Journal of Cardiac Failure Vol. 22 No. 2 2016
Research Letter Association Between Bendopnea and Key Parameters of Cardiopulmonary Exercise Testing in Patients With Advanced Heart Failure
Continuous variables were compared between groups with the use of the t test. Proportions were compared by means of the chi-square test or Fisher exact test as appropriate. Variables associated with VE/VCO2 in univariate analysis (oxygen pulse, paroxysmal nocturnal dyspnea, digoxin) were entered into multivariable linear regression with forward selection, and we then forced bendopnea into the final model. We then included other variables of high clinical relevance into the final model (left ventricular ejection fraction [LVEF], NYHA functional class, and orthopnea). Bendopnea was present in 30 out of 95 subjects (32%). In those with bendopnea, the median time to onset was 9 (interquartile range 8–11) seconds. Baseline characteristics of the cohort stratified by presence of bendopnea are presented in Table 1. Patients with bendopnea had higher NYHA functional class and were more likely to have other symptoms of HF within the preceding 14 days. Patients with versus without bendopnea had a higher VE/VCO2 (35.3 ± 2.7 vs 30.3 ± 6.4; P < .001) and trended toward a lower peak O2 pulse (Table 1). There was no difference between these 2 groups in other CPX parameters, including peak VO2. In univariate regression, bendopnea was associated with VE/VCO2 (β = 4.96; P < .001). Bendopnea remained associated with VE/VCO2 in multivariable regression (β = 3.6; P < .0001). The other variables in the final model from forward selection were male sex (β = 2.6; P = .03) and oxygen pulse (β = −0.72; P < .001). Bendopnea remained associated (P < .001) with VE/VCO2 even when forcing NYHA functional class, orthopnea, and LVEF into the final model. To our knowledge, this is the 1st study to assess whether bendopnea was associated with key CPX parameters. Bendopnea was associated with VE/VCO2 but not peak VO2. VE/VCO2 has been shown to provide additive prognostic information beyond peak VO2.8 VE/VCO2 is also associated with pulmonary venous hypertension.9 Given that bendopnea was associated with an elevated pulmonary capillary wedge pressure,5 an important contributor to secondary pulmonary hypertension,10 it may not be surprising that bendopnea and VE/VCO2 are related. Regardless of their pathophysiologic link, the association of bendopnea with VE/VCO2, the latter a powerful prognostic marker in HF,1,4 strongly suggests that bendopnea is a marker of HF disease severity. In conclusion, bendopnea was common (32%) in patients with systolic HF referred for functional testing and was independently associated with an elevated VE/VCO2. These data suggest that bendopnea is a common marker of disease
To the Editor: Cardiopulmonary exercise testing (CPX) allows risk stratification of heart failure (HF) patients.1 Both low peak oxygen uptake (VO2) and high minute ventilation–carbon dioxide production relationship (VE/VCO2 slope), respectively, are associated with poor prognosis, independently from other clinical and hemodynamic parameters.2–4 Recently, Thibodeau et al characterized a novel symptom of advanced HF: bendopnea, or dyspnea with bending forward.5 Patients with versus without bendopnea had higher supine left ventricular filling pressures, often in the presence of a low cardiac output.5 It is not known whether patients with bendopnea have abnormal exercise responses as assessed by CPX. We prospectively enrolled a convenience sample of 95 adults with systolic HF referred for CPX from March 2014 to March 2015 at the Hospital Universitario de Canarias. The study protocol was approved by that institution’s Review Board. All subjects gave written informed consents. A history and physical examination was completed before the CPX, including assessment of New York Heart Association (NYHA) functional class and measurement of waist and hip circumferences. Subjects were queried about the presence of typical HF symptoms, including orthopnea, within 14 days before enrollment. LVEF was measured within 4 months of enrollment. Bendopnea was assessed as described previously.5 Subjects sat in a chair and bent forward at the waist as if putting on their socks or shoes while an investigator timed the duration to the onset of shortness of breath, as stated to the patient: “tell me when you feel short of breath.”5 Bendopnea was defined as shortness of breath within 30 seconds of bending.5 A symptom-limited CPX was performed with the use of a treadmill ramping protocol as previously described.6,7 Ventilatory expired gas was collected with the use of a metabolic cart (Vmax Encore; Sensormedics, Yorba Linda, California). Breath-by-breath measurements were averaged over 10- or 15-second intervals. Peak VO2 and respiratory exchange ratio were expressed as the highest 10-second averaged sample obtained during the last 20 seconds of testing. VE/VCO2 slope was calculated via least-squares linear regression, and the anaerobic threshold was determined by means of the V-slope method. Peak O2 pulse was calculated as the ratio of peak VO2 to peak exercise heart rate (HR). 163
164 Journal of Cardiac Failure Vol. 22 No. 2 February 2016 Table 1. Characteristics of Patients With and Without Bendopnea Patients With Patients Without Bendopnea Bendopnea (n = 30) (n = 65) P Value Age, y Sex (male), n (%) Medical history, n (%) COPD Atrial fibrillation Diabetes Hypertension Hyperlipidemia Smoking Medications, n (%) ACE-I ARB Aldosterone antagonist Aspirin Beta-blocker Digoxin Diuretic Long-acting nitrate Hydralazine Ischemic cardiomyopathy, n (%) LVEF Physical examination findings BMI, kg/m2 Waist circumference, in. Hip circumference, in. Waist-to-hip ratio Third heart sound, n (%) Rales, n (%) Hepatomegaly, n (%) NYHA functional class, n(%) I II III IV Symptoms in the preceding 14 days, n (%) Dyspnea on exertion Orthopnea PND Lower-extremity swelling Abdominal fullness CPX data Peak VO2, mL kg−1 min−1 VE/VCO2 slope VO2 at anaerobic threshold, mL kg−1 min−1 Peak O2 pulse, mL/ bpm Peak VE, L/min Rest HR (pre-exercise), bpm Peak HR, bpm HRR, bpm
57 ± 14 22 (73)
54 ± 14 46 (71)
.24 .79
3 (10) 7 (23) 3 (10) 4 (13) 2 (7) 11 (37)
7 (11) 19 (29) 15 (23) 19 (29) 26 (40) 19 (29)
.91 .54 .13 .09 .001 .46
25 (83) 5 (17) 17 (57) 17 (57) 25 (83) 13 (43) 30 (100) 6 (20) 6 (20) 17 (57)
51 (79) 12 (19) 38 (59) 27 (42) 52 (80) 33 (51) 65 (100) 16 (25) 16 (25) 27 (42)
.58 .83 .86 .16 .70 .5 .99 .62 .62 .16
26 ± 3.5
26 ± 3.8
.81
26.5 ± 3.8 33.8 ± 1.8
26.1 ± 2.8 33.5 ± 1.7
.63 .36
29.7 ± 2.0 1.14 ± 0.10 4 (13)
29.3 ± 2.1 1.15 ± 0.10 2 (3)
.41 .89 .05
2 (7) 10 (33)
3 (5) 18 (28)
.67 .57 .006
0 (0) 2 (7) 15 (50) 13 (43)
3 (5) 8 (12) 46 (71) 8 (12)
30 (100) 21 (70) 20 (67) 7 (23)
51 (79) 30 (46) 29 (45) 9 (14)
.006 .03 .04 .25
26 (87)
22 (34)
Research Letter Association Between Bendopnea and Key Parameters of Cardiopulmonary Exercise Testing in Patients With Advanced Heart Failure
Continuous variables were compared between groups with the use of the t test. Proportions were compared by means of the chi-square test or Fisher exact test as appropriate. Variables associated with VE/VCO2 in univariate analysis (oxygen pulse, paroxysmal nocturnal dyspnea, digoxin) were entered into multivariable linear regression with forward selection, and we then forced bendopnea into the final model. We then included other variables of high clinical relevance into the final model (left ventricular ejection fraction [LVEF], NYHA functional class, and orthopnea). Bendopnea was present in 30 out of 95 subjects (32%). In those with bendopnea, the median time to onset was 9 (interquartile range 8–11) seconds. Baseline characteristics of the cohort stratified by presence of bendopnea are presented in Table 1. Patients with bendopnea had higher NYHA functional class and were more likely to have other symptoms of HF within the preceding 14 days. Patients with versus without bendopnea had a higher VE/VCO2 (35.3 ± 2.7 vs 30.3 ± 6.4; P < .001) and trended toward a lower peak O2 pulse (Table 1). There was no difference between these 2 groups in other CPX parameters, including peak VO2. In univariate regression, bendopnea was associated with VE/VCO2 (β = 4.96; P < .001). Bendopnea remained associated with VE/VCO2 in multivariable regression (β = 3.6; P < .0001). The other variables in the final model from forward selection were male sex (β = 2.6; P = .03) and oxygen pulse (β = −0.72; P < .001). Bendopnea remained associated (P < .001) with VE/VCO2 even when forcing NYHA functional class, orthopnea, and LVEF into the final model. To our knowledge, this is the 1st study to assess whether bendopnea was associated with key CPX parameters. Bendopnea was associated with VE/VCO2 but not peak VO2. VE/VCO2 has been shown to provide additive prognostic information beyond peak VO2.8 VE/VCO2 is also associated with pulmonary venous hypertension.9 Given that bendopnea was associated with an elevated pulmonary capillary wedge pressure,5 an important contributor to secondary pulmonary hypertension,10 it may not be surprising that bendopnea and VE/VCO2 are related. Regardless of their pathophysiologic link, the association of bendopnea with VE/VCO2, the latter a powerful prognostic marker in HF,1,4 strongly suggests that bendopnea is a marker of HF disease severity. In conclusion, bendopnea was common (32%) in patients with systolic HF referred for functional testing and was independently associated with an elevated VE/VCO2. These data suggest that bendopnea is a common marker of disease
To the Editor: Cardiopulmonary exercise testing (CPX) allows risk stratification of heart failure (HF) patients.1 Both low peak oxygen uptake (VO2) and high minute ventilation–carbon dioxide production relationship (VE/VCO2 slope), respectively, are associated with poor prognosis, independently from other clinical and hemodynamic parameters.2–4 Recently, Thibodeau et al characterized a novel symptom of advanced HF: bendopnea, or dyspnea with bending forward.5 Patients with versus without bendopnea had higher supine left ventricular filling pressures, often in the presence of a low cardiac output.5 It is not known whether patients with bendopnea have abnormal exercise responses as assessed by CPX. We prospectively enrolled a convenience sample of 95 adults with systolic HF referred for CPX from March 2014 to March 2015 at the Hospital Universitario de Canarias. The study protocol was approved by that institution’s Review Board. All subjects gave written informed consents. A history and physical examination was completed before the CPX, including assessment of New York Heart Association (NYHA) functional class and measurement of waist and hip circumferences. Subjects were queried about the presence of typical HF symptoms, including orthopnea, within 14 days before enrollment. LVEF was measured within 4 months of enrollment. Bendopnea was assessed as described previously.5 Subjects sat in a chair and bent forward at the waist as if putting on their socks or shoes while an investigator timed the duration to the onset of shortness of breath, as stated to the patient: “tell me when you feel short of breath.”5 Bendopnea was defined as shortness of breath within 30 seconds of bending.5 A symptom-limited CPX was performed with the use of a treadmill ramping protocol as previously described.6,7 Ventilatory expired gas was collected with the use of a metabolic cart (Vmax Encore; Sensormedics, Yorba Linda, California). Breath-by-breath measurements were averaged over 10- or 15-second intervals. Peak VO2 and respiratory exchange ratio were expressed as the highest 10-second averaged sample obtained during the last 20 seconds of testing. VE/VCO2 slope was calculated via least-squares linear regression, and the anaerobic threshold was determined by means of the V-slope method. Peak O2 pulse was calculated as the ratio of peak VO2 to peak exercise heart rate (HR). 163
164 Journal of Cardiac Failure Vol. 22 No. 2 February 2016 Table 1. Characteristics of Patients With and Without Bendopnea Patients With Patients Without Bendopnea Bendopnea (n = 30) (n = 65) P Value Age, y Sex (male), n (%) Medical history, n (%) COPD Atrial fibrillation Diabetes Hypertension Hyperlipidemia Smoking Medications, n (%) ACE-I ARB Aldosterone antagonist Aspirin Beta-blocker Digoxin Diuretic Long-acting nitrate Hydralazine Ischemic cardiomyopathy, n (%) LVEF Physical examination findings BMI, kg/m2 Waist circumference, in. Hip circumference, in. Waist-to-hip ratio Third heart sound, n (%) Rales, n (%) Hepatomegaly, n (%) NYHA functional class, n(%) I II III IV Symptoms in the preceding 14 days, n (%) Dyspnea on exertion Orthopnea PND Lower-extremity swelling Abdominal fullness CPX data Peak VO2, mL kg−1 min−1 VE/VCO2 slope VO2 at anaerobic threshold, mL kg−1 min−1 Peak O2 pulse, mL/ bpm Peak VE, L/min Rest HR (pre-exercise), bpm Peak HR, bpm HRR, bpm
57 ± 14 22 (73)
54 ± 14 46 (71)
.24 .79
3 (10) 7 (23) 3 (10) 4 (13) 2 (7) 11 (37)
7 (11) 19 (29) 15 (23) 19 (29) 26 (40) 19 (29)
.91 .54 .13 .09 .001 .46
25 (83) 5 (17) 17 (57) 17 (57) 25 (83) 13 (43) 30 (100) 6 (20) 6 (20) 17 (57)
51 (79) 12 (19) 38 (59) 27 (42) 52 (80) 33 (51) 65 (100) 16 (25) 16 (25) 27 (42)
.58 .83 .86 .16 .70 .5 .99 .62 .62 .16
26 ± 3.5
26 ± 3.8
.81
26.5 ± 3.8 33.8 ± 1.8
26.1 ± 2.8 33.5 ± 1.7
.63 .36
29.7 ± 2.0 1.14 ± 0.10 4 (13)
29.3 ± 2.1 1.15 ± 0.10 2 (3)
.41 .89 .05
2 (7) 10 (33)
3 (5) 18 (28)
.67 .57 .006
0 (0) 2 (7) 15 (50) 13 (43)
3 (5) 8 (12) 46 (71) 8 (12)
30 (100) 21 (70) 20 (67) 7 (23)
51 (79) 30 (46) 29 (45) 9 (14)
.006 .03 .04 .25
26 (87)
22 (34)
