Preoperative resting heart rate and colorectal cancer mortality: a robust association, but causality remains unestablished

Colorectal cancer ranks worldwide as the third most common oncologic type for both sexes. Regarding mortality, it is the third leading cause in men, behind only lung and liver cancers, and the fourth leading cause in women, after breast, lung, and cervical cancers (1,2).

Five-year survival for colorectal cancer shows a wide global variation, reflecting disparities in health-care systems and access to early diagnosis and advanced therapies. In the 2010–2014 data, only Israel, South Korea and Australia exceed a 70% survival rate, while 25 countries (including Canada, the United States, Japan, most Western European nations and New Zealand) fall in the 60–69% range. Eighteen countries—among them Mauritius, Peru-Lima, China, Hong Kong and several Eastern-European nations—have 50–59% survival, and less than 50% is observed in Ecuador, Thailand, Russia and India. Between 1995–1999 and 2000–2014, the global trend was an increase in colorectal-cancer survival, with gains of 5–10% in many countries and increases exceeding 20% in China, South Korea and Slovenia (3). These results indicate that, although survival has risen worldwide, significant gaps remain, demanding investment in screening, multimodal treatment and health-care infrastructure in lower-performing regions.

Resting heart rate (RHR) as a predictor of morbidity and mortality for various diseases has been extensively studied, especially in chronic metabolic and cardiovascular disorders (4-6). For cancer, this predictive measure has attracted interest in recent years. A reduced RHR (<60 bpm) has been associated with a lower risk of developing colorectal and lung cancer in male individuals (7). Conversely, an elevated RHR appears as a risk biomarker not only for cancer incidence but also for reduced survival among cancer patients (8,9).

The findings presented by Cho and colleagues in the article entitled “Elevated resting heart rate is an independent risk factor for mortality in patients with colorectal cancer: A retrospective cohort study” (10), recently published in Cancer Epidemiology, Biomarkers & Prevention, reinforce this robust association between pre-operative RHR and colorectal-cancer mortality, but they do not clearly establish causality between the outcomes examined.

The study confirms the hypothesis that a high RHR is an independent predictor of poorer prognosis, specifically of all-cause mortality and colorectal-cancer-specific mortality, even after adjustment for clinical and pathological factors. It is a retrospective cohort study [2010–2015] involving 3,631 patients with stage I–III colorectal cancer who underwent surgery at Severance Hospital (Seoul, South Korea). RHR was measured pre-operatively, and the outcomes analyzed were all-cause mortality and colorectal-cancer-specific mortality.

Patients diagnosed at stage IV were excluded, leaving a gap regarding the association between elevated RHR and poorer prognosis in metastatic disease. Metastasis may be linked to high RHR through various mechanisms, ranging from tumor burden to severe systemic inflammation (11). Moreover, a single-center South-Korean cohort may not represent populations of other ethnicities or health-care systems.

The physiological mechanisms underlying the relationship between RHR and cancer mortality are complex and not yet fully elucidated in the literature. It is suggested that an elevated RHR may reflect a state of sympathetic hyperactivity capable of driving tumor processes. β-adrenergic stimulation increases catecholamine release, favoring angiogenesis, cancer-cell invasion and resistance to apoptosis (12). Simultaneously, the hypothalamic-pituitary-adrenal (HPA) axis raises catecholamine and cortisol levels, which suppress antitumor immune responses (13). In addition, a high resting heart rate may be associated with insulin resistance, which increases circulating insulin-like growth factor 1 (IGF-1) and activates proliferative signaling pathways, such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK) (14). All these mechanisms imply that heightened sympathetic activity could be a fundamental driver of tumor progression, contributing to lower survival and higher cancer mortality (15).

The hypotheses presented by the study are biologically plausible, but sympathetic activity is not directly assessed. Without data on heart-rate variability, maximal oxygen consumption (VO₂ max), inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6), or plasma catecholamines, interpretation remains limited.

A critical limitation is the single RHR measurement taken on the day of surgery. The pre-operative environment creates a physiological “alert” state in which heart rate may be elevated not because of the patient’s baseline characteristics but due to acute anxiety, pain, prolonged fasting and pre-anesthetic medications. The absence of medication data is particularly problematic. Hypertensive patients using β-blockers may have artificially low RHR yet high cardiovascular and inflammatory risk. Conversely, anxious patients without medication may have elevated RHR but a better prognosis. This unmeasured confounding could overestimate the magnitude of the observed association.

The study’s results are robust and clinically impactful, but some caveats must be highlighted. A 3.33-fold higher risk of all-cause mortality and a 2.98-fold higher risk of colorectal-cancer-specific mortality in the highest RHR quintile (≥88 bpm) compared with the lowest (≤66 bpm) represent a striking difference. However, in several analyses, especially in the upper quintiles, the confidence intervals are wide, indicating that while the risk is certainly greater, the precise magnitude of the increase varies considerably.

A point deserving special attention is the heterogeneity among subgroups. The article notes that the association is “more pronounced in patients older than 50 years, with body mass index (BMI) <25 kg/m², with cardiac disease, advanced stage, high American Society of Anesthesiologists (ASA) score, laparoscopic surgery and without adjuvant therapy”. This raises an important question: is the article truly measuring the effect of RHR, or is it capturing a pattern of clinical selection among colorectal-cancer patients?

The statistical analysis employed is robust, with three adjustment models. The most comprehensive model included crucial variables such as tumor-node-metastasis (TNM) stage, comorbidities, type of surgery and adjuvant/neoadjuvant therapies. This is essential for isolating RHR as an independent factor. Nevertheless, some confounders were not measured, such as sleep quality (oncologic patients often experience sleep disturbances that can raise RHR) (16,17) and psychological stress (anxiety and depression, common in cancer diagnosis and treatment, can markedly affect RHR) (18,19).

The literature discusses how improved cardiorespiratory fitness, associated with lower RHR, may act as a protective factor against cancer morbidity and mortality. From a health-promotion perspective, physical exercise is the principal modifiable factor influencing RHR. In particular, long-duration aerobic exercise enhances parasympathetic activity, increases stroke volume and consequently reduces RHR (20,21).

Regular physical activity is recognized as one of the main risk modifiers for the development and progression of various cancers, including colorectal cancer. Epidemiological studies show that individuals who maintain high levels of physical activity have a 20–30% lower risk of colorectal-cancer incidence compared with sedentary persons (22-24). Moreover, regular, safe physical activity after diagnosis and during oncologic treatment can improve treatment response and increase survival (25).

The article suggests that RHR could serve as a useful pre-operative risk marker. This is reasonable as a hypothesis-generating proposition, but it should not be employed for major clinical decisions without prospective validation. In clinical practice, major cardiology guidelines do not consider RHR measurement as a biomarker for cancer-mortality risk management. The guidelines address RHR only within the context of cardiovascular risk, without clinical algorithms that incorporate it for stratification or therapeutic decision-making in cardio-oncology (26,27).

To strengthen the findings presented by the study of Cho et al., future research should adopt a prospective design with multiple measurements of resting heart rate, given the importance of analyzing heart rate variability (28). Detailed information on medication use (e.g., β-blockers, statins), inflammatory biomarkers, cardiorespiratory fitness (VO₂ max, six-minute walk test, accelerometry) and heart-rate variability as a measure of autonomic function should be collected. Lifestyle data are also necessary for a comprehensive biopsychosocial understanding, including measures of physical-activity frequency and intensity, sleep quality, and emotional/psychological stress. Finally, well-designed randomized clinical trials are recommended to test whether lowering RHR, through exercise or pharmacologic interventions, can positively impact survival in patients diagnosed and treated for colorectal cancer.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article has undergone external peer review.

Peer Review File: Available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0218/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0218/coif). D.L.B.d.S. received a productivity grant from CNPq (Brazilian National Council for Scientific and Technological Development), grant number 308168/2020-8. The other author has no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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