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ONLINE APPENDIX Approach to Utilizing CPET in Heart Failure Patients Historically, challenges to performing CPET have included the need for specialized equipment (i.e. a metabolic cart), long metabolic cart “warm-up” times, the need to perform routine equipment calibration, and the lack of standardized lab accreditation and staff competency assessment. In addition, the lack of formal training of health professionals in CPET interpretation limits the comfort level of physicians in interpreting gas exchange patterns. Fortunately, modern metabolic carts that measure gas exchange from expired breaths during exercise are now widely commercially available, calibrate in minutes, and have software systems that facilitate pattern recognition. Furthermore, the physiologic and prognostic significance of gas exchange patterns has come into clearer focus through a growing body of work in applied CPET that has been endorsed by scientific statements.(1-3) A 5-minute period of resting gas exchange measurement permits the patient to become accustomed to breathing into the mouthpiece without hyperventilation, which can confound subsequent exercise gas exchange measurements. Low initial work rate is critical to avoid rapid cessation of exercise in patients with HF. We recommend an initial 3 minute period of unloaded exercise (0 Watts) in order to quantify the isolated metabolic cost of moving the legs (i.e. internal work) prior to measurement of VO2-work rate relationships during incremental ramp exercise (i.e. external work). Because the linearity of O2 uptake during exercise is used to ascertain the ventilatory threshold(4) and to determine a cardiovascular basis for exercise intolerance, it is important to be confident of the linearity of the work rate profile that yielded the response.(5) For cycle ergometry, a ~10 W/min increment is usually appropriate based on previous studies in 1 HF demonstrating achieved workloads of 50-80 Watts which translates to the desired duration of testing (8-11min) shown to optimize peak VO2 measurement.(6) Treadmill protocols should also consist of a gradual increment in speed and grade with an ~10 W/min ramp (for a 70 kg individual), which is the case for the modified Naughton Protocol used in the HF ACTION trial(7) and a customized HF protocol currently used by the NHLBI Heart Failure Network.(8) Of note, treadmill testing, compared to cycle ergometry, results in 7-11% higher peak VO2 values because of activation of more muscle mass with treadmill exercise.(9) The individualized gradual incremental ramp (5-25 W/min) and patient-limited nature of CPET makes the procedure feasible and safe even in patients with advanced cardiovascular diseases, as recently shown by 0.045-0.16% adverse event rates (primarily ventricular tachyarrhythmias) and no deaths in the investigation of over 9000 CPETs performed in populations enriched for heart failure.(10,11) Approach to Measuring Oxygen Uptake, Ventilatory Efficiency, and EOV The O2 uptake at the VT is a reflection of the anaerobic threshold whereby skeletal muscle begins to undergo anaerobic glycolysis to meet metabolic demands. Anaerobic glycolysis produces lactic acid that requires buffering from bicarbonate, which results in a sharp increment in VCO2 out of proportion to VO2, thereby creating a divergence in the VCO2-VO2 relationship that is detectable by the V-slope method. Limitations of the VT measurement include moderate inter-observer and intra-observer variability(12,13) due to difficulty ascertaining VT in some HF patients, particularly those with a high degree of oscillatory ventilation.(1) In recent data from the MECKI (Metabolic Exercise, Cardiac, Kidney Index) study, 9.4% of patients with HFrEF did not have an identifiable VT and failure to detect a VT was an independent predictor of the composite endpoint of cardiovascular death and urgent cardiac transplantation.(14) 2 Ventilatory efficiency assesses the increase in minute ventilation (VE) relative to work rate, VO2, or VCO2, and is most commonly calculated as the linear regression slope of VE versus VCO2 throughout exercise.(1) HF patients (predominantly HFrEF) with a normal VE/VCO2 slope had an 18-month survival of 95% compared to a survival rate of 69% in those with an abnormal slope.(15) When compared to other CPET variables in one study of 142 HFrEF patients, VE/VCO2 slope was the strongest predictor of event-free survival in a multivariate model that included peak VO2, LVEF, age, total lung capacity, and NYHA class.(16) In addition to patients with LV systolic dysfunction, patients with HFpEF often have abnormal VE/VCO2 slope and, in one study of HFpEF patients, VE/VCO2 slope was a stronger predictor of survival than peak VO2.(17) Although ventilatory efficiency is an important gas exchange variable used to detect cardiopulmonary abnormalities and predict outcome in disease states, it does not distinguish between different causes of dyspnea and abnormal functional capacity. Increased VE/VCO2 slope is observed in HF, COPD (in the absence of CO2 retention),(18,19) and PAH.(20,21) The partial pressure of end-tidal CO2 (PETCO2), which similarly reflects PaCO2 and VD/VT, augments with exercise up until the VT in normal individuals. In one study, PETCO2 was found to be most severely reduced in PAH, intermediately reduced in HF, and least reduced in COPD.(22) However, given that the underlying determinants of PETCO2 and VE/VCO2 slope are the same, it is likely that the two variables have similar diagnostic and prognostic capabilities. PETCO2 is lower in patients with HF (HFrEF and HFpEF) than normal patients at rest, is tightly correlated with cardiac output and cardiac index, and decreases as NYHA class increases.(23,24) Furthermore, exercise PETCO2 predicts cardiac-related events in HF patients independent of peak VO2.(25) 3 EOV has been defined differently in a nonstandardized fashion, based on somewhat arbitrary criteria. Oscillations in VE exhibit a characteristic cycle length or period (i.e. time from nadir to nadir for respective oscillations in VE) and amplitude (i.e. the difference between the peak VE during an oscillation and the average of the VE of the two surrounding nadirs in VE).(26,27) Some studies(28,29) have defined EOV as oscillations in VE with a cycle length of 1 min, an amplitude of >15% of resting VE, and a duration of EOV encompassing >60% of total exercise time. In 510 apparently healthy subjects undergoing CPET, EOV was present in 17% of individuals and was found to be more prevalent in females and diabetics and associated with poorer CPET performance.(30) Despite the clear association between EOV and poor prognosis in HF, the mechanistic basis for EOV remains unclear. As with any feedback control system, oscillatory waves in ventilation may arise from: 1) delay in information transfer (i.e. reduced cardiac output resulting in increased circulation time);(31,32) 2) increase in controller gain (i.e. increased chemosensitivity to PaCO2 and PaO2),(33,34) or 3) reduction in system damping (i.e. baroreflex impairment, Fig. 3).(27) Our group and others have linked EOV to circulatory delay by measuring cardiac index (CI) during exercise.(35) We found that the amplitude and cycle length of oscillations were inversely related to exercise CI (r=-0.60 and r=-0.71, respectively, both P0.001). HF subjects with EOV cycle length > 1 minute, which is readily recognizable during non-invasive CPET, demonstrated markedly limited augmentation in CI in response to exercise (i.e. <2 L/min/m2) and changes in EOV amplitude and cycle length over time were inversely related to changes in exercise CI.(35) CPET-based Multivariate Models for Prognostication in Heart Failure 4 In studies examining the relative predictive value of multiple CPET variables for clinical outcomes, EOV and VE/VCO2 slope are consistently retained in multivariate Cox regression models whereas peak VO2 is not.(3,36,37) In 508 HFrEF patients, Sun et al.(37) found that when EOV was observed along with an elevated VE/VCO2 slope, the odds ratio for 6-month mortality increased 4-fold. A CPET score utilizing VE/VCO2 slope ≥34 (7 points), HR recovery ≤6 bpm (5 points), OUES ≤1.4 (3 points), resting PETCO2 <33 mmHg (3 points), and a peak VO2 ≤14 mL/kg/min (2 points) has been validated to predict transplant/MCS-free survival in HF (HFpEF and HFrEF) patients better than peak VO2 alone, with a summed score > 15 indicating the poorest prognosis.(38,39) The use of this CPET score is helpful in risk stratifying Weber class B HF patients (with peak VO2 16-20 ml/kg/min) into low risk and higher risk subgroups.(40) In a recent study examining the prognostic value of combining biomarkers and CPET parameters, NT-proBNP levels in combination with EOV emerged as the most powerful predictor of cardiovascular death in 260 stable HFrEF patients.(41) This study and others have found that combining information obtained from CPET with other clinical and laboratory data can enhance prognostic determination. The MECKI score (Metabolic Exercise, Cardiac, Kidney Index) is a risk model derived from a study of >2700 HFrEF patients that relies on six independent predictors including peak VO2, VE/VCO2 slope, LVEF, renal function, hemoglobin, and serum sodium levels. This score that combines CPET parameters with other indices serves as a strong predictor of 2-year cardiovascular death or urgent cardiac transplant and has emerged as a useful prognostic tool for HFrEF patients.(42) CPET with Imaging 5 Imaging modalities such as echocardiography and radionuclide ventriculography have been combined with CPET to provide additional insights into cardiac performance during exercise. The use of Doppler echocardiography combined with CPET in 459 patients with HF (both HFrEF and HFpEF) to determine the TAPSE-pulmonary artery systolic pressure (PASP) relationship demonstrated that the TAPSE/PASP ratio during exercise was a strong predictor of clinical outcome independent of other CPET ventilation parameters.(43) A TAPSE< 16 mm and PASP ≥ 40 mm Hg in the presence of EOV identified patients with highest cardiac risk. In another investigation, simultaneous exercise echocardiography with CPET identified the right ventricular-pulmonary vascular unit as the primary determinant of the ∆VO2/∆work rate relationship (i.e. aerobic efficiency) in 136 patients with exertional dyspnea.(44) To determine the extent of LV recovery and candidacy for LVAD explantation, echocardiography at low device speeds plays a central role in assessing for normalization of aortic valve opening time, LVEF > 0.45, and LV end-diastolic dimension (LVEDD) < 6 cm.(45) However, these parameters do not assess the reserve capacity of the heart during activity. As a result, our laboratory and others measure serial values of CO and PAWP as well as peak VO2 during incremental ramp exercise at low LVAD speeds to assess intrinsic LV reserve capacity. A peak VO2 in excess of 16 ml/kg/min is the one CPET variable that has been incorporated into assessment algorithms as a threshold for LVAD removal,(46) although an appropriate CO augmentation and PAWP response (i.e. PAWP<20 mmHg and PAWP-CO slope <2 mmHg/L/min) increases confidence that LV reserve capacity has been restored. Further work is required to validate the use of CPET in determining the appropriate timing of LVAD explantation. 6 First-pass radionuclide ventriculography provides a noninvasive method to assess left and right ventricular volume and ejection fraction at rest and with exercise, which permits estimation of cardiac output and stroke volume during CPET.(47) The assessment of resting and peak stroke volume can aid in the diagnosis of disorders of abnormal ventricular compliance such as diastolic HF. In patients with HFrEF, a ventriculographic RVEF <0.40 at rest and during exercise independently predicts HF mortality.(48) The addition of invasive hemodynamic measurements of “forward” Fick CO and ventriculographic “total CO” with CPET also allows for the determination of valvular regurgitant fractions during exercise. The addition of invasive hemodynamic measurements and radionuclide ventriculography with CPET allows for the determination of the relative contributions of heart rate, stroke volume, and peripheral oxygen extraction augmentation to peak VO2. Ideally, treatment of patients with HF will target and optimize all three components of peak VO2 commensurate with the degree of abnormality in each. 7 SUPPLEMENTAL REFERENCES 1. Balady GJ, Arena R, Sietsema K et al. Clinician's Guide to cardiopulmonary exercise testing in adults: a scientific statement from the American Heart Association. Circulation 2010;122:191-225. 2. Gibbons RJ, Araoz PA, Williamson EE. 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European heart journal 2006;27:684-90. 17 CPET Description and Physiologic Variable Relevance Measurement Methodology Required %CV, Threshold Prognostic Exercise Relation to for Significance in Duration pVO2* Abnormal Heart Failure Maximum 4-7% (50- <80% HR 1.13-1.27 for 53) predicted mortality per 1 O2 utilization Peak VO2 Aerobic capacity, gold standard Highest VO2 (average over indicator of maximum 30s) occurring in final minute cardiorespiratory fitness. of max. exercise (49) ml/kg/min decrease (54); +1ml/kg/min leads to an 8% reduction in CV death & HF hospitalization (55) O2 uptake Upon initiation of exercise, Phase 1 Mean response time (MRT) Onset VO2 kinetics reflect CO increase, (56) is 63% of duration to Kinetics Phase 2 reflect peripheral muscle reach steady state VO2. Slow ↑ 18 3 min 5-7% r=-0.37 (56) MRT>60 sec 2.6-fold increased mortality after 10 years (57) adaptation, slow kinetics --> higher reflects impaired metabolic O2 debt adaptation to exercise. Anaerobic Limit of aerobic metabolism during V-slope method (slope of threshold 60% Max 2-7% <40% peak <11ml/kg/min exercise, reflects metabolic switch to regression of breath by breath (51,53,59) predicted confers 5.3x anaerobic metabolism variable VO2 increased mortality CO2 production vs. O2 consumption) (58) O2 pulse (60) Reflects premature leveling or fall in Slope of VO2 versus heart rate Maximum 7% (51) Plateau stroke volume in response to exercise relationship (61-63) r=0.69 pattern 4% <8.5 Flattening pattern r=0.49 ml/min/W associated with 25% (64,65) reduced peak VO2 (i.e. cardiac ischemia, RV uncoupling) Aerobic Reflects metabolic cost (in terms of O2 consumption/Work (W) efficiency O2 uptake) of performing external during incremental exercise work aerobically. (58) 6 min (44) Ventil. 19 Patterns Ventilatory Measure of ventilation required to efficiency exchange 1 L/min of CO2; reflects Slope of least-squares 6 min regression of total minute 5 % (51) VE/ VCO2 6-fold higher r=0.45 (56) slope >34 mortality at 18 right ventricular-pulmonary vascular ventilation VE against CO2 months if >34 in HF function + neural reflexes controlling production (66) (15) ventilatory drive Oscillatory A distinct form of periodic breathing 3+ contiguous, regular ventilation that reflects circulatory delay relative oscillations in VE with to metabolic needs during exercise. 6 min NA Present 3-fold higher mortality (>20% 1-yr amplitude ≥ 25% of VE, mortality) (26,31) persisting for ≥ 60% of exercise (37) O2 + Ventilatory O2 uptake O2 uptake relative to ventilation VO2/logVE slope 6 min Efficiency (VE); a higher value reflects (51,67,68) slope improved adaptation of the r=0.83(68) 20 2-7% <1.47 2-fold higher mortality (69) (OUES) cardiopulmonary circuit to oxygenate and deliver blood for a given VE Supplementary Table. Cardiopulmonary exercise testing gas exchange patterns and their significance %CV indicates coefficient of variance. *r values reflect the correlation coefficient between values of the displayed variable and values of peak VO2. 21