Heart Rate Recovery After 6 Min Walk -- A Powerful Prognostic
Heart Rate Recovery After 6 Min Walk -- A Powerful Prognostic
This was a prospective study of patients with HF referred for functional assessment at San Paolo Hospital, Milan, Italy. Two hundred and fifty-eight patients diagnosed with HF who underwent a 6MWT and CPX between June 1999 and December 2008 were included in the study. Patients who were unable to perform either exercise assessment were excluded from the study. All patients were in NYHA functional classes II and III. Patients with both HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF) were enrolled. HFpEF was defined using the following criteria: (i) signs and symptoms of HF; (ii) presence of preserved LV systolic function (LVEF ≥50%) as assessed by two-dimensional echocardiography; and (iii) documentation of mitral inflow early (E) velocity to mitral annulus early velocity (E′) ≥ 8. Approval by the institutional review board was obtained before the study was initiated, and all patients provided written informed consent to participate in the study. The investigation conforms with the principles outlined in the Declaration of Helsinki.
The 6MWT was performed on a level surface by a physician who was unaware of echocardiographic, CPX, and clinical results. Each subject underwent two 6MWTs performed on separate days. The first test was performed to familiarize the patient with the 6MWT and the second test was performed to obtain true functional performance. In 80 patients, a third 6MWT was performed to test day-to-day reproducibility. Patients were instructed to cover the greatest distance possible during the allotted time, at a self-determined walking speed, and were allowed to pause and rest when needed. The distance covered was measured by a body-borne pedometer with which the total number of steps taken during the 6MWT were used to calculate the 6MWT distance using the equation reported by Roul et al. (d = y × 10 m/x; where d = distance ambulated in m; y = total number of steps during 6MWT; and x = number of steps for each subject to cover 10 m). The distance ambulated in 6 min was also dichotomized using the commonly accepted threshold (6MWT distance ≤/> 300 m). The HR was obtained while standing via electrocardiographic telemetry at rest before the 6MWT, at the end of the 6MWT, and 1 min after the 6MWT. The 6MWT HR reserve was calculated as the difference between the HR at the end of the 6MWT and the resting HR. The 6MWT HRR was defined as the difference between the HR at the end of the 6MWT and 1 min after the 6MWT. The recovery period following the 6MWT was passive and consisted of stationary standing.
Symptom-limited CPX was performed on a bicycle ergometer for all subjects. Pharmacological therapy was maintained during CPX. Individualized ramp protocols were designed to obtain a duration between 8 and 10 min. Ventilatory expired gas analysis was performed using a Sensormedics metabolic cart (Vmax, Yorba Linda, CA, USA). Before each test, the equipment was calibrated according to the manufacturer's specifications using reference gases.
Standard 12-lead ECGs were obtained at rest, each minute during exercise, and for at least 5 min during the recovery phase; blood pressure was measured using a standard cuff sphygmomanometer. The HR was determined at rest, peak exercise, and at 1 min of recovery. The percentage age-predicted maximal HR achieved was determined by the following equation: [peak HR/(220 – age)] × 100. The CPX HR reserve was calculated as the difference between the peak HR and resting HR. The CPX HRR was defined as the difference between peak HR and HR at 1 min following test termination. An active cool-down period of at least 1 min was employed for all tests. In addition, minute ventilation [VE; body temperature, pressure, and saturated (BTPS)], oxygen uptake [VO2; standard temperature, pressure, and dry (STPD)], and carbon dioxide output (VCO2; STPD) were acquired breath-by-breath, averaged over 30 s, and printed using rolling averages every 10 s. The V-slope method was used to measure the anaerobic threshold. Peak VO2 and the peak respiratory exchange ratio (RER) were expressed as the highest 10 s averaged sample obtained during the last 20 s of testing. VE and VCO2 values, acquired from the initiation of exercise to peak, were input into spreadsheet software (Microsoft Excel, Microsoft Corp., Bellevue, WA, USA) to calculate the VE/VCO2 slope via least squares linear regression (y = mx + b, where m = slope). Exercise oscillatory ventilation (EOV) during CPX was defined as previously described in detail. Briefly, criteria for EOV included the presence of ≥3 regular oscillatory fluctuations in VE with a minimal average amplitude of 5 L/min persisting for at least 60% of the entire exercise test. The Modified Borg Rating of Perceived Exertion (RPE) was also obtained throughout the CPX.
Test termination criteria consisted of symptoms (i.e. dyspnoea and/or fatigue), ventricular tachycardia, ≥2 mm of horizontal or downsloping ST-segment depression, or a drop of systolic blood pressure ≥20 mmHg during progressive exercise. A qualified exercise physiologist with physician supervision conducted each exercise test.
The LV chamber dimensions were evaluated using standard procedures. The LVEF was calculated from two-dimensional apical images according to Simpson's method.
Subjects were followed for major cardiac-related events (i.e. cardiac death or urgent transplantation) by hospital and outpatient medical chart review to obtain the high likelihood that all major events were captured. Any death with a cardiac-related discharge diagnosis was considered an event. Clinicians conducting the study measurements were not involved in decisions regarding cause of death or heart transplantation.
A statistical software package (SPSS 19.0, Chicago, IL, USA) was used to perform all analyses. Continuous and categorical data are reported as mean ± standard deviation and percentages, respectively. Independent t-tests and χ tests were used to assess differences in patient characteristics, 6MWT variables, and CPX variables between subjects who remained event free or suffered a major cardiac event during the tracking period and between patients with HFrEF and HFpEF. The area under the receiver operating characteristic (ROC) curve was compared between the 6MWT distance ambulated and 6MWT HRR, and between 6MWT HRR and CPX HRR. Additional diagnostic testing of HRR after the 6MWT and CPX was performed, and included the calculation of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Univariate Cox regression analysis was used to assess the prognostic value of key patient characteristics, 6MWT, and CPX variables. Multivariate Cox regression analysis (forward stepwise method; entry and removal value 0.05 and 0.10, respectively) was used to assess the prognostic value of the 6MWT vs. CPX by using two patient characteristics (age and LVEF), four 6MWT variables (6MWT distance, peak HR, 6MWT HR reserve, and dichotomous 6MWT HRR), and four CPX variables (peak VO2, the VE/VCO2 slope, EOV, and dichotomous CPX HRR) in two separate models using the 6MWT variables and CPX variables. Hazard ratios were also determined according to the established dichotomous classification of HRR (≤/> 12 beats) as well as 6MWT (6MWT distance ≤/> 300 m). Kaplan–Meier analysis was used to assess the differences in survival among subjects according to dichotomous classification of HRR. The log-rank test determined statistical significance among the HRR categories for the Kaplan–Meier analyses. Separate univariate Cox regression analyses of survival in patients with HFrEF and HFpEF using the same 6MWT and CPX variables as above were performed. Separate multivariate Cox regression analyses of survival in patients with HFrEF using the same 6MWT and CPX variables as above were also performed. In patients with HFpEF, separate multivariate Cox regression analyses of survival using two 6MWT variables (6MWT distance and 6MWT dichotomous HRR) and two CPX variables (VE/VCO2 slope and CPX dichotomous HRR) were also performed. A P-value <0.05 was considered statistically significant for all tests.
Methods
This was a prospective study of patients with HF referred for functional assessment at San Paolo Hospital, Milan, Italy. Two hundred and fifty-eight patients diagnosed with HF who underwent a 6MWT and CPX between June 1999 and December 2008 were included in the study. Patients who were unable to perform either exercise assessment were excluded from the study. All patients were in NYHA functional classes II and III. Patients with both HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF) were enrolled. HFpEF was defined using the following criteria: (i) signs and symptoms of HF; (ii) presence of preserved LV systolic function (LVEF ≥50%) as assessed by two-dimensional echocardiography; and (iii) documentation of mitral inflow early (E) velocity to mitral annulus early velocity (E′) ≥ 8. Approval by the institutional review board was obtained before the study was initiated, and all patients provided written informed consent to participate in the study. The investigation conforms with the principles outlined in the Declaration of Helsinki.
6 Min Walk Test Procedures
The 6MWT was performed on a level surface by a physician who was unaware of echocardiographic, CPX, and clinical results. Each subject underwent two 6MWTs performed on separate days. The first test was performed to familiarize the patient with the 6MWT and the second test was performed to obtain true functional performance. In 80 patients, a third 6MWT was performed to test day-to-day reproducibility. Patients were instructed to cover the greatest distance possible during the allotted time, at a self-determined walking speed, and were allowed to pause and rest when needed. The distance covered was measured by a body-borne pedometer with which the total number of steps taken during the 6MWT were used to calculate the 6MWT distance using the equation reported by Roul et al. (d = y × 10 m/x; where d = distance ambulated in m; y = total number of steps during 6MWT; and x = number of steps for each subject to cover 10 m). The distance ambulated in 6 min was also dichotomized using the commonly accepted threshold (6MWT distance ≤/> 300 m). The HR was obtained while standing via electrocardiographic telemetry at rest before the 6MWT, at the end of the 6MWT, and 1 min after the 6MWT. The 6MWT HR reserve was calculated as the difference between the HR at the end of the 6MWT and the resting HR. The 6MWT HRR was defined as the difference between the HR at the end of the 6MWT and 1 min after the 6MWT. The recovery period following the 6MWT was passive and consisted of stationary standing.
Cardiopulmonary Exercise Testing Procedures
Symptom-limited CPX was performed on a bicycle ergometer for all subjects. Pharmacological therapy was maintained during CPX. Individualized ramp protocols were designed to obtain a duration between 8 and 10 min. Ventilatory expired gas analysis was performed using a Sensormedics metabolic cart (Vmax, Yorba Linda, CA, USA). Before each test, the equipment was calibrated according to the manufacturer's specifications using reference gases.
Standard 12-lead ECGs were obtained at rest, each minute during exercise, and for at least 5 min during the recovery phase; blood pressure was measured using a standard cuff sphygmomanometer. The HR was determined at rest, peak exercise, and at 1 min of recovery. The percentage age-predicted maximal HR achieved was determined by the following equation: [peak HR/(220 – age)] × 100. The CPX HR reserve was calculated as the difference between the peak HR and resting HR. The CPX HRR was defined as the difference between peak HR and HR at 1 min following test termination. An active cool-down period of at least 1 min was employed for all tests. In addition, minute ventilation [VE; body temperature, pressure, and saturated (BTPS)], oxygen uptake [VO2; standard temperature, pressure, and dry (STPD)], and carbon dioxide output (VCO2; STPD) were acquired breath-by-breath, averaged over 30 s, and printed using rolling averages every 10 s. The V-slope method was used to measure the anaerobic threshold. Peak VO2 and the peak respiratory exchange ratio (RER) were expressed as the highest 10 s averaged sample obtained during the last 20 s of testing. VE and VCO2 values, acquired from the initiation of exercise to peak, were input into spreadsheet software (Microsoft Excel, Microsoft Corp., Bellevue, WA, USA) to calculate the VE/VCO2 slope via least squares linear regression (y = mx + b, where m = slope). Exercise oscillatory ventilation (EOV) during CPX was defined as previously described in detail. Briefly, criteria for EOV included the presence of ≥3 regular oscillatory fluctuations in VE with a minimal average amplitude of 5 L/min persisting for at least 60% of the entire exercise test. The Modified Borg Rating of Perceived Exertion (RPE) was also obtained throughout the CPX.
Test termination criteria consisted of symptoms (i.e. dyspnoea and/or fatigue), ventricular tachycardia, ≥2 mm of horizontal or downsloping ST-segment depression, or a drop of systolic blood pressure ≥20 mmHg during progressive exercise. A qualified exercise physiologist with physician supervision conducted each exercise test.
Echocardiography
The LV chamber dimensions were evaluated using standard procedures. The LVEF was calculated from two-dimensional apical images according to Simpson's method.
Endpoints
Subjects were followed for major cardiac-related events (i.e. cardiac death or urgent transplantation) by hospital and outpatient medical chart review to obtain the high likelihood that all major events were captured. Any death with a cardiac-related discharge diagnosis was considered an event. Clinicians conducting the study measurements were not involved in decisions regarding cause of death or heart transplantation.
Statistical Analysis
A statistical software package (SPSS 19.0, Chicago, IL, USA) was used to perform all analyses. Continuous and categorical data are reported as mean ± standard deviation and percentages, respectively. Independent t-tests and χ tests were used to assess differences in patient characteristics, 6MWT variables, and CPX variables between subjects who remained event free or suffered a major cardiac event during the tracking period and between patients with HFrEF and HFpEF. The area under the receiver operating characteristic (ROC) curve was compared between the 6MWT distance ambulated and 6MWT HRR, and between 6MWT HRR and CPX HRR. Additional diagnostic testing of HRR after the 6MWT and CPX was performed, and included the calculation of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Univariate Cox regression analysis was used to assess the prognostic value of key patient characteristics, 6MWT, and CPX variables. Multivariate Cox regression analysis (forward stepwise method; entry and removal value 0.05 and 0.10, respectively) was used to assess the prognostic value of the 6MWT vs. CPX by using two patient characteristics (age and LVEF), four 6MWT variables (6MWT distance, peak HR, 6MWT HR reserve, and dichotomous 6MWT HRR), and four CPX variables (peak VO2, the VE/VCO2 slope, EOV, and dichotomous CPX HRR) in two separate models using the 6MWT variables and CPX variables. Hazard ratios were also determined according to the established dichotomous classification of HRR (≤/> 12 beats) as well as 6MWT (6MWT distance ≤/> 300 m). Kaplan–Meier analysis was used to assess the differences in survival among subjects according to dichotomous classification of HRR. The log-rank test determined statistical significance among the HRR categories for the Kaplan–Meier analyses. Separate univariate Cox regression analyses of survival in patients with HFrEF and HFpEF using the same 6MWT and CPX variables as above were performed. Separate multivariate Cox regression analyses of survival in patients with HFrEF using the same 6MWT and CPX variables as above were also performed. In patients with HFpEF, separate multivariate Cox regression analyses of survival using two 6MWT variables (6MWT distance and 6MWT dichotomous HRR) and two CPX variables (VE/VCO2 slope and CPX dichotomous HRR) were also performed. A P-value <0.05 was considered statistically significant for all tests.
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