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To the Editor: Cholinesterase inhibitors (ChEIs), commonly prescribed to treat the symptoms of Alzheimer's disease (AD), have been associated with syncope and bradycardia.1 Because of their action on cholinergic neurotransmission within the autonomic nervous system, these drugs potentially have direct effects on cardiac rhythm and blood pressure (BP),2 but limited information is available on the hemodynamic effects of ChEIs in patients with AD, and the underlying cause of the reported syncopal incidents remains unknown.2 Recent technological developments make it possible to perform detailed measurements of systemic hemodynamics using noninvasive, nonobtrusive methods.3 The hypothesis that orthostatic intolerance causes ChEI-associated syncope in people with AD through altered autonomic control of heart rate and peripheral vascular resistance was tested.

METHODS

  1. Top of page
  2. METHODS
  3. RESULTS
  4. DISCUSSION
  5. ACKNOWLEDGMENTS
  6. REFERENCES

Twenty-one patients newly diagnosed with mild to moderate (Clinical Dementia Rating 0.5–2.0) probable AD according to the National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria were recruited from the memory clinic at Radboud University Nijmegen Medical Center, the Netherlands. After baseline measurement, people with AD started treatment with the ChEI galantamine (8 mg/d for 4 weeks, followed by 16 mg/d).4

Heart rate (HR) (three-lead electrocardiogram (ECG)) and BP (Finapres, Finapres Medical Systems, Amesterdam, the Netherlands) were continuously measured in people with AD and 20 aged-matched healthy controls. Recordings were performed during 5 minutes of sitting rest and during three repetitions of a single sit–stand maneuver (120 seconds sitting followed by 60 seconds standing), which is a valid proxy of standing up from supine and easier to perform in frail older subjects. In 20 patients, measurements were repeated after 10±4 weeks of treatment.

After alignment with the R peaks of the ECG, beat-to-beat mean, systolic, and diastolic values were calculated for BP. HR was calculated from the RR interval. The maximum absolute and percentage changes from standing to sitting were calculated for BP and HR.

Data are presented as means±standard deviations. Normal distribution was tested using Q-Q plots. Group comparisons were made using an independent-sample t-test; for comparisons of people with AD, a paired-sample t-test was used.

RESULTS

  1. Top of page
  2. METHODS
  3. RESULTS
  4. DISCUSSION
  5. ACKNOWLEDGMENTS
  6. REFERENCES

Baseline characteristics and hemodynamics are presented in Tables 1 and 2. Before treatment, HR and mean and diastolic BP were higher in people with AD. Galantamine treatment led to a reduction in mean and diastolic BP but not in HR.

Table 1. Baseline Characteristics in Healthy Controls and Patients with Alzheimer's Disease (AD)
VariableHealthy ControlsPeople with AD
  1. * p<.05. SD=standard deviation.

Baseline characteristic
Age, mean ± SD74.6 ± 2.772.9 ± .7
Male:female15: 59: 12
Body mass index, kg/m2, mean ± SD25.0 ± 2.624.5 ± 3.3
Mini-Mental State Examination, mean ± SD (range 0–30)29.2 ± 1.321.3 ± 4.6*
Cambridge Examination for Mental Disorders of the Elderly cognitive score (range 0–104)Not applicable67.4 ± 13.4
Antihypertensive use
 Diuretic35
 Angiotensin-converting enzyme inhibitor4
 Calcium-channel blocker2
 Beta-blocker27
 Angiotensin II antagonist1
Table 2. Systemic Hemodynamics in Healthy Controls and Patients with Alzheimer's Disease (AD) Before and After Treatment with Galantamine
HemodynamicsMean ± Standard Deviation
Healthy Controls n=20People with AD Before Treatment with Galantamine n=21People with AD Treated with Galantamine n=20
  1. P<.05 compared with * healthy controls , people with AD before treatment with galantamine. Assessed from 5 minutes of measurement during sitting rest.

Heart rate, beats per minute60.3 ± 7.669.5 ± 11.5*67.3 ± 13.0
Blood pressure, mmHg
 Mean77.2 ± 11.987.9 ± 18.8*79.3 ± 13.2
 Systolic120.1 ± 18.9133.8 ± 28.6124.0 ± 22.9
 Diastolic56.2 ± 10.765.6 ± 16.1*58.9 ± 11.7

The sit–stand maneuvers induced a decrease in BP within 20 seconds after standing in all subjects (known as initial orthostatic hypotension). One person with AD was excluded, because baseline BP variability was so strong that it obscured the hemodynamic effect of the sit–stand maneuver. The drop in mean BP (before galantamine) was significantly smaller in people with AD (12.3±6.2 mmHg) than in controls (16.9±8.2 mmHg, P=.02; relative change: AD 15.2±8.1%, control 20.0±10.1%, P=.06). Galantamine did not influence this orthostatic BP response (BP drop after treatment 12.7±7.0 mmHg, P=.72 compared with baseline). The orthostatic HR response was identical in controls (10.5±4.7 bpm) and people with AD (pretreatment 8.9±7.9 bpm, posttreatment 10.7±5.2 bpm, all P>.20) (Table 2).

DISCUSSION

  1. Top of page
  2. METHODS
  3. RESULTS
  4. DISCUSSION
  5. ACKNOWLEDGMENTS
  6. REFERENCES

It was unexpectedly found that orthostatic tolerance was preserved, if not enhanced, in AD. Enhanced sympathetic tone may explain this, given the high BP and HR at baseline in AD. Galantamine lowered resting BP but did not affect orthostatic tolerance or HR. This suggests that negative effects of ChEIs on autonomic control of BP and HR do not mediate the reported greater incidence of syncope in people with AD treated with galantamine.1

ACKNOWLEDGMENTS

  1. Top of page
  2. METHODS
  3. RESULTS
  4. DISCUSSION
  5. ACKNOWLEDGMENTS
  6. REFERENCES

Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper.

JC receives grant support from Internationale Stichting Alzheimer Onderzoek (ISAO; Grant 05516) and the Dutch Heart Foundation, has been a paid speaker for Novartis (producer of the ChEI rivastigmine) and Jansen-Cilag (a subsidiary of Johnson, distributer of galantamine), and is on a data safety management board for GSK. MOR has received unrestricted research grants from Novartis and Jansen-Cilag.

Authors Contributions: van Beek: study design, data collection, data analysis, drafted manuscript. Sijbesma: data collection, data analysis, revised manuscript. Marcel G. M. Olde Rikkert: subject recruitment, revised manuscript. Jurgen A. H. R. Claassen: study design, subject recruitment, supervised experiments, data interpretation, revised manuscript.

Sponsor's Role: Not applicable.

REFERENCES

  1. Top of page
  2. METHODS
  3. RESULTS
  4. DISCUSSION
  5. ACKNOWLEDGMENTS
  6. REFERENCES
  • 1
    Gill SS, Anderson GM, Fischer HD et al. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: A population-based cohort study. Arch Intern Med 2009;169:867873.
  • 2
    Claassen JA, van Beek AH, Olde Rikkert MG. Short review: Acetylcholinesterase-inhibitors in Alzheimer's disease have opposing effects on blood pressure and cerebral perfusion. J Nutr Health Aging 2009;13:231233.
  • 3
    van Beek AH, Claassen JA, Rikkert MG et al. Cerebral autoregulation: An overview of current concepts and methodology with special focus on the elderly. J Cereb Blood Flow Metab 2008;28:10711085.
  • 4
    Qaseem A, Snow V, Cross JT Jr et al. Current pharmacologic treatment of dementia: A clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med 2008;148:370378.