Ambulatory Heart Failure With Reduced Ejection Fraction Research Articles

Optimal Medical Therapy and Outcomes Among Patients With Chronic Heart Failure With Reduced Ejection Fraction

BackgroundOptimal medical therapy (OMT) scoring may stratify clinical risk in real-world chronic heart failure with reduced ejection fraction (HFrEF) by integrating use and dosing of guideline-directed medical therapy (GDMT) for HFrEF. ObjectivesThe purpose of this study was to characterize patients and associated long-term clinical outcomes by OMT score-derived treatment groups. MethodsCHAMP-HF (Change the Management of Patients with Heart Failure) included U.S. outpatients with chronic HFrEF receiving ≥1 GDMT. OMT subgroups were defined as suboptimal (score <3), acceptable (score = 3), and optimal (score ≥4) by baseline use and dose of GDMT, as proposed by the HF Collaboratory consortium. Cox proportional hazard analyses were used to assess for all-cause and cardiovascular death across subgroups, after adjusting for demographic and clinical covariates. ResultsThe authors studied 4,582 participants enrolled in CHAMP-HF with available 2-year follow-up. Median age was 68 years, 1,327 (29%) were women, and 2,842 (62%) were White, non-Hispanic. Median OMT score across the population was 4 (Q1-Q3: 2-5), and 1,628 (35%) had suboptimal, 665 (14%) had acceptable, and 2,289 (50%) had optimal therapy. Participants with optimal treatment were younger, had higher annual household income, and were enrolled from practices with dedicated HF clinics (all P < 0.001) than participants with acceptable or suboptimal treatment. Participants with optimal treatment had lower all-cause death (adjusted HR: 0.77; 95% CI: 0.64-0.92) and cardiovascular death (adjusted HR: 0.79; 95% CI: 0.65-0.96) than those with suboptimal treatment. ConclusionsAcross a large cohort of chronic ambulatory HFrEF, OMT scores stratified risk of all-cause and cardiovascular death.

Heart failure with improved ejection fraction: patient characteristics, clinical outcomes and predictors for improvement.

Heart failure with improved ejection fraction (HFimpEF) is a recently recognized entity presenting a diagnostic and therapeutic challenge. Our aim was to characterize the profile of HFimpEF patients and evaluate predictors for EF lack of improvement among heart failure with reduced ejection fraction (HFrEF) patients. We included ambulatory HFrEF patients (EF≤40%) between January 1, 2015, and September 1, 2022, with two consecutive echocardiography exams at least 6 months apart. HFimpEF was defined as improved EF from ≤40%->40% and by ≥10%. A total of 567 HFrEF patients (72% male, 54.3 ± 14.4 years old) were analyzed. Patients without EF improvement were more likely to be male, had more comorbidities, ischemic cardiomyopathy (ICMP), markers of adverse cardiac remodeling (lower EF and higher left and right ventricular diameters) and presence of late gadolinium enhancement (LGE) in MRI (P < 0.05 for all). In a multivariate analysis, male sex, ICMP, lower EF, larger ventricular size and LGE remained independent predictors for lack of EF improvement. A prediction model for lack of EF improvement including LVEF, LV diameter, diastolic blood pressure and ischemic etiology exhibited an area under the ROC curve of 0.77 (95% CI 0.73-0.81; P < 0.001). HFimpEF patients had better prognosis with lower hospitalizations and mortality rates. Guideline directed medical therapy (GDMT) were associated with improved outcomes in both groups regardless of EF improvement. Lack of improvement in EF among HFrEF patients may be predicted by HF etiology and imaging parameters of adverse cardiac remodeling, and is associated with worse prognosis. GDMT were associated with improved outcomes in both HFimpEF and HFrEF patients.

Increasing rates of screening and treatment of iron deficiency in ambulatory patients with heart failure with reduced ejection fraction: a quality improvement cohort study

IntroductionIron deficiency anaemia (IDA) is common in patients with heart failure (HF) and is associated with advanced HF and increased mortality. Intravenous iron supplementation increases exercise tolerance, improves quality of...

Heart failure with improved ejection fraction: patients' characters and predictors for improvement

Abstract Introduction Heart failure with improved ejection fraction (HFimpEF) is a relatively new definition, which presents a diagnostic and therapeutic challenge. Little is known about these patients' characteristics and predictors for EF improvement. Purpose Characterizing the profile of HFimpEF patients and evaluate predictors for EF improvement within heart failure with reduced ejection fraction (HFrEF) patients. Methods The cohort included ambulatory HFrEF patients (EF≤40%) who had two consecutive echo exams at least 6 months apart in a single tertiary medical center. Patients who improved their EF from ≤40% to &amp;gt;40% and by ≥10% (improved group) were compared to those who did not (not-improved group). Clinical, electrocardiographic and echocardiographic data were collected and compared between the groups. Results A total of 567 HFrEF patients (72% male, 54.3±14.4 years old) were analyzed. Patients without EF improvement (n = 393) were more likely to be male, had more comorbidities and had higher rates of ischemic cardiomyopathy (ICMP), compared with the improved group (n = 174) (Table). Lack of improvement in EF was also associated with lower EF and higher left and right ventricular diameters in the first echo. In a multivariate analysis model adjusted to all statistically significant variables in the univariate analysis, predictors for lack of EF improvement were male sex (adjusted odds ratio [OR] 1.63, 95% CI 1.02-2.61; P = 0.041), ICMP (OR 3.98, 95% CI 2.03-7.81; P&amp;lt;.001), larger left ventricular end diastolic and end systolic diameters (OR 2.07, 95% CI 1.44-2.98 and OR 1.84, 95% CI 1.36-2.5, respectively; P&amp;lt;.001 for both) and enlarged right ventricle (OR 1.93, 95% CI 1.11-3.36; P = 0.02), while higher EF at baseline was a positive predictor for improvement (OR 0.95, 95% CI 0.92-0.98; P = 0.001) (Figure). Interestingly, NYHA functional class was not associated with EF improvement (OR 1.16, 95% CI 0.87-1.55; P = 0.306). Hospitalization and mortality rates were both higher in the not-improved group (median of 1 (IQR 1-2) vs. 0 (IQR 0-1); P&amp;lt;.001 and 24% vs. 13%; P = 0.001, respectively). Patients in both groups were generally treated with high rates of guideline directed medical therapy (GDMT) for HFrEF. Although no correlation was found between GDMT and EF improvement, these drugs were associated with reduced hospitalization and mortality rates in both groups. Conclusions Improvement in EF among HFrEF patients may be predicted by the HF etiology and echocardiographic parameters. HFimpEF patients have better prognosis compared to HFrEF patients. While GDMT was not associated with EF improvement, it improved outcomes in both HFimpEF and HFrEF regardless of EF.

Abstract 13085: Sociodemographic Predictors of NYHA Class Assignment: An Analysis From CHAMP-HF

Background: The New York Heart Association (NYHA) class is the cornerstone of health status assessment in heart failure with reduced ejection fraction (HFrEF). However, prior work has shown marked variability compared to patient-reported health status - measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ). As clinicians determine NYHA, systemic biases may impact class selection. It is unknown if patients’ age, race, sex, BMI, or education influence NYHA class assignment. Aims: To determine whether patient factors (age, race, sex, education, and BMI) predict NYHA class when controlling for KCCQ. Methods: Participants in CHAMP-HF, a prospective registry of ambulatory HFrEF patients, were evaluated by a clinician with a simultaneously completed NYHA and KCCQ-12. Using hierarchical multinomial logistic regression models with site-level random effects to account for clustering by site, we modeled NYHA class on age, Hispanic and Black vs White patients, males vs females, education, and BMI separately while adjusting for baseline KCCQ-12 as a restricted cubic spline. Results: 4,742 participants were included. The table shows model summaries. Of all predictor variables, only age was associated with differential NYHA class assignment. Compared with class I, 5-year increases in age increased the odds of being assigned class II (OR 1.11; 95% CI 1.07-1.16), III (OR 1.2; 95% CI 1.15-1.26) and IV (OR 1.18; 95% CI 1.07-1.31). Conclusions: These results suggest clinicians assign higher NYHA classes to older patients irrespective of patient-reported health status, but there were no differences identified by race, sex, education or BMI. Whether this leads to differential treatment in older patients merits investigation.

PUMPING IRON: A QUALITY IMPROVEMENT STUDY FOR THE TREATMENT OF IRON DEFICIENCY ANEMIA IN AMBULATORY HEART FAILURE PATIENTS

PUMPING IRON: A QUALITY IMPROVEMENT STUDY FOR THE TREATMENT OF IRON DEFICIENCY ANEMIA IN AMBULATORY HEART FAILURE PATIENTS

The effect of empagliflozin on growth differentiation factor 15 in patients with heart failure: a randomized controlled trial (Empire HF Biomarker)

BackgroundPlasma growth differentiation factor-15 (GDF-15) biomarker levels increase in response to inflammation and tissue injury, and increased levels of GDF-15 are associated with increased risk of mortality in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors, which improve outcome in HFrEF, have been shown to increase plasma GDF-15 in diabetic patients. We aimed to investigate the effect of empagliflozin on GDF-15 in HFrEF patients.MethodsThis Empire HF Biomarker substudy was from the multicentre, randomized, double-blind, placebo-controlled Empire HF trial that included 190 patients from June 29, 2017, to September 10, 2019. Stable ambulatory HFrEF patients with ejection fraction of ≤ 40% were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo for 12 weeks. Changes from baseline to 12 weeks in plasma levels of GDF-15, high-sensitive C-reactive protein (hsCRP), and high-sensitive troponin T (hsTNT) were assessed.ResultsA total of 187 patients who were included in this study, mean age was 64 ± 11 years; 85% male, 12% with type 2 diabetes, mean ejection fraction 29 ± 8, with no differences between the groups. Baseline median plasma GDF-15 was 1189 (918–1720) pg/mL with empagliflozin, and 1299 (952–1823) pg/mL for placebo. Empagliflozin increased plasma GDF-15 compared to placebo (adjusted between-groups treatment effect; ratio of change (1·09 [95% confidence interval (CI), 1.03–1.15]: p = 0.0040). The increase in plasma GDF15 was inversely associated with a decrease in left ventricular end-systolic (R = – 0.23, p = 0.031), and end-diastolic volume (R = – 0.29, p = 0.0066). There was no change in plasma hsCRP (1.09 [95%CI, 0.86–1.38]: p = 0.48) or plasma hsTNT (1.07 [95%CI, 0.97–1.19]: p = 0.18) compared to placebo. Patients with diabetes and treated with metformin demonstrated no increase in plasma GDF-15 with empagliflozin, p for interaction = 0·01.ConclusionEmpagliflozin increased plasma levels of GDF-15 in patients with HFrEF, with no concomitant increase in hsTNT nor hsCRP.Trial registration: The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585.

Splanchnic Nerve Block Mediated Changes in Stressed Blood Volume in Heart Failure

ObjectivesThe authors estimated changes of stressed blood volume (SBV) induced by splanchnic nerve block (SNB) in patients with either decompensated or ambulatory heart failure with reduced ejection fraction (HFrEF). BackgroundThe splanchnic vascular capacity is a major determinant of the SBV, which in turn determines cardiac filling pressures and may be modifiable through SNB. MethodsWe analyzed data from 2 prospective, single-arm clinical studies in decompensated HFrEF (splanchnic HF-1; resting hemodynamics) and ambulatory heart failure (splanchnic HF-2; exercise hemodynamics). Patients underwent invasive hemodynamics and short-term SNB with local anesthetics. SBV was simulated using heart rate, cardiac output, central venous pressure, pulmonary capillary wedge pressure, systolic and diastolic systemic arterial and pulmonary artery pressures, and left ventricular ejection fraction. SBV is presented as ml/70 kg body weight. ResultsMean left ventricular ejection fraction was 21 ± 11%. In patients with decompensated HFrEF (n = 11), the mean estimated SBV was 3,073 ± 251 ml/70 kg. At 30 min post-SNB, the estimated SBV decreased by 10% to 2,754 ± 386 ml/70 kg (p = 0.003). In ambulatory HFrEF (n = 14) patients, the mean estimated SBV was 2,664 ± 488 ml/70 kg and increased to 3,243 ± 444 ml/70 kg (p < 0.001) at peak exercise. The resting estimated SBV was lower in ambulatory patients with HFrEF than in decompensated HFrEF (p = 0.019). In ambulatory patients with HFrEF, post-SNB, the resting estimated SBV decreased by 532 ± 264 ml/70 kg (p < 0.001). Post-SNB, with exercise, there was no decrease of estimated SBV out of proportion to baseline effects (p = 0.661). ConclusionsThe estimated SBV is higher in decompensated than in ambulatory heart failure. SNB reduced the estimated SBV in decompensated and ambulatory heart failure. The reduction in estimated SBV was maintained throughout exercise. (Splanchnic Nerve Anesthesia in Heart Failure, NCT02669407; Abdominal Nerve Blockade in Chronic Heart Failure, NCT03453151)

Sacubitril/valsartan for the management of heart failure: A perspective viewpoint on current evidence

Current international guidelines recommend switching angiotensin converting enzyme inhibitors (ACE-i) or angiotensin receptor blockers (ARBs) to sacubitril/valsartan (S/V) in stable outpatients affected by heart failure with reduced ejection fraction (HFrEF) who remain symptomatic despite being on optimal medical therapy. Since these guidelines were published, new data may support further clinical applications and benefits of S/V beyond ambulatory HFrEF patients. The efficacy of S/V seems to be consistent across a wider array of subgroups including age, sex, etiology of HF, comorbidities, EF and estimated cardiovascular risk, with safety and tolerability profiles similar to ACE-I and ARBs. Additional clinical trial data are required to confirm the potential benefits of S/V in patients with mid-range or preserved EF, as suggested by analysis of PARAGON-HF, or in combination with sodium-glucose co-transporter 2 inhibitors or in post-myocardial infarction HF.In this article we summarize the new evidence on the effects and safety profile of S/V in HF and discuss current perspectives and persisting gaps. Currently, available evidence may support S/V as a first-line therapy in outpatient or in-hospital HFrEF patients, and possibly also in HFmrEF patients.

CBIN1 Score (CS) Identifies Ambulatory HFrEF Patients and Predicts Cardiovascular Events.

BackgroundCardiac Bridging Integrator 1 (cBIN1) is a membrane deformation protein that generates calcium microdomains at cardiomyocyte t-tubules, whose transcription is reduced in heart failure, and is released into blood. cBIN1 score (CS), an inverse index of plasma cBIN1, measures cellular myocardial remodeling. In patients with heart failure with preserved ejection fraction (HFpEF), CS diagnoses ambulatory heart failure and prognosticates hospitalization. The performance of CS has not been tested in patients with heart failure with reduced ejection fraction (HFrEF).Methods and ResultsCS was determined from plasma of patients recruited in a prospective study. Two comparative cohorts consisted of 158 ambulatory HFrEF patients (left ventricular ejection fraction (LVEF) ≤ 40%, 57 ± 10 years, 80% men) and 115 age and sex matched volunteers with no known history of HF. N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations were also analyzed for comparison. CS follows a normal distribution with a median of 0 in the controls, which increases to a median of 1.9 (p < 0.0001) in HFrEF patients. CS correlates with clinically assessed New York Heart Association Class (p = 0.007). During 1-year follow-up, a high CS (≥ 1.9) in patients predicts increased cardiovascular events (43% vs. 26%, p = 0.01, hazard ratio 1.9). Compared to a model with demographics, clinical risk factors, and NT-proBNP, adding CS to the model improved the overall continuous net reclassification improvement (NRI 0.64; 95% CI 0.18-1.10; p = 0.006). Although performance for diagnosis and prognosis was similar to CS, NT-proBNP did not prognosticate between patients whose NT-proBNP values were > 400 pg/ml.ConclusionCS, which is mechanistically distinct from NT-proBNP, successfully differentiates myocardial health between patients with HFrEF and matched controls. A high CS reflects advanced NYHA stage, pathologic cardiac muscle remodeling, and predicts 1-year risk of cardiovascular events in ambulatory HFrEF patients. CS is a marker of myocardial remodeling in HFrEF patients, independent of volume status.

Physicians’ guideline adherence is associated with long-term heart failure mortality in outpatients with heart failure with reduced ejection fraction: The QUALIFY international registry

Physicians’ adherence to guideline-recommended therapy is associated with short-term clinical outcomes in heart failure (HF) with reduced ejection fraction (HFrEF). However, its impact on longer-term outcomes is poorly documented. In this analysis we assessed the longer-term association of physicians’ adherence with clinical outcomes, including mortality and unplanned hospitalisations, at 18-month follow-up of the QUALIFY registry (Clinical trial registration ISRCTN87465420) Data at 18 months were available for 6118 ambulatory HFrEF patients from this international prospective observational survey. Adherence was measured as a continuous variable, ranging from 0 to 1, and was assessed with regard to five classes of recommended HF medications and dosages. Most deaths were cardiovascular (CV) (228/394) and HF-related (191/394) and the same was true for unplanned hospitalisations (1175 CV and 861 HF-related hospitalisations, out of a total of 1541). According to univariable analysis, CV and HF deaths were significantly associated with physician adherence to guidelines. In multivariable analysis, HF death was associated with adherence level [subdistribution hazard ratio (SHR) 0.93, 95% confidence interval (CI) 0.87–0.99 per 0.1 unit adherence level increase; P = 0.034] as was composite of HF hospitalisation or CV death (SHR 0.97, 95% CI 0.94–0.99 per 0.1 unit adherence level increase; P = 0.043), whereas unplanned all-cause, CV or HF hospitalisations were not (all-cause: SHR 0.99, 95% CI 0.9–1.02; CV: SHR 0.98, 95% CI 0.96–1.01; and HF: SHR 0.99, 95% CI 0.96–1.02 per 0.1 unit change in adherence score; P = 0.52, P = 0.2, and P = 0.4, respectively). These results suggest that physicians’ adherence to guideline-recommended HF therapies is associated with improved outcomes in HFrEF. Practical strategies should be established to improve physicians’ adherence to guidelines.

Prognostic utility of diastolic dysfunction and speckle tracking echocardiography in heart failure with reduced ejection fraction.

AimsWe hypothesized that grading of diastolic dysfunction (DDF) according to two DDF grading algorithms and strain imaging yields prognostic information on all‐cause mortality in patients with heart failure with reduced ejection fraction (HFrEF).Methods and resultsWe enrolled ambulatory HFrEF (left ventricular ejection fraction < 45%; N = 1 065) patients who underwent echocardiography and speckle tracking assessment of global longitudinal strain (GLS). Patients were stratified according to DDF grades (Grades I–III) according to two contemporary DDF grading algorithms. Prognostic performance was assessed by C‐statistics. Of the originally 1 065 enrolled patients, a total of 645 (61%) patients (age: 67 ± 11 years, male: 72%, ejection fraction: 27 ± 9%) were classified according to both DDF grading algorithms. Concordance between the algorithms was moderate (kappa = 0.48) and the reclassification rate was 33%. During a median follow‐up of 3.3 years (1.9, 4.7 years), 101 (16%) died from all causes. When comparing DDF Grade I vs. Grade III, both algorithms provided prognostic information [Nagueh: (hazard ratio) HR 2.09, 95% confidence interval (CI),1.32–3.31, P = 0.002; Johansen: HR 2.47, 95% CI, 1.57–3.87, P < 0.001]. However, when comparing DDF Grade II vs. Grade III, only the Johansen algorithm yielded prognostic information (Nagueh: HR 1.04, 95% CI, 0.60–1.77, P = 0.90; Johansen: HR 2.26, 95% CI, 1.35–3.77, P = 0.002). We found no difference in prognostic performance between the two algorithms (C‐statistics: 0.604 vs. 0.623, P = 0.24). Assessed by C‐statistics, the most powerful predictors of the endpoint from the two algorithms were E/e'‐ratio (C‐statistics: 0.644), tricuspid regurgitation velocity (C‐statistics: 0.625) and E/A‐ratio (C‐statistics: 0.602). When adding GLS to a combination of these predictors, the prognostic performance increased significantly (C‐statistics: 0.705 vs. C‐statistics: 0.634, P = 0.028).ConclusionsEvaluation of DDF in patients with HFrEF yields prognostic information on all‐cause mortality. Furthermore, adding GLS to contemporary algorithms of DDF adds novel prognostic information.

Physicians' guideline adherence is associated with long-term heart failure mortality in outpatients with heart failure with reduced ejection fraction: the QUALIFY international registry.

Physicians' adherence to guideline-recommended therapy is associated with short-term clinical outcomes in heart failure (HF) with reduced ejection fraction (HFrEF). However, its impact on longer-term outcomes is poorly documented. Here, we present results from the 18-month follow-up of the QUALIFY registry. Data at 18 months were available for 6118 ambulatory HFrEF patients from this international prospective observational survey. Adherence was measured as a continuous variable, ranging from 0 to 1, and was assessed for five classes of recommended HF medications and dosages. Most deaths were cardiovascular (CV) (228/394) and HF-related (191/394) and the same was true for unplanned hospitalizations (1175 CV and 861 HF-related hospitalizations, out of a total of 1541). According to univariable analysis, CV and HF deaths were significantly associated with physician adherence to guidelines. In multivariable analysis, HF death was associated with adherence level [subdistribution hazard ratio (SHR) 0.93, 95% confidence interval (CI) 0.87-0.99 per 0.1 unit adherence level increase; P = 0.034] as was composite of HF hospitalization or CV death (SHR 0.97, 95% CI 0.94-0.99 per 0.1 unit adherence level increase; P = 0.043), whereas unplanned all-cause, CV or HF hospitalizations were not (all-cause: SHR 0.99, 95% CI 0.9-1.02; CV: SHR 0.98, 95% CI 0.96-1.01; and HF: SHR 0.99, 95% CI 0.96-1.02 per 0.1 unit change in adherence score; P = 0.52, P = 0.2, and P = 0.4, respectively). These results suggest that physicians' adherence to guideline-recommended HF therapies is associated with improved outcomes in HFrEF. Practical strategies should be established to improve physicians' adherence to guidelines.

PROGNOSTIC UTILITY OF DIASTOLIC DYSFUNCTION AND SPECKLE TRACKING IN PATIENTS WITH HEART FAILURE WITH REDUCED EJECTION FRACTION

We hypothesized that grading of diastolic dysfunction (DDF) yields prognostic information on all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF). We studied ambulatory HFrEF (n = 917) patients (mean age 67 ± 12 years, EF 27 ± 9%) who underwent

Dynamic ultrasound lung comets improves risk stratification in systolic heart failure assessed by cardiopulmonary exercise testing

While ultrasound lung comets (ULC) at rest provide prognosis information inpatients presenting with heart failure with reduced ejection fraction (HF-rEF), cardiopulmonary exercise testing (CPET) remains reference. This study aims to compare dynamic ULC with CPET measurements and stress echocardiography on HF-rEF patients. Forty patients with HF-rEF (left ventricle ejection fraction below 40%) and 10 control patients matched on age and gender were included. Evaluation was performed by CPET (with oxygen uptake, VO 2 ; carbon dioxide output, VCO 2 ; ventilation, VE), stress echocardiography (with E and Ea wave velocities) and pulmonary echography (with baseline and postexercise ULC). ULC were assessed using a semi-quantitative method (LUS score). Cox regression analysis and areas under receiver-operator-curve (AUROC) analysis were performed on HF-rEF patients with all-cause mortality as main endpoint. One-year mortality was 12.5% among HF-rEF patients. Baseline and postexercise ULC were associated with mortality (respective adjusted hazard-ratio HR = 1.25 (CI 95 = 1.05–1.49, P = 0.01) and HR = 1.38 (CI 95 = 1.11–1.71, P = 0.003), independently from peak VO 2 ). Postexercise ULC tended to be more discriminative than baseline ULC, with respective AUROC = 0.89 ( P = 0.006) and AUROC = 0.79 ( P = 0.038). Discrimination of VE/VCO2 slope was similar (AUROC = 0.92, P = 0.003), peak E/Ea ratio's tended to be lower (AUROC = 0.78, P = 0.045) and peak VO 2 was not discriminative of mortality. Postexercise ULC were correlated with peak VO 2 ( r = −0.31, P = 0.03), VE/VCO 2 slope ( r = 0.58, P < 0.001) and E/Ea ratio ( r = 0.40, P = 0.01). ULC did not vary in healthy patients between baseline and effort ( Table 1 , Fig. 1 ). Dynamic assessment of ULC improves risk stratification of ambulatory HF-rEF patients in addition to CPET measurements such as peak VO 2 .