Exercise and Metabolic Demand in HF With Preserved EF
Exercise and Metabolic Demand in HF With Preserved EF
This study assessed haemodynamic responses to exercise in order to determine how cardiac filling and ejection capacity affect oxygen delivery and extraction to mediate exercise limitation (reduced VO2) in patients with HFpEF. We demonstrate that compared with controls, the increase in CO relative to metabolic requirements (VO2) is fundamentally impaired in HFpEF. CO reserve limitation in HFpEF was coupled to impairments in LV contractile and chronotropic reserve. Increases in LV preload (end-diastolic volume) during exercise were similar in HFpEF patients and controls, but similar preload recruitment in those with HFpEF required three-fold greater increases in LV filling pressures (PCWP), causing secondary elevation in PAP, which may impair right ventricular ejection and further contribute to blunted CO reserve. Increases in AVO2diff at peak exercise were similar in HFpEF patients and controls, but increases relative to absolute O2 consumption were enhanced in those with HFpEF, suggesting peripheral adaptation to the impairment in O2 delivery (CO reserve). These findings were consistently observed during both supine and upright exercise and employing both invasive and non-invasive modalities to assess CO, indicating that in addition to abnormalities in LV diastolic filling, impairments in CO reserve with stress contribute to the impairment in oxygen consumption in patients with HFpEF.
Functional capacity (peak VO2) is similarly impaired in HFpEF and HFrEF. Peak VO2 is an integrated measure of cardiac reserve that is being used to diagnose HFpEF and as an endpoint in clinical trials. Thus, better characterization of the fundamental mechanisms underlying VO2 limitation in HFpEF is essential for improved understanding of pathophysiological mechanisms and to better inform future trial design and identify therapeutic targets.
Most studies have reported that exercise VO2 and CO are individually depressed in HFpEF. However, VO2 and CO at any time during exercise are largely determined by the intensity of work being performed. Thus, group differences in CO might be caused by cardiac limitations or non-cardiovascular factors including patient motivation, peripheral limitations, fitness, or orthopaedic issues. Elevation in cardiac filling pressures (at rest or with stress) is the most conspicuous and consistently observed haemodynamic feature in HFpEF. Non-diastolic limitations have been reported, but their roles have been questioned. Impaired exercise reserve responses in non-diastolic parameters (e.g. HR or contractile response) may not be causal of exercise intolerance, but rather consequence of premature cessation of exercise in response to dyspnoea from high filling pressures, abnormal metabolic–neural signalling, or non-cardiac factors such as deconditioning or obesity. Indeed, textbooks of exercise physiology describe how patients with HFrEF are limited by inadequate CO reserve with exercise, whereas patients with HFpEF have normal CO responses but elevated filling pressures. It has even been questioned whether HFpEF truly represents a form of cardiac failure, since patients are frequently elderly with co-morbidities that might in themselves produce symptoms of effort intolerance that are not directly attributable to cardiac dysfunction.
The current data provide compelling evidence that the reduction in exercise capacity in HFpEF is determined largely by inadequate CO reserve, which, when combined with stress-induced elevations in cardiac filling pressures, markedly limits exercise capacity. The strength of this experimental approach lies in the simultaneous assessment of both whole-body O2 delivery (CO) and O2 consumption (VO2). Because increases in CO during exercise are ultimately driven by increases in VO2, this analysis allows for direct comparisons of exercise responses between patients with HFpEF and controls, without the need to adjust for measures of effort adequacy (such as the respiratory exchange ratio) that are necessary to gauge metabolic status when CO is not directly measured. Intriguingly, scaling CO reserve to external work failed to reveal the cardiac limitation in HFpEF, suggesting that this index is less sensitive to haemodynamic impairments in HFpEF.
The relationship between CO and VO2 is typically depressed in patients with HFrEF, in keeping with the definition of HF as an inability to pump blood adequately to the body at normal filling pressures. However, only one previous study has examined the relationship between CO and VO2 in HFpEF. Bhella and colleagues found that peak VO2 and CO were reduced in HFpEF, similar to the current data, but, when plotting CO relative to VO2, the authors surprisingly found that the enhancement in CO was elevated in HFpEF. The authors speculated that abnormalities in skeletal muscle might generate metabolic signals that drive excessive increases in CO, leading to increased ventricular filling pressures during exercise in HFpEF.
The current data argue against this hypothesis, showing that on average the increase in CO relative to VO2 was impaired in HFpEF. The reasons for the discordant findings are not obvious, although it is notable that the SV enhancement during exercise in HFpEF patients noted by Bhella et al. (+74% increase) was remarkably high, and well in excess of the +16% increase noted in the current study and the –7 to +10% changes with exercise reported by other groups. Secondly, Bhella and colleagues found that the resting VO2 was elevated in the HFpEF patients—suggesting a hypermetabolic state. In contrast, in the current study, the resting O2 consumption (scaled to body mass) was lower in HFpEF. These differences may relate to changes in metabolism reflecting variability in HF severity or chronicity between the two study populations.
Cardiac output reserve limitation in HFpEF was related to impaired SV and HR, similar to previous studies, Inadequate SV (and EF) reserve was due to an inability to reduce LV end-systolic volume with exercise, since end-diastolic volume increased similarly in HFpEF patients and controls. Impaired reduction in end-systolic volume could be caused by inadequate enhancement in contractility, blunted afterload reduction, or both. Previous studies have reported attenuated reductions in systemic vascular resistance (SVR) during exercise in HFpEF patients. In this study, effective arterial elastance (Ea), which characterizes total (resistive and pulsatile) arterial afterload, changed similarly in HFpEF patients and controls. This finding may appear at odds with previous studies showing increased arterial stiffness and impaired flow-mediated dilation in HFpEF. However, it is also known that Ea varies directly with HR, in addition to SVR. Because HR was ~30% higher at peak exercise in controls, this would inflate the exercise Ea value in this group, even if other components of afterload were lower. The similar change in Ea observed during exercise in the current study suggests that the blunted SV and EF responses with exercise in HFpEF patients were caused primarily by limitations in contractile reserve.
Enhancement in LV end-diastolic volume was similar in HFpEF patients and controls, though diastolic reserve was clearly impaired, as evidenced by the three-fold greater elevation in PCWP in HFpEF patients. It is currently unknown if mitigation of PCWP elevation in HFpEF would directly improve aerobic capacity, though a recent trial found that exercise training was associated with a reduced resting E/e' ratio (a marker of PCWP), and the extent of resting E/e' improvement was correlated with the improvement in peak VO2. Elevation in LV diastolic pressure is often considered to limit exercise capacity by provoking dyspnoea, yet it is notable that PCWP increases during exercise in patients with HFpEF were associated with dramatic elevations in PAPs, increasing right ventricular afterload. Given the well-described impact of right ventricular dysfunction on exercise capacity in HFrEF, the enhanced load sensitivity of the right ventricle, and the deleterious impact of increased PCWP on pulsatile right ventricular load, it is likely that PCWP elevation from diastolic dysfunction in HFpEF has additional implications for right ventricular reserve that may also limit CO responses to exercise.
The Fick equation dictates that VO2 is equal to the product of CO and AVO2diff, and patients with HF may display reduced peak VO2 that is related to abnormalities in the latter, the former, or both. We found that AVO2diff at peak exercise was not different between HFpEF patients and controls, though the increase in AVO2diff as a function of VO2 (ΔAVO2 difference/ΔVO2 slope) was enhanced in those with HFpEF. We speculate that this functions to compensate partly for inadequate O2 delivery from CO reserve impairment at submaximal workloads in HFpEF.
The similar increase in peak exercise AVO2diff in cases and controls is similar to recent findings from Maeder and colleagues, but differs from two recent reports showing reduced AVO2diff at peak exercise in HFpEF patients. These discrepancies may relate to the populations studied and different analytical approaches. The latter studies enrolled disease-free controls, as opposed to the current study that included controls with co-morbidities that might influence O2 extraction. Haykowsky et al. performed comparisons of AVO2diff relative to workload (Watts) as opposed to VO2. They also found that the oxygen uptake/work slope was attenuated in HFpEF, meaning that VO2 was lower for any workload in HFpEF. Thus, the ΔAVO2diff/ΔVO2 slope in their HFpEF group might be expected to have been steeper if their data were examined according to VO2.
When CO is reduced, circulation time is increased, which may provide greater time for gas diffusion at the capillaries and greater O2 extraction. Thus, our findings should not be taken to indicate that patients with HFpEF are more 'adept' at peripheral O2 extraction, or that abnormalities in the periphery do not play key roles in limiting exercise capacity in HFpEF, as indicated in multiple recent studies. Indeed, even with limited CO reserve, improvements in peripheral function may be attainable with interventions such as exercise training, probably related to the greater plasticity in the vasculature and skeletal muscle. Future research may clarify whether clinical evaluation of both VO2 and CO reserve will allow for more refined insight as to whether limitations in a specific patient are due predominantly to cardiac or peripheral factors, possibly to better tailor therapy.
Patients with HFpEF and control subjects were drawn from three cohorts, two prospectively enrolled and one retrospective. Cohort 1 was a cath lab referral population, introducing potential bias. The protocols and methods to measure CO were different. However, all are well established, and the finding of impaired CO reserve relative to VO2 was uniformly and consistently observed in both upright and supine exercise when analysed separately and taking into account body position (Table 3; Supplementary material, Table S3). Cardiac pressure and volume were not measured simultaneously during exercise and in the same patient, but pressure and volume data in the three cohorts were included to provide insight into the mechanisms for CO limitation in HFpEF. Importantly, the primary endpoints (CO and VO2) were directly measured at rest and during exercise in all subjects. Baseline differences were present, including greater age, adiposity, beta-blocker use, and creatinine in those with HFpEF. However, all group differences remained highly significant after adjusting for each of these baseline differences. Subjective symptoms (dyspnoea, fatigue) were not quantified, and many subjects did not exercise to their ideal maximum capacity, particularly during supine ergometry, where peak HR and VO2 were lower. However, attainment of true maximal objective exercise workload is not necessary in this analysis, because adequacy of CO reserve was evaluated by scaling it to the physiological variable that drives it (VO2). This study did not assess for the development of mitral regurgitation during exercise, which may also contribute to impaired CO reserve and exertional pulmonary hypertension in HFpEF. Not all HFpEF subjects were taking chronic diuretics (69%), but this prevalence is similar to other studies of compensated HFpEF outpatients.
Discussion
This study assessed haemodynamic responses to exercise in order to determine how cardiac filling and ejection capacity affect oxygen delivery and extraction to mediate exercise limitation (reduced VO2) in patients with HFpEF. We demonstrate that compared with controls, the increase in CO relative to metabolic requirements (VO2) is fundamentally impaired in HFpEF. CO reserve limitation in HFpEF was coupled to impairments in LV contractile and chronotropic reserve. Increases in LV preload (end-diastolic volume) during exercise were similar in HFpEF patients and controls, but similar preload recruitment in those with HFpEF required three-fold greater increases in LV filling pressures (PCWP), causing secondary elevation in PAP, which may impair right ventricular ejection and further contribute to blunted CO reserve. Increases in AVO2diff at peak exercise were similar in HFpEF patients and controls, but increases relative to absolute O2 consumption were enhanced in those with HFpEF, suggesting peripheral adaptation to the impairment in O2 delivery (CO reserve). These findings were consistently observed during both supine and upright exercise and employing both invasive and non-invasive modalities to assess CO, indicating that in addition to abnormalities in LV diastolic filling, impairments in CO reserve with stress contribute to the impairment in oxygen consumption in patients with HFpEF.
Cardiac Output and Peak VO2 in Heart Failure With Preserved Ejection Fraction
Functional capacity (peak VO2) is similarly impaired in HFpEF and HFrEF. Peak VO2 is an integrated measure of cardiac reserve that is being used to diagnose HFpEF and as an endpoint in clinical trials. Thus, better characterization of the fundamental mechanisms underlying VO2 limitation in HFpEF is essential for improved understanding of pathophysiological mechanisms and to better inform future trial design and identify therapeutic targets.
Most studies have reported that exercise VO2 and CO are individually depressed in HFpEF. However, VO2 and CO at any time during exercise are largely determined by the intensity of work being performed. Thus, group differences in CO might be caused by cardiac limitations or non-cardiovascular factors including patient motivation, peripheral limitations, fitness, or orthopaedic issues. Elevation in cardiac filling pressures (at rest or with stress) is the most conspicuous and consistently observed haemodynamic feature in HFpEF. Non-diastolic limitations have been reported, but their roles have been questioned. Impaired exercise reserve responses in non-diastolic parameters (e.g. HR or contractile response) may not be causal of exercise intolerance, but rather consequence of premature cessation of exercise in response to dyspnoea from high filling pressures, abnormal metabolic–neural signalling, or non-cardiac factors such as deconditioning or obesity. Indeed, textbooks of exercise physiology describe how patients with HFrEF are limited by inadequate CO reserve with exercise, whereas patients with HFpEF have normal CO responses but elevated filling pressures. It has even been questioned whether HFpEF truly represents a form of cardiac failure, since patients are frequently elderly with co-morbidities that might in themselves produce symptoms of effort intolerance that are not directly attributable to cardiac dysfunction.
The current data provide compelling evidence that the reduction in exercise capacity in HFpEF is determined largely by inadequate CO reserve, which, when combined with stress-induced elevations in cardiac filling pressures, markedly limits exercise capacity. The strength of this experimental approach lies in the simultaneous assessment of both whole-body O2 delivery (CO) and O2 consumption (VO2). Because increases in CO during exercise are ultimately driven by increases in VO2, this analysis allows for direct comparisons of exercise responses between patients with HFpEF and controls, without the need to adjust for measures of effort adequacy (such as the respiratory exchange ratio) that are necessary to gauge metabolic status when CO is not directly measured. Intriguingly, scaling CO reserve to external work failed to reveal the cardiac limitation in HFpEF, suggesting that this index is less sensitive to haemodynamic impairments in HFpEF.
The relationship between CO and VO2 is typically depressed in patients with HFrEF, in keeping with the definition of HF as an inability to pump blood adequately to the body at normal filling pressures. However, only one previous study has examined the relationship between CO and VO2 in HFpEF. Bhella and colleagues found that peak VO2 and CO were reduced in HFpEF, similar to the current data, but, when plotting CO relative to VO2, the authors surprisingly found that the enhancement in CO was elevated in HFpEF. The authors speculated that abnormalities in skeletal muscle might generate metabolic signals that drive excessive increases in CO, leading to increased ventricular filling pressures during exercise in HFpEF.
The current data argue against this hypothesis, showing that on average the increase in CO relative to VO2 was impaired in HFpEF. The reasons for the discordant findings are not obvious, although it is notable that the SV enhancement during exercise in HFpEF patients noted by Bhella et al. (+74% increase) was remarkably high, and well in excess of the +16% increase noted in the current study and the –7 to +10% changes with exercise reported by other groups. Secondly, Bhella and colleagues found that the resting VO2 was elevated in the HFpEF patients—suggesting a hypermetabolic state. In contrast, in the current study, the resting O2 consumption (scaled to body mass) was lower in HFpEF. These differences may relate to changes in metabolism reflecting variability in HF severity or chronicity between the two study populations.
Determinants of Cardiac Output Limitation
Cardiac output reserve limitation in HFpEF was related to impaired SV and HR, similar to previous studies, Inadequate SV (and EF) reserve was due to an inability to reduce LV end-systolic volume with exercise, since end-diastolic volume increased similarly in HFpEF patients and controls. Impaired reduction in end-systolic volume could be caused by inadequate enhancement in contractility, blunted afterload reduction, or both. Previous studies have reported attenuated reductions in systemic vascular resistance (SVR) during exercise in HFpEF patients. In this study, effective arterial elastance (Ea), which characterizes total (resistive and pulsatile) arterial afterload, changed similarly in HFpEF patients and controls. This finding may appear at odds with previous studies showing increased arterial stiffness and impaired flow-mediated dilation in HFpEF. However, it is also known that Ea varies directly with HR, in addition to SVR. Because HR was ~30% higher at peak exercise in controls, this would inflate the exercise Ea value in this group, even if other components of afterload were lower. The similar change in Ea observed during exercise in the current study suggests that the blunted SV and EF responses with exercise in HFpEF patients were caused primarily by limitations in contractile reserve.
Enhancement in LV end-diastolic volume was similar in HFpEF patients and controls, though diastolic reserve was clearly impaired, as evidenced by the three-fold greater elevation in PCWP in HFpEF patients. It is currently unknown if mitigation of PCWP elevation in HFpEF would directly improve aerobic capacity, though a recent trial found that exercise training was associated with a reduced resting E/e' ratio (a marker of PCWP), and the extent of resting E/e' improvement was correlated with the improvement in peak VO2. Elevation in LV diastolic pressure is often considered to limit exercise capacity by provoking dyspnoea, yet it is notable that PCWP increases during exercise in patients with HFpEF were associated with dramatic elevations in PAPs, increasing right ventricular afterload. Given the well-described impact of right ventricular dysfunction on exercise capacity in HFrEF, the enhanced load sensitivity of the right ventricle, and the deleterious impact of increased PCWP on pulsatile right ventricular load, it is likely that PCWP elevation from diastolic dysfunction in HFpEF has additional implications for right ventricular reserve that may also limit CO responses to exercise.
Arterial–Venous Oxygen Extraction Reserve
The Fick equation dictates that VO2 is equal to the product of CO and AVO2diff, and patients with HF may display reduced peak VO2 that is related to abnormalities in the latter, the former, or both. We found that AVO2diff at peak exercise was not different between HFpEF patients and controls, though the increase in AVO2diff as a function of VO2 (ΔAVO2 difference/ΔVO2 slope) was enhanced in those with HFpEF. We speculate that this functions to compensate partly for inadequate O2 delivery from CO reserve impairment at submaximal workloads in HFpEF.
The similar increase in peak exercise AVO2diff in cases and controls is similar to recent findings from Maeder and colleagues, but differs from two recent reports showing reduced AVO2diff at peak exercise in HFpEF patients. These discrepancies may relate to the populations studied and different analytical approaches. The latter studies enrolled disease-free controls, as opposed to the current study that included controls with co-morbidities that might influence O2 extraction. Haykowsky et al. performed comparisons of AVO2diff relative to workload (Watts) as opposed to VO2. They also found that the oxygen uptake/work slope was attenuated in HFpEF, meaning that VO2 was lower for any workload in HFpEF. Thus, the ΔAVO2diff/ΔVO2 slope in their HFpEF group might be expected to have been steeper if their data were examined according to VO2.
When CO is reduced, circulation time is increased, which may provide greater time for gas diffusion at the capillaries and greater O2 extraction. Thus, our findings should not be taken to indicate that patients with HFpEF are more 'adept' at peripheral O2 extraction, or that abnormalities in the periphery do not play key roles in limiting exercise capacity in HFpEF, as indicated in multiple recent studies. Indeed, even with limited CO reserve, improvements in peripheral function may be attainable with interventions such as exercise training, probably related to the greater plasticity in the vasculature and skeletal muscle. Future research may clarify whether clinical evaluation of both VO2 and CO reserve will allow for more refined insight as to whether limitations in a specific patient are due predominantly to cardiac or peripheral factors, possibly to better tailor therapy.
Limitations
Patients with HFpEF and control subjects were drawn from three cohorts, two prospectively enrolled and one retrospective. Cohort 1 was a cath lab referral population, introducing potential bias. The protocols and methods to measure CO were different. However, all are well established, and the finding of impaired CO reserve relative to VO2 was uniformly and consistently observed in both upright and supine exercise when analysed separately and taking into account body position (Table 3; Supplementary material, Table S3). Cardiac pressure and volume were not measured simultaneously during exercise and in the same patient, but pressure and volume data in the three cohorts were included to provide insight into the mechanisms for CO limitation in HFpEF. Importantly, the primary endpoints (CO and VO2) were directly measured at rest and during exercise in all subjects. Baseline differences were present, including greater age, adiposity, beta-blocker use, and creatinine in those with HFpEF. However, all group differences remained highly significant after adjusting for each of these baseline differences. Subjective symptoms (dyspnoea, fatigue) were not quantified, and many subjects did not exercise to their ideal maximum capacity, particularly during supine ergometry, where peak HR and VO2 were lower. However, attainment of true maximal objective exercise workload is not necessary in this analysis, because adequacy of CO reserve was evaluated by scaling it to the physiological variable that drives it (VO2). This study did not assess for the development of mitral regurgitation during exercise, which may also contribute to impaired CO reserve and exertional pulmonary hypertension in HFpEF. Not all HFpEF subjects were taking chronic diuretics (69%), but this prevalence is similar to other studies of compensated HFpEF outpatients.
