Simple New Noninvasive Exercise Measure Can Risk-Stratify Patients With Dyspnea on Exertion
Key findings
- In previous work, Massachusetts General Hospital researchers linked a novel measure, VO2Rec (time until peak oxygen uptake falls permanently below peak VO2 after exercise testing), to risk of poor outcomes in patients with heart failure
- This study reviewed data on 814 patients with suspected preserved ejection fraction but dyspnea on exertion who underwent cardiopulmonary testing with invasive hemodynamic monitoring
- Time to VO2 recovery of 12.5% (VO2-T12.5%) complemented other physiological measures assessed during exercise, and VO2-T12.5% ≥35 seconds was a threshold for a higher risk of all-cause mortality and heart failure hospitalization
- Data derived from that cohort and from the SEQUOIA-HCM phase 3 trial of aficamten showed that VO2-T12.5% is specific to impaired cardiac performance
- VO2-T12.5% merits incorporation into cardiopulmonary exercise testing based assessments of cardiac reserve capacity and deserves consideration as a clinical trial endpoint when evaluating future cardiac interventions
Patients with heart failure (HF) and reduced ejection fraction are at much greater risk of adverse cardiovascular outcomes if they have a predominantly central cardiac limitation to exercise than if peripheral oxygen use is impaired. However, until now, no noninvasive exercise response patterns were known to specifically reflect cardiocentric exercise limitation.
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In previous work, Gregory D. Lewis, MD, and colleagues linked a novel measure of cardiac reserve capacity, VO2Rec, to risk of poor outcomes in patients with heart failure. They define VO2Rec as the time until peak oxygen uptake (VO2) falls permanently below peak VO2. Dr. Lewis is the director of Heart Failure at Mass General Brigham, medical director of the Heart Transplant Program, and director of the CPET Laboratory at Mass General.
Now, Dr. Lewis and colleagues have determined that prolonged VO2Rec specifically reflects cardiocentric deficits, is prognostic in patients with dyspnea on exertion, and could be used to measure impaired cardiac performance in drug development trials. They report their latest results in Circulation.
Methods
The researchers retrospectively studied 814 consecutive patients with suspected preserved ejection fraction who were referred from May 2011 to November 2022 for evaluation of dyspnea on exertion. They had undergone a cardiopulmonary exercise test (CPET) with invasive hemodynamic monitoring and had at least 3 minutes of post-exercise gas exchange data recorded. VO2Rec was measured as time for VO2 to decline by >0%, >12.5%, >25%, and >50% of peak VO2 (expressed as VO2-T0%, VO2-T12.5%, etc.).
The patients’ medical records were reviewed for the primary outcome: the composite of first HF hospitalization (any hospitalization with HF as a principal cause) or death from any cause.
Key Findings
The results showed that:
- VO2Rec could be easily and uniformly acquired during the 3 minutes of post-exercise recovery
- For identifying impaired cardiac performance, VO2-T12.5% closely tracked with hemodynamic indices and outperformed noninvasive measurements, including peak VO2% predicted, VO2/work slope, and ventilatory efficiency nadir
- During recovery, the calculated arteriovenous O2 content difference, one of the component variables of VO2, normalized more rapidly and uniformly than cardiac output, demonstrating the relative cardiospecificity of VO2-T12.5%
- VO2-T12.5% ≥35 seconds was a threshold for higher risk of all-cause mortality and HF hospitalization (HR, 1.76, P=0.003 when adjusted for age, sex, and body mass index; HR, 1.89, P=0.001 when adjusted separately for peak VO2)
Further Evidence of Cardiospecificity
The researchers then reviewed data on 282 patients who participated in the SEQUOIA-HCM phase 3 trial of aficamten for symptomatic obstructive hypertrophic cardiomyopathy. Because aficamten directly targets myocyte contractility, this trial was considered well-suited to assess further whether VO2-T12.5% is specific for changes in cardiac function.
Recruited between February 1, 2022, and May 15, 2023, the trial participants had cardiac biomarkers measured, underwent CPET on a treadmill or cycle ergometer without invasive hemodynamic measurements, and had rest and Valsalva echocardiography.
Compared with the placebo group, participants treated with aficamten were more likely to show improved VO2-T12.5% by ≥15 seconds (OR, 3.7; number needed to treat, 4.8). Furthermore, in the aficamten group VO2-T12.5% was improved proportionately to improvements in N-terminal pro–B-type natriuretic peptide, high-sensitivity cardiac troponin I, and left ventricular outflow tract obstruction. Dr. Lewis's laboratory served as the CPET Core Laboratory for the SEQUIOA Trial, and applied uniform measures of VO2 recovery to both cohorts.
Proposed Change in Practice
VO2 recovery assessment is noninvasive, simple to perform, and holds promise for helping to ascertain cardiospecific limitations to exercise capacity. Measurement of VO2-T12.5% is warranted in addition to measurement of heart rate recovery for a comprehensive CPET protocol.
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