Sex-related cardiometabolic differences in ME/CFS patients, 2025, Hofmann, Sepúlveda, Westermeier+

[SNT Gatchaman]

Sex-related cardiometabolic differences in ME/CFS patients

Spoiler: Authors

Hofmann; Jeremic; León; Pipper-Krampl; Pfurtscheller; Seifert; Bertinat; Becerra; Sepúlveda; Westermeier

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, debilitating, and multisystem disease that affects more females than males. Core symptoms include persistent fatigue, post-exertional malaise (PEM), unrefreshing sleep, cognitive dysfunction, and orthostatic intolerance. Although the underlying mechanisms are not fully understood, cardiovascular and metabolic imbalances are commonly reported alterations associated with the condition. However, sex-based approaches to better understand these pathophysiological features have received limited attention.

To address this gap, we investigated potential sex-related cardiometabolic differences in female (n = 70) and male (n = 25) ME/CFS patients, compared to healthy controls (female, n = 27; male, n = 18).

Univariate analysis revealed that female patients exhibited higher heart rates during both sitting and standing, but lower pulse pressure index, stroke volume, and stroke volume index during standing, compared to healthy controls. In contrast, male patients showed elevated diastolic blood pressure (BP) in both positions, along with increased mean arterial BP while standing. Circulating levels of advanced oxidation protein products (AOPP), a marker of oxidative stress, were elevated exclusively in male ME/CFS patients, while no differences were observed in females compared to their respective healthy controls. Correlation and multivariate analyses complemented and supported the observed sex-related differences in cardiometabolic parameters, particularly during standing.

In conclusion, our sex-based analysis showing cardiometabolic differences in ME/CFS patients—particularly during standing—may contribute to future research focused on improving patient stratification and developing more tailored clinical management strategies.

HIGHLIGHTS
• In ME/CFS patients, cardiovascular differences are more pronounced during standing in both sexes.

• Male ME/CFS patients show higher levels of AOPP, a marker of oxidative stress, compared to females.

• Cardiometabolic differences related to sex and posture may support clinical stratification in ME/CFS.

Web | Heliyon | Open Access

 

[SNT Gatchaman]

ME/CFS patients were evaluated clinically according to the 1994 Fukuda criteria and/or the 2003 Canadian Consensus Criteria, as previously described. The female cohort included 97 individuals, divided into healthy controls (n = 27; 28 %) and ME/CFS patients (n = 70; 72 %). The male cohort included 43 individuals, divided into healthy controls (n = 18; 42 %) and ME/CFS patients (n = 25; 58 %).

Clinical data provided by the UKMEB included cardiovascular parameters measured during sitting and standing (after 1 min in an upright position), such as heart rate, systolic and diastolic BP. From these primary measures, additional parameters were derived using established formulas: Pulse pressure = systolic BP – diastolic BP; Pulse pressure index = systolic BP/pulse pressure; Mean arterial BP = diastolic BP + 1/3 × pulse pressure. Estimated cardiac output was calculated using the Liljestrand and Zander formula as: Cardiac output = pulse pressure/(systolic BP + diastolic BP) × heart rate [23]. To improve accuracy, adjusted cardiac output ( EST/ADJ ) was derivedEST by applying the calibration factor (K) as described by Pfurtscheller et al. [14,15]: Cardiac output EST/ADJ = K × (pulse pressure/(systolic BP + diastolic BP) × heart rate). Body surface area was calculated using the Burton formula [24] and cardiac index was defined as: Cardiac index = Cardiac output EST/ADJ /body surface area. Stroke volume and stroke volume index were calculated as: Stroke volume = Cardiac output EST/ADJ /heart rate; Stroke volume index = Stroke volume/body surface area.

PP = SBP - DBP

COest = PP / (SBP + DBP) x HR

-> COest = (SBP - DBP) / (SBP + DBP) x HR

COest/adj = K x (SBP - DBP) / (SBP + DBP) x HR

SV = COest/adj / HR

nulling out HR
-> SVest/adj = K x (SBP - DBP) / (SBP + DBP)


The references for the 'K' adjustments are —

[14] Cardiac output calculation using the Liljestrand and Zander formula: is this method applicable during immediate transition after birth? — A post hoc analysis (2024)

[15] Cardiac output and regional-cerebral-oxygen-saturation in preterm neonates during immediate postnatal transition: An observational study (2023)

which are looking at neonates transitioning from fetal circulation to self-supported circulation.

I haven't read these papers or the discussion in this paper yet but I can't imagine the adjustment factor would apply directly in adults. Note though that those papers share co-authors with this paper.

 

[Hutan]

My set point on sex differences in biometric measures relevant to ME/CFS is skepticism. I haven't read the paper yet, but what we have seen so far isn't moving me from that.

Clinical data provided by the UKMEB included cardiovascular parameters measured during sitting and standing (after 1 min in an upright position), such as heart rate, systolic and diastolic BP.

I know from the times when I have tracked cardiovascular measure that my results varied a lot. At times my pulse pressure could be normal, at other times it was very abnormal. Measures of heart rate and blood pressure varied a lot from day to day and within a day. I don't know how many measurements the UK ME Biobank made, but I doubt that a series of measurements were made of one individual.

I suspect that there could be all sorts of confounders (body size, time of waking, time of sample, age, fitness). It's really hard to remove that confounding, but I think you'd probably want to do continuous data collection over a period of a week. Single measurements are hopeless.

 

[Simon M]

I'm not sure the relatively small sample size can support such detailed conclusions. I believe there's a rule of thumb in statistical modelling that you need 10 times as many cases as parameters. I'm not sure how many "cases" we have in this experiment, given that it's looking at male versus female and healthy versus ME/CFS , but even looking at the total individuals, we'd only have enough less to support than half the parameters used in the study.

Maybe I have that wrong, but the study doesn't look right to me.

 

[hotblack]

I know from the times when I have tracked cardiovascular measure that my results varied a lot. At times my pulse pressure could be normal, at other times it was very abnormal. Measures of heart rate and blood pressure varied a lot from day to day and within a day.

Same. I have a lot of v unpleasant cardiovascular symptoms when bad. And have tried HR, BP and HRV to monitor. There’s something here I’m sure, but am not sure of the reliability of these measurements to demonstrate the relationship or of his methodology or the estimation formulas used.

I don't know how many measurements the UK ME Biobank made, but I doubt that a series of measurements were made of one individual

They do longitudinal measures if that’s what you mean? In the same way they do for blood samples. But there is variation so some people have one measurement others 2 or 3 or more IIRC. So there may be a series of measurements for an individual. However I’m not sure how much that tells us given possible confounding factors as you mention. There could be very different conditions and we know just being assessed modifies HR/BP.

 

[SNT Gatchaman]

the study doesn't look right to me.

Apart from the small sample size you noted the orthostatic challenge was just one minute.

cardiovascular measurements in this study were obtained after 1 min of standing, in accordance with UKMEB protocols. While informative, this short duration may not capture delayed orthostatic responses detectable in longer assessments