Author + information
- Received February 9, 2017
- Revision received October 6, 2017
- Accepted October 12, 2017
- Published online February 14, 2018.
- Julian W. Sacre, PhDa,∗ (, )
- Chiew Wong, MD, PhDb,c,
- Yih-Kai Chan, PhDd,
- Melinda J. Carrington, PhDa,d,
- Simon Stewart, PhDa,d and
- Bronwyn A. Kingwell, PhDa
- aBaker Heart & Diabetes Institute, Melbourne, Australia
- bUniversity of Melbourne (Western Clinical School), Melbourne, Australia
- cDepartment of Cardiology—Western Health, The University of Melbourne, Melbourne, Australia
- dMary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia
- ↵∗Address for correspondence:
Dr. Julian W. Sacre, Baker Heart and Diabetes Institute, Level 4, 99 Commercial Road, Melbourne VIC 3004, Australia.
Objectives This study aimed to determine the association of stage B heart failure (SBHF) and its constituent left ventricular (LV) abnormalities with trajectory of exercise capacity over time, and assess whether this association is modified by reversion of these LV abnormalities to normal.
Background The LV abnormalities of SBHF may coincide with a reduction in exercise capacity that precedes the overt exercise intolerance of clinical heart failure (HF). Determining the predictive capacity of established and novel SBHF criteria for exercise capacity decline may improve HF risk stratification.
Methods LV structure/function (echocardiography) and exercise capacity (6-minute walk distance [6MWD]) were assessed at baseline and 3-year follow-up in 268 patients from the NIL-CHF (Nurse-led Intervention for Less Chronic Heart Failure) study (all stage A [SAHF] or SBHF). Changes (Δ) in 6MWD were compared between SAHF and SBHF and across each of 4 constituent components of SBHF: LV hypertrophy, regional wall motion abnormality(ies) (RWMA), left ventricular systolic dysfunction (LVSD) (ejection fraction <45%) and elevated early diastolic filling/annular velocity ratio (E/e’ ≥ 15).
Results Δ6MWD was similar in those with SAHF (n = 141) and SBHF (n = 127; –5 m [95% confidence interval (CI): −21 to +11 m]; covariate-adjusted). However, within the setting of SBHF there was substantive heterogeneity; that is, reductions in 6MWD were observed with persistent elevated E/e’ (−34 m [95% CI: −62 to −6 m]) and persistent LVSD (−41 m [95% CI: −74 to −8 m]), but not with LV hypertrophy (+17 m [95% CI: −15 to +49 m) or RWMA (+5 m [−27 to +36 m]), nor in patients whose elevated E/e’ or LVSD reverted to normal by 3 years (p > 0.10).
Conclusions Elevated E/e’ is associated with a similar degree of exercise capacity decline to LVSD, supporting that both LV functional criteria be considered in distinguishing SBHF from SAHF. That reversion of either manifestation of LV dysfunction was associated with preserved exercise capacity advocates targeting of these factors by HF preventive interventions.
Subclinical left ventricular (LV) impairment due to coronary artery disease, hypertension, diabetes, or other forms of chronic heart disease may be classified as stage B heart failure (SBHF)—an American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) category synonymous with a high risk of future progression to the clinical heart failure (HF) syndrome (1). Aside from structural indicators such as LV hypertrophy, asymptomatic LV systolic dysfunction (i.e., based on reduced ejection fraction [EF] or regional wall motion abnormalities [RWMAs]) has traditionally been the sole functional basis on which SBHF is differentiated from stage A (2). However, broader definitions that incorporate LV diastolic dysfunction have also been advocated, recognizing that a large proportion of HF cases are characterized by preserved EF (3–5).
Given incident exercise intolerance represents a fundamental criterion governing progression from “at-risk” stages (A and B) to clinical HF (stages C and D), the appropriateness of LV functional parameters for inclusion in the SBHF definition may consider, among other factors, their influence on exercise capacity. In this pre-symptomatic setting, exercise capacity can be reduced to a lesser extent than would dictate a stage C classification but still of sufficient magnitude to affect both quality of life and long-term prognosis (6,7). Numerous cross-sectional studies encompassing a broad range of HF risk factors have reported associations of reduced exercise capacity with elevated LV filling pressure indicated by the ratio of early diastolic filling and septal annular velocities (E/e′) (8–11). However, in the context of scarce longitudinal/interventional data, the chronic impact of elevated E/e′ on exercise capacity remains unclear—particularly compared with LV abnormalities that fall within the existing SBHF definition. Also unknown is the relative treatment refractoriness of reductions in exercise capacity due to these abnormalities, which has obvious implications for the utility of the SBHF classification in identifying patient groups toward whom HF preventive efforts should be targeted.
The NIL-CHF (Nurse-led Intervention for Less Chronic Heart Failure) study (12,13) was a trial that evaluated a multidisciplinary HF prevention program in at-risk patients (i.e., at least stage A, but none meeting stage C or D criteria). LV structure/function (echocardiography) and exercise capacity (6-min walk distance [6MWD]) were recorded at baseline and at 3-year follow-up. In the present study, we first tested the hypothesis that global SBHF is independently associated with a decline in exercise capacity over time. Secondly, we undertook to compare the exercise capacity trajectory between components of SBHF recognized by guidelines—that is, LV hypertrophy and LV systolic dysfunction (indicated by reduced EF or RWMA)—and the more novel indicator of elevated E/e′. Finally, we determined whether maintenance or reversion of these LV abnormalities would be associated with worsening of or improvement in exercise capacity, respectively.
The NIL-CHF study cohort (Australian New Zealand Clinical Trials Registry No. 12608000022369) has been described previously (12,13). In brief, it comprised patients with chronic heart disease due to ≥1 HF antecedent (mainly atherosclerotic cardiovascular disease, hypertension, type 2 diabetes, and atrial fibrillation); however, as a trial investigating HF prevention, all patients were required to be free of signs/symptoms indicative of the clinical HF syndrome, as defined by Australian (14) and ACCF/AHA guidelines (1). Thus, according to the ACCF/AHA framework, all patients met criteria for stage A or B HF, with stages C–D excluded. Patients were also required to be 45 years of age or older and free of congenital conditions, significant valve disease, and terminal malignancy. Although recruitment occurred during hospitalization, the baseline assessment was performed 1-month post discharge (at which absence of pre-existing HF was confirmed and after ensuring no acute events or HF-related admissions had occurred in the intervening period).
Of the NIL-CHF intention-to-treat population (n = 611) (13), the candidate sub-cohort for the current study included 299 patients who undertook a 6MWD test, echocardiography, and clinical profiling at both baseline and 3-year follow-up. However, subsequent exclusion of patients with incident clinical HF during the study (n = 12; based on HF-related hospitalization), inability to complete the 6MWD test (n = 16), an acute condition affecting exercise capacity (n = 1), or extreme changes in 6MWD (i.e., greater/less than the third/first quartile ± 3 × interquartile range; n = 2) resulted in a final cohort of n = 268. The study was approved by the Alfred Hospital Human Research Ethics Committee and all patients provided written informed consent.
Medical history, body mass index, blood pressure, blood biochemistry, and lifestyle factors were recorded at baseline and 3 years. Details are provided in the Online Appendix.
Standard 2-dimensional resting echocardiography was performed. A dedicated/experienced echocardiologist adjudicated the presence of RWMA by visual assessment. Diastolic function was characterized from the mitral inflow pattern (including the early diastolic filling [E] and septal annular [e′] velocities derived from pulsed-wave Doppler) (15). Systolic function was based on LV EF (calculated from end-diastolic and end-systolic volumes). LV mass was derived from LV internal dimension and wall thicknesses according to the linear method (cube formula) (16) and indexed to body surface area. Additional details are available in the Online Appendix.
The global definition of SBHF included any of the following 4 LV structural/functional abnormalities (1,5): LV hypertrophy based on LV mass index > 115 g/m2 (men) or > 95 g/m2 (women) (16); any RWMA with preserved EF (i.e., ≥45%); LV systolic dysfunction based on reduced EF < 45% (LVSD); and elevated E/e′ (≥15). Suboptimal image quality precluded RWMA adjudication in 9 patients whose SBHF status was therefore based solely on the other 3 criteria.
The 6MWD test (maximal distance walked in 6-min [meters]) was performed in accordance with American Thoracic Society guidelines (17). Data were interpreted according to accepted thresholds for “small” (20 m) and “large” (50 m) meaningful changes in 6MWD (18,19).
To determine associations of SBHF and its constituent criteria with exercise capacity trajectory, we analyzed a series of linear mixed models with 6MWD as the dependent variable. A factor * time interaction term included in each model—alongside main effects for factor and time and relevant covariates—defined the relative effect of that factor on exercise capacity trajectory. For global SBHF, this was a 2-level factor (i.e., baseline classification of SBHF vs. stage A HF [SAHF]). In subsequent analyses of individual SBHF components, 4-level factors were created that incorporated progression/maintenance/reversion of the LV abnormality over time; that is, for each of LV hypertrophy, RWMA, LVSD, and elevated E/e′, patients were classified as follows:
1. Normal at baseline and 3 years (Normal→Normal)
2. Persistence of abnormality at baseline through to 3 years (Abnormal→Abnormal)
3. New abnormality at 3 years (Normal→Abnormal)
4. Reversion of baseline abnormality by 3 years (Abnormal→Normal)
For each classification/group, exercise capacity trajectory was quantified by its “relative Δ6MWD” (i.e., absolute change in 6MWD from baseline to 3 years minus the absolute change observed in the relevant reference group [e.g., Normal→Normal]). Model covariates included: 1) known determinants of 6MWD — that is, age, sex, height, weight, physical activity, smoking, education, mean arterial pressure, cardiovascular diseases (coronary, cerebrovascular, and peripheral vascular diseases, and atrial fibrillation), and other comorbidities/disease indicators (diabetes, cancer history, depressive symptoms, anemia, and estimated glomerular filtration rate); 2) other risk markers or medications that contributed to the model (p < 0.10) — that is, resting heart rate, poor diet, statin use, and diuretic use; and 3) LV abnormalities other than that being investigated (analyses of individual SBHF components only). The effects of clinical factors on 6MWD trajectory were sought in separate iterations of the same model (also based on relevant factor * time interaction terms; where factors derived from continuous variables were classified on the basis of common clinical cut-points [see the Online Appendix]).
Univariate correlations were assessed using Pearson or Spearman’s rank correlation coefficient, where appropriate. Multiple linear regression (enter method with pairwise exclusion of missing data) was used to describe independent associations between Δ6MWD and specific echocardiographic parameters.
Continuous variables were expressed as mean ± SD or median with interquartile range, depending on normality of distribution. Categorical data were expressed as percentages. Group comparisons were based on Student t test, Mann Whitney U test, or chi-square test, where appropriate. All analyses were undertaken using SPSS Statistics version 22.0 (IBM Corp., Armonk, New York). A value of p < 0.05 defined statistical significance.
Baseline clinical characteristics of the current study cohort compared with excluded patients from the larger NIL-CHF population are displayed in Online Table 1. The analytic sample was younger, had a higher proportion of men, was better-educated, and had lower rates of peripheral vascular disease, diabetes, atrial fibrillation, chronic kidney disease, anemia, depressive symptoms, LV hypertrophy, and elevated E/e′. They also had lower resting heart rate and systolic blood pressure, lower total cholesterol, were more physically active, and less likely to be taking calcium channel blocker and diuretic medications.
SBHF was identified in 47% of the cohort at baseline. Elevated E/e′ was identified in 46 patients (17%), whereas the traditional SBHF criteria of RWMA, LV hypertrophy, and LVSD were identified in 43 (17%), 38 (14%), and 36 (14%) patients, respectively. The distribution of these 4 LV abnormalities contributing to SBHF classification is depicted in Figure 1A. Aside from the RWMA and LVSD groups, which did not overlap by design (i.e., because the RWMA group comprised patients with preserved EF only), individual SBHF components showed relatively limited overlap and were not significantly related to each other. Clinical and echocardiographic characteristics are compared between patients with SAHF and SBHF in Tables 1 and 2, respectively. Those with SBHF were older, showed more prevalent atherosclerotic vascular diseases, cancer history, and anemia, had a lower resting heart rate, worse renal function, and reported higher rates of antithrombotic and β-blockade therapy. By design, SBHF was characterized by higher LV mass index, lower EF and worse diastology.
Figure 2 displays baseline and 3-year 6MWD for each of SAHF and SBHF (covariate-adjusted marginal means). 6MWD was lower in patients with SBHF at both baseline and 3 years (albeit reaching statistical significance only at the latter timepoint). However, no between-group difference in trajectory of 6MWD from baseline to 3 years was observed (relative difference in Δ6MWD for global SBHF compared with SAHF: −5 m [95% confidence interval: −21 to +11]; p = 0.54).
Individual SBHF components
Figure 1B displays the numbers of patients who—between baseline and 3 years—maintained or changed their classification for each of LV hypertrophy, RWMA, LVSD, and elevated E/e′. Clinical and echocardiographic characteristics of the Normal→Normal, Abnormal→Abnormal, and Abnormal→Normal groups (separately defined for each LV abnormality) are reported in Online Tables 2 and 3, respectively.
Exercise capacity of each SBHF component
Adjusted relative Δ6MWD data for each SBHF component is displayed in Figure 3 (corresponding baseline and 3-year data from which relative Δ6MWD was derived are displayed in Online Figure 1). Relative reductions in 6MWD were seen with persistent LVSD and persistent elevated E/e′ (p < 0.05 for both). However, such reductions were not observed in the setting of LVSD or elevated E/e′ reverting to normal (i.e., these patients’ 6MWD trajectories paralleled their respective Normal→Normal reference groups). Moreover, LV hypertrophy and RWMA were not associated with differences in 6MWD trajectory, irrespective of persistence/reversion.
Effects of clinical factors on Δ6MWD are displayed in Figure 4. The only significant predictors of worse 6MWD trajectory were progressively older age and chronic kidney disease (although borderline significant adverse trends were also observed for cancer, anemia, education <12 years, and statin use; p < 0.10).
Exercise capacity trajectory and specific echocardiographic indices
Δ6MWD correlated with baseline e′ (r = 0.15; p = 0.018) and E/e′ (borderline significant; r = −0.11; p = 0.084), but not with baseline LV mass index or EF, nor Δe′, ΔE/e′, ΔLV mass index, or ΔEF. No associations of Δ6MWD with echocardiographic indices (baseline or Δ) were detected in adjusted analyses (i.e., multiple linear regression models featuring the same covariates as aforementioned group-based analyses).
Although SBHF is a broad entity indicative of heightened clinical HF risk relative to SAHF, this study indicates that its constituent LV abnormalities show substantive heterogeneity in their predisposition to exercise capacity decline over 3 years. LV functional, rather than structural abnormalities appeared to hold greatest significance in this respect—not just LVSD (the traditional functional marker of SBHF), but also elevated E/e′ independent of LVSD. Indeed, the effects of LVSD and elevated E/e′ were of a similar clinically meaningful magnitude and accompanied in their predictive capacity for Δ6MWD only by the clinical factors of advanced age and chronic kidney disease. Notably promising from the perspective of HF prevention was the absence of a decline in exercise capacity in individuals whose LVSD and elevated E/e′ reverted to normal.
Trajectory of exercise capacity in subclinical HF
To our knowledge, this is the first study describing change in exercise capacity over time and its relative modulation by LV structural/functional abnormalities and clinical factors in a heterogeneous group of chronic heart disease patients spanning stages A to B of the HF risk continuum (i.e., yet to develop the overt exercise intolerance that would dictate a clinical HF diagnosis). Whereas absolute changes in 6MWD from baseline to 3 years indicated an overall increase in exercise capacity, such an interpretation requires caution given 6MWD is associated with a learning effect (17) that may confound quantitation of the “true” underlying trajectory. Indeed, it was for this reason that our approach was to calculate relative differences in Δ6MWD between different patient subgroups. In this setting, SBHF according to its global definition was not associated with worse exercise capacity trajectory; however, 2 of its 4 individual components were: that is, LVSD (∼41 m worse) and elevated E/e′ (∼33 m worse). That LV hypertrophy and RWMA were by contrast not associated with relative declines over time suggests that their chronic effects may be more benign (i.e., when they do not manifest in concurrent LVSD or elevated E/e′).
Implications for subclinical HF staging criteria
The magnitude by which LVSD and elevated E/e′ predicted worse Δ6MWD was bounded by thresholds typically used to indicate small (20 m) or large (50 m) clinically meaningful effects. These thresholds are, in turn, based on relationships of 6MWD with self-reported physical performance (e.g., perceived walking or stair-climbing ability) (18). The fact that symptoms during such activities are fundamental to determining when a patient makes the transition to stage C HF underscores the potential value of these criteria to denote those patients at greatest risk of progression.
Of LVSD and elevated E/e′, only the former is currently recognized as a SBHF criterion by guidelines (1), although our findings certainly support that elevated E/e′ also be considered. Whereas this concept is not new, previous supporting data have focused on implications for prevalence and prognostic significance (5), rather than for exercise capacity/symptoms. Our data are consistent with cross-sectional evidence of elevated E/e′ coinciding with a reduction in exercise capacity analogous to that observed in the setting of traditional SBHF criteria (9). Since elevated E/e′ is not the only echocardiographic indicator with potential greater sensitivity to detect SBHF compared with traditional criteria, future longitudinal studies would be well-served to examine functional decline in the context of other subclinical LV abnormalities (e.g., impaired global longitudinal strain).
Implications for HF prevention
Of course, only those patients showing persistence of LVSD and elevated E/e′ from baseline to 3 years were adversely affected in their exercise capacity trajectory. Those who showed reversion of LV dysfunction during the study exhibited trajectories akin to patients with normal LV function to begin with. Although relatively small patient numbers precluded examination of which treatments/clinical factors were responsible for LV recovery, these data provide important proof-of-concept that exercise capacity is responsive to interventions that successfully target LV function. According to this concept, we may have expected significant associations between Δ6MWD and changes in LV function expressed as continuous variables; however, these were probably suppressed by the relatively favorable echocardiographic profile of this cohort overall (i.e., with Normal→Normal as the predominant classification, most changes in LV function remained within the range of normal values).
Although 6MWD is a well-established marker of exercise capacity that reflects daily physical functioning, the lack of concurrent maximal exercise testing may have restricted our sensitivity to detect within- and between-group differences in trajectory. Also, clinical differences between the cohort analyzed for this study and the broader NIL-CHF population indicate a selection bias that has obvious consequences for external validity. Sample size was another potential concern. Whereas statistical significance was achieved when mean differences exceeded our nominated threshold of clinical significance, there were too few patients in some subgroups to make valid comparisons (in particular, the small number who developed new LV abnormalities during the study precluded examining whether incident SBHF correlated with exercise capacity decline). Finally—given high prevalence of coronary artery disease in this study—myocardial ischemia may have impacted exercise capacity beyond that which could be accounted for by RWMA assessment. By the same token, the relevance of our findings to nonischemic LV dysfunction is unclear.
Persistent SBHF due to LVSD or elevated E/e′—but not LV hypertrophy or RWMA—was associated with a relative decline in exercise capacity over time. These findings further support the addition of elevated E/e′ as a qualifying criterion for SBHF (currently unrecognized by guidelines) (1). The effects of LVSD and elevated E/e′ were not only independent of, but exceeded that of several clinical factors known to influence exercise capacity. They were also notable for their magnitude—exceeding thresholds known to correspond to reductions in self-perceived physical functioning and quality of life. That patients showing reversion of LVSD or elevated E/e′ appeared to be protected against such exercise decline provides promise from the perspective of therapeutic intervention directed at these LV abnormalities. Identification of new treatment strategies with efficacy for such a purpose should be a future research priority.
COMPETENCY IN MEDICAL KNOWLEDGE: Although less marked than in clinical HF, reductions in exercise capacity of a magnitude known to be clinically relevant are common in its preceding subclinical stages — particularly the asymptomatic LV impairment that characterizes SBHF. Elevated E/e’ may indicate a risk of exercise capacity decline similar to that of reduced EF and exceeding that of other traditional SBHF criteria.
TRANSLATIONAL OUTLOOK: That reversion of LVSD and elevated E/e’ corresponded to exercise capacity levels analogous to those seen in SAHF is promising because it indicates that functional decline during early disease may be reversible. However, the optimal therapeutic strategy to achieve this remains undefined.
The NIL-CHF study was supported by a National Health and Medical Research Council (NHMRC) Project Grant (#472662). The study was also supported in part by the Victorian Government’s Operational Infrastructure Support Program. Drs. Sacre, Stewart, and Kingwell are all supported by NHMRC Fellowships. Dr. Carrington is supported by a Future Leader Fellowship (Award Reference 100802) from the National Heart Foundation of Australia and previously throughout the duration of the NIL-CHF project, a NHMRC Fellowship. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- change from baseline to 3-year follow-up
- 6-minute walk distance
- ratio of early diastolic mitral inflow (E) and septal annular (e’) velocities
- heart failure
- left ventricular
- left ventricular systolic dysfunction
- Nurse-led Intervention for Less Chronic Heart Failure
- regional wall motion abnormality(ies)
- stage A heart failure
- stage B heart failure
- Received February 9, 2017.
- Revision received October 6, 2017.
- Accepted October 12, 2017.
- 2018 American College of Cardiology Foundation
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