ABSTRACT
Background
Adult cancer survivors are at increased risk of heart failure (HF) due to standard risk factors and cancer treatment-related cardiac dysfunction. However, the prevalence and treatment of subclinical/stage B heart failure (SBHF) in this population are not well defined.
Objectives
The REDEEM ( Risk-guided Disease managEment plan to prevEnt heart failure in patients treated with previous cardiotoxic cancer treatMents ) trial will evaluate HF screening and targeted intervention in long-term cancer survivors.
Methods
Survivors ≥40 years old, ≥5 years post potentially-cardiotoxic therapy, and with ≥1 HF risk factor were screened by echocardiography for SBHF (abnormal global longitudinal shortening [GLS], left ventricular hypertrophy [LVH], diastolic dysfunction or abnormal 3-dimensional left ventricular ejection fraction [3D-LVEF]). Those with SBHF were randomized to multidisciplinary cardio-oncology disease management plan (CO-DMP), including neurohormonal blockade, exercise training and risk factor optimization, or usual care. The primary endpoint is change in cardiorespiratory fitness (VO 2 peak) over 6 months.
Results
Of 1,124 survivors screened, 604 underwent echocardiography, and 145 (24%) had SBHF (age 68±18 years; 81% women). Of those eligible for randomization, 64% had breast cancer and 35% had hematological malignancy. Although baseline 3D-LVEF was preserved (52.8 ± 6.8%), subclinical LV dysfunction was common (GLS 15.6 ± 2.1%) and 39% had evidence of functional impairment (VO 2 peak≤18ml/kg/min −1). Abnormal GLS was associated with age, BMI, diabetes and anthracycline exposure, whereas functional impairment was only associated with age. Abnormal GLS and functional impairment were not significantly associated (OR 0.90 [95% CI 0.72–1.11], P =.360).
Conclusions
Risk-based screening can identify a high-risk subpopulation of cancer survivors with SBHF.
Registration
ClinicalTrials.gov NCT04962711, https://www.clinicaltrials.gov/study/NCT04962711
ACE
Angiotensin-Converting Enzyme
AQoL-4D
Assessment of Quality of Life– 4 Dimension
ARB
Angiotensin Receptor Blocker
ARIC HF
Atherosclerosis Risk in Communities– Heart Failure
BMI
Body Mass Index
CAD
Coronary Artery Disease
CO-DMP
Cardio-Oncology Disease Management Plan
CPET
Cardiopulmonary Exercise Test
CVD
Cardiovascular Disease
DASI
Duke Activity Status Index
DD
Diastolic Dysfunction
DM
Diabetes Mellitus
ECG
Electrocardiogram
eGFR
Estimated Glomerular Filtration Rate
EQ-5D-5L
EuroQol Five-Dimension Five-Level Scale
GLS
Global Longitudinal Shortening
HF
Heart Failure
HER2
Human Epidermal Growth Factor Receptor 2
HTN
Hypertension
IPAQ
International Physical Activity Questionnaire
LAVi
Left Atrial Volume Index
LVD
Left Ventricular Dysfunction
LVEF
Left Ventricular Ejection Fraction
LVH
Left Ventricular Hypertrophy
LVMi
Left Ventricular Mass Index
NT-proBNP
N-terminal pro B-type Natriuretic Peptide
PHQ-9
Patient Health Questionnaire–9
REDCap
Research Electronic Data Capture
RER
Respiratory Exchange Ratio
SBHF
Stage B Heart Failure (Subclinical Heart Failure)
T2DM
Type 2 Diabetes Mellitus
TKI
Tyrosine Kinase Inhibitor
TR Vmax
Tricuspid Regurgitation Velocity Maximal
TTE
Transthoracic Echocardiography
VO₂peak
Peak Oxygen Uptake
Background
Modern advances in cancer therapies have led to improvements in cancer survivorship, with 18.1 million cancer survivors in the USA in 2022, representing 5.4% of the population. As this cohort is expected to grow (22.5 million by 2032), so too are the millions of survivors exposed to cardiotoxic therapies. Cardiovascular disease (CVD) accounts for more than 25% of all noncancer related deaths among survivors and heart failure (HF) is the leading cardiac manifestation. Pediatric cancer survivors are 15 times more likely to develop HF compared with their healthy siblings. In adults, observational data and population studies have suggested increased long-term HF risk in adult cancer survivors, , but prospective studies of prevalence are sparse. In the breast cancer and lymphoma population, the cumulative incidence of HF in adult survivors postanthracycline therapy was 7.4% over 15 years. Despite the increased risk, this has not translated to HF surveillance programs being incorporated as a routine part of survivorship care. In the USA, there are no guidelines for long-term prevention of HF among cancer survivors. The European guidelines suggest that echocardiography ‘may be considered’ every 5 years but the evidence base for this is weak and based on expert consensus. Incorporation of subclinical HF (Stage B/SBHF) screening into survivorship-care would provide the opportunity to identify HF at a reversible stage and to initiate therapy to delay/prevent the onset of symptomatic HF. Patients with SBHF benefit from treatment with angiotensin-converting enzyme (ACE) inhibition, beta-adrenoceptor blockade , and lifestyle interventions (including exercise).
The majority of HF in survivorship is only diagnosed when symptomatic HF manifests. This is costly to healthcare systems, accounting for an estimated >$30 billion of spending in the US each year. Diagnosis of HF at this stage is also associated with poor prognosis, with a 2-year mortality of up to 60%. A prevention strategy could prevent or delay such presentations and would be most efficient if it were targeted towards individuals with the greatest HF risk. Most strategies to address cardiotoxicity have focused on the period around the time of chemotherapy. However, the effect of cardiotoxicity is augmented by other cardiac insults over time- including obesity, diabetes mellitus (DM) and hypertension (HTN) – and HF is generally a disease of the elderly. Risk may be assessed by combining clinical features with evidence of SBHF. The presence of impaired global longitudinal shortening (GLS), left ventricular hypertrophy (LVH) and diastolic dysfunction (DD) can reliably detect subclinical LV dysfunction (LVD) in patients with cancer, and earlier than conventional measures, such as LV ejection fraction (LVEF). Identification of SBHF is feasible and can predict the onset of incident HF. Another marker important for predicting risk is functional capacity. Cardiorespiratory fitness (measured objectively as peak oxygen uptake [VO 2 peak]) strongly predicts cardiovascular and all-cause mortality and its utility has been demonstrated in the cancer population. , Impairment of functional capacity has been associated with cardiotoxic cancer therapy and may contribute to the increased HF risk. Interestingly, despite both having prognostic implications, impairment in VO 2 peak does not appear to correlate with markers of subclinical LV dysfunction (ie, abnormal GLS/ BNP). , The dissociation between these predictors of HF risk creates ambiguity in which marker we should be assessing to improve risk stratification. This study will evaluate both SBHF and functional capacity to understand their relationship and predictors in the survivorship population, with the aim of developing a standardized, scalable approach for identifying individuals most at risk for HF in long term survivorship.
Methods
Study design
The REDEEM ( Risk-guided Disease managEment plan to prevEnt heart failure in patients treated with previous cardiotoxic cancer treatMents ) trial is a prospective multicenter randomized controlled-single crossover trial in which HF risk is quantified and reduced in cancer survivors. This paper describes baseline (prerandomization) HF-risk screening process based on clinical risk, demographics and imaging, and the describes the design of the ongoing randomized controlled trial to assess the reversibility and clinical benefits of treating SBHF in cancer survivors. The hypothesis of the REDEEM study is that surveillance testing to detect subclinical LVD and impaired cardiorespiratory fitness can be used to select patients for a multidisciplinary CO-DMP and thereby reduce risk of HF. The REDEEM study was initiated on March 3, 2023; (HREC/70493/Alfred-2021, ClinicalTrials.gov identifier NCT04962711).
Patient selection
Adult cancer survivors ≥40 years old who had undergone potential cardiotoxic treatments (anthracycline, HER2-receptor antagonists, tyrosine kinase inhibitors or left chest radiotherapy) ≥5 years ago and in addition had ≥1 risk factors for HF (DM, HTN, high cholesterol, smoking history, increased body mass index (BMI>25), coronary artery disease) were eligible for recruitment (inclusion and exclusion criteria are listed in Table 1 ). The selection process was based on our previous work suggesting that universal screening would likely be ineffective and that risk factors demonstrate incremental risk in this population. , The age cut-off was chosen to specifically target the adult survivorship population, as survivors of childhood cancer already have evidence justifying risk evaluation. The trial was conducted across 7 tertiary hospitals in Australia (Victoria & Tasmania). Survivors were identified from survivorship/late effect clinics, social media advertising, pharmacy and radiotherapy databases.
Table 1
Inclusion and exclusion criteria.
| Inclusion criteria | ||
| 1 | Participant ≥40 years old | |
| 2 | Previous treatment ≥5 years ago with potential cardiotoxic agent including: | |
| 2-1 | Anthracycline (any dose) OR | |
| 2-2 | HER-2 receptor antagonist (Traztuzumab/ Pertuzumab) OR | |
| 2-3 | Tyrosine kinase inhibitors (eg. Sunitinib) OR | |
| 2-4 | Left chest radiotherapy | |
| 3 | Have ≥ 1 heart failure risk factor | |
| 3-1 | T2DM | |
| 3-2 | Hypertension | |
| 3-3 | High cholesterol | |
| 3-4 | Smoking (current or previous) | |
| 3-5 | Overweight/ Obese (BMI ≥25) | |
| 3-6 | History of coronary artery disease | |
| 4 | Live within a geographically accessible area for follow-up | |
| 5 | Are able and willing to provide written informed consent to participate in the study. The patient will need to be able to communicate fluently with the investigator. The investigator will need to be satisfied that the patient understands the study by having them explain the study plan back to the investigator. | |
| Exclusion criteria | ||
| 1 | Unable to provide written informed consent to participate in this study | |
| 2 | Participating in another clinical research trial where randomized treatment would be unacceptable | |
| 3 | Ejection fraction at baseline echo <40% | |
| 4 | Valvular stenosis or regurgitation of >moderate severity | |
| 5 | History of previous heart failure | |
| 6 | Baseline NYHA >2 | |
| 7 | Systolic BP <110mmHg | |
| 8 | Pulse <60 beats/min if not on a beta blocker | |
| 9 | Inability to acquire interpretable images (identified from baseline echo) | |
| 10 | Contraindications/Intolerance to beta blockers or ACE inhibitors | |
| 11 | Oncologic (or other) life expectancy <12 months or any other medical condition (including pregnancy) that results in the belief (deemed by the Chief Investigators) that it is not appropriate for the patient to participate in this trial | |
| 12 | Already taking both angiotensin converting enzyme inhibitors/angiotensin receptor blockers and beta blockers, or intolerance (or allergy) to both. | |
Clinical evaluation
Baseline HF risk was assessed using structured interviews and questionnaires assessing demographics, medical and cancer history. Data were gathered on age, sex, ethnicity, medical history, cancer type and treatment history, sociodemographic factors, medications, smoking status, quality of life questionnaires (EQ-5D-5L and AQoL-4D), depression status (Patient Health Questionnaires-9), International Physical Activity Questionnaire (IPAQ), Duke Activity Status Index (DASI), BMI, blood pressure, heart rate, electrocardiogram (ECG) and 6-min walking test. Participants’ risk of HF was assessed using the 4-year Atherosclerosis Risk in Communities (ARIC)-HF risk score, which incorporates multiple conventional HF risk factors such as age, sex, blood pressure and comorbidities. Patients at sufficient HF risk proceeded to biochemistry testing and transthoracic echocardiography (TTE) to identify SBHF. Pathology tests included N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, fasting glucose, lipid profile and assessment of renal function (creatinine [mmol/L], eGFR [ml/min/m 2]).
Echocardiography
A standard transthoracic echo exam was followed, with 3D-LVEF (EchoPAC, 4D Auto LVQ, General Electric Medical Systems, Milwaukee, WI) selected preferentially over 2D-LVEF. The diagnosis of SBHF was defined by the presence of abnormal 3D-LVEF, LVH, abnormal GLS or diastolic dysfunction. An abnormal 3D-LVEF was defined as a 3D-LVEF of <51% in women and <50% in men. LV mass was assessed at end-diastole using 2D-guided M-mode in the parasternal long axis (0.8 x [1.04 x (LV internal diameter + interventricular septal diameter + posterior wall diameter) 3 – (LV internal diameter)] 3 + 0.6 g). LVH was defined as a left ventricular mass index (LVMi, indexed to body surface area) >115g/m 2 in men and >95g/m 2 in women. Diastolic dysfunction was assessed by measurement of 4 parameters: transmitral inflow Doppler and mitral annular velocity tissue Doppler (E/e’ >14, septal e’ velocity <7 cm/s or lateral e’ velocity <10cm/s) in the apical 4-chamber view, indexed left atrial volume (LAVi) in a focused 4- and 2-chamber views (LAVi >34ml/m2), and tricuspid regurgitation velocity (TR Vmax) >2.8m/s. Diastolic dysfunction was identified when ≥3 parameters were abnormal or if 2 parameters were abnormal and left atrial reservoir strain (LARS) was ≤19%.
Myocardial peak systolic GLS assessments were performed using 3 apical views at increased frame-rate (50-70 frames/second). Semi-automated 2D-speckle-tracking (EchoPAC, GE Medical Systems, Milwaukee, WI) was applied offline to cine-loops of 5 cardiac cycles. After initial tracing of the endocardial border and software processing, the operator ensured appropriate tissue tracking- segments that were unable to be tracked were excluded. The calculation of average strain was derived from a model of the entire LV. All measures were made in a blinded fashion by a single observer. An abnormal GLS was defined as a reduction of GLS <16%.
The baseline TTE protocol will be replicated at 6- and 12-month follow-up. All baseline and final 3D images will be sent to the core laboratory at the Baker Institute, and a random 10% of images will be quantified at the core lab for verification of on-site measurements.
Cardio-pulmonary exercise test
Participants with identified SBHF underwent a baseline cardio-pulmonary exercise test (CPET) to establish their cardiorespiratory fitness, measured as VO 2 peak. The CPET was conducted on an electronically braked upright cycle ergometer (Lode Excalibur Sport, Lode BV Medical Technology, Groningen, NL) or motorised treadmill (quasar® treadmill, h/p/cosmos Sports & Medical gmbh, Nussdorf-Traunstein, Germany). Breath-by-breath gas exchange and minute ventilation were assessed according to standard guidelines using a calibrated metabolic cart (VyntusTM CPX, Jaeger Medical, Mettawa, IL) with heart rate (HR) and rhythm assessed continuously from a 12-lead ECG. Brachial blood pressure was monitored at rest and at 2-minute intervals throughout the CPET. For tests conducted on a cycle ergometer, cycling commenced with a 1-minute warm-up at 10-50 watts, followed by a ramp protocol that increased power output at a rate of 10-30 watts·minute −1, until volitional exhaustion. Protocols were individualized to each participant’s age, weight and self-reported physical activity levels, with the aim of reaching VO 2 peak within 8-12 minutes. Participants were considered to have reached VO 2 peak if the 2 following criteria were met: 1) a respiratory exchange ratio >1.10 and 2) a peak HR >85% of predicted. VO 2 peak was scaled to participants’ body mass (ml·min·kg −1) and defined as the highest 30-second rolling average calculated from 6 consecutive 5-second VO 2 epochs. Functional impairment was defined as a VO 2 peak ≤ 18.0 mL·kg·min −1 23. This is level has been shown to predict mobility limitations, incident HF and mortality.
Trial design
Computer-generated randomization assigned eligible participants to either a cardio-oncology disease management plan (CO-DMP) or usual care, at a ratio of 1:1 ( Figure 1 ). Randomization was stratified by (i) years since cancer therapy (<10 years, 10-15 years, >15 years) and (ii) cumulative lifetime anthracycline dose (nonanthracycline therapy, <250mg/m2, ≥250mg/m2). Usual care participants will receive standard care with their primary care physician, including an educational brochure on lifestyle and cardiovascular risk factor management. All participants will be followed-up at 6 months with a repeat clinical review, biochemistry, TTE and CPET. Usual care participants will be offered a crossover to the CO-DMP arm if SBHF remains present at 6 months. Further follow-up will continue to 12 months to assess the results of participants who crossed over to intervention at 6 months.
Screening process to identify cancer survivors with subclinical LV dysfunction.
Power calculations
Although asymptomatic, the baseline cardiorespiratory fitness (VO 2 peak) in survivors is analogous to patients with heart failure with preserved ejection fraction, and trials of exercise training in that setting show a 10-15% increment in VO 2 peak. We hypothesized that a 12% increment of VO 2 could be achieved by the CO-DMP, compared with the control population. Using a 2-sided alpha of 0.05 and power of 80%, we calculated that 67 participants per group (134 total) would be required to detect this anticipated increment in aerobic capacity.
Cardio-oncology disease management plan
This multidisciplinary intervention involves lifestyle, exercise and pharmaceutical management.
Optimization of pharmacotherapy comprises optimal BP control (early morning target 140/80mmHg) and provision of myocardial protection with ACE-inhibition and beta blockade, provided by the supervising clinician at each site. Patients allocated to the CO-DMP will be initially treated with ramipril at a dose of 1.25 or 2.5mg (according to baseline systemic arterial pressure), once or twice a day, and gradually up-titrated to 10mg/day, or to the maximal-tolerated dose. In patients receiving at least 2.5mg/day of ramipril, beta adrenoceptor blockade is initiated after completion of the exercise program and titrated to the maximally tolerated dose. The delay in beta-blocker initiation is to avoid blunting of exercise training adaptations and to minimize fatigue or heart rate–related limitations that could reduce adherence. Patients are prescribed either metoprolol tartrate (starting at 25mg twice daily, maximum 100mg twice daily) or bisoprolol (starting at 2.5mg daily, maximum 10mg daily). Dose-equivalents of other agents are used if for some reason, the planned agents are not tolerated. Angiotensin receptor blockers are substituted if side effects occur from ACE-inhibition. Participants are reviewed (including blood pressure and heart rate data) every 2 weeks during the up-titration phase. Side-effects (eg. light headedness, fatigue, cough) and medication compliance are assessed. If patients complain of side-effects or the HR is <50/minute, dosages are down-titrated to that prior to the last increment.
Exercise training is individualized, and analogous to cardiac rehabilitation. The goal is to progressively increase exercise frequency, intensity, and duration of exercise over a 12-week period. An exercise physiologist (EP) provides each participant with an individualized program developed from their CPET and includes high intensity interval, moderate base pace and maximal steady state exercise sessions and resistance training. The program is delivered via a number of approaches including in-person supervised training, synchronous videoconferencing and unsupervised home exercise software. Patients are provided with a training calendar and objective tools for tracking and recording physical activity (eg, heart-rate monitor and diary). After completion of the supervised phase, participant contact with the EP is stepped-down to fortnightly contact to maintain engagement with the exercise program. During the consults adherence to the exercise program is documented and recorded on REDCap (Research Electronic Data Capture) by the EP.
Participants with symptoms consistent with myocardial dysfunction (dyspnea, reduced exercise capacity), side effects of therapy (fatigue), progression of myocardial dysfunction (EF <50%, dyspnea, reduced exercise capacity) or provocation of asthma may discontinue therapy but will remain in the study and be assessed on an intention-to-treat analysis.
Endpoints
The primary outcome is the change in cardiorespiratory fitness from baseline to 6 months in CO-DMP vs usual care as determined by VO 2 peak on CPET. Secondary endpoints focus on the prevention of further deterioration of cardiac function, measured by an absolute change in LVEF and GLS, resolution of SBHF physiology and feasibility of a heart failure screening program in survivors (assessed by patient adherence to medical and exercise therapy, adverse event rates and completion of follow-up CPET and echocardiography).
Safety
All adverse events and serious adverse events are recorded for safety evaluation. Regular assessments of physical examinations, ECGs, vital signs and laboratory results are also being conducted. Cardiac events are recorded and include: sudden death, cardiac death, symptomatic HF requiring hospital admission, serious arrhythmias requiring treatment, and conduction disturbances requiring a permanent pacemaker implantation. Routine monitoring of adverse events will be provided to an independent medical monitor.
Data collection and management
Information is gathered in a standardized manner using REDCap hosted at the Baker Heart and Diabetes Institute. , Clinical reviews are performed at designated time points during the trial with a window of ± 1 month to allow for flexibility in scheduling. At the conclusion of the trial, a verification of 5% of the study data against original source documents will be performed by an independent study monitor.
Statistical analysis
The primary analysis will be undertaken when a minimum of 6 months of follow-up is completed on all participants under continuing observation. Efficacy analyses of VO 2 results will be performed by ANCOVA, to correct for baseline data. Analyses will be performed on the basis of intention to treat, irrespective of training or medication adherence. Endpoint data analyses will also compare change between intervention and usual care subjects using linear and logistic regression to obtain the effect size of the implemented risk factor management program relative to other likely determinants of risk factor modification. Missing data will be addressed by multiple imputation. Baseline characteristics were compared between groups using pooled t-tests for continuous variables and Pearson’s chi-square tests for categorical variables. Predictors of impaired exercise and cardiac function were assessed using univariable and multivariable logistic regression. A 2-sided alpha of 0.05 was used to determine statistical significance.
Results
Patient characteristics
Between March 2023 and May 2025, a total of 1,124 cancer survivors underwent screening for HF risk ( Figure 1 ). There was a marked female predominance, reflecting breast cancer as the most common underlying etiology, and the mean time from completion of cancer therapy was 15.8 years (Supplementary Table 1). Differences between the 54% of patients considered to have sufficient risk to justify further evaluation were primarily based on cancer therapy, as well as age and risk factors.
Clinical and echocardiographic features of the 604 participants screened for SBHF are shown in Table 2 . Most were breast cancer survivors (73%), followed by individuals with a history of lymphoma (20%) and leukemia (6%). Prevalent comorbidities included smoking (44%), hyperlipidemia (40%) and hypertension (37%). The mean ARIC HF 4-year risk was 3.3 ± 4.4%. The average NT-proBNP was elevated at 142.7 ± 163ng/L.
Table 2
Baseline characteristics and differences in patients with and without SBHF.
| Total | No SBHF | SBHF | P † | |
|---|---|---|---|---|
| ( n = 604) | ( n = 459) | ( n = 145) | ||
| Age, mean ± 2SD | 64.9 ± 17.4 | 64.1 ± 16.8 | 67.6 ± 18.3 | <.001 |
| Female | 521 (86.3%) | 404 (88.0%) | 117 (80.7%) | .025 |
| Years since diagnosis | 15.9 ± 7.5 | 15.5 ± 7.5 | 17.0 ± 7.6 | .045 |
| Lifestyle/risk-factors | ||||
| Former smoker | 234 (42.2%) | 176 (42.3%) | 58 (41.7%) | .904 |
| Current smoker | 14 (2.5%) | 10 (2.4%) | 4 (2.9%) | .758 |
| BMI (kg/m 2) | 28.1 ± 5.3 | 27.8 ± 5.2 | 29.2 ± 5.3 | .005 |
| ARIC 4-year risk (%) | 3.3 ± 4.4 | 2.8 ± 3.7 | 5.1 ± 5.9 | <.001 |
| Comorbidities | ||||
| Hypertension | 205 (36.5%) | 147 (34.9%) | 58 (41.4%) | .166 |
| Hyperlipidaemia | 239 (39.6%) | 171 (37.3%) | 68 (46.9%) | .040 |
| Coronary disease | 9 (1.6%) | 4 (1.0%) | 5 (3.6%) | .034 |
| Diabetes mellitus | 66 (11.8%) | 41 (9.8%) | 25 (18.1%) | .008 |
| Medications | ||||
| ACE-inhibitor | 35 (5.9%) | 22 (4.9%) | 13 (9.0%) | .068 |
| Beta blocker | 177 (29.5%) | 126 (27.7%) | 51 (35.2%) | .085 |
| Cancer type | ||||
| Breast cancer | 440 (73.2%) | 347 (76.1%) | 93 (64.1%) | .005 |
| Lymphoma | 119 (20.0%) | 77 (17.0%) | 42 (29.2%) | .002 |
| Leukaemia | 36 (6.1%) | 28 (6.3%) | 8 (5.6%) | .757 |
| Other cancer type | 27 (4.5%) | 22 (4.8%) | 5 (3.4%) | .495 |
| Cardiotoxic therapies | ||||
| Anthracycline | 259 (43.0%) | 173 (37.9%) | 86 (59.3%) | <.001 |
| Cumulative dose (mg/m 2) | 311.3 ± 134.0 | |||
| HER-2 antagonist | 49 (8.1%) | 41 (8.9%) | 8 (5.5%) | .189 |
| Chest radiotherapy | 58 (9.6%) | 3 (0.7%) | 55 (37.9%) | <.001 |
| Prescribed dose (Gy) | 42.3 ± 12.4 | |||
| Pathology | ||||
| NT-proBNP (ng/L) | 142.7 ± 163.0 | 120.1 ± 111.0 | 195.1 ± 236.6 | <.001 |
| NT-proBNP > 125 | 141 (34.3%) | 83 (28.9%) | 58 (46.8%) | <.001 |
| Creatinine (mmol/L) | 72.4 ± 17.6 | 71.0 ± 15.5 | 75.7 ± 21.2 | .013 |
| eGFR (mL/min/1.73m 2) | 78.5 ± 13.0 | 79.5 ± 12.2 | 76.2 ± 14.4 | .020 |
| eGFR < 60 | 39 (9.7%) | 22 (7.9%) | 17 (13.6%) | .076 |
| LV function | ||||
| LVEDV (ml) | 92.5 ± 23.8 | 91.1 ± 22.4 | 96.4 ± 27.5 | .024 |
| LVEDV index (ml/m 2) | 50.4 ± 11.2 | 50.1 ± 10.5 | 51.4 ± 13.0 | .209 |
| LVESV (ml) | 38.5 ± 12.5 | 36.4 ± 11.1 | 44.6 ± 14.2 | <.001 |
| LVESV index (ml/m 2) | 20.9 ± 6.0 | 20.0 ± 5.3 | 23.8 ± 6.9 | <.001 |
| LVEF (3D %) ‡ | 58.0 ± 6.1 | 59.7 ± 4.8 | 52.8 ± 6.8 | <.001 |
| GLS (%) | 18.5 ± 2.5 | 19.4 ± 1.9 | 15.6 ± 2.1 | <.001 |
| Diastolic dysfunction | ||||
| E/e’ >14 | 14 (2.6%) | 3 (0.7%) | 11 (9.3%) | <.001 |
| LAV index >34ml/m2 | 188 (32.0%) | 147 (33.0%) | 41 (28.9%) | .363 |
| TR Vmax >2.8m/s | 7 (1.9%) | 3 (1.1%) | 4 (4.7%) | .036 |
| Septal e’ <7cm/s | 265 (46.0%) | 169 (38.9%) | 96 (68.1%) | <.001 |
| Lateral e’ <10cm/s | 335 (57.7%) | 230 (52.2%) | 105 (75.0%) | <.001 |
| Stage B Heart Failure Criteria | ||||
| 3D LVEF <50/51% § | 43 (29.9%) | |||
| GLS <16% | 109 (76.2%) | |||
| LVH | 22 (15.9%) | |||
| Diastolic dysfunction | 9 (6.2%) | |||
| Exercise capacity | ||||
| Peak RER | 1.2 ± 0.1 | |||
| Peak workload (W) | 123.9 ± 48.9 | |||
| Peak VO 2 (L/min) | 1.6 ± 0.5 | |||
| Peak VO 2 (ml/kg/min) | 19.7 ± 5.2 | |||
| Peak VO 2 ≤18ml/kg/min | 57 (39.3%) |
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