E2 ModeratePreliminaryPEM not requiredObservationalPeer-reviewedReviewed
Amplified amplitudes of circadian rhythms and nighttime hypotension in patients with chronic fatigue syndrome: improvement by inopamil but not by melatonin.
van de Luit, L, van der Meulen, J, Cleophas, T J et al. · Angiology · 1998 · DOI
Quick Summary
This study found that people with ME/CFS have unusually large swings in heart rate and blood pressure throughout the day and night, even though the overall pattern matches healthy controls. Importantly, their nighttime blood pressure drops too low (below 100 mm Hg systolic), which may contribute to fatigue and other symptoms. When treated with a heart-strengthening medication called inopamil, nighttime blood pressure improved, but melatonin actually made it worse.
Why It Matters
This is one of the first quantitative characterizations of circadian rhythm abnormalities in ME/CFS, providing objective physiological evidence linking disturbed autonomic function to fatigue. The finding that nighttime hypotension may be correctable with specific medications offers a potential therapeutic target and suggests ME/CFS involves treatable cardiovascular regulation dysfunction.
Observed Findings
- CFS patients showed 2.8-fold amplified 12-hour heart rate rhythms compared to controls (p<0.001)
- CFS patients showed 2.8-fold and 9.0-fold amplified 24-hour systolic and diastolic blood pressure rhythms (p<0.001 and p<0.0001)
- CFS patients had consistently low nighttime systolic blood pressure (below 100 mm Hg)
- Inopamil treatment reduced nighttime hypotension in 4 treated patients (p<0.05)
- Melatonin treatment worsened nighttime hypotension in the same patients (p<0.02)
Inferred Conclusions
- ME/CFS involves pathologically amplified circadian oscillations in cardiovascular parameters despite preserved rhythm synchronization with healthy controls
- Nighttime hypotension is a characteristic cardiovascular feature of ME/CFS that may contribute to symptom burden
- Positive inotropic agents (inopamil) may beneficially stabilize nighttime blood pressure in ME/CFS, whereas melatonin supplementation may be counterproductive
Remaining Questions
- Do amplified circadian rhythms directly cause or contribute to fatigue, or are they a secondary marker of autonomic dysfunction?
- What is the optimal dosing and long-term safety of inopamil in ME/CFS patients, and does it improve fatigue or functional outcomes?
What This Study Does Not Prove
This study does not prove that amplified circadian rhythms cause ME/CFS fatigue, only that the association exists. The small 4-week pilot treatment trial cannot establish efficacy or optimal dosing of inopamil or definitively rule out melatonin, and open-label design means results are vulnerable to placebo effects. Causality between nighttime hypotension and symptoms remains unestablished.
Tags
Symptom:FatigueUnrefreshing Sleep
Biomarker:Blood Biomarker
Method Flag:No ControlsSmall SampleExploratory OnlyWeak Case Definition
Metadata
- DOI
- 10.1177/000331979804901105
- PMID
- 9822046
- Review status
- Editor reviewed
- Evidence level
- Single-study or moderate support from human research
- Last updated
- 12 April 2026
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
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