Cardiac Reserve and Exercise Capacity: Insights from Combined Cardiopulmonary and Exercise Echocardiography Stress Testing Nicola Riccardo Pugliese, MD, Nicol  o De Biase, MD, Lorenzo Conte, MD, Luna Gargani, MD, PhD, Matteo Mazzola, MD, Iacopo Fabiani, MD, PhD, Andrea Natali, MD, Frank L. Dini, MD, PhD, Paolo Frumento, PhD, Javier Rosada, PhD, Stefano Taddei, MD, Barry A. Borlaug, MD, and Stefano Masi, MD, PhD, Pisa and Pavia, Italy; and Rochester, Minnesota Background: Cardiopulmonary exercise testing (CPET) represents the gold standard to estimate peak oxygen consumption (VO 2 ) noninvasively. To improve the analysis of the mechanisms behind effort intolerance, we examined whether exercise stress echocardiography measurements relate to directly measured peak VO 2 during exercise in a large cohort of patients within the heart failure (HF) spectrum. Methods: We performed a symptom-limited graded ramp bicycle CPET exercise stress echocardiography in 30 healthy controls and 357 patients: 113 at risk of developing HF (American College of Cardiology/American Heart Association stage A-B) and 244 in HF stage C with preserved (HFpEF, n = 101) or reduced ejection frac- tion (HFrEF, n = 143). Results: Peak VO 2 significantly decreased from controls (23, 21.7–29.7 mL/kg/minute; median, interquartile range) to stage A-B (18, 15.4-20.7 mL/kg/minute) and stage C (HFpEF: 13.6, 11.8-16.8 mL/kg/minute; HFrEF: 14.2, 10.7-17.5 mL/kg/minute). A regression model to predict peak VO 2 revealed that peak left ventricular (LV) systolic annulus tissue velocity (S 0 ), peak tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (right ventricle-pulmonary artery coupling), and low-load left atrial (LA) reservoir strain/E/e’ (LA compliance) were independent predictors, in addition to peak heart rate, stroke volume, and workload (adjusted R 2 = 0.76, P < .0001). The model was successfully tested in subjects with atrial fibrillation (n = 49) and with (n = 224) and without (n = 163) beta-blockers (all P < .01). Peak S 0 showed the highest accuracy in predicting peak VO 2 < 10 mL/kg/minute (cut point # 7.5 cm/sec, area under the curve = 0.92, P < .0001) and peak VO 2 > 20 mL/kg/minute (cut point > 12.5 cm/sec, area under the curve = 0.84, P < .0001) in com- parison with the other cardiac variables of the model (P < .05). Conclusions: Peak VO 2 is directly related to measures of LV systolic function, LA compliance, and right ventricle-pulmonary artery coupling, in addition to heart rate and stroke volume and independently of work- load, age, and sex. The evaluation of cardiac mechanics may provide more insights into the causes of effort intolerance in subjects from HF stages A-C. (J Am Soc Echocardiogr 2020;-:---.) Keywords: Cardiopulmonary exercise test, Exercise stress echocardiography, Cardiac function, Heart failure Cardiopulmonary exercise testing (CPET) is a noninvasive, reliable tool to estimate global oxygen consumption (VO 2 ), evaluate ventila- tory response, and study metabolic and cardiovascular physiology. 1 At the same time, exercise stress echocardiography (ESE) offers a noninvasive, thorough cardiac evaluation at rest and during exer- cise. 1,2 Therefore, the combined CPET-ESE approach provides a mul- tiparametric integrated interpretation of the cardiopulmonary function, which can be used to improve characterization and From the Department of Clinical and Experimental Medicine, University of Pisa (N.R.P., N.D.B., M.M., A.N., S.T., S.M.); Cardiology Unit, Ospedale Castelnuovo Garfagnana (L.C.); Institute of Clinical Physiology, C.N.R. (L.G.); Fondazione Toscana G. Monasterio (I.F.), Pisa; Area Cardiologica, Casa di Cura Villa Esperia, Salice Terme (F.L.D.), Pavia; Department of Political Sciences, University of Pisa (P.F.); and Fourth Unit of Internal Medicine, University Hospital of Pisa (J.R.), Pisa, Italy; and Division of Cardiovascular Diseases, Department of Medicine, Mayo Clinic (B.A.B.), Rochester, Minnesota. The last two authors should be considered the same in author order. Conflicts of Interest: None. Reprint requests: Dr. Nicola Riccardo Pugliese, MD, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma, 67, 56126, Pisa, Italy (E-mail: n.r.pugliese88@gmail.com). 0894-7317/$36.00 Copyright 2020 by the American Society of Echocardiography. All rights reserved. https://doi.org/10.1016/j.echo.2020.08.015 1