Allison Sayre, MSN, WHNP and Corey Schuler, PhD, FNP, CNS
Fatigue is one of the most common, yet and least understood symptoms experienced by people with coronary artery disease (CAD). It is often persistent, difficult to quantify, and poorly explained by traditional cardiac metrics alone. For many patients, fatigue becomes the symptom that most limits daily life, even when cardiac function appears stable. This disconnect has prompted a deeper question and that is, could fatigue in coronary artery disease reflect not only cardiac impairment, but also underlying shifts in hormonal systems that regulate energy, stress, and recovery?
A pivotal study by Bunevicius and colleagues directly addresses this question by examining fatigue in relation to thyroid axis hormones and cortisol in patients with CAD. [1] Unlike many studies that interpret fatigue indirectly, this investigation used validated fatigue scales and carefully evaluated endocrine markers. This offers a unique level of clarity on how fatigue and physiology intersect in this population.
Fatigue as a Measurable, Biologically Relevant Symptom
In their cross-sectional study, Bunevicius et al. evaluated 83 patients with CAD enrolled in a cardiac rehabilitation program. Fatigue was assessed using the Multidimensional Fatigue Inventory and the Dutch Exertion Fatigue Scale. This enabled the authors to distinguish between physical, exertional, and mental fatigue. [1] This distinction critical, as fatigue is often not felt as a single sensation, and the involvement of different biological systems may illicit different fatigue experiences.
Interestingly, these authors observed that fatigue severity showed little relationship to exercise capacity, or traditional coronary artery disease severity markers. [1] Instead, fatigue was independently associated with endocrine variables, even after adjusting for age, sex, body mass index, prior myocardial infarction, heart failure, diabetes, depression, and anxiety. [1] This finding reframes fatigue in coronary artery disease as more than a byproduct of deconditioning or mood. It points toward physiology.
The Thyroid Axis: Energy Regulation at the Center of Fatigue
One of the strongest findings was the relationship between thyroid hormones and fatigue. Lower free triiodothyronine (free T3) concentrations were independently associated with greater physical fatigue. Lower free thyroxine (free T4) concentrations were associated with greater exertional fatigue. [1] Both of these associations remained significant after comprehensive adjustment for confounding variables.
T3 is the biologically active thyroid hormone that governs metabolic rate, mitochondrial activity, and energy utilization at the tissue level. Even subtle reductions in circulating or tissue-level T3 can influence how much energy the body is willing to expend. [2] In CAD patients, this may present as reduced stamina, slower recovery, and persistent physical fatigue, without meeting the criteria for overt thyroid disease. [1][3]
But get this. The study excluded patients with known thyroid disorders. This reinforces the authors claim that these associations reflect physiological variation within the normal range, not undiagnosed hypothyroidism. [1] This supports the idea that thyroid signaling, rather than thyroid pathology, may be central to fatigue perception in CAD.
Cortisol and Stress Adaptation
Cortisol’s role in fatigue proved to be a bit more nuanced. In contrast to physical and exertional fatigue, mental fatigue was associated with lower morning cortisol levels and a blunted diurnal cortisol change. [1] This pattern suggests altered hypothalamic–pituitary–adrenal (HPA) axis regulation, rather than excessive stress hormone exposure.
Low or flattened cortisol rhythms have been linked to impaired stress adaptability and reduced physiological resilience. [1] Rather than signaling “low stress,” this pattern may reflect a system that has difficulty mounting or modulating an appropriate stress response. In the context of CAD, this could contribute to cognitive fatigue, difficulty concentrating, and mental exhaustion. All of which are symptoms frequently reported during recovery and rehabilitation.
These findings underscore an important principle: cortisol–fatigue relationships are domain-specific and non-linear. High cortisol may characterize acute illness or cardiovascular stress, while low or blunted cortisol responses may emerge in more chronic, recovery-phase states. [4]
Integrating Newer Evidence
More recent work by Javid and colleagues complements this framework by examining cortisol and T3 patterns in hospitalized cardiovascular patients. They found higher cortisol levels and lower circulating T3 in patients with cardiovascular disease compared with healthy controls, with significant associations in regression models. [5]
While Javid et al. did not directly measure fatigue, their findings align with Bunevicius et al. by highlighting a recurring hormonal signature in cardiovascular populations. Both groups reported stress-related cortisol activation alongside reduced active thyroid hormone signaling. Taken together, these studies suggest that fatigue in CAD may emerge along a continuum, from acute stress physiology to longer-term adaptive conservation, rather than from a single hormonal abnormality.
An Energy-Conservation Lens
Alternatively, the patterns described by Bunevicius et al. point toward altered energy regulation rather than system failure. Reduced T3 signaling may reflect a downshift in metabolic pace, while altered cortisol rhythms may signal limited stress-response flexibility. In the short term, these shifts can be protective. Over time, they may constrain energy availability and shape the lived experience of fatigue.
If the body downshifts T3 availability during stress or illness, this can be interpreted as a protective energy-conservation strategy, or less metabolic “push” during periods of strain. [2][4] When stress signals persist, however, that same strategy may also contribute to prolonged fatigue and reduced vitality.
Clinical meaning
The takeaway is not that fatigue in CAD should be treated as an endocrine disorder. Rather, these findings invite more nuanced conversations. Fatigue that feels disproportionate to activity or cardiac findings may reflect underlying hormonal regulation rather than motivation, mood, or effort.
Thyroid hormone and cortisol levels are independently associated with fatigue severity in CAD, even when psychological factors are accounted for. [1] This supports the importance of implementing a treatment model of shared decision-making in which patient symptoms are taken seriously, and explored within their full physiological context.
For clinicians and patients engaging in shared decision-making, this reframes the conversation to include these important understandings:
- Fatigue that feels disproportionate to activity may warrant looking beyond cardiac mechanics alone, especially when stress physiology is clearly engaged.
- Assessing active thyroid hormone signaling and cortisol, interpreted in context and timing, may offer additional insight rather than definitive answers. [1]
Conclusions
Fatigue in CAD is real, measurable, and biologically meaningful. Evidence from Bunevicius et al. shows that variations in thyroid axis hormones and cortisol are independently associated with different dimensions of fatigue in CAD patients. [1] More recent data from Javid et al. reinforces that stress and thyroid signaling are commonly altered in cardiovascular disease states. [5]
Together, these findings suggest that fatigue may be a signal of how the body is allocating energy under strain. Understanding that signal does not promise quick fixes, but it does replace dismissal with curiosity. And in that shift away from minimizing fatigue severity to interpreting it, new possibilities for support and recovery can begin.
Disclaimer:
The information provided is for educational purposes only. Consult your physician or healthcare practitioner if you have specific questions before instituting any changes in your daily lifestyle including changes in diet, exercise, and supplement use.
Allison Sayre, MSN, WHNP is a board-certified women’s health nurse practitioner with advanced expertise in hormonal health, integrative gynecology, and patient-centered care across the lifespan. She holds a Master of Science in Nursing and has served as both a clinical provider and educator in functional and conventional women’s health settings. At ARG, Allison contributes to medical education, clinical protocol development, and strategic content that supports the evolving needs of women's healthcare practitioners.
Corey Schuler, PhD, FNP, CNS has dedicated his career to advancing the science and clinical art of integrative medicine and serves as director of medical affairs for Allergy Research Group. He is a family nurse practitioner and practices holistic primary care at Synergy Family Physicians in White Bear Lake, Minnesota.