vs 17.1 +/- 0.1 min, p less than 0.001) and in the anaerobic threshold (9.5 +/- 0.7 vs 12.0 +/- 1.0 min, p less than 0.02) in trained patients, while no changes were observed in the untrained group. At entry, in both groups, spectral profile of heart rate variability was characterized by a predominant LF component and a smaller HF component with no further modification after head-up tilt. After 4 weeks, in resting conditions, no significant changes in spectral components were observed in both trained and untrained patients. After physical training, head-up tilt produced significant modifications in spectral profile with an increase in the LF component (84 +/- 3 vs 69 +/- 5 nu, p less than 0.01) and a decrease in the HF component (7 +/- 1 vs 19 +/- 4 nu, p less than 0.05) in trained patients, while no changes were observed in the untrained patients. Our data suggest that in postmyocardial infarction patients, 4 weeks of physical training may induce an improvement in the autonomic balance with a restoration toward normal in the reflex activity of the system.

Heart rate variability as an index of sympathovagal interaction after acute myocardial infarction.

By analysis of spectral components of heart rate variability, sympathovagal interaction was assessed in patients after acute myocardial infarction (AMI). At 2 weeks after AMI (n = 70), the low-frequency component was significantly greater (69 +/- 2 vs 53 +/- 3 normalized units [NU], p less than 0.05) and the high-frequency component was significantly smaller (17 +/- 1 vs 35 +/- 3 NU) than in 26 age-matched control subjects. This difference was likely to reflect an alteration of sympathovagal regulatory outflows with a predominance of sympathetic activity. At 6 (n = 33) and 12 (n = 29) months after AMI, a progressive decrease in the low- (62 +/- 2 and 54 +/- 3 NU) and an increase in the high-frequency (23 +/- 2 and 30 +/- 2 NU) spectral components was observed, which suggested a normalization of sympathovagal interaction. An increase in sympathetic efferent activity induced by tilt did not further modify the low-frequency spectral component (78 +/- 3 vs 74 +/- 3 NU) in a subgroup of 24 patients at 2 weeks after AMI. Instead, 1 year after AMI, this maneuver was accompanied by an increase in the low-frequency component (77 +/- 3 vs 53 +/- 3 NU, p less than 0.05) of a magnitude similar to the one observed in control subjects (78 +/- 3 vs 53 +/- 3 NU). These data indicate that the sympathetic predominance that is detectable 2 weeks after AMI is followed by recovery of vagal tone and a normalization of sympathovagal interaction, not only during resting conditions, but also in response to a sympathetic stimulus.

Effects of verapamil, nifedipine, and dilazep on left ventricular relaxation in the conscious dog.

The cardiac systolic and diastolic effects of the two major calcium blockers, verapamil and nifedipine, were studied and compared with those produced by dilazep, a relatively new vasodilator with calcium blocking properties, in conscious instrumented dogs to avoid the complications of anaesthesia and recent surgery. Mean arterial pressure was reduced by nifedipine and dilazep but not by verapamil, whereas peak left ventricular pressure was reduced only by dilazep and verapamil. Consistent tachycardia occurred, the rate being highest with nifedipine and lowest with dilazep. Left ventricular dP/dt was unaffected by dilazep, reduced by verapamil, and increased by nifedipine; this increase was no longer observed after beta adrenergic blockade. Ventricular relaxation was assessed by calculating the time relaxation constant, tau. Verapamil increased tau significantly only after beta adrenergic blockade, whereas nifedipine and dilazep reduced it both before and after beta adrenergic blockade. These data suggest that reflex beta adrenergic mechanisms may modulate the effects of calcium blockade on both systolic and diastolic performance.

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 degrees upright tilt, controlled respiration (n = 16) and acute (n = 10) and chronic (n = 12) beta-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 approximately 0.25 Hz and a low frequency at approximately 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%) with a low frequency:high frequency ratio of 21 +/- 4. Acute beta-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 beta-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.(ABSTRACT TRUNCATED AT 400 WORDS)

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 less than 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Power spectral density of heart rate variability as an index of sympatho-vagal interaction in normal and hypertensive subjects.

Instantaneous heart rate reflects sympatho-vagal influences on pace-maker activity. Hence computer analysis of heart rate variability might provide a quantitative index of that interaction. The power spectral density (PSD) estimate of heart rate variability was obtained in normal controls and in uncomplicated hypertensives, both at rest and during a non-hypotensive sympathetic stimulus (tilting). In normal controls PSD shows three major peaks of frequencies P1 = 0.07, P2 = 0.12, P3 = 0.25 cycles/beat. P1, which is associated with sympathetic activity, represents only a minor portion of total variability at rest, while becoming predominant with tilting. P2 and P3 are associated with vagal activity, and represent the major part of variability at rest, while they are reduced by tilting. In hypertensive patients PSD is altered, as P1 is already predominant at rest and increases only slightly with tilting. Thus PSD of heart rate variability is capable of detecting an early alteration in sympatho-vagal balance of cardiac control present in uncomplicated hypertension.