PATHOPHYSIOLOGIC BASIS FOR VASODEPRESSOR SYNCOPE

~~

~~

0733-8651/97 $0.00

SYNCOPE

+ .20

PATHOPHYSIOLOGIC BASIS FOR VASODEPRESSOR SYNCOPE Carlos A. Morillo, MD, Kenneth A. Ellenbogen, MD, and L. Fernando Pava, MD

The routine use of head-up tilt testing for the evaluation of recurrent unexplained syncope has indicated that the vasodepressor (vasovagal, neurocardiogenic) response may be responsible in up to 50% of cases of recurThe rent unexplained syncope.6,14, 55, 70, 73, vasodepressor response may be triggered by a myriad of stimuli, including orthostatic stress (head-up tilt, lower body negative pressure), emotional stress, relative or absolute blood loss, and severe pain. Similarly, data suggest that other clinical syndromes, such as carotid sinus hypersensitivity or micturition syncope, share a common reflex pathway with the classic vasodepressor response (Fig. l).73,78, Io6, 177, 180 Interest in elucidating the mechanisms responsible for the control of arterial blood pressure have intrigued physiologists and physicians for more than a century. Hunter (1728-1729) may have inadvertently reported the first description of a vasodepressor response when he wrote: "I bled a lady but she fainted and while she continued in the fit the color of the blood that came from the vein was a fine scarlet. The circulation was very languid."123It has been speculated that Hunter noticed the effects of vasodilatation during syncope.2o7By the late nineteenth century, Hill" suggested that emotional syncope results from withdrawal of vasomotor

neural traffic. This view was further supported in 1932 by Lewisls4 who introduced the term vusovugul suggesting that both vasodilatation and bradycardia were involved in the vasodepressor response. Lewis demonstrated that bradycardia was vagally mediated; however, despite prevention of bradycardia with atropine, hypotension persisted.M Further interest in the pathophysiology of this syndrome was triggered by the frequent observation of vasodepressor responses in in51, 52, %, 165 jured soldiers during World War This interest was renewed in the 1960s by the advent of aerospace medicine in an attempt to understand the physiology of G forceinduced vasodepressor syncope.", 43, 195 The introduction of head-up tilt as a clinical diagnostic tool in 1986 by Kenny and associatesn revived the interest in elucidating the mechanism of vasodepressor syncope.78,131, 133, 176 Activation of left ventricular vaga1-C mechanoreceptors owing to a sympathetically mediated increase in contractility in an empty or preload reduced left ventricular cavity leading to a reflex increase in vagal efferent traffic and sympathetic withdrawal to skeletal muscle arterioles and splanchnic venules has been usually regarded as the potential mechanism of vasodepressor syncope (Fig. 2).12,69, 95, 199 This view, largely supported by experimental evi-

From the Department of Medicine, Universidad Industrial de Santander, Laboratory of Autonomic Physiology and Cardiac Electrophysiology (CAM); and Department of Cardiology and Cardiovascular Sciences, Fundacidn Cardiovascular del Oriente Colombiano (CAM, LFP), Bucaramanga, Santander, Colombia; and Department of Medicine, and Cardiac Electrophysiology, Medical College of Virginia, Richmond, Virginia ( W E )

CARDIOLOGY CLINICS VOLUME 15 * NLIMBER 2 MAY 1997

233

234

MORILLO et a1

Arterial Baroreceptors

Cardiopulmonary Baroreceptors (NCS)

(CW

GI tract

Bladder

@ostprandial syncope)

(micturition syncope)

Sympathetic s+ Withdrawal

Bradycardia

Hypotension

Figure 1. Afferent and efferent reflex pathways in neurocardiogenic syncope. CSH = carotid sinus hypersensitivity: NCS = neurocardiogenic syncope; PS = parasympathetic; S = sympathetic.

TILT LBNP HEMORRHAGE

VBP REFLEX

0 CATECHOLS

+/- BRADYCARDIA HYPOTENSION

Q Inotropy

SYNCOPE

Q Contractility Figure 2. Hemodynamic and autonomic changes provoked by physiologic stimuli that lead to vasodepressor syncope. LBNP = lower-body negative pressure.

PATHOPHYSIOLOGIC BASIS FOR VASODEPRESSOR SYNCOPE

dence obtained from cats by 0berg1lGlz1and Thor6nls6,lS7 and rats in the mid 1970s prevailed until the observation of vasodepressor syncope in heart transplant recipients re%, 142, 204 Species ported by several differences in the genesis of the vasodepressor response may be responsible for this discrepancy.lMMorita and V a t n e F observed in conscious dogs sympathoexcitation and tachycardia as the initial response to hemorrhage. Progressive hemorrhage led to sympathetic withdrawal and bradycardia. Interruption of cardiac afferents or arterial baroreceptors, however, was unable to prevent the onset of the vasodepressor response.1o9These findings suggest that cardiac afferents may not be required to trigger the vasodepressor response and have been met with the proposal of alternative hypotheses. This article focuses on the current knowledge regarding the neuroendocrine, hemodynamic, and neurophysiologic components of the vasodepressor response and proposes a unifying hypothesis for vasodepressor syncope. PHYSIOLOGIC RESPONSE TO ORTHOSTATIC STRESS

Neural mechanisms responsible for the control of blood pressure are modulated by

235

arterial and cardiopulmonary baroreceptors that regulate arterial pressure and vascular lol, 132, 133, 212 Aortic and catone in humans.2,4* rotid sinus arterial baroreceptor discharge is directly related to stretching caused by arterial pressure. These receptors send afferent impulses to the brain stem that inhibit efferent sympathetic cardiac and peripheral circulation activity and increase cardiac vagal activity. Central regulation of this system is believed to be largely mediated by the rostral ventral lateral medulla.20 This area is the major source of tonic excitatory input to sympathetic preganglionic motor neurons in the spinal cord. Arterial baroreceptors are connected by myelinated and unmyelinated fibers in the X and IX cranial nerves. These nerve terminals synapse with neurons in the tractus nucleus solitarius and project to the ventral lateral medulla synapsing with neurons in the caudal ventral lateral medulla. This circuit is completed by axons in the caudal ventral lateral medulla that synapse with the excitatory neurons in the rostral ventral lateral medulla (Fig. 3). The neurotransmitter involved in this circuit is most likely gammaaminobutyric acid (GABA).20 Abrupt falls in arterial blood pressure result in increased efferent sympathetic nerve traffic with vagal ~ i t h d r a w a l . ' ~In ~ -con'~~

Figure 3. Central arterial baroreceptor reflex pathways. CVLM = caudate ventral lateral medulla; NA = nucleus ambigus; NTS = nucleus tractus solitarius; RVLM = rostral ventral lateral medulla; (-) = inhibitory stimuli; (+) = excitatory stimuli.

236

MORILLO et a1

trast, when arterial blood pressure rises, these receptors increase their firing rate, resulting in sympathetic withdrawal and bradycardia mediated by increased cardiac vagal efferent activity. This tightly regulated reflex response serves as a buffer for spontaneous changes in arterial blood pressure.19o Cardiopulmonary baroreceptors are located in the pulmonary vasculature junctions and in the left ventricle.2,133, lS3,212 These mechanoreceptors discharge during systole, and their firing rate is directly related to the myocardial contraction force and the level of intracardiac filling pressures.”*,133, lS7, 203 Cardiopulmonary mechanoreceptors also send afferent impulses (via vaga1-C fibers) to the brain stem that result in withdrawal of sympathetic efferent activity. Reductions in intracardiac filling pressures that do not significantly alter heart rate or arterial blood pressure, as during mild hemorrhage or lowlevel lower body negative pressure, determine a reduced discharge firing rate of these receptors resulting in increased sympathetic efferent 133, In contrast, increased intracardiac filling pressures that do not result in significant changes in arterial blood pressure or heart rate increase cardiopulmonary mechanoreceptor discharge rate, resulting in sympathetic withdrawal.57,133 Orthostatic stress activates a variety of complex neurohumoral and hemodynamic changes in response to blood pooling of approximately 800 mL in the lower limbs.133,178, 190, 197 Active standing elicits an immediate increase in systolic blood pressure and heart rate followed by further increases in blood pressure and subsequent slowing of heart rate.22,23 This response has been attributed to a reflex originating in the contracting postural muscles or a central command mechanism, mediated initially by vagal withdrawal (20 to 30 seconds) followed by arterial baroreceptor activation.22The response to orthostatic stress induced by head-up tilt is slightly different and characterized by gradual increase in both systolic and diastolic blood pressure in addition to a less marked change in heart rate. Nonetheless, it appears that the reflex pathways activated during tilt are similar to those activated by active standing. The net response is an increase in sympathetic activity associated with vagal withdrawal mediated largely by cardiopulmonary and arterial baroreceptors. Animal data have suggested an important role of vestibulosympathetic reflexes that may modulate peripheral vasoconstric-

tion before significant drops in blood pressure providing feed-forward compensation to orthostatic stress.209 NEUROENDOCRINE CHANGES IN VASOVAGAL SYNCOPE Orthostatic stress is associated with a variety of neuroendocrine alterations that have been described by several investigators.l8T25, 60, 130, 194 Arterial baroreceptor regulation is part of the intricate design of servocontrol loop mechanism^.^^, I9O Volume control is of vital importance in the maintenance of orthostasis and is modulated by complex neuroendocrine regulation of water and salt ba1an~e.l~. 190 Catecholamines, renin-angiotensin-aldosterone system, and antidiuretic hormone (vasopressin) as well as serotonin and other neuropeptides are involved. Catecholamines Increase in plasma noradrenaline concentration in the minutes preceding the vasodepressor response followed by stable or declining levels at the time of syncope have been reported by several groups.5,25, 50, 136, 190 Conversely, increased plasma adrenaline levels have been reported in most subjects during vasodepressor syncope triggered by nitrogly~erine,’~~ head-up tilt, or central hypovolemia induced by venous tourniq~ets.’~~, 140, 146, I9O The paradoxic increase in adrenaline levels may be considered partly responsible for the hypotension associated with the vasodepressor response. Adrenaline produces beta-adrenergic dilatation in both the skeletal muscle and the splanchnic resistance vessels at concentrations measured in humans under stress.139,140, 166 Increased adrenaline levels may oppose the vasoconstriction needed to maintain blood pressure. Further support for this finding is provided by less vasodilatation achieved after adrenale~tomy.~, I9O Renin Orthostatic stress is initially associated with increases in renin subsequently followed by increased plasma levels of angiotensin II.122* l90, 210 The magnitude of this rise depends on the effective circulatory volume.1s8,190 Most human studies have reported decreased

PATHOPHYSIOLOGICBASIS FOR VASODEPRESSOR SYNCOPE

plasma renin activity before the onset of vasodepressor syncope induced by head-up tilt.49, 122, 167, 190 Renin levels rise again after the subject returns to the supine position. Vasopressin

Plasma osmolality is the primary influence of vasopressin secretion.15,190 Changes in blood pressure and nausea secondarily regulate vasopressin regulation.46, 47, 150, 192 Gradual hemorrhage in conscious rabbits is related to increased vasopressin levels before the onset of hypotension and bradycardia. This fall in blood pressure and the rise in vasopressin levels may be prevented, in dogs, by blocking cardiac nerves, supporting the role of ventric201 In humans, howular mechanoreceptors.200, ever, vasopressin response to acute blood volume changes in cardiac transplant recipients is comparable to that in normal controls.28 This suggests that human vasopressin release is not exclusively mediated by cardiac reflexes. Vasopressin levels directly related to augmented vasoconstrictor response are triggered only by abrupt hypotension, such as during hemorrhage and vasodepressor syncope.'36,'%, I5O Ventricular C-fiber mechanoreceptors send impulses that activate the vomit center and result in general vagal discharge with reflex relaxation of the stomach.'50,169 Additionally, nausea is a potent stimulus for vasopressin secretion by activating central cholinergic pathway^.^, 150, 192 Nausea is a frequent prodromal symptom of vasodepressor syncope; however, a rise in plasma vasopressin does not discriminate between central or ventricular release of vasopressin. Vasopressin may also be involved in the vasodepressor response by sensitizing cardiac vagal afferent nerves', 3, l8 and possibly by modulating arterial baroreflex gainz9 Serotonin

The role of serotonin regulation in cardiovascular control has become evident. Similarly the relationship between serotonin regulation and vasovagal syncope has been stressed by Grubb and Morgan and c011eagues'~~ have reported that serotonin is related to the renal sympathetic inhibition observed during marked hemorrhage in rats. During controlled hemorrhage, animals were either administered saline p-chlorophenylaline

237

(PCPA), a serotonin synthesis blocker, or methysergide (serotonin receptor blocker). PCPA eliminated the vasodepressor reflex during hemorrhage, and methysergide increased renal sympathetic traffic, also preventing the development of the vasovagal response.'o3 These findings suggest that serotoninergic modulation may be critical for the maintenance of sympathetic traffic. Abboud' has reported that central administration of serotonin could induce hypotension, inhibition of central sympathetic nerve activity, and increased adrenal sympathetic activity. All these effects can be blocked by PCPA. Abboud' also hypothesizes that central serotonin may act at a central level inhibiting sympathetic outflow. Matzen and c o - w ~ r k e r sinvestigated ~~ the effects of acute intravenous administration of selective serotonin blockers during head-up tilt. They reported that 5-hydroxytryptamine (5-HT) 1 and 2 receptor antagonism (methysergide) did not affect heart rate or blood pressure responses but markedly attenuated orthostatic changes in plasma noradrenaline, prolactin, beta-endorphins, and plasma renin activity. 5-HTz receptor antagonism (ketanserin) reduced the tolerated tilt time but had no neurohormonal effects. In contrast, 5-HTz receptor antagonism (ondansetron) abolished the adrenomedullary response to tilt-induced hypotension without affecting cardiovascular tolerance or pituitary-adrenal response. These findings suggest that central serotoninergic modulation may be involved in the modulation of cardiovascular and neurohumoral responses to central volume depletion in humans. Pancreatic Polypeptide

Pancreatic polypeptide secretion is modulated by glucose levels and the presence of food in the stomach, mediated by cholinergic fibers in the vagus nerve.156Hypotension and bradycardia provoked during head-up tilt in healthy subjects is accompanied by marked increases in pancreatic polypeptide concentration, indicative of increased abdominal va147 This increase does not precede gal tone.146, the onset of symptoms. The significance of this finding remains to be established. Opiates

Opiates have been implicated in the vasodilator response to acute hemorrhage in con-

238

MORILLO et a1

scious rabbits and during orthostatic stress in humans.73,90-93, 96, 141, 151-153 Endogenous opiates play an important role in the modulation of baroreflex function and sympathetic outMorita and co11eagues109reported that high doses of naloxone (an opiate receptor antagonist) reversed renal sympathetic traffic withdrawal during controlled hemorrhage in rabbits, suggesting that opiates may be implicated in the mechanism of vasodepressor syncope. Infusion of methionine-enkephalin (an opiate receptor agonist) causes renal sympathoinhibition with hypotension that is significantly reduced after pretreatment with naloxone.'O9,133 Similarly, Rubin and co-worke r reported ~ ~ a ~significant ~ increase in baroreceptor gain after the administration of naloxone compared to DAMME (a metenkephalin analogue) during head-up tilt in normal subjects. Further support for these findings has been reported by Perna and and Wallbridge and who documented significant increases in beta-endorphin levels before the onset of the vasodepressor response during head-up tilt. Similarly, naloxone has been reported to potentiate cardiopulmonary baroreflex sympathetic control in humans155and increase muscle sympathetic nerve activity during isometric suggesting that endogenous opioids may restrain sympathetic neural outflow. Naloxone, however, has not been proven to prevent the onset of vasovagal syncope in h~mans.9~. 171 It is possible that betaendorphins reset baroreflex gain and precipitate central sympathoinhibition leading to hypotension and brady~ardia.'~~, lS1,191 Endothelin, Cyclic Guanosine Monophosphate, Adenosine The role of the vascular endothelium in the vasodepressor response has been postulated by K a ~ f r n a n nand ~ ~ other investigators. Increased plasma endothelin levels have been reported to be markedly increased before the onset of vasodepressor syncope during headup tilt." Endothelial cells synthesize nitric oxide (NO), a potent va~odilator.~~, lz4 Vasodilatation related to NO is mediated by the reactivation of guanylate cyclase, which leads to dephosphorylation of the light chain of myosin in part by hyperpolarization of vascular smooth muscle cells.21,lo2 Increased vagal activity and increased acetylcholine release are observed during vasovagal syncope.48,76 Ace-

tylcholine is a potent stimulator of endothelial cellular NO synthesis and may contribute to the vasodilatation observed during the vasodepressor response. Preliminary data from Kaufmann and indicate marked activation of NO as documented by a severalfold (220%) increase in urinary cyclic guanosine monophosphate (cGMP) (a biologic marker of NO) potentially contributing to the vasodilatation observed in vasodepressor syncope. Experimental evidence supporting this hypothesis has been obtained in rats.143 Stimulation of endogenous NO release with infusions of L-arginine result in reduced blood pressure, heart rate, and renal sympathetic nerve traffic. In contrast, administration of Ng-methyl-L-arginine inhibits NO endogenous release and results in increased blood pressure and renal sympathetic nerve traffic. The significance of these findings in human vasodepressor responses remains unclear. It may be speculated, however, that centrally released NO could precipitate hypotension, bradycardia, and sympathoinhibition resulting in vasodepressor syncope.133Finally, adenosine has been shown to be a potential trigger for vasovagal ~ y n c 0 p e . lAdenosine ~~ may be an endogenous modulator of cardiac excitatory afferent nerves.

HEMODYNAMIC CHANGES The hemodynamic changes precipitated by central hypovolemia that precede and accompany the vasodepressor response have been studied since the late 1920s by Sheehan.161 Cardiac output measured by single-indicatordilution and Fick methods remains either unchanged or falls below control values with a fall in total peripheral resistance during the early phase of spontaneous, posthemorrhagic, or head-up tilt-induced syncope.", 36, 45, 50, 67, 71, 138, 159, 160, 161, 202. 206 Vasodepressor responses provoked by lower body negative pressure in the sitting position elicit an early increase in heart rate and a drop in blood pressure, followed by marked bradycardia and a further fall in blood pressure, l minute before the onset of syncope.113, 114 Changes in stroke volume, cardiac output, and arterial pressure almost invariably precede the onset of bradycardia.170The drop in peripheral vascular resistance is not properly compensated for by a rise in cardiac output. Prolonged lower body negative pressure elicits increase in splanch-

PATHOPHYSIOLOGIC BASIS FOR VASODEPRESSOR SYNCOPE

nic vasoconstriction, but renal vascular resis193 tance remains un~hanged.6~. Characterization of the changes that occur in left ventricular contractility during tilt-induced vasodepressor responses was first reported by Shalev and c011eagues.'~~ These authors showed an exaggerated reduction in left ventricular volume assessed by transthoracic echocardiography during orthostatic stress in syncopal patients. Similarly a significant decrease in end-diastolic area and a marked increase in left ventricular fractional shortening indicative of increased contractility in an empty chamber were also reported. Similar findings have been reported by other loo, 117,*08 and have been used to support the role of ventricular mechanoreceptors in the genesis of the vasodepressor response. Mizumaki and colleagues100compared left ventricular dimensions in three groups of subjects, 20 control subjects, 13 with isoproterenol-independent induced vasodepressor syncope, and 14 patients with vasodepressor syncope provoked by head-up tilt and isoproterenol infusion. Left ventricular size and contractility were assessed by echocardiography, and spectral analysis was used to determine sympathovagal balance. Patients with isoproterenol-independent syncope had an exaggerated decrease in left ventricular size associated with sympathetic predominance before the onset of syncope. In contrast, in patients with isoproterenol-dependent syncope, increases in sympathetic activity were observed only during isoproterenol infusion. These findings suggest that different responses of peripheral vasomodulation in addition to hypersensitivity of mechanoreceptors may play a role in the genesis of the vasodepressor response. Lee and colleagues,s1 however, were unable to document a significant change in left ventricular end-diastolic or end-systolic dimensions in patients with and without a tilt-induced vasodepressor response, suggesting that changes in ventricular dimensions may not be necessary for the development of the vasodepressor response in humans. These findings suggest that increased cardiac contractility with subsequent mechanoreceptor activation may not be essential to trigger the vasodepressor response in humans. Venous behavior during vasodepressor syncope has been almost exclusively assessed in the limbs, despite the fact that the contribution to cardiovascular control may be inconseq ~ e n t i a l Epstein .~~ and colleagues36demon-

239

strated that veins retain their vasoconstrictive ability during vasodepressor syncope. Nonetheless, most studies of vasodepressor syncope induced by controlled hemorrhage have shown a drop in central venous pressure.'O, 11, 16, lI3, 159 The role of central venous pressure changes during vasodepressor syncope remains difficult to understand. A reduction in cardiac output at the onset of syncope may increase central venous pressure and mask the effects of peripheral ~enodi1atation.l~~ Yawning and altered breathing pattern, which commonly precede clinical vasodepressor episodes, may further contribute to the reduction in atrial pressure^."^ Askenazy and Askenasp have documented inhibition of muscle sympathetic nerve activity associated with parasympathetic predominance during frequent yawning episodes recorded in a healthy subject. This observation suggests that centrally mediated yawning may be related to the onset of the vasodepressor response by triggering central nervous system muscle sympathetic nerve activity withdrawal. It has also been speculated by some investigators that hypocapnia associated with presyncopal hyperventilation may amplify the vasodepressor response by triggering cerebral vasoconstriction and systemic vasodilatation.60,170, 190 Volume changes during venous occlusions are largely due to filling of the deep venous spaces.24Capacitance vessel compliance is primarily determined by the surrounding skeletal muscle tone; therefore, decreased skeletal muscle tone increases orthostatic pooling. Additionally, it has been shown that gastrocnemius intramuscular pressure during orthostatic stress, provoked by upright tilt, is lower in subjects with a vasodepressor res p ~ n s e . Hargraves ~l and M ~ i used r ~ a~ radionuclide technique to monitor minute-by-minUte changes in peripheral venous volumes after orthostatic stress in 31 patients with unexplained syncope. Six patients became syncopal during head-up tilt and were noted to have a greater increase in calf venous volumes after orthostatic stress. Similarly the most interesting finding was a markedly reduced venous tone variability in the patients that became syncopal.63These observations suggest that the underlying abnormality in patients with vasodepressor syncope may lie within the peripheral veins possibly involving smooth muscle or the endothelial response. Benditt and collaborator~~~ studied the characteristics of subcutaneous microvas-

240

MORILLO et a1

cular blood flow during vasodepressor responses provoked during upright tilt. These investigators used a laser Doppler flowmetry method to assess changes in subcutaneous microvascular flow during head-up tilt in 13 patients (9 positive tilt and 4 negative tilt response). A progressive decrease in subcutaneous blood flow was observed associated with an increase in average blood flow oscillation frequency as well as a reduction in the oscillation amplitude before the onset of vasodepressor ~yncope.'~ These findings are consistent with progressive sympathetic peripheral withdrawal. Finally, a reduced blood volume has been documented in patients with vasodepressor syncope,'6,72 although orthostatic changes in plasma volume and capillary filtration rate are comparable between syncopal and nonsyncopal Central and peripheral blood volume redistribution may be more critical than total blood volume. Support for this view is derived from studies that have documented reversion of a vasodepressor response by rapidly elevating central venous and arterial pressure by inflating an antigravity 206 Further support for this hypothesis has been provided by El-Sayed and Hainsw0rth,3~who were able to reduce the incidence of vasodepressor responses after randomly assigning a series of patients to a high salt intake compared to placebo. The beneficial effects of refransfusion suggest that central blood volume regulation plays a major role in the hemodynamic adaptation to orthostatic stress in vasodepressor syncope.11, 17, 34,58, 89, 113, 158, 190, 206, 207

NEUROPHYSIOLOGIC CHANGES

The role of reflex neural control of heart rate, blood pressure, and venous vascular response in patients with vasodepressor syncope has been emphasized by several investigators. It has been widely suggested that autonomic disturbances play a determinant role in the genesis of the vasodepressor response. Several methods of evaluating the autonomic response, however, have been reported, and differences in methodology may account for some discrepancies in results. Nonetheless, there seems to be agreement that autonomic function assessed either by time or frequency domain analyses of heart rate variability at rest in the supine position are similar in syncopal and nonsyncopal

subjects.6,80, 82, 87, 88, 105, 127-129, 162, 168, 173, 174, 189, 196 The effects of orthostatic stress on time and frequency domain analyses of heart rate variability have also been reported by several groups. Abi-Samra and colleagues6 and Pongiglione and associates128were among the first to report increased heart rate variability, measured as the difference between the shortest and longest R-R intervals and R-R interval standard deviation, during head-up tilt. These findings were interpreted as indicative of increased cardiac vagal activity during orthostatic stress in patients with vasodepressor syncope. Further insight into the autonomic alterations triggered by orthostatic stress were reported by Lepicovska and colwho used time-frequency mapping analyses of heart rate and blood pressure during upright tilt and documented an impaired withdrawal of respiratory frequencies (vagal). Morillo and reported similar findings by assessing time and frequency domain analyses of heart rate variability during the initial 5 minutes of upright tilt, suggesting that the inappropriate withdrawal of vagal activity may be secondary to impaired arterial baroreceptor response to orthostatic stress. Similar findings in the time domain have been reported by Lippman and coworker~.~~ Additionally the role of slow cardiovascular oscillations was elegantly studied by Novak and colleagues116by analyzing time-frequency mapping of heart rate and blood pressure variability during upright tilt in 23 patients with vasodepressor syncope and 10 control subjects. The most interesting finding of this study was the observation of augmented low-frequency oscillations (0.01 to 0.05 Hz) in blood pressure at the onset of tilt, followed shortly by a significant reduction in amplitude and irregular oscillations with disappearance of these oscillations before the onset of syncope. The physiologic significance of low-frequency oscillations in blood pressure remain unclear. It has been postulated, however, that these rhythms may reflect the central part of the autonomic nervous system integrated at the brain stem leve1.116If this is true, it can be speculated that diminution of blood pressure slow rhythms before the onset of syncope are an early sign of central sympathoinhibition that results in baroreflex gain resetting with subsequent baroreflex inhibition. These findings may be consistent with the preliminary report of blunted arterial baroreceptor response to pharmacologic chal-

PATHOPHYSIOLOGIC BASIS FOR VASODEPRESSOR SYNCOPE

lenge documented in patients with tilt-induced vasodepressor syncope.1o7,ll1 Similar findings have been reported by France,40who documented decreased descending spontaneous arterial baroreceptor sensitivity at rest in a group of subjects that presented a vasodepressor response during blood donation. Interestingly, increased ascending spontaneous arterial baroreceptor sensitivity was noted in the vasodepressor group when painful stimuli achieved by thigh-cuff stimulation were tested. and Eckberg Convertino and c011eagues~~ and F r i t s ~ hwere ~ ~ able to reduce markedly cardiovagal baroreceptor sensitivity in 11 healthy subjects after 30 days of head-down tilt. Orthostatic tolerance was markedly impaired, and four subjects became syncopal within 5 minutes of standing. Similarly a greater reduction in arterial baroreflex sensitivity was documented in the fainting subjects suggesting a primary role of arterial baroreceptor compliance in orthostatic tolerance. More recently, Weise and collaborators205 documented that head-down tilt markedly reduced the 0.1 Hz frequency band of systolic blood pressure variability and was associated with increased susceptibility to orthostatic hypotension, suggesting that impaired arterial baroreceptor sensitivity is related to orthostatic intolerance. These findings indicate that regardless of the trigger that provokes the vasodepressor response (i.e., central or peripheral), impaired arterial baroreflex sensitivity appears to contribute significantly to the pathophysiology of the vasodepressor response. Further insight into the potential contribution of sympathoinhibition to the mechanism of the vasodepressor response has been gained by several investigators who have recorded muscle sympathetic nerve activity during neurocardiogenic syncope triggered by orthostatic stress using either the upright posture or lower body negative pressure.68,85* lo4, 110, lM, 172 Mosqueda-Garcia and colleaguesl10 documented markedly blunted cardiovagal arterial baroreflex responses to nitroprusside stepwise infusions in addition to gradual and progressive reduction in sympathetic nerve activity before the onset of syncope. Smith and collaborator^^^^ and Lewis and co-workersS5reported an abrupt decrease in sympathetic activity that precedes the onset of bradycardia by 20 seconds. The authors also documented an abrupt withdrawal in sympathetic activity 20 seconds before the onset of

241

syncope provoked by head-up tilt (Fig. 4).lO4 Similarly a marked reduction in sympathetic baroreflex outflow activity was documented in all patients when challenged with an intravenous bolus of nitroprusside.lM These findings suggest that impaired arterial baroreflex mediated outflow sympathetic activity plays a role in the genesis of vasodepressor syncope.149These findings, however, do not rule out the existence of central sympathoinhibition associated with central baroreceptor resetting. Mosqueda-Garcia and colleagues11z documented improved orthostatic tolerance and increased arterial baroreceptor gain after the administration of y0himbh-w (a centrally acting sympathomimetic) in a group of patients with refractory neurocardiogenic syncope. This novel observation further emphasizes the importance of central sympathetic regulation in the pathogenesis of the vasodepressor response. Finally, the role of impaired cardiopulmonary baroreceptor response has also been studied in patients with vasodepressor syncope. Sneddon and c o - ~ o r k e r s reported '~~ an augmented cardiopulmonary baroreceptor response assessed by forearm vascular responses to lower body negative pressure. The same investigators documented immediately impaired vasoconstrictor response to upright tilt long before the onset of syncope,175further suggesting an abnormality in cardiopulmonary baroreceptor response to orthostatic stress. Thomson and evaluated forearm vascular response to erect exercise in a group of 28 patients with recurrent vasodepressor syncope and 30 controls. Forearm vascular resistance fell significantly in the vasodepressor syncope group indicating that patients with vasodepressor syncope have impaired venous vasoconstriction responses in the forearm during dynamic exercise. The same group of investigators have further expanded their observations by measuring splanchnic capacitance with radionuclide techniques during erect exercise in 25 patients with documented vasodepressor syncope.1s5 Vasodepressor patients had a smaller decrease in venous volume than control subjects. Paradoxic vasodilatation or failure to vasoconstrict in both resistance and capacitance vessels during erect exercise results in vasodepressor syncope. Finally, Manyari and colleaguesg4reported a markedly decreased vasoconstrictor response to mental stress in patients with recurrent neurocardiogenic syncope. All together, these studies support the

242

MORILLO et a1

I

0

70

I

I

140

time, s Figure 4. Spontaneous episode of vasodepressor syncope induced by head-up tilt is shown. Continuous recordings of ECG, R-R interval, muscle sympathetic nerve activity, and arterial blood pressure are displayed. Arrowheads indicate onset of symptoms associated with marked changes in blood pressure and compensatory increases in muscle sympathetic activity. Dashed line indicates onset of syncope associated with abrupt muscle sympathetic activity withdrawal followed by hypotension and bradycardia.

role of impaired autonomic venous tone regulation as part of the mechanisms that lead to the vasodepressor response. CEREBRAL BLOOD FLOW AUTOREGULATION The role of central blood flow regulation in the pathophysiology of the vasodepressor response has been widely promoted. Supportive evidence, however, is scarce. Grubb and c o - ~ o r k e r smeasured ~~ middle cerebral artery flow using transcranial Doppler during upright tilt in 30 patients. Twenty developed vasodepressor syncope and were characterized by a marked decrease in diastolic velocity and increased pulsatility index. These findings were interpreted as indicative of increased cerebrovascular resistance secondary to arteriolar vasoconstriction distal to the isonation point of the middle cerebral artery. The authors concluded that abnormal baroreceptor responses triggered during vasode-

pressor syncope result in impaired cerebral autoregulation with paradoxic vasoconstrict i ~ n These . ~ ~ findings have been reproduced by others with different techniques.44,lZ5 Passant and c o - ~ o r k e r selegantly '~~ documented changes in cortical blood flow during headup tilt in patients with vasodepressor syncope by measuring regional cerebral blood flow by the 133-Xe method. The authors documented a distinct reduction in overall hemispheric blood flow in addition to a markedly reduced frontal flow with increased postcentral flow in patients that developed vasodepressor syncope. A reduced autoregulatory cerebral blood flow reserve was also hypothesized as the potential mechanism.125, 182 Regional differences in cerebral blood flow may explain the myriad of visceral symptoms that usually precede the onset of vasodepressor syncope. In a unique study, Levine and colleagues83studied 13 subjects during progressive lower body negative pressure and measured systemic flow, regional forearm flow, and blood pressure and calculated sys-

PATHOPHYSIOLOGICBASIS FOR VASODEPRESSOR SYNCOPE

temic vascular resistance and forearm vascular resistance. Changes in brain blood flow were estimated from changes in the blood flow velocity in the middle cerebral arteries using transcranial Doppler. This study documented cerebral vasoconstriction in healthy humans during graded orthostatic stress. The magnitude of the central response was deemed small in comparison with the changes in forearm vascular resistance and systemic vascular resistance. In healthy individuals, greater falls in cardiac volumes are associated with greater sympathetic activation. With greater reductions in blood volume, sympathetic activation increases in response to baroreceptor mediated increases. In susceptible individuals, however, impaired baroreflex response to orthostatic stress may lead to abrupt central sympathetic withdrawal mediated by marked cerebral vasoconstriction and changes in regional cerebral blood flow. Diehl and colleagues3' registered transcranial Doppler middle cerebral blood flow in 20 patients with tilt-induced vasodepressor syncope, further supporting the role of cerebral vasoconstriction in the genesis of vasodepressor syncope. Finally, Njeman~e,"~ in a case report, registered transcranial Doppler flow from the middle cerebral artery in a heart transplant recipient with an isoproterenol head-up tilt-provoked vasodepressor response. Consistent with the aforementioned findings, cerebral vasoconstriction and reduced cerebral blood flow were also documented in a seemingly cardiac-denervated patient. These findings further support the role for central sympathoinhibition as a primary pathophysiologic event in the genesis of the vasodepressor response. The role of the vasovagal response in human physiology remains a puzzle. Given the appropriate stimulus, a vasodepressor response may be elicited in any susceptible or healthy subject. It has been speculated that the vasodepressor response may be a remnant of the playing dead reaction observed in threatened animals.190Antagonizing the arterial baroreceptor reflex by accentuating hypotension during severe hemorrhagic shock 147 Rapid reduction in may be deleteri~us.'~~, myocardial oxygen demand, however, may be cardioprotective when excessive cardiac strain is present.', 190 The combination of critically reduced venous return and reflex bradycardia during the vasodepressor event is counteracted by restoring the supine position and increasing venous return, allowing a bet-

243

ter diastolic filling time with recovery of arterial blood pressure. The vasodepressor response may be the price paid by evolving into erect mammals constantly subject to orthostatic stress. SUMMARY

The current knowledge regarding the pathophysiologic basis of the vasodepressor response was reviewed. The balance of evidence indicates that the mechanoreceptor hypothesis seems unlikely to be the sole afferent alteration that leads to the vasodepressor response. Alternative afferent mechanisms should include neurohumoral mediated sympathoinhibition triggered by opioid mechanisms as well as impaired endothelial and NO responses to orthostatic stress in susceptible individuals. It is possible that impaired cardiovagal and sympathetic outflow control of arterial baroreceptors is enhanced by the aforementioned mechanisms. The role of central sympathoinhibition and vagal excitation triggered directly from pathways within the temporal lobe or triggered by alterations in regional cerebral blood flow should be considered as potential alternative mechanisms.26 Efferent autonomic outflow during vasodepressor syncope include sympathetic neural outflow withdrawal in addition to activation of parasympathetic outflow to the heart and abdominal viscera. Further human research is needed to understand the underlying mechanisms that result in the described neural and vascular responses. ACKNOWLEDGMENT The authors wish to thank Maria E. Camacho, MD, and Dwain L. Eckberg, MD, for critically reviewing and editing the manuscript.

References 1. Abboud FM: Ventricular syncope: Is the heart a sensory organ? N Engl J Med 320:390, 1989 2. Abboud F M Integration of reflex responses in the control of blood pressure and vascular resistance. Am J Cardiol44:903, 1979 3. Abboud FM, Aylward PE, Floras JS, et al: Sensitization of aortic and cardiac baroreceptors by arginine vasopressin in mammals. J Physiol (Lond) 377:251, 1986 4. Abboud FM, Eckberg DL, Johannson UJ, et al: Carotid and cardiopulmonary baroreceptor control of splanchnic and forearm vascular resistance during

244

MORILLO et a1

venous pooling in man. J Physiol (Lond) 286:173, 1979 5. Abe H, Kobayasi H, Nakashima Y, et al: Plasma catecholamines and cyclic AMP response during head-up tilt test in patients with neurocardiogenic (vasodepressor) syncope. PACE 18:1419, 1995 6. Abi-Samra F, Malony JD, Fouad-Tarazi FM, et al: The usefulness of head-up tilt testing and hemodynamic investigations in the work-up of syncope of unknown origin. PACE 11:1202, 1988 7. Abrahamsson H, Thorkn P: Vomiting and reflex vagal relaxation of the stomach elicited from heart receptors in the cat. Acta Physiol Scand 88:433,1973 8. Askenazy JJM, Askenasy N: Inhibition of muscle sympathetic activity during yawning. Clin Auton Res 6:237, 1996 9. Barcroft H, Brod J, Hejl Z , et al: The mechanism of the vasodilatation in the forearm muscle during stress (mental arithmetic). Clin Sci 19:577, 1960 10. Barcroft H, Edholm OG: On the vasodilatation in human skeletal muscle during post-hemorrhagic fainting. J Physiol 104:161, 1945 11. Barcroft H, Edholm OG, McMichael J, et al: Posthaemorrhagic fainting: Study by cardiac output and forearm flow. Lancet 1:489, 1944 12. Bearn AG, Billing B, Edholm OG, et al: Hepatic flow and carbohydrate changes in man during fainting. J Physiol (Lond) 115:442, 1951 13. Benditt DG, Chen MY, Hansen R, et al: Characterization of subcutaneous microvascular blood flow during tilt table-induced neurally mediated syncope. J Am Coll Cardiol 25:70, 1995 14. Benditt DG, Ferguson DW, Grubb BP, et a1 Tilt table testing for assessing syncope. J Am Coll Cardiol 28:263, 1996 15. Bennett T, Gardiner SM: Involvement of vasopressin in cardiovascular regulation. Cardiovasc Res 19:57, 1985 16. Bergenwald L, Freyschuss U, Sjostrand T: The mechanism of orthostatic and haemorrhagic fainting. Scand J Clin Lab Invest 37209, 1977 17. Bergenwald L, Freyschuss U, Melcher A, et al: Circulatory and respiratory adaptation in man to acute withdrawal and reinfusion of blood. Pflugers Arch 355:307, 1975 18. Bie P, Secher NH, Astrup A, et al: Cardiovascular and endocrine responses to head-up tilt and vasopressin infusion in humans. Am J Physiol 251:R735, 1986 19. Billman GE, Dickey DT, Teoh KK, et al: Effects of central venous blood volume shifts on arterial baroreflex control of heart rate. Am J Physiol 241:H571, 1981 20. Bishop VS Central nervous system regulation of cardiovascular homeostasis. New Horizons 2:415, 1994 21. Bolotina V, Najibi S, Palacino J, et al: Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 368850, 1994 22. Borst C, van Brederode JFM, Wieling W, et al: Mechanisms of initial blood pressure response to postural change. Clin Sci 67321, 1984 23. Borst C, Weiling W, van Brederode JFM, et al: Mechanisms of initial heart rate response to postural change. Am J Physiol243:H676, 1982 24. Buckey JC, Peschock RM, Blomqvist CG: Deep venous contribution to hydrostatic blood volume change in the human leg. Am J Cardiol62:449, 1988

25. Chosy JJ, Graham DT Catecholamines in vasovagal fainting. J Psychosom Res 9:189, 1965 26. Constantin L, Martins JB, Fincham RW, et al: Bradycardia and syncope as manifestations of partial epilepsy. J Am Coll Cardiol 25:900, 1990 27. Convertino VA, Doerr DF, Eckberg DL, et a1 Headdown bed rest impairs vagal baroreflex responses and provokes orthostatic hypotension. J Appl Physiol 68:1458, 1990 28. Convertino VA, Thompson CA, Benjamin BA, et al: Haemodynamics and ADH responses to central blood volume shifts in cardiac-denervated humans. Clin Physiol 10:55, 1990 29. Cowley AW, Quillen EW, Skelton M M Role of vasopressin in cardiovascular regulation. Fed Proc Fed Am SOCExp Biol42:170, 1983 30. Dickinson CJ: Fainting precipitated by collapse-firing of venous baroreceptors. Lancet 342970, 1993 31. Diehl RR, Linden D, Chalkiadaki A, et al: Transcranial Doppler during neurocardiogenic syncope. Clin Auton Res 6:71, 1996 32. Ebert PA, Austen WG, Greenfield LJ: Effect of neurogenic reflexes on heart rate during systemic hypotension. Am J Physiol 203:457, 1960 33. Eckberg DL, Fritsch JM: Influence of ten-day headdown bed-rest on human carotid baroreceptor-cardiac reflex function. Acta Physiol Scand 144:69, 1992 34. El-Sayed H, Hainsworth R Relationship between plasma volume, carotid baroreceptor sensitivity and orthostatic tolerance. Clin Sci 88:463, 1988 35. El-Sayed H, Hainsworth R: Salt supplement increases plasma volume and orthostatic tolerance in patients with unexplained syncope. Heart 75:134, 1996 36. Epstein SE, Stampfer M, Beiser G D Role of the capacitance and resistance vessels in vasovagal syncope. Circulation 37524,1968 37. Farrel PA, Ebert TJ, Kampine JP: Naloxone augments muscle sympathetic nerve activity during isometric exercise in humans. Am J Physiol 260:E379, 1991 38. Fitzpatrick AP, Banner N, Cheng A, et al: Vasovagal syncope may occur after orthotopic heart transplantation. J Am Coll Cardiol 21:1132, 1993 39. Fitzpatrick A, Williams T, Ahmed R, et al: Echocardiographic and endocrine changes during vasovagal syncope induced by prolonged tilt-up test. Eur J Cardiac Pacing Electrophysiol2121, 1992 40. France C: Baroreflex sensitivity during noxious stimulation in vasovagal reactors to blood donation. Int J Psychophysiol 19:13, 1995 41. Freeman EN, Shaffer SA, Schecter SA, et al: The effect of total sympathectomy on the occurrence of shock from hemorrhage. J Clin Invest 27359, 1938 42. Gauer OH, Henry JP: Negative (- Gz) acceleration in relation to arterial oxygen saturation, subendocardial hemorrhage and venous pressure in the forehead. Aerosp Med 35:533, 1964 43. Gauer OH, Thron HL: Postural changes in the circulation. In:Handbook of Physiology, Section 2: Circulation. Washington, DC, American Physiological Society, 1965, p 2409 44. Giller CA, Levine BD, Meyer Y, et al: The cerebral hemodvnamics of normotensive hvDovolemia dur,1 ing lower-body negative pressure. J Neurosurg 76:961, 1992 45. Glick G, Yu PN: Hemodynamic changes during spontaneous vasovagal reactions. Am J Med 34:42, 1963

PATHOPHYSIOLOGICBASIS FOR VASODEPRESSOR SYNCOPE 46. Goetz KL, Wang BC, Sundet W D Comparative effects of cardiac receptors and sinoaortic baroreceptors on elevations of plasma vasopressin and renin activity elicited by hemorrhage. J Physiol 79:440, 1984 47. Goldsmith SR Baroreflex control of vasopressin secretion in normal humans. In Cowley AW, Liard JF, Ausiello DA (eds): Vasopressin: Cellular and Integrative Functions. New York, Raven Press, 1988, p 389 48. Goldstein DS, Keiser H R Pressor and depressor responses after choliergic blockade in humans. Am Heart J 107974,1984 49. Goldstein DS, Spanarkel M, Pitterman A, et a1 Circulatory control mechanisms in vasodepressor syncope. Am Heart J 1041071, 1982 50. Goldstein RE, Beiser GD, Stampfer M, et al: Impairment of autonomically mediated heart rate control in patients with cardiac dysfunction. Circ Res 36:571, 1975 51. Grant RT, Reeve EB Clinical observations on airraid casualties. BMJ 2293, 1941 52. Grant RT, Reeve EB: Clinical observations on airraid casualties. BMJ 2329, 1941 53. Grubb BP, Gerard G, Roush K, et al: Cerebral vasoconstriction during head-upright tilt-induced vasovagal syncope. Circulation &1:1157,1991 54. Grubb BP, Kosinski DJ: Serotonin and syncope: An emerging connection? Eur J Cardiac Pacing Electrophysiol5:306, 1995 55. Grubb BP, Kosinski D Current trends in etiology, diagnosis, and management of neurocardiogenic syncope. Curr Opin Cardiol 11:32, 1996 56. Grubb B, Samoil D, Kosinski D, et a1 The use of serotonin reuptake for the treatment of recurrent syncope due to carotid sinus hypersensitivity unresponsive to dual chamber cardiac pacing. PACE 171434,1994 57. Gupta BN, Thames M D Behaviour of left ventricular mechanoreceptors with myelinated and nonmyelinated afferent vagal afferent fibres in cats. Circ Res 52:291, 1983 58. Hagan RD, Diaz FJ, Hovarth S M Plasma volume changes with movement to supine and standing positions. J Appl Physiol45:414, 1978 59. Hainsworth R The importance of vascular capacitance in cardiovascular control. News Physiol Sci 5220, 1990 60. Hainsworth R Fainting. In Bannister R (ed): Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. Oxford, Oxford University Press, 1988, p 142 61. Hainsworth R, El-Bedawi KM: Orthostatic tolerance in patients with unexplained syncope. Clin Auton Res 4:239, 1994 62. Halliwill JR, Dietz NM, Joyner MJ: Active vasodilation during fainting: A hypothesis revisited. Clin Auton Res 6:233, 1996 63. Hargraves AD, Muir A L Lack of variation in venous tone potentiates vasovagal syncope. Br Heart J 67486, 1992 64. Hill L The influence of the force of gravity on the circulation of the blood. J Physiol (Lond) 18:15,1895 65. Hirsch AT, Levenson DJ, Cutler SS, et al: Regional vascular responses to prolonged lower body negative pressure in normal subjects. Am J Physiol 257H219, 1989 66. Jacobs MC, Goldstein DS, Willemsen JJ, et al: Neurohumoral antecedents of vasodepressor reactions. Eur J Clin Invest 25754, 1995

245

67. Jacobsen TN, Converse RL, Victor RG: Contrasting effects of propranolol on sympathetic nerve activity and vascular resistance during orthostatic stress. Circulation 853072, 1992 68. Jardine DL, Ikran H, Crozier IG: Autonomic control of asystolic vasovagal syncope. Heart 75:528, 1996 69. Jarisch A, Zotterman Y Depressor reflexes from the heart. Acta Physiol %and 16:31, 1948 70. Kapoor WN, Smith MA, Miller N L Upright tilt testing in evaluating syncope: A comprehensive literature review. Am J Med 9778, 1994 71. Karp HR, Weissler AM, Heyman A: Vasodepressor syncope: EEG and circulatory changes. Arch Neurol 5:94, 1961 72. Kauffmann H: Head-up tilt, lower body pressure, pacemakers and vasovagal syncope. Clin Auton Res 4231, 1994 73. Kaufmann H: Neurally mediated syncope: Pathogenesis, diagnosis and treatment. Neurology 45:S12, 1995 74. Kaufmann H, Berman J, Oribe E, et al: Possible increase in EDRF/NO in neurally mediated syncope [abstr]. Clin Auton Res 3:69, 1993 75. Kaufmann H, Oribe E, Oliver JA: Plasma endothelin during upright tilt: Relevance for orthostatic hypotension? Lancet 338:1542, 1991 76. Kellog DL, Pergola PE, Piest KL, et al: Cutaneous active vasodilation in humans is mediated by cholinergic nerve cotransmission. Circ Res 771222,1995 77. Kenny RA, Ingram A, Bayliss J, et al: Head-up tilt: A useful test for investigating unexplained syncope. Lancet 1:1352, 1986 78. Kosinski D, Grubb BP, Temesey-Amos P: Pathophysiologic aspects of neurocardiogenic syncope: Current concepts and new perspectives. PACE 18:716, 1995 79. Kravik SE, Keil LC, Geelen G, et al: Effect of antigravity suit inflation on cardiovascular, PRA, and PVP responses in humans. J Appl Physiol 62766, 1986 80. Kuchar D, West P, Cook A, et a1 Identification of vasovagal mechanism using the valsalva maneuver [abstr]. PACE 17747, 1994 81. Lee TM, Chen MF, Su SF, et al: Excessive myocardial contraction in vasovagal syncope demonstrated by echocardiography during head-up tilt test. Clin Cardiol 19:137, 1996 82. Lepicovska V, Novak P, Nadeau R Time-frequency mapping in syncope. Clin Auton Res 2317, 1992 83. Levine BD, Giller CA, Lane LD, et al: Cerebral versus systemic hemodynamics during graded orthostatic stress in humans. Circulation 90298, 1994 84. Lewis T: Vasovagal syncope and the carotid sinus mechanism with comments on Gower’s and Nothangel’s syndrome. BMJ 1:873,1932 85. Lewis WR, Smith ML, Carlson MD, et al: Peripheral sympathoinhibition precedes hypotension and bradycardia during neurally mediated vasovagal syncope [abstr]. PACE 17747, 1994 86. Lightfoot JT, Rowe SA, Fortney SM: Occurrence of presyncope in subjects without ventricular innervation. Clin Sci 85:695, 1993 87. Lippman N, Stein K, Lerman B B Failure to decrease parasympathetic tone during upright tilt predicts a positive tilt-table test. Am J Cardiol 75:591, 1995 88. Lipsitz LA, Mietus J, Moody GB, et al: Spectral characteristics of heart rate variability before and during postural tilt. Circulation 81:1803, 1990 89. Lord S, McComb JM: Syncope and salt. Heart 75:114, 1996

246

MORILLO et a1

90. Ludbrook J, Graham WF: The role of cardiac receptor and arterial baroreceptor reflexes in control of the circulation during acute change of blood volume in the conscious rabbit. Circ Res 54:42&435, 1984 91. Ludbrook J, Potocnik SJ, Woods RL Simulation of acute hemorrhage in unanaesthetized rabbits. Clin Exp Pharmacol Physiol 15575-584, 1988 92. Ludbrook J, Ventura S The decompensatory phase of acute hypovolemia in rabbits involves a central d,-opioid receptor. Eur J Pharmacol 252:113-116, 1994 93. Madsen P, Klokker M, Olesen HL, et al: Naloxoneprovoked vaso-vagal response to head-up tilt in men. Eur J Appl Physiol 70246, 1995 94. Manyari D, Rose S, Tyberg J, et a1 Abnormal reflex venous function in patients with neuromediated syncope. J Am Coll Cardiol 271730, 1996 95. Mark AL The Bezold-Jarisch reflex revisited: Clinical implications of inhibitory reflexes originating in the heart. J Am Coll Cardiol 1:90, 1983 96. Matsumura K, Abe I, Tominaga M, et a1 Differential modulation by m- and d-opioids on baroreceptor reflex in conscious rabbits. Hypertension 19:648, 1992 97. Matzen S, Secher NH, Knigge U, et al: Effect of serotonin receptor blockade on endocrine and cardiovascular responses to head-up tilt in humans. Acta Physiol Scand 149:163, 1993 98. Mayerson HS, Burch G E Relationships of tissue (subcutaneous and intramuscular) and venous pressure to syncope induced in man by gravity. Am J Physiol 128:258, 1940 99. McMichael J: Clinical aspects of shock. JAMA 124275, 1944 100. Mizumaki K, Fujiki A, Tani M, et al: Left ventricular dimensions and autonomic balance during headup tilt differ between patients with isoproterenoldependent and isoproterenol-independentneurally mediated syncope. J Am Coll Cardiol 26164, 1995 101. Mohanty PK, Thames MD, Arrowood JA, et al: Impairment of cardiopulmonary baroreflex after cardiac transplantation in humans. Circulation 75:914, 1987 102. Moncada S, Palmer RM, Higgs E A Nitric oxide: Physiology, pathophysiology and pharmacology. Pharmacol Rev 43:109, 1991 103. Morgan DA, Thoren P, Wilczynski E, et al: Serotonergic mechanisms mediate renal sympatho-inhibition during severe hemorrhage in rats. Am J Physiol 255:H496, 1988 104. Morillo CA, Ellenbogen KA, Wood MA, et a1 Impaired cardio-vagal and muscle sympathetic baroreflex outflow in patients with head-up tilt induced neurally mediated syncope [abstr]. Circulation 94:I544, 1996 105. Morillo CA, Klein GJ, Jones DL, et al: Time and frequency domain analyses of heart rate variability during orthostatic stress in patients with neurally mediated syncope. Am J Cardiol 74:1258, 1994 106. Morillo CA, Wood MA, Gilligan DM, et al: Diagnostic utility of mechanical, pharmacological and orthostatic stimulation of the carotid sinus in patients with unexplained syncope [abstr]. J Am Coll Cardiol 27207A, 1996 107. Morillo CA, Wood MA, Stambler BS, et al: Impaired baroreflex sensitivity in patients with recurrent neurally mediated syncope predicts head-up tilt outcome [abstr]. PACE 18:838, 1995 108. Morita H, Nishida Y, Motochigawa H, et al: Opiate

receptor-mediated decrease in renal nerve activity during hypotensive hemorrhage in conscious rabbits. Circ Res 63:165, 1988 109. Morita H, Vatner SF: Effects of hemorrhage on renal nerve activity in conscious dogs. Circ Res 57788, 1985 110. Mosqueda-Garcia R, Ananthran V, Robertson D: Progressive sympathetic withdrawal preceding syncope evoked by upright-tilt [abstr]. Circulation 88384, 1993 111. Mosqueda-Garcia R, Desai T, Jarai Z, et al: Decreased baroreflex sensitivity in patients with recurrent neurocardiogenic syncope [abstr]. Circulation 903-316, 1994 112. Mosqueda-Garcia R, Furlan R, Femandez-Violante R, et a1 Enhancement of central noradrenergic outflow prevents neurally mediated syncope [abstr]. Clin Auton Res 6:290, 1996 113. Murray RH, Thompson LJ, Bowers JA, et al: Hemodynamic effects of graded hypovolemia and vasodepressor syncope induced by lower body negative pressure. Am Heart J 76:799, 1968 114. Newberry PD, Hatch AW, MacDonald J M Cardiorespiratory events preceding syncope induced by a combination of lower body negative pressure and head-up tilt. Aerosp Med 41:373, 1970 115. Njemanze PC: Isoproterenol induced cerebral hypoperfusion in a heart transplant recipient. PACE 16491, 1993 116. Novak V, Novak P, Kus T, et al: Slow cardiovascular rhythms in tilt and syncope. J Clin Neurophysiol 12:64, 1995 117. Nwosu EA, Rahko PS, Hanson P, et al: Hemodynamic and volumetric response of the left ventricle to upright tilt testing. Am Heart J 128:106, 1994 118. Oberg B, Thor6n P: Studies on left ventricle receptors, signalling in non-medullated vagal afferents. Acta Physiol Scand 85:145, 1972 119. Oberg B, ThorCn P:Increased activity in left ventricular receptors during hemorrhage or occlusion of caval veins in the cat: A possible cause of the vasovagal reaction. Acta Physiol Scand 85:164, 1972 120. Oberg B, White S: Circulatory effects of interruption and stimulation of cardiac vagal afferents. Acta Physiol Scand 80383, 1970 121. Oberg B, White S The role of vagal cardiac nerves and arterial baroreceptors in the circulatory adjustments to hemorrhage in the cat. Acta Physiol Scand 80:395, 1970 122. Oparil S, Vassaux C, Sanders CA, et al: Role of renin in acute postural homeostasis. Circulation 41239, 1970 123. Palmer J F Works of John Hunter. London, 1837 124. Palmer RM, Ashton DS, Moncada S: Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333:664, 1988 125. Passant U, Warkentin S, Minthon L, et al: Cortical ' blood flow during head up postural change in subjects with orthostatic hypotension. Clin Auton Res 3311, 1993 126. Pema GP, Ficola U, Pellegrino M, et al: Increase of plasma beta endorphins in vasodepressor syncope. Am J Cardiol 65:929, 1990 127. Perry JC, Garson A: The child with recurrent syncope: Autonomic function testing and beta-adrenergic hypersensitivity. J Am Coll Cardioll71168,1991 128. Pongiglione G, Fish FA, Strasburger JF, et al: Heart rate and blood pressure response to upright tilt in young patients with unexplained syncope. J Am Coll Cardiol 16:165, 1990

PATHOPHYSIOLOGICBASIS FOR VASODEPRESSOR SYNCOPE 129. Pruvot E, Vesin JM, Schlaepfer J, et a1 Autonomic imbalance assessed by heart rate variability analysis in vasovagal syncope. PACE 172201,1994 130. Quail AW, Woods RL, Komer P I Cardiac and arterial baroreceptor influences in release of vasopressin and renin during hemorrhage. Am J Physiol 21:H1120, 1987 131. Rea RF: Neurally mediated hypotension and bradycardia: Which nerves? How mediated? J Am Coll Cardiol 141633, 1989 132. Rea RF, Eckberg DL: Carotid baroreceptor-muscle sympathetic relation in humans. Am J Physiol 253R929,1987 133. Rea RF, Thames M D Neural control mechanisms and vasovagal syncope. J Cardiovasc Electrophysiol 4587,1993 134. Resta TC, Resta JM, Walker B R Role of endogenous opioids and serotonin in the hemodynamic response to hemorrhage during hypoxia. Am J Physiol 269:H1597, 1995 135. Robertson D, Johnson DA, Robertson RM, et al: Comparative assessment of stimuli that release neuronal and adrenomedullary catecholamines in man. Circulation 59:637, 1979 136. Robinson BJ, Johnson RH:Why does vasodilatation occur during syncope? Clin Sci 74:347, 1988 137. Rothe C F Venous system: Physiology of the capacitance vessels. In Shepherd JT, Abboud FM (eds): Handbook of Physiology, Section 2: Cardiovascular System. Washington, DC, American Physiological Society, 1984, p 397 138. Rowell LB Human Circulation: Regulation During Physical Stress. New York, Oxford University Press, 1986, p 137 139. Rowell LB, Blackmon JR Hypotension induced by central hypovolemia and hypoxemia. Clin Physiol 9:269, 1989 140. Rowell LB, Seals DR Sympathetic activity during graded central hypovolemia in hypoxemic humans. Am J Physiol259H1197, 1990 141. Rubin PC, McLean K, Reid J L Endogenous opioids and baroreflex control in humans. Hypertension 5:535, 1983 142. Rudas L, Pflugfelder PW, Kostuk WJ: Vasodepressor syncope in a cardiac transplant recipient: A case of vagal reinnervation? Can J Cardiol8:403, 1992 143. Sakuma I, Togashi H, Yoshioka M, et al: NG-MethylL-arginine, an inhibitor of L-arginine-derived nitric oxide synthesis stimulates renal sympathetic nerve activity in vivo: A role for nitric oxide in the central regulation of sympathetic tone? Circ Res 70:607, 1992 144. Samoil D, Grubb BP: Vasovagal (neurally mediated) syncope: Pathophysiology, diagnosis and therapeutic approach. Eur J Cardiac Pacing Electrophysiol 4:234, 1992 145. Sander-Jensen K, Mehlsen J, Stadeager C, et al: Increase in vagal activity during hypotensive lowerbody negative pressure in humans. Am J Physiol 253(Regul Integr Comp Physiol):R149, 1988 146. Sander-Jensen K, Mehlsen J, Secher NH,et al: Progressive central hypovolemia in man resulting in vasovagal syncope? Haemodynamic and endocrine variables during venous torniquets of the thighs. Clin Physiol7231, 1987 147. Sander-Jensen K, Secher NH, Astrup A, et al: Hypotension induced by passive head-up tilt: endocrine and circulatory mechanisms. Am J Physiol 251(Regul Integr Comp Physiol):R742, 1986

247

148. Sander-Jensen K, Secher NH, Bie P, et a1 Vagal slowing of the heart during hemorrhage: Observations from 20 consecutive hypotensive patients. BMJ 292364,1986 149. Sanders JS, Ferguson D W Profound sympatho-inhibition complicating hypovolemia in humans. Ann Intem Med 111:439, 1989 150. Sanders JS, Mark AL, Ferguson D W Importance of aortic baroreflex in regulation of sympathetic responses during hypotension: Evidence from direct sympathetic nerve recordings in humans. Circulation 79:83, 1989 151. Schadt JC, Gaddis RR: Cardiovascular responses to hemorrhage and naloxone in conscious barodenervated rabbits. Am J Physiol251(Regul Integr Comp Physiol):R909, 1986 152. Schadt JC, Hasser EM: Interaction of vasopressin and opioids during rapid hemorrhage in conscious rabbits. Am J Physiol26O(Regul Integr Comp Physiol):R373, 1991 153. Schadt JC, Ludbrook J: Hemodynamic and neurohumoral responses to acute hypovolemia in conscious mammals. Am J Physiol260H305, 1991 154. Scherrer U, Vissing S, Morgan B, et al: Vasovagal syncope after infusion of a vasodilator in a hearttransplant recipient. N Engl J Med 322602, 1990 155. Schobel HP, Oren RM, Mark AL, et a1 Naloxone potentiates cardiopulmonary baroreflex sympathetic control in normal humans. Circ Res 70:172,1992 156. Schwartz TW: Pancreatic polypeptide: A hormone under vagal control. Gastroenterology 85:1411,1983 157. Shalev Y, Gal R, Tchou PJ, et al: Echocardiographic demonstration of decreased left ventricular dimensions and vigorous myocardial contraction during syncope induced by head-up tilt. J Am Coll Cardiol 18746, 1991 158. Shannon RP, Wei JY, Rosa RM, et al: The effect of age and sodium depletion on cardiovascular response to orthostasis. Hypertension 8438, 1986 159. Sharpey-Schafer EP: Emergencies in general practice: Syncope. BMJ 1:506, 1956 160. Sharpey-Schafer EP, Hayter CJ, Barlow DE: Mechanism of acute hypotension from fear or nausea. BMJ 2878, 1958 161. Sheehan HL: The pathology of obstetric shock. J Obstet Gynecol 46:218, 1939 162. Sheldon R, Riff K Changes in heart rate variability during fainting. Chaos 30257,1991 163. Shen WK, Hammill C, Munger TM, et al: Adenosine: Potential modulator of vasovagal syncope. J Am Coll Cardiol 28:146, 1996 164. Shen YT, Knight DR, Thomas JX, et a1 Relative roles of cardiac receptors and arterial baroreceptors during hemorrhage in conscious dogs. Circ Res 66397,1990 165. Shenkin HA, Cheney RH, Govons SR, et a1 On the diagnosis of hemorrhage in man: A study of volunteers bled large amounts. Am J Med Sci 208421,1944 166. Shepherd JT, Vanhouette P M The Human Cardiovascular System: Facts and Concepts. New York, Raven Press, 1980 167. Shvartz E, Convertino VA, Keil LC, et a1 Orthostatic fluid-electrolyte and endocrine responses in fainters and nonfainters. J Appl Physiol51:1404, 1981 168. Simone F, Buonomo C, Nozzoli C, et al: Vasovagal reactions induced by head-up tilt and test of vagal cardiac function. J Auton Nerv Syst 30:S145, 1990 169. Sleight P: Cardiac vomiting. Br Heart J 46:5, 1981

248

MORILLO et a1

170. Smith JJ: Circulatory Response to the Upright Posture. Boca Raton, FL, CRC Press, 1990, p 30 171. Smith ML, Carlson MD, Thames MD: Naloxone does not prevent vasovagal syncope during simulated orthostasis in humans. J Autonom Nerv Syst 45:1, 1991 172. Smith ML, Lewis WR, Carlson MD: Sympatho-inhibition precedes frank hypotension and bradycardia during vasovagal syncope [abstr]. FASEB J 8:A603, 1994 173. Sneddon JF, Bashir Y, Murgatroyd FD, et a1 Do patients with neurally mediated syncope have augmented vagal tone? Am J Cardiol 721314, 1993 174. Sneddon JF, Counihan PJ, Bashir Y, et al: Assessment of autonomic function in patients with neurally mediated syncope: Augmented cardiopulmonary baroreceptor responses to graded orthostatic stress. J Am Coll Cardiol 21:1193, 1993 175. Sneddon JF, Counihan PJ, Bashir Y, et al: Impaired immediate vasoconstrictor responses in patients with recurrent neurally mediated syncope. Am J Cardiol 71:72, 1993 176. Sra JS, Akhtar M: Cardiac pacing during neurocardiogenic (vasovagal) syncope. J Cardiovasc Electrophysiol 6751, 1995 177. Sra JS, Jazayeri MR, Dhala A, et al: Neurocardiogenic syncope: Diagnosis, mechanisms, and treatment. Cardiol Clin 11:183,1993 178. Stevens PM: Cardiovascular dynamics during orthostasis and the influence of intravascular instrumentation. Am J Cardiol 17211, 1966 179. Sutton R Time to reconsider the mechanism of vasovagal syncope. Eur J Cardiac Pacing Electrophysiol 49, 1994 180. Sutton R, Petersen MEV The clinical spectrum of neurocardiogenic syncope. J Cardiovasc Electrophysiol 6:569, 1995 181. Szilagyi JE: Opioid modulation of baroreceptor reflex sensitivity in dogs. Am J Physiol252:H733,1987 182. Talman WT, Dragon DN, Ohta H Baroreflexes influence autoregulation of cerebral blood flow during hypertension. Am J Physiol 267H1183, 1994 183. Thames MD, Klopfenstein HS, Abboud FM,et al: Preferential distribution of inhibitory cardiac receptors with vagal afferents to the inferior posterior wall of the left ventricle activated during coronary occlusion in the dog. Circ Res 43512, 1978 184. Thomson HL, Atherton JJ, Khafagi FA, et a1 Failure of reflex vasoconstriction during exercise in patients with vasovagal syncope. Circulation 93:953, 1996 185. Thomson HL, Lele SS, Atherton JJ, et al: Abnormal forearm vascular responses during dynamic leg exercise in patients with vasovagal syncope. Circulation 922204, 1995 186. Thorkn P: Role of cardiac C fibers in cardiovascular control. Rev Physiol Biochem Pharmacol 863, 1979 187. Thorkn P, Donald DE, Shepherd JT: Role of heart and lung receptors with nonmedullated vagal afferents in circulatory control. Circ Res 3811-2, 1976 188. Tuck ML, Dluhy RG, Williams GH: Sequential responses of renin-angiotensin-aldosteroneaxis to acute postural change: Effect of dietary sodium. J Lab Clin Med 86:754, 1975 189. van Lieshout EJ, van Lieshout JJ, ten Harkel ADJ, et al: Cardiovascular response to coughing: Its value in the assessment of autonomic nervous control. Clin Sci 77305, 1989 190. van Lieshout JJ, Wieling W, Karemaker JM, et al: The vasovagal response. Clin Sci 81:575, 1991

191. Vatner SF, Boettcher DH, Heyndrickx GR, et al: Reduced baroreflex sensitivity with volume loading in conscious dogs. Circ Res 37236, 1975 192. Verbalis JG, Richardson DW, Stricker E M Vasopressin release in response to nausea-producing agents and cholecysokinin in monkeys. Am J Physiol 252(Regul Integr Comp Physiol):R749, 1987 193. Victor RG, Thorkn P, Morgan DA, et al: Differential control of adrenal and renal sympathetic nerve activity during hemorrhagic hypotension in rats. Circ Res 64686, 1989 194. Vingerhoets AJJM: Biochemical changes in two subjects succumbing to syncope. Psychosom Med 46:95, 1984 195. Vogt FB: Tilt table and plasma volume changes with short term deconditioning experiments. Aerosp Med 39:564,1967 196. Wahbha MMAE, Morley CA, Al-Shamma YMH, et al: Cardiovascular reflex responses in patients with unexplained syncope. Clin Sci 77547, 1989 197. Wallace W, Sharpey-Schafer EP: Blood changes following controlled hemorrhage in man. Lancet 2393, 1941 198. Wallbridge DR, MacIntyre HE, Gray CE, et al: Increase in plasma by endorphins precedes vasodepressor syncope. Br Heart J 71:597, 1994 199. Wallin BG, Sundlof G: Sympathetic outflow to muscles during vasovagal syncope. J Auton Nerv Syst 6287, 1982 200. Wang BC, Flora-Ginter G, Leadley RJ, et al: Ventricular receptors stimulate vasopressin release during hemorrhage. Am J Physiol 254(regul Integr Comp Physiol):R204, 1988 201. Wang BC, Sundet WD, Hakumakaki MOK, et al: Vasopressin and renin responses to hemorrhage in conscious, cardiac denervated dogs. Am J Physiol 245:H399,1983 202. Warren JV, Brannon ES, Stead EA, et al: The effect of venesection and the pooling of blood in the extremities on the atrial pressure and cardiac output in normal subjects with observations on acute circulatory collapse in three instances. J Clin Invest 24:337, 1945 203. Waxman MB, Asta JA, Cameron DA: Vasodepressor reaction induced by inferior vena cava occlusion and isoproterenol in the rat. Circulation 892401, 1994 204. Waxman MB, Cameron DA, Wald RW: Role of ventricular vagal afferents in the vasovagal reactions. J Am Coll Cardiol21:1138, 1993 205. Weise F, London GM, Guerin AP, et al: Effect of head-down tilt on cardiovascular control in healthy subjects: A spectral analytic approach. Clin Sci 88:87, 1995 206. Weissler AM, Warren JV, Estes EH, et al: Vasodepressor syncope: Factors influencing cardiac output. Circulation 15:875, 1957 207. Weissler AM, Warren JV:Vasodepressor syncope. Am Heart J 40:786, 1959 208. Yamanouchi Y, Jaalouk S, Shehadeh AA, et al: Changes in left ventricular volume in head-up tilt in patients with vasovagal syncope: An echocardiographic study. Am Heart J 131:73-80, 1996 209. Yates BJ, Miller A D Properties of sympathetic reflexes elicited by natural vestibular stimulation: Implications for cardiovascular control. J Neurophysiol 712087, 1994 210. Zanchetti A S Neural regulation of renin release. Circulation 56:691, 1977

PATHOPHYSIOLOGIC BASIS FOR VASODEPRESSOR SYNCOPE 211. Ziegler MG, Echon C, Wilner KD, et al: Sympathetic nervous withdrawal in vasodepressor (vasovagal) reaction. J Auton Nerv Syst 17273, 1986

249

212. Zoller RP, Mark Al, Abboud FM, et al: The role of low pressure baroreceptors in reflex vasoconstrictor responses in man. J Clin Invest 51:2967, 1971

Address reprint requests to Carlos A. Morillo, MD Fundaci6n Cardiovascular del Oriente Colombiano Autopista Floridablanca Urb El Bosque Bucaramanga, Santander, Colombia