Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Pulsatile hemodynamics in congestive heart failure.

Pulse pressure, an indirect measure of vascular stiffness and pulsatile load, predicts clinical events in congestive heart failure (CHF), suggesting that abnormal pulsatile load may contribute to CHF. This study was designed to assess more direct measures of central pulsatile load in CHF. Noninvasive hemodynamic evaluations were performed in 28 subjects with CHF and 40 controls using calibrated tonometry of the brachial, radial, femoral, and carotid arteries along with echocardiographic assessment of left ventricular outflow tract (LVOT) diameter and Doppler flow. Characteristic impedance (Z(c)) was calculated as the ratio of DeltaP (carotid) and DeltaQ (LVOT flow) in early systole. Carotid-radial (CR-PWV) and carotid-femoral (CF-PWV) pulse wave velocities were calculated from tonometry. Augmentation index was assessed from the carotid waveform. Total arterial compliance (TAC) was calculated using the area method. Brachial pulse pressure was elevated (62+/-16 versus 53+/-15 mm Hg, P=0.015) in CHF because of lower diastolic pressure (66+/-10 versus 73+/-9 mm Hg, P=0.003). CHF had higher Z(c) (225+/-76 versus 184+/-66 dyne. sec. cm(-5), P=0.020). CF-PWV did not differ (9.7+/-2.7 versus 9.2+/-2.0, P=0.337), whereas CR-PWV was lower in CHF (8.6+/-1.4 versus 9.4+/-1.5, P=0.038). There was no difference in TAC (1.4+/-0.5 versus 1.4+/-0.6 mL/mmHg, P=0.685), and augmentation index was lower in CHF (8+/-17 versus 21+/-13%, P=0.001). CHF subjects have elevated central pulsatile load (Z(c)), which is not apparent in global measures such as augmentation index or TAC, possibly because of contrasting changes in central and peripheral conduit vessels. This increased pulsatile load represents an important therapeutic target in CHF.

Functional nicotinic acetylcholine receptors that mediate ganglionic transmission in cardiac parasympathetic neurons.

Nicotinic acetylcholine receptors (nAChRs) mediate ganglionic transmission in the peripheral autonomic nervous system in mammals. Functional neuronal nAChRs have been shown to assemble from a combination of alpha and beta subunits, including alpha3, alpha5, alpha7, beta2, and beta4 in RNA-injected oocytes, but the subunit composition of functional neuronal nAChRs in vivo in mammals remains unknown. We examined the subunit composition of functional nAChRs in the intracardiac parasympathetic ganglion in a physiologically intact system in vivo. We report here that localized perfusion of the canine intracardiac ganglion in situ with an antagonist specific for nAChRs containing an alpha3/beta2 subunit interface (alpha-conotoxin MII 100-200 nm) resulted in reversible attenuation of the sinus cycle length (SCL) response by approximately 70% to electrical stimulation of the preganglionic vagus nerve. Perfusion with antagonist specific for receptors containing an alpha3/beta4 subunit interface (alpha-conotoxin AuIB 1 micrometer) resulted in attenuation in SCL responses (approximately 20%) compared with baseline when applied by itself, but not in animals pretreated with alpha-conotoxin MII. Perfusion of the ganglion with alpha-bungarotoxin (1 micrometer, which blocks alpha7 receptors) caused a reduction in SCL response by approximately 30% compared with baseline when perfused on its own and when added after blockade with MII and AuIB. Perfusion with hexamethonium bromide resulted in complete blockade of ganglionic transmission, confirming total perfusion of the ganglion and the nicotinic nature of ganglionic transmission at this synapse. Immunohistochemistry using monoclonal antibodies against specific nicotinic subunits confirmed the presence of alpha3, alpha7, beta2, and beta4 subunits. We conclude that functional ganglionic transmission in the canine intracardiac ganglion is mediated primarily by receptors containing an alpha3/beta2 subunit interface, with a smaller contribution by receptors containing alpha7 nAChRs. Despite the presence of beta4 subunits in functional channels, a contribution of a distinct alpha3/beta4 receptor population that does not include an alpha3/beta2 subunit interface was less clear.

Ganglionic mechanisms contribute to diminished vagal control in heart failure.

BACKGROUND: Previous work has shown that spontaneous and stimulated vagal activity is diminished in heart failure (HF) despite upregulation of functional postsynaptic cholinergic mechanisms. We therefore examined function of the postganglionic neuron in the paced canine model of HF as a possible site for diminished control. METHODS AND RESULTS: We measured sinus cycle length changes in response to electrical stimulation of preganglionic and postganglionic parasympathetic neurons innervating the sinoatrial node in control and HF dogs (both, n=8). Cervical vagus stimulation (preganglionic) demonstrated attenuated responses in the HF group at all levels of stimulation (P<0.05). Stimulation of the right atrial fat pad, containing both postganglionic nerves and terminals of preganglionic neurons, showed no such difference between control and HF (200+/-25 versus 192+/-18 ms). To ensure that preganglionic input and different levels of baseline sympathetic activity did not contribute to the group difference, similar stimulations were done in the presence of ganglionic and beta-adrenergic blockade. Under these conditions, postganglionic stimulation showed smaller changes in sinus cycle length, but the HF group response remained significantly higher than in controls (76+/-10 versus 20+/-2 ms; P<0. 01), indicating that the difference was independent of preganglionic input and sympathetic activity. CONCLUSIONS: A component of attenuated parasympathetic control in HF is located within the peripheral efferent limb. This defect is located within the parasympathetic ganglion. Future work should be focused on determining mechanisms of attenuated ganglionic transmission so that means targeted at restoring vagal activity can be developed.

Reflexes mediated by cardiac sympathetic afferents during myocardial ischaemia: role of adenosine.

1. Myocardial ischaemia and infarction activate vagal and sympathetic sensory endings in the ischaemic myocardium, resulting in powerful reflex effects. The vagal afferents are either mechano- or chemosensitive, whereas sympathetic afferents may be mechano-, chemosensitive or both. 2. Activation of vagal afferents results in sympathoinhibitory, cardioinhibitory, vasodepressor responses. Cardiac sympathetic afferents activated during myocardial ischaemia mediate sympathoexcitatory, vasoconstrictor cardioaccelerator responses. 3. The focus of the present review is on the activation of sympathetic afferents by myocardial ischaemia and on the resulting reflex responses that they mediate. 4. These endings are more likely to be activated as the degree of ischaemia progresses from subendocardial towards transmural. They are evenly distributed between the anterior and inferoposterior wall. Although it has been suggested that these endings are activated by bradykinin, recent evidence indicates that they are activated by adenosine released from the ischaemic myocardium. Results from our laboratory indicate that this effect is due to the activation of adenosine A1, but not adenosine A2 receptors. 5. Activation of ventricular vagal and sympathetic afferent fibres during myocardial ischaemia in humans is responsible for the autonomic changes observed and, in the case of the sympathetic afferents, for the sensation of angina pectoris.

Reflex control of sympathetic activity during ventricular tachycardia in dogs: primary role of arterial baroreflexes.

BACKGROUND: The determinants of hemodynamic outcome during ventricular tachycardia (VT) are not well understood. In the present study, we addressed the relative contributions of arterial and cardiopulmonary baroreflexes to the sympathetic and arterial pressure responses to VT or ventricular pacing (VP) in dogs with inducible VT. METHODS AND RESULTS: Responses of renal sympathetic nerve activity (RSNA), pulmonary capillary wedge pressure (PCWP), and mean arterial pressure (MAP) to induced VT or VP (220 to 280 beats per minute) were determined in 12 dogs with a healed anteroapical infarction and inducible VT and in 8 control dogs. The responses were determined with all reflexes intact, after selective denervation of either arterial or cardiopulmonary baroreflexes, and after combined denervation. Differences between intact and denervated conditions were used to assess the relative effects of each baroreflex. In the infarct group, responses during VT were comparable to those during VP. RSNA and PCWP increased significantly (P<.01), whereas MAP decreased significantly (P<.001) during VT or VP with baroreflexes intact in both groups. The increase in RSNA and the recovery of MAP during sustained VP were greater in the infarct group (P<.05); in addition, the increase in PCWP was greater in the infarct group (P<.05). Arterial baroreflex denervation abolished the increased RSNA and recovery of MAP during VP in both groups. After cardiopulmonary baroreflex denervation, the increase in RSNA was augmented in both groups (control group more than infarct group), but recovery of MAP was increased further only in the control group. CONCLUSIONS: These results suggest that arterial baroreflex mediated sympathoexcitation plays an important role in determining the hemodynamic outcome during VT, whereas cardiopulmonary baroreflexes play only a modest modulatory role.

Enalaprilat augments arterial and cardiopulmonary baroreflex control of sympathetic nerve activity in patients with heart failure.

OBJECTIVES: This study sought to determine the effects of enalaprilat on reflex control of sympathetic nerve activity. BACKGROUND: Angiotensin-converting enzyme inhibitors decrease mortality in patients with congestive heart failure. Their efficacy appears to be related importantly to antiadrenergic effects, the mechanism for which has not been determined. Because baroreflexes tonically inhibit sympathetic outflow, and baroreflexes are blunted in heart failure, we hypothesized that these agents reduce sympathetic activity by augmenting baroreflexes. METHODS: We assessed baroreflex control of sympathetic nerve activity and heart rate in patients with congestive heart failure and in control subjects before and after enalaprilat (0.02 mg/kg body weight intravenously). Arterial baroreflexes were perturbed by bolus administration of sodium nitroprusside and phenylephrine. Cardiopulmonary baroreflexes were perturbed by lower body negative pressure and head-down tilt. Muscle sympathetic nerve activity was recorded by microneurography. RESULTS: Enalaprilat decreased systolic blood pressure in patients with heart failure and control subjects. Sympathetic nerve activity increased in control subjects but decreased in patients with heart failure after enalaprilat despite reductions in central venous pressure in this group. Baroreflex control of sympathetic nerve activity was unchanged by enalaprilat in control subjects. In patients with heart failure, both arterial and cardiopulmonary baroreflex control of sympathetic nerve activity was enhanced by enalaprilat. Baroreflex control of heart rate was unchanged by enalaprilat in either group. CONCLUSIONS: Enalaprilat augments both arterial and cardiopulmonary baroreflex control of sympathetic activity in heart failure. These augmented inhibitory influences are associated with a reduction in sympathetic outflow and may contribute to the beneficial effects of angiotensin-converting enzyme inhibitors in heart failure.

Treatment with enalapril fails to prevent impaired cardiopulmonary baroreflex control in dogs with left ventricular dysfunction.

That the cardiopulmonary baroreflex control of sympathetic nerve activity is impaired in dogs with left ventricular (LV) dysfunction has been shown previously. This study tested the hypothesis that treatment with the angiotensin-converting enzyme inhibitor enalapril prevents or delays the development of abnormalities of cardiopulmonary baroreflexes in dogs with LV dysfunction. Serial changes in LV volumes and neurohumoral profiles (plasma norepinephrine and renin activity) were assessed in conscious dogs with progressive LV dysfunction due to rapid ventricular pacing. Enalapril 5 mg orally twice daily was administered from days 4 to 12 of pacing. Cardiopulmonary baroreflexes were assessed in enalapril-treated paced dogs (n = 8) and untreated paced dogs (n = 8) by recording changes in renal nerve activity and pulmonary capillary wedge pressure during volume infusion in anesthetized sinoaortic denervated dogs on day 12 of rapid pacing. There was no difference in LV volume in the two groups. Neurohumoral factors were similar in both groups except for the expected high plasma renin activity in enalapril-treated dogs. Hemodynamic parameters also were comparable in the two groups. Cardiopulmonary baroreflex sensitivity for enalapril-treated dogs was not different from that of untreated paced dogs, and baroreflex gain in both groups was significantly lower than for the nonpaced control dogs (P < .05). Despite adequate converting enzyme blockade, treatment with enalapril failed to prevent the development of attenuated cardiopulmonary baroreflex control of sympathetic nerve activity in dogs with developing LV dysfunction.

Altered vagal and sympathetic control of heart rate in left ventricular dysfunction and heart failure.

We investigated alterations in autonomic control of heart rate in conscious dogs with left ventricular (LV) dysfunction in the presence and absence of heart failure (HF) due to rapid pacing. In dogs with LV dysfunction but no HF, indexes of parasympathetic control decreased significantly after only 4 days of pacing. In dogs with fully developed HF, both vagal and sympathetic contributions were small. Vagomimetic doses of atropine increased both R-R interval (419 +/- 25 to 466 +/- 34 ms, P < 0.05) and standard deviation (SD) of the R-R interval (13 +/- 2 to 34 +/- 9 ms, P < 0.05). The digitalis glycoside deslanoside (Cedilanid-D) alone prolonged R-R interval (420 +/- 33 to 492 +/- 44 ms, P < 0.01) and tended to increase SD (14 +/- 4 to 28 +/- 8 ms, P = 0.08). After Cedilanid-D, low-dose atropine resulted in no significant further change in R-R interval or SD. These data indicate that changes in vagal control of heart rate become apparent at a very early developmental stage of LV dysfunction, and we speculate that this may provide important prognostic information in patients who are at risk for developing progressive myocardial dysfunction and HF.

Cardiorespiratory reflex control in rats with left ventricular dysfunction.

Patients with heart failure exhibit a neurohumoral excitatory state and abnormal baroreflex control of the cardiovascular system. We determined whether arterial baroreflexes are impaired during left ventricular dysfunction (LVD) caused by chronic myocardial infarction in the absence of congestive heart failure and whether abnormal central mechanisms contribute to this impairment. Baroreceptors were stimulated in anesthetized rats with and without LVD by increasing arterial pressure with phenylephrine. Lumbar sympathetic nerve and phrenic nerve activity as well as heart rate were recorded. Rats were divided into different groups based on infarct size. Rats with moderate LVD showed impaired baroreflex control of sympathetic, ventilatory, and heart rate responses. Baroreflex gains were inversely related to the size of the infarct. The central gain for sympathetic nerve activity, obtained by using electrical stimulation of the aortic depressor nerve, also was impaired. Baroreflex control of the cardiorespiratory system is thus impaired in rats with moderate LVD in the absence of congestive heart failure. The attenuated baroreflexes are likely due to abnormal afferent mechanisms, although central mechanisms contribute to the impaired barosympathetic reflex.

Abnormalities of baroreflex control in heart failure.

This brief review summarizes abnormalities of arterial and cardiopulmonary baroreflex control of heart rate and sympathetic nerve activity. The potential role of these abnormalities in the development of the neurohumoral excitatory state associated with heart failure is discussed. Major emphasis is placed on the identification of important issues still to be investigated in this area. The potential importance of altered cardiovascular reflexes in the context of the interaction of the patient with heart failure and environmental stresses is discussed. The use of the canine rapid ventricular pacing model of biventricular failure in the investigation of abnormalities of baroreflexes in heart failure is emphasized. Insights obtained from this model should be extended to human investigations.

Activation of cardiac sympathetic afferents: effects of exogenous adenosine and adenosine analogues.

Adenosine is released during myocardial ischemia and can cause angina-like chest pain when given by intracoronary administration. We tested the hypothesis that intracoronary adenosine activates cardiac sympathetic afferent fibers and results in reflex sympathoexcitation. In dogs with sinoaortic denervation and vagotomy, we administered 2 mg of adenosine into the left anterior descending artery over 2 min. Before dipyridamole infusion, intracoronary adenosine resulted in no change in blood pressure or renal sympathetic nerve activity. After dipyridamole infusion, which blocks adenosine uptake, intracoronary adenosine resulted in a peak increase in sympathetic activity of 34 +/- 7%. We also investigated the adenosine-receptor subtype responsible for this sympathoexcitatory response. We found that the adenosine1 agonist N6-cyclopentyladenosine elicited a dose-dependent sympathoexcitatory response similar to adenosine but that the adenosine2 agonist 5'-(N-cyclopropyl)carboxamidoadenosine failed to elicit a sympathoexcitatory response. We conclude that adenosine activates cardiac sympathetic afferent fibers and leads to a sympathoexcitatory response due to activation of adenosine1 receptors.

Reflex sympathoexcitation by cardiac sympathetic afferents during myocardial ischemia. Role of adenosine.

BACKGROUND: Stimulation of cardiac sympathetic afferents during myocardial ischemia has been attributed to bradykinin released from the ischemic myocardium. Recent data from human studies suggest that adenosine may serve as this mediator. Our experiments were done to determine whether reflex sympathoexcitatory responses to activation of cardiac sympathetic afferents during myocardial ischemia could be inhibited by blockade of adenosine receptors and augmented by increasing the local concentrations of adenosine in the ischemic myocardium. METHODS AND RESULTS: Experiments were done in 29 anesthetized dogs with bilateral vagotomy and carotid sinus denervation. Activation of cardiac sympathetic afferent fibers was induced by occlusion of the left anterior descending coronary artery (LAD) combined with rapid atrial pacing (pacing rate, 200 beats per minute). LAD occlusion plus rapid atrial pacing increased renal sympathetic nerve activity by 20 +/- 4% before but by only 7 +/- 1% after administration of aminophylline (100 mg i.v.), an adenosine receptor antagonist. In contrast, LAD occlusion during rapid atrial pacing increased renal sympathetic nerve activity by 18 +/- 8% before and 61 +/- 15% after treatment with dipyridamole (0.57 mg/kg i.v.), an inhibitor of adenosine reuptake. In a separate group of dogs, LAD occlusion during rapid atrial pacing increased renal sympathetic nerve activity similarly before and after sham treatment. CONCLUSIONS: These data suggest that adenosine released during myocardial ischemia activates cardiac sympathetic afferents to cause reflex sympathoexcitation. These findings are consistent with observations made in humans that suggest that adenosine is the mediator of the sensation of angina pectoris, which also results from stimulation of cardiac sympathetic afferents.

Control of sympathetic nerve activity by vagal mechanoreflexes is blunted in heart failure.

BACKGROUND: Previous studies have documented abnormalities of arterial baroreflexes in animals and patients with congestive heart failure. This study determined whether cardiopulmonary reflex control of sympathetic nerve activity was abnormal in a canine model of low-output heart failure induced by rapid ventricular pacing. METHODS AND RESULTS: We stimulated mechanoreceptors throughout the cardiopulmonary region by volume expansion and left atrial mechanoreceptors selectively by inflating small balloons at the junctions of the pulmonary veins and left atrium. Responses of renal sympathetic nerve activity and left atrial and systemic arterial pressures were recorded. In the control group, 15% volume expansion raised left atrial pressure 3.5 +/- 0.8 mm Hg and resulted in a 70 +/- 8% reduction in renal nerve activity. In the heart failure group, 15% volume expansion resulted in a 6.8 +/- 3.0 mm Hg rise in left atrial pressure with only a 16 +/- 20% reduction in renal nerve activity (p < 0.01). When volume expansion was performed after pretreatment with hemorrhage to lower left atrial pressure to the normal range in the heart failure group, the markedly attenuated response in the heart failure group persisted. After vagotomy, volume expansion elicited no change in renal nerve activity. Inflation of the atrial balloons caused a 28 +/- 9% reduction in renal sympathetic nerve activity and a 13 +/- 4 mm Hg decrease in arterial pressure in the control group. Renal nerve activity (-5 +/- 3%) and mean arterial pressure (-1 +/- 1 mm Hg) did not change with balloon inflation in the heart failure group. CONCLUSIONS: We conclude that dogs with low-output heart failure exhibit marked attenuation of cardiopulmonary mechanoreflex control of sympathetic nerve activity. This attenuated response is mediated via cardiac vagal afferent fibers and is due to either abnormalities in cardiopulmonary baroreceptors or abnormalities in the central nervous system.

Procainamide inhibits sympathetic nerve activity in rabbits.

Procainamide has been used extensively for the treatment of ventricular arrhythmias. It is widely held that the sympathetic nervous system plays an important role in the pathogenesis of ventricular arrhythmias. We investigated the possibility that procainamide has effects on the sympathetic nervous system by determining the responses to procainamide of postganglionic renal and preganglionic lumbar nerve activity in rabbits with sinoaortic and vagal denervation. Bolus administration of procainamide (3, 7, and 15 mg/kg) resulted in dose-dependent decreases in renal sympathetic nerve activity (26%, 38%, and 57%, respectively). These boluses resulted in plasma levels of procainamide of 13.3, 23.6, and 41.7 micrograms/ml, respectively. The same doses of procainamide resulted in decreases in lumbar nerve activity of 36%, 36%, and 41%, respectively. In a separate group of rabbits pretreated with hexamethonium (n = 8), 15 mg/kg procainamide reduced lumbar nerve traffic by 38%. Infusion of procainamide at 1 mg/kg/min over 20 minutes (n = 9) resulted in a decrease in renal sympathetic nerve activity of 20% with a plasma level of 11 micrograms/ml. Sham-treated rabbits (n = 8) exhibited an 18% increase in traffic over a comparable period of time. We conclude that procainamide inhibits lumbar and renal sympathetic nerve activity through effects on the brain or spinal cord. The influence of procainamide on sympathetic nerve activity may contribute importantly to its efficacy in the therapy of ventricular arrhythmias.

A simplified technique for the production of heart failure in the dog by rapid ventricular pacing.

Prolonged rapid ventricular pacing (VP) in dogs produces low output heart failure (HF) characterized by cardiomegaly, ascites, and elevated plasma renin and norepinephrine levels. Commercially available pacemaker generators have a protective circuit that prevents pacing at rapid rates. Previously, investigators have had to use either external temporary pacemakers or customized generators to pace at rates greater than 130 beats per minute (bpm). The authors have developed a simple method to perform rapid VP by gluing magnets on Medtronic VVI generators, which allows programming in a temporary mode to sustain rates up to 400 bpm. Our results using 10 generators in 55 dogs demonstrates that HF is produced in all dogs when VP is maintained at 250 bpm for an average of 28 days. Technical difficulties during our early experience with this technique included magnets becoming unglued, loss of capture, and wound complications requiring generator removal. Thus, our method reuses commercially available generators to rapidly pace the ventricles and induce HF.

Autonomic pathophysiology in heart failure: carotid baroreceptor-cardiac reflexes.

We evaluated reflex cardiac responses mediated by carotid baroreceptors in 14 patients with treated congestive heart failure and 14 age-matched healthy subjects. We used a neck chamber to deliver two types of pressure change: 5 s of continuous 50-mmHg suction and an R wave triggered, ramped neck pressure-suction sequence. Reflex latencies (functions of baroreflex arc duration) were comparable in heart failure patients and healthy subjects. However, the average maximum baroreflex slope (gain) was less in heart failure patients than healthy subjects (2.0 vs. 3.5 ms/mmHg, P less than 0.010), the R-R interval response range was smaller (91 vs. 188 ms, P = 0.002), and the resting R-R interval position on stimulus-response relation (operational point) was significantly (13 vs. 40%, P = 0.001) closer to threshold. Stepwise regression analysis suggested that baseline R-R interval variability, used as an index of ongoing vagal-cardiac nerve traffic, and the inverse of antecubital vein plasma norepinephrine level, used as an index of sympathetic nerve activity, contributed significantly to the prediction of abnormal carotid baroreceptor-cardiac reflex responses. Thus our results suggest that in heart failure patients, carotid baroreceptor-cardiac reflex abnormalities are related significantly to ongoing abnormalities of vagal and sympathetic cardiovascular outflow.

Baroreflex control of renal sympathetic nerve activity is preserved in heart failure despite reduced arterial baroreceptor sensitivity.

The purpose of this study was to determine if arterial baroreflex control of sympathetic nerve traffic is impaired in heart failure. We recorded renal nerve activity during changes in arterial pressure while simultaneously recording from aortic baroreceptor afferent fibers in 10 dogs with heart failure induced by rapid ventricular pacing and in 10 sham animals. Sensitivity of the aortic baroreceptors (percent change in nerve activity per millimeters mercury change in mean arterial pressure) was reduced in the heart failure group (heart failure, 2.3 +/- 0.3; sham, 3.6 +/- 0.4, p = 0.02). Despite the reduced sensitivity of aortic baroreceptors in heart failure, there was no difference in the baroreflex gain of renal nerve activity (heart failure, -5.5 +/- 1.4; sham, -5.8 +/- 1.3, p = NS). These values tended to decrease in both groups after vagotomy. The relation between baroreceptor input and renal sympathetic output, or central baroreflex gain (percent change in renal nerve activity divided by percent change in aortic nerve activity) was similar in both groups before vagotomy (heart failure, -2.4 +/- 0.6; sham, -2.3 +/- 0.5, p = NS). Vagotomy reduced central gain in the sham group (-0.9 +/- 0.1, p = 0.03) but not in the heart failure group (-1.7 +/- 0.5, p = NS), suggesting that the contribution of vagal afferents in the baroreflex arc is reduced in heart failure. Baroreflex control of R-R interval was attenuated in heart failure when assessed by blood pressure elevation but not reduction, indicating abnormal parasympathetic but preserved cardiac sympathetic mechanisms in heart failure. Thus, dogs with heart failure exhibit reduced sensitivity of aortic baroreceptors but preserved baroreflex control of renal nerve activity. Reduced baroreceptor sensitivity with preservation of baroreflex control of sympathetic nerve activity may contribute to the sympathoexcitatory state known to exist in heart failure.

Ventricular sensory endings mediate reflex bradycardia during coronary arteriography in humans.

It has been suggested that the response to the intracoronary injection of radiographic contrast is reflex in origin and results from stimulation of ventricular sensory endings. Cardiac transplantation results in denervation of the ventricles, and thus, may interrupt the afferent limb of this reflex. In contrast, the recipient sinus node and atrial remnant remain innervated, leaving the efferent cardiac limb of this reflex intact. We hypothesized that if contrast-induced reflex bradycardia and hypotension occurred from stimulation of ventricular chemosensitive endings, then this response would be abolished after cardiac transplantation. To test this hypothesis, we determined the changes in recipient (innervated) and donor (denervated) sinus-node rates (SNR) and mean arterial pressure during selective right (RCA) and left coronary artery (LCA) injection during arteriography in cardiac transplant patients and in patients with intact cardiac innervation. An increase in the recipient SNR was observed in cardiac transplant patients during left and right coronary injections (LCA, 6.6 +/- 1.7 beats/min; RCA, 2.4 +/- 1.4 beats/min) compared with a decrease in the control subjects (LCA, -15.3 +/- 2.3 beats/min; RCA, -6.9 +/- 1.9 beats/min; p less than 0.05 vs. control). This occurred despite significant and comparable decreases in mean arterial pressure in cardiac transplant patients (LCA, -12.7 +/- 2.3 mm Hg; RCA, -11.4 +/- 2.2 mm Hg) and control subjects (LCA, -18.7 +/- 1.7 mm Hg; RCA, -10.7 +/- 1.6 mm Hg). The donor SNR slowed for LCA injection (-5.4 +/- 2.1 beats/min, p less than 0.05) and RCA injection (-3.0 +/- 1.7 beats/min), which, for the LCA, was less than the slowing of control subjects (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The long-term increase of baseline and reflexly augmented levels of human vagal-cardiac nervous activity induced by scopolamine.

We tested the hypothesis that transdermal scopolamine increases vagal-cardiac nervous outflow over the long term in 16 healthy young men. Twenty-four hours after application of one scopolamine patch, the average RR interval was increased by 13% and the average standard deviation of the RR interval (taken as an index of the level of vagal-cardiac nervous activity) was increased by 31%. Baroreceptor-cardiac reflex responsiveness (as reflected by prolongation of RR interval provoked by graded neck suction) also was increased substantially. These findings suggest that vagal-cardiac nervous activity can be augmented pharmacologically in man on a long-term basis. Since vagal outflow influences cardiac electrical properties in an important way, these findings may have therapeutic implications.