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Relationship between central sympathetic activity and stages of human hypertension
AJH
2004; 17:217–222
Relationship Between Central Sympathetic Activity and Stages of Human Hypertension Paul A. Smith, Lee N. Graham, Alan F. Mackintosh, John B. Stoker, and David A. S. G. Mary Background: The magnitude of sympathetic hyperactivity in essential hypertension (EHT) varies with its severity and complications. There are no data on sympathetic nerve activity in borderline (BHT) or whitecoat hypertension (WHT) relative to the various stages of EHT, despite suggestions that both lead to established EHT and organ damage through sympathetic mechanisms. We planned to determine the magnitude of sympathetic nerve activity in patients with BHT and WHT in relation to normality and various stages of sustained EHT.
nerve activity as the mean frequency of multiunit discharge (MSNA) and that of single-units (s-MSNA).
Methods: We examined 90 untreated subjects comprising matched groups with BHT (n ⫽ 13), WHT (n ⫽ 12), Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure EHT stage 1 (EHT-1 n ⫽ 12), EHT stages 2 and 3 (EHT-2/3 n ⫽ 14), high–normal pressure (HN n ⫽ 14), and normal pressure (NT n ⫽ 13), as well as a group with EHT complicated by left ventricular hypertrophy (EHT⫹LVH n ⫽ 12). We quantified muscle sympathetic
Conclusions: Central sympathetic activity was greatest in BHT, early stage, and complicated EHT, and as such is likely to play an integral role in the development of hypertension and its complications. Sympathetic hyperactivity occurs in WHT, but to a lesser extent than in BHT. Am J Hypertens 2004;17:217–222 © 2004 American Journal of Hypertension, Ltd.
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Results: We found a greater (at least P ⬍ .01) mean central sympathetic frequency in BHT (75 ⫾ 5.8 impulses/ 100 beats), EHT-1 (76 ⫾ 4.0 impulses/100 beats), and EHT⫹LVH (79 ⫾ 4.3 impulses/100 beats) than in EHT2/3 (57 ⫾ 3.1 impulses/100 beats), WHT (52 ⫾ 3.6 impulses/100 beats), HN (42 ⫾ 3.9 impulses/100 beats), and NT (33 ⫾ 3.6 impulses/100 beats). BHT hyperactivity was closer to that of EHT, whereas WHT was closer to NT.
Key Words: Sympathetic nervous system, hypertension, action potentials.
ssential hypertension (EHT) is a common condition and a major cardiovascular risk factor. Although EHT is characterized by an abnormal and sustained increase in arterial pressure in the absence of an identifiable cause, other intermittent forms of hypertension have also been described. For instance, the term borderline hypertension (BHT) has been used to reflect intermittent and mildly hypertensive levels of arterial pressure,1,2 and white coat hypertension (WHT) to indicate hypertensive values obtained only in the clinic setting.3,4 Both conditions have been reported to share some of the adverse outcomes of sustained EHT.2,4 –7 The pathogenesis of BHT and WHT and their modes of progression have not been fully established, although sympathetic hyperactivity has been suggested to play an important role,5,8 –10 as it does in essential hypertension.11–13
Direct and quantitative assessment of peripheral sympathetic nerve activity supplying the vessels of skeletal muscles (MSNA) by microneurography,14 has found MSNA hyperactivity relative to matched normal groups in the majority of published reports on EHT.15,16 More recently, the mean frequency of single units of efferent sympathetic nerve activity (s-MSNA) was found to be increased in uncomplicated EHT, and more markedly so in mild EHT than in more severe disease.17 An increase in both MSNA and s-MSNA has also been reported in WHT10 and in EHT with left ventricular hypertrophy (EHT⫹LVH).18 As yet, there are no data from adequately matched groups of subjects on the relative magnitude of sympathetic hyperactivity in BHT and WHT in comparison to the various stages of EHT. The present trial was planned to determine the relative
Received May 12, 2003. First decision July 24, 2003. Accepted October 21, 2003. From the Department of Cardiology, Leeds Teaching Hospitals, Leeds, United Kingdom. This work was funded by the British Heart Foundation (Grant No.
FS/2000068). Address correspondence and reprint requests to Dr. Paul A. Smith, Cardio-Respiratory Unit, St. James’s University Hospital, Beckett Street, Leeds LS9 7TF, United Kingdom; e-mail: paulsmith.leeds@ ukgateway.net
© 2004 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
0895-7061/04/$30.00 doi:10.1016/j.amjhyper.2003.10.010
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Table 1. Clinic details of the seven study groups Variable
NT
HN
WHT
BHT
EHT-1
EHT-2/3 EHT ⴙ LVH
Number (female) 13 (7) 14 (8) 12 (6) 13 (8) 12 (6) 14 (5) 12 (6) Age (y) 45 ⫾ 3.5 46 ⫾ 3.0 46 ⫾ 3.9 48 ⫾ 3.7 47 ⫾ 3.1 46 ⫾ 3.0 48 ⫾ 3.0* Age range (y) 24–63 26–60 23–62 26–65 30–65 30–65 30–62 BMI (kg/m2) 27 ⫾ 0.8 27 ⫾ 0.8 29 ⫾ 0.9 28 ⫾ 1.3 29 ⫾ 0.9 28 ⫾ 1.3 28 ⫾ 1.0* Weight (kg) 78 ⫾ 2.2 77 ⫾ 3.7 80 ⫾ 2.2 79 ⫾ 4.1 80 ⫾ 2.9 80 ⫾ 2.5 80 ⫾ 3.7* Heart rate (beats/min) 68 ⫾ 3.2 69 ⫾ 2.6 74 ⫾ 2.2 69 ⫾ 2.6 66 ⫾ 2.7 69 ⫾ 3.1 63 ⫾ 2.2† Systolic BP (mm Hg) 126 ⫾ 1.6 132 ⫾ 1.2 150 ⫾ 1.7 144 ⫾ 1.9 151 ⫾ 1.2 171 ⫾ 3.6 176 ⫾ 5.0‡ Diastolic BP (mm Hg) 77 ⫾ 1.9 83 ⫾ 0.8 94 ⫾ 0.9 90 ⫾ 1.2 93 ⫾ 1.8 106 ⫾ 1.4 106 ⫾ 4.3‡ MAP (mm Hg) 93 ⫾ 1.8 99 ⫾ 0.9 113 ⫾ 0.9 108 ⫾ 1.3 112 ⫾ 1.2 128 ⫾ 1.7 129 ⫾ 4.3‡ BMI ⫽ body mass index; BP ⫽ blood pressure; MAP ⫽ mean arterial pressure. Data are mean ⫾ SEM. One-way ANOVA, * P ⬎ .5, † P ⬎ .05, ‡ P ⬍ .0001.
magnitude of central sympathetic vasoconstrictor nerve output to the peripheral vascular bed in BHT, WHT, and various grades of severity of EHT. For this purpose the technique of microneurography was used to quantify resting central sympathetic output in age- and body weightmatched groups of patients with uncomplicated EHT, WHT, and BHT, and also in EHT⫹LVH. Groups with normotension (NT) and high–normal arterial pressure (HN) were also studied for comparison.
Methods Subjects The study involved 100 newly diagnosed and untreated white subjects who were examined between 1999 and 2002. All patients were screened by history, physical, and laboratory examination. Patients were excluded if there was evidence of arrhythmia or chronic disease that may influence the autonomic nervous system. Similarly, patients with hypertension secondary to renal artery stenosis, pheochromocytoma, and primary hyperaldosteronism were excluded from the study. Ten subjects were excluded because of an inability to obtain stable microneurographic data. All subjects had similar occupational status (sedentary jobs) and dietary habits. The latter was used to deduce a sodium intake of approximately 400 mmol/d at entry into the study. Recruitment of all patients was intended for the present study and has not included any who were reported previously, except 5 patients with WHT.10 During each clinic visit, blood pressure (BP) was determined from the average of three readings taken in the seated position over a period of 30 min after at least 10 min of rest. Such BP measurements were repeated monthly and the average BP of at least three separate clinic visits was used to determine clinic BP status. The resulting arterial pressure was used to classify groups with established hypertension according to the Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) criteria.19 Thus NT had systolic or diastolic pressures of ⬍130 and ⬍85 mm Hg, respectively, HN had
either systolic pressure of 130 to 139 mm Hg or diastolic pressure of 85 to 89 mm Hg, EHT-1 had systolic or diastolic pressure of 140 to 159 or 90 to 99 mm Hg, EHT-2/3 had respective values of ⱖ160 or ⱖ100 mm Hg. For the other groups, BHT was defined according to previously published research1,2,6,8 as arterial pressure intermittently more than 140/90 mm Hg on at least two separate occasions, whereas WHT was defined as sustained clinic arterial pressure of ⱖ140/90 mm Hg with a daytime ambulatory BP of ⬍130/80 mm Hg. Finally, the EHT⫹LVH group was defined according to electrocardiographic and echocardiographic criteria. All groups were matched for age and body mass index. We also matched WHT with EHT-1, and EHT-2/3 with EHT⫹LVH in respect of clinic arterial pressure. The proportion of subjects with a family history of hypertension was similar in each of the seven groups (5/13, 5/14, 6/12, 7/13, 5/12, 6/14, and 5/12). The number of subjects and clinic details of the seven groups are given in Table 1, and their ambulatory BP (ABP) data are shown in Table 2. Each subject provided informed written consent to the investigation, which was performed under the approval of the Leeds Health Authority Ethical Committee. Protocol All studies were performed under similar conditions between the hours of 9 AM and noon, and subjects were asked to have only a light breakfast and to empty their bladder before commencing the study.17 They were also asked to avoid nicotine and caffeine products for 12 h, and alcohol and strenuous exercise for 24 h before investigation. Subjects were studied in the semisupine position in a darkened laboratory in which the temperature was constant at 22° to 24°C. Arterial pressure was measured from the arm using a standard mercury sphygmomanometer. Changes in heart rate and arterial pressure were monitored and recorded using a standard electrocardiogram and a Finapres device (Finapres 2300; Ohmeda, Hatfield, United Kingdom), and blood flow to the muscle of the left calf was obtained using standard venous occlusion plethysmography. All measure-
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Table 2. Ambulatory details of the seven study groups Variable
NT
HN
WHT
BHT
EHT-1
EHT-2/3 EHT ⴙ LVH
Daytime SBP (mm Hg) 118 ⫾ 0.9 122 ⫾ 2.0 121 ⫾ 1.9 136 ⫾ 1.5 147 ⫾ 1.2 156 ⫾ 2.7 Daytime DBP (mm Hg) 74 ⫾ 1.5 76 ⫾ 1.5 74 ⫾ 1.0 83 ⫾ 0.7 89 ⫾ 1.7 101 ⫾ 2.6 Daytime MAP (mm Hg) 89 ⫾ 0.9 91 ⫾ 0.3 90 ⫾ 1.1 101 ⫾ 0.6 107 ⫾ 1.2 119 ⫾ 2.7 Daytime HR (beats/min) 75 ⫾ 4.0 81 ⫾ 0.3 83 ⫾ 2.0 80 ⫾ 2.8 82 ⫾ 1.4 81 ⫾ 4.6 Night-time SBP (mm Hg) 96 ⫾ 2.0 102 ⫾ 1.3 101 ⫾ 1.7 107 ⫾ 3.8 131 ⫾ 1.4 144 ⫾ 3.3 Night-time DBP (mm Hg) 63 ⫾ 2.8 68 ⫾ 1.7 66 ⫾ 1.2 69 ⫾ 2.9 80 ⫾ 1.7 85 ⫾ 4.7 Night-time MAP (mm Hg) 79 ⫾ 0.8 79 ⫾ 0.6 78 ⫾ 1.0 82 ⫾ 3.0 97 ⫾ 1.5 105 ⫾ 2.8 Night-time HR (beats/min) 70 ⫾ 4.9 69 ⫾ 1.9 69 ⫾ 1.6 66 ⫾ 3.0 74 ⫾ 2.7 67 ⫾ 3.9
158 99 119 81 142 84 103 70
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
8.2† 4.0† 5.2† 3.6* 9.3† 3.5† 6.8† 4.4*
SBP ⫽ systolic arterial pressure; DBP ⫽ diastolic arterial pressure; MAP ⫽ mean arterial pressure; HR ⫽ heart rate. Data are mean ⫾ SEM. One-way ANOVA, * P ⬎ .5, † P ⬍ .0001.
ments were obtained during the steady state after a rest period of at least 10 min duration. Microneurography Postganglionic muscle sympathetic nerve activity was recorded from the right peroneal nerve as previously described,14,17 without knowledge of the clinical characteristics of the subjects. Muscle sympathetic nerve activity was differentiated from skin activity by previously accepted criteria.14 The neural signal was amplified (⫻ 50,000) and was sampled at 12,000 samples/sec. Multiunit bursts were obtained after filtering (bandwidth of 700 to 2000 Hz), and integrating (time constant 0.1 sec), and alongside other data were digitized at 2000 samples/sec (8 bits). Single units (s-MSNA) with vasoconstrictor properties were obtained from the raw action potential neurogram by adjusting the electrode position and confirmed by consistent action potential morphology using on-line storage oscilloscope and fast monitor sweep.17,20 Their vasoconstrictor function was assessed by appropriate responses to spontaneous changes in arterial pressure, the Valsalva maneuver, and isometric hand-grip exercise. Measurement of calf vascular resistance confirmed the vasoconstrictor function of the observed neural activity. Data were obtained from 5-min recordings during the steady state at rest. Both s-MSNA and MSNA were counted from the same record and over the same period of time, hemodynamic, and respiratory variables. Spikes of s-MSNA were objectively counted using an electronic discriminator and were quantified as mean frequency of impulses per minute and per 100 cardiac beats to avoid interference by the length of the cardiac cycle.21 The bursts of MSNA were identified by inspection when the signal-to-noise ratio was greater than 3, and were quantified in a similar manner. The variability of measuring both s-MSNA and MSNA in this laboratory was similar and did not exceed 10%,17 and there were no systematic differences between the mean frequencies of two s-MSNA units obtained in the same recordings.
Other Procedures The ABP monitoring was performed independently using an oscillometric device (TRACKER NIBP2, Reynolds Medical Ltd., Hertford, United Kingdom). This device is known to satisfy the requirements of the Association for the Advancement of Medical Instrumentations (AAMI, Arlington, VA), with a difference from the reference auscultatory method of less than 5 ⫾ 8 mm Hg (mean ⫾ SD). Patients were asked to follow their ordinary daily activities and to go to bed not later than midnight. Measurements were taken at half-hour intervals during the daytime and every hour at night to avoid discomfort. This frequency has been assessed in Leeds by comparing it to measurements obtained every 15 min during the day, and every half-hour at night. The coefficient of variation (proportion of 1 SD to the mean measurement) for both systolic and diastolic pressure amounted to 6%. Electrocardiographic voltage criteria were used to identify subjects with suspected LVH, and standard two-dimensional M-mode echocardiography (Philips SONOS 5500, Philips Medical Systems, Andover, MA) was used to measure left ventricular dimensions. Using American Society of Echocardiography recommendations,22 LVH was accepted if measures of either the posterior wall or interventricular septum exceeded 11 mm. Statistical Analysis We used within-subject and between-group comparisons. The former used the differences between the mean frequency of s-MSNA and MSNA as obtained from the same recordings. The latter compared the levels of mean frequency of s-MSNA and MSNA between the matched groups, as expressed per 100 beats and per minute. Oneway ANOVA with Newman-Keuls post-test comparisons were used to compare s-MSNA, MSNA, and their differences between the seven groups. Values of P ⬍ .05 were considered statistically significant. Data are presented as mean ⫾ SEM.
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FIG. 2. Examples of recordings obtained from normal control (NT) subjects and those with borderline hypertension (BHT) to illustrate the difference between the mean frequency of s-MSNA obtained from the raw action potential (AP) and that of MSNA obtained from bursts of muscle sympathetic nerve activity (Bursts). ECG ⫽ electrocardiogram.
FIG. 1. s-MSNA and MSNA, quantified per 100 cardiac beats and per minute, for the seven groups. Compared with borderline hypertension (BHT), *P at least ⬍ .05. Compared with white-coat hypertension (WHT), †P at least ⬍ .05. Compared with normal pressure (NT), ‡P at least ⬍ .05. Compared with high–normal pressure (HN), §P at least ⬍ .05. Compared with essential hypertension stage 1 (EHT-1), ¶P at least ⬍ .05. Compared with EHT stages 2 and 3 (EHT 2/3), #P at least ⬍ .05.
Results The groups were matched (Table 1) for age, body weight, and body mass index (BMI), and there were no significant differences in the gender ratio (2 ⫽ 2.14; P ⫽ .9). Clinic indices of arterial pressure were significantly greater in established hypertension, BHT, and WHT than in the normotensive groups (at least P ⬍ .05), and did not differ between EHT-2/3 and EHT⫹LVH, or between WHT, BHT, and EHT-1 groups. The heart rate was insignificantly higher in WHT than in the other groups. The daytime ABP data (Table 2) in established hypertension were significantly (at least P ⬍ .05) greater than NT, HN, and WHT. There were no significant differences in ambulatory heart rate. As we previously reported in separate study populations,17,18 all measures of s-MSNA and MSNA in the established hypertensive groups (EHT-1, EHT-2/3, and EHT⫹LVH) were significantly greater than in NT and HN groups (Fig. 1). Also, s-MSNA hyperactivity was greater in EHT-1 than in EHT-2/3 despite similar levels of MSNA hyperactivity. In BHT and WHT all measures of sympathetic activity were significantly greater than in NT (Fig. 1). The sympathetic hyperactivity in BHT was similar to that in EHT-1, and significantly greater than in WHT. However,
although measures of s-MSNA hyperactivity were significantly greater in BHT than in EHT-2/3, those of MSNA hyperactivity were similar. Also, both measures of s-MSNA hyperactivity in BHT were similar to those in EHT⫹LVH, although the measures of MSNA hyperactivity were significantly greater in EHT⫹LVH. Within-subject analysis, as illustrated in example of recordings in Fig. 2, showed that both measures of sMSNA hyperactivity were greater than those of MSNA, particularly in BHT, EHT-1, and EHT⫹LVH (Fig. 1). Furthermore, the difference between s-MSNA and MSNA attained statistical significance (P ⬍ .05) in BHT (13.5 ⫾ 4.8 per 100 beats) and EHT-1 (15.8 ⫾ 3.7 per 100 beats), compared with NT (1.8 ⫾ 0.7 per 100 beats), HN (4.8 ⫾ 1.0 per 100 beats), WHT (4.6 ⫾ 1.1 per 100 beats), and EHT-2/3 (4.2 ⫾ 0.6 per 100 beats). The difference in EHT⫹LVH amounted to 9.8 ⫾ 3.9 per 100 beats.
Discussion The present investigation has for the first time shown that the increase in central sympathetic neural discharge to the periphery occurs to a greater extent in BHT, EHT-1, and EHT⫹LVH relative to EHT-2/3 and WHT. This is consistent with the theory that central sympathetic hyperactivity may be involved in the pathogenesis of EHT, that its persistence increases the likelihood of complication by LVH, and that in turn this may then modulate the sympathetic hyperactivity. The findings also provide an explanation for the relatively benign nature of WHT and suggest that patients with BHT may be at greater cardiovascular risk. Our findings involved between-group and within-subject comparisons. For the between-group comparisons, we avoided recognized confounding factors,10,17 which in-
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cluded environmental conditions, visceral distension,23,24 race,25 age,26 body weight, and BMI.27 Also, the heart rate was similar between the groups, although its average was slightly higher in WHT group as has previously been reported.3,5 To avoid the confounding effect of arterial pressure,12,15,17 our WHT groups were also matched for clinic arterial pressure with EHT-1 group, and the daytime and night-time ABP were similar in NT, HN, and WHT, and in EHT-2/3 and EHT⫹LVH. For within-subject comparisons, s-MSNA and MSNA frequencies were obtained from the same recordings of each subject during the steady state. Thus both frequencies were obtained within the same biological environment and as such avoided confounding factors that may affect the measurements differently. s-MSNA has been considered to represent a quantitative measure of central sympathetic discharge to the periphery, whereas MSNA represents overall sympathetic discharge relating to a number of different firing units and including new fiber recruitments arising from central or reflex effects.10,17,20 For the purpose of this study, and as proposed by other groups,28 the excessive increase in s-MSNA relative to that in MSNA obtained over the same period of time, was taken to indicate a predominant central sympathetic hyperactivity. On the other hand, a disproportionate increase in MSNA would infer the operation of peripheral reflex effects as well, thus resulting in the addition of newly recruited units. These considerations imply that our BHT and EHT-1 groups had greater central increase in sympathetic discharge relative to HN, WHT, and EHT-2/3 groups. The present findings in EHT with and without LVH have confirmed our previously published data in separate populations.17,18 However, the present study has also provided the novel evidence that sympathetic hyperactivity occurs in BHT. Previously reported data have not been consistent as to the presence,8,9 or absence1,29 of MSNA hyperactivity. We also found for the first time that sympathetic hyperactivity in BHT was as great in magnitude as that seen in EHT-1 and EHT⫹LVH, and was greater than in WHT. This confirmed our previous report indicating that WHT sympathetic hyperactivity was not as great as that in EHT,10 and showed that WHT sympathetic activity was closer in magnitude to values obtained in the HN group than in the EHT groups. It is also notable that applying the new JNC-730 or European Society of Hypertension31 guidelines to our data would not change the finding of sympathetic hyperactivity in EHT. In addition, as the category EHT-1 remains unchanged and because EHT-2 and EHT-3 have been combined in JNC-7 as is the case in this study, our findings still indicate that the magnitude of sympathetic nerve hyperactivity is greater in established mild EHT than in more severe EHT. The present findings have implications regarding the involvement of central sympathetic hyperactivity in the pathogenesis and progression of EHT.11–13 Thus the greater s-MSNA than MSNA hyperactivity in milder (BHT and EHT-1) and complicated hypertension
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(EHT⫹LVH) is consistent with the proposition that central sympathetic hyperactivity is usually encountered during the early stages of arterial pressure elevation. In some patients this sympathetic hyperactivity may persist to result in target organ damage, whereas in others with lesser sympathetic hyperactivity the arterial pressure may be maintained or increased by other mechanisms such as hormonal, reflex, and structural changes.11–13 Furthermore, changes in the operation of reflex systems may also occur as a result of complications of hypertension,32 leading to modulation of the sympathetic hyperactivity. In this respect, the greater increase in MSNA frequency in EHT⫹LVH may be considered to imply the occurrence of newly recruited nerve fibers as a result of reflex activation that may involve altered stimulation of ventricular or coronary receptors.33 Other implications involve potential cardiovascular risks in WHT and BHT. Despite similarities in their hemodynamic and metabolic profiles,5 the risk of target organ damage and progression to established EHT is reported to be considerable in BHT,2,5,6 but not consistently so in WHT.3 Our findings that sympathetic hyperactivity in WHT was similar to HN group and significantly less than that of BHT and EHT groups may help to explain the differing risk profiles in WHT and BHT, and also the mild nature of risk in WHT and the discrepancies in demonstrating it in the published literature.3,4 In conclusion, the present investigation has shown for first time that the magnitude of central sympathetic hyperactivity in BHT was similar to that in EHT-1 or EHT⫹LVH, but significantly greater than that seen in both WHT and EHT-2/3. These findings are consistent with the theory that central sympathetic hyperactivity may be involved in the pathogenesis of EHT, as it is seen in BHT and milder hypertension, and that its persistence increases the likelihood of development of LVH. Also, it may explain the smaller and inconsistent cardiovascular risk in WHT relative to BHT.
Acknowledgments We thank Jeff Bannister, BSc, and Julie Corrigan for technical assistance.
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Relationship Between Central Sympathetic Activity and Stages of Human Hypertension Paul A. Smith, Lee N. Graham, Alan F. Mackintosh, John B. Stoker, and David A. S. G. Mary Background: The magnitude of sympathetic hyperactivity in essential hypertension (EHT) varies with its severity and complications. There are no data on sympathetic nerve activity in borderline (BHT) or whitecoat hypertension (WHT) relative to the various stages of EHT, despite suggestions that both lead to established EHT and organ damage through sympathetic mechanisms. We planned to determine the magnitude of sympathetic nerve activity in patients with BHT and WHT in relation to normality and various stages of sustained EHT.
nerve activity as the mean frequency of multiunit discharge (MSNA) and that of single-units (s-MSNA).
Methods: We examined 90 untreated subjects comprising matched groups with BHT (n ⫽ 13), WHT (n ⫽ 12), Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure EHT stage 1 (EHT-1 n ⫽ 12), EHT stages 2 and 3 (EHT-2/3 n ⫽ 14), high–normal pressure (HN n ⫽ 14), and normal pressure (NT n ⫽ 13), as well as a group with EHT complicated by left ventricular hypertrophy (EHT⫹LVH n ⫽ 12). We quantified muscle sympathetic
Conclusions: Central sympathetic activity was greatest in BHT, early stage, and complicated EHT, and as such is likely to play an integral role in the development of hypertension and its complications. Sympathetic hyperactivity occurs in WHT, but to a lesser extent than in BHT. Am J Hypertens 2004;17:217–222 © 2004 American Journal of Hypertension, Ltd.
E
Results: We found a greater (at least P ⬍ .01) mean central sympathetic frequency in BHT (75 ⫾ 5.8 impulses/ 100 beats), EHT-1 (76 ⫾ 4.0 impulses/100 beats), and EHT⫹LVH (79 ⫾ 4.3 impulses/100 beats) than in EHT2/3 (57 ⫾ 3.1 impulses/100 beats), WHT (52 ⫾ 3.6 impulses/100 beats), HN (42 ⫾ 3.9 impulses/100 beats), and NT (33 ⫾ 3.6 impulses/100 beats). BHT hyperactivity was closer to that of EHT, whereas WHT was closer to NT.
Key Words: Sympathetic nervous system, hypertension, action potentials.
ssential hypertension (EHT) is a common condition and a major cardiovascular risk factor. Although EHT is characterized by an abnormal and sustained increase in arterial pressure in the absence of an identifiable cause, other intermittent forms of hypertension have also been described. For instance, the term borderline hypertension (BHT) has been used to reflect intermittent and mildly hypertensive levels of arterial pressure,1,2 and white coat hypertension (WHT) to indicate hypertensive values obtained only in the clinic setting.3,4 Both conditions have been reported to share some of the adverse outcomes of sustained EHT.2,4 –7 The pathogenesis of BHT and WHT and their modes of progression have not been fully established, although sympathetic hyperactivity has been suggested to play an important role,5,8 –10 as it does in essential hypertension.11–13
Direct and quantitative assessment of peripheral sympathetic nerve activity supplying the vessels of skeletal muscles (MSNA) by microneurography,14 has found MSNA hyperactivity relative to matched normal groups in the majority of published reports on EHT.15,16 More recently, the mean frequency of single units of efferent sympathetic nerve activity (s-MSNA) was found to be increased in uncomplicated EHT, and more markedly so in mild EHT than in more severe disease.17 An increase in both MSNA and s-MSNA has also been reported in WHT10 and in EHT with left ventricular hypertrophy (EHT⫹LVH).18 As yet, there are no data from adequately matched groups of subjects on the relative magnitude of sympathetic hyperactivity in BHT and WHT in comparison to the various stages of EHT. The present trial was planned to determine the relative
Received May 12, 2003. First decision July 24, 2003. Accepted October 21, 2003. From the Department of Cardiology, Leeds Teaching Hospitals, Leeds, United Kingdom. This work was funded by the British Heart Foundation (Grant No.
FS/2000068). Address correspondence and reprint requests to Dr. Paul A. Smith, Cardio-Respiratory Unit, St. James’s University Hospital, Beckett Street, Leeds LS9 7TF, United Kingdom; e-mail: paulsmith.leeds@ ukgateway.net
© 2004 by the American Journal of Hypertension, Ltd. Published by Elsevier Inc.
0895-7061/04/$30.00 doi:10.1016/j.amjhyper.2003.10.010
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Table 1. Clinic details of the seven study groups Variable
NT
HN
WHT
BHT
EHT-1
EHT-2/3 EHT ⴙ LVH
Number (female) 13 (7) 14 (8) 12 (6) 13 (8) 12 (6) 14 (5) 12 (6) Age (y) 45 ⫾ 3.5 46 ⫾ 3.0 46 ⫾ 3.9 48 ⫾ 3.7 47 ⫾ 3.1 46 ⫾ 3.0 48 ⫾ 3.0* Age range (y) 24–63 26–60 23–62 26–65 30–65 30–65 30–62 BMI (kg/m2) 27 ⫾ 0.8 27 ⫾ 0.8 29 ⫾ 0.9 28 ⫾ 1.3 29 ⫾ 0.9 28 ⫾ 1.3 28 ⫾ 1.0* Weight (kg) 78 ⫾ 2.2 77 ⫾ 3.7 80 ⫾ 2.2 79 ⫾ 4.1 80 ⫾ 2.9 80 ⫾ 2.5 80 ⫾ 3.7* Heart rate (beats/min) 68 ⫾ 3.2 69 ⫾ 2.6 74 ⫾ 2.2 69 ⫾ 2.6 66 ⫾ 2.7 69 ⫾ 3.1 63 ⫾ 2.2† Systolic BP (mm Hg) 126 ⫾ 1.6 132 ⫾ 1.2 150 ⫾ 1.7 144 ⫾ 1.9 151 ⫾ 1.2 171 ⫾ 3.6 176 ⫾ 5.0‡ Diastolic BP (mm Hg) 77 ⫾ 1.9 83 ⫾ 0.8 94 ⫾ 0.9 90 ⫾ 1.2 93 ⫾ 1.8 106 ⫾ 1.4 106 ⫾ 4.3‡ MAP (mm Hg) 93 ⫾ 1.8 99 ⫾ 0.9 113 ⫾ 0.9 108 ⫾ 1.3 112 ⫾ 1.2 128 ⫾ 1.7 129 ⫾ 4.3‡ BMI ⫽ body mass index; BP ⫽ blood pressure; MAP ⫽ mean arterial pressure. Data are mean ⫾ SEM. One-way ANOVA, * P ⬎ .5, † P ⬎ .05, ‡ P ⬍ .0001.
magnitude of central sympathetic vasoconstrictor nerve output to the peripheral vascular bed in BHT, WHT, and various grades of severity of EHT. For this purpose the technique of microneurography was used to quantify resting central sympathetic output in age- and body weightmatched groups of patients with uncomplicated EHT, WHT, and BHT, and also in EHT⫹LVH. Groups with normotension (NT) and high–normal arterial pressure (HN) were also studied for comparison.
Methods Subjects The study involved 100 newly diagnosed and untreated white subjects who were examined between 1999 and 2002. All patients were screened by history, physical, and laboratory examination. Patients were excluded if there was evidence of arrhythmia or chronic disease that may influence the autonomic nervous system. Similarly, patients with hypertension secondary to renal artery stenosis, pheochromocytoma, and primary hyperaldosteronism were excluded from the study. Ten subjects were excluded because of an inability to obtain stable microneurographic data. All subjects had similar occupational status (sedentary jobs) and dietary habits. The latter was used to deduce a sodium intake of approximately 400 mmol/d at entry into the study. Recruitment of all patients was intended for the present study and has not included any who were reported previously, except 5 patients with WHT.10 During each clinic visit, blood pressure (BP) was determined from the average of three readings taken in the seated position over a period of 30 min after at least 10 min of rest. Such BP measurements were repeated monthly and the average BP of at least three separate clinic visits was used to determine clinic BP status. The resulting arterial pressure was used to classify groups with established hypertension according to the Sixth Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-VI) criteria.19 Thus NT had systolic or diastolic pressures of ⬍130 and ⬍85 mm Hg, respectively, HN had
either systolic pressure of 130 to 139 mm Hg or diastolic pressure of 85 to 89 mm Hg, EHT-1 had systolic or diastolic pressure of 140 to 159 or 90 to 99 mm Hg, EHT-2/3 had respective values of ⱖ160 or ⱖ100 mm Hg. For the other groups, BHT was defined according to previously published research1,2,6,8 as arterial pressure intermittently more than 140/90 mm Hg on at least two separate occasions, whereas WHT was defined as sustained clinic arterial pressure of ⱖ140/90 mm Hg with a daytime ambulatory BP of ⬍130/80 mm Hg. Finally, the EHT⫹LVH group was defined according to electrocardiographic and echocardiographic criteria. All groups were matched for age and body mass index. We also matched WHT with EHT-1, and EHT-2/3 with EHT⫹LVH in respect of clinic arterial pressure. The proportion of subjects with a family history of hypertension was similar in each of the seven groups (5/13, 5/14, 6/12, 7/13, 5/12, 6/14, and 5/12). The number of subjects and clinic details of the seven groups are given in Table 1, and their ambulatory BP (ABP) data are shown in Table 2. Each subject provided informed written consent to the investigation, which was performed under the approval of the Leeds Health Authority Ethical Committee. Protocol All studies were performed under similar conditions between the hours of 9 AM and noon, and subjects were asked to have only a light breakfast and to empty their bladder before commencing the study.17 They were also asked to avoid nicotine and caffeine products for 12 h, and alcohol and strenuous exercise for 24 h before investigation. Subjects were studied in the semisupine position in a darkened laboratory in which the temperature was constant at 22° to 24°C. Arterial pressure was measured from the arm using a standard mercury sphygmomanometer. Changes in heart rate and arterial pressure were monitored and recorded using a standard electrocardiogram and a Finapres device (Finapres 2300; Ohmeda, Hatfield, United Kingdom), and blood flow to the muscle of the left calf was obtained using standard venous occlusion plethysmography. All measure-
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Table 2. Ambulatory details of the seven study groups Variable
NT
HN
WHT
BHT
EHT-1
EHT-2/3 EHT ⴙ LVH
Daytime SBP (mm Hg) 118 ⫾ 0.9 122 ⫾ 2.0 121 ⫾ 1.9 136 ⫾ 1.5 147 ⫾ 1.2 156 ⫾ 2.7 Daytime DBP (mm Hg) 74 ⫾ 1.5 76 ⫾ 1.5 74 ⫾ 1.0 83 ⫾ 0.7 89 ⫾ 1.7 101 ⫾ 2.6 Daytime MAP (mm Hg) 89 ⫾ 0.9 91 ⫾ 0.3 90 ⫾ 1.1 101 ⫾ 0.6 107 ⫾ 1.2 119 ⫾ 2.7 Daytime HR (beats/min) 75 ⫾ 4.0 81 ⫾ 0.3 83 ⫾ 2.0 80 ⫾ 2.8 82 ⫾ 1.4 81 ⫾ 4.6 Night-time SBP (mm Hg) 96 ⫾ 2.0 102 ⫾ 1.3 101 ⫾ 1.7 107 ⫾ 3.8 131 ⫾ 1.4 144 ⫾ 3.3 Night-time DBP (mm Hg) 63 ⫾ 2.8 68 ⫾ 1.7 66 ⫾ 1.2 69 ⫾ 2.9 80 ⫾ 1.7 85 ⫾ 4.7 Night-time MAP (mm Hg) 79 ⫾ 0.8 79 ⫾ 0.6 78 ⫾ 1.0 82 ⫾ 3.0 97 ⫾ 1.5 105 ⫾ 2.8 Night-time HR (beats/min) 70 ⫾ 4.9 69 ⫾ 1.9 69 ⫾ 1.6 66 ⫾ 3.0 74 ⫾ 2.7 67 ⫾ 3.9
158 99 119 81 142 84 103 70
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
8.2† 4.0† 5.2† 3.6* 9.3† 3.5† 6.8† 4.4*
SBP ⫽ systolic arterial pressure; DBP ⫽ diastolic arterial pressure; MAP ⫽ mean arterial pressure; HR ⫽ heart rate. Data are mean ⫾ SEM. One-way ANOVA, * P ⬎ .5, † P ⬍ .0001.
ments were obtained during the steady state after a rest period of at least 10 min duration. Microneurography Postganglionic muscle sympathetic nerve activity was recorded from the right peroneal nerve as previously described,14,17 without knowledge of the clinical characteristics of the subjects. Muscle sympathetic nerve activity was differentiated from skin activity by previously accepted criteria.14 The neural signal was amplified (⫻ 50,000) and was sampled at 12,000 samples/sec. Multiunit bursts were obtained after filtering (bandwidth of 700 to 2000 Hz), and integrating (time constant 0.1 sec), and alongside other data were digitized at 2000 samples/sec (8 bits). Single units (s-MSNA) with vasoconstrictor properties were obtained from the raw action potential neurogram by adjusting the electrode position and confirmed by consistent action potential morphology using on-line storage oscilloscope and fast monitor sweep.17,20 Their vasoconstrictor function was assessed by appropriate responses to spontaneous changes in arterial pressure, the Valsalva maneuver, and isometric hand-grip exercise. Measurement of calf vascular resistance confirmed the vasoconstrictor function of the observed neural activity. Data were obtained from 5-min recordings during the steady state at rest. Both s-MSNA and MSNA were counted from the same record and over the same period of time, hemodynamic, and respiratory variables. Spikes of s-MSNA were objectively counted using an electronic discriminator and were quantified as mean frequency of impulses per minute and per 100 cardiac beats to avoid interference by the length of the cardiac cycle.21 The bursts of MSNA were identified by inspection when the signal-to-noise ratio was greater than 3, and were quantified in a similar manner. The variability of measuring both s-MSNA and MSNA in this laboratory was similar and did not exceed 10%,17 and there were no systematic differences between the mean frequencies of two s-MSNA units obtained in the same recordings.
Other Procedures The ABP monitoring was performed independently using an oscillometric device (TRACKER NIBP2, Reynolds Medical Ltd., Hertford, United Kingdom). This device is known to satisfy the requirements of the Association for the Advancement of Medical Instrumentations (AAMI, Arlington, VA), with a difference from the reference auscultatory method of less than 5 ⫾ 8 mm Hg (mean ⫾ SD). Patients were asked to follow their ordinary daily activities and to go to bed not later than midnight. Measurements were taken at half-hour intervals during the daytime and every hour at night to avoid discomfort. This frequency has been assessed in Leeds by comparing it to measurements obtained every 15 min during the day, and every half-hour at night. The coefficient of variation (proportion of 1 SD to the mean measurement) for both systolic and diastolic pressure amounted to 6%. Electrocardiographic voltage criteria were used to identify subjects with suspected LVH, and standard two-dimensional M-mode echocardiography (Philips SONOS 5500, Philips Medical Systems, Andover, MA) was used to measure left ventricular dimensions. Using American Society of Echocardiography recommendations,22 LVH was accepted if measures of either the posterior wall or interventricular septum exceeded 11 mm. Statistical Analysis We used within-subject and between-group comparisons. The former used the differences between the mean frequency of s-MSNA and MSNA as obtained from the same recordings. The latter compared the levels of mean frequency of s-MSNA and MSNA between the matched groups, as expressed per 100 beats and per minute. Oneway ANOVA with Newman-Keuls post-test comparisons were used to compare s-MSNA, MSNA, and their differences between the seven groups. Values of P ⬍ .05 were considered statistically significant. Data are presented as mean ⫾ SEM.
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FIG. 2. Examples of recordings obtained from normal control (NT) subjects and those with borderline hypertension (BHT) to illustrate the difference between the mean frequency of s-MSNA obtained from the raw action potential (AP) and that of MSNA obtained from bursts of muscle sympathetic nerve activity (Bursts). ECG ⫽ electrocardiogram.
FIG. 1. s-MSNA and MSNA, quantified per 100 cardiac beats and per minute, for the seven groups. Compared with borderline hypertension (BHT), *P at least ⬍ .05. Compared with white-coat hypertension (WHT), †P at least ⬍ .05. Compared with normal pressure (NT), ‡P at least ⬍ .05. Compared with high–normal pressure (HN), §P at least ⬍ .05. Compared with essential hypertension stage 1 (EHT-1), ¶P at least ⬍ .05. Compared with EHT stages 2 and 3 (EHT 2/3), #P at least ⬍ .05.
Results The groups were matched (Table 1) for age, body weight, and body mass index (BMI), and there were no significant differences in the gender ratio (2 ⫽ 2.14; P ⫽ .9). Clinic indices of arterial pressure were significantly greater in established hypertension, BHT, and WHT than in the normotensive groups (at least P ⬍ .05), and did not differ between EHT-2/3 and EHT⫹LVH, or between WHT, BHT, and EHT-1 groups. The heart rate was insignificantly higher in WHT than in the other groups. The daytime ABP data (Table 2) in established hypertension were significantly (at least P ⬍ .05) greater than NT, HN, and WHT. There were no significant differences in ambulatory heart rate. As we previously reported in separate study populations,17,18 all measures of s-MSNA and MSNA in the established hypertensive groups (EHT-1, EHT-2/3, and EHT⫹LVH) were significantly greater than in NT and HN groups (Fig. 1). Also, s-MSNA hyperactivity was greater in EHT-1 than in EHT-2/3 despite similar levels of MSNA hyperactivity. In BHT and WHT all measures of sympathetic activity were significantly greater than in NT (Fig. 1). The sympathetic hyperactivity in BHT was similar to that in EHT-1, and significantly greater than in WHT. However,
although measures of s-MSNA hyperactivity were significantly greater in BHT than in EHT-2/3, those of MSNA hyperactivity were similar. Also, both measures of s-MSNA hyperactivity in BHT were similar to those in EHT⫹LVH, although the measures of MSNA hyperactivity were significantly greater in EHT⫹LVH. Within-subject analysis, as illustrated in example of recordings in Fig. 2, showed that both measures of sMSNA hyperactivity were greater than those of MSNA, particularly in BHT, EHT-1, and EHT⫹LVH (Fig. 1). Furthermore, the difference between s-MSNA and MSNA attained statistical significance (P ⬍ .05) in BHT (13.5 ⫾ 4.8 per 100 beats) and EHT-1 (15.8 ⫾ 3.7 per 100 beats), compared with NT (1.8 ⫾ 0.7 per 100 beats), HN (4.8 ⫾ 1.0 per 100 beats), WHT (4.6 ⫾ 1.1 per 100 beats), and EHT-2/3 (4.2 ⫾ 0.6 per 100 beats). The difference in EHT⫹LVH amounted to 9.8 ⫾ 3.9 per 100 beats.
Discussion The present investigation has for the first time shown that the increase in central sympathetic neural discharge to the periphery occurs to a greater extent in BHT, EHT-1, and EHT⫹LVH relative to EHT-2/3 and WHT. This is consistent with the theory that central sympathetic hyperactivity may be involved in the pathogenesis of EHT, that its persistence increases the likelihood of complication by LVH, and that in turn this may then modulate the sympathetic hyperactivity. The findings also provide an explanation for the relatively benign nature of WHT and suggest that patients with BHT may be at greater cardiovascular risk. Our findings involved between-group and within-subject comparisons. For the between-group comparisons, we avoided recognized confounding factors,10,17 which in-
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cluded environmental conditions, visceral distension,23,24 race,25 age,26 body weight, and BMI.27 Also, the heart rate was similar between the groups, although its average was slightly higher in WHT group as has previously been reported.3,5 To avoid the confounding effect of arterial pressure,12,15,17 our WHT groups were also matched for clinic arterial pressure with EHT-1 group, and the daytime and night-time ABP were similar in NT, HN, and WHT, and in EHT-2/3 and EHT⫹LVH. For within-subject comparisons, s-MSNA and MSNA frequencies were obtained from the same recordings of each subject during the steady state. Thus both frequencies were obtained within the same biological environment and as such avoided confounding factors that may affect the measurements differently. s-MSNA has been considered to represent a quantitative measure of central sympathetic discharge to the periphery, whereas MSNA represents overall sympathetic discharge relating to a number of different firing units and including new fiber recruitments arising from central or reflex effects.10,17,20 For the purpose of this study, and as proposed by other groups,28 the excessive increase in s-MSNA relative to that in MSNA obtained over the same period of time, was taken to indicate a predominant central sympathetic hyperactivity. On the other hand, a disproportionate increase in MSNA would infer the operation of peripheral reflex effects as well, thus resulting in the addition of newly recruited units. These considerations imply that our BHT and EHT-1 groups had greater central increase in sympathetic discharge relative to HN, WHT, and EHT-2/3 groups. The present findings in EHT with and without LVH have confirmed our previously published data in separate populations.17,18 However, the present study has also provided the novel evidence that sympathetic hyperactivity occurs in BHT. Previously reported data have not been consistent as to the presence,8,9 or absence1,29 of MSNA hyperactivity. We also found for the first time that sympathetic hyperactivity in BHT was as great in magnitude as that seen in EHT-1 and EHT⫹LVH, and was greater than in WHT. This confirmed our previous report indicating that WHT sympathetic hyperactivity was not as great as that in EHT,10 and showed that WHT sympathetic activity was closer in magnitude to values obtained in the HN group than in the EHT groups. It is also notable that applying the new JNC-730 or European Society of Hypertension31 guidelines to our data would not change the finding of sympathetic hyperactivity in EHT. In addition, as the category EHT-1 remains unchanged and because EHT-2 and EHT-3 have been combined in JNC-7 as is the case in this study, our findings still indicate that the magnitude of sympathetic nerve hyperactivity is greater in established mild EHT than in more severe EHT. The present findings have implications regarding the involvement of central sympathetic hyperactivity in the pathogenesis and progression of EHT.11–13 Thus the greater s-MSNA than MSNA hyperactivity in milder (BHT and EHT-1) and complicated hypertension
221
(EHT⫹LVH) is consistent with the proposition that central sympathetic hyperactivity is usually encountered during the early stages of arterial pressure elevation. In some patients this sympathetic hyperactivity may persist to result in target organ damage, whereas in others with lesser sympathetic hyperactivity the arterial pressure may be maintained or increased by other mechanisms such as hormonal, reflex, and structural changes.11–13 Furthermore, changes in the operation of reflex systems may also occur as a result of complications of hypertension,32 leading to modulation of the sympathetic hyperactivity. In this respect, the greater increase in MSNA frequency in EHT⫹LVH may be considered to imply the occurrence of newly recruited nerve fibers as a result of reflex activation that may involve altered stimulation of ventricular or coronary receptors.33 Other implications involve potential cardiovascular risks in WHT and BHT. Despite similarities in their hemodynamic and metabolic profiles,5 the risk of target organ damage and progression to established EHT is reported to be considerable in BHT,2,5,6 but not consistently so in WHT.3 Our findings that sympathetic hyperactivity in WHT was similar to HN group and significantly less than that of BHT and EHT groups may help to explain the differing risk profiles in WHT and BHT, and also the mild nature of risk in WHT and the discrepancies in demonstrating it in the published literature.3,4 In conclusion, the present investigation has shown for first time that the magnitude of central sympathetic hyperactivity in BHT was similar to that in EHT-1 or EHT⫹LVH, but significantly greater than that seen in both WHT and EHT-2/3. These findings are consistent with the theory that central sympathetic hyperactivity may be involved in the pathogenesis of EHT, as it is seen in BHT and milder hypertension, and that its persistence increases the likelihood of development of LVH. Also, it may explain the smaller and inconsistent cardiovascular risk in WHT relative to BHT.
Acknowledgments We thank Jeff Bannister, BSc, and Julie Corrigan for technical assistance.
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