Much Potential but Many U n a n s w e re d Q u e s t i o n s f o r Hi g h - I n t e n s i t y I n t e r m i t t e n t E x e rc i s e Tr a i n i n g f o r Pa t i e n t s w ith H ear t Failure Sherry O. Pinkstaff, PhD, PT KEYWORDS Heart failure Exercise High intensity Intermittent Interval
KEY POINTS
INTRODUCTION There is a robust trove of scientific studies that support the positive physical and mental health benefits associated with aerobic exercise for apparently healthy individuals. This evidence underlies the government-backed physical activity guidelines, which suggest 30 minutes of moderate-intensity exercise on most if not all days of the week.1,2 These recommendations also suggest that more vigorous exercise can be performed on fewer days for the same benefit, a recommendation that reflects the inverse doseresponse relationship between physical activity and disease.3–5 Those benefits include significant reductions in the risk factors associated with cardiovascular disease (CVD). There is also ample
evidence for the use of aerobic exercise in CVD patient populations to improve numerous healthrelated outcomes. Aerobic exercise was once contraindicated for patients with HF. In the early days of its use in this patient population, no greater than moderate-intensity training was recommended. Current guidelines recommend that patients with clinically stable HF perform aerobic MICE training (ie, 50%–80% of peak capacity) for up to 45 minutes on most days of the week.6,7 Since the 1980s, many studies have demonstrated the safety and effectiveness of aerobic MICE in patients with HF.8 Despite these positive results, a recent large, multicenter, randomized clinical trial, Heart Failure: A Controlled Trial Investigating Outcomes of
Disclosures: This author has no conflicts of interest to disclose. Physical Therapy Program, Department of Clinical and Applied Movement Sciences, University of North Florida, 1 UNF Drive, Jacksonville, FL 32224, USA E-mail address: [email protected] Heart Failure Clin 11 (2015) 133–148 http://dx.doi.org/10.1016/j.hfc.2014.08.008 1551-7136/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
heartfailure.theclinics.com
Moderate-intensity continuous exercise (MICE) has been the clinical standard for patients with heart failure (HF) but evidence is mounting for the effectiveness of high-intensity intermittent exercise (HIIE). HIIE is associated with clinically significant improvements in peak oxygen consumption (VO2peak) as well as many other variables associated with exercise capacity and cardiovascular function. The number of studies in which HIIE was used to treat patients with HF remains small, representing fewer than 200 patients. HIIE has not been associated with adverse events in the studies conducted to date. More research is needed before HIIE can become the clinical standard for patients with HF.
134
Pinkstaff Exercise Training (HF-ACTION), demonstrated no overall improvement in all-cause mortality and hospitalization.9 Importantly, after adjusting for highly prognostic clinical values for the same endpoints, exercise training did result in a modest prognostic improvement. Nonetheless, to many investigators, this remains a disappointing result. Recently clinicians and researchers have begun to investigate HIIE training as an intervention for this patient population. This type of training has been used extensively in healthy populations, in the context of athletic performance. A vast majority of the studies investigating the effect have been done in these populations. Although many fewer studies have been conducted in a patient population representing a much smaller number of patients, the results are promising. HIIE training seems safe and improves physiology, quality of life, and functional capacity.10–14 Many unanswered questions, however, remain. Therefore, the objective of this review is to define HIIE, discuss its physiologic benefit for patients with HF, outline the studies that have been conducted to date, and discuss the issues that need to be resolved before this exercise intervention is more widely embraced by the clinical community.
PRINCIPLES OF HIGH-INTENSITY INTERMITTENT EXERCISE HIIE involves the use of short periods of exercise interspersed with rest periods. The duration and intensity of the exercise and rest can be varied in numerous ways. The American College of Sports Medicine defines intensity as a percentage of heart rate (HR) reserve or VO2 reserve (VO2R). These are relative values that must be individually prescribed. Hard or very hard intensity is 60% to less than 85% and 85% to less than 100%, respectively. Exercise training at greater than 100% HR reserve (HRR) or VO2R has been used primarily for athletic training and is not considered for this review. For comparison, moderate intensity is defined as 40% to less than 60% HR reserve or VO2R. The rationale for HIIE is that the short periods of exercise followed by rest periods allow for greater time spent at a higher intensity of exercise (compared with continuous exercise).15 This greater intensity requires different energy production pathways to be used as well as additional muscle fiber recruitment. Together, these provide an increased potential for both central and peripheral adaptation. In a study of more than 5000 apparently healthy men and women, relative exercise training intensity was more important than duration in reducing the risk of all-cause and coronary heart disease mortality.15
There seems to be a mechanistic basis for this exercise intensity dependence. HF is characterized on the cellular level by dysfunctional cardiomyocyte activity. Aerobic exercise can repair or reverse some of these pathologic changes, especially when that exercise is high intensity (>90% of VO2peak). In animal studies, the physiologic adaptations to chronic exercise training are explained by changes to cardiomyocyte function. In rats and mice, improvement in cardiac pump function, as a result of positive changes to the cardiomyocyte, is achieved by high-intensity exercise.16 Furthermore, it has been suggested that for patient populations, high-intensity exercise training may be required for positive central adaptations, such as cardiac dilatation, ejection fraction, stroke volume, or other systolic parameters.17
EFFICACY/PHYSIOLOGIC BENEFITS OF HIIE TRAINING Acute Effects Recent studies have evaluated the acute effects of HIIE training in patients with HF (Table 1). In the most recent, a total of 13 patients with systolic HF were randomized to perform a single bout of high HIIE or MICE during which gas exchange and central hemodynamic factors were measured.18 The HIIE bout resulted in similar cardiac output (CO), stroke volume, and oxygen extraction compared with MICE. Importantly, the hemodynamic response to HIIE was stable throughout the training session. This stability is consistent with the lack of adverse events in this cohort, a finding that is similar to other published accounts of this type of training. Participants also tended to rate the perceived exertion lower and were more likely to be able to complete the bout of HIIE. This study complements an earlier study that demonstrated that when compared with steady state exercise, HIIE resulted in comparable increases in left ventricular (LV) ejection fraction, stroke volume, CO, ratings of leg fatigue, and dyspnea.19 The investigators also concluded that these results spoke to the safety of HIIE training. Tomczak and colleagues20 used MRI to assess the changes in biventricular function after a single bout of HIIE. The major finding was that biventricular function improved with a decrease in end-systolic volume and an increase in LV ejection fraction. The investigators suggested this improvement may be related to reduced systemic peripheral resistance or alternatively to improved cardiomyocyte contractility. Diastolic function was also improved as demonstrated by an
High-Intensity Intermittent Exercise Training increased peak untwisting rate, resulting in improved LV suction and diastolic filling.
Chronic Adaptations Most of the studies evaluating the effects of HIIE have been chronic training studies using various protocols, with some making comparisons to MICE and others with nonexercise standard care. All these studies find benefit from HIIE. The major benefits fall into several categories: exercise capacity, ventilatory efficiency, ventilatory threshold (VT)/anaerobic threshold (AT), cardiac and vascular function, and quality of life. The following discussion is a synopsis of the main outcomes assessed. See Table 1 for an overview of the main findings of each study. Exercise capacity The importance of exercise capacity in terms of prognosis in the context of health and disease cannot be overstated. Small improvements in exercise capacity, as measured by changes in VO2peak, can have a profound impact on the risk of all-cause and cardiovascular morbidity and mortality.21 It follows that the major goal of aerobic exercise training is to improve cardiorespiratory fitness. There is also a dose-response relationship where greater improvements in aerobic capacity are associated with greater reductions in risk. Wisløff and colleagues10 showed that 12 weeks of exercise training resulted in a 46% increase in VO2peak for those performing HIIE compared with a 14% increase for those performing MICE. Freyssin and colleagues12 used an 8-week HIIE program, which resulted in a 27% increase in VO2peak. In a study by Fu and colleagues,13 patients with HF undergoing an HIIE program for 12 weeks had a 22% increase in VO2peak. Similarly, in a 16-week program comparing HIIE to MICE training, Smart and Steele22 reported a significant increase (21%) only in the former group. Finally, in a recent study, Chrysohoou and colleagues11 looked at the effect of 12 weeks of HIIE training and demonstrated a 31% improvement in VO2peak. In all of these studies, with the exception of that by Smart and Steele22, the absolute increase in VO2 was greater than 1 metabolic equivalent (MET), a clinically relevant increase. A systematic review of 33 studies representing more than 100,000 apparently healthy subjects demonstrated 13% and 15% risk reductions for all-cause and cardiovascular-related mortality for each 1 MET in aerobic capacity, respectively.21 Six-minute walk test (6MWT) distance has been shown to correlate moderately well with VO2peak in patients with HF.23 It has been used in many studies as a surrogate for VO2peak and to measure
changes in exercise capacity after aerobic training. Similarly, total exercise time during an exercise test and peak work rate (WRpeak) also correlated with exercise capacity. Nilsson and colleagues24 showed that following 16 weeks of HIIE training, patients increased their walking distance and exercise time significantly. The exercise training group was compared with a standard care nonexercising group. In the same group of patients, the long-term effects of exercise training were investigated. After 12 months, the gains in measures of exercise capacity were still significant.25 Freyssin and colleagues12 also used 6MWT distance and exercise time to measure change in functional capacity after an 8-week training protocol. This study showed a 47% increase in exercise time for the HIIE group versus a 12% increase for the MICE group. Similarly, 6MWT distance increased 12% and 6%, respectively, for the HIIE and MICE groups. Chrysohoou and colleagues11 demonstrated a 13% improvement in 6MWT distance and a 25% improvement in WRpeak. The chronotropic response to exercise is related to the health of the autonomic nervous system and has been found impaired in patients with HF.26 Specifically, HRR is slowed in patients with HF and is hastened in the highly fit.27 HRR can be improved with chronic MICE training.28 Only one study has considered this variable in an investigation using HIIE. Dimopoulos and colleagues29 found that although 16 weeks of MICE and HIIE training both improved VO2peak, only MICE training resulted in a significant improvement in HRR in the first minute of recovery. Ventilatory efficiency Measures of ventilatory efficiency describe how much ventilation is required for a given VO2 or carbon dioxide production. The slope of the ratio of minute ventilation to carbon dioxide elimination (VE/VCO2) has been shown highly prognostic for morbidity and mortality in patients with HF.30 The oxygen uptake efficiency slope (OUES) is a mathematically derived variable based on the slope of VO2 (Y axis) and the log transformation of VE (X axis). This variable has also been shown important in the assessment of patients with HF.31 The findings for the effects of HIIE training are more mixed for these variables. For example, in the study by Fu and colleagues,13 both of these variables were significantly improved (higher OUES and lower VE/VCO2 slope) in the HIIE group but not in the MICE or control groups. Smart and Steele22 also confirm a reduction in VE/VCO2 slope after 16 weeks of HIIE training. In contrast, there was no significant improvement in the VE/VCO2 slope for the
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Pinkstaff
Table 1 Patient demographics, intervention parameters, main outcomes, and adverse events for chronic and acute training studies
Citation
HF Inclusion Criteria
Chronic Training Studies Stable systolic Chrysohoou et al,11 2014 dilated or ischemic HF, NYHA class II–IV, LVEF 50%
Iellamo et al,42 2013
Stable ischemic HF (last MI >6 mo prior), NYHA class II or III, LVEF 40% with pulmonary edema of cardiac origin
HIIE (n 5 14, 9 men): 3-min intervals at 80% VO2peak; 3 min active rest at 40% VO2peak MICE (n 5 13, 8 men): 60% VO2peak for 30 min Control (n 5 13, 9 men): general advice about home-based physical activity 3 d/wk for 12 wk Exercise mode: cycling (BE)
1 Subject each discontinued in HIIE and control group 2 Subjects discontinued in MICE group No reason given for subject dropouts
(continued on next page)
High-Intensity Intermittent Exercise Training
HIIE group experienced improvements in VE, VO2, VCO2, work rate; no changes in the same for the MICE or control groups HIIE group had higher OUES and lower VE/VCO2 slope compared with MICE HIIE resulted in increased CO, decreased TPR, and increased LVEF; these values remained unchanged in MICE and declined for the control group (except LVEF, which remained unchanged) HIIE enhanced cerebral/ muscular blood flow and muscular O2 utilization during exercise HIIE significantly reduced markers of inflammation/ oxidative stress HIIE significantly decreased MLWHF and increased the score for SF-36 physical and mental subclass No significant changes in measures of fitness or ventilatory efficiency occurred in the MICE or the control group MICE significantly decreased only the disease-specific QOL score
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Pinkstaff
Table 1 (continued)
Citation
HF Inclusion Criteria
Freyssin et al,12 2012
Stable chronic HF, LV ejection fraction
KEY POINTS
INTRODUCTION There is a robust trove of scientific studies that support the positive physical and mental health benefits associated with aerobic exercise for apparently healthy individuals. This evidence underlies the government-backed physical activity guidelines, which suggest 30 minutes of moderate-intensity exercise on most if not all days of the week.1,2 These recommendations also suggest that more vigorous exercise can be performed on fewer days for the same benefit, a recommendation that reflects the inverse doseresponse relationship between physical activity and disease.3–5 Those benefits include significant reductions in the risk factors associated with cardiovascular disease (CVD). There is also ample
evidence for the use of aerobic exercise in CVD patient populations to improve numerous healthrelated outcomes. Aerobic exercise was once contraindicated for patients with HF. In the early days of its use in this patient population, no greater than moderate-intensity training was recommended. Current guidelines recommend that patients with clinically stable HF perform aerobic MICE training (ie, 50%–80% of peak capacity) for up to 45 minutes on most days of the week.6,7 Since the 1980s, many studies have demonstrated the safety and effectiveness of aerobic MICE in patients with HF.8 Despite these positive results, a recent large, multicenter, randomized clinical trial, Heart Failure: A Controlled Trial Investigating Outcomes of
Disclosures: This author has no conflicts of interest to disclose. Physical Therapy Program, Department of Clinical and Applied Movement Sciences, University of North Florida, 1 UNF Drive, Jacksonville, FL 32224, USA E-mail address: [email protected] Heart Failure Clin 11 (2015) 133–148 http://dx.doi.org/10.1016/j.hfc.2014.08.008 1551-7136/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
heartfailure.theclinics.com
Moderate-intensity continuous exercise (MICE) has been the clinical standard for patients with heart failure (HF) but evidence is mounting for the effectiveness of high-intensity intermittent exercise (HIIE). HIIE is associated with clinically significant improvements in peak oxygen consumption (VO2peak) as well as many other variables associated with exercise capacity and cardiovascular function. The number of studies in which HIIE was used to treat patients with HF remains small, representing fewer than 200 patients. HIIE has not been associated with adverse events in the studies conducted to date. More research is needed before HIIE can become the clinical standard for patients with HF.
134
Pinkstaff Exercise Training (HF-ACTION), demonstrated no overall improvement in all-cause mortality and hospitalization.9 Importantly, after adjusting for highly prognostic clinical values for the same endpoints, exercise training did result in a modest prognostic improvement. Nonetheless, to many investigators, this remains a disappointing result. Recently clinicians and researchers have begun to investigate HIIE training as an intervention for this patient population. This type of training has been used extensively in healthy populations, in the context of athletic performance. A vast majority of the studies investigating the effect have been done in these populations. Although many fewer studies have been conducted in a patient population representing a much smaller number of patients, the results are promising. HIIE training seems safe and improves physiology, quality of life, and functional capacity.10–14 Many unanswered questions, however, remain. Therefore, the objective of this review is to define HIIE, discuss its physiologic benefit for patients with HF, outline the studies that have been conducted to date, and discuss the issues that need to be resolved before this exercise intervention is more widely embraced by the clinical community.
PRINCIPLES OF HIGH-INTENSITY INTERMITTENT EXERCISE HIIE involves the use of short periods of exercise interspersed with rest periods. The duration and intensity of the exercise and rest can be varied in numerous ways. The American College of Sports Medicine defines intensity as a percentage of heart rate (HR) reserve or VO2 reserve (VO2R). These are relative values that must be individually prescribed. Hard or very hard intensity is 60% to less than 85% and 85% to less than 100%, respectively. Exercise training at greater than 100% HR reserve (HRR) or VO2R has been used primarily for athletic training and is not considered for this review. For comparison, moderate intensity is defined as 40% to less than 60% HR reserve or VO2R. The rationale for HIIE is that the short periods of exercise followed by rest periods allow for greater time spent at a higher intensity of exercise (compared with continuous exercise).15 This greater intensity requires different energy production pathways to be used as well as additional muscle fiber recruitment. Together, these provide an increased potential for both central and peripheral adaptation. In a study of more than 5000 apparently healthy men and women, relative exercise training intensity was more important than duration in reducing the risk of all-cause and coronary heart disease mortality.15
There seems to be a mechanistic basis for this exercise intensity dependence. HF is characterized on the cellular level by dysfunctional cardiomyocyte activity. Aerobic exercise can repair or reverse some of these pathologic changes, especially when that exercise is high intensity (>90% of VO2peak). In animal studies, the physiologic adaptations to chronic exercise training are explained by changes to cardiomyocyte function. In rats and mice, improvement in cardiac pump function, as a result of positive changes to the cardiomyocyte, is achieved by high-intensity exercise.16 Furthermore, it has been suggested that for patient populations, high-intensity exercise training may be required for positive central adaptations, such as cardiac dilatation, ejection fraction, stroke volume, or other systolic parameters.17
EFFICACY/PHYSIOLOGIC BENEFITS OF HIIE TRAINING Acute Effects Recent studies have evaluated the acute effects of HIIE training in patients with HF (Table 1). In the most recent, a total of 13 patients with systolic HF were randomized to perform a single bout of high HIIE or MICE during which gas exchange and central hemodynamic factors were measured.18 The HIIE bout resulted in similar cardiac output (CO), stroke volume, and oxygen extraction compared with MICE. Importantly, the hemodynamic response to HIIE was stable throughout the training session. This stability is consistent with the lack of adverse events in this cohort, a finding that is similar to other published accounts of this type of training. Participants also tended to rate the perceived exertion lower and were more likely to be able to complete the bout of HIIE. This study complements an earlier study that demonstrated that when compared with steady state exercise, HIIE resulted in comparable increases in left ventricular (LV) ejection fraction, stroke volume, CO, ratings of leg fatigue, and dyspnea.19 The investigators also concluded that these results spoke to the safety of HIIE training. Tomczak and colleagues20 used MRI to assess the changes in biventricular function after a single bout of HIIE. The major finding was that biventricular function improved with a decrease in end-systolic volume and an increase in LV ejection fraction. The investigators suggested this improvement may be related to reduced systemic peripheral resistance or alternatively to improved cardiomyocyte contractility. Diastolic function was also improved as demonstrated by an
High-Intensity Intermittent Exercise Training increased peak untwisting rate, resulting in improved LV suction and diastolic filling.
Chronic Adaptations Most of the studies evaluating the effects of HIIE have been chronic training studies using various protocols, with some making comparisons to MICE and others with nonexercise standard care. All these studies find benefit from HIIE. The major benefits fall into several categories: exercise capacity, ventilatory efficiency, ventilatory threshold (VT)/anaerobic threshold (AT), cardiac and vascular function, and quality of life. The following discussion is a synopsis of the main outcomes assessed. See Table 1 for an overview of the main findings of each study. Exercise capacity The importance of exercise capacity in terms of prognosis in the context of health and disease cannot be overstated. Small improvements in exercise capacity, as measured by changes in VO2peak, can have a profound impact on the risk of all-cause and cardiovascular morbidity and mortality.21 It follows that the major goal of aerobic exercise training is to improve cardiorespiratory fitness. There is also a dose-response relationship where greater improvements in aerobic capacity are associated with greater reductions in risk. Wisløff and colleagues10 showed that 12 weeks of exercise training resulted in a 46% increase in VO2peak for those performing HIIE compared with a 14% increase for those performing MICE. Freyssin and colleagues12 used an 8-week HIIE program, which resulted in a 27% increase in VO2peak. In a study by Fu and colleagues,13 patients with HF undergoing an HIIE program for 12 weeks had a 22% increase in VO2peak. Similarly, in a 16-week program comparing HIIE to MICE training, Smart and Steele22 reported a significant increase (21%) only in the former group. Finally, in a recent study, Chrysohoou and colleagues11 looked at the effect of 12 weeks of HIIE training and demonstrated a 31% improvement in VO2peak. In all of these studies, with the exception of that by Smart and Steele22, the absolute increase in VO2 was greater than 1 metabolic equivalent (MET), a clinically relevant increase. A systematic review of 33 studies representing more than 100,000 apparently healthy subjects demonstrated 13% and 15% risk reductions for all-cause and cardiovascular-related mortality for each 1 MET in aerobic capacity, respectively.21 Six-minute walk test (6MWT) distance has been shown to correlate moderately well with VO2peak in patients with HF.23 It has been used in many studies as a surrogate for VO2peak and to measure
changes in exercise capacity after aerobic training. Similarly, total exercise time during an exercise test and peak work rate (WRpeak) also correlated with exercise capacity. Nilsson and colleagues24 showed that following 16 weeks of HIIE training, patients increased their walking distance and exercise time significantly. The exercise training group was compared with a standard care nonexercising group. In the same group of patients, the long-term effects of exercise training were investigated. After 12 months, the gains in measures of exercise capacity were still significant.25 Freyssin and colleagues12 also used 6MWT distance and exercise time to measure change in functional capacity after an 8-week training protocol. This study showed a 47% increase in exercise time for the HIIE group versus a 12% increase for the MICE group. Similarly, 6MWT distance increased 12% and 6%, respectively, for the HIIE and MICE groups. Chrysohoou and colleagues11 demonstrated a 13% improvement in 6MWT distance and a 25% improvement in WRpeak. The chronotropic response to exercise is related to the health of the autonomic nervous system and has been found impaired in patients with HF.26 Specifically, HRR is slowed in patients with HF and is hastened in the highly fit.27 HRR can be improved with chronic MICE training.28 Only one study has considered this variable in an investigation using HIIE. Dimopoulos and colleagues29 found that although 16 weeks of MICE and HIIE training both improved VO2peak, only MICE training resulted in a significant improvement in HRR in the first minute of recovery. Ventilatory efficiency Measures of ventilatory efficiency describe how much ventilation is required for a given VO2 or carbon dioxide production. The slope of the ratio of minute ventilation to carbon dioxide elimination (VE/VCO2) has been shown highly prognostic for morbidity and mortality in patients with HF.30 The oxygen uptake efficiency slope (OUES) is a mathematically derived variable based on the slope of VO2 (Y axis) and the log transformation of VE (X axis). This variable has also been shown important in the assessment of patients with HF.31 The findings for the effects of HIIE training are more mixed for these variables. For example, in the study by Fu and colleagues,13 both of these variables were significantly improved (higher OUES and lower VE/VCO2 slope) in the HIIE group but not in the MICE or control groups. Smart and Steele22 also confirm a reduction in VE/VCO2 slope after 16 weeks of HIIE training. In contrast, there was no significant improvement in the VE/VCO2 slope for the
135
136
Pinkstaff
Table 1 Patient demographics, intervention parameters, main outcomes, and adverse events for chronic and acute training studies
Citation
HF Inclusion Criteria
Chronic Training Studies Stable systolic Chrysohoou et al,11 2014 dilated or ischemic HF, NYHA class II–IV, LVEF 50%
Iellamo et al,42 2013
Stable ischemic HF (last MI >6 mo prior), NYHA class II or III, LVEF 40% with pulmonary edema of cardiac origin
HIIE (n 5 14, 9 men): 3-min intervals at 80% VO2peak; 3 min active rest at 40% VO2peak MICE (n 5 13, 8 men): 60% VO2peak for 30 min Control (n 5 13, 9 men): general advice about home-based physical activity 3 d/wk for 12 wk Exercise mode: cycling (BE)
1 Subject each discontinued in HIIE and control group 2 Subjects discontinued in MICE group No reason given for subject dropouts
(continued on next page)
High-Intensity Intermittent Exercise Training
HIIE group experienced improvements in VE, VO2, VCO2, work rate; no changes in the same for the MICE or control groups HIIE group had higher OUES and lower VE/VCO2 slope compared with MICE HIIE resulted in increased CO, decreased TPR, and increased LVEF; these values remained unchanged in MICE and declined for the control group (except LVEF, which remained unchanged) HIIE enhanced cerebral/ muscular blood flow and muscular O2 utilization during exercise HIIE significantly reduced markers of inflammation/ oxidative stress HIIE significantly decreased MLWHF and increased the score for SF-36 physical and mental subclass No significant changes in measures of fitness or ventilatory efficiency occurred in the MICE or the control group MICE significantly decreased only the disease-specific QOL score
137
138
Pinkstaff
Table 1 (continued)
Citation
HF Inclusion Criteria
Freyssin et al,12 2012
Stable chronic HF, LV ejection fraction
