Heart rate – natural killer activity
A study by Hyoju Oh et al., published in the journal Frontiers in Immunology reports that in a large population of healthy adults a higher resting heart rate (RHR) is linked to low natural killer cell activity (NKA). The natural killer cell activity was estimated by measuring the amount of interferon-gamma (IFN-γ) released by activated natural killer cells.
Background
Resting heart rate (RHR) is a key physiological indicator that reflects the intrinsic pacemaker activity of the sinoatrial node simply measured by reliable methods like manual palpation or electrocardiography.
Elevated RHR has been associated with a higher level of inflammation and an increased risk of cardiovascular diseases, including hypertension, heart failure, atrial fibrillation, diabetes mellitus, metabolic syndrome, and even cognitive function, making it a valuable prognostic marker in clinical settings.
Natural Killer (NK) cells, key players in innate immunity, swiftly identify and eliminate virus-infected or abnormal cells without prior sensitization. By lysing transformed or infected cells, they limit tumor growth and viral infections. Thus, reduced NKA has been associated with an increased susceptibility to infections and increased risk of various types of cancer.
Since their identification in the 1970s, NK cells have been described as critical contributors to the immune control of cancer cells. Of note, their presence in the peripheral blood correlates with better prognosis in melanoma, breast, prostate, renal cell, and colorectal cancers, and of note, low NK cell activity is associated with increased cancer risk.
Interestingly, both, in vitro, epinephrine/adrenaline and isoproterenol (β-agonist), or in vivo, β-receptor agonists administration result in suppression of NK activity. In patients with heart failure, a condition characterized by chronically high levels of plasma norepinephrine/noradrenaline, these levels correlate with anergy in the cytotoxicity of circulating NK cells (cf. Elenkov et al. 2000). Moreover, several lines of evidence suggest that stress, which is accompanied by increased levels of peripheral catecholamines (CAs), also inhibits NK cell activity.
It appears that NK cells are the most ‘sensitive’ cells to the suppressive effect of stress, and not surprisingly, in the past, NK cell activity has been used as a bona fide index of stress-induced suppression of cellular immunity (for review see M. Irwin, 1994). The potent suppressive effect of CAs on NK cell activity is probably due to the fact that NK cells possess the highest number of β2-ARs among lymphoid cells.
Of note, increases in catecholamines have been shown to induce changes in migration of lymphocytes, in particular NK cells. And adrenaline (epinephrine) and noradrenaline (norepinephrine) modulate the migratory capacity of human NK cells via spleen-independent beta 2-adrenoceptor mechanism.
Results
In the Frontiers in Immunology report, the cross-sectional study included 7,500 subjects; low NKA was defined as IFN-γ level <500 pg/mL. Subjects were categorized into four groups according to RHR as follows: C1 (≤ 60 bpm), C2 (60–70 bpm), C3 (70–80 bpm), and C4 (≥ 80 bpm).
The study reports the prevalence of low NKA being highest in individuals with higher RHR. Even after adjusting for various confounding factors, higher RHR remained significantly associated with greater odds of low NKA.
Thus, individuals in the highest RHR category (≥80) had the poorest metabolic and inflammatory profiles, including higher DBP, WBC counts, C-Reactive Protein (CRP), insulin, and HOMA-IR, and lower IFN-γ levels suggesting that elevated RHR is a marker of both metabolic and cardiovascular risk.
The progressive increase in the prevalence of low NKA with higher RHR indicates a dose-response relationship, suggesting that elevated RHR correlates with a greater likelihood of impaired immune function.
The results of this study are consistent with previous findings, as subjects with lower NKA showed significantly higher RHR, along with elevated WBC counts and CRP levels, indicating a state of chronic inflammation. This pro-inflammatory environment is known to contribute to insulin resistance and metabolic dysregulation, which are central to the development of metabolic syndrome.
Conclusion and Implications
As stated by the authors, the majority of studies focus on the potential of HRV as a predictive marker of immunity, but there is no extensive body of research specifically linking between RHR, the simplest physiological indicator, and immune function.
The significant link between elevated RHR and low NKA, described here, suggests the usefulness of RHR, a simple indicator reflecting increased sympathetic nervous system activity and stress, in predicting reduced immune function.
As discussed by the authors, the study suggests that individuals with elevated RHR may be at a heightened risk for cardiovascular disease. Furthermore, stress can lead to autonomic nervous system imbalance and increased heart rate, both of which are associated with suppressed NK cell activity. This supports the idea that stress-induced increases in RHR may compromise immune function.
As mentioned above, lower NKA was associated with elevated CRP levels. As interleukin-6 (IL-6) seems to be a better predictor of future cardiovascular events than CRP, it would be of interest to find out whether a similar association exists between NK activity and IL-6 levels.
Updates
2025a
A 2025 review by et al. discussed the current literature on natural killer cell dysfunction after various psychological stressors, based on the type of stressor, its duration, the age of exposure, and the species studied.
Highlights
- There is an inverse relationship between psychological stress and natural kill cell activity in humans.
- Sexually dimorphic effects of psychological stressors on NK cell number and function, with an overall immunosuppressive phenotype in females.
- Mice may be inadequate models of study when assessing the effect of psychological stress on natural killer cell function.
More detailed information from this review:
- Following acute time-limited stressors (primarily measured in the laboratory setting) NK cell function decreases across animals alike (mice, rats, chickens, pigs and monkeys); this is in contrast with humans, in which NK cell number and function increases. Longer durations are associated with greater intensity, and post-traumatic stress is associated with decreased NK cell number and function.
- The effects on NK cell activity were lower in loser or subdominant animals and associated with post-traumatic stress, chronic fatigue, and loneliness. Attempts at rehabilitation were unsuccessful in mitigating the deleterious effects of remote stressors on natural killer cell activity.
- The psychological stressors exert sexually dimorphic effects on NK cell number and function, with an immunosuppressed phenotype in female rats and female humans. The opposite effect is seen with mice, with an immunosuppressed phenotype in male mice.
- Of the subjects with decreased NK cell activity (NKCA) peripheral NK cell subsets seem to reveal a relative increase in the proportion of CD56bright / CD56dim subsets, suggesting a decreased cytotoxic phenotype. Patients with Hodgkin lymphoma are reported to have a shift in peripheral blood NK cells toward a NK CD56bright subset with an elevated expression of PD-1.
Overall, the authors of this review highlighted how psychological stressors alone, if prolonged and exposed at an early age, can negatively impact NKCA and place those affected at greater risk of infectious disease and oncologic processes.
Of note, according to authors the data reviewed suggests that psychological stressors exert sexually dimorphic effects on NK cell number and function, with an immunosuppressed phenotype in females. Mice have the opposite effect in comparison to humans, suggesting they are an inappropriate model of study in this area.
2025b
A 2025 study by Renad M Alhamawi et al. explored the harmful effects of anxiety and sleep disturbance on the immune system, particularly NK cells.
In this cross-sectional study, the investigators found that approximately 75% of female students reported Generalized anxiety disorder (GAD) at different levels of severity, and 50% reported sleeping disturbance suggestive of insomnia.
Furthermore, the authors reported a significant reduction of NK cells, observed among participants experiencing severe GAD-7 symptoms. The negative association between the frequency and number of circulating NK cells and the total scores of GAD-7 was observed among students who reported experiencing insomnia. Interestingly, students with symptoms of GAD-7 had a lower percentage and number of circulatory NK cells and their subpopulation—CD16+CD56dim and CD16+CD56high—compared to normal students.
Moreover, among students who were suffering from insomnia, higher GAD-7 scores were negatively associated with the proportion of total peripheral NK cells.
Background
GAD is one of the most prevalent mental conditions globally, and it is frequently associated with sleep disturbances such as insomnia. These mental health conditions are developing among the younger generation, particularly the young female population. These disorders can disrupt the normal functioning of various human body systems, including the immune system. Such impacts ultimately compromise overall health and quality of life.
Conclusion
The authors concluded that there is an urgent need to investigate how anxiety and sleep disturbance impact immune function.
According to the authors, understanding how these psychological stressors influence the distribution and activity of immune cells, especially peripheral NK cells, may provide valuable insights into the mechanisms underlying infections, inflammation and tumorigenesis. These findings could support the development of novel strategies to raise awareness about the physiological consequences of anxiety and insomnia, ultimately helping in the prevention of immune-related disorders and cancer.
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