Clinical and Hemodynamic Associations and Prognostic Implications of Ventilatory Efficiency in Patients With Preserved Left Ventricular Systolic Function.

Background: Ventilatory efficiency (minute ventilation required to eliminate carbon dioxide, VE/VCO2) during exercise potently predicts outcomes in advanced heart failure with reduced ejection fraction, but its prognostic significance for at-risk individuals with preserved left ventricular systolic function is unclear. We aimed to characterize mechanistic determinants and prognostic implications of VE/VCO2 in a single-center dyspneic referral cohort (MGH-ExS [Massachusetts General Hospital Exercise Study]) and in a large sample of community-dwelling participants in the FHS (Framingham Heart Study). Methods: Maximum incremental cardiopulmonary exercise tests were performed. VE/VCO2 was assessed as the slope pre- and post-ventilatory anaerobic threshold (VE/VCO2(pre-VATslope), VE/VCO2(post-VATslope)), the slope throughout exercise (VE/VCO2(overall-slope)), and as the lowest 30-second value (VE/VCO2(nadir)). Results: In the MGH-ExS (N=493, age 56 +/- 15 years, 61% women, left ventricular ejection fraction 64 +/- 8%), higher VE/VCO2(nadir) was associated with lower peak exercise cardiac output and steeper increases in exercise pulmonary capillary wedge pressure (both P<0.0001). VE/VCO2(nadir) (hazard ratio, 1.34 per 1-SD unit [95% CI, 1.10-1.62] P=0.003) was associated with future cardiovascular hospitalization/death and outperformed classical VE/VCO2 measures used in heart failure with reduced ejection fraction (VE/VCO2(overall-slope)). In FHS (N=1936, age 54 +/- 9 years, 53% women), VE/VCO2 measures taken in low-to-moderate intensity exercise (including VE/VCO2(pre-VATslope), VE/VCO2(nadir)) were directly associated with cardiovascular risk factor burden (smoking, Framingham cardiovascular disease risk score, and lower fitness; all P<0.001). Conclusions: Impaired ventilatory efficiency is associated with cardiovascular risk in the community and with adverse hemodynamic profiles and future hospitalizations/death in a referral population, highlighting the prognostic importance of easily acquired submaximum exercise ventilatory gas exchange measurements in broad populations with preserved left ventricular systolic function.