"Meta-analysis: statistical alchemy for the 21st century": discussion. A plea for a more balanced view of meta-analysis and systematic overviews of the effect of health care interventions

Ventricular arrhythmias and disturbed autonomic control, as reflected by abnormal heart rate variability (HRV), are related to hemodynamic impairment in chronic heart failure (CHF). We investigated the effects of orally (p.o.) administered isomazole, a new phosphodiesterase (PDE) inhibitor with calcium-sensitizing properties, on hemodynamics, ventricular arrhythmias, and HRV and examined a possible interaction between these parameters. Hemodynamic measurements and ambulatory ECG monitoring were performed in 12 patients with stable CHF class III-IV after single doses of isomazole 5-30 mg. Pulmonary wedge pressure decreased after 5, 10, 20, and 30 mg, but cardiac output, (CO) increased only after the higher doses [20 mg, + 20% (p = 0.031)] of isomazole. HR did not change. Mean arterial and pulmonary artery pressure, (MAP, PAP) decreased significantly in the 10- and 20-mg groups [10 mg, -6% (p = 0.035) and -14% (p < 0.001) respectively; 20 mg, -13% (p = 0.047) and -31% (p = 0.006), respectively]. Isomazole did not exert a significant effect on ventricular arrhythmias in the subsequent 24 h after acute dosing. Analysis of HRV showed that rMSSD and pNN50 (parameters of vagal tone) tended to increase after isomazole administration. Normalized high-frequency power during the day increased from 17.4 to 22.3 nu (p < 0.05), whereas low frequency tended to decrease from 52.7 to 48.2 nu (p = 0.06). Acute isomazole administration improves hemodynamics but has no effect on ventricular arrhythmias. The HRV variability data suggest development of an increase in vagal control of HR, parallel to the acute hemodynamic improvement after isomazole. Withdrawal of vagal control of HR in CHF may be a reversible process.     

Oxygen uptake kinetics during low level exercise in patients with heart failure: relation to neurohormones, peak oxygen consumption, and clinical findings

OBJECTIVE: To investigate whether oxygen uptake (VO2) kinetics during low intensity exercise are related to clinical signs, symptoms, and neurohumoral activation independently of peak oxygen consumption in chronic heart failure. DESIGN: Comparison of VO2 kinetics with peak VO2, neurohormones, and clinical signs of chronic heart failure. SETTING: Tertiary care centre. PATIENTS: 48 patients with mild to moderate chronic heart failure. INTERVENTIONS: Treadmill exercise testing with "breath by breath" gas exchange monitoring. Measurement of atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and noradrenaline. Assessment of clinical findings by questionnaire. MAIN OUTCOME MEASURES: O2 kinetics were defined as O2 deficit (time [rest to steady state] x DeltaVO2 -sigmaVO2 [rest to steady state]; normalised to body weight) and mean response time of oxygen consumption (MRT; O2 deficit/DeltaVO2). RESULTS: VO2 kinetics were weakly to moderately correlated to the peak VO2 (O2 deficit, r = -0.37, p < 0.05; MRT, r = -0.49, p < 0.001). Natriuretic peptides were more closely correlated with MRT (ANF, r = 0.58; BNP, r = 0.53, p < 0.001) than with O2 deficit (ANF, r = 0.48, p = 0.001; BNP, r = 0.37, p < 0.01) or peak VO2 (ANF, r = -0.40; BNP, r = -0.31, p < 0.05). Noradrenaline was correlated with MRT (r = 0. 33, p < 0.05) and O2 deficit (r = 0.39, p < 0.01) but not with peak VO2 (r = -0.20, NS). Symptoms of chronic heart failure were correlated with all indices of oxygen consumption (MRT, r = 0.47, p < 0.01; O2 deficit, r = 0.39, p < 0.01; peak VO2, r = -0.48, p < 0. 01). Multivariate analysis showed that the correlation of VO2 kinetics with neurohormones and symptoms of chronic heart failure was independent of peak VO2 and other variables. CONCLUSIONS: Oxygen kinetics during low intensity exercise may provide additional information over peak VO2 in patients with chronic heart failure, given the better correlation with neurohormones which represent an index of homeostasis of the cardiovascular system.     

Increased endogenous nitric oxide synthase inhibitor in patients with congestive heart failure

Nitric oxide (NO) plays a role in controlling vascular tone and regulates the contractile properties of cardiac myocytes. Patients with heart failure exhibit high plasma levels of nitrite/nitrate (NOx), a stable metabolite of NO, and of cytokines such as tumor necrosis factor-alpha, a potent inducer of NO synthase. An increase in inducible NO synthase activity has been found in cardiac tissue from patients with dilated cardiomyopathy. These findings raise the possibility that local or systemic overproduction of NO induced by cytokines exerts a chronic negative inotropic effect on the myocardium and may have detrimental effects on systemic hemodynamics in patients with heart failure. Plasma levels of NG,NG-dimethylarginine (asymmetric dimethylarginine; ADMA), a circulating endogenous NO synthase inhibitor, were measured in control subjects and patients with valvular, hypertensive, or ischemic heart diseases or idiopathic cardiomyopathy. The plasma levels of NOx and ADMA were assessed by high performance liquid chromatography. The plasma levels of NOx and ADMA were significantly elevated in patients with heart failure. Both NOx and ADMA were positively correlated with New York Heart Association functional class. There was a significant inverse correlation between plasma NOx and ejection fraction, as estimated by echocardiography. A significant relationship between plasma NOx and ADMA was found only in patients with moderate to severe heart failure (r=0.41, p=0.01). Findings suggest a compensatory role of a circulating endogenous NO synthase inhibitor against induced NO synthase activity in patients with heart failure.     

Hemodynamic response to in situ latissimus dorsi muscle stimulation: implications in dynamic cardiomyoplasty

Dynamic cardiomyoplasty (DCM) involves the electrical stimulation of a pedicled latissimus dorsi muscle flap wrapped around the falling ventricle as a means of cardiac assist. To further elucidate a potential neurohumoral mechanism for improvement of cardiac output after myoplasty, we evaluated the hemodynamic effects of in situ stimulation of the latissimus dorsi muscle (in the absence of cardiomyoplasty). In seven mongrel dogs, a nerve cuff electrode (Medtronic 6901) was placed around the left thoracodorsal nerve (TDN). This was attached to a pulse generator (Medtronic, Itrel 7420), delivering a 4.0 volt, 0.19 second on, 0.81 second off, 33 Hz, 210 microsecond pulse width, cyclic bursts similar to that used in DCM. Stroke volume index (SVI) and other hemodynamic parameters as well as plasma norepinephrine (NE) levels were measured at five stages: baseline, stimulator on at 0, 2, and 5 minutes, and stimulator off at 30 minutes after. The animals were then subjected to 4 weeks of rapid pacing at 240 beats/min (Medtronic 8329) to induce heart failure, and as the rapid pacing was discontinued, measurements were repeated as above. After rapid pacing, cardiac function was significantly depressed, and NE was elevated (133 +/- 69 versus 500 +/- 353 pg/mL, p < 0.05). In the normal hearts, TDN stimulation increased SVI, heart rate, systemic pressure, and NE levels. In heart failure, however, no significant changes in cardiac function and NE levels were noted. In conclusion, our data indicate that in the normal hearts, afferent impulses from TDN stimulation alone may augment cardiac function by means of a neurohumoral effect that is not seen in severe heart failure. The implications of these findings in DCM are discussed.     

N(N)-nicotinic blockade as an acute human model of autonomic failure

Pure autonomic failure has been conceptualized as deficient sympathetic and parasympathetic innervation. Several recent observations in chronic autonomic failure, however, cannot be explained simply by loss of autonomic innervation, at least according to our current understanding. To simulate acute autonomic failure, we blocked N(N)-nicotinic receptors with intravenous trimethaphan (6+/-0.4 mg/min) in 7 healthy subjects (4 men, 3 women, aged 32+/-3 years, 68+/-4 kg, 171+/-5 cm). N(N)-Nicotinic receptor blockade resulted in near-complete interruption of sympathetic and parasympathetic efferents as indicated by a battery of autonomic function tests. With trimethaphan, small postural changes from the horizontal were associated with significant blood pressure changes without compensatory changes in heart rate. Gastrointestinal motility, pupillary function, saliva production, and tearing were profoundly suppressed with trimethaphan. Plasma norepinephrine level decreased from 1.1+/-0.12 nmol/L (180+/-20 pg/mL) at baseline to 0.23+/-0.05 nmol/L (39+/-8 pg/mL) with trimethaphan (P<.001). There was a more than 16-fold increase in plasma vasopressin (P<.01) and no change in plasma renin activity. We conclude that blockade of N(N)-cholinergic receptors is useful to simulate the hemodynamic alterations of acute autonomic failure in humans. The loss of function with acute N(N)-cholinergic blockade is more complete than in most cases of chronic autonomic failure. This difference may be exploited to elucidate the contributions of acute denervation and chronic adaptation to the pathophysiology of autonomic failure. N(N)-Cholinergic blockade may also be applied to study human cardiovascular physiology and pharmacology in the absence of confounding baroreflexes.     

Association between cardiac autonomic function and coping style in healthy subjects

The link between personality and cardiac function is insufficiently characterized. We postulated that in a healthy population, cardiac autonomic function is linked to coping style. In 276 healthy volunteers, between the ages of 18 and 71, the Utrecht Coping List was used to evaluate different coping strategies. Trait anxiety was scored by the Spielberger State Trait Anxiety Inventory. A 24-hour Holter recording was used to calculate heart rate variability (HRV). For HRV parameters and coping mechanisms this study demonstrated gender-specific differences and correlations with age. In men (n = 141) higher active coping was associated with less global autonomic activity or SDANN (rs = -0.27, P < 0.001). This relationship was most prevalent in young (18-30 years) men (rs = -0.45, P < 0.005). Higher expression of negative emotions or anger was related to both higher vagal (rs = 0.23 for rMSSD, P < 0.01) tone and higher LF power (rs = 0.23, P < 0.01). In young men expression of negative emotions or anger was associated with LF power (rs = 0.37, P < 0.01) and in middle-aged (31-50 years) men with vagal tone (rs = 0.43 for rMSSD, P < 0.005) and heart rate (rs = -0.41, P < 0.005). Higher comforting ideas was related to higher LF power (rs = 0.23 for LF power, P < 0.005), and this especially in middle-aged men (rs = 0.37, P < 0.01). In women (n = 135), no significant correlations between coping style and HRV indices were found. We conclude that in normal individuals, at least in men, our findings suggest a relationship between coping style and cardiac autonomic function.     

Effects of prostacyclin on the pulmonary vascular tone and cardiac contractility of patients with pulmonary hypertension secondary to end-stage heart failure

Long-term administration of prostacyclin (PGI2) improves the hemodynamic state, symptoms, and survival in patients with primary pulmonary hypertension, but it increases mortality in patients with heart failure despite obvious hemodynamic benefits when it is given acutely. We evaluated the mechanisms of action of PGI2 in patients with heart failure and secondary pulmonary hypertension. Nineteen patients with end-stage heart failure and pulmonary hypertension, all candidates for heart transplantation, underwent right- and left sided cardiac catheterization with micromanometer-tipped catheters and were tested for PGI2 at incremental doses. PGI2 infusion significantly improved pulmonary hemodynamics with a 47% reduction in pulmonary vascular resistance (p=0.0003) and a doubling of pulmonary artery compliance (p <0.0001), reflecting improvement in pulmonary vascular tone. The dose of PGI2 necessary to reach this hemodynamic effect correlated significantly to the baseline severity of pulmonary artery compliance (r=0.54, p=0.01). Furthermore, PGI2 produced a significant positive inotropic effect (contractile element maximum velocity increased from 1.10+/-0.09 to 1.33+/-0.13 circ/s, p <0.009). The hemodynamic effects of PGI2 infusion were independent of the plasma and urinary levels of endogen prostaglandins. Thus, PGI2 at therapeutic doses exerts a positive inotropic effect in patients with heart failure, which may explain the increased mortality rate observed with the long-term use of PGI2 in this type of patient. The spectacular acute benefits on right ventricular afterload, however, may be useful in unstable patients with heart failure and secondary pulmonary hypertension or in transplanted patients with acute right ventricular failure of the donor heart.     

Analysis of heart rate variability demonstrates effects of development on vagal modulation of heart rate in healthy children

OBJECTIVES: Analysis of heart rate variability (HRV) has been found to be a useful method of assessing cardiovascular autonomic control, but normal values for standard HRV measures in children have not been established. We analyzed HRV in 60 healthy children aged 3 to 15 years to determine normal values and to assess the effects of development on cardiac autonomic control with the use of ambulatory electrocardiographic monitoring. RESULTS: The high-frequency (HF) component, an index of cardiac autonomic tone, increased significantly with age from 3 to 6 years (p < 0.01) and decreased with age from 6 to 15 years (p < 0.01), and the magnitude of HF correlated significantly with the R-R intervals. Thus the changes in cardiac autonomic tone could be described as a simple equation using age and heart rate. CONCLUSIONS: We present normal values and changes in the cardiac autonomic system during childhood after HRV analysis, which could lead to a better understanding and treatment of cardiac disease in children.     

Decreasing parasympathetic tone activity and proarrhythmic effect after radiofrequency catheter ablation--differences in ablation site

Holter ECG was used to evaluate changes in heart rate variability (HRV), indicators of the autonomic nervous system, and arrhythmia before and after radiofrequency (RF) catheter ablation in patients with symptomatic supraventricular tachycardia. Ablation targets in 43 patients included the atrioventricular (AV) nodal pathway (AVNRT, n = 17), a right free wall accessory pathway (n = 10), a septal accessory pathway (n = 6), and a left free wall accessory pathway (n = 10). The High frequency component (0.15 - 0.40 Hz) or pNN50 of HRV analysis, indicating parasympathetic activity, significantly decreased immediately after RF ablation in the AVNRT and septal accessory pathway groups, but not in the right or left wall groups. In contrast, in all four groups, ventricular premature contractions (VPCs) significantly increased in most of the patients, and ventricular tachycardia occurred in a few of the patients immediately after RF ablation. There was no serious arrhythmia. These alterations in HRV analysis and arrhythmia returned to the control level after 1 week or more. VPCs after RF ablation did not consistently increase as a result of the reduced parasympathetic tone activity, but at the lesion near the conduction system, the increase in VPCs was inhibited by higher parasympathetic tone activity, because the parasympathetic nerve fibers and receptors were distributed in these lesions.     

The short-term effects of digoxin in patients with right ventricular dysfunction from pulmonary hypertension

OBJECTIVE: Studies on the effects of digoxin in patients with right ventricular failure and normal left ventricular function have not been performed. We evaluated the short-term effects of digoxin administration in patients with primary pulmonary hypertension on hemodynamics, neurohormones, and baroreceptor responsiveness. DESIGN: This was a prospective study with patients serving as their own controls. SETTING: University Hospital Intensive Care Unit with central monitoring. PATIENTS: Seventeen patients with primary pulmonary hypertension and symptomatic heart failure were enrolled. INTERVENTIONS: Following baseline hemodynamics, neurohormonal samples were drawn and the heart rate response to change in blood pressure following a challenge of phenylephrine and nitroprusside were recorded. One mg of intravenous digoxin was given and the measurements repeated after 2 hours. RESULTS: Following digoxin there was a significant increase in cardiac output (3.49+/-1.2 to 3.81+/-1.2 L/min., p=0.028), a significant fall in norepinephrine (680+/-89 to 580+/-85 pg/ml, p=.013), and a significant increase in atrial natriuretic peptide (311+/-44 to 421+/-9 pg/ml, p=0.01). All of the patients had changes in heart rate and blood pressure following phenylephrine and nitroprusside challenge, but there was no significant difference in the change in heart rate response to change in blood pressure when rechallenged after digoxin treatment. CONCLUSION: Digoxin produces a modest increase in cardiac output in patients with pulmonary hypertension and right ventricular failure, as well as a significant reduction in circulating norepinephrine. No detectable effects of digoxin on baroreceptor responsiveness were apparent. The use of digoxin in pulmonary hypertension is warranted.     

Hyperventilation alters colonic motor and sensory function: effects and mechanisms in humans

BACKGROUND & AIMS. Hyperventilation-induced hypocapnia affects hemodynamic function and enhances colonic motility. The aims of this study were to determine the effects of hypocapnic hyperventilation on colonic motility and sensation in health and to explore the putative neurohumoral mechanisms. METHODS: In experiment 1, colonic tone, sensation, plasma levels of cortisol, beta-endorphin, selected gut neuropeptides, norepinephrine, epinephrine, and splanchnic blood volume were measured during two sequences of hypocapnic hyperventilation. In experiment 2, colonic tone and sensation were assessed during eucapnic hyperventilation and abdominal compression. RESULTS: Hypocapnic hyperventilation, but not eucapnic hyperventilation or abdominal compression, significantly increased colonic tone and sensitivity to balloon distention (P = 0.017) without altering humoral mediators or splanchnic blood volume. Plasma norepinephrine level increased (P = 0.017) and splanchnic blood volume decreased (P = 0.028) during 5 minutes after hyperventilation, consistent with homeostatic responses. CONCLUSIONS: Increased colonic tone and sensation during hypocapnic hyperventilation are not caused by colonic compression. These effects of hyperventilation are not mediated humorally but may result from direct metabolic effects of hypocapnia on colonic muscle or from changes in central autonomic control of colonic smooth muscle.     

The hypertension of autonomic failure and its treatment

We studied the incidence and severity of supine hypertension in 117 patients with severe primary autonomic failure presenting to a referral center over a 9-year period. Patients were uniformly characterized by disabling orthostatic hypotension, lack of compensatory heart rate increase, abnormal autonomic function tests, and unresponsive plasma norepinephrine. Fifty-four patients had isolated autonomic impairment (pure autonomic failure). Sixty-three patients had central nervous system involvement in addition to autonomic impairment (multiple-system atrophy). Patients were studied off medications, in a metabolic ward, and on a controlled diet containing 150 mEq of sodium. Fifty-six percent of patients had supine diastolic blood pressure > or =90 mm Hg. The prevalence of hypertension was slightly greater in females (63%) than in males (52%). Potential mechanisms responsible for this hypertension were investigated. No correlation was found between blood volume and blood pressure. Similarly, plasma norepinephrine (92+/-15 pg/mL) and plasma renin activity (0.3+/-0.05 ng/mL per hour) were very low in the subset of patients with pure autonomic failure and supine hypertension (mean systolic/diastolic pressure, 177 +/- 6/108 +/- 2 mm Hg, range 167/97 to 219/121). Supine hypertension represents a challenge in the treatment of orthostatic hypotension. We found these patients to be particularly responsive to the hypotensive effects of transdermal nitroglycerin. Doses ranging from 0.025 to 0.1 mg/h decreased systolic blood pressure by 36+/-7 mm Hg and may effectively treat supine hypertension overnight, but the dose should be individualized and used with caution.     

Rhythms in the central nervous system and 1/f fluctuations of the heart rate

We have developed a system to analyze heart rate variability (HRV) (power spectral array of the HRV) during 24 h ambulatory electrocardiographic monitoring. Several rhythms (circadian and several ultradian rhythms) were observed in the power spectral array of the heart rates and 1/f-like fluctuations in the log-log scaled heart rate power spectrum. The circadian change of the heart rate is closely related to the body temperature rhythm. The 90 min rhythm of HRV during sleep was suspected to be produced by the sleep cycle (REM/NREM) and the lower frequency peak of the HRV was coherent with oscillation in amplitude modulated respiration. These circadian and ultradian rhythm as assessed by heart rate variability exist both in normal subjects and in patients with autonomic failure. The power of the high frequency band decreases in subjects with autonomic failure. The power of low frequency components increases during periodic breathing or Cheyne-Stokes respiration. Log-log scaled analysis of the power spectrum of HRV disclosed that the slope of the HRV is markedly modulated by the range of the frequency applied for the least square regression line analysis. The increased power that might be produced by periodic breathing and decreased power in patients with autonomic failure might strongly modulate the slope of the log-log scaled HRV. It is concluded that the power spectral array of the HRV during 24 h period is useful in the detection of circadian and ultradian rhythm, and log-log scaled power spectra might be useful in the overall integration of the heart rate dynamics produced by the central nervous system. The several rhythm factors that might be produced by the central nervous system might modulate 1/f fluctuations of the HRV.     

Effects of a new cardiotonic phosphodiesterase III inhibitor, olprinone, on cardiohemodynamics and plasma hormones in conscious pigs with heart failure

We examined the effects of a novel phosphodiesterase III inhibitor, olprinone, on the cardiohemodynamics and plasma hormones in conscious pigs with pacing-induced heart failure. After pacing for 5-10 days, cardiac output (CO) decreased from 2.25 +/- 0.17 to 1.67 +/- 0.13 L/min (n = 8, p < 0.01) and stroke volume (SV) decreased from 20.1 +/- 2.1 to 12.0 +/- 1.6 ml (n = 8, p < 0.01), whereas left arterial pressure (LAP) increased from 2.8 +/- 1.2 to 16.7 -/+ 0.9 mm Hg (n = 7, p < 0.001) and systemic vascular resistance (SVR) increased from 38.7 +/- 3.5 to 49.8 +/- 4.2 mm Hg/L/min (n = 8, p < 0.01). Sequential intravenous infusions of 0.03, 0.3, and 3.0 microg/kg/min of olprinone at 30-min intervals to eight pigs caused dose-dependent increases in the decreased CO, SV, and maximal rate of rise in left ventricular pressure (LV dP/dt(max)) and decreased the elevated LAP and SVR. Olprinone at 3.0 microg/kg/min maximally increased CO, SV, and LV dP/dt(max) by 40.0 +/- 10.8% (p < 0.05 vs. vehicle), 25.6 +/- 6.9% (p < 0.05), and 43.9 +/- 11.2% (p < 0.01), respectively, and brought about a slight increase in heart rate and decreases in LAP and SVR, by 35.9 +/- 7.3% (p < 0.001) and 27.9 +/- 4.8% (p < 0.01), respectively. Olprinone did not affect the rate-pressure product. In addition, olprinone produced significant decreases in the plasma levels of atrial natriuretic peptide and cyclic guanosine monophosphate, with no changes in the plasma levels of cyclic adenosine monophosphate and catecholamines or plasma renin activity. These findings indicate that the short-term intravenous infusions of olprinone ameliorated the decreased left ventricular function without affecting myocardial oxygen consumption or the sympathetic nervous system in conscious pigs with heart failure.     

Solitary fibrous tumour: clinicopathological, immunohistochemical, and ultrastructural analysis of 12 cases arising in soft tissues, nasal cavity and nasopharynx, urinary bladder and prostate

Heart-rate variability (HRV), a measure of fluctuation around the mean heart rate, reflects the sympathetic and parasympathetic balance of the autonomic nervous system, and is an excellent technique to study cardiovascular tone in patients with neurological injuries. The purpose of this study was to determine whether abnormal HRV is present in patients with traumatic brain injury (TBI) during the post-acute recovery phase. Using a prospective, case/control design, we performed 24-h ambulatory ECG monitoring in seven TBI patients and in seven controls (C). There was a significant difference in root mean squared successive difference of RR intervals (C 40.4 +/- 10.3, TBI 23.3 +/- 16.5, p = 0.04) between TBI and C. Four patients with TBI (compared to one control) had abnormal standard deviation of the RR interval. When these four patients were compared to their matched controls, significant differences were found in frequency domain measure (In total power: TBI 4.4 +/- 0.9 ms2, C 7.1 +/- 1.4 ms2, In low frequency: TBI 3.3 +/- 1.1 ms2, C 6.4 +/- 1.4 ms2; In high frequency TBI 2.0 +/- 1.0 ms2, C 4.8 +/- 1.3 ms2, all p < 0.05). Thus, abnormalities in both time and frequency domains of HRV are present in TBI during the post-acute recovery phase.     

Transmission electron microscopy studies of (111) twinned silver halide microcrystals

Minimal information is available on the autonomic response to exercise under adverse environmental conditions. Traditionally, pharmacological blockade has been used to study autonomic responsiveness but, owing to its invasive nature, such studies have been limited in their scope. Recent advances in electrocardiographic tape recording, telemetry and associated computing systems have provided investigators with noninvasive methods for assessing the autonomic response to various physiological stressors. This article describes methods for the analysis of heart rate variability (HRV) and discusses the reports of those who have used HRV analysis to evaluate autonomic regulation during exercise, heat exposure and the combination of these 2 stressors. Spectral analysis of HRV reduces variations in the R-R interval into component sine waves of differing amplitude and frequency. Amplitude (variance) is displayed as a function of frequency, and power (cumulative variance) is calculated for specified frequency ranges (< 0.03 Hz, 0.03 to 0.15 Hz and 0.15 to 0.5 Hz). Parasympathetic nervous system activity can be inferred from the several indices of high frequency power; however, the estimation of sympathetic nervous system activity from low frequency power is more problematic. Data on HRV have shown that sympathovagal regulation during exercise is dependent on the intensity of the activity and the environmental conditions. At the onset of exercise, heart rate is increased by a reduction in vagal tone and a temporary increase in sympathetic tone. A continuation of physical activity is associated with a continued withdrawal of vagal activity and an attenuation of sympathetic nervous system tone. However, with the additional stimulus of a heated environment, sympathetic activity remains increased throughout exercise.     

High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril

OBJECTIVES: To determine dose-related clinical and neurohumoral effects of angiotensin-converting enzyme (ACE) inhibitors in patients with chronic heart failure (CHF), we conducted a double-blind, placebo-controlled, randomized study of three doses (2.5 mg, 5 mg and 10 mg) of the long-acting ACE inhibitor imidapril. BACKGROUND: The ACE inhibitors have become a cornerstone in the treatment of CHF, but whether high doses are more effective than low doses has not been fully elucidated, nor have the mechanisms involved in such a dose-related effect. METHODS: In a parallel group comparison, the effects of three doses of imidapril were examined. We studied 244 patients with mild to moderate CHF (New York Heart Association class II-III: +/-80%/20%), who were stable on digoxin and diuretics. Patients were treated for 12 weeks, and the main end points were exercise capacity and plasma neurohormones. RESULTS: At baseline, the four treatment groups were well-matched for demographic variables. Of the 244 patients, 25 dropped out: 3 patients died, and 9 developed progressive CHF (3/182 patients on imidapril vs. 6/62 patients on placebo, p < 0.05). Exercise time increased 45 s in the 10-mg group (p = 0.02 vs. placebo), but it did not significantly change in the 5-mg (+16 s), and 2.5-mg (+11 s) imidapril group, compared to placebo (+3 s). Physical working capacity also increased in a dose-related manner. Plasma brain and atrial natriuretic peptide decreased (p < 0.05 for linear trend), while (nor)epinephrine, aldosterone and endothelin were not significantly affected. Renin increased in a dose-related manner, but plasma ACE activity was suppressed similarly (+/-60%) on all three doses. CONCLUSIONS: Already within 3 months after treatment initiation, high-dose ACE inhibition (with imidapril) is superior to low-dose. This is reflected by a more pronounced effect on exercise capacity and some of the neurohormones, but it does not appear to be related to the extent of suppression of plasma ACE.     

Hemodynamic and norepinephrine responses to pacing-induced heart failure in conscious sinoaortic-denervated dogs

The present study was undertaken to determine the effects of chronic sinoaortic (baroreceptor) denervation (SAD) on the hemodynamic and sympathetic alterations that occur in the pacing-induced model of congestive heart failure. Two groups of dogs were examined: intact (n = 9) and SAD (n = 9). Both groups of dogs were studied in the control (prepace) state and each week after the initiation of ventricular pacing at 250 beats/min. After the pacemaker was turned off, hemodynamic and plasma norepinephrine levels returned toward control levels in the prepaced state and after 1 and 2 wk of pacing. However, by 3 wk all hemodynamic and norepinephrine levels remained relatively constant over the 10-min observation period with the pacemaker off. With the pacemaker off, left ventricular end-diastolic pressure went from 2.7 +/- 1.4 (SE) mmHg during the prepace state to 23.2 +/- 2.9 mmHg in the heart failure state in intact dogs (P < 0.01). Left ventricular end-diastolic pressure increased to 27.1 +/- 2.2 mmHg from a control level of 4.2 +/- 1.9 mmHg i SAD dogs (P < 0.0003). Mean arterial pressure significantly decreased in intact and SAD dogs. Resting heart rate was significantly higher in SAD dogs and increased to 135.8 +/- 8.9 beats/min in intact dogs and 136.1 +/- 6.5 beats/min in SAD dogs. There were no significant differences in the hemodynamic parameters between intact and SAD dogs after pacing. Plasma norepinephrine was significantly lower in intact than in SAD dogs before pacing (197.7 +/- 21.6 vs. 320.6 +/- 26.6 pg/ml; P < 0.005). In the heart failure state, plasma norepinephrine increased significantly in both intact (598.3 +/- 44.2 pg/ml) and SAD (644.0 +/- 64.6 pg/ml) groups. There were no differences in the severity or the magnitude of the developed heart failure state in SAD vs. intact dogs. We conclude from these date that the arterial baroreflex is not the sole mechanism for the increase in sympathetic drive in heart failure.     

Protein and calorie effects on progression of induced chronic renal failure in cats

This study was designed to determine if there is a difference in autonomic regulation induced by posture change between postmenopausal and young women. To evaluate autonomic nervous system function, spectral analysis of heart rate variability (HRV) was done in postmenopausal women (n = 13, 46-59 years of age), age-matched men (n = 8, 45-55 years of age), and young women (n = 10, 20-37 years of age) for 3-min periods of controlled frequency breathing (15 breaths/min) in supine followed by sitting positions. In the supine position, the R-R interval variation in older persons decreased significantly compared with that during the follicular phase in young women. Furthermore, the high-frequency (HF) components of HRV, which reflect only parasympathetic activity, were lower in older subjects than in young women. Following a change of position from supine to sitting, the HF component did not change significantly in the postmenopausal women or the men, but the low/high frequency (LF/HF) component ratio, which reflects the balance of autonomic nerve activities, increased significantly in the men. These results suggest that cardiac parasympathetic tone may be reduced in older persons in comparison with young women. Furthermore, arterial baroreflex control of parasympathetic nerve activity caused by posture changes is impaired in the postmenopausal women and aged-matched men. The baroreflex control of the sympathetic component is maintained in the men but not in the postmenopausal women. These differences might result in part from changes in the level of female hormones.     

Effect of roasted soybeans and corn on performance and ruminal and blood metabolites of dairy calves

Respiratory sinus arrhythmia (RSA) has been used as a non-invasive estimate of vagal tone to determine whether the reduction in resting heart rate commonly seen when humans are exposed to increases in the ambient pressure is associated with changes in vagal autonomic control. Two sets of divers (n = 4) were examined during two simulated saturation dives, one to 46 atmospheres absolute (ATA) and another to 37 ATA. A significant reduction in resting heart rate was seen in both dives upon exposure to high pressure compared with controls at 1 ATA. The reduction in heart rate seen at increased pressure was consistent regardless of respiratory rate, indicating that moderate changes in respiratory rate do not affect heart rate under these conditions. No changes in the overall magnitude of RSA were observed over a range of respiratory rates during either dive compared with control values at 1 ATA. During both dives, RSA was significantly larger (P < 0.05) at low respiratory rates compared with higher rates for both 1 ATA controls and at high pressure. The presence of a hyperbaric bradycardia strongly suggests that vagal tone is altered during hyperbaric exposure; however, the lack of change in the magnitude of RSA at high pressure brings into question the viability of using RSA as an accurate indicator of vagal tone and this lack of correspondence deserves further investigation.