Prognostic role of resting heart rate in patients with colorectal cancer

We thank Dr. de Oliveira and Dr. Bezerra de Souza for their thoughtful Editorial Commentary (1) on our study (2). We accept their central point: a retrospective analysis based on a single preoperative resting heart rate (RHR) measurement can demonstrate an association with colorectal cancer (CRC) mortality but cannot establish that this relationship is causal. We presented our findings accordingly, and we welcome the opportunity to address the methodological concerns raised, to situate the work in its broader context, and to outline how the underlying hypothesis might be tested more directly.

The commentary rightly notes that a single RHR recorded on the day of surgery may reflect transient influences such as anxiety, pain, fasting, or pre-anesthetic medication rather than habitual autonomic tone. We share this concern. Because such measurement error is likely to be non-differential with respect to subsequent mortality, it would generally tend to attenuate rather than exaggerate an association; we cannot, however, quantify its net effect without repeated measurements, and we therefore interpret the estimates cautiously, particularly for the highest RHR quintile, where the confidence intervals are wide. Several analyses nonetheless suggest that the finding is not an artifact of a single measurement. In a companion gastric-cancer cohort from our group, in which RHR was recorded on several separate postoperative days, elevated RHR was consistently associated with worse survival, higher recurrence, and more major complications across these repeated measurements (3); and in the present study the estimates were essentially unchanged when RHR from the day before surgery was used in place of the day-of-surgery value. Results were also stable when early deaths within the first three months were excluded to limit reverse causation, and when patients with pre-existing cardiac, metabolic, renal, hepatic, or respiratory disease were excluded. These analyses reduce, but do not remove, the concern, and they cannot substitute for prospective data with serial measurement.

We also acknowledge the further limitations the commentary identifies. We lacked information on heart rate-modifying medications, most importantly β-blockers; their omission is a genuine source of potential confounding that our exclusion analyses can only partly mitigate. The registry likewise did not capture lifestyle, cardiorespiratory fitness (CRF), sleep, or psychological distress, each of which can influence RHR and may independently affect prognosis, nor did it include direct indices of sympathetic activity such as heart-rate variability (HRV), inflammatory markers, or catecholamines. We therefore regard the mechanistic interpretation in our paper as provisional.

The single-center Korean cohort further limits generalizability to other populations and care settings, and replication in independent, multi-ethnic cohorts will be important; we have begun collaborations toward this end. Our restriction to stage I–III disease was a deliberate design choice intended to evaluate RHR as a preoperative marker in curative-intent surgery, where preoperative factors are most actionable. As the commentary notes, this leaves the prognostic role of RHR in metastatic disease unexamined, which we regard as a distinct question now under separate investigation rather than a settled one. We further address the commentary’s question of whether these findings reflect RHR itself or a pattern of clinical selection. The subgroup analyses should be regarded as exploratory and hypothesis-generating; the primary association persisted in the fully adjusted model across the entire cohort, and the observed effect modification by factors such as age, body-mass index, stage, and comorbidity does not by itself indicate that the association reflects clinical selection rather than RHR itself, although it does warrant cautious interpretation and prospective confirmation.

These observations are consistent with a broader pattern our group has reported, in which elevated RHR has been associated with adverse outcomes across breast, colorectal, and gastric cancer and with colorectal adenoma recurrence (3-7). Because these studies share related limitations, we regard their consistency as supportive context rather than as evidence that confounding or selection has been excluded in any one of them. One link we consider informative is physiological: in the Fenland Study, RHR served as a population-level proxy for CRF (8), a well-established determinant of cancer outcomes. Several features of an elevated-RHR phenotype could plausibly account for the prognostic signal, including autonomic dysregulation, low CRF, β-adrenergic signaling (9,10), systemic inflammation, and insulin-IGF-1 axis activation (11); identifying which of these predominates will require direct, multimodal measurement rather than further observational analysis.

We endorse the commentary’s emphasis on prospective work. Our planned studies pair serial RHR with HRV, accelerometry-based activity and fitness, inflammatory and metabolic biomarkers, structured medication ascertainment, and psychosocial measures within a multicenter CRC cohort, followed by interventions testing whether lowering RHR and improving CRF through structured exercise affects survival. The Colon Health and Life-Long Exercise Change (CHALLENGE) trial, led by one of the co-authors of our work (12,13), reported improved disease-free and overall survival with a postoperative exercise program in stage III colon cancer, supports the plausibility of this approach. We would add that the modest representation of RHR in current cardiology and cardio-oncology guidelines reflects the early stage of the evidence rather than an absence of clinical value. Many determinants of an elevated RHR, including low CRF, adiposity, smoking, heavy alcohol use, and chronic psychological stress acting through sympathetic activity, are themselves recognized correlates of cancer prognosis; RHR may therefore function as an accessible, integrative marker of several prognostically relevant exposures rather than only as a covariate to be adjusted for. Because prognostic utility does not require established causality, and because RHR is inexpensive, non-invasive, and already recorded for nearly every surgical patient, it may merit fuller consideration as a prognostic marker, with its formal role to be defined by prospective study. We thank the commentators again for an exchange that engages constructively with our work and helps to define the next steps. In summary, we regard elevated preoperative RHR as a clinically relevant, hypothesis-generating prognostic marker whose causal basis remains to be established and whose mechanisms and clinical utility we are now working to clarify prospectively.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Gastrointestinal Oncology. The article did not undergo external peer review.

Funding: This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea Government (2024S1A5C3A02043449).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jgo.amegroups.com/article/view/10.21037/jgo-2026-0676/coif). The authors have 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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