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Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, JapanDivision of Cardiovascular Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan
Address for correspondence: Masaru Obokata, MD, PhD, Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan, Tel: +81-27-220-8145; Fax: +81-27-220-8158
Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, JapanDivision of Cardiovascular Medicine, National Defense Medical College, Tokorozawa, Saitama, Japan
Hospitalization with a first episode of heart failure (HF) is a serious event associated with poor clinical outcomes in HF with preserved ejection fraction (HFpEF). Identification of HFpEF via detection of elevated left ventricular (LV) filling pressure at rest or during exercise may allow early intervention. Benefits of mineralocorticoid receptor antagonists (MRAs) in established HFpEF are reported but MRAs are not well studied in early HFpEF without prior HF hospitalization.
Methods
We retrospectively studied 197 patients with HFpEF without prior hospitalization but diagnosed by exercise stress echocardiography or catheterization. We examined changes in natriuretic peptide (NP) levels and echocardiographic parameters reflecting diastolic function following MRA initiation.
Results
Of the 197 patients with HFpEF, MRA was initiated for 47 patients. After a median 3-month follow-up, reduction in NT-proBNP levels from baseline to follow-up was greater in patients who were treated with MRA than in those who were not (-200 [-544 to -31] pg/mL vs. 67 [-95 to 456] pg/mL, p<0.0001 in 50 patients with paired data). Similar results were observed for the changes in BNP levels. Reduction in the left atrial volume index was also greater in the MRA-treated group than in the non-MRA-treated group after a median 7-month follow-up (77 patients with paired echocardiographic data). Patients with lower LV global longitudinal strain experienced a greater reduction in NT-proBNP levels following MRA treatment. In the safety assessment, MRA modestly decreased renal function but did not change potassium levels.
Conclusions
Our results suggest the potential benefits of MRA for early-stage HFpEF.
Early identification of the disease prior to the first HF hospitalization may improve outcomes. Detection of elevated left ventricular (LV) filling pressure at rest or during physiological stress, such as exercise, is emphasized as the key objective evidence to identifying HFpEF at an earlier disease stage.
Role of Diastolic Stress Testing in the Evaluation for Heart Failure with Preserved Ejection Fraction: A Simultaneous Invasive-Echocardiographic Study.
The Clinical Use of Stress Echocardiography in Non-Ischaemic Heart Disease: Recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
Multimodality imaging in patients with heart failure and preserved ejection fraction: an expert consensus document of the European Association of Cardiovascular Imaging.
How to diagnose heart failure with preserved ejection fraction: The HFA-PEFF diagnostic algorithm: A consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).
2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial.
but very little is known about how patients with early HFpEF could be treated, especially those without prior HF hospitalization but diagnosed by the presence of elevated LV filling pressure during exercise testing.
Time to Clinical Benefit of Dapagliflozin and Significance of Prior Heart Failure Hospitalization in Patients With Heart Failure With Reduced Ejection Fraction.
Kjeldsen SE, von Lueder TG, Smiseth OA, et al. Medical Therapies for Heart Failure With Preserved Ejection Fraction. Hypertens (Dallas, Tex 1979). 2020;75(1):23-32. doi:10.1161/HYPERTENSIONAHA.119.14057
Mineralocorticoid receptor antagonists (MRAs) may mitigate LV diastolic dysfunction and improve clinical outcomes in patients with HFpEF, possibly by suppressing RAAS-mediated cardiac fibrosis and hypertrophy.
Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial.
Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial.
The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart “OMics” in AGEing (HOMAGE) randomized clinical trial.
Association of Active and Passive Components of LV Diastolic Filling With Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Mechanistic Insights From Spironolactone Response.
The American College of Cardiology, American Heart Association, and Heart Failure Society of America guidelines now recommend that patients with HFpEF be treated with an MRA (class IIb).
2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
findings from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial and others suggest potential benefits of MRA in early-stage HFpEF.
The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart “OMics” in AGEing (HOMAGE) randomized clinical trial.
Association between long-term prescription of aldosterone antagonist and the progression of heart failure with preserved ejection fraction in hypertensive patients.
Accordingly, we hypothesized that MRA treatment could have potential benefits among patients with early HFpEF who have no history of hospitalization for HF. To test this hypothesis, we examined changes in natriuretic peptide (NP) levels and echocardiographic parameters reflecting diastolic function following MRA initiation in HFpEF patients without prior HF hospitalization but diagnosed by elevated LV filling pressure at rest or during exercise stress testing.
METHODS
Study Population
Consecutive patients who were referred to our echocardiographic laboratory for exercise stress echocardiography for evaluation of exertional dyspnea between October 2019 and October 2022 were retrospectively screened. The participants were required to have no history of hospitalization for HF. The diagnosis of HFpEF was determined using the established Heart Failure Association (HFA) Pre-test assessment, Echocardiography & natriuretic peptide, Functional testing, Final etiology (HFA-PEFF) algorithm proposed by the HFA of the European Society of Cardiology.
How to diagnose heart failure with preserved ejection fraction: The HFA-PEFF diagnostic algorithm: A consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).
Briefly, the HFA-PEFF score was calculated as the sum of echocardiographic functional (maximum 2 points), morphological (maximum 2 points), and NP (maximum 2 points) domains. Points were added to the HFA-PEFF score depending on the findings of the exercise stress echocardiography (added 2 points if the ratio of early diastolic mitral annular velocity to early diastolic transmitral inflow velocity [E/e’ ratio] during exercise ≥15 and added 3 points if E/e’ ratio during exercise ≥15 with tricuspid regurgitant velocity [TRV] during exercise >3.4 m/sec). A diagnosis of HFpEF was confirmed if the total HFA-PEFF score was ≥ 5 points. Patients with elevated invasively measured LV filling pressures (pulmonary capillary wedge pressure > 15 mmHg at rest and/or ≥ 25 mmHg during exercise) on exercise right heart catheterization were also classified as having HFpEF.
Patients with EF < 50%, significant left-sided valvular heart disease (> moderate regurgitation, > mild stenosis), infiltrative, restrictive, or hypertrophic cardiomyopathy, non-group II pulmonary artery hypertension, and exercise-induced pulmonary hypertension without elevation in the E/e’ ratio were excluded. Patients who underwent catheter ablation for atrial fibrillation (AF) after indexed exercise stress echocardiography were also excluded because restoration of sinus rhythm may affect NP levels.
From this HFpEF group, patients with at least one follow-up NP assessment or resting echocardiographic evaluation in a compensated (outpatient) state (that was performed a minimum of > 1 month from baseline assessment) were identified (Figure 1). When patients had multiple follow-up NP data, the one within 6 months and most distant from the baseline assessment was used. Participants were required to have either pair of B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) level measurements. This study was approved by our institutional review board, as was the waiver for obtaining informed consent. The article's data may be shared upon reasonable request to the corresponding author.
Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American society of echocardiography and the European association of cardiovascular imaging.
All studies were interpreted by well-trained sonographers who were blinded to medication and NP data. LV systolic function was assessed by EF and global longitudinal strain (GLS). GLS was obtained by averaging peak longitudinal strains from four-, two-, and three-chamber apical views (EchoPAC, GE, Milwaukee, Wisconsin) and were reported as absolute values. Early diastolic mitral inflow velocity (E-wave) was measured at the mitral leaflet tips and early diastolic mitral tissue velocity (e’) at the septal annulus was recorded to obtain septal E/e’ ratio. The left atrial (LA) volume was calculated using the disk method. LA volume and LV mass were then indexed to the body surface area. Right atrial pressure (RAP) at rest was estimated from the diameter of the inferior vena cava and its respiratory change.
Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American society of echocardiography and the European association of cardiovascular imaging.
+ estimated RAP. The most recent study (distant from the baseline assessment) was used for follow-up echocardiography.
Exercise Stress Echocardiography
All participants underwent supine ergometry exercise stress echocardiography, starting at 20 W for 5 min, increasing in 20-W increments in 3-min stages until the subject reported exhaustion, as previously reported.
The Clinical Use of Stress Echocardiography in Non-Ischaemic Heart Disease: Recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
Mitral E-wave, septal e’ velocity, E/e’ ratio, and TRV were recorded at rest and during each stage of exercise. Doppler measurements represent the mean of two beats in sinus rhythm and more than or equal to three beats in AF.
Outcome Assessments
Patients with HFpEF were divided based on MRA use (spironolactone, eplerenone, or esaxerenone) or non-use after indexed exercise stress echocardiography. Treatment was determined by the attending cardiologists’ clinical judgment based on their evaluation, including exercise stress echocardiography results. The primary outcome was to compare changes in NP levels from baseline to follow-up evaluation between the groups. The secondary outcomes were echocardiographic parameters reflecting diastolic function, including LV mass index, E/e’ ratio, and LA volume index (LAVI).
Statistical Analysis
Data are reported as the mean (SD), median (IQR), or number (%) unless otherwise specified. Between-group differences were compared using the unpaired t-test, Wilcoxon’s rank-sum test, or chi-square test, as appropriate. All tests were two-sided, with a significance level of P < 0.05. All statistical analyses were performed using JMP 15.2.0 (SAS Institute, Cary, NC, USA).
RESULTS
Baseline Demographics
A total of 215 patients met the inclusion criteria of HFpEF (Figure 1). Of the 215 patients, 18 were excluded because they had undergone catheter ablation after indexed exercise stress echocardiography, resulting in 197 patients for the final analysis. Overall, 122 patients (62%) were diagnosed with HFpEF based solely on the resting evaluation, and the remaining 75 (38%) were diagnosed after exercise stress testing. Of the 197 patients, 47 were diagnosed based on right heart catheterization at rest or during exercise. Comparisons of the baseline clinical characteristics according to MRA status are presented in Supplemental Table S1.
Of the 197 patients with HFpEF, paired NP data were available for 93 patients (NT-proBNP, n=50; BNP, n=47), of which MRA was initiated for 37 patients (40%). Sensitivity analysis comparing baseline characteristics between the patients with paired NP data (n=93) and those without (n=104) showed similar results (Supplemental Table S2). Table 1 summarizes the baseline clinical demographics according to the MRA status in patients with paired NP levels. There were no significant differences in age, sex, body mass index, major comorbidities, medication use, vital signs, or NP levels between patients with and without MRA treatment. As expected, renal function was impaired in patients without MRA compared to those who received MRA, but potassium levels were similar between the groups. The LV mass, size, EF, LV diastolic function, and right heart parameters at rest were similar between the groups. Exercise capacity, as assessed by exercise intensity, exercise time, and peak oxygen consumption, did not differ between patients with and without MRA treatment, with similar E/e’ ratios and TRV during peak exercise (Table 1).
Table 1Baseline Characteristics among Patients with Paired NP Data.
The median follow-up duration between baseline and follow-up NP assessments did not differ between patients with and without MRA treatment (3.3 [2.1-5.1] months vs. 3.4 [2.7-5.1] months, p=0.78). There were no differences in the rate of initiation or increase of non-MRA agents between the baseline and follow-up assessments (Supplemental Table S3). The reduction in NT-proBNP levels from baseline to follow-up was greater in patients who were treated with MRA than in those who were not (-200 [-544 to -31] pg/mL vs. 67 [-95 to 456] pg/mL, p<0.0001) (Figure 2A). Similar results were observed for the changes in BNP levels (-25 [-191 to 1] pg/mL vs. 7 [-18 to 44] pg/mL, p=0.005) (Figure 2B). When NT-proBNP and BNP were combined, percent decreases in NP levels were consistently greater in patients with MRA treatment than in those without MRA treatment (-39 [-56 to -21] % vs. 28 [-20 to 73] %, p<0.0001). Patients with a lower GLS at rest or higher E/e’ ratio during peak exercise demonstrated a greater reduction in NT-proBNP levels following MRA initiation (Figure 2C-D). Although a reduction in renal function was greater in the MRA-treated group than the non-MRA-treated group (Figure 3A-B), it was modest (median changes in creatinine and estimated glomerular filtration rate; +0.08 mg/dL and -4.5 ml/min/1.74 m2, respectively). Changes in potassium levels were similar between the groups (Figure 3C). Details of the changes in laboratory data from the baseline to follow-up evaluations are presented in Supplemental Table S4.
Figure 2Changes in NT-proBNP and BNP (A) Change in NT-proBNP from baseline to follow-up was significantly lower in patients with MRA treatment than in those without. (B) Similarly, change in BNP levels was lower in the MRA group than non-MRA group. (C-D) Following initiation of MRA, patients with a lower left ventricular global longitudinal strain (LVGLS) at rest or higher E/e’ ratio during peak exercise demonstrated greater reduction in NT-proBNP levels. Boxes represent medians and interquartile ranges, and whiskers represent 10th and 90th percentiles. BNP, B-type natriuretic peptide; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide.
Figure 3Changes in laboratory data (A-B) Change in creatinine levels was higher and that in estimated glomerular filtration rate (eGFR) was lower in the MRA-treated group than non-MRA group. (C) Change in potassium level was similar between the groups. Boxes represent medians and interquartile ranges, and whiskers represent 10th and 90th percentiles. MRA indicates mineralocorticoid receptor antagonist.
Paired echocardiographic data at baseline and follow-up were available for 77 patients with HFpEF for whom MRA was initiated after indexed exercise stress echocardiography (Figure 1). Sensitivity analysis comparing baseline demographics between the patients with paired echocardiographic data and those without (n=120) showed that patients with paired echocardiographic data were younger, predominantly women, and had a lower prevalence of AF and higher E/e’ ratio during exercise than those without (Supplemental Table S5). Table 2 demonstrates no differences in clinical and echocardiographic characteristics according to MRA status, except for peak exercise TRV. The median duration between the baseline and follow-up assessments was similar between patients with and without MRA treatment (7.3 [5.3-11.8] months vs. 8.6 [6.1-12.9] months, p=0.23). There were no differences in the rate of initiation or increase of non-MRA drugs between the assessments (Supplemental Table S6). The reduction in LAVI was greater in patients with MRA treatment than in those without MRA treatment (Figure 4A). Consistently, the percent reduction in LAVI was also greater in the MRA group than in non-MRA group (-6.7 [-27.7 to 12.2] % vs. 9.5 [-8.0 to 28.0] %, p=0.01). After MRA initiation, patients with HFpEF and lower LV ejection fraction (LVEF) demonstrated greater decreases in LAVI (r=0.54, p=0.03) (Figure 4B). Details for changes in echocardiographic parameters from baseline to follow-up evaluations are presented in Supplemental Table S7.
Table 2Baseline Characteristics among Patients with Paired Echocardiographic Data
Figure 4Changes in left atrial volume (A) Change in left atrial volume index (LAVI) was lower in patients with MRA than those without. (B) Patients with a lower left ventricular ejection fraction (LVEF) at baseline experienced greater reduction in LAVI at follow-up. Boxes represent medians and interquartile ranges, and whiskers represent 10th and 90th percentiles. MRA indicates mineralocorticoid receptor antagonist.
To the best of our knowledge, this is the first study to investigate the changes in NP levels and echocardiographic parameters following MRA initiation for patients with early-stage HFpEF without prior HF hospitalization but diagnosed by evidence of elevated LV filling pressure. MRA initiation lowered NP levels and reduced LAVI in patients with early HFpEF. In safety assessments, MRA modestly decreased renal function but did not increase serum potassium levels. This study provides new insights into the potential benefits of MRA treatment for patients with early-stage HFpEF before their first HF hospitalization.
Clinical outcomes in patients with HFpEF remain poor. In addition to limited treatment options, the potential reason for the poor prognosis may be related to delays in diagnosis and therapeutic intervention.
This is based on previous observations showing that patients with even prior HF hospitalization experienced a higher risk of clinical events than those who had never been hospitalized.
Based on this background, a paradigm shift to early identification may allow for more timely intervention. Increases in LV filling pressure at rest or during exercise are fundamental abnormalities in HFpEF.
Role of Diastolic Stress Testing in the Evaluation for Heart Failure with Preserved Ejection Fraction: A Simultaneous Invasive-Echocardiographic Study.
The Clinical Use of Stress Echocardiography in Non-Ischaemic Heart Disease: Recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
Multimodality imaging in patients with heart failure and preserved ejection fraction: an expert consensus document of the European Association of Cardiovascular Imaging.
How to diagnose heart failure with preserved ejection fraction: The HFA-PEFF diagnostic algorithm: A consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).
2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
In this study, we examined patients presenting with dyspnea, and the presence of HFpEF was established based on the HFA-PEFF algorithm, including exercise stress testing. Participants had no pulmonary congestion on chest radiography, less peripheral edema, modestly elevated NP levels, and, according to our definition, no prior history of HF hospitalization, suggesting that they were in an early stage of the disease.
Role of Diastolic Stress Testing in the Evaluation for Heart Failure with Preserved Ejection Fraction: A Simultaneous Invasive-Echocardiographic Study.
Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial.
However, evidence gaps exist regarding how patients with early HFpEF could be treated, especially those without prior HF hospitalization but diagnosed by evidence of elevated LV filling pressure during exercise testing.
Time to Clinical Benefit of Dapagliflozin and Significance of Prior Heart Failure Hospitalization in Patients With Heart Failure With Reduced Ejection Fraction.
These comorbidities can promote cardiac structural changes and diastolic dysfunction by inducing cardiac hypertrophy, fibrosis, and stiffening through activation of RAAS.
Kjeldsen SE, von Lueder TG, Smiseth OA, et al. Medical Therapies for Heart Failure With Preserved Ejection Fraction. Hypertens (Dallas, Tex 1979). 2020;75(1):23-32. doi:10.1161/HYPERTENSIONAHA.119.14057
Efficacy and safety of spironolactone in the heart failure with mid-range ejection fraction and heart failure with preserved ejection fraction: A meta-analysis of randomized clinical trials.
Effect of Mineralocorticoid Receptor Antagonists on Cardiac Structure and Function in Patients With Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction: A Meta-Analysis and Systematic Review.
Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial.
The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart “OMics” in AGEing (HOMAGE) randomized clinical trial.
Association between long-term prescription of aldosterone antagonist and the progression of heart failure with preserved ejection fraction in hypertensive patients.
but MRAs have not been well studied in early HFpEF without prior HF hospitalization. In the TOPCAT trial (history of HF hospitalization within 12 months: 71.5%), spironolactone reduced the rate of the primary outcomes among patients enrolled on the basis of an elevated NP level but not among those enrolled on the basis of a previous HF hospitalization.
Furthermore, previous studies demonstrated that MRA was associated with a reduction in NP levels or improvement in LV diastolic function in patients at high risk of HFpEF with raised NP levels (possibly pre-HFpEF).
The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart “OMics” in AGEing (HOMAGE) randomized clinical trial.
Association between long-term prescription of aldosterone antagonist and the progression of heart failure with preserved ejection fraction in hypertensive patients.
Based on these findings, we examined the effects of MRA on LV diastolic function in patients with early HFpEF without prior HF hospitalization. The strength of our study is that all participants underwent exercise stress echocardiography and had evidence of of elevated LV filling pressure at rest or during exercise. We demonstrated that NP levels and LA volume were decreased to a greater extent in patients who underwent MRA treatment than in those who did not. Treatment with MRA can improve water and sodium retention, which may lower LV filling pressures.
Efficacy and safety of spironolactone in the heart failure with mid-range ejection fraction and heart failure with preserved ejection fraction: A meta-analysis of randomized clinical trials.
This might lead to a reduction in NP levels and LA volume, as observed in this study. While baseline characteristics were well-balanced between the MRA and non-MRA groups, renal function was better in the MRA group, which may have influenced the response to MRA. Despite the reduction in LA volume, we found no reduction in the E/e' ratio after MRA initiation. Although the reason remains unknown, this may be similar to that observed in the Prospective comparison of ARNI with ARB on Management Of heart failUre with preserved ejectioN fraction (PARAMOUNT) trial, in which LA volume was decreased following ARNI treatment, but the E/e’ ratio was not.
The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: A phase 2 double-blind randomised controlled trial.
Table 3Comparisons of Clinical Characteristics in between the present study and previous studies examining MRA
Author (Year) (Study name)
Design
Subjects
N (MRA group)
Age (years)
Female
BMI (kg/m2)
HTN
Diuretics
Prior HF Hospitalization
BNP NT-proBNP (pg/mL)
Present study
Observational Study
HFpEF without HF hospitalization
197 (47)
75
66%
23.6
89%
32%
0%
BNP 115 NT-proBNP 429
Kosmala (2011)
RCT
Metabolic Syndrome
79 (40)
58
52%
32.8
100%
48%
Not reported
Not reported
Mottram (2004)
RCT
Hypertension with LVDD
29 (14)
61
60%
29.8
100%
43%
Not reported
BNP 29.3 -
Jun (2016)
Observational Study
Hypertension with LVH
195 (65)
67
54%
25.3
100%
11%
0%
Not reported
Cleland (2021)
RCT (HOMAGE)
CAD or high-risk of CAD with raised NP
527 (265)
73
23%
28.4
81%
17%
0%
- NT-proBNP 172
Kosmala (2016)
RCT (STRUCTURE)
HFpEF
131 (67)
68
81%
29.7
91%
64%
21%**
BNP 54 -
Edelmann (2013)
RCT (Aldo-DHF)
HFpEF
422 (213)
67
52%
28.9
92%
55%
38%**
- NT-proBNP 179
Kurrelmeyer (2014)
RCT
HFpEF
48 (24)
66
100%
29.4
88%
83%
58%**
BNP 139 -
Deswal (2011)
RCT* (PAAM-PEF)
HFpEF
44 (21)
72
5%
30.1
100%
95%
43%
BNP 255 -
Pitt (2014)
RCT (TOPCAT)
HFpEF
3445 (1722)
69
52%
31
91%
82%
71.5%**
BNP 235 NT-proBNP 1017
Values are mean, median, or %. *Eplerenone was used otherwise spironolactone. **History of HF hospitalization within previous 12 months. Aldo-DHF indicates the ‘aldosterone receptor blockade in DHF’ trial; BMI, body mass index; BNP, B-type natriuretic peptide; CAD, coronary artery disease; DOE, dyspnea on exertion; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HOMAGE, the heart ‘OMics’ in AGEing randomized clinical trial; HTN, hypertension; LVDD, left ventricular diastolic dysfunction; LVH, left ventricular hypertrophy; MRA, mineralocorticoid receptor antagonist; NP, natriuretic peptide; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PAAM-PEF, the Randomized Aldosterone Antagonism in Heart Failure With Preserved Ejection Fraction Trial; RCT, randomized control trial; STRUCTURE, the SpironolacTone in myocaRdial dysfUnCTion with redUced exeRcisE capacity trial; TOPCAT, Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist.
We further demonstrated that HFpEF patients with relatively lower systolic function (LVEF and GLS) experienced a greater reduction in NT-proBNP levels and LA volume following MRA treatment. This is in accordance with the results of the TOPCAT trial showing a greater benefit from spironolactone treatment in patients with a lower EF.
There has been a similar possible benefit of angiotensin receptor neprilysin inhibitor (ARNI), angiotensin receptors, and beta blockers among patients with an EF below normal.
Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.
The results of this study and others suggest that patients with early HFpEF and EF closer to 50% have more significant benefits from MRA treatment. Elevated NP levels and larger LA volume are associated with an increased risk of outcomes.
Further studies are warranted to determine whether MRA treatment in early HFpEF can prevent initial hospitalization for HF and improve outcomes in this population.
Limitations
This was a non-randomized, retrospective observational study. All participants were referred for exercise stress echocardiography, introducing selection and referral bias. The sample size was modest. The current study included a subset of patients with either paired NP or echocardiographic data, limiting generalizability.
Conclusions
MRA treatment lowered NP levels and LA volume in HFpEF patients without prior HF hospitalization but diagnosed by the evidence of elevated LV filling pressure during exercise testing. Our results suggest potential benefits of MRA for early-stage HFpEF.
Acknowledgments
Dr. Obokata received research grants from the Fukuda Foundation for Medical Technology, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, Nippon Shinyaku; the Takeda Science Foundation; the Japanese Circulation Society; the Japanese College of Cardiology; and the JSPS KAKENHI 21K16078.
Role of Diastolic Stress Testing in the Evaluation for Heart Failure with Preserved Ejection Fraction: A Simultaneous Invasive-Echocardiographic Study.
The Clinical Use of Stress Echocardiography in Non-Ischaemic Heart Disease: Recommendations from the European Association of Cardiovascular Imaging and the American Society of Echocardiography.
Multimodality imaging in patients with heart failure and preserved ejection fraction: an expert consensus document of the European Association of Cardiovascular Imaging.
How to diagnose heart failure with preserved ejection fraction: The HFA-PEFF diagnostic algorithm: A consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).
2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.
Regional variation in patients and outcomes in the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT) trial.
Time to Clinical Benefit of Dapagliflozin and Significance of Prior Heart Failure Hospitalization in Patients With Heart Failure With Reduced Ejection Fraction.
Kjeldsen SE, von Lueder TG, Smiseth OA, et al. Medical Therapies for Heart Failure With Preserved Ejection Fraction. Hypertens (Dallas, Tex 1979). 2020;75(1):23-32. doi:10.1161/HYPERTENSIONAHA.119.14057
Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: the Aldo-DHF randomized controlled trial.
The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart “OMics” in AGEing (HOMAGE) randomized clinical trial.
Association of Active and Passive Components of LV Diastolic Filling With Exercise Intolerance in Heart Failure With Preserved Ejection Fraction: Mechanistic Insights From Spironolactone Response.
Association between long-term prescription of aldosterone antagonist and the progression of heart failure with preserved ejection fraction in hypertensive patients.
Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American society of echocardiography and the European association of cardiovascular imaging.
Efficacy and safety of spironolactone in the heart failure with mid-range ejection fraction and heart failure with preserved ejection fraction: A meta-analysis of randomized clinical trials.
Effect of Mineralocorticoid Receptor Antagonists on Cardiac Structure and Function in Patients With Diastolic Dysfunction and Heart Failure With Preserved Ejection Fraction: A Meta-Analysis and Systematic Review.
The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: A phase 2 double-blind randomised controlled trial.
Heart failure with mid-range ejection fraction in CHARM: characteristics, outcomes and effect of candesartan across the entire ejection fraction spectrum.
This research was supported by grants from the Takeda Science Foundation.
Disclosures
Dr. Obokata received speaker honoraria from Novartis, Otsuka pharmaceutical, Boehringer-Ingelheim, and Bayer. Dr. Ishii received speaker honoraria from AstraZeneca Inc., Bayer Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan, Bristol-Myers Squibb Inc., Daiichi-Sankyo Pharma Inc., MSD K. K., Mitsubishi Tanabe Pharma Co., Ltd., Mochida Pharmaceutical Co., Ltd., Novartis Japan, and Pfizer Japan Inc.and received scholarship funds or donations from Boehringer Ingelheim Japan and Bristol-Myers Squibb Inc.
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