INTRODUCTION: DOES CARDIAC FUNCTION MATTER MOST IN HEART FAILURE?
Chronic heart failure (HF) is a clinical syndrome that is a leading cause of hospitalizations and mortality in developed countries (11,30). HF is a syndrome that burdens patients but also poses significant challenges to health care systems and providers (11,23). HF is no longer considered primarily an impairment in systolic function, but it is now recognized that nearly half of HF cases are patients with preserved ejection fraction (HFpEF) (4,28,30). Most importantly, however, the evidence currently indicates that HFpEF share a mortality risk similar to HF patients with reduced ejection fraction (HFrEF) (4,28).
The New York Heart Association (NYHA) functional classification system is useful for assessing syndrome severity and prognosis in HF (11). Classification of HF using NYHA criteria is based on symptoms (e.g., dyspnea, fatigue, or peripheral edema) and perception of exercise tolerance. However, despite the value of the NYHA class system for the clinical evaluation of HF, little evidence suggests that NYHA functional class correlates with the magnitude of objective signs of cardiovascular impairment in these patients (31,34). The lack of close association between NYHA functional class and cardiovascular impairment in HF is noteworthy because observations from cardiopulmonary exercise testing suggest that direct measurements of cardiac and/or pulmonary system function provide information that strongly relate to prognosis in patients (9,13,18,28,34). Therefore, complementary to the NYHA functional class system is the Weber-Janicki classification system, which suggests that evaluation of functional impairment (e.g., exercise tolerance) based on traditional cardiopulmonary responses (e.g., oxygen uptake and cardiac index) during exercise testing is critical in the clinical evaluation of HF (36). As such, the numerous but variable evidence supporting the current models for the clinical classification of HF has led our group to question which system, index, or indices are optimal for evaluating syndrome severity and prognosis in HF.
HF syndrome is a pathophysiological state that evolves because of impaired cardiac function concurrent with comorbidities, which frequently include hypertension and coronary artery diseases (11,28,30). Closely associated with mortality in HF and commonly recognized as consequences of this cardiovascular syndrome include pulmonary system and cardiac dysfunction irrespective of preserved or reduced ejection fraction percentage (EF%) classification (9,11,13,18,28,39). Cardiac dysfunction in HF often is described using values of cardiac output (Q), stroke volume (SV), or resting EF% that are abnormally low and may be useful for estimating syndrome severity and prognosis in HFrEF and HFpEF (8,11,18,28). Despite the common use of resting EF% to describe HF severity in the clinical setting, this index is a poor indicator of exercise tolerance and cardiac reserve (i.e., change from rest to peak exercise) in these individuals (32). In contrast, although Q and SV measures at rest may not encapsulate fully the magnitude of cardiac dysfunction in HF, exercise cardiac function assessment is known to elicit hemodynamic responses that provide critical information pertaining to the magnitude of absolute and reserve cardiac impairment in these patients (1,5,11,28). Furthermore, it has been demonstrated that exercise cardiac hemodynamic responses may be the strongest indicators of prognosis in HF (18,37).
In addition to the more recognized impairments related to cardiac dysfunction or low ventilatory efficiency (i.e., high ratio of minute ventilation to the production of carbon dioxide (VE/VCO2 slope)), HF patients also have been observed to demonstrate low forced expiratory volume in 1 s, attenuated capacity for gas transfer within lungs, and low oxygen consumption (VO2) (24,25,27,33,39). Moreover, when assessed during exercise, pulmonary system function worsens in HF, which is consistent with the increased hemodynamic stress imposed on the lungs caused by the hemodynamic backup of fluid as a result of the blunted Q and SV responses to exercise in these individuals (8,24,25,27,39). Nevertheless, despite the supporting evidence highlighting the value of pulmonary or ventilatory markers in describing syndrome severity or predicting prognosis in HF, independent use of these indices in comparison with cardiac hemodynamics for the clinical classification of patients remains open to question (18,37).
Therefore, although there is ample evidence that demonstrates the importance of the information gathered from symptoms and signs of HF that comprise the criteria for NYHA functional and Weber-Janicki classification systems, the question “What surrogate index or indices of cardiac and/or pulmonary function best estimate syndrome severity and prognosis in HF?” remains a challenge. Although the factors that may influence the answer to the above question are broad, to ensure brevity and conciseness, we aimed to focus our answer to this question with evidence that favors metrics related closely to the blood flow and pressure-generating capability of the heart, particularly during exercise, in determining a robust index or set of indices for the clinical classification of HF irrespective of categorization based on EF%.
Cardiac pumping capacity and cardiac pumping reserve in healthy individuals and in HF may be described using nontraditional measures such as cardiac power (CP) and stroke work (SW) (18,22). In contrast to Q and SV, both CP (Q × mean arterial pressure (MAP)) and SW (SV × MAP) directly account for the contribution of cardiac blood flow to the maintenance of arterial pressure that are both necessary for the maintenance of perfusion pressure and oxygen delivery to metabolically active tissue. Exercise measures of CP and SW in HF are suggested to be particularly useful in describing cardiac responsiveness to hemodynamic stress such as that caused by exercise (i.e., cardiac reserve) (18,22). Moreover, observations from exercise studies suggest that CP and SW may be the strongest indicators of prognosis in HF compared with traditional measures of Q and SV, as well as in comparison with ventilatory markers (18,22). Indirect noninvasive measurements of CP and SW, which include circulatory power (CircP = VO2 × MAP) and pulse work (PW = VO2/heart rate × MAP), respectively, also may estimate cardiac pumping capacity while being valuable indices for predicting prognosis in HF (7,38).
Therefore, because of an emerging body of evidence supporting the use of nontraditional measures of cardiac pumping capacity for assessing syndrome severity and prognosis related to cardiac dysfunction in HF, we hypothesized that both direct and indirect metrics specific to estimating cardiac pumping capacity, specifically during exercise, can be used to strengthen the clinical classification of HFrEF and HFpEF. We present this hypothesis schematically in Figure 1, which suggests that the strength of index for the evaluation of HF increases moving from top to bottom, in addition to exercise evaluation demonstrating a higher value compared with rest.
TECHNIQUES USED FOR MEASURING CARDIAC FUNCTION IN HEART FAILURE
The optimal technique for estimating Q and SV is the direct Fick method (15,17); however, this technique requires arterial catheterization with arterial and mixed venous blood samples that make it not only invasive but impractical for routine clinical and research use. Other techniques that require right heart catheterization (e.g., thermodilution or continuous Q) can be used for measuring not only Q and SV but also cardiac pressures (15). However, similar to direct Fick, these right heart catheterization techniques are highly invasive and require the availability of a catheterization laboratory and cardiology team.
In contrast, echocardiography (ECHO) is a noninvasive technique that can be used to describe both cardiac structure and function and, therefore, has become widely used in clinical and research settings for assessing cardiac health in HF. Validation studies have presented evidence that suggests that ECHO agrees with the “gold standard” (i.e., direct Fick) for estimating Q and SV at rest and during exercise in HF (16,19). However, use of ECHO for the precise and accurate measurement of Q and SV at rest and particularly during exercise poses its own set of challenges, namely, that it is a highly user-dependent technique requiring highly skilled trained sonographers to acquire images and equally skilled cardiologists to interpret the images accurately for clinical purposes (20).
Accordingly, there remains considerable interest in other noninvasive techniques such as inert gas breathing (e.g., acetylene, nitrous oxide, or carbon dioxide gases) for the measurement of cardiac hemodynamics at rest and during exercise in HF. Observations from comparison studies that have tested cardiac hemodynamic measurements using inert gas breathing in comparison with invasive (i.e., direct Fick and thermodilution) or noninvasive (i.e., ECHO or oxygen pulse (O2pulse)) techniques are promising and suggest that inert gas breathing is an adequate technique for the assessment of cardiac hemodynamics in patient populations (2,15,17). Our group recently demonstrated that the acetylene rebreathing technique can provide similar estimates of SV when compared with ECHO or standard gas exchange (i.e., O2pulse) techniques at rest or at peak exercise in healthy individuals and in HFpEF. Others also have demonstrated that inert gas breathing or standard gas exchange closely agrees with direct Fick at rest and during exercise in healthy individuals and in HFrEF (2,15,33).
IS CLINICAL CLASSIFICATION OF HEART FAILURE AT REST OUTDATED?
Despite the numerous techniques available for estimating cardiac hemodynamics, each with limitations, we sought to illustrate in this review that indices descriptive of cardiac function during exercise are optimal for the clinical classification of HF, whereas traditional measures of cardiac function at rest may be better served for identifying the potential presence of cardiac abnormalities in HF. For example, previous observations suggest that both invasive (radionuclide, cardiac index) and noninvasive (ECHO, EF%) estimates of resting left ventricular function do not relate directly to the degree of exercise intolerance (i.e., VO2peak) in HFrEF (14). Others have demonstrated that resting Q and SV measured using noninvasive CO2 rebreathe also do not correlate with exercise tolerance in HFrEF (12). In contrast, it has been observed that, despite weak relationships between resting measures of cardiac function and exercise tolerance in HFrEF, exercise measures of cardiac index correlate closely with VO2max and exercise duration in these patients (32). More importantly, it also was demonstrated that HF patients with a higher VO2max (>10.0 mL kg-1 min-1) had a lower mortality rate (14% vs 77%) at 1-yr follow-up versus HF patients with a low VO2max (<10.0 mL kg-1 min-1), suggesting that evaluation of cardiac function during exercise is superior at predicting mortality outcomes when compared with evaluation at rest (32). In further support of exercise testing as a method for the clinical evaluation of HF, results of 6-min walk testing have been shown to correlate directly with VO2peak as well as predict short-term prognosis (i.e., <1 yr) in these patients (6). Thus, although invasive or noninvasive techniques can be used reliably to identify the presence of impaired cardiac function at rest in HF, it remains unclear whether functional and prognostic implications of cardiac dysfunction associated with HF can be described adequately by measurement of cardiac function at rest in these patients.
WHAT IS THE VALUE OF PEAK OXYGEN UPTAKE VERSUS PEAK CARDIAC FUNCTION?
The contribution of exercise tolerance testing using VO2 or its estimate, 6-min walk test, for estimating functional capacity or prognosis cannot be ignored in HF. HF patients with a low VO2peak (e.g., <10–14 mL kg -1 min-1) are suggested to be at higher risk for mortality compared with patients with a higher VO2peak (e.g., >10–14 mL kg-1 min-1) (11,32). Also a consideration, assessment of VO2peak or 6-min walk test requires the use of no advanced technology and are readily available tests in most clinical and research settings. In contrast, reliable and accurate measurement of cardiac hemodynamics via catheterization laboratories or imaging modalities can be variable and highly dependent on factors related to equipment or physician availability, technician experience, or cost of technology.
Despite the encouraging observations from studies of VO2peak in HF in addition to potential limitations influential in preventing cardiac hemodynamic assessment during exercise, several noteworthy observations suggest that symptoms, signs, and prognosis in HF directly relate to cardiac pump dysfunction and, hence, exercise cardiac hemodynamic evaluation may be essential for the clinical classification of these patients (7,18,32,37). Support for cardiac hemodynamic measures such as CP suggests that assessment of this index during exercise predicts survival to the greatest extent compared with traditional measures of cardiovascular function in HFrEF (18,37). Furthermore, consistent among studies of CP are observations that demonstrate that higher survival among HF patients is associated with individuals who have the highest levels of peak CP at baseline (18,37). Also, although VO2peak may relate to survival in HF, it is suggested that VO2peak contributes no additional value for assessing survival risk independent of measures directly related to cardiac pumping capacity measured during exercise in HF patients (18,37). We argue, therefore, that although a valuable component in describing Weber-Janicki functional class in HF, VO2 provides information that may not be consistently relied on to be unique and directly specific in estimating cardiac pumping capacity perhaps because VO2 is a metric that is highly influenced by noncardiac factors (e.g., motivation, muscle deconditioning, peripheral oxygen extraction, and/or abnormal pressor reflexes) in this population (18,29,36,37). We and others before us recommend that independent measures of VO2 should not be used as direct surrogates for the blood flow and pressure-generating capability of the heart during exercise in HF (18,37).
THE CARDIAC PUMPING CAPACITY MODEL IN HEART FAILURE
Consistent with observations that describe the clinical value of assessing cardiac hemodynamics during exercise, particularly cardiac pumping capacity in HFrEF (7,18,37), we have observed recently in HFpEF no contradictory evidence, which is presented in Tables 1 and 2 as well as in Figure 2. HF patients with preserved EF% (N = 18; EF% = 62.2% ± 1.3%), although demonstrating similarities in peak stroke volume index (SVI) in comparison with healthy individuals (N = 26; age, height, weight, and body surface area not significantly different between groups; body mass index significantly higher in HFpEF), clearly demonstrated a deficit in cardiac pumping capacity, which is evident when comparing both direct and indirect peak and reserve (absolute or relative change rest to peak exercise) indices between groups. As such, in an attempt to better understand the value of cardiac pumping capacity in HFpEF, we aimed to study relationships between cardiac pumping capacity and exercise tolerance in this population. We also sought to understand whether VO2peak alone or in parallel with other factors (i.e., blood pressure) can be used as a surrogate estimate for cardiac pumping capacity during exercise in HFpEF.
Exercise Tolerance in Heart Failure
Our group has demonstrated previously that healthy non-highly trained individuals share curvilinear relationships between VO2 and Q during exercise that was observed to be largely attributable to concurrent nonlinear adjustments in heart rate versus VO2 or SV relationships during exercise (3). In contrast, observations from a study including a sample of moderate-severity HFrEF suggest that VO2peak weakly relates to both peak Q and cardiac index in these patients (6). Others also have observed in HFrEF that exercise measures of cardiac index correlate closely with both VO2 and exercise duration (32). As such, it was not unexpected that linear regressions presented in Figures 3 and 4 between VO2 and SVI, QI, CP, or SW at rest and at peak exercise were variable among HFpEF and healthy individuals. In support of the present hypothesis and in contrast to healthy individuals, we demonstrate in Table 3 and Figures 3 and 4 that peak exercise measures of cardiac hemodynamics consistently related to exercise tolerance (i.e., VO2peak, exercise duration, and exercise peak power output) to a greater extent compared with resting measures.
Our observations presented in Table 3 may suggest that VO2 and VO2reserve were the strongest predictors of exercise tolerance in comparison with cardiac hemodynamics in HFpEF and in healthy individuals. Although, it may be necessary to reexamine the interpretation of these observations when considering the model of blood flow and pressure generation described by CP and CircP (7,18,37). Therefore, after accounting for arterial pressure generated with VO2 (i.e., CircP), VO2 does not predict exercise tolerance to a greater extent compared with cardiac function indices such as CP in HFpEF. Moreover, on examining differences in coefficients of determination between HFpEF and healthy individuals in Table 3, it is apparent that healthy individuals rely more on the capacity for VO2 in determining exercise tolerance in comparison with HFpEF. Whereas, consistent with dysfunctional cardiac pumping capacity in HF, exercise tolerance in HFpEF seems to depend on the rise in cardiac pumping capacity to a greater extent compared with healthy individuals.
Cardiac Hemodynamic Reserve and Exercise Intolerance in Heart Failure
Differences in cardiac hemodynamic reserve between HFpEF and healthy individuals could have been attributable to mechanisms uncovered in recent studies by our group in HFrEF and HFpEF (1,26). For example, observations from Olson et al. (26) suggest that, in an attempt to accommodate excessive metabolic demands of inefficient ventilation during exercise in HFrEF, when paralleled with limited cardiac reserve, muscles of the respiratory system detrimentally attain necessary blood flow intended for metabolically active skeletal muscle. This deprives metabolically active skeletal muscle of oxygen and nutrients essential for meeting the demands of exercise (26). Moreover, the findings from Abudiab et al. (1) indicate that low exercise tolerance in HFpEF may be related primarily to impairment in the ability to increase cardiac hemodynamics (i.e., low cardiac reserve) and secondarily to attenuations in VO2, which are observations consistent with the present hypothesis as well as the abnormal blood flow distribution model described by Olson et al. (26) in HFrEF. Hence, it could be suggested that the detrimental effects of attenuated cardiac reserve in HF is exacerbated further by metabolic activity of respiratory muscles that require augmented perfusion during exercise and therefore contributory to excessive and inefficient metabolic activity of the heart. This influence of respiratory muscles on blood flow distribution during exercise could lead to a critical reduction in skeletal muscle perfusion. Thus, a decreased power-generating capability of skeletal muscle may contribute to premature fatigue and low exercise tolerance in HF patients.
However, it also is evident that simply increasing cardiac hemodynamic reserve does not independently improve exercise tolerance in HF. For example, when HF patients receive inotropic therapy (e.g., dobutamine or cardiac resynchronization therapy), observations suggest that there is neither a consistent beneficial response to therapy nor a uniform improvement in exercise tolerance among these individuals (10,21). In the case of responders and nonresponders, exercise tolerance still seems to be related to the relative magnitude of cardiac impairment estimated during exercise that is consistent with observations from studies that did not include interventions to increase inotropy (7,10,18,37).
Therefore, considered together, previous observations and the present discussion provide compelling and thought-provoking reasons why exercise exposes associations between exercise intolerance and impaired cardiac pumping capacity in HFpEF. HF patients with preserved EF% demonstrated significantly lower peak cardiac hemodynamics (i.e., QI, CP, SW, O2pulse index, CircP, and PW) in comparison with healthy individuals (Table 1). HF patients with preserved EF% also demonstrated significantly lower cardiac reserve (i.e., cardiac index, CP, and CircP) compared with healthy individuals (Table 2). Thus, low peak and reserve cardiac function seem to translate into lower exercise tolerance in HFpEF compared with healthy individuals.
Noncardiac Factors Exacerbate the Effects of Low Cardiac Pumping Capacity in Heart Failure
There are ample data to support the description of mechanisms that may explain reasons for symptoms that are common in HF. For example, a promising theory is the “muscle hypothesis” posed by Piepoli et al. (29), which suggests that exercise intolerance and abnormal cardiovascular function in HF are related to the influence of peripheral neural factors on the exacerbation of tonic sympathoexcitation in these patients. In support of this theory, we recently demonstrated that contraction and/or metabolically activated neural feedback from skeletal muscle nerve fibers contributes to ventilatory inefficiency and augmentation of peripheral arterial pressure during exercise in HFrEF (27), which perhaps could be mechanistically related to the imbalanced blood flow distribution model posed by Olson et al. (26) during exercise in HFrEF. In contrast, we also have demonstrated that neither metabolite- nor mechanical-sensitive neural feedback from skeletal muscle afferents directly influences cardiac hemodynamics during exercise in HFrEF (35). Thus, it could be expected that, in the absence of increased inotropy during exercise that would normally contribute to the maintenance of arterial pressure, a critical response of the cardiovascular system may be to increase peripheral vascular resistance to mobilize blood flow in an attempt to maintain arterial pressure and to accommodate coronary, respiratory, and skeletal muscle circulation. With a limited capacity to increase myocardial contractile reserve, perhaps related to an impaired Frank-Starling mechanism that could be associated with ischemic/necrotic cardiac tissue and nonresponsive cardiac β-adrenergic receptors, HF patients may be relatively “preload” insensitive and instead rely heavily on decreased afterload for adjustments in cardiac hemodynamics. Hence, blunted myocardial contractile reserve, when mirrored with increases in the metabolic demands of cardiac, respiratory, and skeletal muscle during exercise, results in poor organ perfusion, metabolic inefficiency, and an overall systemic energy deficit. These deficits are accompanied by abnormalities that may be described by skeletal muscle ischemia, truncated oxygen and nutrient delivery, and attenuation in skeletal muscle power–generating capability, all of which likely contribute to exercise intolerance in HF.
SUMMARY AND FUTURE DIRECTIONS
Cardiac hemodynamics at rest, although effective for potentially identifying or confirming the presence of abnormal cardiac function in HF, do not seem to be strong indicators of functional capacity (i.e., exercise tolerance) or prognosis. Therefore, resting cardiac function should not be used independently for the clinical classification of HF. Alternatively, assessment of VO2 during exercise testing has the potential to estimate both functional capacity as well as prognosis in HF. However, recent findings suggest that, although useful as an adjunct clinical and research tool, VO2 alone does not demonstrate clinical value similar to that of cardiac hemodynamics and also should not be considered a direct surrogate for estimating cardiac pumping capacity in HF. Therefore, traditional measurements of cardiac hemodynamics, which include Q, QI, SV, or SVI, during exercise testing should be considered strong indicators of functional capacity and prognosis in HF. Moreover, when available, the assessment of cardiac hemodynamics should be described using the cardiac pumping capacity model that accounts for not only the hemodynamic generating capabilities of the heart but also, equally important, the pressure-generating potential as well. Measurement of CP and to a lesser extent CircP during exercise should be considered robust metrics for describing relationships between cardiac function, functional capacity, and the clinical classification of HF.
In conclusion, although we suggest that our response to the question “What surrogate index or indices of cardiac or pulmonary function best estimate syndrome severity and prognosis in HF?” is well supported while addressing several of the notable inconsistencies in the literature to date on this topic, we acknowledge that there are still numerous gaps in the understanding of the clinical and bench knowledge of HF. The controversy and challenges to the present remarks may stem from the lack of systematic consensus among scientists as to the mechanistic pathways posed to explain many of the yet undefined and complex relationships between the physiology, biology, and biochemistry intrinsic to the pathophysiology of HF. Observations to date suggest that assessment of cardiac pumping capacity during exercise provides valuable insight concerning the magnitude of cardiac impairment in addition to closely relating to signs, symptoms, and prognosis, which are critical for the clinical classification of HF patients.
This work was funded by HL-108962-05.
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