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Abnormal autonomic control of the cardiovascular system in syndrome X
Abnormal Autonomic Control of the Cardiovascular System in Syndrome X Giuseppe M.C. Rosano, MD, Piotr Ponikowski, MD, Stamatis Adamopoulos, MD, Peter Collins, MD, Philip A. Poole-Wilson,MD, Andrew J.S. Coats, DM, and Juan Carlos Kaski, MD, with the technical assistance of Christine A. O’Sullivan, BSC Anomalies of autonomic control of the coronary circulation may play a role in the development of syndrome X (an@na pectoris, ischemic-appear ing resutts on exercise test, and normal coronary arteriograms). Twenty-six patients with syndrome X and 20 healthy sex- and age-matched control subjects were studied by means of analysis of heart rate variability durhrg 24-hour Holter monitoring. Spectral and nonspectral parameters of heart rate variability were investigated. Mean heart rate was similar in patients with syndrome X and in control subjects. Patients with syndrome X had significantly lower standard devia tion of all normal RR intervals, a lower percentage of adjacent normal RR intervals ~50 ms in difference (126.4 + 22 vs 149 f 43 ms, p ~0.05; 6.3 f 4 vs 11.2 -c 7%, p <0.05; respectively), and a trend toward lower values of time-domain parameters. Lower values of total power and low frequency were also observed in patients with syndrome X (1273 + 693 vs 1790 r 989 ms*, p ~0.05; 406 + 176 vs 729 -c 455 ms*, p ~0.01, respectively). An inverse correlation between heart rate and measures of heart rate variability was found in syndrome X but not in control subjects. Hi* and low-frequency power showed a similar circadian pattern in syndrome X patients and control subjects. Patients and control subjects were then allocated into 2 groups according to the median RR duration: syndrome Xl and control 1 with high mean heart rate, and syndrome X2 and control 2 with low mean heart rate. The syndrome Xl group had a significantly lower standard deviatlon of all normal RR intervals, root-meausquare diierence of successive RR intervals, percentage of adjacent normal RR inter vals ~50 ms different, and high and low frequency than did the syndrome X2, control 1, and control 2 groups. In conclusion, patients with syndrome X have a sympathovagal balance shifted toward sympathetic predominance that is more evident in those with an increased mean
From the National Heart & Lung Institute, Royal Brompton National Heart & Lung Hospital, and St. George’s Hospital, London, United Kingdom. Manuscript received June 18, 1993; revised manuscript received November, 1, 1993, and accepted November 2. Address for reprints: Giuseppe M.C. Rosano, MD, Department of Cardiac Medicine, National Heart & Lung Institute, Dovehouse Street, London SW3 6LY, United Kingdom.
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THE AMERICANJOURNALOF CARDIOLOGY VOLUME73
heart rate. This dysfunction appears to persist throughout the 24 hours and may indicate heterogeneity in autonomic function in syndrome X. (Am J Cardiol19~73:1174-1179)
A
ngina pectoris is usually associatedwith atheromatous coronary artery disease,but angina-like chest pain can occur in the absenceof significant coronary artery stenoses.1,2The association of angina pectoris, positive exercise test results, and angiographitally normal coronary arteries in the absenceof other forms of heart diseaseis referred to as syndrome X.3 A reduction in coronary flow reserve due to alterations of vasomotor tone at the microvascular level may be the cause of chest pain in a proportion of these patients.4,5 The autonomic nervous system modulates coronary artery tone,“8 and abnormalities of autonomic control may result in a reduction of coronary blood flo~.s-~~Patients with syndrome X may have an increased sympathetic drive.12-” Altered autonomic nervous control of the coronary microcirculation could play a role in the development of syndrome X, becauseincreased sympathetic activity could account for the primary reduction in coronary blood flow at rest,t3and explain the reduced vasodilator reserve demonstratedby some patients with syndrome X during stress.I6 However, despite suggestions of an increased sympathetic drive, o-blockade failed to show any benefit in patients with syndromeX.t8 The characteristics of the autonomic nervous control of the cardiovascular system in patients with syndrome X have not been studied. Study of heart rate variability is a useful and accurate noninvasive method for assessing autonomic control of the cardiovascular system.19 Spectral and nonspectral analysis of heart rate variability have been used extensively to investigate the activity of the cardiac sympathetic and parasympatheticnervous system in patients with a variety of cardiac conditions including myocardial infarction20 and heart failure.21The present study assesses,by means of heart rate variability analysis, the characteristicsof autonomic control of heart rate in patients with syndrome X and comparesthem with those of an age- and sex-matched control population. ME7HODS Syndrome X patients:
The patient group consisted of 26 consecutive nonsmoking patients with syndrome X (6 men and 20 women, mean age 5.5f 6 years, range
JUNE 15,1994
TABLE I Clinical Characteristics of Patients with Syndrome X and of Normal Control Subjects Syndrome X
Control Subjects
Number of patients
26
20
Mean age (years)
55 r 6 20 (77%)/6 (23%)
55 k 6 15 (75%)/5 (25%)
12 0 2
6 0 1
0
1
Women/men Risk factors for coronary artery drsease Family hrstory Cigarette smokers Serum total cholesterol (>ZlOmg/dl) Fasting blood glucose f>llOmg/dl) Holter monitonng ST-segment depressron (patients) Eprsodeslpatrentiday Symptomatic episodes Mean ST-segment depression (mm)
16
0
4 40 (62%) 1.6 ? 0.3
0 0 0
TABLE II Correlation Coefficients Between Mean RR and Indexes of Heart Rate Variability in Patients with Syndrome X and in Normal Control Subjects Control Syndrome X Standard deviation of all normal RR intervals Standard deviation of 5-minute mean RR intervals Standard deviation Natural log of root-mean-square of difference of successive RR intervals Natural log of percentage of adjacent normal RR intervals > 50 ms different Natural log of total power Natural log of low frequency Natural log of high frequency
Subjects
0.393 0.238*
0.401 0.379
0.653* 0.64*
0.044 0.023
0.674t
0.003
0.574* 0.452* 0.611t
0.004 0.112 0.0003
‘p <0.05; tp
dependent observers.The Marquette Laser Holter System (ST-segment analysis and arrhythmia analysis pro(min) gram, version 5.7 software, Marquette Electronics Inc., Values are expressed as mean ? SD. Milwaukee, Wisconsin) was used for the tape analysis. The number of episodesof transient myocardial ischemia 46 to 67). The diagnosis was based on the presenceof (horizontal or downsloping ST-segment shift 20.1 mV typical exertional angina, positive exercise test results, from baseline) and the duration of the ST-segmentdeand angiographically normal coronary arteries,in the ab- pression were recorded.The frequency histogram of the sence of coronary artery spasm, cardiomyopathy, con- normal RR intervals was displayed and electrocardiogestive heart failure, valvular heart disease (including gram strips of the intervals in both tails of RR distribumitral valve prolapse), systemic hypertension, left ven- tion were visually checked.Furthermore, a histogram of tricular hypertrophy, or conduction abnormalities.‘3*22~23the consecutive RR ratio was analyzed and cycles outLeft ventricular hypertrophy was ruled out by M-mode side 80% to 120% of preceding RR intervals were exechocardiography. A positive response in the electro- cluded from further analysis. This preliminary analysis cardiogram was defined as a horizontal or downsloping allowed the exclusion of artifacts, premature beats or ST-segmentdepression2 1 mm at 60 ms after the J point, post-extrasystolicpausesfrom further analysis. All tapes occurring in 26 consecutive complexes. In patients in were subsequently analyzed to measureheart rate variwhom there was a clinical suspicion of coronary artery ability using a commercially available and validated prospasm,this type of test was excluded using hyperventi- gram (Marquette heart rate variability program, Marquette Electronics Inc., Milwaukee, Wisconsin). lation or ergonovine tests, or both. Heart rate variability analysis: NONSPECTRAL ANALcontrd sum Twenty healthy,nonsmokingsedentary sex- and age-matchedsubjects(5 men and 15women, YSIS: The following time-domain measurementsof heart mean age 55 + 5.6 years, range 46 to 67) were used as rate variability were calculated from 24-hour electroa control group; none had cardiovascular symptoms or cardiographic recordings: mean of all normal RR intervals, standarddeviation of all normal RR intervals, stanevidence of cardiovascular disease. Halter monitorh@ All syndrome X patients and dard deviation of 5-minute mean RR intervals, mean of control subjects underwent 24-hour Holter monitoring, all 5-minute standard deviation of RR intervals, rootwithout therapy,using a 2-channel amplitude modulated mean-squaredifference of successiveRR intervals, and tape recorder (Marquette 8500, Marquette Electronics percentageof adjacentnormal RR intervals >50 ms difInc., Milwaukee, Wisconsin). Holter monitoring was re- ferent. SPECTRAL ANALYSIS:Spectral measurements were peated in 12 subjects (7 patients and 5 controls) in order to assessthe reproducibility of the heart rate vari- computed by fast-Fourier transform analysis. Spectral ability measurements.Patients were askednot to smoke plots were used to identify 2 subsetsof the frequencyor drink caffeine-containing drinks and not to change domain: low- (0.04 to 0.15 Hz) and high- (0.15 to 0.40 their normal daily activities during the period of Holter Hz) frequency power. Spectral power was quantified in monitoring. The 24-hour Holter monitoring of syndrome these 2 frequency band widths. Spectral plots were X and controls was begun at 11A.M. and ended at the squared to quantify power in the 2 frequency bands (in same hour of the following day. Syndrome X and con- ms2). Total oscillatory power between 0.01 and 1.00 Hz trols were studied on similar nonworking days and were was also calculated. The ratio of low- to high-frequency askedto adhere to their normal daily nonworking activ- power was also calculated. This is an established index of sympathovagal balance, and high values for the ratio ities. Two leads, a modified inferior lead and CM5, were indicate predominanceof sympatheticnervous activity.24 used for monitoring. Recordings were analyzed by 2 in- To assessthe intra- and the interoperator variability, 12 Mean duration of episode
17 c 23
0
HEART RATE VARIABILITY IN SYNDROME X 1175
of heart rate variability was <5% in the 12 subjects in whom electrocardiographic monitoring was repeated. No difference was found in any heart rate variability parameter after either 5 or 30 days of washout in the 5 patients who were taking B blockers. Mean RR duration was similar in syndrome X patients and controls (787 f 98 vs 830 f 83 ms, p = NS). Patients with syndrome X had lower values of standard deviation of all normal RR intervals and in the percentage of adjacent normal RR intervals >50 ms different than control subjects(126 f 22 vs 149+ 43 ms, p ~0.05; 6.3 + 4 vs 11.2f 7%, p ~0.05; respectively). A trend toward lower values of all the other time-domain parameters was also observed in patients with syndrome X. Table II showsthe correlation betweenthe measurements of heart rate variability and the RR interval in syndrome X patients and in controls. Patients with syndrome X, but not control subjects,had a significant inverse correlation between all measuresof heart rate variability, with the exception of the standarddeviation of all normal RR intervals, and mean RR. Patients with syndrome X had significantly lower values of total power and low-frequency power than controls (1273 _+693 vs 1790 + 989 ms2,p ~0.05; 406 f 176 vs 729 + 455 ms2,p ~0.01, re-
tapes, randomly selected, were reanalyzed by both operators. Data analysis Data are expressedas mean + 1 SD or as percentages where appropriate. Between-group comparisonswere assessedby analysis of variance with individual comparisonsby Scheffe’sF test corrected for multiple comparisons (Superanova and Statview statistical packages,Abbacus). Correlations were analyzedby the least-squaresmethod. RESULTS Patient characteristics: Clinical and electrocardiographic characteristicsof patients with syndrome X and control subjectsare listed in Table I. Transient episodes of ST-segment depression were detected in 16 patients with syndrome X, but none of the control subjects had ST-segment shifts during Holter monitoring. Exercise capacity was similar in syndrome X and in control subjects, but exercise test results were negative in control subjects. Spectral and nmspectral
analysis of heart rate
Differences among operators for heart rate variability measurementswere <5%, and intraobserver variability was also ~5%. The variability for all indexes variability:
low frequency
1400
(ma*)
1200 1
0’
11
1
I
I
t
13
lb
17
19
high frequency
I
I
I
4
I
1
3
6
7
9
I
co, .._....
-3x2
-sx1
7oor
I
21 23 hours
----co2
(ma ‘1
BOO
600 400 300
0’
11
I
I
I
,
13
16
17
19
-9x1
1176
-3x2
I
1
I
I
I
1
21 23 hours
1
3
5
7
9
I
co,
.--- co2
THE AMERICANJOURNALOF CARDIOLOGY VOLUME73
JUNE 15, 1994
FIGURE 1. Low- (top) and high (bottom) frequency power in patients with syndrome X and in control subjects with high (COl) and low (COZ) heart rate during Halter monitoring. Patients with syndrome X and higher heart rate @Xl) had depressed values of both measure merits throughout the 24 hours corn pared with values in patients with syndrome X and lower heart rate (SXZ) and the 2 control groups.
TABLE III Indexes of Heart Rate Variability in Patients with Syndrome X and in Normal Control Subjects
Age (years) Women Mean RR (ms) Standard deviation of all normal RR intervals (ms) Standard deviation of 5-minute mean RR intervals (ms) Standard deviation (ms) Root-mean-square of difference of successive RR intervals (ms) Percentage of adjacent normal RR intervals > 50 ms different f%) High frequency (rns? Low frequency (ms*) Total power (msz) Low-frequency/High-frequency ratio
Syndrome Xl (n = 13)
Syndrome X2 (n = 13)
Control 1 (n = 10)
Control 2 (n = 10)
54 2 5 11 716 2 44 113 + 17*
55 + 7 9 a76 + 7 139 2 20
55 + 6 8 785 r 57 136 + 32
55 + 5 7 891 _t 48 162 + 50
105 -c 18*
124 2 22
123 lr 33
148 k 56
20.7 + 3*
57.5 -+ 9 32.4 f 8
55k 15 31.3 f 10
5ak 17 33.7 2 11
3 + 1t
9.6 + 5
9.9 -t 7
12.5 + 8
41.3 2 5*
a4 336 843 4.3
*p ~0.05; tp
+ 33t -c 134t f 277* + 1.4*
226 645 1703 2.84
119 329 721 0.72
219 769 1681 3.6
r + 2 k
163 508 1123 1.6
219 688 1790 3.25
k + 5 k
125 329 1098 1.1
X2, control 1 and control 2.
spectively) together with a trend toward lower values of high-frequency power and a higher low-frequency/highfrequency ratio. Based on the suggestion of previous studies12J3that somepatients with syndromeX have a higher meanheart rate on Holter monitoring which could indicate an increasedsympathetic drive, patients with syndromeX and controls were subdivided into 2 groups according to the mean 24-hour RR interval for the whole group. Four groups were therefore created: syndrome Xl and control 1 with RR interval greater than median RR interval, and syndrome X2 and control 2 with lower RR interval than median, with the aim of further evaluating heart rate variability parameters. All 4 groups had similar mean age and male/female distribution (Table III). Time- and frequency-domain measurementsof heart rate variability in these 4 groups are listed in Table III. Syndrome
low/high
2 + + f
Xl patients had significantly depressedvalues of spectral and nonspectral measurementsof heart rate variability when comparedwith the other 3 groups. No difference was seen among control subjects (control 1, control 2) and between these 2 control groups and syndrome X2 patients. Circadian pattern of heart rate variability: Patients with syndrome X and controls had similar circadian profiles of spectral indexes of heart rate variability. The absolute values of both low and high frequencies, however, were significantly depressedonly in syndrome X 1 patients when comparedwith syndrome X2 and control 1 and 2 subjects (Figure 1). Syndrome Xl patients also showed similar patterns but higher values of lowfrequency/high-frequency ratio throughout the 24 hours than did syndrome X2 and normal subjects (Figure 2). No significant difference was seenin values and pattern
frequency
“r
0”““’ 11
’ 15
”
”
19
”
23
’
”
3
’
”
”
7
” 10
hours
-sx2
-
SXl
--- - co1
--...-- co2
FIGURE 2. Low-frequency/hi~uency ratio in patients with syndrome X and in control subjects with him (COl) and low (CO?) heart rate during Halter monitoring. Patlents with syndrome X and higher heart rate (SXI) had higher values throughout the 24 bows than patkmts with syndrome X and lower heart rate (SX2) and the 2 control groups.
HEARTRATEVARIABILITYIN SYNDROMEX 1177
of low-frequency/high-frequency ratio between syndrome X2 and the 2 control groups (control 1 and control 2). DISCUSSION Our results suggest that patients with syndrome X have an imbalance of the autonomic control of the cardiovascular system and that this is more pronounced in patients with increasedmeanheart rate. The male/female ratio, the mean age and the clinical features of our patients with syndrome X are similar to those reported in other large series12J4*23,25-27 and are therefore representative of the condition referred to as syndrome X. The control group was selected strictly to match the study population not only in terms of age and gender,but also in the degreeof daily physical activities and, if possible, emotional stress.Cigarette smoking may also infiuence heart rate variability; therefore we selecteda nonsmoking population. Importantly, in our study there were no major differences in daily activities, exercise tolerance, and influence of the working environment between syndrome X and controls before and during Holter monitoring. The results were found to be reproducible. Although the detection of transient myocardial ischemia was not a primary end point of this study, our syndromeX patients had ST-segmentchangessimilar to those reported in other studies.13No difference was found in heart rate variability measurementsbetween syndrome X patients with or without episodes of STsegmentdepression. Contrary to the findings of Galassi et a&l2the 24-hour mean heart rate in the present study did not differ between patients with syndromeX and controls (even when the groups were subdivided by median RR duration). Therefore, in our study,the differencesin heart rate variability parameters between syndrome X and controls were not purely a reflection of different mean heart rate in syndrome X patients and control subjects. Patients with syndrome X had depressedvalues of spectral and nonspectral parametersof heart rate variability. In patients with syndrome X we observed an inversecorrelation betweenmean daily heart rate and measurementsof heart rate variability, suggesting that there is a continuous spectrum of alteration of the autonomic nervous control of the cardiovascular systemin patients with syndrome X, and that this is more altered in patients with a higher heart rate. The fact that the autonomic control of the cardiovascular systemis more impaired in patients with syndromeX and higher heart rate explains why, when patients with syndrome X were analyzed as one group, only a statistically significant trend toward lower values was found for most of the heart rate variability parameters. Thus, the subdivision of the groups of syndrome X patients appearsjustified because it allowed us to identify and better analyze patients who had a relatively higher heart rate and therefore more impaired autonomic control of the cardiovascular system. No significant differencesin any of the heart rate variability measurementswere found in controls when classified according to the mean heart rate. In contrast, among patients with syndrome X, a subgroup with
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THE AMERICANJOURNALOF CARDIOLOGY VOLUME73
higher meanheart rate had markedly depressedheart rate variability, in both time and frequency domains, indicative of a more impaired sympathovagal control of the cardiovascular system. Our results are supported by other studies12*13 in which a significantly higher heart rate in patients with syndrome X than in controls was found and bdings were interpreted as an indication of the presenceof an increased sympathetic drive. Standard deviation of all normal RR intervals is frequently used for the assessmentof changesin the autonomic control of the cardiovascular systern2* Although it has been shown to be of clinical value, it is inlluenced by external factors and therefore does not provide satisfactory insight into the physiologic mechanisms controlling heart rate. In contrast, the root-mean-square of the difference of successiveRR intervals, and the percentageof adjacentnormal RR intervals that are >50 ms different (which are dependent on the analysis of successive RR intervals) are more sensitive indexes of parasympathetic activity. High-frequency power is considered to be a pure index of parasympatheticactivity becauseit reflectsthe influence of the respiratory sinus arrhythmia.19The clinical importance of low-frequency power remains controversial. Under strictly controlled laboratory conditions, lowfrequency power is intluenced predominantly,but not exclusively, by the parasympatheticsystem.i9However, on 24-hour Holter monitoring, low-frequency power is influenced by both sympathetic and parasympathetic activity.19*24The finding of depressedvalues of spectral components of heart rate variability in the group of patients with syndrome X with higher heart rate further cot&m the presenceof an imbalance of the autonomic control of the cardiovascular system in these patients. The circadian profile of spectral componentsof heart rate variability was analyzed in order to assessthe circadian neurovegetativepattern in both syndrome X and controls. Low- and high-frequency power, and low-frequency/high-frequency ratio showed similar circadian profiles in patients and controls, although patients with syndrome X who had higher mean heart rate had significantly lower values of high- and low-frequency power throughout the 24 hours. These patients also had an increased low-frequency/high-frequency ratio when comparedwith syndromeX patients who had lower heart rate, and with control subjects. These findings suggest that, although the imbalance of the autonomic control of cardiovascular functions in this subgroupof patients persists throughout the day, the circadian pattern of neural control of the cardiovascular systemis preserved. A limitation of the present study is the sole use of parametersof heart rate variability for the assessmentof the neural control of the cardiovascular systembecause there is no linear relation between the sympathetic and parasympatheticactivity and thesemeasurements.However, these indexes have been widely used for this purpose in several studies investigating the function of the autonomic nervous system. Thus, patients with syndrome X appear to have an imbalance of the sympathovagal control of the cardiovascular system shifted toward sympathetic predomi-
JUNE 15, 1994
nance. This increased sympathetic drive is associated with an increased mean heart rate. These alterations of the autonomic nervous control of cardiac function may play a pathogenetic role in the syndrome by influencing coronary vasomotor tone.
1. Phibbs B, Fleming T, Ewy GA, Butman S, Ambrose J, Gorlin R, Orme E, Mason J. Frequency of normal coronary arteriograms in three academic medical centers and one community hospital. Am J Car&/ 1988;62:472-474, 2. Kemp HG, Elliott WC, Gorlin R. The angina1 syndrome with normal coronary arteriography. Tram Assoc Am Physicians 1967;80:59-70. 3. Kemp HG Jr. Left ventricular function in patients with angina1 syndrome and normal coronary arteriograms. Am .I Cardiol 1973;32:375-376. 4. Cannon RO, Epstein SE. “Microvascular angina” as a cause of chest pain with angiographically normal coronary arteries. Am J Cardin/ 1988;61: 1338-1343. 5. Maseri A, Crea F, Kaski JC, Crake T. Mechanisms of angina pectoris in syndrome X. J Am Coil Cordial 199 I ; 17:499-506. 6. Chilian WM, Ackell PH. Trammural differences in sympathetic coronary constriction during exercise in the presence of coronary stenosis. Circ RES 1988;62: 216225. 7. Gwirtz PA, Stone HL. Coronary blood flow changes following activation of adrenergic receptors in the conscious dog. Am J Physiol 1982:243:H 13-H 19. 8. Heusch G. Control of coronary vasomotor tone in ischaemic myocardium by local metabolism and neurohumoral mechanisms. ELII. Heart J 1991; 12(Suppl F):99-106. 9. Buftington CW, Feigl EO. Adrenergic coronary vasoconstriction in the presence of coronary stenosis in the dog. Circ Res 1981:48:416-+23. 10. Heusch G. Alpha-adrenergic mechanisms in myocardlal ischemia. Circu&ion 1990;81:1-13. 11. Raizner AE, Chahine RA, Ishimori T, Verani MS, Zacca N, Jamal N, Mdler RR, Luchi RJ. Provocation of coronary artery spasm by the cold pressor test. Hemodynamic, aneriogmphic and quantitative angiographic observations. Circulation 1980:62:925-932. 12. Galassi AR, Kaski JC, Crea F, Pupita G, Gavrielides S, Tousoullis D, Maseri A. Heart rate response during exercise testing and ambulatory ECG momtoring in patients with syndrome X. Am Hem? J 1991;122:458463. 13. Kaski JC, Crea F, Nihoyannopoulos P, Hackett D, Maseri A. Transient myocardial ischemia during daily life in patients with syndrome X. Am J Cardiol 1986; 58:1242-1247. 14. Romeo F, Gaspardone A, Ciavolella M, Gioffrk P, Reale A. Verapamil versur
acebutolol for syndrome X. Am .I Cardiol 1988;62:312-313. 15. Mammohansingh P, Parker JO. Angina pectoris with normal coronary arteriogmms: hemodynamic and metabolic response to atria1 pacing. Am Hrurr ./ 1975;90:555-561. 1s. Greenberg MA, Grose RM, Neuburger N, Silverman R, Strain JE, Cohen MV. Impaired coronary vasodilator responsiveness as a cause of lactate production during pacing-induced ischemia in patients with angina pectoris and normal coronary arteries. J Am Coil Cardiol 1987:9:743-75 I. 17. Montorsi P, Fabbiocchi F, Loaldi A, Annoni L, Polese A, De Cesare N, Guarzi M. Coronary adrenergic hyperreactivity in patients with syndrome X and abnormal electrocardiogram at rest. Am J Cmdrol 1991:68:1698-1703. 19. Galassl AR, Kaski JC, Pupita G, Vejar M, Crea F, Maseri A. Lack of evidence for alpha-adrenergic receptor-mediated mechanisms in the genesis of ischemia in syndrome X. Am J Cardiol 1989;64:264-269. 19. Pomeranz B. Macaulay RJ, Caudill MA, Kutz I, Adam D, Gordon D, Kilbom KM, Barger AC, Shannon DC, Cohen RI, Benjon H. Assessment of autonomic function in human5 by heart rate spectral analysis. Am J Plysiol 1985:248: HlSl-Hl53. 20. Lombardi F, Sandrone G, Pempmner S. Sala R, Garimoldi M. Cemtti S, Baselh G, Pagani M, Mall&i A. Heart rate variability as an index of sympathovagal interaction after acute myocardial infarction. Am J Cordial 1987;60: 1239-1245. 21. Caaolo G, Balli E, Taddei T. Amuhasi I, Gori C. Decreased spontaneous heart rate variability in congestive heart fadwe. Am J Cnrdiol 1989;64: 1162-l 167. 22. Maseri A, Crea F, Kaski JC, Crake T. Mechanisms of angina pectoris in syndrome X [editorial]. J Am Co// Cardiol 1991:17:499%SO6. 23. Rosano GM, Lindsay DC, Poole-Wilson PA. Syndrome X: an hypothesis for cardiac pain without ischaemia. Car-diologia 1991;36:885-895. 24. Pagani M, Lombardi F, Guzzetti S, Rimoldi 0. Furlan R, Pizdnelli P, Sandrone G, Malfatto G, Dell’Orto S, Piccaluga E. Turiel M, Baselli G, Cemtti S, Malliani A. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res 1986;59:178-193. 25. Turiel M, Galassi AR, Glazier JJ, Kaski JC, Maseri A. Pain threshold and tolerance in women with syndrome X and women with stable angina pectoris. Am J 1987:60:503-507. Cordial 26. Sax FL, Cannon RO, Hanson C, Epstein SE. Impaired forearm vasodilator reserve in patients with microvascular angina. N Enfil J Mrd 1987;317:136&1370. 27. Camici PG, Marmccini P, Lorenzom R, Buzzigoli G, Pecori N, Perissinotto A, Ferrannini E, L’Abbate A, Marzilli M. Coronary hemodynamics and myocardial metabohsm in patients with syndrome X: response to pacing stress. .I Am Co// Curdial 1991:17:1461-1470. 2.S. Bigger JT Jr, Kleiger RE, Fleiss JL, Rolnitzky LM, Steinman RC, Miller JP. Components of heart rate variability measured during healing of acute myocardial infarction. Am .I Car-dial 1988;61:208-215.
HEARTRATEVARIABILITYINSYNDROMEX 1179
,,,
From the National Heart & Lung Institute, Royal Brompton National Heart & Lung Hospital, and St. George’s Hospital, London, United Kingdom. Manuscript received June 18, 1993; revised manuscript received November, 1, 1993, and accepted November 2. Address for reprints: Giuseppe M.C. Rosano, MD, Department of Cardiac Medicine, National Heart & Lung Institute, Dovehouse Street, London SW3 6LY, United Kingdom.
1174
THE AMERICANJOURNALOF CARDIOLOGY VOLUME73
heart rate. This dysfunction appears to persist throughout the 24 hours and may indicate heterogeneity in autonomic function in syndrome X. (Am J Cardiol19~73:1174-1179)
A
ngina pectoris is usually associatedwith atheromatous coronary artery disease,but angina-like chest pain can occur in the absenceof significant coronary artery stenoses.1,2The association of angina pectoris, positive exercise test results, and angiographitally normal coronary arteries in the absenceof other forms of heart diseaseis referred to as syndrome X.3 A reduction in coronary flow reserve due to alterations of vasomotor tone at the microvascular level may be the cause of chest pain in a proportion of these patients.4,5 The autonomic nervous system modulates coronary artery tone,“8 and abnormalities of autonomic control may result in a reduction of coronary blood flo~.s-~~Patients with syndrome X may have an increased sympathetic drive.12-” Altered autonomic nervous control of the coronary microcirculation could play a role in the development of syndrome X, becauseincreased sympathetic activity could account for the primary reduction in coronary blood flow at rest,t3and explain the reduced vasodilator reserve demonstratedby some patients with syndrome X during stress.I6 However, despite suggestions of an increased sympathetic drive, o-blockade failed to show any benefit in patients with syndromeX.t8 The characteristics of the autonomic nervous control of the cardiovascular system in patients with syndrome X have not been studied. Study of heart rate variability is a useful and accurate noninvasive method for assessing autonomic control of the cardiovascular system.19 Spectral and nonspectral analysis of heart rate variability have been used extensively to investigate the activity of the cardiac sympathetic and parasympatheticnervous system in patients with a variety of cardiac conditions including myocardial infarction20 and heart failure.21The present study assesses,by means of heart rate variability analysis, the characteristicsof autonomic control of heart rate in patients with syndrome X and comparesthem with those of an age- and sex-matched control population. ME7HODS Syndrome X patients:
The patient group consisted of 26 consecutive nonsmoking patients with syndrome X (6 men and 20 women, mean age 5.5f 6 years, range
JUNE 15,1994
TABLE I Clinical Characteristics of Patients with Syndrome X and of Normal Control Subjects Syndrome X
Control Subjects
Number of patients
26
20
Mean age (years)
55 r 6 20 (77%)/6 (23%)
55 k 6 15 (75%)/5 (25%)
12 0 2
6 0 1
0
1
Women/men Risk factors for coronary artery drsease Family hrstory Cigarette smokers Serum total cholesterol (>ZlOmg/dl) Fasting blood glucose f>llOmg/dl) Holter monitonng ST-segment depressron (patients) Eprsodeslpatrentiday Symptomatic episodes Mean ST-segment depression (mm)
16
0
4 40 (62%) 1.6 ? 0.3
0 0 0
TABLE II Correlation Coefficients Between Mean RR and Indexes of Heart Rate Variability in Patients with Syndrome X and in Normal Control Subjects Control Syndrome X Standard deviation of all normal RR intervals Standard deviation of 5-minute mean RR intervals Standard deviation Natural log of root-mean-square of difference of successive RR intervals Natural log of percentage of adjacent normal RR intervals > 50 ms different Natural log of total power Natural log of low frequency Natural log of high frequency
Subjects
0.393 0.238*
0.401 0.379
0.653* 0.64*
0.044 0.023
0.674t
0.003
0.574* 0.452* 0.611t
0.004 0.112 0.0003
‘p <0.05; tp
dependent observers.The Marquette Laser Holter System (ST-segment analysis and arrhythmia analysis pro(min) gram, version 5.7 software, Marquette Electronics Inc., Values are expressed as mean ? SD. Milwaukee, Wisconsin) was used for the tape analysis. The number of episodesof transient myocardial ischemia 46 to 67). The diagnosis was based on the presenceof (horizontal or downsloping ST-segment shift 20.1 mV typical exertional angina, positive exercise test results, from baseline) and the duration of the ST-segmentdeand angiographically normal coronary arteries,in the ab- pression were recorded.The frequency histogram of the sence of coronary artery spasm, cardiomyopathy, con- normal RR intervals was displayed and electrocardiogestive heart failure, valvular heart disease (including gram strips of the intervals in both tails of RR distribumitral valve prolapse), systemic hypertension, left ven- tion were visually checked.Furthermore, a histogram of tricular hypertrophy, or conduction abnormalities.‘3*22~23the consecutive RR ratio was analyzed and cycles outLeft ventricular hypertrophy was ruled out by M-mode side 80% to 120% of preceding RR intervals were exechocardiography. A positive response in the electro- cluded from further analysis. This preliminary analysis cardiogram was defined as a horizontal or downsloping allowed the exclusion of artifacts, premature beats or ST-segmentdepression2 1 mm at 60 ms after the J point, post-extrasystolicpausesfrom further analysis. All tapes occurring in 26 consecutive complexes. In patients in were subsequently analyzed to measureheart rate variwhom there was a clinical suspicion of coronary artery ability using a commercially available and validated prospasm,this type of test was excluded using hyperventi- gram (Marquette heart rate variability program, Marquette Electronics Inc., Milwaukee, Wisconsin). lation or ergonovine tests, or both. Heart rate variability analysis: NONSPECTRAL ANALcontrd sum Twenty healthy,nonsmokingsedentary sex- and age-matchedsubjects(5 men and 15women, YSIS: The following time-domain measurementsof heart mean age 55 + 5.6 years, range 46 to 67) were used as rate variability were calculated from 24-hour electroa control group; none had cardiovascular symptoms or cardiographic recordings: mean of all normal RR intervals, standarddeviation of all normal RR intervals, stanevidence of cardiovascular disease. Halter monitorh@ All syndrome X patients and dard deviation of 5-minute mean RR intervals, mean of control subjects underwent 24-hour Holter monitoring, all 5-minute standard deviation of RR intervals, rootwithout therapy,using a 2-channel amplitude modulated mean-squaredifference of successiveRR intervals, and tape recorder (Marquette 8500, Marquette Electronics percentageof adjacentnormal RR intervals >50 ms difInc., Milwaukee, Wisconsin). Holter monitoring was re- ferent. SPECTRAL ANALYSIS:Spectral measurements were peated in 12 subjects (7 patients and 5 controls) in order to assessthe reproducibility of the heart rate vari- computed by fast-Fourier transform analysis. Spectral ability measurements.Patients were askednot to smoke plots were used to identify 2 subsetsof the frequencyor drink caffeine-containing drinks and not to change domain: low- (0.04 to 0.15 Hz) and high- (0.15 to 0.40 their normal daily activities during the period of Holter Hz) frequency power. Spectral power was quantified in monitoring. The 24-hour Holter monitoring of syndrome these 2 frequency band widths. Spectral plots were X and controls was begun at 11A.M. and ended at the squared to quantify power in the 2 frequency bands (in same hour of the following day. Syndrome X and con- ms2). Total oscillatory power between 0.01 and 1.00 Hz trols were studied on similar nonworking days and were was also calculated. The ratio of low- to high-frequency askedto adhere to their normal daily nonworking activ- power was also calculated. This is an established index of sympathovagal balance, and high values for the ratio ities. Two leads, a modified inferior lead and CM5, were indicate predominanceof sympatheticnervous activity.24 used for monitoring. Recordings were analyzed by 2 in- To assessthe intra- and the interoperator variability, 12 Mean duration of episode
17 c 23
0
HEART RATE VARIABILITY IN SYNDROME X 1175
of heart rate variability was <5% in the 12 subjects in whom electrocardiographic monitoring was repeated. No difference was found in any heart rate variability parameter after either 5 or 30 days of washout in the 5 patients who were taking B blockers. Mean RR duration was similar in syndrome X patients and controls (787 f 98 vs 830 f 83 ms, p = NS). Patients with syndrome X had lower values of standard deviation of all normal RR intervals and in the percentage of adjacent normal RR intervals >50 ms different than control subjects(126 f 22 vs 149+ 43 ms, p ~0.05; 6.3 + 4 vs 11.2f 7%, p ~0.05; respectively). A trend toward lower values of all the other time-domain parameters was also observed in patients with syndrome X. Table II showsthe correlation betweenthe measurements of heart rate variability and the RR interval in syndrome X patients and in controls. Patients with syndrome X, but not control subjects,had a significant inverse correlation between all measuresof heart rate variability, with the exception of the standarddeviation of all normal RR intervals, and mean RR. Patients with syndrome X had significantly lower values of total power and low-frequency power than controls (1273 _+693 vs 1790 + 989 ms2,p ~0.05; 406 f 176 vs 729 + 455 ms2,p ~0.01, re-
tapes, randomly selected, were reanalyzed by both operators. Data analysis Data are expressedas mean + 1 SD or as percentages where appropriate. Between-group comparisonswere assessedby analysis of variance with individual comparisonsby Scheffe’sF test corrected for multiple comparisons (Superanova and Statview statistical packages,Abbacus). Correlations were analyzedby the least-squaresmethod. RESULTS Patient characteristics: Clinical and electrocardiographic characteristicsof patients with syndrome X and control subjectsare listed in Table I. Transient episodes of ST-segment depression were detected in 16 patients with syndrome X, but none of the control subjects had ST-segment shifts during Holter monitoring. Exercise capacity was similar in syndrome X and in control subjects, but exercise test results were negative in control subjects. Spectral and nmspectral
analysis of heart rate
Differences among operators for heart rate variability measurementswere <5%, and intraobserver variability was also ~5%. The variability for all indexes variability:
low frequency
1400
(ma*)
1200 1
0’
11
1
I
I
t
13
lb
17
19
high frequency
I
I
I
4
I
1
3
6
7
9
I
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-3x2
-sx1
7oor
I
21 23 hours
----co2
(ma ‘1
BOO
600 400 300
0’
11
I
I
I
,
13
16
17
19
-9x1
1176
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21 23 hours
1
3
5
7
9
I
co,
.--- co2
THE AMERICANJOURNALOF CARDIOLOGY VOLUME73
JUNE 15, 1994
FIGURE 1. Low- (top) and high (bottom) frequency power in patients with syndrome X and in control subjects with high (COl) and low (COZ) heart rate during Halter monitoring. Patients with syndrome X and higher heart rate @Xl) had depressed values of both measure merits throughout the 24 hours corn pared with values in patients with syndrome X and lower heart rate (SXZ) and the 2 control groups.
TABLE III Indexes of Heart Rate Variability in Patients with Syndrome X and in Normal Control Subjects
Age (years) Women Mean RR (ms) Standard deviation of all normal RR intervals (ms) Standard deviation of 5-minute mean RR intervals (ms) Standard deviation (ms) Root-mean-square of difference of successive RR intervals (ms) Percentage of adjacent normal RR intervals > 50 ms different f%) High frequency (rns? Low frequency (ms*) Total power (msz) Low-frequency/High-frequency ratio
Syndrome Xl (n = 13)
Syndrome X2 (n = 13)
Control 1 (n = 10)
Control 2 (n = 10)
54 2 5 11 716 2 44 113 + 17*
55 + 7 9 a76 + 7 139 2 20
55 + 6 8 785 r 57 136 + 32
55 + 5 7 891 _t 48 162 + 50
105 -c 18*
124 2 22
123 lr 33
148 k 56
20.7 + 3*
57.5 -+ 9 32.4 f 8
55k 15 31.3 f 10
5ak 17 33.7 2 11
3 + 1t
9.6 + 5
9.9 -t 7
12.5 + 8
41.3 2 5*
a4 336 843 4.3
*p ~0.05; tp
+ 33t -c 134t f 277* + 1.4*
226 645 1703 2.84
119 329 721 0.72
219 769 1681 3.6
r + 2 k
163 508 1123 1.6
219 688 1790 3.25
k + 5 k
125 329 1098 1.1
X2, control 1 and control 2.
spectively) together with a trend toward lower values of high-frequency power and a higher low-frequency/highfrequency ratio. Based on the suggestion of previous studies12J3that somepatients with syndromeX have a higher meanheart rate on Holter monitoring which could indicate an increasedsympathetic drive, patients with syndromeX and controls were subdivided into 2 groups according to the mean 24-hour RR interval for the whole group. Four groups were therefore created: syndrome Xl and control 1 with RR interval greater than median RR interval, and syndrome X2 and control 2 with lower RR interval than median, with the aim of further evaluating heart rate variability parameters. All 4 groups had similar mean age and male/female distribution (Table III). Time- and frequency-domain measurementsof heart rate variability in these 4 groups are listed in Table III. Syndrome
low/high
2 + + f
Xl patients had significantly depressedvalues of spectral and nonspectral measurementsof heart rate variability when comparedwith the other 3 groups. No difference was seen among control subjects (control 1, control 2) and between these 2 control groups and syndrome X2 patients. Circadian pattern of heart rate variability: Patients with syndrome X and controls had similar circadian profiles of spectral indexes of heart rate variability. The absolute values of both low and high frequencies, however, were significantly depressedonly in syndrome X 1 patients when comparedwith syndrome X2 and control 1 and 2 subjects (Figure 1). Syndrome Xl patients also showed similar patterns but higher values of lowfrequency/high-frequency ratio throughout the 24 hours than did syndrome X2 and normal subjects (Figure 2). No significant difference was seenin values and pattern
frequency
“r
0”““’ 11
’ 15
”
”
19
”
23
’
”
3
’
”
”
7
” 10
hours
-sx2
-
SXl
--- - co1
--...-- co2
FIGURE 2. Low-frequency/hi~uency ratio in patients with syndrome X and in control subjects with him (COl) and low (CO?) heart rate during Halter monitoring. Patlents with syndrome X and higher heart rate (SXI) had higher values throughout the 24 bows than patkmts with syndrome X and lower heart rate (SX2) and the 2 control groups.
HEARTRATEVARIABILITYIN SYNDROMEX 1177
of low-frequency/high-frequency ratio between syndrome X2 and the 2 control groups (control 1 and control 2). DISCUSSION Our results suggest that patients with syndrome X have an imbalance of the autonomic control of the cardiovascular system and that this is more pronounced in patients with increasedmeanheart rate. The male/female ratio, the mean age and the clinical features of our patients with syndrome X are similar to those reported in other large series12J4*23,25-27 and are therefore representative of the condition referred to as syndrome X. The control group was selected strictly to match the study population not only in terms of age and gender,but also in the degreeof daily physical activities and, if possible, emotional stress.Cigarette smoking may also infiuence heart rate variability; therefore we selecteda nonsmoking population. Importantly, in our study there were no major differences in daily activities, exercise tolerance, and influence of the working environment between syndrome X and controls before and during Holter monitoring. The results were found to be reproducible. Although the detection of transient myocardial ischemia was not a primary end point of this study, our syndromeX patients had ST-segmentchangessimilar to those reported in other studies.13No difference was found in heart rate variability measurementsbetween syndrome X patients with or without episodes of STsegmentdepression. Contrary to the findings of Galassi et a&l2the 24-hour mean heart rate in the present study did not differ between patients with syndromeX and controls (even when the groups were subdivided by median RR duration). Therefore, in our study,the differencesin heart rate variability parameters between syndrome X and controls were not purely a reflection of different mean heart rate in syndrome X patients and control subjects. Patients with syndrome X had depressedvalues of spectral and nonspectral parametersof heart rate variability. In patients with syndrome X we observed an inversecorrelation betweenmean daily heart rate and measurementsof heart rate variability, suggesting that there is a continuous spectrum of alteration of the autonomic nervous control of the cardiovascular systemin patients with syndrome X, and that this is more altered in patients with a higher heart rate. The fact that the autonomic control of the cardiovascular systemis more impaired in patients with syndromeX and higher heart rate explains why, when patients with syndrome X were analyzed as one group, only a statistically significant trend toward lower values was found for most of the heart rate variability parameters. Thus, the subdivision of the groups of syndrome X patients appearsjustified because it allowed us to identify and better analyze patients who had a relatively higher heart rate and therefore more impaired autonomic control of the cardiovascular system. No significant differencesin any of the heart rate variability measurementswere found in controls when classified according to the mean heart rate. In contrast, among patients with syndrome X, a subgroup with
1178
THE AMERICANJOURNALOF CARDIOLOGY VOLUME73
higher meanheart rate had markedly depressedheart rate variability, in both time and frequency domains, indicative of a more impaired sympathovagal control of the cardiovascular system. Our results are supported by other studies12*13 in which a significantly higher heart rate in patients with syndrome X than in controls was found and bdings were interpreted as an indication of the presenceof an increased sympathetic drive. Standard deviation of all normal RR intervals is frequently used for the assessmentof changesin the autonomic control of the cardiovascular systern2* Although it has been shown to be of clinical value, it is inlluenced by external factors and therefore does not provide satisfactory insight into the physiologic mechanisms controlling heart rate. In contrast, the root-mean-square of the difference of successiveRR intervals, and the percentageof adjacentnormal RR intervals that are >50 ms different (which are dependent on the analysis of successive RR intervals) are more sensitive indexes of parasympathetic activity. High-frequency power is considered to be a pure index of parasympatheticactivity becauseit reflectsthe influence of the respiratory sinus arrhythmia.19The clinical importance of low-frequency power remains controversial. Under strictly controlled laboratory conditions, lowfrequency power is intluenced predominantly,but not exclusively, by the parasympatheticsystem.i9However, on 24-hour Holter monitoring, low-frequency power is influenced by both sympathetic and parasympathetic activity.19*24The finding of depressedvalues of spectral components of heart rate variability in the group of patients with syndrome X with higher heart rate further cot&m the presenceof an imbalance of the autonomic control of the cardiovascular system in these patients. The circadian profile of spectral componentsof heart rate variability was analyzed in order to assessthe circadian neurovegetativepattern in both syndrome X and controls. Low- and high-frequency power, and low-frequency/high-frequency ratio showed similar circadian profiles in patients and controls, although patients with syndrome X who had higher mean heart rate had significantly lower values of high- and low-frequency power throughout the 24 hours. These patients also had an increased low-frequency/high-frequency ratio when comparedwith syndromeX patients who had lower heart rate, and with control subjects. These findings suggest that, although the imbalance of the autonomic control of cardiovascular functions in this subgroupof patients persists throughout the day, the circadian pattern of neural control of the cardiovascular systemis preserved. A limitation of the present study is the sole use of parametersof heart rate variability for the assessmentof the neural control of the cardiovascular systembecause there is no linear relation between the sympathetic and parasympatheticactivity and thesemeasurements.However, these indexes have been widely used for this purpose in several studies investigating the function of the autonomic nervous system. Thus, patients with syndrome X appear to have an imbalance of the sympathovagal control of the cardiovascular system shifted toward sympathetic predomi-
JUNE 15, 1994
nance. This increased sympathetic drive is associated with an increased mean heart rate. These alterations of the autonomic nervous control of cardiac function may play a pathogenetic role in the syndrome by influencing coronary vasomotor tone.
1. Phibbs B, Fleming T, Ewy GA, Butman S, Ambrose J, Gorlin R, Orme E, Mason J. Frequency of normal coronary arteriograms in three academic medical centers and one community hospital. Am J Car&/ 1988;62:472-474, 2. Kemp HG, Elliott WC, Gorlin R. The angina1 syndrome with normal coronary arteriography. Tram Assoc Am Physicians 1967;80:59-70. 3. Kemp HG Jr. Left ventricular function in patients with angina1 syndrome and normal coronary arteriograms. Am .I Cardiol 1973;32:375-376. 4. Cannon RO, Epstein SE. “Microvascular angina” as a cause of chest pain with angiographically normal coronary arteries. Am J Cardin/ 1988;61: 1338-1343. 5. Maseri A, Crea F, Kaski JC, Crake T. Mechanisms of angina pectoris in syndrome X. J Am Coil Cordial 199 I ; 17:499-506. 6. Chilian WM, Ackell PH. Trammural differences in sympathetic coronary constriction during exercise in the presence of coronary stenosis. Circ RES 1988;62: 216225. 7. Gwirtz PA, Stone HL. Coronary blood flow changes following activation of adrenergic receptors in the conscious dog. Am J Physiol 1982:243:H 13-H 19. 8. Heusch G. Control of coronary vasomotor tone in ischaemic myocardium by local metabolism and neurohumoral mechanisms. ELII. Heart J 1991; 12(Suppl F):99-106. 9. Buftington CW, Feigl EO. Adrenergic coronary vasoconstriction in the presence of coronary stenosis in the dog. Circ Res 1981:48:416-+23. 10. Heusch G. Alpha-adrenergic mechanisms in myocardlal ischemia. Circu&ion 1990;81:1-13. 11. Raizner AE, Chahine RA, Ishimori T, Verani MS, Zacca N, Jamal N, Mdler RR, Luchi RJ. Provocation of coronary artery spasm by the cold pressor test. Hemodynamic, aneriogmphic and quantitative angiographic observations. Circulation 1980:62:925-932. 12. Galassi AR, Kaski JC, Crea F, Pupita G, Gavrielides S, Tousoullis D, Maseri A. Heart rate response during exercise testing and ambulatory ECG momtoring in patients with syndrome X. Am Hem? J 1991;122:458463. 13. Kaski JC, Crea F, Nihoyannopoulos P, Hackett D, Maseri A. Transient myocardial ischemia during daily life in patients with syndrome X. Am J Cardiol 1986; 58:1242-1247. 14. Romeo F, Gaspardone A, Ciavolella M, Gioffrk P, Reale A. Verapamil versur
acebutolol for syndrome X. Am .I Cardiol 1988;62:312-313. 15. Mammohansingh P, Parker JO. Angina pectoris with normal coronary arteriogmms: hemodynamic and metabolic response to atria1 pacing. Am Hrurr ./ 1975;90:555-561. 1s. Greenberg MA, Grose RM, Neuburger N, Silverman R, Strain JE, Cohen MV. Impaired coronary vasodilator responsiveness as a cause of lactate production during pacing-induced ischemia in patients with angina pectoris and normal coronary arteries. J Am Coil Cardiol 1987:9:743-75 I. 17. Montorsi P, Fabbiocchi F, Loaldi A, Annoni L, Polese A, De Cesare N, Guarzi M. Coronary adrenergic hyperreactivity in patients with syndrome X and abnormal electrocardiogram at rest. Am J Cmdrol 1991:68:1698-1703. 19. Galassl AR, Kaski JC, Pupita G, Vejar M, Crea F, Maseri A. Lack of evidence for alpha-adrenergic receptor-mediated mechanisms in the genesis of ischemia in syndrome X. Am J Cardiol 1989;64:264-269. 19. Pomeranz B. Macaulay RJ, Caudill MA, Kutz I, Adam D, Gordon D, Kilbom KM, Barger AC, Shannon DC, Cohen RI, Benjon H. Assessment of autonomic function in human5 by heart rate spectral analysis. Am J Plysiol 1985:248: HlSl-Hl53. 20. Lombardi F, Sandrone G, Pempmner S. Sala R, Garimoldi M. Cemtti S, Baselh G, Pagani M, Mall&i A. Heart rate variability as an index of sympathovagal interaction after acute myocardial infarction. Am J Cordial 1987;60: 1239-1245. 21. Caaolo G, Balli E, Taddei T. Amuhasi I, Gori C. Decreased spontaneous heart rate variability in congestive heart fadwe. Am J Cnrdiol 1989;64: 1162-l 167. 22. Maseri A, Crea F, Kaski JC, Crake T. Mechanisms of angina pectoris in syndrome X [editorial]. J Am Co// Cardiol 1991:17:499%SO6. 23. Rosano GM, Lindsay DC, Poole-Wilson PA. Syndrome X: an hypothesis for cardiac pain without ischaemia. Car-diologia 1991;36:885-895. 24. Pagani M, Lombardi F, Guzzetti S, Rimoldi 0. Furlan R, Pizdnelli P, Sandrone G, Malfatto G, Dell’Orto S, Piccaluga E. Turiel M, Baselli G, Cemtti S, Malliani A. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympatho-vagal interaction in man and conscious dog. Circ Res 1986;59:178-193. 25. Turiel M, Galassi AR, Glazier JJ, Kaski JC, Maseri A. Pain threshold and tolerance in women with syndrome X and women with stable angina pectoris. Am J 1987:60:503-507. Cordial 26. Sax FL, Cannon RO, Hanson C, Epstein SE. Impaired forearm vasodilator reserve in patients with microvascular angina. N Enfil J Mrd 1987;317:136&1370. 27. Camici PG, Marmccini P, Lorenzom R, Buzzigoli G, Pecori N, Perissinotto A, Ferrannini E, L’Abbate A, Marzilli M. Coronary hemodynamics and myocardial metabohsm in patients with syndrome X: response to pacing stress. .I Am Co// Curdial 1991:17:1461-1470. 2.S. Bigger JT Jr, Kleiger RE, Fleiss JL, Rolnitzky LM, Steinman RC, Miller JP. Components of heart rate variability measured during healing of acute myocardial infarction. Am .I Car-dial 1988;61:208-215.
HEARTRATEVARIABILITYINSYNDROMEX 1179
,,,