JAW Vol. 16, No. I July 1990: 165-70
165
interval
to
~mtervals~ were assesse
atienb (ia 4 at baseli
The causes of syncope in seemingly normal children, adolescents and young adults are not completely known. The sporadic and unpredictable occurrence of syncope in affected patients and the extensive and frequently unrewarding cardiac and neurologic investigations that such patients undergo make syncope a diagnostic challenge. In susceptible older persons with recurrent syncope, the upright tilt test, with or without isoproterenol infusion, has recently been shown (I-5) to be effective in reproducing syhlcopeor near syncope; symptoms elicited by upright tilt have been assoFrom the Children’s Memorial Hospital. Department of Pediatrics. Northwestern University, Chicago, Illinois. Dr. Pongiglione was a visiting Research Associate from Instituto Giannina Gaslini Children’s Hospital. Genoa. Italy. Manuscript received Octlaber 13. 1989; revised manuscript received January 30, 1990, accepted Fe brlrary 21, 1990. Address for reorints: D. ‘Woudrow Benson. Jr.. MD. PhD. Division of Cardiology, No. 21. Children’s Memorial Hospital. 2700 Children’s Plaza. Chicago, !Ilinois 60614. 0 WJOby the American
College of Cardiology
ciated with hy~otension and bradycardia in these older persons. The purpose of this study is to describe a noninvasive protocol for the upright tilt test and to evaluate its efficacy for eliciting syncope or near syncope among a selected group of seemingly normal young patients with unexplained syncope.
ed as a transient loss of e~m~ti~~s.Syncope consciousness and muscle tone that by history w41snot suggestive of other altered states of consciousness. Near syncope (presyncope) was defined as premonitory signs and symptoms of imminent syncope (that is, severe lightheadedness, severe weakness, transient bearing loss or graying vision). Patient e~ar~ct@rist~cs. There were 1I msle and 9 female patients, ranging in age from 7 to 22 years (mean 12.5).The 073%1097/90/$3.50
166
JACC Vol. 16. No. 1 July 199&16.(-70
PONGIGLIONE ET AL. UPRIGHT TILT IN YOUNG PATIENTS
number of previous syncopal episodes ranged from 3 to 30. No patient was taking any cardioactive medicine at the time of study. Previous investigations had failed to identify a cause for syncope and included a thorough cardiac and neurologicevaluation, as well as a I2 lead electrocardiogram (ECG) (20 of 20 patients), 224 h of ambulatory ECG monitoring (15 of 20 patients), two-dimensionalechocardiogram (16 of 20 patients), electroencephalogram (18 of 20 patients), fasting blood sugar measurement (I9 of 20 patients), exercise stress test (3 of 20 patients), computed axial tomogram (4 of 20 patients) and nuclear magnetic resonance images of the head (2 of 20 patients). Upright tilt test protocol. Written informed consent was obtained before the procedure. Parents were informed and their consent was obtained before the tilt test was performed on minors. The procedure was performedin the fasting state. without sedation and on an outpatient basis. The patients walked to the laboratory and were positioned on a Quinton hydraulic table modified with a foot board to permit weight bearing, Heart rate was monitored continuously with a MAC 1 electrocardiograph (Marquette Electronics), and 15to 30 s ECG recordings (recording speed 25 mm/s) were obtained every minute throughout the study. Blood pressure and average heart rate were measured at I min intervals using the Dinamap system (Criticon). which computes blood pressure over a period of I5 to 30 s and provides reliable readings for values >30 mm Hg systolic and >20 mm Hg mean blood pressure. Blood pressures lower than these values or rapidly changing values do not give a measurable signal on the Dinamap display. When symptoms developed, the Dinamap system was recycled to obtain measurements every 30 s. After 5 to 10 ruin of recording in the supine position, the patient was tilted to a 90’ upright position for I5 min. If symptoms did not develop in the baseline state. the patient was returned to the supine position and isoproterenol infusion was started at a low dose (0.02to 0.04 &kg per min). After heart rate and blood pressure stabilized (approximately 5 to IOmin), the patient was tilted upright. This protocol was repeated at successive stages using medium (0.05to 0.06 Clglkgper min) and high (0.07 to 0.1 &kg per min) isoproterenol infusion doses. TIte study IWS terminnted if syncope or presyncope occwred, the high isoproterenol infusion stage was completed without symptoms or severe intolerance (for example. severe headache or nausea) to the isoproterenol infusion occurred. Isoproterenol was not administered to patients who developed symptoms in the baseline state, For the purpose of analysis, fear stages were designated: WY I = 5 to IOmin in the supine position in the baseline state, stage 2 = I5 min in the upright position in the baseline state. stage 3 = 5 to IO min in the supine position at the maximal isoproterenol infusion dose and stage 4 = 15min in the upright position at the ;naximal isoproterenol infusion dose.
Dataacquisitionand statisticalana~ysis~Mean heart rate and mean blood pressure were averaged for the 3 min before upright tilt (stages I and 3). and mean heart rate and mean blood pressure recordings for up to 3 min before onset of symptoms during upright tilt (stages 2 and 4) were averaged. The RR intervals were digitized off line from the ECG tracings (recorded at 25 mm/s) using a digitizing board (Calcomp). Consecutive RR intervals were measured from the last minute recorded in the supine position (stages I and 3) and from the minute preceding the onset of symptoms during upright tilt (stages 2 and 4). The .following variables were eralaated daring supine observation, upright tilt and at the time of symptoms:
cardiac rhythm, average heart rate, average blood pressure, average RR interval and heart rate variability. Heart rate variability was described by I) the standard deviation of the RR interval, 2) the standard deviation of the RR interval expressed as a percent of the mean RR interval, 3) the mean of the absolute difference between consecutive RR intervals, and 4) the mean of the abs&e difference between consecutive RR intervals expressed 2’; 9 percent of the mean RR interval. In patients who did not develop symptoms in stage 2 or 4, measurements were made at the time corresponding to the average time of symptom development in stage 2 or 4 in symptomatic patients. Statistics.Analysis of varianceand Student’s t test for paired and unpaired comparisons were performed as appropriate, using the Statistical Program for Social Sciences/PC statistical package. s Occurrenceof symptomsduring uprighttilt. No patient developed symptomswhen supine, but I6 of 20 patients developed symptoms during upright tilt. Specifically, no patient developed symptoms of presyncope or syncope during stage I, but four patients developed symptoms during stage 2 (group I). In these four patients, the average time to symptom onset after upright tilt was 8.5 min (range 2.5 to 12.5).No patient became symptomatic during stage 3, but I2 patients developed presyncope or syncope during stage 4 (group 2). After upright tilt with isoproterenol (stage 4), the average time to symptom onset was 4 min (range I to IO). Finally. four patients did not develop symptoms during the study (group 3). Heart
Rate
and
Blood Pressure
Supinebaseline(stage1). No differencein the mean heart rate, mean blood pressure (Fig. I) or heart rate variability (Fig. 2 and 3) was found among the three grolopsof patients during stage I. Uprigbttilt baseline(stage2). In comparisonwith values in stage I, the increase in mean heart rate and mean blood
JACC Vol. 16. No. I July 1990:165-70
arisen of mean heart rate ( r the three patient groups du 01. Patients were supine during stages I and 3 and upright during stages 2 and 4. Isoproterenol was administered stages 3 and 4. Group 1 (circles) symptoms during stage 2; group 2 developed symptoms duringstage4; withoutsymptoms during the study. group 3 and stages 2 and 3 versus stage 1.
pressure (Fig. I) and the decrease (Fig. 2 and 3) was similar in patients upright tilt. In group 2 patients, blo
ure 2. Variability of the ing the four stages of the study p as the standard deviation of tbe expressed as a percent of the mean intervals were measured from the la minute preceding the onset of symptoms arable time were made 0.05 for group 2 versus group 3 and stages 2 and 3 versusstage 1; **p -=I0.05 for stage 4 versusstage 3; other sy
ean of the absolute di between consecIntervals (Fig. 3). §iga~fica~t heart rate variabilitywas normalized s. Three distinct
terns of heart rate
received isoproterenol were observed. These isoproterenol was similar in both groups; compared with baseline measurements, the mean heart rate increased significantly (Fig. 1) but mean blood ssure did not change significantlyin either group. variabilitydecreased (Fig. 2 and 3, lower panels) this variability was normalized to the mean RR interval, no change occurred
mean RR interval were not significant, but heart rate variility was strikingly different in patients who subsequently veloped symptoms (group 2) com~arcd with those who did not (group 3). Variabilityin RR interval was often obvious in patients who subsequently developed symptoms (Fig. 4). This is further illustrated by comparison of highly significant differences in the standard deviation of the RR interval (Fig.
erns were characterized as car-
A cardioinhibitory response was characterized by a dramatic decrease in heart rate (maximal RR interval 6.5 to i I s) at the onset of symptoms. This tern occurred in three
patients who developed symptoms d A vasodepressor response was observed in tnjo patients. In both patients, the development of syncope during upright iated with a detilt with isoproterenol infusion was a [mean 381and to crease in blood pressure (to 62/24mm g [mean 361, ~es~ectively~and a concomitant increase in the sinus rate (cycle length 270 and 4 respectively). In these two patients, the fastest heart rate (shortest cycle length) occurred at the time of symptoms. A mixed respome characterized by both heart rate slowing and blood pressure decrease was observed in I1 patients. This occurred during stage 2 in I patient and in stage
4 in IOpatients. In six patients, the average blood pressure was 50 mm Hg (range 45 to 54). and in five patients it was too
168
PONGIGLIONE ET AL. UPRIGHT TILT IN YOUNG PATIENTS
JACC Vol. 16. No. 1 July 1!BOz165-70
cycle length of 580 to 1,200ms and 1 patient had a ventricular escape rhythm with a cycle length of 880 ms (Fig. 6). s. Patients who did not develop symp tams during upright tilt or upright tilt plus isoprotere~~~ experienced very little change in mean blood pressure with or without isoproterenol infusion, and their heart rate increased appropriately.
most (go%)young, seemd recurrent syncope, upright tilt results in hypotension or bradycardia, or both, and reproduces symptoms, thus providing a plausible explanation for the cause of recurrent syncope in these patients. On the basis of heart rate and blood pressure changes associated with development of symptoms, three types of response were identified: cardioinhibitory, vasodepressor an Figure 3. Variabilityof the RR interval for the three patient groups
duringthe four stages of the study protocol. Variabilityis assessed as the absolute value of differences in adjacent RR intervals (RRDIF) and is expressed as a percent of the mean RR interval (RR-DIF%).*p < 0.05 for group 2 versus group 3 and stages 2 and 3 versus stage 1;**p < 0.05for stage4 versus stage 3; other symbols as in Figures I and 2.
low to be measured (mean 520 mm I-Q). Three of the li patients remained in sinus rhythm with a maximal cycle length increase to 700, 880 and 900 ms, respectively; 7 patients showed a junctional escape rhythm with a maximal
Figure 4. Electrocardiographic leads I, II and III showingRR intervalvariabilityduring the minute before to development of syncope during upright tilt with isoproterenol infusion in a 19 year old man.
reduction in left ventricular volume during both the baseline state and isoproterenol infusion. It has been postulated that vigorous contraction of the relatively empty left ventricle activates myocardial sensory receptors, which, in susceptible persons, initiates an inhibitory reflex that results in hypotension or bradycardia, or both. The reduction in ventricular volume during upright tilt is analogous to that which occurs during bemorr~age and is known to result in activation of vagal afferent fibers (74). A number of agents, including isoproterenol, have been shown to sensitize these vagal afferent fibers, and beta,-adrenergic antagonists decrease fiber activity (9). dycardia that occurs during the inhibitory reflex is thou to be mediated by parasympathetic activation, whereas hypotension resulting from dilation of resistance vessels and constriction of the capacitance vessels is believed to be due to sympathetic inhibition (8-I 1). rise. Heart rate and blood pressure TY during symptoms of syncope or presyncope induced by upright tilt with or without isoproterenol have been reported to be similar in normal subjects without a prior history of syncope (3,ll) and in patients with a history of unexplained syncope (1-S). With few exceptions, symptoms have developed in association with modest hypotension and bradycardia. as exemplified by the mixed response in patients we studied. This is in contrast to the carotid sinus hypersensitivity syndrome, in which symptom occurrence has been associated with marked hypotension alone (vasodepressor) or marked heart rate slowing alone (cardioinhibitory), or botb (12). Chen et al. (1) observed that the principal difference between the mixed response in carotid sinus hypersensitivity syndrome and the hypotension and bradycardia associated with upright tilt was the time of occurrence of the
JACC Vol. 16. No. il July 1990:165-70
average time to the >12 s before the Moo
reflex arcs or act
---..-
-,.:
. _9,.
170
JACC Vol. 16. No. I July 1990:165-70
PONGIGLIONEETAL. UPRIGHTTILTINYOUNGPATIENTS
either index may vary depending on the mean RR interval, both were normalized for the mean RR interval.
6. Paley HW. McDonald IG, Blumenthal J, Mailot J. The effecls of posture and isoproterenol on the velocity of left ventricular conlraclion in man. J Clin Invest 1971:50:2283-94.
No signijicant difference in any index of heart rate variability was present among the groups during supine recordings. Duringupright tilt with isoproterenol, indexes of
7. Oberg B. Thoren P. Increased activity in left ventricular receptors during hemorrhage or occlusion of canal veins in the cat: a possible cause of the vasevagal reaction. Acta Physiol Stand 1972;85:164-73.
Because
heart rate variability were significantly greater in symptomatic versus asymptomatic patients. To the best of our knowledge, increased heart rate variability has not been previously described in this setting. Understanding the basis for this increased variability may provide important insight into the inhibitory reflex elicited by upright tilt. Conclusions, The finding that upright tilt produces different patterns of alteration in heart rate, blood pressure and heart rate variability illustrates the complexity of the neurally mediated responses to apparent activation of cardiac sensory receptors. These varied responses may have important implications ccith regard to natural history and therapy of syncope in seemingly healthy young patients.
1. Chen MY, Goldenberg IF. Milstein S. et al. Cardiac. electrophysiologic and hemodynamic correlates of neurally mediated syncope. Am J Cardiol 1989;63:66-72. 2. Waxman MB, Yao L. Douglas AC. Wald RW. Roseman J. lsoproterenol induction of vasodepressor-type reaction in vasodepressor-prone persons. Am J Cardiol 1989:63:58-65. 3. Almquist A. Goldenberg IF. Milstein S. et al. Provocation of bradycardia and hypotension by isoproterenol .and upright posture in patients with unexplained syncope. N Engl J Med 198933203346~51. 4. Kenny RA. Ingram A. Bayliss J. Sutton R. Head-up tilt: a useful test for investigating unexplained syncope. Lance1 1986~1352-4. 5. Milstein S. Buetikofer J, Lesser J, et al. Cardiac asystole: a manifestation of neurally mediated hypotension-bradycardia. J Am Coil Cardiol 1989; 1411626-32.
8. Mark AL. The Bezold-Jarisch reflex revisited: clinical implications of inhibitory reflexes originating in the heart. J Am Coil Cardiol 1983;1:90102. 9. Abboud FM. Ventricular syncope. Is the heart a sensory organ? N Engl 3 Med 1989:320:390-2. IO. Epstein SE. Slampfer M, Beiser GD. Role of capacitance and resistance vessels in vasovagal syncope. Circulation 1968;37:524-33. II. Weissler AM, Warren JV. Estes EH Jr. McIntosh HD, Leonard JJ. Vasodepressor syncope: factors influencing cardiac output. Circulation 1957;15:875-82. 12. Walter PF. Crawley IS. Domey ER. Carotid sinus hypersensitivity and syncope. Am J Cardiol 1978:42:3%-403. 13. Almquist A, Gomick C. Benson DW Jr, Dunnigan A. Benditt DC. Carotid sinus hypersensitivity: evaluation of the vasodepressor component. Circulation 1985:71:927-36. 14. Akselrod S. Gordon D. Madwed JB, Snidman NC, Shannon DC, Cohen RJ. Hemodynamic regulation: investigation by speck4 analysis. Am J Physiol 1985:249:H867-75. 15. Vybiral T. Bryg RJ, Maddens ME, Boden WE. Effect of passive tilt on sympathetic and parasympathetic components of heart rate variability in normal subjects. Am J Cardiol 1989;63: I 117-20. 16. Lombardi F. Sandrone G. Pempruner S. et al. Heart rate variability as an index of sympathovagal interaction after acute myocardial infarction. Am 3 Cardiol 1987:til239-45. 17. Billman GE. Hoskins RS. Time-series analysis of heart rate variability during submaximal exercise: evidence for reduced cardiac vagal tone in animals susceptible to ventricular fibrillation.
Circulation
1989;80:146-57.
18. Martin GJ. Magid NM, Myers G. et al. Heart rate variability and sudden death secondary to coronary artery disease during ambulatory electrocardiographic monitoring. Am J Cardiol 1987;60:86-99.
165
interval
to
~mtervals~ were assesse
atienb (ia 4 at baseli
The causes of syncope in seemingly normal children, adolescents and young adults are not completely known. The sporadic and unpredictable occurrence of syncope in affected patients and the extensive and frequently unrewarding cardiac and neurologic investigations that such patients undergo make syncope a diagnostic challenge. In susceptible older persons with recurrent syncope, the upright tilt test, with or without isoproterenol infusion, has recently been shown (I-5) to be effective in reproducing syhlcopeor near syncope; symptoms elicited by upright tilt have been assoFrom the Children’s Memorial Hospital. Department of Pediatrics. Northwestern University, Chicago, Illinois. Dr. Pongiglione was a visiting Research Associate from Instituto Giannina Gaslini Children’s Hospital. Genoa. Italy. Manuscript received Octlaber 13. 1989; revised manuscript received January 30, 1990, accepted Fe brlrary 21, 1990. Address for reorints: D. ‘Woudrow Benson. Jr.. MD. PhD. Division of Cardiology, No. 21. Children’s Memorial Hospital. 2700 Children’s Plaza. Chicago, !Ilinois 60614. 0 WJOby the American
College of Cardiology
ciated with hy~otension and bradycardia in these older persons. The purpose of this study is to describe a noninvasive protocol for the upright tilt test and to evaluate its efficacy for eliciting syncope or near syncope among a selected group of seemingly normal young patients with unexplained syncope.
ed as a transient loss of e~m~ti~~s.Syncope consciousness and muscle tone that by history w41snot suggestive of other altered states of consciousness. Near syncope (presyncope) was defined as premonitory signs and symptoms of imminent syncope (that is, severe lightheadedness, severe weakness, transient bearing loss or graying vision). Patient e~ar~ct@rist~cs. There were 1I msle and 9 female patients, ranging in age from 7 to 22 years (mean 12.5).The 073%1097/90/$3.50
166
JACC Vol. 16. No. 1 July 199&16.(-70
PONGIGLIONE ET AL. UPRIGHT TILT IN YOUNG PATIENTS
number of previous syncopal episodes ranged from 3 to 30. No patient was taking any cardioactive medicine at the time of study. Previous investigations had failed to identify a cause for syncope and included a thorough cardiac and neurologicevaluation, as well as a I2 lead electrocardiogram (ECG) (20 of 20 patients), 224 h of ambulatory ECG monitoring (15 of 20 patients), two-dimensionalechocardiogram (16 of 20 patients), electroencephalogram (18 of 20 patients), fasting blood sugar measurement (I9 of 20 patients), exercise stress test (3 of 20 patients), computed axial tomogram (4 of 20 patients) and nuclear magnetic resonance images of the head (2 of 20 patients). Upright tilt test protocol. Written informed consent was obtained before the procedure. Parents were informed and their consent was obtained before the tilt test was performed on minors. The procedure was performedin the fasting state. without sedation and on an outpatient basis. The patients walked to the laboratory and were positioned on a Quinton hydraulic table modified with a foot board to permit weight bearing, Heart rate was monitored continuously with a MAC 1 electrocardiograph (Marquette Electronics), and 15to 30 s ECG recordings (recording speed 25 mm/s) were obtained every minute throughout the study. Blood pressure and average heart rate were measured at I min intervals using the Dinamap system (Criticon). which computes blood pressure over a period of I5 to 30 s and provides reliable readings for values >30 mm Hg systolic and >20 mm Hg mean blood pressure. Blood pressures lower than these values or rapidly changing values do not give a measurable signal on the Dinamap display. When symptoms developed, the Dinamap system was recycled to obtain measurements every 30 s. After 5 to 10 ruin of recording in the supine position, the patient was tilted to a 90’ upright position for I5 min. If symptoms did not develop in the baseline state. the patient was returned to the supine position and isoproterenol infusion was started at a low dose (0.02to 0.04 &kg per min). After heart rate and blood pressure stabilized (approximately 5 to IOmin), the patient was tilted upright. This protocol was repeated at successive stages using medium (0.05to 0.06 Clglkgper min) and high (0.07 to 0.1 &kg per min) isoproterenol infusion doses. TIte study IWS terminnted if syncope or presyncope occwred, the high isoproterenol infusion stage was completed without symptoms or severe intolerance (for example. severe headache or nausea) to the isoproterenol infusion occurred. Isoproterenol was not administered to patients who developed symptoms in the baseline state, For the purpose of analysis, fear stages were designated: WY I = 5 to IOmin in the supine position in the baseline state, stage 2 = I5 min in the upright position in the baseline state. stage 3 = 5 to IO min in the supine position at the maximal isoproterenol infusion dose and stage 4 = 15min in the upright position at the ;naximal isoproterenol infusion dose.
Dataacquisitionand statisticalana~ysis~Mean heart rate and mean blood pressure were averaged for the 3 min before upright tilt (stages I and 3). and mean heart rate and mean blood pressure recordings for up to 3 min before onset of symptoms during upright tilt (stages 2 and 4) were averaged. The RR intervals were digitized off line from the ECG tracings (recorded at 25 mm/s) using a digitizing board (Calcomp). Consecutive RR intervals were measured from the last minute recorded in the supine position (stages I and 3) and from the minute preceding the onset of symptoms during upright tilt (stages 2 and 4). The .following variables were eralaated daring supine observation, upright tilt and at the time of symptoms:
cardiac rhythm, average heart rate, average blood pressure, average RR interval and heart rate variability. Heart rate variability was described by I) the standard deviation of the RR interval, 2) the standard deviation of the RR interval expressed as a percent of the mean RR interval, 3) the mean of the absolute difference between consecutive RR intervals, and 4) the mean of the abs&e difference between consecutive RR intervals expressed 2’; 9 percent of the mean RR interval. In patients who did not develop symptoms in stage 2 or 4, measurements were made at the time corresponding to the average time of symptom development in stage 2 or 4 in symptomatic patients. Statistics.Analysis of varianceand Student’s t test for paired and unpaired comparisons were performed as appropriate, using the Statistical Program for Social Sciences/PC statistical package. s Occurrenceof symptomsduring uprighttilt. No patient developed symptomswhen supine, but I6 of 20 patients developed symptoms during upright tilt. Specifically, no patient developed symptoms of presyncope or syncope during stage I, but four patients developed symptoms during stage 2 (group I). In these four patients, the average time to symptom onset after upright tilt was 8.5 min (range 2.5 to 12.5).No patient became symptomatic during stage 3, but I2 patients developed presyncope or syncope during stage 4 (group 2). After upright tilt with isoproterenol (stage 4), the average time to symptom onset was 4 min (range I to IO). Finally. four patients did not develop symptoms during the study (group 3). Heart
Rate
and
Blood Pressure
Supinebaseline(stage1). No differencein the mean heart rate, mean blood pressure (Fig. I) or heart rate variability (Fig. 2 and 3) was found among the three grolopsof patients during stage I. Uprigbttilt baseline(stage2). In comparisonwith values in stage I, the increase in mean heart rate and mean blood
JACC Vol. 16. No. I July 1990:165-70
arisen of mean heart rate ( r the three patient groups du 01. Patients were supine during stages I and 3 and upright during stages 2 and 4. Isoproterenol was administered stages 3 and 4. Group 1 (circles) symptoms during stage 2; group 2 developed symptoms duringstage4; withoutsymptoms during the study. group 3 and stages 2 and 3 versus stage 1.
pressure (Fig. I) and the decrease (Fig. 2 and 3) was similar in patients upright tilt. In group 2 patients, blo
ure 2. Variability of the ing the four stages of the study p as the standard deviation of tbe expressed as a percent of the mean intervals were measured from the la minute preceding the onset of symptoms arable time were made 0.05 for group 2 versus group 3 and stages 2 and 3 versusstage 1; **p -=I0.05 for stage 4 versusstage 3; other sy
ean of the absolute di between consecIntervals (Fig. 3). §iga~fica~t heart rate variabilitywas normalized s. Three distinct
terns of heart rate
received isoproterenol were observed. These isoproterenol was similar in both groups; compared with baseline measurements, the mean heart rate increased significantly (Fig. 1) but mean blood ssure did not change significantlyin either group. variabilitydecreased (Fig. 2 and 3, lower panels) this variability was normalized to the mean RR interval, no change occurred
mean RR interval were not significant, but heart rate variility was strikingly different in patients who subsequently veloped symptoms (group 2) com~arcd with those who did not (group 3). Variabilityin RR interval was often obvious in patients who subsequently developed symptoms (Fig. 4). This is further illustrated by comparison of highly significant differences in the standard deviation of the RR interval (Fig.
erns were characterized as car-
A cardioinhibitory response was characterized by a dramatic decrease in heart rate (maximal RR interval 6.5 to i I s) at the onset of symptoms. This tern occurred in three
patients who developed symptoms d A vasodepressor response was observed in tnjo patients. In both patients, the development of syncope during upright iated with a detilt with isoproterenol infusion was a [mean 381and to crease in blood pressure (to 62/24mm g [mean 361, ~es~ectively~and a concomitant increase in the sinus rate (cycle length 270 and 4 respectively). In these two patients, the fastest heart rate (shortest cycle length) occurred at the time of symptoms. A mixed respome characterized by both heart rate slowing and blood pressure decrease was observed in I1 patients. This occurred during stage 2 in I patient and in stage
4 in IOpatients. In six patients, the average blood pressure was 50 mm Hg (range 45 to 54). and in five patients it was too
168
PONGIGLIONE ET AL. UPRIGHT TILT IN YOUNG PATIENTS
JACC Vol. 16. No. 1 July 1!BOz165-70
cycle length of 580 to 1,200ms and 1 patient had a ventricular escape rhythm with a cycle length of 880 ms (Fig. 6). s. Patients who did not develop symp tams during upright tilt or upright tilt plus isoprotere~~~ experienced very little change in mean blood pressure with or without isoproterenol infusion, and their heart rate increased appropriately.
most (go%)young, seemd recurrent syncope, upright tilt results in hypotension or bradycardia, or both, and reproduces symptoms, thus providing a plausible explanation for the cause of recurrent syncope in these patients. On the basis of heart rate and blood pressure changes associated with development of symptoms, three types of response were identified: cardioinhibitory, vasodepressor an Figure 3. Variabilityof the RR interval for the three patient groups
duringthe four stages of the study protocol. Variabilityis assessed as the absolute value of differences in adjacent RR intervals (RRDIF) and is expressed as a percent of the mean RR interval (RR-DIF%).*p < 0.05 for group 2 versus group 3 and stages 2 and 3 versus stage 1;**p < 0.05for stage4 versus stage 3; other symbols as in Figures I and 2.
low to be measured (mean 520 mm I-Q). Three of the li patients remained in sinus rhythm with a maximal cycle length increase to 700, 880 and 900 ms, respectively; 7 patients showed a junctional escape rhythm with a maximal
Figure 4. Electrocardiographic leads I, II and III showingRR intervalvariabilityduring the minute before to development of syncope during upright tilt with isoproterenol infusion in a 19 year old man.
reduction in left ventricular volume during both the baseline state and isoproterenol infusion. It has been postulated that vigorous contraction of the relatively empty left ventricle activates myocardial sensory receptors, which, in susceptible persons, initiates an inhibitory reflex that results in hypotension or bradycardia, or both. The reduction in ventricular volume during upright tilt is analogous to that which occurs during bemorr~age and is known to result in activation of vagal afferent fibers (74). A number of agents, including isoproterenol, have been shown to sensitize these vagal afferent fibers, and beta,-adrenergic antagonists decrease fiber activity (9). dycardia that occurs during the inhibitory reflex is thou to be mediated by parasympathetic activation, whereas hypotension resulting from dilation of resistance vessels and constriction of the capacitance vessels is believed to be due to sympathetic inhibition (8-I 1). rise. Heart rate and blood pressure TY during symptoms of syncope or presyncope induced by upright tilt with or without isoproterenol have been reported to be similar in normal subjects without a prior history of syncope (3,ll) and in patients with a history of unexplained syncope (1-S). With few exceptions, symptoms have developed in association with modest hypotension and bradycardia. as exemplified by the mixed response in patients we studied. This is in contrast to the carotid sinus hypersensitivity syndrome, in which symptom occurrence has been associated with marked hypotension alone (vasodepressor) or marked heart rate slowing alone (cardioinhibitory), or botb (12). Chen et al. (1) observed that the principal difference between the mixed response in carotid sinus hypersensitivity syndrome and the hypotension and bradycardia associated with upright tilt was the time of occurrence of the
JACC Vol. 16. No. il July 1990:165-70
average time to the >12 s before the Moo
reflex arcs or act
---..-
-,.:
. _9,.
170
JACC Vol. 16. No. I July 1990:165-70
PONGIGLIONEETAL. UPRIGHTTILTINYOUNGPATIENTS
either index may vary depending on the mean RR interval, both were normalized for the mean RR interval.
6. Paley HW. McDonald IG, Blumenthal J, Mailot J. The effecls of posture and isoproterenol on the velocity of left ventricular conlraclion in man. J Clin Invest 1971:50:2283-94.
No signijicant difference in any index of heart rate variability was present among the groups during supine recordings. Duringupright tilt with isoproterenol, indexes of
7. Oberg B. Thoren P. Increased activity in left ventricular receptors during hemorrhage or occlusion of canal veins in the cat: a possible cause of the vasevagal reaction. Acta Physiol Stand 1972;85:164-73.
Because
heart rate variability were significantly greater in symptomatic versus asymptomatic patients. To the best of our knowledge, increased heart rate variability has not been previously described in this setting. Understanding the basis for this increased variability may provide important insight into the inhibitory reflex elicited by upright tilt. Conclusions, The finding that upright tilt produces different patterns of alteration in heart rate, blood pressure and heart rate variability illustrates the complexity of the neurally mediated responses to apparent activation of cardiac sensory receptors. These varied responses may have important implications ccith regard to natural history and therapy of syncope in seemingly healthy young patients.
1. Chen MY, Goldenberg IF. Milstein S. et al. Cardiac. electrophysiologic and hemodynamic correlates of neurally mediated syncope. Am J Cardiol 1989;63:66-72. 2. Waxman MB, Yao L. Douglas AC. Wald RW. Roseman J. lsoproterenol induction of vasodepressor-type reaction in vasodepressor-prone persons. Am J Cardiol 1989:63:58-65. 3. Almquist A. Goldenberg IF. Milstein S. et al. Provocation of bradycardia and hypotension by isoproterenol .and upright posture in patients with unexplained syncope. N Engl J Med 198933203346~51. 4. Kenny RA. Ingram A. Bayliss J. Sutton R. Head-up tilt: a useful test for investigating unexplained syncope. Lance1 1986~1352-4. 5. Milstein S. Buetikofer J, Lesser J, et al. Cardiac asystole: a manifestation of neurally mediated hypotension-bradycardia. J Am Coil Cardiol 1989; 1411626-32.
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