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Circulation. 1995;92:555-561

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(Circulation. 1995;92:555-561.)
© 1995 American Heart Association, Inc.

Articles

Early Left Ventricular Dysfunction Elicits Activation of Sympathetic Drive and Attenuation of Parasympathetic Tone in the Paced Canine Model of Congestive Heart Failure

Presented in part at the 65th Scientific Sessions of the American Heart Association, New Orleans, La, November 16-19, 1992.

Gregory M. Eaton, MD; Robert J. Cody, MD; Enrico Nunziata, MSBME; Philip F. Binkley, MD

From the Department of Medicine, Division of Cardiology, the Ohio State University, Columbus.

Correspondence to Dr Gregory M. Eaton, Department of Internal Medicine, Division of Cardiology, The Ohio State University, 1654 Upham Dr, 631 Means Hall, Columbus, OH 43210.


*    Abstract
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 *Abstract
down arrowIntroduction
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down arrowResults
down arrowDiscussion
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Background Although autonomic imbalance is known to be characteristic of patients with clinically overt symptomatic congestive heart failure, it is currently unknown whether this autonomic response arises early in the course of left ventricular dysfunction or is restricted to the later stages of circulatory failure.

Methods and Results This investigation utilized the technique of spectral analysis of heart rate variability in a paced canine model of congestive heart failure that permits an examination of autonomic activity at the earliest stages of ventricular dysfunction to determine whether early systolic dysfunction in congestive heart failure is characterized by autonomic imbalance, which may contribute to subsequent myocardial and vascular dysfunction. The results indicate that autonomic imbalance as reflected in an abnormal pattern of heart rate variability evolves early in the course of ventricular systolic dysfunction consisting of both a significant increase in sympathetically influenced low-frequency heart rate variability and a significant reduction of parasympathetically mediated high-frequency variability. This was quantified by a marked and significant increase in the area under the low-frequency region from 0.053±0.037 (beats per minute)2 at baseline to 0.182±0.143 (beats per minute)2 at 48 hours to 0.253± 0.202 (beats per minute)2 after 7 days of pacing (ANOVA, P<.04). The area under the high-frequency region of the curve showed a decrease from a baseline value of 0.945±0.037 (beats per minute)2 to 0.811±0.152 (beats per minute)2 at 48 hours to 0.733±0.197 (beats per minute)2 after 7 days of pacing (ANOVA, P<.03). This resulted in a shift in autonomic balance away from parasympathetic tone and toward augmented sympathetic drive as reflected by the ratio of high- to low-frequency areas from a baseline value of 15.2±9.6 to 10.1±6.89 at 48 hours and 0.004±0.001 at 7 days (ANOVA, P<.01).

Conclusions The results indicate that autonomic imbalance as reflected in an abnormal pattern of heart rate variability evolves early in the course of ventricular systolic dysfunction consisting of both a significant increase in sympathetically influenced low-frequency heart rate variability and a significant reduction of parasympathetically mediated high-frequency variability. The early appearance of these autonomic abnormalities suggests that autonomic imbalance plays a significant role in promoting the progression of circulatory failure.


Key Words: heart failure • heart rate • spectrum analysis


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Chronic ventricular dysfunction is characterized by aberrations of the neuroendocrine axis that consist in part of a marked imbalance of the autonomic nervous system.1 2 3 4 5 This imbalance comprises a marked augmentation of sympathetic drive as well as an attenuation of parasympathetic tone.6 7 8 9 10 11 12 This disruption of autonomic balance appears to significantly contribute to the vasoconstriction that accompanies ventricular failure. The resultant sustained vasoconstriction and subsequent elevation in ventricular afterload may perpetuate further ventricular failure and contribute to progression of symptoms of congestive heart failure. The development of congestive heart failure in a paced canine model is also associated with the activation of the renin-angiotensin system and increases in plasma norepinephrine.13 14 15 Previously we have shown that the induction of congestive heart failure in this model resulted in alterations in the autonomic profile as defined by the technique of spectral analysis of heart rate variability, which resemble those seen in humans with ventricular failure.16 Specifically, a significant increase in sympathetically influenced low-frequency heart rate variability and reduction of parasympathetically governed high-frequency variability were observed.16 Although autonomic imbalance is known to be characteristic of patients with clinically overt symptomatic congestive heart failure, it is currently unknown whether this autonomic response arises early in the course of left ventricular dysfunction or is restricted to the later stages of circulatory failure.

The identification of early neuroendocrine activation has important therapeutic implications because early introduction of treatment designed to alter this autonomic imbalance may prevent progression of ventricular dysfunction and the development of clinical heart failure. This investigation utilized the technique of spectral analysis of heart rate variability in a paced canine model of congestive heart failure that permits an examination of autonomic activity at the earliest stages of ventricular dysfunction to determine whether early systolic dysfunction in congestive heart failure is characterized by autonomic imbalance, which may contribute to subsequent myocardial and vascular dysfunction. The results indicate that autonomic imbalance as reflected in an abnormal pattern of heart rate variability evolves early in the course of ventricular systolic dysfunction consisting of both a significant increase in sympathetically influenced low-frequency heart rate variability and a significant reduction of parasympathetically mediated high-frequency variability. The early appearance of these autonomic abnormalities in the evolution of ventricular dysfunction suggests that autonomic imbalance plays a significant role in promoting the progression of circulatory failure.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
Prospective Evaluation of Autonomic Dysfunction in a Paced Canine Model of Congestive Heart Failure
To prospectively examine the evolution of autonomic dysfunction in congestive heart failure with gradual and progressive induction of ventricular systolic dysfunction, studies were performed in closed chest, conditioned beagles aged 1 to 2 years. The protocol was reviewed and approved by the Animal Use Committee of the Ohio State University. Closed chest implantation of a transvenous pacemaker and vascular cannulae was performed in six conditioned beagles as previously described.17 Briefly, a screw-in unipolar pacemaker lead (model 5300, Medtronic) was positioned under fluoroscopic guidance in the right ventricular apex after exposure and cannulation of the right jugular vein, with anesthesia maintained with vaporized halothane and nitrous oxide. The pacemaker lead was connected to a programmable pulse generator (Medtronic model 5985), which was secured in a subcutaneous pocket. 8F Silastic introducers for insertion of arterial and venous catheters were then secured via a right carotid arteriotomy and the jugular venotomy for subsequent hemodynamic monitoring. The pacemaker was telemetrically programmed to discharge at its minimum rate of 30 beats per minute, with an amplitude that did not stimulate ventricular contraction. The animals were then observed for stable postoperative recovery.

Induction of Congestive Heart Failure
After a 5-day recovery period from pacemaker implantation, the animals were transported to the catheterization laboratory and placed in the left lateral recumbent position on the fluoroscopy table. The scalar ECG was recorded using electrodes attached to the forelimbs and hind limbs of each animal for 4 minutes on FM tape using a Racal V Store tape recorder at a tape speed of 7.5 inches per second. From these recordings, measures of heart rate variability were generated as outlined below. Upon completion of the ECG recordings, the animals were lightly sedated with acepromazine (0.55 mg/kg body wt). In all animals, a two-dimensionally directed M-mode echocardiogram was performed from the right parasternal window with a Hewlett-Packard 77020A ultrasound system. M-Mode echocardiographic recordings were used to derive the percent fractional shortening of the left ventricle, and ejection fraction was derived from apical two-dimensional images of the ventricle. After acquisition of baseline left ventricular systolic performance, hemodynamic parameters including thermodilution-derived cardiac output and recordings of central aortic pressure were obtained in each of the canines.

After acquisition of the baseline scalar ECG, hemodynamics, and assessment of ventricular function, the pacemaker was telemetrically programmed to pace at 250 beats per minute with verification of consistent capture of the right ventricle. At 48 hours and again after 7 days of rapid ventricular pacing, the animals were lightly anesthetized, and rapid ventricular pacing was interrupted. During this interruption of pacing, hemodynamic and echocardiographic assessment and recording of the scalar ECG were repeated as outlined for the baseline study. The hemodynamic measures and recordings of the scalar ECG were obtained 30 minutes after interruption of ventricular pacing in each of the canines. Pilot studies from our laboratory demonstrate that hemodynamic measurements and assessment of left ventricular function do not significantly vary when acquired at periods of up to 90 minutes after discontinuation of pacing and thus agree with prior reports demonstrating stable measures of ventricular performance and hemodynamic variables during interruption of pacing.18

Spectral Analysis of Heart Rate Variability
Spectral analysis of heart rate variability was performed as previously reported by our laboratory.16 The tape-recorded ECG signal was preprocessed with use of an antialiasing filter and digitized by means of a 12-bit analog-to-digital converter board (Metrobyte Co) installed in an IBM/AT computer at a sampling rate of 512 Hz. Once digitized, the ECG signal was passed through a digital bandpass filter having a central frequency of 85 Hz. A dynamic user-interactive threshold technique was applied to the filtered signal to detect R waves and compute the RR interval sequence. Subsequently, the RR interval sequences were passed through a statistical filter to eliminate rapid transitions due to signal detection faults. Data points outside the 95% confidence interval of the previous 10 points were eliminated, and a point derived by linear interpolation of the preceding and following points was substituted. The data were demeaned, and low-frequency drift in the resultant heart rate variability signal was eliminated through a detrending algorithm that applied a 50-degree polynominal fit to low-frequency oscillations in heart rate variability. This polynominal fit was then subtracted from the original heart rate variability signal to yield data submitted to analysis. The heart rate versus time series was then passed through a Parzen window, and the power spectrum density of heart rate variability was generated with use of the modified periodogram method of Welch.19 This method is based on the multiple computation and average of the fast Fourier transform of overlapped data segments.19 With this method, the variance of the estimated power spectral density is reduced by a factor proportional to the number of data segments used. The power spectral density was then normalized so that the total power was equal to the signal mean square. A plot of the values of the power spectrum density against frequency was then generated. An area under the curve method was used to quantify the power within specified frequencies. Specifically, the total area, the area under the low-frequency (0.02 to 0.1 Hz) region of the curve, which contains information regarding sympathetic nerve activity, and the high-frequency (>0.1 Hz) region, which reflects parasympathetic tone, were calculated.6 20 21 22 In addition, to compare relative contribution of high- and low-frequency variability, the ratios of high-frequency to total area, low-frequency to total area, and high-frequency to low-frequency area were computed. Thus, the relative balance of parasympathetic and sympathetic tone may be quantified by this system of analysis.

Statistical Analysis
All data are expressed as mean±SD. Changes in the measures of left ventricular systolic function, hemodynamic variables, and parameters of heart rate variability derived from the power density spectrum were assessed by ANOVA for repeated measures. Significant differences between specific time points were tested for by least-squares mean post hoc comparison. Statistical significance was defined at the P<.05 level.


*    Results
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*Results
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Ventricular Function at Baseline, 48 Hours, and 7 Days of Rapid Ventricular Pacing
Baseline values for the echocardiographically derived fractional shortening and ejection fraction were 40±7% and 60±7%, respectively (Fig 1Down). After 48 hours of rapid ventricular pacing, mild left ventricular systolic dysfunction was noted, with a fractional shortening of 22±5% and ejection fraction of 37±6% (both P<.002 compared with baseline). By 7 days, there was no additional change in derived fractional shortening; however, a further numeric decrease was observed in the ejection fraction to 30±4% (P<.001 compared with baseline).



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  		Figure 1. Bar graph shows baseline, 48-hour, and 7-day mean and standard deviation values for percent fractional shortening (solid bars) and ejection fraction (hatched bars) expressed as percent. Baseline values for fractional shortening and ejection fraction were 40±7% and 60±7%. After 48 hours of rapid ventricular pacing, mild left ventricular dysfunction was noted, with a fractional shortening of 22±5% and ejection fraction of 37±6%. By 7 days there was no additional change in derived fractional shortening; however, a further numeric decrease was observed in the ejection fraction to 30±4% (P<.001 compared with baseline).

Baseline and 7-day values for cardiac output, systemic vascular resistance, mean arterial pressure, and heart rate are outlined in Fig 2Down. Concomitant with the reduction in global left ventricular systolic function, there was a reduction in the thermodilution-derived cardiac output from 3.4±1.0 L/min to 2.2±0.3 L/min, as represented in Fig 2ADown. Systemic vascular resistance at 7 days measured 2464±430 dyne · s · cm5 and did not differ from the baseline value of 2285±768 dyne · s · cm5 (Fig 2BDown). However, as we have previously reported, significant changes in conduit vessel compliance as reflected by an increase in the aortic input impedance spectrum are noted at this time.17 Mean arterial pressure decreased from 89.9±20 mm Hg to 67±5 mm Hg (Fig 2CDown, P<.09 compared with baseline), with a numeric but nonsignificant decrease in heart rate from 123±27 beats per minute to 100±30 beats per minute (Fig 2DDown).



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  		Figure 2. Bar graphs show hemodynamic values (mean and standard deviations) for the study: Cardiac output (2A), systemic vascular resistance (2B), mean arterial pressure (2C), and heart rate (2D) at baseline and after 7 days of rapid ventricular pacing. Concomitant with the reduction in global left ventricular systolic function, there was a reduction in the thermodilution-derived cardiac output from 3.4±1 to 2.2±0.3 L/min as represented in 2A. Systemic vascular resistance at 7 days measured 2464±430 dyne · s · cm5 and did not differ from the baseline value of 2285±768 dyne · s · cm5 (2B). Mean arterial pressure decreased from 89.9±20 to 67±5 mm Hg (2C, P<.09 compared with baseline), with a numeric but nonsignificant decrease in heart rate from 123±27 beats per minute to 100±30 beats per minute (2D).

Power Density Spectrum of Heart Rate Variability
The baseline power density spectrum of canines is characterized by a predominance of the high-frequency, parasympathetically mediated region reflective of the well-recognized vagal tone of these animals.21 22 With the onset of mild left ventricular systolic dysfunction, significant changes in the power density spectrum were observed and were characterized by augmentation of the low-frequency band of heart rate variability, which is influenced by the sympathetic nervous system, and attenuation of the parasympathetically mediated high-frequency area (Figs 3Down and 4Down). This was quantified by a marked and significant (ANOVA, P<.04) increase in the area under the low-frequency region from 0.053±0.037 (beats per minute)2 at baseline to 0.182±0.143 (beats per minute)2 at 48 hours to 0.253±0.202 (beats per minute)2 after 7 days of pacing. By least-squares means posttest comparison, it was found that the values at 7 days were significantly greater than either baseline or 48 hours (P<.01). The area under the high-frequency region of the curve showed a significant (ANOVA, P<.01) decrease from a baseline value of 0.945±0.037 (beats per minute)2 to 0.811±0.152 (beats per minute)2 at 48 hours to 0.733±0.197 (beats per minute)2 after 7 days of pacing. The value at 7 days was significantly reduced compared with the baseline and 48-hour values (P<.01). As a result of these changes, a shift in autonomic balance from parasympathetic tone and toward augmented sympathetic drive was noted, as reflected by a significant (ANOVA, P<.01) decrease in the ratio of high- to low-frequency areas from a baseline value of 15.2±9.6 to 10.1±6.89 at 48 hours and 0.004±0.001 at 7 days. The value at 7 days was significantly less (P<.005 by least-squares mean analysis) than the values at baseline and 48 hours (Fig 5Down).



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  		Figure 3. Bar graph shows power density spectrum of low-frequency area (mean and standard deviations) for the study. After 7 days of rapid ventricular pacing, there was a marked and significant (ANOVA, P<.04) increase in the area under the low-frequency region from 0.053±0.037 (beats per minute)2 at baseline to 0.182±0.143 (beats per minute)2 at 48 hours to 0.253±0.202 (beats per minute)2 after 7 days of pacing. By least-squares mean posttest comparison, it was found that the values at 7 days were significantly greater than either baseline or 48 hours (2D) (P<.01).



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  		Figure 4. Bar graph shows power density spectrum of the high-frequency area (mean and standard deviations) over the time periods. The area under the high-frequency region of the curve showed a significant (ANOVA, P<.01) decrease from a baseline value of 0.945±0.037 (beats per minute)2 to 0.811±0.152 (beats per minute)2 at 48 hours to 0.733±0.197 (beats per minute)2 after 7 days of pacing. The value at 7 days was significantly reduced compared with the baseline and 48-hour values (P<.01).



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  		Figure 5. Bar graph shows power density spectrum of the ratio of high- to low-frequency areas (mean and standard deviations). As a result of the changes in low- and high-frequency areas observed after 7 days of rapid ventricular pacing, a shift in autonomic balance from parasympathetic tone and toward augmented sympathetic drive was noted as reflected by a significant (ANOVA, P<.01) decrease in the ratio of high- to low-frequency areas from a baseline value of 15.2±9.6 to 10.1±6.9 at 48 hours and 0.004±0.001 at 7 days. The value at 7 days was significantly less (P<.005 by least-squares mean analysis) than the values at baseline and 48 hours.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
This investigation demonstrates that the autonomic imbalance that accompanies congestive heart failure in a paced canine model of ventricular failure occurs early in the course of left ventricular systolic dysfunction and is characterized by both augmented sympathetic drive and attenuation of parasympathetic tone. It is well known that both in humans and in animals, clinically overt congestive heart failure is associated with neurohumoral excitation characterized by increased plasma levels of norepinephrine and activation of the renin-angiotensin-aldosterone system.1 2 3 4 5 13 14 15 23 24 25 26 Autonomic dysfunction is a prominent element in the spectrum of neurohormonal aberrations that characterize chronic congestive heart failure, with augmented sympathetic drive a universal component of these abnormalities. This increase in sympathetic drive contributes to the increased peripheral vascular tone and consequent elevation of ventricular afterload, classic features in chronic congestive heart failure. A significant component of the increased plasma norepinephrine in heart failure patients is a result of increased central efferent sympathetic neural outflow as recorded with direct measurements of sympathetic nerve activity.27 Abnormalities both in the response to upright tilt and in sinus node function in congestive heart failure have been attributed to a withdrawal of parasympathetic tone.8 9 10 Given the purported role of the parasympathetic nervous system in promoting vasodilation in regional vascular beds, this autonomic imbalance creates an environment conducive to vasoconstriction and attendant increases in ventricular afterload.28

Prior investigations in humans and in the paced canine model of congestive heart failure have demonstrated that with clinical and echocardiographic evidence of severe ventricular dysfunction, the heart rate power spectral density displays a virtual absence of high-frequency variability and a pronounced augmentation of the low-frequency region of the curve.16 These changes are indicative of an autonomic imbalance consisting of parasympathetic withdrawal and augmented sympathetic drive. The results of the current investigation demonstrate (1) the changes in the autonomic profile occur early and with only mild left ventricular systolic dysfunction, (2) with the technique of spectral analysis of heart rate variability, one can distinguish the relative contributions of parasympathetic and sympathetic tone, which may contribute to further ventricular dysfunction, and (3) the augmentation of sympathetic drive and attenuation of parasympathetic tone seen at this early stage of ventricular dysfunction occurred concurrently and were progressive throughout the 7 days of study.

This investigation utilized the technique of spectral analysis of heart rate variability as a probe of the sympathetic and parasympathetic limbs of the autonomic nervous system. The variability of physiological signals such as heart rate has been found to be influenced by the autonomic nervous system.29 30 31 32 33 34 35 36 Frequency-specific variations in heart rate variability have been ascribed to the sympathetic and parasympathetic nervous systems.6 19 21 22 27 31 32 High-frequency variations >0.1 Hz are governed exclusively by the parasympathetic nervous system.21 22 27 The variability ascribed to the sympathetic influence and mediated by ß-adrenergic activity are contained exclusively in the frequency band <0.1 Hz.20 21 22 Spectral analysis of heart rate variability allows quantification of the contribution of these specific frequency bands to the overall variability of heart rate. The resultant power spectrum density in essence provides a dynamic map of the component limbs of the autonomic nervous system. Recent investigations have demonstrated that analysis of the proportional content of heart rate variability can be reflective of changes in sympathetic tone as measured by muscle sympathetic nerve activity.36 Although it is recognized that the low-frequency band of heart rate variability is subject to regulation by parasympathetic influence as well as sympathetic activity, the reduction in parasympathetic tone reflected by the decrease in high-frequency heart rate variability would tend to lead to a reduction in low-frequency variability. The fact that variability in the low-frequency region increased in the face of a reduction in parasympathetic tone would therefore suggest that sympathetic activity, which also regulates this band, has increased.

The observed early change in the autonomic profile, reflected by augmentation of sympathetic drive and attenuation of parasympathetic tone, occurred before significant changes developed in peripheral arterial tone as reflected in the systemic vascular resistance. Kienzle et al37 studied the relation of ambulatory 24- to 48-hour heart rate variability recordings to functional class and hemodynamic alterations in 23 patients with congestive heart failure. None of the measures of heart rate variability were significantly related to hemodynamic parameters or functional class. However, a negative relation was observed between measures of heart rate variability and indicators of sympathoexcitation. The authors concluded that the changes in heart rate variability that accompanied symptomatic congestive heart failure were not an indicator of the severity of disease but rather a marker of sympathoexcitation. Such a finding would be expected of a factor that plays an early role in the response to and progression of circulatory failure and indeed is supported by the findings of the current investigation. At this early stage of left ventricular systolic dysfunction, where no change was yet observed in peripheral arterial tone, a marked reduction in parasympathetic tone and augmentation of sympathetic drive was readily apparent. However, we have previously reported that significant changes in characteristic aortic impedance do occur at this time, and the temporal relation between reduced conduit vessel compliance and the autonomic changes observed in the current investigation suggests that such early changes in large vessel tone may be in part autonomically mediated.17

The identification of early neurohumoral modulation of cardiovascular function has important therapeutic implications. Data from the Studies of Left Ventricular Dysfunction (SOLVD) suggest that neuroendocrine activation as measured with plasma hormonal values of norepinephrine, atrial natriuretic factor, and arginine vasopressin occurs in patients with left ventricular dysfunction before symptomatic congestive heart failure develops.38 Considering the likely role of the neuroendocrine axis in the early progression of ventricular failure that has been suggested in clinical trials such as SOLVD, the identification of a marked autonomic imbalance early in the course of ventricular dysfunction in this model provides a further mechanistic rationale for the initiation of therapeutic interventions at this asymptomatic stage of congestive heart failure. Prior observations in humans suggest that treatment with angiotensin-converting enzyme inhibitors is associated with restoration of the autonomic imbalance characteristic in congestive heart failure toward normal.39 This restoration of autonomic balance is derived in part from sustained augmentation of parasympathetic tone. In ischemic heart disease, reduction of parasympathetic tone is thought to contribute to the occurrence of malignant arrhythmias and sudden death. If such mechanisms are operative in the setting of congestive heart failure, then the early reduction in parasympathetic tone identified in the current investigation may represent an important determinant of the well-recognized risk of sudden death in patients with congestive heart failure. Accordingly, a component of the benefit derived from early angiotensin-converting enzyme inhibition therapy may consist of the demonstrated capacity of these agents to augment parasympathetic tone.39 40 41 42

Indeed, recent publications of large trials in humans have demonstrated that converting enzyme inhibitors, when given to asymptomatic patients early in the course of ventricular dysfunction, result in fewer hospitalizations and improved survival over the study period.43 44 45 46 47 Pfeffer et al48 49 have shown a similar beneficial effect of long-term angiotensin-converting enzyme inhibition in preventing left ventricular remodeling and improving survival in rats after infarction. The beneficial effect of ß-blockers in post–myocardial infarction patients is in part attributed to their effect on blunting the sympathoexcitatory state that exists in this patient population, a therapeutic benefit that is no longer apparent when trials that used ß-blockers with intrinsic sympathomimetic activity were analyzed separately.50 51 52 53 Thus, the identification of a marked autonomic imbalance early in the course of ventricular dysfunction in this model provides a rationale for beginning therapeutic interventions at this asymptomatic stage of congestive heart failure.

Progressive neuroendocrine activation has been described not only in humans with congestive heart failure but by other investigators in the paced canine model of congestive heart failure.13 14 15 This paced canine model of congestive heart failure has been shown to produce a state of progressive biventricular dysfunction characterized by increases in plasma norepinephrine, aldosterone, atrial natriuretic factor, and renin similar to that occurring in humans with the gradual onset of clinically detectable congestive heart failure. The marked augmentation of sympathetic drive and attenuation of parasympathetic tone identified early in the evolution of congestive heart failure in this model suggest a mechanism by which treatments that prevent the progressive neuroendocrine activation perhaps can retard the progression of ventricular failure and evolution of heart failure symptoms. Abnormal early sympathetic activity may contribute, for instance, to renin release, as macula densa control of renin release is directly responsive to sympathetic stimulation.

The mechanisms underlying the altered autonomic profile of enhanced sympathetic drive and attenuated parasympathetic tone remain unclear, although experimental and emerging clinical investigations indicate that it may arise in part from impairment of cardiopulmonary and arterial baroreflexes.54 55 56 57 58 59 Ferguson et al55 compared forearm vascular responses of patients with heart failure with the orthostatic stress produced by lower body negative pressure, intra-arterial infusion of norepinephrine, and the cold pressor test. Heart failure patients developed significant vasoconstriction during infusion of norepinephrine and tended to have vasoconstriction during cold pressor testing. In contrast, the same patients failed to vasoconstrict and actually vasodilated during cardiopulmonary baroreceptor unloading with lower body negative pressure, suggesting that a selective impairment of baroreflex-mediated vasoconstrictor responses exists in patients with heart failure. In addition, patients with ventricular dysfunction fail to develop significant bradycardia after vasopressor-induced elevations of arterial pressure and also have a depressed tachycardic response to lowering of blood pressure.55

Studies in the paced canine model would lend further support to the functional changes occurring in cardiopulmonary and arterial baroreflexes in heart failure.57 59 Grima et al60 demonstrated that heart failure in this model was associated with attenuated baroreflex sensitivity and that 48 hours into recovery from pacing, baroreflex sensitivity had returned to baseline values. The rapid recovery of baroreflex sensitivity from the heart failure state was attributed to a functional rather than structural abnormality.

Summary
The results of this study demonstrate that early left ventricular dysfunction in this pacing model of congestive heart failure is associated with marked changes in the autonomic profile, which were apparent by 7 days and were characterized by enhanced sympathetic drive and attenuated parasympathetic tone. This early change in the autonomic profile at this stage of mild global left ventricular dysfunction probably contributes to the progression of myocardial and vascular dysfunction characteristic of clinically overt congestive heart failure. The mechanisms underlying this change in the autonomic profile remain uncertain, although existing experimental and clinical evidence suggests a functional abnormality in cardiopulmonary and arterial baroreflexes. This early activation of sympathetic drive and attenuation of parasympathetic tone have important therapeutic implications for asymptomatic patients at the earliest stage of congestive heart failure in preventing the myocardial and vascular sequelae of this disease.


*    Acknowledgments
 
This study was supported in part by a grant from the Ohio Affiliate of the American Heart Association, Columbus, Ohio; the National Center of the American Heart Association, Dallas, Tex; the Seward Schooler Family Foundation, Columbus, Ohio; and a Merck Research Labs Medical School Grant, West Point, Pa. Dr Eaton is the recipient of a Sanofi-Winthrop Research Fellowship Award in cardiovascular medicine. The authors wish to thank John Meimer and Patricia S. Hatton for technical assistance.

Received November 14, 1994; revision received January 18, 1995; accepted January 22, 1995.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

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