Enrico Nunziata

Parasympathetic withdrawal is an integral component of autonomic imbalance in congestive heart failure : Demonstration in human subjects and verification in a paced canine model of ventricular failure

Although enhanced sympathetic tone is a well recognized component of the autonomic profile characteristic of congestive heart failure, the contribution of parasympathetic withdrawal to this autonomic imbalance is less well described. The technique of spectral analysis of heart rate variability provides a dynamic map of sympathetic and parasympathetic tone and was thus used to define the nature of sympathetic-parasympathetic interactions in humans with idiopathic dilated cardiomyopathy and in a paced canine model of congestive heart failure. Humans with cardiomyopathy were found to have an augmentation of the sympathetically mediated low frequency area of the power density spectrum. Parasympathetic withdrawal was demonstrated by significant reductions in the parasympathetically mediated high frequency area (p less than 0.05) and the ratio of high to low frequency areas (p less than 0.01). Administration of atropine to normal subjects resulted in a significant reduction in the high frequency area (p less than 0.05) and the high/low frequency area ratio, both of which decreased within the range noted in patients with congestive heart failure. Administration of isoproterenol in normal subjects led to an augmentation of the low frequency area but to only a small decrease in the high/low frequency area ratio. Induction of congestive heart failure in a paced canine model resulted in alterations in the autonomic profile that resembled those seen in humans with ventricular failure. The prominent high frequency region of the spectrum at baseline, indicating a predominance of parasympathetic tone, was absent after the evolution of congestive heart failure, and there was a marked augmentation of the low frequency region of the spectrum.(ABSTRACT TRUNCATED AT 250 WORDS)

Sustained augmentation of parasympathetic tone with angiotensin-converting enzyme inhibition in patients with congestive heart failure

OBJECTIVES The objective of this investigation was to evaluate the changes in parasympathetic tone associated with long-term angiotensin-converting enzyme inhibitor therapy in patients with congestive heart failure. BACKGROUND Angiotensin-converting enzyme inhibitors provide hemodynamic and symptomatic benefit and are associated with improved survival in patients with congestive heart failure. Angiotensin II, whose production is ultimately inhibited by these agents, exerts significant regulatory influence on a variety of target organs including the central and peripheral nervous systems. Accordingly, it would be anticipated that angiotensin-converting enzyme inhibitors would significantly alter the autonomic imbalance characteristic of patients with congestive heart failure and that this influence over neural mechanisms of cardiovascular control may significantly contribute to the hemodynamic benefit and improved survival associated with angiotensin-converting enzyme inhibitor therapy. METHODS In the current investigation, changes in autonomic tone associated with long-term administration of an angiotensin-converting enzyme inhibitor were measured using spectral analysis of heart rate variability in 13 patients with congestive heart failure who were enrolled in a double-blind randomized placebo-controlled trial of the angiotensin-converting enzyme inhibitor zofenopril. Both placebo and treatment groups were balanced at baseline study in terms of functional class, ventricular performance and autonomic tone. RESULTS After 12 weeks of therapy with placebo, there was no change in total heart rate variability, parasympathetically governed high frequency heart rate variability or sympathetically influenced low frequency heart rate variability. In contrast, therapy with zofenopril was associated with a 50% increase in total heart rate variability (p = 0.09) and a significant (p = 0.03) twofold increase in high frequency heart rate variability, indicating a significant augmentation of parasympathetic tone. CONCLUSIONS These results demonstrate that long-term treatment of patients having congestive heart failure with an angiotensin-converting enzyme inhibitor is associated with a restoration of autonomic balance, which derives in part from a sustained augmentation of parasympathetic tone. Such augmentation of vagal tone is known to be protective against malignant ventricular arrhythmias in patients with ischemic heart disease and therefore may have similar benefit in the setting of ventricular failure, thus contributing to the improved survival associated with angiotensin-converting enzyme inhibitor therapy in patients with congestive heart failure.

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

BACKGROUND Although autonomic imbalance is known to be characteristics 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.

Influence of positive inotropic therapy on pulsatile hydraulic load and ventricular-vascular coupling in congestive heart failure☆

The aortic input impedance spectrum provides a description of the total hydraulic load imposed on the left ventricle and may be used to assess the coupling of the ventricle to the vasculature. The adaptation of the vasculature to positive inotropic intervention was examined in 10 patients with idiopathic dilated cardiomyopathy to test the hypothesis that increased myocardial contractility is matched by complementary changes in aortic impedance that optimize ventricular-vascular coupling and maximize power transfer to the circulation. High fidelity intravascular recordings of aortic pressure and flow were obtained at baseline study and during infusion of dobutamine to derive the aortic input impedance spectrum. In eight patients in whom increased staged infusion of dobutamine resulted in a significant increase in stroke volume (22.3 +/- 14.5 ml/beat increase over baseline), the significant (p less than 0.05) increase in the maximum of the first derivative left ventricular pressure pulse (dP/dt) was accompanied by significant decreases in characteristic impedance of the aorta (138 +/- 88 to 92 +/- 44 dyne.s.cm-5) wave reflection index (238 +/- 144 to 109 +/- 59 dyne.s.cm-5), and low frequency moduli of impedance. Effective positive inotropic therapy with dobutamine in the setting of congestive heart failure is accompanied by complementary changes in the aortic impedance spectrum, which represent a matching of impedance to the increased contractile state of the ventricle and facilitation of ventricular-vascular coupling.

Assessment of autonomic tone over a 24-hour period in patients with congestive heart failure: Relation betweeen mean heart rate and measures of heart rate variability☆

Patients with congestive heart failure (CHF) are characterized by an imbalance of the autonomic nervous system, which may contribute to the progression of circulatory failure and influence survival. However, it is still unclear whether CHF is characterized by a suppression of the diurnal variation in autonomic tone that is observed in normal subjects. To characterize the circadian variation in autonomic tone in patients with ventricular failure, ambulatory 24-hour Holter monitor recordings were obtained in 20 patients with CHF; 4-minute epochs of data from every hour of each 24-hour recording were selected. For each epoch we calculated the mean heart rate (HR) and, by applying spectral analysis of heart rate variability (HRV), we quantified the magnitude of the total (0.02 to 0.9 Hz), sympathetically governed low frequency variability (0.02 to 0.1 Hz), and parasympathetically mediated high-frequency variability (0.1 to 0.9 Hz). These areas were also expressed as a ratio to total variability and a ratio of high to low variability. A highly significant change in the mean HR over 24 hours was observed (p = 0.0001); no changes in the measures of HRV were obtained (p < 0.3). No significant correlation was found between mean HR and any frequency domain measures. We conclude that the sustained imbalance of autonomic tone over a 24-hour period, as shown by the spectral analysis of HRV, may promote the progression of circulatory failure and predispose patients with CHF to malignant ventricular arrhythmias and sudden cardiac death.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of spectral measures of heart rate variability as markers of disease progression in patients with chronic congestive heart failure not treated with angiotensin-converting enzyme inhibitors

Measures of heart rate variability in the frequency domain quantify autonomic activity. However, the relation of these measures to the severity of ventricular dysfunction in patients with congestive heart failure remains uncertain. We applied spectral analysis of heart rate variability to 24-hour Holter monitor recordings obtained from 20 patients with congestive heart failure who were not treated with angiotensin-converting enzyme inhibitors to determine whether significant changes in parameters of heart rate variability reflect the progression of symptoms in patients with ventricular failure. Both total and low-frequency heart rate spectral power were seen to decrease with worsening New Heart Associate (NYHA) functional class. A significant (p = 0.04) higher total power was noted in NYHA class II than in class III patients (3.0 x 10(-3) +/- 3.6 10(-4) and 2.5 x 10(-3) +/- 5.9 x 19(-4) [beats/min]2, respectively). Similarly, low-frequency heart rate spectral power was significantly (p = 0.008) higher in class II than in class III patients (1.7 x 10(-3) +/- 4.6 x 10(-4) and 1.1 x 10(-3) +/- 3.5 x 10(-4) [beats/min]2, respectively). Only the low-frequency component of the spectrum was directly correlated with left ventricular ejection fraction (LVEF) (r = 0.40) with a trend toward statistical significance (p = 0.07). Measures of heart rate variability and the changes in autonomic tone that they reflect may therefore serve as markers of the extent of disease progression in patients with congestive heart failure.

Effect of Tactile Stimulation Pulse Characteristics on Sensation Threshold and Power Consumption

The psychophysical responses of human subjects to vibratory tactile stimulation of the skin were investigated experimentally. The parameters, of the waveform important to the minimization of power consumed by the tactile array of electromechanical vibrators and the maximization of the skin sensitivity to the stimulus were explored to develop optimum stimulation. Parameters investigated included the amplitude, frequency, and duty cycle of the current waveform used to drive the vibrators as well as the number of pulses per stimulating burst and the recovery time between bursts. Graphical techniques were used to determine, the optimal combination of the parameters which gave a stimulus that excited the skin to above tactile threshold while maintaining at a relative minimum the power required for the stimulus. The optimal stimulation waveform contains a burst of 10 rectangular pulses of 4% duty cycle separated by a period of nonstimulation of 2 s. Such a waveform can elicit a sensitivity of 29.4 mA−1 consuming only 55 μW of power.

Influence of flosequinan on autonomic tone in congestive heart failure : implications for the mechanism of the positive chronotropic effect and survival influence of long-term vasodilator administration

The vasodilator flosequinan has been shown to be effective in the management of symptoms of congestive heart failure but has been found to influence survival adversely when administered in selected doses. A moderate positive chronotropic response accompanies long-term administration of this agent, which may be associated with an activation of the neurohormonal axis that itself may contribute to the reported increase in mortality. This investigation used the technique of spectral analysis of heart rate variability to examine the autonomic response to long-term flosequinan administration in 39 patients enrolled in a double-blind placebo-controlled trial of this vasodilator to determine whether autonomic mechanisms account for the observed changes in heart rate. Although heart rate significantly increased in the flosequinan-treated patients, parasympathetic tone increased and sympathetic drive decreased compared with placebo, as reflected by high- and low-frequency heart rate variabilities, respectively. It is concluded that (1) autonomic inputs to the myocardium that would be expected to produce increases in heart rate do not result from long-term flosequinan administration; (2) accordingly, a direct positive chronotropic effect must account for the heart rate changes observed with this vasodilator; and (3) the increased mortality associated with the administration of this agent in the doses examined does not appear to result from reflex changes in autonomic tone and must result from other properties of this vasodilator.

Heart Rate Alternans

Pulsus alternans has long been recognized as a manifestation of severe congestive heart failure [1, 2]. In contrast to the beat-to-beat oscillation in blood pressure that occurs with pulsus alternans, rapid beat-to-beat variations in heart rate are characteristically absent in the setting of ventricular failure [3, 4]. This results in part from the marked attenuation of parasympathetic tone in congestive heart failure, which governs such rapid fluctuations in heart period [3-5]. Further, because of the reduction in baroreflex sensitivity in patients with congestive heart failure, it has been thought unlikely that heart rate would vary in an instantaneous fashion in response to the rapid changes in systolic pressure that occur with pulsus alternans. We describe an unexpected beat-to-beat variation in heart rate, or heart rate alternans, in a patient with congestive heart failure; this heart rate alternans is a previously unrecognized manifestation of pulsus alternans. Methods Case Report A 55-year-old white woman with idiopathic dilated cardiomyopathy had an angiographically measured ejection fraction of 19% and had New York Heart Association functional class III symptomatic congestive heart failure. She was referred to Ohio State University Hospital for further management of congestive heart failure. As part of her evaluation, she had hemodynamic assessment of her response to vasodilator administration using a protocol that was reviewed and approved by the Human Use Review Board of The Ohio State University; the patient provided informed consent. The patient had received nitroglycerin ointment, 1 inch every 8 hours, and had received furosemide for management of heart failure symptoms before admission. In accordance with the protocol, nitrates and diuretic agents were withheld on the evening before the hemodynamic evaluation. Hemodynamic Evaluation A 6-fr Millar catheter (Millar Instruments, Houston, Texas) with a micromanometer pressure transducer was inserted through the femoral artery using aseptic techniques and was positioned in the central aorta for high-fidelity measurement of central aortic pressure. A balloon-tipped catheter with a thermistor was inserted through the subclavian vein and positioned in the pulmonary artery for monitoring pulmonary artery pressures and thermodilution cardiac output. Heart rate and rhythm were monitored using standard electrocardiographic leads. After catheter insertion, equilibration of the hemodynamic state (defined as less than 10% variation in three consecutive measurements of cardiac output, pulmonary arterial pressure, and aortic pressure) was established. Throughout the hemodynamic evaluation, a mean heart rate of 97 beats/min and an average blood pressure of 119/67 mm Hg (mean blood pressure, 83 mm Hg) were seen. Electrocardiographic results taken at 4-minute intervals and simultaneous measurements of aortic pressure were recorded on frequency-modulation tape for generation of the power-density spectra of heart rate and blood pressure variability as measures of autonomic tone [4]. These signals were subsequently digitized at a sampling rate of 512 Hz/channel using a 12-bit analog-to-digital converter installed in a microcomputer. From the digitized spectra, the power-density spectra of heart rate and blood pressure variability were generated as previously reported by our laboratory [4]. The power-density spectrum represents the magnitude of variability of a signal (heart rate or blood pressure), shown on the vertical axis, that is attributable to a given frequency, shown on the horizontal axis (Figure 1). In this way, the frequencies at which heart rate and blood pressure oscillate are determined. Figure 1. Power-density spectrum of heart rate variability in a patient with congestive heart failure. Results The results of the spectral analysis of heart rate and blood pressure variability in our patient before vasodilator administration are shown in Figure 1. The spectrum of heart rate variability during pulsus alternans contrasts markedly with that typically observed in patients with congestive heart failure [3, 4]. The typical pattern Figure 1, panel A) in patients with congestive heart failure is an absence of variability in frequencies greater than 0.1 Hz, reflecting a lack of any oscillations in heart rate at the higher frequency ranges, which are governed by the parasympathetic nervous system [4]. In contrast, the spectrum obtained during pulsus alternans in our patient Figure 1, panel B] has an unexpected peak at a very high frequency; this is the dominant peak in the spectrum and indicates a beat-to-beat alternation in heart rate. The corresponding power-density spectrum of systolic blood pressure variability shows a peak at exactly the same frequency as that noted in the spectrum of heart rate variability Figure 1, panel C). Therefore, the unexpected high-frequency peak in heart rate variability coincided with a high-frequency oscillation in systolic blood pressure. Indeed, the blood pressure recording shows a persistent two-beat cycle of alternating high- and low-amplitude blood pressure waveforms that fulfill the classic definition of pulsus alternans Figure 2 [1, 2]. Thus, a beat-to-beat alternation in heart rate, or heart rate alternans, was found to accompany pulsus alternans. Figure 2. Electrocardiogram (top) and central aortic pressure recording (bottom) obtained immediately before and during the onset of pulsus alternans. arrow The electrocardiogram recorded during pulsus alternans Figure 2 shows that a sinus mechanism was maintained throughout this period and that, accordingly, the alternation in blood pressure was not simply the mechanical response to an atrial or ventricular bigeminal rhythm. That the high-frequency variation in heart rate was strictly associated with pulsus alternans was confirmed by spectral analysis of heart rate variability on a segment of heart rate data acquired during a period in which pulsus alternans was not observed. The spectrum shown in Figure 1, panel A typifies the usual spectrum of heart rate variability observed in congestive heart failure [3, 4] and shows the disappearance of heart rate alternans in the absence of pulsus alternans. Discussion Although pulsus alternans has long been noted as a manifestation of severe ventricular failure [1, 2], our report describes heart rate alternans, which is a previously unrecognized manifestation of pulsus alternans. Electrical alternans, consisting of beat-to-beat changes in the amplitude or configuration of the QRS complex, sometimes accompanies pulsus alternans [1]. However, to our knowledge, a beat-to-beat variation in heart period recorded on the electrocardiogram has not been previously reported. Indeed, such a rapid oscillation in instantaneous heart rate is uncharacteristic for patients with ventricular failure; these patients typically have an absence of heart rate variability in frequency ranges greater than 0.1 Hz Figure 1 [3, 4]. This inability to produce rapid variations in heart rate has been ascribed to a reduction of parasympathetic tone, which, under normal conditions, is responsible for modulating rapid fluctuations in heart rate [3, 4]. Our patient had an uncharacteristic beat-to-beat alternation in heart period (heart rate alternans) that appears to have been a response to beat-to-beat changes in the amplitude of systolic blood pressure (pulsus alternans) and that constitutes a new mechanism for high-frequency oscillations in heart rate. The mechanism for these observations in a single patient is speculative. However, the reduced baroreflex sensitivity that is typical for patients with congestive heart failure is analogous to a low-gain feedback control system in which uncontrolled oscillations in signals typically occur [6]. Therefore, if this mechanism pertains in this setting, an oscillation in blood pressure may produce an oscillation in heart rate that persists because of low-gain feedback control. Indeed, Figure 2 shows the initiation of pulsus alternans in our patient and indicates that a fluctuation in blood pressure preceded alterations in heart rate. This finding suggests that the variation in heart rate was initiated by a change in blood pressure and was not due to a primary alteration in cardiac cycle length or even a cyclic alteration in a higher-order control mechanism that would simultaneously affect heart rate and blood pressure. Our report shows that in patients with congestive heart failure, heart period may vary in a beat-to-beat fashion coincident with the beat-to-beat alternations in systolic blood pressure that define pulsus alternans. This heart rate alternans, therefore, is a new element in the spectrum of findings that constitute cardiac alternans [1] and defines an important exception to the observation that high-frequency heart rate variability is substantially attenuated in patients with congestive heart failure. Furthermore, this type of high-frequency heart rate oscillation has not been previously reported. This heart rate alternans differs from the classic peaks that arise from respiratory-linked changes in vagal tone. We used a spectral analysis technique that is extremely sensitive to changes in heart period variability; thus, the heart period oscillations that we were able to record may not have otherwise been clinically evident. This may account for the fact that heart rate alternans had not been described until we used this relatively new technique to analyze physiologic signals. Because our observation was made in a single patient, it remains to be determined whether heart rate variability is a consistent, concomitant finding in patients with pulsus alternans and whether heart rate alternans occurs in other disease states that also have abnormal autonomic and baroreflex circulatory control mechanisms.

Differing autonomic response to dobutamine in the presence and absence of ischemia: implications for the autonomic contribution to positive inotropic intervention

Although it is well recognized that dobutamine is a powerful positive inotropic agent mediating increased myocardial contractility through direct beta-adrenergic stimulation, the mechanism of its overall circulatory effects appears more complex than that which may be ascribed solely to this direct action on the myocardium. Previous investigations have implied that reflex alterations in autonomic balance may contribute significantly to the response to this agent, but direct evidence describing such a response has not been reported. The objective of this investigation was to assess changes in autonomic tone induced by dobutamine in the presence and absence of ischemia through the measurement of heart rate variability in patients undergoing dobutamine stress echocardiography. Of 25 consecutive patients undergoing dobutamine stress echocardiography, 16 were found to have unequivocal evidence for or against the presence of ischemia during dobutamine infusion. Heart rate data from these 16 patients were submitted for spectral analysis of heart rate variability and quantification of parasympathetically governed high-frequency heart rate variability and sympathetically influenced low-frequency heart rate variability. Of the 16 patients nine were not found to have evidence for ischemia (group 1), and seven were found to have echocardiographic findings consistent with dobutamine-induced ischemia (group 2). The two groups significantly differed (p = 0.04) in the change in parasympathetic tone associated with dobutamine with a significant (p = 0.04) increase in parasympathetic tone in group 1 and a numeric decrease in group 2. A significant (p = 0.04) decrease in sympathetic tone was noted in group 1 as reflected by low-frequency heart rate variability with a numeric increase in this measure in group 2.(ABSTRACT TRUNCATED AT 250 WORDS)