Author + information
- Received May 2, 2018
- Accepted May 3, 2018
- Published online July 30, 2018.
- Josep Lupón, MD, PhDa,b,c,d,
- Giovana Gavidia-Bovadilla, MSce,f,
- Elena Ferrer, MDb,
- Marta de Antonio, MD, PhDa,b,
- Alexandre Perera-Lluna, PhDf,g,h,
- Jorge López-Ayerbe, MDb,
- Mar Domingo, MD, PhDa,
- Julio Núñez, MD, PhDd,i,j,
- Elisabet Zamora, MD, PhDa,b,c,d,
- Pedro Moliner, MDa,b,
- Patricia Díaz-Ruata, MScf,g,
- Javier Santesmases, MDa and
- Antoni Bayés-Genís, MD, PhDa,b,c,d,∗ (, )@hgermanstrias@UABBarcelona
- aHeart Failure Unit, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
- bCardiology Department, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain
- cDepartment of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain
- dCentro de Investigatión Biomédica en Red (CIBER) Cardiovascular, Instituto de Salud Carlos III, Madrid, Spain
- eDepartment of e-Health, Eurecat, Technological Center of Catalonia, Barcelona, Spain
- fDepartament d’Enginyeria de Sistemes, Automàtica i Informàtica Industrial, Universitat Politècnica de Catalunya, Barcelona, Spain
- gNetworking Biomedical Research Centre in Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid, Spain
- hInstitut de Recerca Pediàtrica Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain
- iCardiology Department, Hospital Clínico Universitario, INCLIVA, València, Spain
- jDepartment of Medicine, Universitat de València, València, Spain
- ↵∗Address for correspondence:
Dr. Antoni Bayés-Genís, Heart Institute, Department of Medicine, Universitat Autònoma de Barcelona, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n 08916 Badalona, Spain.
Background Long-term trajectories of left ventricular ejection fraction (LVEF) in heart failure (HF) are incompletely characterized.
Objectives This study sought to examine LVEF trajectories in HF with reduced LVEF (<40%) and mid-range LVEF (40% to 49%) and the prognostic impact of LVEF dynamic changes over 15-year follow-up.
Methods In this prospective, consecutive, observational registry of real-life HF outpatients, the authors performed 2-dimensional echocardiography at baseline and on a structured schedule after 1 year and then every 2 years up to 15 years.
Results The mean number of LVEF measurements in the 1,160 included patients was 3.6 ± 1.7. As a whole, Loess curves of long-term LVEF trajectories showed an inverted U shape with a marked rise in LVEF during the first year, maintained up to a decade, and a slow LVEF decline thereafter (p for trajectory <0.001). This pattern was more pronounced in HF of nonischemic origin and in women. Patients with new-onset HF (≤12 months) had a higher early increase in LVEF, whereas patients with ischemic HF showed a lower LVEF increase at 1 year; both groups had a relative plateau thereafter. Patients with HF with mid-range LVEF had less of an increase (3 ± 9%) than those with HF with reduced LVEF (9 ± 12%) during the first year (p < 0.001), but the groups overlapped after 15 years. Patients who died had lower final LVEF and worse LVEF dynamics in the immediately preceding period than survivors.
Conclusions LVEF trajectories vary in HF depending on a number of disease modifiers, but an inverted U-shaped pattern with lower LVEF at both ends of the distribution emerged. A declining LVEF in the preceding period was associated with higher mortality.
Heart failure (HF) is a multifaceted syndrome that results in a wide spectrum of symptoms, ranging from exercise intolerance to fluid overload and congestion, and is associated with cardiac functional and structural abnormalities (1). Symptoms, together with left ventricular ejection fraction (LVEF), are currently the basis for diagnosis and management in HF. Both have been pivotal in clinical trials over the past 3 decades, providing the evidence base criteria for management of HF with depressed systolic function. HF with depressed systolic function is currently divided into 2 categories according to the most recent guidelines of the European Society of Cardiology (ESC): HF with reduced LVEF (HFrEF) and HF with mid-range LVEF (HFmrEF) (2).
Advances in HF treatment, including drug therapy, devices, coronary revascularization, and valvular repair (3), have achieved an increase or even normalization of LVEF in a substantial number of patients, which is known to carry a better prognosis (4–6); however, longitudinal analysis of LVEF trajectories over time is incomplete. Preliminary reports have been variable in size and follow-up, mainly in selected patients with shorter follow-up (6–11). Furthermore, the impact of LVEF dynamic changes on survival over time is not entirely characterized. Accordingly, the aim of the present study was to prospectively assess LVEF trajectories and outcomes over the long term (up to 15 years) in a real-life cohort of patients with HF and depressed systolic function of diverse causes.
Study population and outcomes
All consecutive ambulatory patients referred to a structured multidisciplinary HF clinic of a university hospital between August 2001 and December 2015, regardless of etiology, were considered for the study. During the 15-year period, clinical pathways and referral geographic area, covering ∼850,000 inhabitants in the northern Barcelona Metro Area, remained stable. The criteria for clinical practice referral to the HF clinic were HF with at least 1 hospitalization, depressed systolic function, or both (12).
All patients were seen regularly during follow-up visits at the HF clinic according to their clinical needs and treated according to a unified protocol. Follow-up visits included a minimum of 1 visit with a nurse every 3 months and 1 visit with a physician (cardiologist, internist, or family physician) every 6 months (Online Figure 1), as well as optional visits with specialists in geriatrics, psychiatry, and rehabilitation (12). During the baseline visit, patients provided written consent for the use of their clinical data for research purposes.
The main inclusion criteria for the present study were having had at least 2 echocardiography measurements, one at baseline and the other during follow-up. Patients undergoing heart transplantation or cardiac resynchronization therapy after the second echocardiography study were censored at the time of the intervention.
The study was performed in compliance with the law protecting personal data, in accordance with the international guidelines on clinical investigation of the World Medical Association’s Declaration of Helsinki.
LVEF was scheduled to be assessed at baseline and at 1, 3, 5, 7, 9, 11, 13, and 15 years of follow-up (Online Figure 1) by 2-dimensional echocardiography by image expert cardiologists. LVEF was obtained from apical 2- and 4-chamber views and calculated with the Simpson method. All echocardiograms were revised for accuracy by expert staff.
Categorical variables were expressed as absolute numbers and percentages. Continuous variables were expressed as the mean ± SD or median (quartile 1 to quartile 3) according to normal or non-normal distributions. Normal distribution was assessed with normal Q to Q plots. Loess (locally weighted error sum of squares) curves were plotted for the whole cohort and the pre-specified study subgroups. Loess regression is a nonparametric approach developed in 1988 (13). Loess curves are useful to observe trend or relationship on nonlinear data observed over time. Loess moves along data looking at chunks at a time, fitting a set of local regression lines computed on observed data (missing values are omitted) and connecting these lines to make a smooth line. Missingness because of loss to follow-up was assumed to be at random because there was no evidence that not attending to the scheduled visit had anything to do with LVEF. Locally weighted regression is based on a weight function that gives the greatest weight to observations that are closest to the focal observation. Statistical analyses of LVEF change over time were performed by linear mixed-effects (LME) modeling. LME takes into account the group-level structure in the data by simultaneous assessing effects within and across groups. LME models incorporate both fixed effects and random effects (14) and describe the relationship between a response and the covariates that have been observed along with the response (15). In this study, LME models were developed to evaluate and compare the effect of time over the LVEF change for pre-specified subgroups according to etiology of HF, duration of HF at baseline, LVEF ESC classification (HFrEF vs. HFmrEF), and sex. We hypothesized that there are important individual-level effects and that patients have similar rates of change over time. Thus, we fitted random intercepts LME models in which the measured value of LVEF was assumed to have a set of parameters fixed across individuals, including a specific random effect per each individual. Because the form of the Loess curves suggests at least a quadratic in time, all LME models included both the linear term time and the quadratic term timeˆ2 as fixed effects. By adding the quadratic term timeˆ2 to the models, we could evaluate whether the effect of time changed significantly as the time progressed. The Wald chi-square test was applied to evaluate how confident our estimates of the effect of time on LVEF values were. Comparisons of LVEF between groups were also performed at every time point of the study with paired Student’s t-test. Comparisons between included and excluded patients and between alive and dead patients were performed with the Student’s t-test, Mann-Whitney U test, or chi-square test, as appropriate. Statistical analyses were performed with SPSS 21 (SPSS, Chicago, Illinois) and R (A Language and Environment for Statistical Computing) by R Core Team (R Foundation for Statistical Computing, Vienna, Austria, 2017). For LME models, we used the nlme R package, version 3.1-131 by Pinheiro, Bates, DebRoy, Sarkar and R Core Team (2017). A 2-sided p < 0.05 was considered significant.
A total of 1,921 patients were admitted to the HF clinic from August 2001 to December 2015, 1,656 of whom had LVEF <50%. After exclusion criteria were applied, 1,160 had a minimum of 2 LVEF measurements and constituted the study population (Online Figure 2). Table 1 shows clinical, biochemical, echocardiographic, and treatment characteristics of the studied cohort at baseline, as well as treatment during follow-up. The main etiology was ischemic heart disease (56%), followed by dilated cardiomyopathy (14%). Medical treatment was optimized during follow-up (Table 1). Online Table 1 compares patients included and not included (lack of a second echocardiogram) to address group bias. Although some differences were found, the variables primarily associated with LVEF dynamics, such as sex, etiology, baseline LVEF, and HF duration, showed no statistical differences.
A total of 4,183 echocardiograms were performed during the study period. The prospective echocardiography schedule and the distribution of echocardiograms performed per patient (mean 3.6 ± 1.7, ranging from 2 in 398 patients to 9 in 16 patients) are shown in Online Figures 1 and 3, respectively. Survival curves and causes of death are shown in Online Figure 4 and Online Table 2, respectively. Mean LVEF values were 30 ± 8% (n = 1,160), 38 ± 12% (n = 1,024), 41 ± 13% (n = 803), 41 ± 12% (n = 471), 43 ± 12% (n = 302), 43 ± 12% (n = 187), 42 ± 12% (n = 126), 41 ± 10% (n = 73), and 42 ± 9% (n = 38) at baseline and 1, 3, 5, 7, 9, 11, 13, and 15 years, respectively. LVEF dynamic trajectories of the entire cohort at every time point are illustrated in Figure 1A. Paired data comparisons showed statistical differences between baseline and 1 year (p < 0.001), between 1 and 3 years (p < 0.001), and between 5 and 7 years (p = 0.002) (Online Table 3). As a whole, Loess splines of long-term LVEF trajectories showed an inverted U shape, with a marked rise in LVEF during the first year, maintained up to a decade, and a slow LVEF decline thereafter (p for trajectory <0.001) (Central Illustration). A more pronounced increase in LVEF during the first year was observed in new-onset HF (≤12 months) than in patients with longer HF duration at the baseline visit, followed by a plateau (Figure 1B) (p < 0.001 for both trajectories; p < 0.001 between groups).
Figure 2 shows LVEF trajectories relative to HF etiology. Ischemic HF patients showed a moderate LVEF increase at 1 year, with a relative plateau thereafter. Nonischemic HF patients showed a more pronounced bump at 1 year and a more prolonged increase during follow-up than those with ischemic HF (∼7 to 10 LVEF points; p < 0.001 for both trajectories; p < 0.001 between groups) (Figure 2A). The greatest LVEF increase was observed in hypertensive HF (Figure 2B). Among nonischemic etiologies, the LVEF increase tended to be more limited in time (3 years) in toxic (chemotherapy) and valvular HF, whereas it extended to a decade in dilated cardiomyopathy and hypertensive HF and declined thereafter. Alcohol-induced cardiomyopathy as an etiology was associated with full recovery in the long-term (p < 0.001 for all trajectories).
Relative to ESC HF classification, patients with HFrEF experienced a steep rise the first year (9 ± 12%), with a slight upward trend during follow-up. By contrast, patients with HFmrEF showed a poorer LVEF increase (3 ± 9%) during the first year (p < 0.001 vs. HFrEF) and thereafter showed a downward trend. Hypertensive etiology (10.7% vs. 6.3%, p = 0.03) was significantly more frequent in HFmrEF, whereas alcohol toxicity tended to be more frequent in HFrEF (3.2% vs. 6.4%, p = 0.09).
Remarkably, at 15 years, HFmrEF was associated with slightly lower LVEF than HFrEF (p = 0.98; p < 0.001 for both trajectories; p < 0.001 between groups) (Figure 3A). The evolution of HFrEF showed that 56% of patients did not move out of the HFrEF category, whereas 21% and 23% moved to the HFmrEF and HF with preserved ejection fraction (HFpEF) categories, respectively. By contrast, patients who had HFmrEF at baseline were fairly equally distributed across HFrEF (25%), HFmrEF (39%), and HFpEF (36%) at the end of follow-up (Figure 3B).
Women demonstrated higher LVEF than men both at baseline (p < 0.001) and up to 9 years later (p = 0.001) (Figure 4). In addition, LVEF recovery was significantly higher in women than in men (p = 0.02) during the first year, without significant differences thereafter. After 9 years of follow-up, women tended to show a decline and had values that were practically equal to those of men at 15 years (p = 0.54) (p < 0.001 for both trajectories; p < 0.004 between sexes).
Online Figure 5 shows LVEF trajectories relative to HF hospitalization in the precedent year. A significant difference was found (p < 0.001), with greater early improvement in patients with previous hospitalization and a pronounced inverted-U shape during follow-up. Of note, among hospitalized patients, the majority were patients with HF of short duration (<1 year; p < 0.001) and mainly HFrEF (88%; p < 0.001).
Remarkably, during each study period, patients who died had lower previous LVEF than survivors (Figure 5A) and had worse LVEF dynamics in the immediately preceding study period (changes between the 2 previous LVEF assessments) during most of the follow-up (Figure 5B). Online Figure 6 shows Loess curves for LVEF trajectories of surviving patients at 15 years, the entire cohort, and decedents during follow-up.
The present study is notable for its prospective assessment of LVEF trajectories in a consecutive real-life cohort of HF patients with depressed systolic function of diverse etiologies managed according to a structured HF clinic and echocardiographic schedule for 15 years. Remarkably, long-term HF mortality remains too high, with a 15-year mortality of 72%, yet the majority of patients alive were adequately studied. The 2 main relevant findings are as follows. First, LVEF trajectories are highly variable depending on etiology, HF duration at baseline visit, ESC classification, and sex but as a whole show a significant improvement at 1 year, with an LVEF rise up to a decade and a slow LVEF decline thereafter (Central Illustration). Second, a declining LVEF in the preceding period is associated with higher mortality. Each of these aspects is discussed below.
Most studies of HF with depressed systolic function, including clinical trials and observational studies, report only a single LVEF measurement, generally obtained at baseline. Nevertheless, HF includes multiple diverging patient-oriented phenotypes, resulting in a wide spectrum of time-dependent LVEF trajectories. Dunlay et al. (9) were among the first to report an LVEF increase of 6.9% over 5 years in a retrospective study begun in 1984 (before the first consensus trial was even published), which is far from the benefit achieved with current therapies. The transient nature of LVEF recovery has been described previously. Cioffi et al. (7), in a small prospective study, observed that LVEF normalization was subsequently lost in 55% of patients in the subsequent 2 years. De Groote et al. (8) reported that 25% of patients with LVEF recovery after β-blocker treatment experienced LVEF decline over time and that these patients were at higher risk for cardiovascular mortality. Finally, in a cohort of patients with dilated cardiomyopathy, Merlo et al. (10) reported a 37% LVEF deterioration over time among those who experienced an initial LVEF rise. Our findings confirm these earlier data, but in a large cohort prospectively followed up over 15 years. We observed a LVEF increase up to a decade that thereafter began a slow decline. This U-shaped curve showed a variable time-dependent peak among different HF etiologies.
A remarkable finding of the current study is the striking inverted U-shaped LVEF trajectory for patients with HF of nonischemic etiology. We maintained neurohormonal blockade treatment in all patients irrespective of LVEF improvement, but continuing treatment in patients with significant LVEF improvement remains controversial. Our data support that LVEF improvement in most patients represents myocardial remission rather than true myocardial recovery indicative of myocardial cure, and the decision to discontinue maintenance HF therapy, namely, ß-blockers, angiotensin-converting enzyme inhibitors, and mineralocorticoid receptor antagonists, requires careful consideration (16). A different pattern was observed for alcohol-related HF, which showed a continuous increase in LVEF to full recovery, thus suggesting that in the absence of alcohol consumption, discontinuation of treatment could be an option.
Relative to the new HF classification of the ESC, we observed that patients with baseline HFrEF experienced a more pronounced LVEF increase than those with HFmrEF. HFrEF patients had worse LVEF at ≤7 years, but survivors in both HF categories progressively overlapped, and those with HFmrEF even tended to have worse numbers than those with HFrEF at 15 years. Whether HFmrEF is truly a distinct pathophysiological entity or rather represents a transitional phenotype is the subject of debate. In many instances, HFmrEF might be a transition phenotype of patients with HFrEF who are recovering (6,17). Indeed, in a cohort of patients with HF from Olmsted County, Minnesota, when the change in LVEF over time was quantified, LVEF increased by ∼7% over 5 years in the HFrEF group (9). Our long-term data support the characterization of HFmrEF as just a snapshot on the way toward recovering or declining left ventricular systolic function rather than as a stable phenotype (18). Indeed, as shown in Figure 3, only slightly more than one-third of patients initially classified as having HFmrEF remained in that category during the full-term follow-up, whereas one-third evolved to HFpEF and 25% were categorized as having HFrEF. How to treat these patients is as yet unknown. At present, patients with HFmrEF receive inconsistent treatment, with some clinicians using HFrEF therapy (as we do) and others awaiting more evidence and guideline recommendations.
Sex differences were also observed, including better LVEF dynamics among women, who had higher baseline and subsequent LVEF measurements up to 9 years. The exact mechanism underlying these differences is unclear, but sex-related differences in cardiac remodeling and the protective effects of estrogen against apoptosis could be among the explanations (19).
The potential of a “survival effect” in the reported Loess curves through follow-up should not be underestimated. In point of fact, in the present study, we observed that patients who died had lower final LVEF values and worse LVEF dynamics in the preceding study period. This has important clinical implications, and further research is needed to understand it better. Whether the beneficial effects of ß-blockers and angiotensin-affecting drugs in reverse remodeling are partially lost in the long-term because of a certain degree of drug resistance remains unclear. The long-term effect of sacubitril/valsartan eventually could shed some light on this issue. Nevertheless, clear guidance is lacking on what to do for patients who experience a decline in LVEF over time despite optimal medical treatment. Remarkably, even taking into account the so-called survival effect, very long-term survival was accompanied by a progressive LVEF decay, which varied in intensity depending on the discussed clinical covariates.
LVEF was assessed by transthoracic echocardiography in routine clinical care. However, in the current registry, all echocardiograms were scheduled prospectively and at pre-specified intervals, not at the discretion of the patient’s physician, and were not retrospectively analyzed. We acknowledge that the intraobserver and interobserver variability of echocardiography-derived LVEF is ∼5%; however, taking into account the large number of studies performed, we can assume that such variability was randomly distributed during follow-up. Furthermore, contrast echocardiography might be superior in the evaluation of left ventricular remodeling parameters; however, it is infrequently used in clinical practice, usually only in selected patients. Three-dimensional echocardiography and cardiac magnetic resonance imaging would evaluate left ventricular function and volumes more precisely, but they are not broadly used in clinical practice. As in all published studies of changes in left ventricular function during follow-up, our analyses were performed in “completers,” that is, patients with both baseline and at least 1-year echocardiography data available for analysis. We cannot fully exclude some bias in Loess spline curves due to dropout, because we could not statistically distinguish between autonomous time trends and pseudo-upward trends because of successive dropout of fatalities with lower initial LVEF values. Missingness because of loss to follow-up was assumed to be at random. Furthermore, Loess spline curve estimations at the end of follow-up are less robust because of the limited number of patients. At present, there is a lack of evidence-based data on the best treatment for HFmrEF patients, but in our HF clinic, we managed them as HFrEF. Mineralocorticoid receptor antagonists, ivabradine, and sacubitril/valsartan have been included in the therapeutic portfolio when they were included in international guidelines. How the introduction of such therapies influenced long-term LVEF is incompletely characterized.
The study cohort was a general HF population treated at a specific multidisciplinary HF clinic in a tertiary care hospital, with most patients referred from the cardiology department; thus, there was a predominance of relatively young men with HF of ischemic etiology, and an almost exclusively white population, so the results may not be able to be fully extrapolated to other populations. Of note, a common protocol of treatment was applied to all patients, thus limiting possible bias introduced by different management strategies or treatment protocols. However, dose change/discontinuation and drug reintroduction occur often during follow-up, and it is not possible to analyze the influence of all these changes in LVEF evolution. The reduced number of patients revascularized over the 15-year follow-up prevented us from knowing the actual impact of revascularization on LVEF dynamics above and beyond guideline-directed medical therapy.
Each patient with cardiac dysfunction will follow an individual trajectory within a wide spectrum of LVEF, depending on the number of disease modifiers. LVEF trajectories vary depending on HF etiology, HF duration, ESC classification, and sex. In this study, nonischemic HF patients showed a pattern of temporal myocardial remission without full recovery (except most alcohol-derived cases). Patients with ischemic HF showed an LVEF increase mainly during the first year and then remained stable. A declining LVEF in the preceding period was associated with higher mortality.
COMPETENCY IN MEDICAL KNOWLEDGE: The trajectories of left ventricular ejection fraction (LVEF) as it changes over time vary in patients with heart failure (HF) depending on several disease modifiers (e.g., HF etiology and duration, patient sex), but an inverted U-shaped pattern with lower LVEF early and late in the course typically occurs. A declining LVEF in the preceding period is associated with higher mortality.
TRANSLATIONAL OUTLOOK: Contemporary medical treatment of HF with depressed ejection fraction is associated with an early rise in LVEF, followed by a plateau for about a decade and a slow decline thereafter. Treatments that extend myocardial recovery for a longer period of time could reduce mortality.
The authors thank Beatriz González, Roser Cabanes, Margarita Rodríguez, Carmen Rivas, Violeta Díaz, Nuria Benito, and Alba Ros, nurses in the HF unit, for data collection and their invaluable work in the unit. The authors also thank physicians Nuria Vallejo, Francisco Gual, Albert Teis, and Gladys Juncà from the echocardiography laboratory of the cardiology service for their valuable daily work. The authors also acknowledge Redes Temáticas de Investigación Cooperativa en Salud (RETICS) and Red Cardiovascular (RD12/0042/0047).
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- European Society of Cardiology
- heart failure
- heart failure with mid-range left ventricular ejection fraction
- HF with preserved ejection fraction
- heart failure with reduced left ventricular ejection fraction
- linear mixed-effects
- locally weighted error sum of squares
- left ventricular ejection fraction
- Received May 2, 2018.
- Accepted May 3, 2018.
- 2018 American College of Cardiology Foundation
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