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Cerebral hemodynamics in young hypertensive subjects and effects of atenolol treatment
Journal of the Neurological Sciences 159 (1998) 115–119
Cerebral hemodynamics in young hypertensive subjects and effects of atenolol treatment Elio Troisi a , Antonio Attanasio b , Maria Matteis a , Maura Bragoni a , Bruno C. Monaldo c , a ,c a ,c , Carlo Caltagirone , Mauro Silvestrini * b
a IRCCS ‘ S. Lucia’, Rome, Italy Department of Internal Medicine, ‘ Tor Vergata’ University of Rome, 00144 Rome, Italy c Neurological Clinic, ‘ Tor Vergata’ University of Rome, 00144 Rome, Italy
Received 5 February 1998; received in revised form 30 March 1998; accepted 6 April 1998
Abstract The aim of this study was to evaluate changes in cerebral hemodynamics in young patients with uncomplicated hypertension before and after effective antihypertensive treatment with a beta-blocker drug. Changes in mean flow velocity in the middle cerebral artery from normal condition to hypercapnia were evaluated by means of a transcranial Doppler in 42 hypertensive patients and 21 healthy subjects comparable for age and sex distribution. We obtained hypercapnia with breath-holding and evaluated cerebrovascular reactivity with the breath-holding index (BHI). After a baseline evaluation (time 0), patients were randomly assigned to a placebo (group 1) or atenolol (group 2) therapy. The evaluation was repeated after 30 (time 1) and 60 (time 2) days of treatment. Before treatment, hypertensive patients had significantly lower BHI values (0.9660.1 group 1 and 0.8560.3 group 2) than controls (1.6960.4) (P,0.0001). During treatment, mean blood pressure significantly decreased in group 2 patients. In the same group, BHI values significantly increased with respect to the pre-treatment evaluation: 1.3960.2 at time 1 and 1.4460.2 at time 2 (P,0.0001). On the contrary, mean blood pressure and BHI values remained unchanged in the placebo group. Furthermore, BHI values were significantly higher in group 2 than in group 1 patients at times 1 (P,0.001) and 2 (P,0.0001). These findings suggest that hypertension causes reduced capability of cerebral vessels to adapt to functional changes. This condition, which is reversible after treatment, could be implicated in the increased susceptibility to ischemic stroke in hypertension. 1998 Published by Elsevier Science B.V. All rights reserved. Keywords: Transcranial Doppler ultrasonography; Hypertension; Cerebral blood flow; Cerebrovascular reactivity; Antihypertensive therapy
1. Introduction Many investigations have shown a close correlation between hypertension and vascular diseases [3,9]. In chronic hypertensive patients, atherosclerosis and complex alterations in the arteries and arterioles develop progressively [10]. The involvement of cerebral vessels in these pathological changes is believed to be directly responsible for increased susceptibility to ischemic stroke. In addition to anatomical changes, hypertension causes *Corresponding author. Tel.: 139 6 5914436; fax: 139 6 5922086.
marked adaptive changes in cerebral circulation. Cerebrovascular resistance is elevated to maintain a resting cerebral blood flow (CBF) of the same magnitude as that in normotensive subjects [22]. Moreover, it is recognized that in individuals with chronic hypertension, the CBF autoregulation curve is shifted to the right compared with that of normotensive individuals [19,22]. This hemodynamic status causes a decrease in the capability of cerebral vessels to respond with further adaptive modifications to local and systemic situations requiring rapid changes in brain perfusion. Thus, susceptibility to cerebral ischemia is increased in hypertensive patients [24]. This unfavourable
0022-510X / 98 / $19.00 1998 Published by Elsevier Science B.V. All rights reserved. PII: S0022-510X( 98 )00147-6
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E. Troisi et al. / Journal of the Neurological Sciences 159 (1998) 115 – 119
condition seems to be, at least in part, reversible. In fact, there is both clinical and experimental evidence that longstanding and effective treatment of hypertension is associated with a strong reduction in the risk of cerebrovascular disease [3,6]. The responses of cerebral blood flow to changes in the partial carbon-dioxide (CO 2 ) arterial pressure may be useful in the evaluation of hypertensive cerebral involvement. Cerebrovascular reactivity to hypercapnia can be easily explored with transcranial Doppler ultrasonography (TCD) [16,21]. Previous studies have shown an association between reduced cerebrovascular reactivity and conditions of increased risk of ischemic stroke [28,21]. In this study, we aimed to test the cerebrovascular reactivity in young adult hypertensive patients before and after pharmacological treatment with a beta-blocker drug.
2. Materials and methods After giving informed consent, 42 young early-stage essential hypertensive patients (19 men, 23 women, mean age6SD: 3467) selected from consecutive subjects examined in the cardiology outpatient service of S. Eugenio University Hospital, from September 1996 to August 1997, participated in the study. Patients with secondary hypertension or diabetes mellitus were excluded. All included patients had mild-to-moderate essential hypertension. They belonged to stage I or II of the World Health Organization classification and showed no concurrent illness, including respiratory tract disorders. No patients were undergoing antihypertensive treatment. Cerebrovascular diseases were excluded by taking a careful history, neurological examination and brain CT. Extracranial and transcranial Doppler showed no sign of carotid and intracranial stenosis. Table 1 shows the mean values for arterial acid–base
parameters, hemoglobin concentration, hematocrit and serum chemistries on admission. The study was performed at 8 a.m. All subjects had abstained from alcohol and caffeine-containing beverages for at least 10 h prior to the study. Assumption of any kind of drugs in the week preceding the study and in the interval between different examinations was considered an exclusion criterion. Right middle cerebral artery (MCA) mean flow velocity (MFV) was continuously monitored by means of a Multi-Dop X / TCD transcranial Doppler instrument (DWL Elektronische Systeme GmbH, Esaote Biomedica). One dual 2 MHz transducer fitted on a headband and placed on the temporal bone window was used to obtain a continuous measurement. Vascular reactivity was examined by calculating the breath-holding index (BHI). This index is obtained by dividing the percent increase in MFV occurring during breath-holding by the length of time (s) subjects hold their breath after a normal inspiration [15]. The study was carried out in a quiet room with subjects lying in a comfortable supine position without any visual or auditory stimulation. The MFV at rest was obtained by continuous recording of a 1 min period of normal room air breathing. After a breathholding period of 30 s, the MFV over 4 s was recorded. The efficacy of the breath-holding was checked by means of a respiratory activity monitor (Normocap-oxy, Datex). Mean blood pressure (MBP) and heart rate (HR) were continuously monitored by means of a blood pressure monitor (2300 Finapress, Ohmeda). Twenty-one healthy normotensive subjects, comparable for age and sex, served as the control group. All subjects involved in the study were right-handed [18]. After randomization balanced for age and sex, patients were divided into two equal groups: group 1 took one tablet of placebo daily and group 2 one tablet of atenolol 50 mg daily for a two-month period. Evaluation of vascular reactivity was repeated after 30 and 60 days (times 1 and 2) of treatment. All recordings were
Table 1 Blood chemistries and blood gas parameters in control group and in two groups of hypertensive patients (treatment with placebo or atenolol)
Blood chemistries (mg / dl) Blood sugar Triglyceride Total cholesterol Creatinine Hematocrit (%) Hemoglobin concentration (g / dl) Arterial acid–base parameters Pa CO 2 (mm / Hg) Pa O 2 (mm / Hg) pH Standard deviations are reported in parentheses.
Normotensive subjects (n521)
Hypertensive patients with placebo (n521)
Hypertensive patients with atenolol (n521)
83 (12) 143 (23) 189 (21) 0.9 (0.2) 43.1 (5.3)
89 (22) 132 (12) 176 (31) 0.8 (0.1) 41.2 (3.4)
82 (13) 139 (25) 197 (15) 1.0 (0.3) 42.5 (4.5)
14.1 (1.5)
13.3 (1.1)
13.7 (0.9)
41.2 (3.1) 76.3 (6.9) 7.41 (0.02)
40.1 (2.7) 78.9 (5.9) 7.42 (0.03)
41.1 (3.0) 78.7 (7.1) 7.42 (0.02)
E. Troisi et al. / Journal of the Neurological Sciences 159 (1998) 115 – 119 Table 2 Values of mean blood pressure (MBP), heart rate (HR), mean flow velocity (MFV) and breath-holding index (BHI) in controls and in hypertensive patients before treatment with placebo (group 1) or atenolol 50 mg daily (group 2)
Patients Group 1 Group 2 Controls
MBP
HR
MFV
BHI
102.2 (7.4) 103.1 (5.0) 85.5 (5.4)
70.7 (10.0) 70.6 (6.9) 71.4 (5.9)
61.2 (8.2) 59.9 (10.1) 58.1 (7.0)
0.96 (0.1) 0.85 (0.3) 1.69 (0.4)
Standard deviations are reported in parentheses.
made by two examiners, who were blind regarding the subjects’ clinical status and pharmacological treatment. The study was approved by the local ethics committee. The MBP, HR, MFV and BHI values at baseline in controls and patients were compared using a one-way ANOVA with group (controls, group 1 and group 2 patients) as the between-subject factor. The possible changes induced by pharmacological treatment were evaluated by means of a two-way ANOVA (dependent factors: MBP, HR, MFV and BHI values) with Group (group 1 and group 2 patients) as the between factor and Time (baseline, times 1 and 2) as the within factor.
117
3. Results Baseline mean values of MBP, HR, MFV and BHI in controls and in patients are shown in Table 2. The group effect was significant for MBP (F578.9, P,0.0001 with 2 and 60 df) and BHI (F558.7, P,0.0001 with 2 and 61 df). A post-hoc comparison (Scheffe’s test) revealed that MBP values were significantly lower in controls than in group 1 and group 2 patients (P,0.0001); BHI values were significantly higher in controls than in group 1 and group 2 patients (P,0.0001). There was no significant difference between the two groups of patients for any of the three variables. No significant difference in HR and MFV was found among the three groups. Fig. 1 shows the mean values of BHI, MBP, HR, and MFV in the two groups of patients at baseline and after 30 and 60 days of treatment with placebo or atenolol. Regarding BHI, the group effect was significant (F5 25.1, P,0.0001 with 1 and 40 df) because considering all three values, the mean BHI value was higher in group 2 than in group 1 (1.22 versus 0.93). The time effect was significant (F542.3, P,0.0001 with 2 and 80 df). In fact, considering both groups of patients, BHI significantly changed, passing from the baseline (0.9) to time 1 (1.19)
Fig. 1. Mean values of mean blood pressure (MBP), breath-holding index (BHI), heart rate (HR) and mean flow velocity (MFV) in the right middle cerebral artery at baseline, and at 30 (time 1) and 60 (time 2) days of treatment with placebo (group 1) or atenolol (group 2).
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to time 2 (1.15). Finally, the group X time interaction was significant (F558.1, P,0.0001 with 2 and 80 df). In fact, while the BHI values remained substantially unchanged in group 1, in group 2 the values significantly increased after treatment. The post-hoc analysis (Sheffe’s test) showed that in group 2, BHI values were significantly lower at baseline than at times 1 and 2 (P,0.0001). There was no difference between times 1 and 2. On the contrary, in group 1 no comparisons were significant. Furthermore, BHI values were significantly higher in group 2 than in group 1 patients at times 1 and 2 (P,0.0001). Regarding the other variables considered, the group X time interactions were significant for MBP (F578.1, P, 0.0001 with 2 and 80 df) and HR (F521.2, P,0.0001 with 2 and 80 df). The group X time interaction was not significant for MFV. A post-hoc comparison (Sheffe’s test) showed that the mean values of each variable significantly decreased passing from baseline to time 1 (MBP: P, 0.0001; HR: P,0.0001), 2 (MBP: P,0.0001; HR: P, 0.0001) only in patients treated with atenolol. No difference was observed between times 1 and 2. On the contrary, placebo treatment did not produce any significant changes in MBP, MFV or HR. Also for these variables, there was a significant difference between group 1 and group 2 patients at times 1 (MBP: P50.004; HR: P,0.0001) and 2 (MBP: P,0.0001; HR: P,0.0001).
4. Discussion The aim of antihypertensive treatment is to prevent target organ damage. Hypertensive cerebral involvement should be evaluated before a cerebrovascular accident occurs. Our findings demonstrate that marked changes in cerebral hemodynamics are present in young hypertensive patients with presumed early-stage hypertension. In fact, cerebrovascular reactivity to hypercapnia, reflecting the functioning of the small arteries and arterioles, was decreased in the hypertensive patients compared to the normotensive subjects. Experimental studies have suggested that hypertension reduces the distensibility of arterioles [2]. Impaired functioning of small arteries could attenuate cerebrovascular responses to dilator stimuli, such as autoregulatory expansion of vascular bed during hypercapnia. Other studies have suggested that adequate antihypertensive therapy may normalize impaired cerebral blood flow autoregulation in the early stages of chronic hypertension [12]. Since hypertension seems to be the most powerful risk factor for stroke in young more than in old subjects [4], it is possible to hypothesize that adaptive hemodynamic changes to maintain adequate brain perfusion in an unfavourable systemic condition, such as arterial hypertension, may predispose to ischemic damage. Our finding of reduced reactivity to hypercapnia in hypertensive patients associated with values of resting MFV similar
to that of normal subjects suggests the presence of normal cerebral hemodynamics in basal conditions probably sustained by functional vascular changes; these in turn could be responsible for reduced possibility of further adaptive modifications in response to stimulation like hypercapnia. Controversies about cerebral hemodynamics in hypertension emerge from various investigations. In fact, CO 2 reactivity in hypertensive humans has been variously reported to be impaired [27] or preserved [26]. Moreover, studies employing different CBF assessment techniques in hypertensive patients have described opposite findings. Aizawa et al. [1] found higher CBF in hypertensive than in normal subjects. On the other hand, a reduction of CBF in hypertension has been described repeatedly [6,17,20]. This may be due to methodological differences such as the fact that in some cases patients did not stop taking antihypertensive agents or hypertensive patients had different degrees of atherosclerosis or microvascular hypertensive diseases. Regarding TCD studies, both increased and normal flow velocity has been reported in the cerebral arteries [5,14,25]. Also in this case, differences in the selection of patients may have influenced the results. In fact, one of these studies [25] in which cerebral hemodynamics were compared in young early-stage and chronic hypertensive subjects showed a different pattern of cerebral artery flow velocity and pulsatility suggesting a different degree of vascular functional and anatomical changes between early and late stages of hypertension. Our results suggest the presence of a hemodynamic alteration and, in particular, a reduction in the capability of intracranial vessels to correctly respond to stimulation that in normal conditions promotes vasodilatation. This situation can be explained by decreased cerebrovascular reserve and less effectiveness of cerebral circulation to respond to systemic and local changes. In this respect, our findings seem to correlate well with the recent demonstration that in hypertension, the oxygen extraction fraction is increased [17]. In fact, previous studies have shown the contribution of decreased CO 2 vascular responses to the presence of an elevated regional oxygen extraction fraction [7,8,11]. This compensatory increase in oxygen use may protect the brain against circulatory dysfunction but at the same time it reduces the possibility of any further adaptation. An important aspect of our investigation is that after effective antihypertensive treatment, cerebrovascular reactivity to hypercapnia became comparable to that of normotensive subjects. Moreover, we found that the favourable effect of the beta-blocker drug on cerebral hemodynamics was strictly associated with changes in blood pressure. In fact, the increase in cerebrovascular reactivity had the same time course as the decrease in MBP. These effects were already evident after one month of treatment; they further improved at the second evaluation performed 60 days after the beginning of therapy. These facts can also be interpreted as suggesting the importance of hemodynamic factors in the occurrence of stroke. In fact, the
E. Troisi et al. / Journal of the Neurological Sciences 159 (1998) 115 – 119
reversibility of the predisposition to stroke in hypertension after treatment can be more convincingly related to a modification of hemodynamic than of structural factors such as atherosclerotic lesions. In a recent study, Lemne et al. [13] showed that vascular structural changes occurring in hypertensive patients seem to be related more to general associated atherosclerotic risk factors than to blood pressure alone. In this regard, no other vascular risk factor was present in our patients except for hypertension. The peculiarity of the hemodynamic changes in the brain may also be involved in the effectiveness of antihypertensive treatment in the prevention of brain but not heart ischemic problems [23]. Further studies on larger number of patients are needed to confirm the clinical utility of TCD in hypertension and, in particular, in the evaluation of the extent of cerebrovascular impairment and of the effectiveness of pharmacological therapy.
References [1] Aizawa T, Tazaki Y, Gotoh F. Cerebral circulation in cerebrovascular diseases. World Neurol 1961;2:635–45. [2] Baumbach GL, Heistad DD. Cerebral circulation in chronic arterial hypertension. Hypertension 1988;12:89–95. [3] Chobanian AV. Vascular effects of systemic hypertension. Am J Cardiol 1992;69:3E–7E. [4] Curb JD, Abbott RD, MacLean CJ, Rodriguez BL, Burchfiel CM, Sharp DS, Webster Ross G, Yano K. Age-related changes in stroke risk in men with hypertension and normal blood pressure. Stroke 1996;27:819–24. [5] Ferrara LA, Mancini M, Iannuzzi R, Marotta T, Gaeta I, Pasanisi F, Postiglione A, Guida L. Carotid diameter and blood flow velocities in cerebral circulation in hypertensive patients. Stroke 1995;26:418– 21. [6] Fujii K, Weno BL, Baumbach GL, Heistad DD. Effects of antihypertensive treatment on focal cerebral infarction. Hypertension 1992;19:713–6. [7] Herold S, Brown MM, Frackowiak RSJ, Mansfield AO, Thomas DJ, Marshal J. Assessment of cerebral hemodynamic reserve: correlation between PET parameters and CO 2 reactivity measured by intravenous 133-xenon injection technique. J Neurol Neurosurg Psychiat 1988;51:1045–50. [8] Hirano T, Minematsu K, Hasegawa Y, Tanaka Y, Hayashida K, Yamaguchi T. Acetazolamide reactivity on 123 I-IMP-single photon emission computed tomography in patients with major cerebral artery occlusive disease: correlation with positron emission tomography parameters. J Cereb Blood Flow Metab 1994;14:763–70. [9] Jerntorp P, Berglund G. Stroke registry in Malmoe, Sweden. Stroke 1992;23:357–61. [10] Jones JV, Fitch W, MacKenzie ET. Lower limit of cerebral blood flow autoregulation in experimental renovascular hypertension in the baboon. Circ Res 1976;39:555–7.
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[11] Kanno I, Uemura K, Higano S, Murakami M, Iida H, Miura S, Shishido F, Inugami A, Sayama I. Oxygen extraction fraction at maximally vasodilated tissue in the ischemic brain estimated from the regional CO 2 responsiveness measured by positron emission tomography. J Cereb Blood Flow Metab 1988;8:227–35. [12] Kuriyama Y, Sawada T, Omae T. Antihypertensive drugs and cerebral circulation. In: Omae T, Zanchetti A, editors. How should elderly hypertensive patients be treated? Tokyo: Springer–Verlag, 1989:69–81. [13] Lemne C, Jogestrand T, de Faire U. Carotid intima-media thickness and plaque in borderline hypertension. Stroke 1995;26:34–9. [14] Malatino LS, Bellofiore S, Costa MP, Lo Manto G, Finocchiaro F, Di Maria GU. Cerebral blood flow velocity after hyperventilationinduced vasoconstriction in hypertensive patients. Stroke 1992;23:1728–32. [15] Markus HS, Harrison MJG. Estimation of cerebrovascular reactivity using transcranial Doppler, including the use of breath-holding as the vasodilatory stimulus. Stroke 1992;23:668–73. [16] Markwalder TM, Grolimund P, Seiler RW, Roth F, Aaslid R. Dependency of blood flow velocity in the middle cerebral artery on end-tidal carbon dioxide partial pressure. J Cereb Blood Flow Metab 1984;4:368–72. [17] Nakane H, Ibayashi S, Fujii K, Irie K, Sadoshima S, Fujishima M. Cerebral blood flow and metabolism in hypertensive patients with cerebral infarction. Angiology 1995;46:801–10. [18] Oldfield RC. The assessment and analysis of handedness: the Edinburgh Inventory. Neuropsychologia 1971;9:97–113. [19] Paulson OB, Strandgaard S, Edvinsson L. Cerebral autoregulation. Cerebrovasc Brain Metab Rev 1990;2:161–92. [20] Rodriguez G, Arvigo F, Marenco S, Nobili F, Romano P, Sandini G, Rosadini G. Regional cerebral blood flow in essential hypertension: data evaluation by mapping system. Stroke 1987;18:13–20. [21] Silvestrini M, Troisi E, Matteis M, Cupini LM, Caltagirone C. Transcranial Doppler assessment of cerebrovascular reactivity in symptomatic and asymptomatic severe carotid stenosis. Stroke 1996;27:1970–3. [22] Strandgaard S, Olesen J, Skinhoj E, Lassen A. Autoregulation of brain circulation in severe hypertension. Br Med J 1973;1:507–10. [23] Strandgaard S, Paulson OB. Cerebrovascular consequences of hypertension. Lancet 1994;344:519–21. [24] Strandgaard S, Paulson OB. Cerebrovascular damage in hypertension. J Cardiovasc Risk 1995;2:34–9. [25] Sugimori H, Ibayashi S, Irie K, Ooboshi H, Nagao T, Fujii K, Sadoshima S, Fujishima M. Cerebral hemodynamics in hypertensive patients compared with normotensive volunteers. A transcranial Doppler study. Stroke 1994;25:1384–9. [26] Tominaga S, Strandgaard S, Uemura K, Ito K, Kutsuzawa T, Lassen NA. Cerebrovascular CO 2 reactivity in normotensive and hypertensive man. Stroke 1976;7:507–10. [27] Yamamoto M, Meyer JS, Sakai F, Yamaguchi F. Aging and cerebral vasodilatator responses to hypercarbia-responses in normal aging and in persons with risk factors for stroke. Arch Neurol 1980;37:489–96. [28] Yonas H, Smith HA, Durham SR, Pentheny SL, Johnson DW. Increased stroke risk predicted by compromised cerebral blood flow reactivity. J Neurosurg 1993;79:483–9.
Cerebral hemodynamics in young hypertensive subjects and effects of atenolol treatment Elio Troisi a , Antonio Attanasio b , Maria Matteis a , Maura Bragoni a , Bruno C. Monaldo c , a ,c a ,c , Carlo Caltagirone , Mauro Silvestrini * b
a IRCCS ‘ S. Lucia’, Rome, Italy Department of Internal Medicine, ‘ Tor Vergata’ University of Rome, 00144 Rome, Italy c Neurological Clinic, ‘ Tor Vergata’ University of Rome, 00144 Rome, Italy
Received 5 February 1998; received in revised form 30 March 1998; accepted 6 April 1998
Abstract The aim of this study was to evaluate changes in cerebral hemodynamics in young patients with uncomplicated hypertension before and after effective antihypertensive treatment with a beta-blocker drug. Changes in mean flow velocity in the middle cerebral artery from normal condition to hypercapnia were evaluated by means of a transcranial Doppler in 42 hypertensive patients and 21 healthy subjects comparable for age and sex distribution. We obtained hypercapnia with breath-holding and evaluated cerebrovascular reactivity with the breath-holding index (BHI). After a baseline evaluation (time 0), patients were randomly assigned to a placebo (group 1) or atenolol (group 2) therapy. The evaluation was repeated after 30 (time 1) and 60 (time 2) days of treatment. Before treatment, hypertensive patients had significantly lower BHI values (0.9660.1 group 1 and 0.8560.3 group 2) than controls (1.6960.4) (P,0.0001). During treatment, mean blood pressure significantly decreased in group 2 patients. In the same group, BHI values significantly increased with respect to the pre-treatment evaluation: 1.3960.2 at time 1 and 1.4460.2 at time 2 (P,0.0001). On the contrary, mean blood pressure and BHI values remained unchanged in the placebo group. Furthermore, BHI values were significantly higher in group 2 than in group 1 patients at times 1 (P,0.001) and 2 (P,0.0001). These findings suggest that hypertension causes reduced capability of cerebral vessels to adapt to functional changes. This condition, which is reversible after treatment, could be implicated in the increased susceptibility to ischemic stroke in hypertension. 1998 Published by Elsevier Science B.V. All rights reserved. Keywords: Transcranial Doppler ultrasonography; Hypertension; Cerebral blood flow; Cerebrovascular reactivity; Antihypertensive therapy
1. Introduction Many investigations have shown a close correlation between hypertension and vascular diseases [3,9]. In chronic hypertensive patients, atherosclerosis and complex alterations in the arteries and arterioles develop progressively [10]. The involvement of cerebral vessels in these pathological changes is believed to be directly responsible for increased susceptibility to ischemic stroke. In addition to anatomical changes, hypertension causes *Corresponding author. Tel.: 139 6 5914436; fax: 139 6 5922086.
marked adaptive changes in cerebral circulation. Cerebrovascular resistance is elevated to maintain a resting cerebral blood flow (CBF) of the same magnitude as that in normotensive subjects [22]. Moreover, it is recognized that in individuals with chronic hypertension, the CBF autoregulation curve is shifted to the right compared with that of normotensive individuals [19,22]. This hemodynamic status causes a decrease in the capability of cerebral vessels to respond with further adaptive modifications to local and systemic situations requiring rapid changes in brain perfusion. Thus, susceptibility to cerebral ischemia is increased in hypertensive patients [24]. This unfavourable
0022-510X / 98 / $19.00 1998 Published by Elsevier Science B.V. All rights reserved. PII: S0022-510X( 98 )00147-6
116
E. Troisi et al. / Journal of the Neurological Sciences 159 (1998) 115 – 119
condition seems to be, at least in part, reversible. In fact, there is both clinical and experimental evidence that longstanding and effective treatment of hypertension is associated with a strong reduction in the risk of cerebrovascular disease [3,6]. The responses of cerebral blood flow to changes in the partial carbon-dioxide (CO 2 ) arterial pressure may be useful in the evaluation of hypertensive cerebral involvement. Cerebrovascular reactivity to hypercapnia can be easily explored with transcranial Doppler ultrasonography (TCD) [16,21]. Previous studies have shown an association between reduced cerebrovascular reactivity and conditions of increased risk of ischemic stroke [28,21]. In this study, we aimed to test the cerebrovascular reactivity in young adult hypertensive patients before and after pharmacological treatment with a beta-blocker drug.
2. Materials and methods After giving informed consent, 42 young early-stage essential hypertensive patients (19 men, 23 women, mean age6SD: 3467) selected from consecutive subjects examined in the cardiology outpatient service of S. Eugenio University Hospital, from September 1996 to August 1997, participated in the study. Patients with secondary hypertension or diabetes mellitus were excluded. All included patients had mild-to-moderate essential hypertension. They belonged to stage I or II of the World Health Organization classification and showed no concurrent illness, including respiratory tract disorders. No patients were undergoing antihypertensive treatment. Cerebrovascular diseases were excluded by taking a careful history, neurological examination and brain CT. Extracranial and transcranial Doppler showed no sign of carotid and intracranial stenosis. Table 1 shows the mean values for arterial acid–base
parameters, hemoglobin concentration, hematocrit and serum chemistries on admission. The study was performed at 8 a.m. All subjects had abstained from alcohol and caffeine-containing beverages for at least 10 h prior to the study. Assumption of any kind of drugs in the week preceding the study and in the interval between different examinations was considered an exclusion criterion. Right middle cerebral artery (MCA) mean flow velocity (MFV) was continuously monitored by means of a Multi-Dop X / TCD transcranial Doppler instrument (DWL Elektronische Systeme GmbH, Esaote Biomedica). One dual 2 MHz transducer fitted on a headband and placed on the temporal bone window was used to obtain a continuous measurement. Vascular reactivity was examined by calculating the breath-holding index (BHI). This index is obtained by dividing the percent increase in MFV occurring during breath-holding by the length of time (s) subjects hold their breath after a normal inspiration [15]. The study was carried out in a quiet room with subjects lying in a comfortable supine position without any visual or auditory stimulation. The MFV at rest was obtained by continuous recording of a 1 min period of normal room air breathing. After a breathholding period of 30 s, the MFV over 4 s was recorded. The efficacy of the breath-holding was checked by means of a respiratory activity monitor (Normocap-oxy, Datex). Mean blood pressure (MBP) and heart rate (HR) were continuously monitored by means of a blood pressure monitor (2300 Finapress, Ohmeda). Twenty-one healthy normotensive subjects, comparable for age and sex, served as the control group. All subjects involved in the study were right-handed [18]. After randomization balanced for age and sex, patients were divided into two equal groups: group 1 took one tablet of placebo daily and group 2 one tablet of atenolol 50 mg daily for a two-month period. Evaluation of vascular reactivity was repeated after 30 and 60 days (times 1 and 2) of treatment. All recordings were
Table 1 Blood chemistries and blood gas parameters in control group and in two groups of hypertensive patients (treatment with placebo or atenolol)
Blood chemistries (mg / dl) Blood sugar Triglyceride Total cholesterol Creatinine Hematocrit (%) Hemoglobin concentration (g / dl) Arterial acid–base parameters Pa CO 2 (mm / Hg) Pa O 2 (mm / Hg) pH Standard deviations are reported in parentheses.
Normotensive subjects (n521)
Hypertensive patients with placebo (n521)
Hypertensive patients with atenolol (n521)
83 (12) 143 (23) 189 (21) 0.9 (0.2) 43.1 (5.3)
89 (22) 132 (12) 176 (31) 0.8 (0.1) 41.2 (3.4)
82 (13) 139 (25) 197 (15) 1.0 (0.3) 42.5 (4.5)
14.1 (1.5)
13.3 (1.1)
13.7 (0.9)
41.2 (3.1) 76.3 (6.9) 7.41 (0.02)
40.1 (2.7) 78.9 (5.9) 7.42 (0.03)
41.1 (3.0) 78.7 (7.1) 7.42 (0.02)
E. Troisi et al. / Journal of the Neurological Sciences 159 (1998) 115 – 119 Table 2 Values of mean blood pressure (MBP), heart rate (HR), mean flow velocity (MFV) and breath-holding index (BHI) in controls and in hypertensive patients before treatment with placebo (group 1) or atenolol 50 mg daily (group 2)
Patients Group 1 Group 2 Controls
MBP
HR
MFV
BHI
102.2 (7.4) 103.1 (5.0) 85.5 (5.4)
70.7 (10.0) 70.6 (6.9) 71.4 (5.9)
61.2 (8.2) 59.9 (10.1) 58.1 (7.0)
0.96 (0.1) 0.85 (0.3) 1.69 (0.4)
Standard deviations are reported in parentheses.
made by two examiners, who were blind regarding the subjects’ clinical status and pharmacological treatment. The study was approved by the local ethics committee. The MBP, HR, MFV and BHI values at baseline in controls and patients were compared using a one-way ANOVA with group (controls, group 1 and group 2 patients) as the between-subject factor. The possible changes induced by pharmacological treatment were evaluated by means of a two-way ANOVA (dependent factors: MBP, HR, MFV and BHI values) with Group (group 1 and group 2 patients) as the between factor and Time (baseline, times 1 and 2) as the within factor.
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3. Results Baseline mean values of MBP, HR, MFV and BHI in controls and in patients are shown in Table 2. The group effect was significant for MBP (F578.9, P,0.0001 with 2 and 60 df) and BHI (F558.7, P,0.0001 with 2 and 61 df). A post-hoc comparison (Scheffe’s test) revealed that MBP values were significantly lower in controls than in group 1 and group 2 patients (P,0.0001); BHI values were significantly higher in controls than in group 1 and group 2 patients (P,0.0001). There was no significant difference between the two groups of patients for any of the three variables. No significant difference in HR and MFV was found among the three groups. Fig. 1 shows the mean values of BHI, MBP, HR, and MFV in the two groups of patients at baseline and after 30 and 60 days of treatment with placebo or atenolol. Regarding BHI, the group effect was significant (F5 25.1, P,0.0001 with 1 and 40 df) because considering all three values, the mean BHI value was higher in group 2 than in group 1 (1.22 versus 0.93). The time effect was significant (F542.3, P,0.0001 with 2 and 80 df). In fact, considering both groups of patients, BHI significantly changed, passing from the baseline (0.9) to time 1 (1.19)
Fig. 1. Mean values of mean blood pressure (MBP), breath-holding index (BHI), heart rate (HR) and mean flow velocity (MFV) in the right middle cerebral artery at baseline, and at 30 (time 1) and 60 (time 2) days of treatment with placebo (group 1) or atenolol (group 2).
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to time 2 (1.15). Finally, the group X time interaction was significant (F558.1, P,0.0001 with 2 and 80 df). In fact, while the BHI values remained substantially unchanged in group 1, in group 2 the values significantly increased after treatment. The post-hoc analysis (Sheffe’s test) showed that in group 2, BHI values were significantly lower at baseline than at times 1 and 2 (P,0.0001). There was no difference between times 1 and 2. On the contrary, in group 1 no comparisons were significant. Furthermore, BHI values were significantly higher in group 2 than in group 1 patients at times 1 and 2 (P,0.0001). Regarding the other variables considered, the group X time interactions were significant for MBP (F578.1, P, 0.0001 with 2 and 80 df) and HR (F521.2, P,0.0001 with 2 and 80 df). The group X time interaction was not significant for MFV. A post-hoc comparison (Sheffe’s test) showed that the mean values of each variable significantly decreased passing from baseline to time 1 (MBP: P, 0.0001; HR: P,0.0001), 2 (MBP: P,0.0001; HR: P, 0.0001) only in patients treated with atenolol. No difference was observed between times 1 and 2. On the contrary, placebo treatment did not produce any significant changes in MBP, MFV or HR. Also for these variables, there was a significant difference between group 1 and group 2 patients at times 1 (MBP: P50.004; HR: P,0.0001) and 2 (MBP: P,0.0001; HR: P,0.0001).
4. Discussion The aim of antihypertensive treatment is to prevent target organ damage. Hypertensive cerebral involvement should be evaluated before a cerebrovascular accident occurs. Our findings demonstrate that marked changes in cerebral hemodynamics are present in young hypertensive patients with presumed early-stage hypertension. In fact, cerebrovascular reactivity to hypercapnia, reflecting the functioning of the small arteries and arterioles, was decreased in the hypertensive patients compared to the normotensive subjects. Experimental studies have suggested that hypertension reduces the distensibility of arterioles [2]. Impaired functioning of small arteries could attenuate cerebrovascular responses to dilator stimuli, such as autoregulatory expansion of vascular bed during hypercapnia. Other studies have suggested that adequate antihypertensive therapy may normalize impaired cerebral blood flow autoregulation in the early stages of chronic hypertension [12]. Since hypertension seems to be the most powerful risk factor for stroke in young more than in old subjects [4], it is possible to hypothesize that adaptive hemodynamic changes to maintain adequate brain perfusion in an unfavourable systemic condition, such as arterial hypertension, may predispose to ischemic damage. Our finding of reduced reactivity to hypercapnia in hypertensive patients associated with values of resting MFV similar
to that of normal subjects suggests the presence of normal cerebral hemodynamics in basal conditions probably sustained by functional vascular changes; these in turn could be responsible for reduced possibility of further adaptive modifications in response to stimulation like hypercapnia. Controversies about cerebral hemodynamics in hypertension emerge from various investigations. In fact, CO 2 reactivity in hypertensive humans has been variously reported to be impaired [27] or preserved [26]. Moreover, studies employing different CBF assessment techniques in hypertensive patients have described opposite findings. Aizawa et al. [1] found higher CBF in hypertensive than in normal subjects. On the other hand, a reduction of CBF in hypertension has been described repeatedly [6,17,20]. This may be due to methodological differences such as the fact that in some cases patients did not stop taking antihypertensive agents or hypertensive patients had different degrees of atherosclerosis or microvascular hypertensive diseases. Regarding TCD studies, both increased and normal flow velocity has been reported in the cerebral arteries [5,14,25]. Also in this case, differences in the selection of patients may have influenced the results. In fact, one of these studies [25] in which cerebral hemodynamics were compared in young early-stage and chronic hypertensive subjects showed a different pattern of cerebral artery flow velocity and pulsatility suggesting a different degree of vascular functional and anatomical changes between early and late stages of hypertension. Our results suggest the presence of a hemodynamic alteration and, in particular, a reduction in the capability of intracranial vessels to correctly respond to stimulation that in normal conditions promotes vasodilatation. This situation can be explained by decreased cerebrovascular reserve and less effectiveness of cerebral circulation to respond to systemic and local changes. In this respect, our findings seem to correlate well with the recent demonstration that in hypertension, the oxygen extraction fraction is increased [17]. In fact, previous studies have shown the contribution of decreased CO 2 vascular responses to the presence of an elevated regional oxygen extraction fraction [7,8,11]. This compensatory increase in oxygen use may protect the brain against circulatory dysfunction but at the same time it reduces the possibility of any further adaptation. An important aspect of our investigation is that after effective antihypertensive treatment, cerebrovascular reactivity to hypercapnia became comparable to that of normotensive subjects. Moreover, we found that the favourable effect of the beta-blocker drug on cerebral hemodynamics was strictly associated with changes in blood pressure. In fact, the increase in cerebrovascular reactivity had the same time course as the decrease in MBP. These effects were already evident after one month of treatment; they further improved at the second evaluation performed 60 days after the beginning of therapy. These facts can also be interpreted as suggesting the importance of hemodynamic factors in the occurrence of stroke. In fact, the
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reversibility of the predisposition to stroke in hypertension after treatment can be more convincingly related to a modification of hemodynamic than of structural factors such as atherosclerotic lesions. In a recent study, Lemne et al. [13] showed that vascular structural changes occurring in hypertensive patients seem to be related more to general associated atherosclerotic risk factors than to blood pressure alone. In this regard, no other vascular risk factor was present in our patients except for hypertension. The peculiarity of the hemodynamic changes in the brain may also be involved in the effectiveness of antihypertensive treatment in the prevention of brain but not heart ischemic problems [23]. Further studies on larger number of patients are needed to confirm the clinical utility of TCD in hypertension and, in particular, in the evaluation of the extent of cerebrovascular impairment and of the effectiveness of pharmacological therapy.
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