Low Blood Pressure in Down's Syndrome
A Link With Alzheimer's Disease?
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Abstract
Low blood pressure is reported in Down's syndrome (DS). To assess this and determine whether low pressure results from the disease or from long-term residence in hospital, we measured blood pressure with a random-zero sphygmomanometer in three groups of patients: 52 DS inpatients, 62 DS outpatients, and 60 outpatients with other forms of mental handicap. Relative to normal reference populations, blood pressure was low in both DS inpatients (systolic, score −33 mm Hg, P<.0001) and DS outpatients (−25 mm Hg, P<.0001). It was normal in non-DS outpatients (−4.0 mm Hg, P=.3). Blood pressure rose normally with age in the non-DS group but not in the DS group. We conclude that blood pressure is low in DS and that this is a feature of the disease rather than of the protected environment in which patients live. A mechanism related to trisomy 21 is likely, and there may be a link with Alzheimer's disease (AD) because blood pressure is also low in Alzheimer's and a high proportion of DS patients develop this disease. If, as is likely, blood pressure is lowered in Alzheimer's by the neuropathy, the same neuropathy developing early in DS may also reduce blood pressure.
There are reports of low BP in DS, lower than in other forms of mental handicap and lower than in a normal population.1 2 However, the patients in these studies were long-term hospital residents, which may itself lower BP. Psychiatric inpatients also have low BP that is not related to treatment or psychiatric diagnosis; it is not present on admission but appears gradually as a failure of BP to rise normally with age.3 Such failure is seen in patients with physical disease living in the long term in a hospital,4 in healthy women residing long-term in a nunnery,5 and in entire populations living in isolated circumstances.6
A study of BP in DS needs to be controlled for these effects. Such study is necessary because if low BP is a feature of DS, an inquiry on mechanisms will turn on the relation of arterial pressure and trisomy 21. There may be a link here with AD, a condition that often develops in DS7 and in some familial forms maps to chromosome 218 and also has low BP (see “Discussion”). Our plan was to determine whether BP is low in DS patients living in and out of the hospital and whether BP is low or normal in outpatients with other forms of mental handicap of similar degree.
Methods
Patients
BP was measured in 174 patients with mental handicap who were divided into three groups. Group A was 52 patients with DS (36 male), all long-term residents either in The Royal Scottish National Hospital for the Mentally Handicapped or in Merchiston Hospital. Group B included 62 patients with DS (35 male) living at home or in a hostel attending by day one of five ATCs where BP was measured. Group C was 60 patients (39 male) who did not have DS but had a mental handicap of similar degree; all lived at home or in a hostel attending by day the same ATCs as the patients in group B. The study began in 1983 with BP measured by one of the researchers (R.M.) in groups A and B; later measurements were by the same researcher and a second one (A.McG.). For assessment of changes with age, measurements were repeated 10 years later (by R.M.) in 22 group B patients. Clinical features of DS were present in every patient; chromosome analysis in 19 showed trisomy 21 in 18 patients and Robertsonian translocation in 1 [(46,XX,−14)+t(14q21q)]. Medical staff examined all patients; 1 with congenital heart disease was excluded. Three others with precordial systolic murmurs considered insignificant and pressures of 108/69, 108/58, and 109/77 mm Hg were included. There were no other exclusions. The study was a near-complete sample of all available cases.
Reference Populations
Comparison was made with four reference populations: (1) Subjects attending outpatient clinics of a London hospital; a conventional sphygmomanometer was used for BP measurement, and phase IV diastolic BP was recorded9 ; (2) the Renfrew/Paisley survey,10 11 a population study with diastolic BP (phase V) measured by a London School of Hygiene sphygmomanometer in Renfrew and a Hawksley RZS in Paisley; (3) Glasgow cohort studies, with measurements by RZS (phase V diastolic) in cohorts aged 15, 35, and 55 years12 ; and (4) the Scottish Heart Health Study,13 with an RZS used and phase V diastolic recorded. Because agreement between populations was reasonable (Fig 1⇓), the method of Hamilton et al14 was used for calculation of the deviation of a patient's BP from the reference populations (Table 1⇓). From this, a systolic BP score was derived14 that was adjusted for sex and corrected for age (to 60 years). The two hospitals, five ATCs, and two of the reference populations11 12 were within 20 miles of central Glasgow.
Blood Pressure in the Study Groups and Deviations From Reference Populations
Blood Pressure
Two researchers (R.M. and A.McG.) were trained to use the RZS by research sisters of the Medical Research Council (MRC) Blood Pressure Unit, one of whom (G.D.) also trained nurses measuring pressure in the cohort studies.12 Measurements by the two researchers agreed well when simultaneous recordings were made in the right and left arms of a series of patients.
All patients in this study had three BP measurements (phase V diastolic BP recorded), one on each of three occasions up to 2 weeks apart; the mean of these was used in analysis. Measurements were in the morning, with subjects seated, after 5 minutes of relaxation, and with the sphygmomanometer at heart level. For group A, measurements were made in the ward or occupational therapy department, and for groups B and C, in an ATC. The RZS used was serviced regularly. BP was also measured by ambulatory monitor (model 90207, SpaceLabs Inc) programmed to reduce pressure in steps of 4 mm Hg and to record hourly. Height and weight were measured in 57 DS patients (22 female).
Consent was obtained from patients, from the Superintendent for studies at The Royal Scottish National Hospital, from the Ethics Committee of The Royal Alexandra Hospital for studies at Merchiston Hospital, and from the Social Work Department for studies in ATCs. Consent was also obtained from next of kin or guardian or, in their absence, from the consultant in charge (inpatients) or from staff at the ATC. The form of the study was explained to all patients. Fewer than 20 patients refused, and none that participated experienced any ill effects.
Results
Reference Populations
BP increased with age in our four reference populations (Fig 1⇑). The regression for phase IV diastolic BP in the Hamilton data9 was not higher than that for phase V diastolic BP in the three other populations (Fig 1⇑); differences between populations were more marked for systolic BP in women (Fig 1⇑).
Group A: DS Inpatients
BP was low in long-term DS inpatients. Low systolic and diastolic BPs relative to reference populations were seen in both men and women (Figs 2 and 3⇓⇓, Table 1⇑). Systolic score was −32.8 mm Hg, significantly lower (P<.0001) by this amount than BP in the reference population after adjustment for age and sex (Table 2⇓).
Systolic Blood Pressure Scores
Group B: DS Outpatients
BP was also low in DS patients living outside the hospital (Figs 2 and 3⇑⇑, Table 1⇑); systolic score was −25.4 mm Hg, again a highly significant (P<.0001) downward deviation from the reference population (Table 2⇑). Scores were not significantly different in DS inpatients and outpatients (Table⇑s 1 and 2). The patient with translocation (see “Methods”) had a pressure of 97/47 mm Hg.
Ambulatory monitoring in five DS patients confirmed the low BP (daytime average, 105/63 mm Hg), which was similar to that recorded by the RZS (101/62 mm Hg) (Table 3⇓, Fig 4⇓). In four of these patients, BP decreased at night, but in the patient whose BP by day was lowest, BP did not decrease at night (Fig 4⇓).
Records of ambulatory BP from five DS inpatients. Mean daytime and nighttime BP values and comparison with daytime recording of BP in the same patients by RZS are shown in Table 3⇓.
Ambulatory Blood Pressure Monitoring in Five Patients With Down's Syndrome
Data in Figs 2 and 3⇑⇑ suggest a failure of BP to rise with age in DS patients; regressions were flatter than those of reference populations. This was confirmed by repeat measurements after 10 years in 22 DS patients. In these individuals, BP did not increase with time; the trend was for a decrease (Fig 5⇓). The downward deviation from control subjects increased significantly with time (P=.004, Fig 5⇓).
Changes of systolic and diastolic BP over 10 years in 22 subjects. Mean values (triangles) for systolic and diastolic BP in men and women were lower on the second occasion but not significantly so (paired t for systolic in men, 1.896; P=.08). Systolic BP score decreased significantly: +2.27 mm Hg at the first measurement and −17.73 mm Hg at the second (paired t, 3.24; P=.004).
Group C: Other Forms of Mental Handicap
A different picture emerged in patients with other forms of mental handicap living in the same semiprotected environment as DS outpatients (group B): Systolic and diastolic BPs and systolic BP score were higher than in DS patients and insignificantly different from values in the reference populations (Figs 2 and 3⇑⇑, Tables 1 and 2⇑⇑). Thus, in this semiprotected environment outside the hospital, DS patients showed subnormal pressure and no rise with age, and non-DS patients showed normal pressure and a normal rise with age.
High BP was more common in the non-DS patients, 5 of whom were diagnosed as hypertensive and were receiving hypotensive drugs. No DS patient was so diagnosed or treated. Of 60 non-DS patients, 19 had diastolic BP greater than 90 mm Hg; only 1 of 114 DS patients had a level this high (χ2=36.6, P<.001). One female DS patient with BP of 103/65 mm Hg was taking a diuretic for other reasons; 2 others with DS were taking drugs that might lower BP (lofepramine in one [BP 77/41 mm Hg] and thioridazine in the other [BP 92/52 mm Hg]). Values in 3 DS women taking oral contraceptives were 103/81, 109/75, and 83/53 mm Hg.
Relation of BP to Height and Weight
In DS men, weight related positively and significantly to systolic BP (r=.50, P<.01) and systolic score (r=.48, P<.01). Body mass index (weight [kilograms] divided by height [meters squared]) also related to systolic and diastolic BPs (r=.62 and r=.43, respectively; both P<.01). Height was not significantly related to BP or BP score. In women, numbers were smaller and correlations insignificant.
Discussion
Methodology and Artifacts
DS has high mortality, particularly in early life.15 Is BP low in DS because those individuals with highest pressure have the highest mortality, a selective effect favoring survival of patients with low pressure? Against this is the large reduction of mortality seen in adult DS patients in recent years15 and the rarity in DS of CHD,1 15 the most common cause of death in patients with highest pressure. Also, among DS patients who did survive, BP remained low and did not rise with age (Fig 5⇑).
BP was measured by the Hawksley RZS, which is less susceptible to observer bias than the conventional sphygmomanometer used in previous studies of DS.1 2 Although the RZS does underestimate BP,16 it does so by only between 1.0 and 3.8 mm Hg systolic.16 17 18 19 This is insufficient to explain the subnormality seen here in DS patients (Table 1⇑). Also, BP is not underestimated when all measurements are by the RZS, for example, when comparing DS and non-DS groups (Figs 2 and 3⇑⇑, Table 1⇑). Low BP was confirmed in DS patients with the use of ambulatory monitoring; ambulatory values were lower than BP values in a general population measured by the same technique.20
Is BP Lowered in DS by an Environmental Factor?
Low BP in DS patients living inside and outside the hospital suggests that a hospital environmental factor does not entirely explain this phenomenon in DS. Lower BP in DS than in non-DS patients, both living outside the hospital, further suggests that BP is not lowered in DS by an environmental factor acting outside the hospital. Together, data from our study and others2 3 4 suggest that although there are factors in the hospital environment that contribute to lower BP, these are not responsible for the low BP in DS. A mechanism related to trisomy 21 is more likely.
The cheerful disposition of DS patients, a well-recognized feature of trisomy 21, might contribute to lowering of BP, but we did not design our study to assess this. The similarity of BP values in the presence and absence of doctors (Table 3⇑) also raises the possibility of a diminished white coat pressor response (see Reference 21) in DS patients, but our observations here were in five patients only.
Cystathionine β-Synthase
Links are suggested in DS among low BP, low risk of CHD,1 and protection against CHD from increased cystathionine β-synthase.22 The gene for this enzyme is on chromosome 21, and increased enzyme levels have been reported22 but not by all researchers.23 The evidence linking arterial pressure with CHD and CHD with the enzyme is clear.24 The link between the enzyme and arterial pressure is less clear.
BP and Growth in Children
Mechanisms controlling growth in children may also influence arterial pressure later in adult life.25 Growth, particularly the increase in height, is retarded in DS children.26 Is BP lowered in DS adults by underactivity of a growth-promoting mechanism in childhood? Our data are not helpful here. Although arterial pressure was significantly related to weight and body mass index in DS patients, it was not significantly related to height. This correlation pattern is seen in a general population27 ; it is not special to DS.
Neuropathology of DS: A Link With AD?
It is more likely that BP is lowered in DS by the widespread neuropathy. This is apparent in fetal life and then later as a failure of growth and maturation in the brain, with loss of neurones28 29 and dendrites.30 Cholinergic nerves are particularly vulnerable.31 Reports of postural hypotension32 and the failure of heart rate and BP to rise normally with maximum exercise33 34 suggest autonomic failure in DS. Maximum exercise capacity is lower in patients with DS than in individuals with other forms of mental handicap.34
By 35 years of age, most DS patients additionally have pathological features of AD: atrophy of neurones, β-amyloid plaques and deposits, neurofibrillary tangles, and β-amyloid cerebral angiopathy.7 8 35 Although most of these lesions also occur in elderly nondemented control subjects, they are fewer in number at a given age.7 36 By the age of 45 years, almost half of DS patients have clinical manifestations of AD as well.15 These observations are relevant because low BP is also seen in AD (discussed below), and 46% of our DS patients were 35 years old or older.
AD and DS are also linked at the molecular level (see References 7, 8, 37, and 38). Some familial forms of AD map to chromosome 21, and closely related on the proximal part of its long arm is the gene coding for β-amyloid precursor protein. This and its product β-A4 protein are favored candidates for AD.7 37 38 Supporting this is the recent demonstration of AD neuropathy in transgenic mice bearing the mutant β-amyloid precursor protein gene of one of the familial forms of AD.39
Low BP in AD
BP is low in AD, lower than in elderly control subjects and lower than in other forms of dementia.40 41 42 43 Burke and colleagues42 reported serial measurements of BP in three patients with AD. In each, BP was falling at or before the time of diagnosis, and in one, the fall was marked. Although there is a resemblance here with serial measurements in DS (Fig 5⇑), we cannot say whether a decrease of BP in DS is an early manifestation of AD. There is considerable difficulty in diagnosing early AD in patients who already have DS and mental handicap.
Postural hypotension is also reported in AD and has sympathetic and cholinergic components.43 44 Neuropathological findings also point to cholinergic deficits in AD and DS.31 42 45 Another feature shared by the two diseases is the rarity of hypertension (present study and References 40 and 41) and of atherosclerosis and CHD.1 15 40 46 47
Nerve centers and neurotransmitters regulating arterial pressure (see Reference 48) are often affected in AD.42 A deficiency of glutamate or norepinephrine could impair synaptic transmission; a deficiency of γ-aminobutyric acid could enhance it.48 Lesions of AD are present in the C1 adrenergic system,42 a control center for the BP baroreflex.42 48 Other centers and transmitters affected are glutamate and norepinephrine in the hippocampus,38 49 γ-aminobutyric acid in the amygdala,38 acetylcholine in the caudate nucleus,31 and norepinephrine in the locus coeruleus.38 Although there is clear potential here for a net hypotensive effect, the balance of mechanisms producing it is not clear. Lesions of the C1 system are very likely to be involved.42
Could BP be lowered in DS by the same neuropathy? The AD neuropathy developing in DS is said to be indistinguishable from that developing in the common sporadic form of AD (see Reference 35). The important and probably primary β-amyloid lesion is already visible by a specific histochemical technique in DS children. Thereafter, the density of lesions increases to reach a plateau after 50 years of age.35 Interestingly, at this stage, the lesions are more conspicuous in DS than in sporadic AD.35 β-Amyloid precursor protein is also measurable in plasma, and here too the concentration is higher in DS than in AD.50 If neuropathy lowers BP in AD, the same neuropathy developing in DS, certainly earlier and probably to a greater degree, is likely to contribute to BP lowering here as well.
Regional Cerebral Perfusion Is Reduced in AD
A reduced regional cerebral perfusion is well recognized in AD. The technique usually used to measure it is single photon emission computed tomography.51 The reduction of perfusion is mainly in the temporoparietal cortex52 53 54 55 and hippocampus56 and matches in degree the deficit of cognition.53 54 The most widely favored interpretation (see References 42 and 52) is that neurone death reduces the oxygen requirement and blood flow falls to match demand. Normally, regional blood flow in the brain is closely coupled to local metabolic demand.57 In AD, cell death is seen to be produced by a mechanism other than underperfusion, for example, by a toxic effect of β-amyloid (see discussion above and Reference 58). Several workers have considered an additional process in which underperfusion contributes to neuropathology: an ischemic mechanism perhaps.59 60 For example, Englund and colleagues60 suggest that ischemia aggravated by low BP produces in white matter selective incomplete infarction, axon death, and demyelination. This is a different and less-specific neuropathy than the gray matter lesions of AD, but it often occurs in AD with the gray matter lesions.60 61
Low BP could contribute to underperfusion only if pressure fell below the level at which cerebral autoregulation is able to maintain flow by vasodilatation (see References 57 and 62). However, in this event, underperfusion would be generalized, and studies of cerebral perfusion52 53 54 55 56 show that this is not the case: The underperfusion in AD is localized mainly to temporoparietal and hippocampal regions. For low BP to contribute to underperfusion in these circumstances, local failure of autoregulation is needed as well. That this might be present in AD is suggested in one study52 showing a reduction of the vasodilator response to CO2 most marked in temporoparietal regions.
Thus, it is likely that neuropathy lowers BP in DS and AD and that the same β-amyloid neuropathy may lower BP in both disorders. A case has been made for underperfusion or low BP causing further (and different) neuropathy. More evidence is needed here.
In conclusion, BP is low in DS patients, equivalent at 60 years of age to a systolic BP 29 mm Hg lower than that in a general population. Long-term hospital residence, which can lower BP, is not responsible. More likely, a neuropathy affects BP control centers. BP is also low in AD, a condition frequently developing in DS. We suspect that the mechanism lowering BP is the same in both conditions.
Selected Abbreviations and Acronyms
AD | = | Alzheimer's disease |
ATC | = | Adult Training Centre |
BP | = | blood pressure |
CHD | = | coronary heart disease |
DS | = | Down's syndrome |
RZS | = | random-zero sphygmomanometer |
Acknowledgments
Prof A.F. Lever is supported by grants from the Medical Research Council (MRC G94/24751) and the British Heart Foundation (PG 94/117). We thank Ann Matheson for secretarial help and Randa Reid for the literature search.
- Received January 19, 1996.
- Revision received February 2, 1996.
- Accepted April 2, 1996.
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- Low Blood Pressure in Down's SyndromeRhona A. Morrison, Alice McGrath, Gillian Davidson, Jehoiada J. Brown, Gordon D. Murray and Anthony F. LeverHypertension. 1996;28:569-575, originally published October 1, 1996https://doi.org/10.1161/01.HYP.28.4.569
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