Hyperventilation-Induced Heart Rate Response as a Marker of Cardiovascular Risk - Large-Scale Validation from the Courtois Cardiovascular Signature Program

Q: What are the key findings of this study?

Hyperventilation-induced heart rate change (ΔHR) was significantly attenuated in cardiovascular disease patients compared to non-patients (mean 17.7 vs 23.2 bpm; Cohen's d = 0.469, p < 0.001).

Q: What is the clinical evidence from this study?

Study design: Cross-Sectional. Population: Cardiovascular disease risk spectrum (Zero-Risk to established atherosclerotic cardiac disease) (n=3134). Intervention: Hyperventilation-induced heart rate response (ΔHR) during 60-second paced hyperventilation vs. Non-patients (Zero-Risk, 1-2 Risk Factors, and High-Risk groups without established cardiovascular disease). Primary outcome: Hyperventilation-induced heart rate change (ΔHR, bpm) in cardiovascular disease patients vs non-patients (SMD 0.469, p=<0.001).

Q: What does this research mean for the field?

Hyperventilation-induced heart rate response is significantly attenuated in patients with established cardiovascular and atherosclerotic disease compared to individuals without disease, serving as a potential non-invasive rule-out screening marker. Novelty: ClaimNovelty.CONFIRMATORY. Consensus alignment: ConsensusAlignment.NEUTRAL.

Q: What question did this study set out to answer?

To validate whether hyperventilation-induced change in heart rate (ΔHR) is attenuated across cardiovascular risk strata and evaluate its utility as an equipment-light screening marker.

Matthias G. Friedrich; Margherita Leo; Abhinav Sharma; George Thanassoulis; Nadia Giannetti

doi:10.21203/rs.3.rs-11048120/v1

October 14, 2026Open Access

Hyperventilation-Induced Heart Rate Response as a Marker of Cardiovascular Risk - Large-Scale Validation from the Courtois Cardiovascular Signature Program

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Key result

Cardiovascular disease is linked to ~6-bpm lower hyperventilation-induced heart rate response.

SMD −0.469
P<0.001
n=3,134

Why the study?

Hyperventilation-induced change in heart rate is attenuated in cardiovascular patients, but validation of this response in a large cohort was lacking.

Does hyperventilation-induced heart rate change (ΔHR) during a 60-second paced breathing maneuver discriminate across cardiovascular risk categories and identify established cardiovascular disease in a large prospective cohort?

Key Points

To validate whether hyperventilation-induced change in heart rate (ΔHR) is attenuated across cardiovascular risk strata and evaluate its utility as an equipment-light screening marker.
Analyzed 3,134 participants from the Courtois Cardiovascular Signature Program classified across five risk tiers from zero-risk individuals to established atherosclerotic cardiac disease.
Calculated ΔHR as heart rate at the end of 60 seconds of paced hyperventilation minus resting baseline.
Evaluated diagnostic accuracy using age-adjusted ANCOVA and logistic regression models to assess discrimination and predictive values across prevalence settings.
Median ΔHR decreased monotonically across risk categories from 24.0 bpm [IQR 16.0–33.0] in zero-risk participants to 15.0 bpm [IQR 9.2–22.0] in atherosclerotic cardiac disease (Kruskal-Wallis H = 145.2, p < 0.001).
After age adjustment, ΔHR remained significantly lower only in cardiovascular disease (β = −4.06 bpm, p = 0.001) and atherosclerotic cardiac disease (β = −5.82 bpm, p < 0.001), while intermediate risk groups did not differ from zero-risk controls.
A logistic model combining age and ΔHR achieved an AUC of 0.659 [95% CI: 0.633–0.684] with LR+ of 2.17 and LR− of 0.49, providing a negative predictive value of 97.5% at 5% disease prevalence.

Study Design

Type

Cross-Sectional (n=3,134)

Multicenter

No

Structured PICO

Does hyperventilation-induced heart rate change (ΔHR) during a 60-second paced breathing maneuver discriminate across cardiovascular risk categories and identify established cardiovascular disease in a large prospective cohort?

P

Population

3,134 adults (mean age 56.6 years, 54.1% female) across five pre-specified cardiovascular risk categories from zero-risk healthy individuals to established atherosclerotic cardiac disease examined cross-sectionally at a single Canadian center.

E

Exposure

Standardized breathing-enhanced oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR) protocol at rest in a supine position, involving 60 seconds of paced hyperventilation at a target rate of 30 breaths per minute guided by pre-recorded voice commands, followed by a maximal voluntary end-exhalatory breath-hold sustained for ≥40 seconds.

C

Comparator

Comparison across the five pre-defined cardiovascular risk categories (using Zero-Risk healthy individuals as the reference group) and binary comparison between Patients (Cardiovascular Disease + Atherosclerotic Cardiac Disease, n=548) and Non-Patients (Zero-Risk, 1-2 Risk Factors, and High-Risk, n=2,586).

O

Outcome

Hyperventilation-induced heart rate change (ΔHR), defined as maximal heart rate at the end of the 60-second paced hyperventilation period (HV-HR) minus resting baseline heart rate (BL-HR) recorded from the MRI-compatible ECG trace, and its diagnostic discrimination (AUC, sensitivity, specificity, PPV, NPV, LR+, LR-) for cardiovascular disease status.surrogate

Main Result

Standardized Mean Difference: 0.469

Absolute Event Rate: 17.7% vs 23.2%

p-value: p=<0.001

This large-scale validation confirms that hyperventilation-induced heart rate response is independently attenuated in established cardiovascular disease and, when adjusted for age, provides high negative predictive value (97.5% at 5% prevalence) as a simple, equipment-light rule-out pre-screening marker in low-prevalence settings.

Limitations

Cross-sectional design precludes assessment of longitudinal change or clinical outcomes
Medication data, including beta-blockers, were not systematically available across the cohort, preventing formal adjustment for pharmacological HR suppression
Risk group classification was based on clinical assessment and risk scoring rather than imaging-confirmed diagnoses, which may introduce misclassification
All AUC estimates are in-sample and have not been externally validated
High within-group variability (CV 48-63%) and a 23.2% adverse breathing maneuver event rate
Age-specific probability thresholds may be necessary for optimal clinical deployment
Single-centre study conducted at the McGill University Health Centre
Vasoactive medications were not routinely withheld prior to the study
Substantial individual-level and acquisition variability, with within-group coefficients of variation for ΔHR ranging from 48% to 63%
High rate of acquisition quality issues, including a 23.2% adverse breathing maneuver event rate, a 6.8% rate of breath-hold duration below 40 seconds, and a 30.9% incomplete OS-CMR sequence rate
Limited rule-in diagnostic performance at higher disease prevalence levels and inability of the gatekeeper framework to simultaneously achieve a miss rate <10% and a gate-out fraction >25%

Implication

Should not yet guide clinical decisions; leaves open prospective validation of ΔHR for autonomic risk assessment.

Abstract

Hyperventilation-induced change in heart rate (ΔHR) is attenuated in cardiovascular patients, but validation in a large cohort was lacking. We analysed 3,134 participants from the Courtois Cardiovascular Signature Program (CCVSP), spanning five pre-specified cardiovascular risk categories from zero-risk healthy individuals to established atherosclerotic cardiac disease. ΔHR was defined as heart rate at end of 60-second paced hyperventilation minus resting baseline. ΔHR decreased monotonically across risk groups (Kruskal-Wallis H = 145.2, p < 0.001), from a median of 24.0 bpm [IQR 16.0–33.0] in Zero-Risk participants to 15.0 bpm [9.2–22.0] in those with atherosclerotic cardiac disease. After age adjustment, only the established cardiovascular and atherosclerotic disease groups remained significantly attenuated; intermediate risk groups did not. A logistic model incorporating age and ΔHR achieved an AUC of 0.659 [95% CI: 0.633–0.684], with LR + 2.17 and LR − 0.49, yielding a negative predictive value of 97.5% at 5% prevalence. An enhanced model adding history-based variables (sex, smoking, diabetes, hypertension, family history) achieved an AUC of 0.710 [95% CI: 0.686–0.735]. This study validates, in the largest prospective cohort to date, that hyperventilation-induced ΔHR is attenuated in cardiovascular disease. Age-adjusted ΔHR provides a clinically meaningful rule-out performance in low-prevalence settings, supporting its use as a simple, equipment-light pre-screening marker.

Discussion

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Cite This Study

Friedrich et al. (2026) conducted a cross-sectional in Cardiovascular disease risk spectrum (Zero-Risk to established atherosclerotic cardiac disease) (n=3,134). Hyperventilation-induced heart rate response (ΔHR) during 60-second paced hyperventilation vs. Non-patients (Zero-Risk, 1-2 Risk Factors, and High-Risk groups without established cardiovascular disease) was evaluated on Hyperventilation-induced heart rate change (ΔHR, bpm) in cardiovascular disease patients vs non-patients (SMD 0.469, p=<0.001). Hyperventilation-induced heart rate change (ΔHR) was significantly attenuated in cardiovascular disease patients compared to non-patients (mean 17.7 vs 23.2 bpm; Cohen's d = 0.469, p < 0.001).

synapsesocial.com/papers/6ae28f41cbadf70daf6c4479 https://doi.org/10.21203/rs.3.rs-11048120/v1

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Hyperventilation-Induced Heart Rate Response as a Marker of Cardiovascular Risk - Large-Scale Validation from the Courtois Cardiovascular Signature Program

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

Hyperventilation-Induced Heart Rate Response as a Marker of Cardiovascular Risk - Large-Scale Validation from the Courtois Cardiovascular Signature Program

Key Points

Study Design

Structured PICO

Main Result

Limitations

Implication

Abstract

Discussion

Cite This Study

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