Hemodynamic Phenotyping in ME/CFS and ANOCA: Complementary Insights from Coronary Function Testing and [iCPET], 2026, Mackay+

[SNT Gatchaman]

Hemodynamic Phenotyping in ME/CFS and ANOCA: Complementary Insights from Coronary Function Testing and Invasive Cardiopulmonary Exercise Testing
Zoë Mackay; Samit Shah; Jose Gomez Villalobos; Nida Latif; Adith Arun; Phillip Joseph; Paul Heerdt; Inderjit Singh

This single-center cohort study sought to evaluate the association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and Angina with Non-Obstructive Coronary Arteries (ANOCA), by determining the observed frequency of ME/CFS among patients with ANOCA diagnosed by coronary function testing (CFT). Additionally, we performed an exploratory analysis of the diagnostic utility of invasive cardiopulmonary exercise testing (iCPET) in ME/CFS patients with CFT-confirmed ANOCA, with the aim of identifying the predominant physiological mechanism responsible for exertional limitation in this population.

Systematic medical record review of 261 patients with CFT-confirmed ANOCA was performed using standardized diagnostic criteria to identify concurrent ME/CFS diagnosis.

ME/CFS was identified in 47 patients, representing an observed frequency of 18%. The only statistically significant difference between ANOCA patients with and without ME/CFS was a higher frequency of connective tissue disease in the ME/CFS group (p = 0.0221). In a separate cohort of 27 patients with ME/CFS who underwent iCPET, 24 patients (89%) had CFT-confirmed ANOCA. The diagnosis of ANOCA by CFT prompted a change in medical management in 81% of patients in this cohort.

iCPET revealed a primary peripheral limitation to exercise, characterized by impaired peak systemic oxygen extraction despite normal peak oxygen delivery. This study demonstrates a clinically significant association between ME/CFS and ANOCA.

These findings underscore the clinical value of CFT in patients with ME/CFS and exertional chest pain and highlight iCPET as a complementary tool for hemodynamic phenotyping in this population. Prospective studies incorporating simultaneous CFT and iCPET with molecular phenotyping are warranted.

Web | DOI | PDF | American Journal of Physiology-Heart and Circulatory Physiology | Open Access

 

[Hutan]

ME/CFS was identified in 47 patients, representing an observed frequency of 18%.

That seems extraordinary.

ANOCA is defined by the presence of anginal symptoms in the absence of obstructive epicardial coronary artery disease.6 Historically regarded as a relatively benign condition, accumulating evidence demonstrates that ANOCA carries a higher mortality risk than the general population and is associated with substantial morbidity.6-8 ANOCA affects up to 3-4 million individuals annually in the United States, and similar to ME/CFS, there is a female preponderance with women comprising 50-70% of the affected population.2

Coronary function testing (CFT) is the reference standard for diagnosis of ANOCA. CFT enables identification of distinct ANOCA endotypes – including vasospastic angina (VA), coronary microvascular dysfunction (CMD), endothelial dysfunction, and myocardial bridge – each carrying distinct pathophysiological mechanisms and therapeutic implications. CFT-guided identification of these endotypes can help guide precision-based treatment strategies that improve symptoms and long-term outcomes.2,6,8,9

Despite this clinical and potential mechanistic overlap (Figure 1), the frequency of ME/CFS in ANOCA has not been formally characterized, and the potential contribution of microvascular coronary disease to the symptom burden of ME/CFS remains largely unexplored. Establishing this association requires not only invasive CFT to assess coronary vasomotor function but also tools capable of capturing the broader hemodynamic consequences of microvascular dysfunction during physiological stress.

Invasive cardiopulmonary exercise testing (iCPET) can help address the latter by providing direct hemodynamic assessment during exercise and has been used to identify “preload insufficiency, impaired oxygen extraction, and chronotropic incompetence in patients with unexplained exertional intolerance — findings increasingly recognized in ME/CFS.5,10 Importantly, iCPETenables simultaneous measurement of all three components of the Fick equation, allowing precise anatomical localization of exercise limitation to central cardiac, pulmonary, or peripheral domains. Whether iCPET can identify a primary peripheral limitation to exercise – distinct from central cardiac dysfunction – in patients with concurrent ANOCA and ME/CFS remains unknown. To date, no study has systematically applied both modalities to characterize the cardiopulmonary phenotype in this unique and underrecognized patient population.

 

[Hutan]

This retrospective, single-center study included 261 patients who were diagnosed with ANOCA based on CFT between 2017-2025. All participants were found to have nonobstructive coronary arteries, defined as diameter stenosis of < 50% angiographic stenosis, or with fractional flow reserve (FFR) of > 0.80 or non-hyperemic pressure ratio of > 0.89 for any stenosis ≥ 50% but ≤70%.11 All 261 participants had undergone clinically indicated CFT with bolus thermodilution using a standardized protocol and were diagnosed with an ANOCA endotype, as defined by the Coronary Vasomotor Disorders International Study Group criteria.12

I'm looking out for reasons why people with ME/CFS might particularly end up at this clinic. I haven't seen a reason yet.

We then performed a medical record review to determine how many of these confirmed ANOCA patients met criteria for ME/CFS. One reviewer (author ZM) searched each patient’s medical record for documentation satisfying the diagnostic criteria for ME/CFS according to the Institute of Medicine/National Academy of Medicine. A diagnosis of ME/CFS was confirmed if a patient met the three required major criteria (chronic fatigue for ≥ 6 months, post-exertional malaise, and unrefreshing sleep) and one minor criteria (either cognitive impairment or orthostatic intolerance).4 Descriptive statistics were then used to compare ANOCA patients with ME/CFS to ANOCA patients without ME/CFS.

Maybe this is the issue though? It looks like the diagnosis is done retrospectively from medical records, and it involved looking for the individual symptoms of ME/CFS

• chronic fatigue for >6 months
• post-exertional malaise
• unrefreshing sleep
• + cognitive impairment or othrostatic intolerance

I can't imagine medical records would note 'post-exertional malaise' unless the person actually had a diagnosis of ME/CFS. So, I'm assuming post-exertional malaise was inferred from other things. Maybe exertion intolerance would qualify? i.e. feeling bad after exercise? In which case, you've got people with heart issues feeling tired, struggling with exertion and feeling a bit 'off' and dizzy. Which sounds like, well, people with heart issues.

Even if that is the case, there still could be value in identifying a differential diagnosis I guess.

 

[Hutan]

Zoë Mackay; Samit Shah; Jose Gomez Villalobos; Nida Latif; Adith Arun; Phillip Joseph; Paul Heerdt; Inderjit Singh

Ah, there's a connection between Inderjit Singh and David Systrom - they have co-authored papers.

 

[Hutan]

I haven't finished reading the paper, but taking a break. There might be something worth checking out more.

 

[Jonathan Edwards]

If ANOCA has no clearly defined pathology but is diagnosed on a tightness inthe chest on exertion without coronary artery disease it may not be that surprising that somepeople with ME/CFS would qualify for the diagnosis.

And when most of this cardiac stuff seems to come from retrospectively selected patient studies it all gets a bit difficult to make sense of.

 

[Amw66]

Potential confounders ?
Location may play a part . Some areas simply have higher rates of heart conditions ( speaking from west coast of Scotland ) .
Age may factor into this too - heart issues can be related to other conditions , and potentially polypharmacy , which are more associated with older folks . We can't appreciate the full medical picture .
Interesting though
Would this tie back to "sticky blood " / inflexible blood cells somehow ?

 

[Hutan]

If ANOCA has no clearly defined pathology but is diagnosed on a tightness inthe chest on exertion without coronary artery disease it may not be that surprising that somepeople with ME/CFS would qualify for the diagnosis.

I thought that to start with, a sort of functional chest pain syndrome. But, they say this

Coronary function testing (CFT) is the reference standard for diagnosis of ANOCA. CFT enables identification of distinct ANOCA endotypes – including vasospastic angina (VA), coronary microvascular dysfunction (CMD), endothelial dysfunction, and myocardial bridge – each carrying distinct pathophysiological mechanisms and therapeutic implications. CFT-guided identification of these endotypes can help guide precision-based treatment strategies that improve symptoms and long-term outcomes.2,6,8,9

So, I'm not sure. Maybe there is actual measurable dysfunction? - I'd have to check out the references.

 

[Jonathan Edwards]

So, I'm not sure. Maybe there is actual measurable dysfunction? - I'd have to check out the references.

That list looks pretty speculative to me. How do they measure the 'endothelial dysfunction' group I wonder? If these arall quite different pathophysiologies then we would want to know which ones had a high rate of ME/CFS. I haven't read the paper I am afraid. It would be unlikely that there was a true association with all types. Unfortunately, my past experience of reading through these cardiac studies is that you end up being very unclear what was shown. Maybe this group is different, but the write up looks familiar.

 

[Hutan]

If these are all quite different pathophysiologies

I had the same thought. They are grouped together because they all are not something i.e. Chest pain without obstructive coronary arteries. Each of the subsets sounds to be quite different things. There might be something interesting here for us, but it's hard to muster the enthusiasm to find out.

 

[Jonathan Edwards]

And don't forget that even if you have coronary artery narrowing on your angio there is no easy way to know that your chest pain is due to that. Chest pain is common in people over 60. Some coronary narrowing is almost universal. My friends with chest pain are mostly not much the wiser even knowing they have some narrow bits and had a stent put in!