Effect of local and remote ischemic preconditioning on endothelial function in young people and healthy or hypertensive elderly people.

To verify whether age affects remote preconditioning, we compared healthy young people (mean age = 28.0 years, SD: 7.2), healthy elderly people (age = 69.2 years, SD: 5.0), and hypertensive elderly people (group 3, age = 72.8 years, SD: 3.9). Each group included 10 participants. The flow-mediated-dilation (FMD) was measured after local (same arm) and remote (leg) ischemic preconditioning. Healthy elderly people had the greatest increase of FMD after ischemic preconditioning compared to baseline (173% after local and 181% after remote preconditioning) and young participants the smallest increase (77% after local and 69% after remote preconditioning) while hypertensive elderly had an intermediate increase (P for comparison across groups: 0.347 for local and 0.064 for remote preconditioning). However, absolute values of FMD after preconditioning were much lower in elderly hypertensive than in healthy young adults. Remote preconditioning increases endothelial reactivity in healthy and hypertensive elderly. The potential clinical relevance of this finding deserves consideration.

Dissociation between ACE activity and autonomic response to ACE inhibition in patients with heart failure.

BACKGROUND: Administration of angiotensin-converting enzyme (ACE) inhibitors to patients with congestive heart failure has been shown to increase parasympathetic tone as indicated by increases in high-frequency heart rate variability. The mechanism for this effect, including its relation to changes in baroreflex activity, blood pressure variability, and suppression of ACE activity, remains undefined. This study was designed to test the relation of these variables, which may govern changes in autonomic activity, to the previously described increase in parasympathetic tone. METHODS: Seven patients with heart failure received a 3-hour infusion of the ACE inhibitor enalaprilat. Hemodynamic variables and parameters of heart rate and blood pressure variability, baroreflex gain derived from the interaction of heart rate and blood pressure variability, and serum ACE activity were measured during and after the infusion. Measures of heart rate and blood pressure variability were also compared against a historic control group. RESULTS: Serum ACE activity was significantly suppressed throughout and after enalaprilat infusion. Hemodynamic measures did not change other than a small decline in right atrial and pulmonary capillary wedge pressures. Parasympathetic tone showed an initial significant increase with a peak at 2 hours but then declined below baseline 8 hours after initiation of enalaprilat infusion. Sympathetically influenced low-frequency heart rate variability was significantly increased above baseline in the enalaprilat treatment group 8 hours after initiation of the infusion. Baroreflex gain showed a significant trend to an increase with the maximum value coinciding with the peak in parasympathetic tone. There was no change in blood pressure variability in the enalaprilat group and no change in baroreflex gain, heart rate variability, or blood pressure variability in the control group. CONCLUSIONS: Parasympathetic tone and baroreflex gain increased with parenteral administration of an ACE inhibitor but subsequently decreased below baseline values despite continued suppression of serum ACE activity. The dissociation between ACE suppression and autonomic response to ACE inhibition indicates that enzyme systems not reflected by plasma ACE activity or independent from the classic pathways of angiotensin formation contribute to the regulation of the autonomic response to ACE inhibition in patients with heart failure. The absence of significant change in hemodynamic variables or in blood pressure variability indicates that these autonomic changes are not an indirect reflex response to ACE inhibitor-induced vasodilation or hemodynamic baroreceptor stimulation.

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.

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)

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.

Assessment of autonomic tone over a 24-hour period in patients with congestive heart failure: relation between 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)

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.

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.

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)

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.

Differences between handwritten and automatic blood pressure records.

Comparison of 46 handwritten and electromechanically generated blood pressure records revealed substantial differences between the recordings. The highest automated record pressures exceeded the highest pressures found in corresponding handwritten records. Similarly, the lowest pressures from automated records were lower than those from handwritten records. Seventeen records (37%) had at least three automatic blood pressure determinations with values substantially in excess of the most extreme values recorded by hand. No handwritten record contained a diastolic pressure above 110 mmHg. Discrepancies between handwritten and automatic records may arise from one or more causes. Among these are readings captured automatically but not observed by the anesthesiologist, faulty reconstruction of handwritten records from memory, and bias in favor of less controversial values.

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 microW of power.