Diminished Circadian Heart Rate Fluctuations: A Potent Predictor of 21-Year Mortality in Patients with Diabetes

Highlights

Circadian heart rate (HR) fluctuations, measured via 24-hour ambulatory monitoring, serve as a robust long-term predictor of mortality in both type 1 and type 2 diabetes. Low 24-hour HR standard deviation (SD) is associated with a two-fold increase in the risk of cardiovascular mortality over a 21-year period. Blunted nocturnal heart rate dipping (<10%) correlates significantly with a higher prevalence of cardiac autonomic neuropathy and nephropathy. Ambulatory blood pressure monitoring (ABPM) provides an underutilized, cost-effective opportunity for cardiovascular risk stratification beyond simple blood pressure metrics.

Background: The Autonomic Nexus in Diabetes

The intersection of metabolic dysfunction and cardiovascular health is largely governed by the autonomic nervous system (ANS). In patients with diabetes mellitus, autonomic imbalance—characterized by sympathetic overactivity and parasympathetic withdrawal—is a well-documented precursor to major adverse cardiovascular events (MACE). While heart rate variability (HRV) is a known marker of autonomic health, its integration into routine clinical practice has been limited by the need for specialized equipment and complex analysis. Circadian heart rate fluctuations, which can be easily derived from standard 24-hour ambulatory blood pressure monitoring (ABPM), offer a more accessible window into the patient’s autonomic integrity. Despite this, the long-term prognostic value of these fluctuations, particularly spanning decades, has remained insufficiently explored until now.

Study Design: The CHAMP1ON Cohort Analysis

This study represents a secondary analysis of the CHAMP1ON cohort, focusing on 349 adults with either type 1 or type 2 diabetes. At baseline, all participants underwent 24-hour ABPM, which simultaneously recorded heart rate data. The primary metrics of interest were the 24-hour heart rate standard deviation (SD) and the nocturnal heart rate dip. The median 24-hour HR SD was 30.4 beats per minute (bpm); participants were categorized into ‘low’ or ‘high’ fluctuation groups based on this median. Nocturnal dipping was defined as a decrease in heart rate of at least 10% during sleep compared to daytime averages. The researchers tracked survival and clinical outcomes over a median follow-up of 21 years, encompassing 6,251 person-years. This longitudinal depth provides a rare look at the life-course impact of autonomic signatures in a high-risk population.

Key Findings: Quantifying the Long-term Risk

Prevalence of Microvascular Complications

At the outset, participants with low circadian HR fluctuations and blunted nocturnal dips exhibited a significantly more adverse cardiometabolic profile. These individuals had a 12% to 23% higher prevalence of established microvascular complications, most notably cardiac autonomic neuropathy (CAN) and diabetic nephropathy. This suggests that impaired HR fluctuations are not merely markers of future risk but are concurrent with existing end-organ damage.

Cardiovascular and All-Cause Mortality

Over the 21-year follow-up, 136 deaths occurred, with 73.5% (100 deaths) attributed to cardiovascular causes. The data revealed a stark divergence in survival curves based on heart rate metrics. Participants in the low 24-hour HR SD group faced an adjusted hazard ratio (aHR) of 2.00 (95% CI 1.30–3.08, P = 0.002) for cardiovascular mortality compared to those with high fluctuations. All-cause mortality was also significantly higher in this group (aHR 1.61, 95% CI 1.13–2.29, P = 0.009).

The Impact of Blunted Nocturnal Dipping

The absence of a physiological heart rate dip during the night was equally predictive. Patients with a blunted nocturnal HR dip (<10%) showed a higher risk for cardiovascular mortality (aHR 1.63, 95% CI 1.08–2.46, P = 0.019) and all-cause mortality (aHR 1.69, 95% CI 1.20–2.38, P = 0.003). These findings remained significant even after adjusting for traditional risk factors, including age, duration of diabetes, and mean blood pressure levels.

Expert Commentary: Mechanistic Insights and Clinical Utility

The biological plausibility of these findings rests on the ‘circadian clock’ of the cardiovascular system. A healthy heart rate should exhibit significant variability, reflecting the heart’s ability to respond to internal and external stressors. In diabetes, chronic hyperglycemia and inflammation damage the vagus nerve and lead to a ‘fixed’ heart rate, characterized by a lack of nocturnal dipping and reduced overall variability. This state of ‘autonomic rigidity’ is a precursor to lethal arrhythmias and heart failure.

From a clinical perspective, the most compelling aspect of this study is the accessibility of the data. Most patients with diabetes and hypertension already undergo ABPM. By simply extracting the heart rate SD and dipping percentage from these existing reports, clinicians can identify high-risk patients who may require more aggressive cardioprotective therapy or closer monitoring. However, it is important to note that as a retrospective analysis, this study cannot establish direct causality. Furthermore, while the follow-up is impressively long, the baseline measurements were taken at a single point in time, which may not account for changes in glycemic control or medication use over the subsequent two decades.

Conclusion: A New Tool for Risk Stratification

The 21-year results from the CHAMP1ON cohort underscore that impaired circadian heart rate fluctuations are not just physiological curiosities but are potent indicators of long-term mortality. In an era where precision medicine often relies on expensive genomic or proteomic markers, the use of ABPM-derived heart rate data offers a refreshingly inexpensive and widely available tool. Integrating these metrics into standard clinical assessments could significantly enhance our ability to predict and potentially prevent cardiovascular death in the diabetic population.

Funding and References

The study was supported by various institutional grants associated with the University of Pisa and metabolic research initiatives. No specific commercial conflicts of interest were reported by the primary authors.

References

1. Nesti L, Chiriacò M, Sacchetta L, et al. Circadian heart rate fluctuations predict cardiovascular and all-cause mortality in type 2 and type 1 diabetes: a 21-year retrospective longitudinal study. Eur J Prev Cardiol. 2026;33(1):101-110. doi:10.1093/eurjpc/zwae305.

2. Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation. 2007;115(3):387-397.

3. Benichou T, Pereira B, Mermillod M, et al. Heart rate variability in type 2 diabetes: A systematic review and meta-analysis. PLoS One. 2018;13(11):e0205169.