Mackay Z; Yale School of Medicine, USA
Shah S; Villalobos JG; Latif N; et al

American Journal of Physiology – Heart & Circulatory Physiology.
331(5):H1485-H1494, 2026 Nov 01.

This single-center cohort study sought to evaluate the association between
myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and angina
with nonobstructive coronary arteries (ANOCA), by determining the observed
frequency of ME/CFS among patients with ANOCA diagnosed by coronary
function testing (CFT). In addition, 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. NEW & NOTEWORTHY This study demonstrates a clinically
significant association between myalgic encephalomyelitis/chronic fatigue
syndrome (ME/CFS) and angina with nonobstructive coronary arteries
(ANOCA), with 18% of patients with coronary function testing-confirmed
ANOCA meeting diagnostic criteria for ME/CFS. Invasive cardiopulmonary
exercise testing (iCPET) in patients with concurrent ME/CFS and ANOCA
reveals a primary peripheral, not cardiac, limitation to exercise. These
findings highlight the complementary roles of coronary function testing
and iCPET for hemodynamic phenotyping in this underrecognized patient
population.