Journal of the American College of Cardiology
Volume 68, Issue 17, October 2016 DOI: 10.1016/j.jacc.2016.07.763
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Original Investigation

Effect of Aldosterone Antagonism on Exercise Tolerance in Heart Failure With Preserved Ejection Fraction

Wojciech Kosmala, Aleksandra Rojek, Monika Przewlocka-Kosmala, Leah Wright, Andrzej Mysiak and Thomas H. Marwick

Author + information

vol. 68 no. 17 1823-1834
DOI: 
https://doi.org/10.1016/j.jacc.2016.07.763
Published By: 
Journal of the American College of Cardiology
Print ISSN: 
0735-1097
Online ISSN: 
1558-3597
History: 
  • Received April 28, 2016
  • Revision received July 19, 2016
  • Accepted July 20, 2016
  • Published online October 25, 2016.
Copyright & Usage: 
American College of Cardiology Foundation

Author Information

  1. Wojciech Kosmala, MD, PhDa,b,c,
  2. Aleksandra Rojek, MD, PhDa,
  3. Monika Przewlocka-Kosmala, MD, PhDa,c,
  4. Leah Wright, BSb,c,
  5. Andrzej Mysiak, MD, PhDa and
  6. Thomas H. Marwick, MD, PhDb,c,∗ (tom.marwick{at}bakeridi.edu.au)
  1. aCardiology Department, Wroclaw Medical University, Wroclaw, Poland
  2. bMenzies Institute for Medical Research, University of Tasmania, Hobart, Australia
  3. cBaker IDI Heart and Diabetes Institute, Melbourne, Australia
  1. ↵∗Reprint requests and correspondence:
    Dr. Thomas H. Marwick, Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia and Baker IDI Heart and Diabetes Institute, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, P.O. Box 6492, Melbourne, Victoria 3004, Australia.

Abstract

Background Impaired functional capacity is a hallmark of patients with heart failure with preserved ejection fraction (HFpEF). Despite the association of HFpEF with reduced myocardial compliance attributed to fibrosis, spironolactone has not been shown to alter outcomes—perhaps reflecting the heterogeneity of underlying pathological mechanisms.

Objectives The authors sought to identify improvement in exercise capacity with spironolactone in the subset of patients with HFpEF with exercise-induced increase in ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e′) reflecting elevation of left ventricular (LV) filling pressure.

Methods In this randomized, blinded, parallel-group, placebo-controlled trial, 150 subjects (age 67 ± 9 years) with exertional dyspnea (New York Heart Association functional class II to III, left ventricular ejection fraction >50%, diastolic dysfunction, and exertional E/e′ >13), excluding those with ischemic heart disease, were recruited in a tertiary cardiology center. Patients were randomized to 6 months of oral spironolactone 25 mg/day or matching placebo. Primary outcomes were improvements in peak oxygen uptake (VO2) and exertional E/e′ ratio, and secondary outcomes were improvements in exercise blood pressure response and global LV longitudinal strain.

Results At follow-up, 131 patients completed therapy—64 taking spironolactone and 67 placebo. At baseline, subjects had substantial exercise limitation (peak VO2 64 ± 17% predicted). The spironolactone group showed improvement in exercise capacity (increment in peak VO2 [2.9 ml/min/kg (95% confidence interval [CI]: 1.9 to 3.9 ml/min/kg) vs. 0.3 ml/min/kg (95% CI: −0.5 to 1.1 ml/min/kg); p < 0.001], anaerobic threshold [2.0 ml/min/kg (95% CI: 0.9 to 3.2 ml/min/kg) vs. −0.9 ml/min/kg (95% CI: −3.4 to 1.6 ml/min/kg); p = 0.03], and O2 uptake efficiency [0.19 (95% CI: 0.06 to 0.31) vs. −0.07 (95% CI: −0.17 to 0.04); p = 0.002]), with reduction in exercise-induced increase in E/e′ (−3.0 [95% CI: −3.9 to −2.0] vs. 0.5 [95% CI: −0.6 to 1.6]; p < 0.001). There was a significant interaction of spironolactone and change in E/e′ on VO2 (p = 0.039).

Conclusions In patients with HFpEF and abnormal diastolic response to exertion, improvement in exercise E/e′ mediates the beneficial effect of spironolactone on exercise capacity. Identification of exercise-induced increase in LV filling pressure in patients with HFpEF may define a subgroup with warranting trial of spironolactone.

Key Words

Heart failure with preserved ejection fraction (HFpEF) is responsible for approximately 50% of prevalent heart failure (HF), and has a high morbidity and mortality (1,2). An increase in the prevalence of HFpEF is likely to continue with the aging of the population and high proportions of hypertension, diabetes, and obesity (2,3). However, no specific treatment for this condition appears to be effective, which could be in part due to diagnostic challenges and the heterogeneity of the HFpEF phenotype (4–6). The latter is probably responsible for diverse results with novel therapeutic options for HFpEF: negative (7) or only partly positive (8) for spironolactone, negative for nitric oxide (9) and sildenafil (10), and both positive (11) and negative (12) for ivabradine.

Among the multifactorial mechanisms and associated conditions accounting for the development and progression of HFpEF (13), exercise-induced elevation of left ventricular (LV) filling pressure (FP) is a distinctive hemodynamic abnormality, linked with reduced myocardial compliance attributed to fibrosis (14,15). In this context, mineralocorticoid receptor antagonism (MRA)—thought to act in part through an antifibrotic mechanism in patients with HF with reduced ejection fraction (16–18)—could be considered a reasonable therapeutic option to investigate further. Although clinical trials of MRA in subjects with HFpEF have not shown prognostic benefit (7,8), these elderly patients may seek improved functional capacity and symptom status as much as longer survival. Given this, we postulated that an antifibrotic effect of spironolactone might reduce the increment in estimated LVFP, thus alleviating exercise intolerance, and that patients with abnormal diastolic response to exertion might be the appropriate target population for this therapy. Accordingly, the STRUCTURE (SpironolacTone in myocaRdial dysfUnCTion with redUced exeRcisE capacity) trial was designed to identify improvement in exercise capacity with spironolactone in HFpEF with an exercise-induced increase in the echo Doppler-derived ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e′), reflecting LVFP.

Methods

Study design

The STRUCTURE trial (12614000088640) was a prospective, randomized, blinded, parallel-group, placebo-controlled study to evaluate the hypothesis that therapy with spironolactone 25 mg/day for 6 months would improve exercise capacity in patients with HFpEF and an abnormal LV diastolic response to exertion. Patients were recruited between 2011 and 2015 in Wroclaw, Poland, with a core laboratory in Hobart, Australia, for independent adjudication of the primary endpoint. The study was conducted in accordance with the Declaration of Helsinki and was approved by the ethics committee of each center. Written informed consent was provided by all subjects before involvement in the study.

Patient selection

Patients satisfying the criteria of HFpEF (19) (see the Online Appendix) were recruited from hospital clinics at a tertiary cardiology center. Patients who presented with signs or symptoms of HF (dyspnea, fatigue, and exercise intolerance) consistent with New York Heart Association functional class II or III, with preserved LV ejection fraction (>50%), and with evidence of diastolic dysfunction (6,20), were considered suitable for screening. Elevated brain natriuretic peptide (BNP) or additional echocardiographic abnormalities (detailed in the Online Appendix) were used to confirm the diagnosis of HFpEF in subjects with an inconclusive E/e′ of 8 to 15. Potential subjects underwent an exercise test and were enrolled in the presence of post-exercise E/e′ >13 (reflecting elevation of LVFP during exertion) and impaired exercise capacity. The initial study design included patients with >20% impairment relative to age- and sex-predicted normal ranges; however, as this was too restrictive, we enrolled patients with all levels of impaired exercise capacity according to the reference equation by Wasserman (21). All subjects underwent coronary angiography to exclude significant coronary stenoses as a potential determinant of exercise limitation.

Exclusion criteria were:

  • • Atrial fibrillation or flutter

  • • Resting heart rate >90 beats/min

  • • Ischemic heart disease (defined by a positive coronary angiogram or inducible ischemia during exercise testing)

  • • Moderate or worse valvular heart disease

  • • Primary myocardial diseases

  • • Established or suspected pulmonary diseases (spirometry results <80% of age- and sex-specific reference values)

  • • Hemoglobin ≤11 g/dl

  • • Adrenocortical, hepatic, rheumatic, neoplastic, skeletal, thyroid, and renal diseases (including renal insufficiency with serum creatinine >1.5 mg/dl [132 μmol/l])

  • • Hyperkalemia >5.0 mmol/l

  • • Known intolerance or treatment with an MRA within the last 3 months

  • • Concomitant therapy with a potassium-sparing agent

  • • Current lithium use

  • • Pregnancy

Study protocol, randomization, and masking

Eligible patients were randomly allocated to either spironolactone 25 mg/day or matching placebo (120 mg/day of microcellulose). The randomization procedure was performed in blocks of 10 sequentially-numbered, opaque, sealed envelopes with an allocation ratio of 1:1. The study coordinator, who was not involved in study procedures, was responsible for drug randomization and dispensing. Patients and investigators performing the assessments and data analysis were blinded to group assignment. Follow-up visits for the evaluation of clinical status, adherence to therapy, and biochemistry were scheduled at 1 week and then monthly. At baseline and 6-month follow-up, patients underwent cardiopulmonary exercise testing, resting and immediate post-exercise echocardiogram, and blood sampling for BNP and galectin-3 levels. Enrollees continued to receive other prescribed treatments throughout the study period.

The indications for withdrawal of study medication were the occurrence of significant hyperkalemia (≥5.5 mmol/l), renal impairment (creatinine >2.0 mg/dl [180 μmol/l], or >2× the baseline value), unacceptable side effects, or withdrawal of informed consent.

Outcomes

The study was completed when all available patients were retested at follow-up. Coprimary outcomes were change at 6 months in exercise capacity (assessed by peak VO2) and exertional E/e′ (reflecting LVFP). The secondary outcomes included change at follow-up in exercise blood pressure (BP) response and post-treatment global longitudinal myocardial deformation (GLS) measured by 2-dimensional strain.

Cardiopulmonary exercise testing

Symptom-limited treadmill exercise testing was performed using a modified Bruce protocol with standard ECG and BP monitoring. Ventilation, oxygen uptake, and carbon dioxide production were monitored continuously and peak oxygen uptake (peak VO2) was calculated as the average oxygen consumption during the last 30 s of exercise. Exercise capacity was also evaluated in metabolic equivalents on the basis of the peak exercise intensity from treadmill speed and grade (22), and respiratory exchange ratio (RER) was measured in the usual way. The oxygen-uptake efficiency slope (OUES), a measure of cardiorespiratory reserve that does not require a maximal exercise effort, was calculated from oxygen consumption and minute ventilation as originally described (23). All cardiopulmonary exercise testing reports including the primary outcome measure (peak VO2) were analyzed by the independent blinded laboratory.

Echocardiography

Echocardiography was carried out using standard equipment (Vivid e9, General Electric Medical Systems, Milwaukee, Wisconsin). The same imaging protocol was used at baseline and follow-up visits and performed by the same sonographer. Images were saved in digital format on a secure server for offline analysis. Cardiac dimensions, wall thickness, and LV and left atrial (LA) volumes were measured according to standard recommendations (24). All cardiac volumes were indexed to body surface area. Cardiac output was calculated as the product of heart rate and stroke volume.

LV inflow was assessed by pulsed wave Doppler from the apical 4-chamber view with the sample volume located between the tips of mitral leaflets and included peak early (E) and late diastolic flow velocity, and deceleration time of E-wave. Pulsed-wave tissue Doppler was used to establish peak early diastolic tissue velocity (e′) at the septal and lateral portions of the mitral annulus. The ratio of peak mitral inflow early diastolic velocity to e′ velocity (E/e′) was determined to approximate LVFP. On the basis of previous validation, exertional septal E/e′ >13 was considered as a marker of exercise-induced elevation of LV filling pressure (25).

Speckle tracking imaging

Myocardial deformation was evaluated by semiautomated 2-dimensional speckle tracking (Echopac version 113, GE, Horten, Norway) in the 3 apical views at a temporal resolution of 60 to 90 frames/s. The average negative value on the strain curve was presented as global longitudinal strain (GLS). The apical 4- and 2-chamber views were used to evaluate LA longitudinal strain, and the onset of the P-wave was accepted as the 0 reference point to determine deformation at atrial contraction (the first negative component) and total LA deformation (the sum of peak negative and peak positive components). All echocardiographic indexes were averaged over 3 consecutive cardiac cycles.

Ventriculo-arterial coupling

The ventriculo-arterial coupling (VAC) ratio was computed as the quotient of arterial and LV end-systolic elastance indexes, whereby effective arterial elastance index and LV end-systolic elastance index were calculated as the ratio of end-systolic pressure to stroke volume index and end-systolic volume index, respectively. End-systolic pressure was derived from the equation: 0.9 × brachial systolic BP.

Heart rate reserve (reflecting the chronotropic response during exertion) was assessed as the change in heart rate from rest to peak exercise expressed as a percentage of the predicted heart rate reserve (i.e., the difference between the predicted maximal heart rate and the resting heart rate).

Blood assays

Peripheral venous blood samples were drawn between 8:00 am and 9:00 am after 30 min of rest in the supine position, and then frozen at −70°C until assayed. Serum galectin-3 levels were quantified by ELISA kits (BioVendor Inc., Brno, Czech Republic). Intra-assay and interassay coefficients of variation were 6.3% and 8.7%, respectively. BNP was measured using a commercially available fluorescence immunoassay (Triage BNP Test, Biosite Diagnostics Inc., San Diego, California).

Statistical analysis

As no intervention trial with spironolactone with an exercise endpoint in HFpEF was available at the time of designing this study, effect sizes were obtained from a 1-min (∼15%) increment in treadmill time from angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker therapy (26). Assuming exercise capacity to show a treatment response of 15% and an SD of 30%, a sample size of 65 patients/group was chosen to provide 90% power to show a difference in exercise capacity at a 2-sided α of 0.05. To allow for dropouts, the number of patients in each arm was increased to 75.

All patients had complete data for the primary and secondary outcomes, although full gas exchange-derived data at both baseline and follow-up were available in 120 patients (60 patients/arm). No imputation of the data was performed. Analyses for investigated variables, including the primary and secondary endpoints, followed the same analytic approach. Between-group comparisons were carried out with an unpaired 2-sided Student t test for continuous variables and chi-square test for categorical variables. Homogeneity of variance was assessed by the Levene test. Longitudinal analyses were performed by a mixed-design analysis of variance for repeated measures, with the test of interest being an interaction of treatment and time (baseline to 6 months) on the dependent variable. The subgroup analysis on the basis of categorization according to the peak RER was accomplished in an exploratory manner. Associations between peak VO2 and potential contributors were studied with the use of multiple regression analysis, with the inclusion of variables in the models on the basis of clinical significance. Interaction between treatment and change in E/e′ at follow-up was tested using a general linear model. Effect size was evaluated using the Cohen’s d method. Skewed variables (BNP and galectin-3) were log-transformed before being analyzed. Changes in particular parameters with intervention were calculated by subtracting the baseline value from the follow-up value and were expressed in the units of their measurements. The reproducibility of echocardiographic endpoints (E/e′ and GLS) was evaluated by the Bland-Altman method (mean difference and 95% confidence interval [CI]), intraclass correlation coefficient, and coefficient of variation. All analyses were performed with standard statistical software (Statistica for Windows 12, StatSoft Inc., Tulsa, Oklahoma). The level of statistical significance was set at a 2-sided p value <0.05. No adjustments for multiple comparisons were intended, except for the primary endpoints.

Results

Patients

Of 251 patients screened from November 2011 to February 2015, 150 were suitable for randomization to spironolactone or placebo (Figure 1). A total of 19 subjects (13%) discontinued study participation before the 6-month follow-up visit and were not considered in the analysis. Baseline demographic, clinical, echocardiographic, hemodynamic, and exercise characteristics were similar between the spironolactone and placebo groups (Tables 1, 2, 3, and 4). There were no differences between both arms in the proportion of patients graded according to the severity of LV diastolic dysfunction. In all patients who were considered grade III, the restriction was reversible, as indicated by a positive response to the Valsalva maneuver. Patients with resting E/e′ >13 (11 in each arm) demonstrated further increase in E/e′ during exercise.

Central Illustration
Central Illustration

Aldosterone Antagonism in HFpEF: Improvement in Exercise Capacity at Follow-Up

Δ = change from baseline to follow-up; CI = confidence interval; HFpEF = heart failure with preserved ejection fraction; VO2 = oxygen uptake.

Figure 1
Figure 1

Study Flow Diagram

Eligible patients (n = 150) were randomized to spironolactone or placebo, and 131 patients completed the study and were suitable for analysis.

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Table 1

Clinical and Demographic Characteristics of the Study Population

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Table 2

Baseline and Follow-Up Resting Echocardiography in the Treatment and Placebo Groups

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Table 3

Baseline and Follow-Up Cardiopulmonary Exercise Testing in the Treatment and Placebo Groups

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Table 4

Baseline and Follow-Up Hemodynamic and Myocardial Reserve (i.e., Exercise Increment) in the Treatment and Placebo Groups

Exercise capacity

In comparison with placebo, treatment with spironolactone significantly improved peak VO2, the spironolactone arm also showed favorable changes in metabolic equivalents, exercise time, OUES, anaerobic threshold, and RER at follow-up (Table 3, Central Illustration).

Echocardiography

Of the 2 imaging endpoints, significant improvement with spironolactone, relative to placebo, was demonstrated for exercise E/e′, but not GLS (p = 0.15). In addition, comparisons with the placebo arm revealed that spironolactone improved resting LV diastolic function, as evidenced by lateral e′ and E/e′; improved LA function, as shown by total LA strain; increased exertional e′; and reduced LV mass and LA size. In comparison with placebo, there were no significant changes with the active treatment in other echocardiographically-derived parameters, both in resting values or functional reserve (Tables 2 and 4).

Hemodynamics

Peak heart rate at exercise and heart rate reserve significantly increased at follow-up in the spironolactone group. No changes were found in maximal exertional BP. Although resting systolic (p = 0.02) and diastolic BP (p = 0.05) decreased from baseline to follow-up with spironolactone, these changes were not significant compared with placebo (Tables 3 and 4).

Blood markers

No significant alterations were noted at follow-up in circulating BNP and galectin-3 in both study arms (Online Table 1).

Subgroup analysis

Significant improvement with spironolactone (as compared with placebo) was found in subgroups above and below an RER of 1 (the achievement of which was used to define maximum effort), with the effect size being medium at RER >1 and large at RER <1. The effect of spironolactone on exercise E/e′ showed a large effect size in both subgroups. In the group with RER <1 at baseline, spironolactone was associated with an increase in RER, which was not observed in patients treated with placebo (Figure 2).

Figure 2
Figure 2

Exercise Capacity, Exertional E/e′, and Respiratory Exchange According to Baseline RER and Allocation to Treatment

↑RER-S: RER ≥1 and treatment with spironolactone; n = 43 (mean baseline RER 1.07 ± 0.06). ↑RER-P: RER ≥1 and treatment with placebo; n = 41 (mean baseline RER 1.06 ± 0.05). ↓RER-S: RER <1 and treatment with spironolactone; n = 19 (mean baseline RER 0.94 ± 0.05). ↓RER-P: RER <1 and treatment with placebo; n = 23 (mean baseline RER 0.93 ± 0.05). Δ = change from baseline to follow-up; BL = baseline; CI = confidence interval; E = peak early diastolic mitral flow velocity; e′ = peak early diastolic mitral annular velocity; RER = respiratory exchange ratio; VO2 = oxygen uptake.

Determinants of improvement in exercise capacity

A series of multivariable models adjusted for clinical and demographic covariates (Table 5) showed that improvement in exercise capacity was independently associated with change in exertional increase in E/e′ and VAC from baseline to follow-up, as well as baseline galectin-3; however, low R2 values of the models are indicative of a relatively poor model fit. Treatment with spironolactone and change in exercise E/e′ showed a significant interaction with respect to improvement in peak VO2 (p = 0.039).

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Table 5

Multivariable Associations of Improvement in Exercise Capacity (Increase in Peak VO2)

A model was also developed to identify the independent associations of improvement in LA strain with spironolactone therapy. After adjustment for potential associations including age, coexistence of hypertension and diabetes, body mass index, baseline galectin-3 level, and change in resting E/e′ and LA volume from baseline to follow-up, the only independent correlate of change of atrial strain was exertional increase in E/e′ (β = −0.24; SE 0.09; p = 0.008).

Adverse events

Adverse events during follow-up were rare (Online Table 2). Spironolactone was associated with a small increase in serum potassium (Online Table 1). In 2 patients experiencing hyperkalemia (>5.5 mmol/l), the study drug was temporarily discontinued, and after the adjustment of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker dosing and decrease in serum potassium level, the treatment was reinstituted.

Loss to follow-up

There were no significant differences in all patient characteristics presented in Online Table 3 between the groups of enrollees with complete and incomplete follow-up.

Reproducibility

The intraobserver and inter-observer variability of echocardiographic measurements of imaging outcomes—E/e′ ratio and GLS—were assessed in 15 randomly selected examinations, and were analyzed twice by 2 observers blinded to patient clinical data on 2 separate days with the time interval of 2 weeks (Online Table 4).

Discussion

The STRUCTURE study demonstrated that the addition of spironolactone to existing therapy for 6 months in patients with HFpEF and abnormal diastolic response to exertion led to increased exercise capacity independent of changes in BP, and that improvement in LV diastolic filling at exercise (exercise E/e′ ratio) might be a contributor to this beneficial effect (Central Illustration).

Mineralocorticoid inhibition and HFpEF

MRA controls HF by reducing BP, renal sodium reabsorption, LV hypertrophy, endothelial dysfunction, and myocardial fibrosis (13,27). Increased myocardial stiffness is an important contributor to impaired cardiac performance in HFpEF, associated with aldosterone effects on myocardial collagen content. Spironolactone antagonizes the biological effects of aldosterone, and reduction of fibrosis is associated with improved LV function (28–30), as well as improvement in the clinical outcomes of HF with reduced ejection fraction (31,32). In this study, the improvement in exercise capacity at 6-month follow-up was associated with improvement in LV diastolic response to exercise—a relationship reinforced by finding a significant interaction between active treatment and the exercise E/e′ response in their effect on peak VO2.

Treatment with spironolactone caused a significant reduction of BP at rest, leaving exertional BP unchanged; however, the improvement in exercise capacity was independent of this hypotensive effect.

In contrast to the post hoc analysis of the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) data (33), spironolactone-induced improvement in GLS did not reach statistical significance in our HFpEF population. However, the degree of post-treatment change was similar between both studies, and significant differences might be expected with a larger sample size.

Assessment of exercise response and disease severity

The advantage of this study over previous trials was that the assessment of LV function was performed both at rest and immediately post-exercise. It is possible that previous negative studies with spironolactone may have been related to the diagnostic challenges of HFpEF and the heterogeneity of HFpEF phenotypes. Several issues likely to account for the differences in the therapeutic response to MRA between this investigation and previous trials warrant emphasis. Selection of patients on the basis of exercise-induced increase in E/e′ (suggesting the elevation of LVFP), might have helped to select the HFpEF subgroup that is most responsive to MRA. The clinical profile of the study population, with lower circulating BNP and lower incidence of emergency hospitalizations for HF, suggests a less severe stage of disease. This might be crucial for the potential of spironolactone to improve/reverse myocardial pathologies and, together with a narrower spectrum of comorbidities (the absence of ischemic heart disease and atrial fibrillation), should be taken into consideration when making comparisons with the Aldo-DHF (Aldosterone Receptor Blockade in Diastolic Heart Failure) and TOPCAT trials.

Despite maximal effort, a proportion of patients with HF do not attain an RER >1 (34,35). This is particularly the case for HFpEF, in which an increase in LVFP is likely to precede the development of impaired peripheral perfusion and metabolic acidosis, with the resulting increase in exhaled CO2. This scenario may explain the inability of one-third of our patients to reach expected levels of RER. The significant increase in RER with active therapy in patients with pre-treatment RER <1 (which was not seen in patients receiving placebo, as well as in the subgroups with pre-treatment RER >1) may be due to improvement in exertional diastolic function with spironolactone, delaying the rise of LVFP that limited baseline exercise capacity. Indeed, although spironolactone had a beneficial effect on exercise capacity and diastolic performance in strata of RER >1 and <1, the effect size was higher in the subgroup with an initially lower respiratory exchange. These findings are supported by the results of OUES—a parameter reflecting cardiorespiratory reserve regardless of RER values.

Analogous to the ALDO-DHF trial (7), spironolactone significantly improved LV diastolic function at rest and reduced LV mass, both of which were independent of a decrease in resting BP. However, these alterations were not associated with clinical benefit. Among the independent contributors to the improvement in exercise capacity was the exertional drop in VAC, reflecting the physiological interaction between LV contractile response and vasodilation. As the change in VAC at follow-up did not improve significantly with active treatment, it seems unlikely that this mediates spironolactone-specific effects.

Favorable changes in LV function and structure imparted by spironolactone were paralleled by improvements in LA size and function. The post-treatment increase in LA strain was independent of changes in resting LV diastolic filling and LA volume, but was associated with improved exercise E/e′. Thus, the effect of spironolactone on resting LA deformation appears to be at least partially mediated by the amelioration of the impaired LV diastolic response to exercise.

Biomarker responses

No changes in resting BNP level were observed with treatment, which might be attributable both to low baseline values in most patients and limited accuracy of this marker in HFpEF. The response to spironolactone was inversely related to baseline galectin-3 levels. The actual value of this marker in HFpEF remains uncertain (36); however, higher galectin-3 may reflect more advanced and less reversible myocardial fibrosis. This might indicate the need for further assessment of the diagnostic potential of galectin-3, especially in the context of antifibrotic interventions.

Study limitations

First, although validated against invasive hemodynamic measurements in previous studies, the E/e′ ratio is only a surrogate measure of LVFP. Irrespective of whether E/e′ corresponds to actual hemodynamics, this parameter was effective in both patient selection and assessment of response. Second, we excluded patients with atrial fibrillation or myocardial ischemia, as the former could compromise the accuracy of echocardiographic measurements, and the latter could influence the interpretation of exercise capacity. Nonetheless, these measures limit the external validity of our study. Third, the applicability of our results to subjects with more severely advanced HFpEF and less reversible myocardial pathology is uncertain. Fourth, the research design, with a modest sample size and single-center recruitment, might affect the generalizability of our findings.

Conclusions

The results of this study of spironolactone for the treatment of HFpEF show that this therapeutic intervention may provide a beneficial effect on exercise capacity in patients with an exercise-induced increase in E/e′.

Perspectives

COMPETENCY IN PATIENT CARE AND PROCEDURAL SKILLS: In patients with HFpEF, in whom exercise is associated with echocardiographic correlates of elevated LVFP, treatment with spironolactone leads to improvement in functional capacity.

TRANSLATIONAL OUTLOOK: Further studies are needed to assess the generalizability of these observations to patients with concurrent myocardial ischemia, atrial fibrillation, and specific disease states associated with HFpEF and to those in whom elevated left heart failing pressure during exercise is assessed by other methods.

Appendix

Appendix

For an expanded Methods section and supplemental tables, please see the online version of this article.

Footnotes

Abbreviations and Acronyms
FP
filling pressure
GLS
global longitudinal myocardial deformation
HF
heart failure
HFpEF
heart failure with preserved ejection fraction
LA
left atrial
MRA
mineralocorticoid receptor antagonism
OUES
oxygen-uptake efficiency slope
peak VO2
peak oxygen uptake
RER
respiratory exchange ratio
VAC
ventriculo-arterial coupling
  • Received April 28, 2016.
  • Revision received July 19, 2016.
  • Accepted July 20, 2016.

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