Capacity In Heart Failure Research Articles

Ferric carboxymaltose and exercise capacity in heart failure with preserved ejection fraction and iron deficiency: the FAIR-HFpEF trial.

Evidence is lacking that correcting iron deficiency (ID) has clinically important benefits for patients with heart failure with preserved ejection fraction (HFpEF). FAIR-HFpEF was a multicentre, randomized, double-blind trial designed to compare intravenous ferric carboxymaltose (FCM) with placebo (saline) in 200 patients with symptomatic HFpEF and ID (serum ferritin < 100 ng/mL or ferritin 100-299 ng/mL with transferrin saturation < 20%). The primary endpoint was change in 6-min walking test distance (6MWTD) from baseline to week 24. Secondary endpoints included changes in New York Heart Association class, patient global assessment, and health-related quality of life (QoL). The trial was stopped because of slow recruitment after 39 patients had been included (median age 80 years, 62% women). The change in 6MWTD from baseline to week 24 was greater for those assigned to FCM compared to placebo [least square mean difference 49 m, 95% confidence interval (CI) 5-93; P = .029]. Changes in secondary endpoints were not significantly different between groups. The total number of adverse events (76 vs. 114) and serious adverse events (5 vs. 19; rate ratio 0.27, 95% CI 0.07-0.96; P = .043) was lower with FCM than placebo. In patients with HFpEF and markers of ID, intravenous FCM improved 6MWTD and was associated with fewer serious adverse events. However, the trial lacked sufficient power to identify or refute effects on symptoms or QoL. The potential benefits of intravenous iron in HFpEF with ID should be investigated further in a larger cohort.

Diabetes mellitus is associated with low exercise capacity and impaired peripheral vasodilation in patients with heart failure − a propensity score-matched study

AimsDiabetes mellitus (DM) and heart failure (HF) share vascular, skeletal and metabolic abnormalities that can reduce exercise capacity. We investigated whether exercise capacity differ in patients with type 2 DM compared to those without DM with HF of similar severity. Methods and resultsThe Studies Investigating Co-morbidities Aggravating HF (SICA-HF) prospectively enrolled 615 patients with chronic HF, 259 (42.1 %) of whom had DM. We assembled a propensity score-matched cohort of 231 pairs of patients with HF with or without DM who were balanced on age, sex and variables reflecting HF severity. Patients with DM had lower median peak VO2 (15.7 [13.0–19.1] vs. 17.3 [14.1–21.0] ml/min/kg; p = 0.005). Forearm blood flow reserve (per 1 ml/min/100 ml increase) was associated with lower exercise capacity (peak VO2 ≤ 16.6 ml/min/kg) in patients with DM (OR, 0.92; 95 % CI, (0.85–0.98; p = 0.014), but not in those without DM (OR, 0.98; 95 % CI, 0.93–1.02). A similar heterogeneity was also observed for HDL cholesterol. ConclusionsDiabetes is associated with a reduced exercise capacity in patients with HF. Most predictors of lower exercise capacity in HF are similar regardless of DM except impaired vascular function and lower HDL cholesterol which predict lower exercise capacity only in those with DM.

Relationship between NT-proBNP, echocardiographic abnormalities and functional status in patients with subclinical siabetic cardiomyopathy

IntroductionPersons with diabetes are at risk for developing a cardiomyopathy through several pathophysiological mechanisms independent of traditional risk factors for heart failure. Among those with diabetic cardiomyopathy (DbCM), the relationship between natriuretic peptides, cardiac structural abnormalities and functional capacity is largely unknown.MethodsIn this prespecified subgroup analysis of the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) trial, 685 participants with asymptomatic DbCM underwent baseline echocardiography data, laboratory investigations, and functional assessments. Participants were stratified by N-terminal pro-B type natriuretic peptide (NT-proBNP) quartiles, and correlation with echocardiographic and functional parameters were assessed using Spearman correlation test.ResultsThe median NT-proBNP was 71 (Q1, Q3: 33, 135) ng/L. No association was observed between NT-proBNP concentrations and echocardiographic parameters of either diastolic or systolic dysfunction including global longitudinal strain, left ventricular ejection fraction, left ventricular mass index, left atrial volume index, E/E’, or right ventricular systolic pressure. In contrast, NT-proBNP was significantly correlated with overall Kansas City Cardiomyopathy Questionnaire score (rho = − 0.10; p = 0.007), the Physical Activity Scale in the Elderly (rho = − 0.12; p = 0.004), duration of cardiopulmonary exercise testing (rho = − 0.28; p < 0.001), peak VO2 (rho = − 0.26; p < 0.001), and ratio of minute ventilation/carbon dioxide production (rho = 0.12; p = 0.002). After adjustment for known confounders, the correlation with Physical Activity Scale in the Elderly and overall Kansas City Cardiomyopathy Questionnaire score was no longer significant.ConclusionAmong patients with subclinical DbCM, elevated NT-proBNP concentrations are associated with worse health status, lower activity levels, and reduced functional capacity, but not with cardiac structural abnormalities. These findings suggest that regardless of cardiac structural abnormalities, biomarker concentrations reflect important deterioration in functional capacity in affected individuals.Trial registrationARISE-HF, NCT 04083339 Date Registered August 23, 2019.Graphical abstractAbnormal ECHO defined as Myocardial Global Longitudinal Strain < − 16 or left ventricular mass index > 95 for females or > 115 for males or E/e’ >13 or left atrial volume index > 34. †Normal ECHO is defined as the absence of these abnormalities. Low NT-proBNP is defined as < 71 ng/L while high NT-proBNP is defined as ≥ 71 ng/L.

Left ventricular volume and maximal functional capacity in heart failure with preserved ejection fraction: Size matters.

Emerging evidence suggests that smaller left ventricular volumes may identify subjects with lower cardiorespiratory fitness. Whether left ventricular size predicts functional capacity in patients with heart failure with preserved ejection fraction (HFpEF) is unclear. This study aimed to explore the association between indexed left ventricular end-diastolic volume (iLVEDV) and maximal functional capacity, assessed by peak oxygen consumption (peakVO2), in stable outpatients with HFpEF. We prospectively analysed data from 133 consecutive stable outpatients who underwent cardiopulmonary exercise testing and echocardiography on the same day. Data were validated in a cohort of HFpEF patients from San Paolo Hospital, Milan, Italy. A multivariable linear regression assessed the association between iLVEDV and peakVO2. The mean age was 73.2 ± 10.5 years, and 75 (56.4%) were women. The median iLVEDV, indexed left ventricular end-systolic volume, and left ventricular ejection fraction were 46 ml/m2 (30-56), 15 ml/m2 (11-19), and 66% (60-74%), respectively. The median peakVO2 and percentage of predicted peakVO2 were 11 ml/kg/min (9-13) and 64.1% (53-74.4), respectively. Adjusted linear regression analysis showed that smaller iLVEDV was associated with lower peakVO2 (p = 0.0001). In the validation cohort, adjusted linear regression analysis showed a consistent pattern: a smaller iLVEDV was associated with a higher likelihood of reduced peakVO2 (p = 0.004). In stable outpatients with HFpEF, a smaller iLVEDV was associated with a lower maximal functional capacity. These findings suggest a need for further studies to understand the pathophysiological mechanisms underlying these observations and to explore targeted treatment strategies for this patient subgroup.

Impact of Atrial Fibrillation on Functional Capacity in Heart Failure With Reduced Ejection Fraction Secondary to Non-Ischaemic Cardiomyopathy

Impact of Atrial Fibrillation on Functional Capacity in Heart Failure With Reduced Ejection Fraction Secondary to Non-Ischaemic Cardiomyopathy

Different levels of continuous training improve echocardiographic parameters, quality of life, and functional capacity in heart failure with reduced ejection fraction patients

Abstract Background Various comorbidities and physiological alterations contribute to the complexity of heart failure conditions, influencing the optimal approach to exercise-based rehabilitation. Purpose This study sought to investigate and compare the effects of continuous training at three distinct intensities, specifically examining left ventricular (LV) remodeling, functional capacity, and quality of life in patients with heart failure with reduced ejection fraction (HFrEF). Methods In a randomized control trial, 60 male patients (mean age: 54.33 ± 2.35 years) diagnosed with HFrEF were randomly assigned to three groups: 1) High-Intensity Continuous Training group (HICT), 2) Moderate-Intensity Continuous Training group (MICT), and 3) Low-Intensity Continuous Training group (LICT). All participants underwent training on a bicycle ergometer three times per week for 12 weeks. Echocardiographic parameters (left ventricular ejection fraction, left ventricular end-diastolic dimension, left ventricular end-systolic dimension, N-terminal pro–B-type natriuretic peptide (NT-proBNP)), quality of life (assessed through the Minnesota Living with Heart Failure Questionnaire), and functional capacity (measured by the 6-minute walking test) were evaluated before and after the study. Results The HICT group exhibited the most significant improvements in all assessed variables compared to the other two groups (P &amp;lt; 0.05). These findings were consistently observed across all measured outcomes. Conclusion It was deduced that High-Intensity Continuous Training (HICT) emerged as the most advantageous approach in enhancing echocardiographic measures, NT-proBNP levels, quality of life, and functional capacity among patients with heart failure and reduced ejection fraction (HFrEF).

CA125 outperforms NT-proBNP in the prediction of maximum aerobic capacity in heart failure with preserved ejection fraction and kidney dysfunction.

Heart failure with preserved ejection fraction (HFpEF) often coexists with chronic kidney disease (CKD). Exercise intolerance is a major determinant of quality of life and morbidity in both scenarios. We aimed to evaluate the associations between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and carbohydrate antigen 125 (CA125) with maximal aerobic capacity (peak VO2) in ambulatory HFpEF and whether these associations were influenced by kidney function. This single-centre study prospectively enrolled 133 patients with HFpEF who performed maximal cardiopulmonary exercise testing. Patients were stratified across estimated glomerular filtration rate (eGFR) categories (<60ml/min/1.73m2 versus ≥60ml/min/1.73m2). The mean age of the sample was 73.2±10.5years and 56.4% were female. The median of peak VO2 was 11.0ml/kg/min (interquartile range 9.0-13.0). A total of 67 (50.4%) patients had an eGFR <60ml/min/1.73m2. Those patients had higher levels of NT-proBNP and lower peak VO2, without differences in CA125. In the whole sample, NT-proBNP and CA125 were inversely correlated with peak VO2 (r=-0.43, P<.001 and r=-0.22, P=.010, respectively). After multivariate analysis, we found a differential association between NT-proBNP and peak VO2 across eGFR strata (P for interaction=.045). In patients with an eGFR ≥60ml/min/1.73m2, higher NT-proBNP identified patients with poorer maximal functional capacity. In individuals with eGFR <60ml/min/1.73m2, NT-proBNP was not significantly associated with peak VO2 [β=0.02 (95% confidence interval -0.19-0.23), P=.834]. Higher CA125 was linear and significantly associated with worse functional capacity without evidence of heterogeneity across eGFR strata (P for interaction=.620). In patients with stable HFpEF, NT-proBNP was not associated with maximal functional capacity when CKD was present. CA125 emerged as a useful biomarker for estimating effort intolerance in HFpEF irrespective of the presence of CKD.

Accuracy of the 6-Minute Walk Test for Assessing Functional Capacity in Patients With Heart Failure With Preserved Ejection Fraction and Other Chronic Cardiac Pathologies: Results of the ExIC-FEp Trial and a Meta-Analysis

BackgroundHeart diseases, particularly heart failure, significantly impact patient quality of life and mortality rates. Functional capacity assessment is vital for predicting prognosis and risk in these patients. While the cardiopulmonary exercise test is considered the gold standard, the 6-minute walk test has emerged as a more accessible alternative. However, the screening accuracy and optimal cut-off points of the 6-minute walk test for detecting severely reduced functional capacity in cardiac pathologies, including heart failure with preserved ejection fraction, are unclear. The study aimed to analyse the diagnostic accuracy of the 6-minute walk test for detecting reduced functional capacity, defined as VO2max < 14 ml/kg/min, compared with the cardiopulmonary exercise test in participants with heart failure with preserved ejection fraction using data from the “Ejercicio en Insuficiencia Cardiaca con Fracción de Eyección Preservada” (ExIC-FEp) trial; and to compare these results with previous studies investigating the screening accuracy for assessing functional capacity of the 6-minute walk test in participants with other chronic cardiac pathologies through a meta-analysis.ResultsThe ExIC-FEp trial involved 22 participants with heart failure with preserved ejection fraction, who were not treated with beta-blockers, using the cardiopulmonary exercise test, specifically VO2max, as the reference test. The 6-minute walk test had a sensitivity of 70%, a specificity of 80%, and an area under the curve of 76% in the ExIC-FEp trial. Five studies were included in the meta-analysis showing a sensitivity of 79%, a specificity of 78%, and an area under the curve of 85%.ConclusionIn conclusion, the 6-minute walk test holds promise as a screening tool for assessing functional capacity in heart failure with preserved ejection fraction and chronic heart diseases, with a VO2max < 14 ml/kg/min as a reference point. It demonstrates moderate to good screening accuracy. However, the screening accuracy and optimal cut-off points of the 6-minute walk test for detecting severely reduced functional capacity, regardless of aetiology, are unclear.Trial RegistrationNCT05726474. Registered 16 February 2023, https://clinicaltrials.gov/study/NCT05726474.

Association of epicardial fat with cardiac structure and function and exercise capacity in heart failure with preserved ejection fraction: A systematic review and meta-analysis

BackgroundStudies have reported the association of epicardial adipose tissue (EAT) with cardiac structure and function as well as exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF), yielding inconsistent results. We aimed to conduct a meta-analysis of studies on the association of EAT with cardiac structure and function and exercise capacity in HFpEF patients. Methods and ResultsWe searched studies examining the association of EAT quantified by echocardiography, computed tomography, or magnetic resonance imaging (MRI) with cardiac structure and function or exercise capacity in HFpEF patients through PubMed, Web of Science, and Scopus. In cases of significant heterogeneity (I2 > 50 %), data were pooled using a random-effects model; otherwise, a fixed-effects model was used. We identified five echocardiography studies (n = 825) and six MRI studies (n = 562), but found no computed tomography studies. In the echocardiography studies, EAT thickness correlated positively with left ventricular (LV) mass (Prandom < 0.01) and negatively with LV global longitudinal strain (Prandom < 0.01) and peak exercise oxygen uptake (Pfix < 0.001). In the MRI studies, EAT volume correlated positively with LV mass (Pfix < 0.01), left atrial volume (Pfix < 0.001), and the ratio of LV early diastolic mitral inflow to early diastolic mitral annular velocity (E/e’; Prandom < 0.01) and negatively with LV ejection fraction (Pfix < 0.01) and LV global longitudinal strain (Pfix < 0.001). ConclusionOur meta-analysis indicates a potential association of increased EAT with altered cardiac structure and function and exercise intolerance in HFpEF patients. However, our meta-analysis included only two or three studies for each outcome and thus further studies are necessary to confirm our findings.

Conduction system pacing improved cardiac functions and functional capacity in heart failure with reduced ejection fraction and right bundle branch block

Abstract Conduction system pacing (CSP) is increasingly accepted as an alternative to biventricular pacing in heart failure (HF) patients with left bundle branch block (LBBB) and non-LBBB. However, its efficiency in right bundle branch block (RBBB) is ill-defined. Herein, we report on the clinical outcomes of CSP in HFrEF patients with wide QRS complex and RBBB morphology. His-bundle (HBP) or LBB-area pacing (LBBAP) was attempted as a primary strategy in patients with RBBB, QRS duration ≥130 ms and left ventricular ejection fraction (LV EF) &amp;lt;35% and NYHA class II to IV HF despite optimized medical treatment for at least 6 months. Data on functional status, NT-pro-BNP levels and echocardiographic parameters were collected during follow-up and expressed as mean ± SEM, Statistical significance was calculated with Student’s paired t-test and chi square distribution. CSP was performed in 12 RBBB-HF patients (age 64.3±2.9 years) with mean QRS duration of 150±4 msec and baseline LV EF of 25.4±2.3%. The aetiology of HF was ischaemic (6 patients) and non-ischaemic cardiomyopathy (6 patients). During the procedure, HBP was achieved in 7 and LBBAP in 5 patients, resulting in a significant reduction in the QRS-duration (115±2.6 msec, P&amp;lt;0.0001) as compared with baseline value. CSP improved LV function (LV EF= 31.8±2.8%, P=0.009) as well as NYHA functional class (25% of the patients with NYHA II and 75% with NYHA III before vs. 33% with NYHA I, 33% with NYHA II and 33% with NYHA III after CSP, P=0.048) as compared to what was obtained prior to the procedure. A numerical decrease was also found in NT-proBNP levels (4735±2606 ng/ml before CSP vs. 3972±1883 ng/ml after CSP) which did not reach the level of statistical significance (P=0.45). In conclusion, CSP improved both quality of life and LV function in HFrEF patients with RBBB. Our results support the use of CSP in HFrEF patients with QRS width&amp;gt;130msec and RBBB morphology.

Hyperlactataemia is a marker of reduced exercise capacity in heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is associated with an array of central and peripheral haemodynamic and metabolic changes. The exact pathogenesis of exercise limitation in HFpEF remains uncertain. Our aim was to compare lactate accumulation and central haemodynamic responses to exercise in patients with HFpEF, non-cardiac dyspnoea (NCD), and healthy volunteers. Right heart catheterization with mixed venous blood gas and lactate measurements was performed at rest and during symptom-limited supine exercise. Multivariable analyses were conducted to determine the relationship between haemodynamic and biochemical parameters and their association with exercise capacity. Of 362 subjects, 198 (55%) had HFpEF, 103 (28%) had NCD, and 61 (17%) were healthy volunteers. This included 139 (70%) females with HFpEF, 77 (75%) in NCD (P=0.41 HFpEF vs. NCD), and 31 (51%) in healthy volunteers (P<0.001 HFpEF vs. volunteers). The median age was 71 (65, 75) years in HFpEF, 66 (57, 72) years in NCD, and 49 (38, 65) years in healthy volunteers (HFpEF vs. NCD or volunteer, both P<0.001). Peak workload was lower in HFpEF compared with healthy volunteers [52W (interquartile range 31-73), 150W (125-175), P<0.001], but not NCD [53W (33, 75), P=0.85]. Exercise lactate indexed to workload was higher in HFpEF at 0.08mmol/L/W (0.05-0.11), 0.06mmol/L/W (0.05-0.08; P=0.016) in NCD, and 0.04mmol/L/W (0.03-0.05; P<0.001) in volunteers. Exercise cardiac index was 4.5L/min/m2 (3.7-5.5) in HFpEF, 5.2L/min/m2 (4.3-6.2; P<0.001) in NCD, and 9.1L/min/m2 (8.0-9.9; P<0.001) in volunteers. Oxygen delivery in HFpEF was lower at 1553mL/min (1175-1986) vs. 1758mL/min (1361-2282; P=0.024) in NCD and 3117mL/min (2667-3502; P<0.001) in the volunteer group during exercise. Predictors of higher exercise lactate levels in HFpEF following adjustment included female sex and chronic kidney disease (both P<0.001). HFpEF is associated with reduced exercise capacity secondary to both central and peripheral factors that alter oxygen utilization. This results in hyperlactataemia. In HFpEF, plasma lactate responses to exercise may be a marker of haemodynamic and cardiometabolic derangements and represent an important target for future potential therapies.

Association between N-terminal pro-brain natriuretic peptide and maximal functional capacity in heart failure with preserved ejection fraction: The modifying role of obesity

This study investigates the association between maximal functional capacity (peakVO2) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in 133 ambulatory patients with heart failure with preserved ejection fraction (HFpEF), focusing on patients with obesity. Across all participants, NT-proBNP inversely correlated with peakVO2. However, this association varied based on obesity status. In patients without obesity, there was an inverse relationship between NT-proBNP and peakVO2, while no significant correlation was observed in patients with obesity. These findings suggest that in stable ambulatory HFpEF, NT-proBNP did not predict peakVO2 in patients with obesity.

Effectiveness of exercise-based cardiac rehabilitation for patients with left ventricular assist device: A systematic review and meta-analysis.

Exercise-based cardiac rehabilitation (EBCR) improves functional capacity in heart failure (HF). However, data on the effect of EBCR in patients with advanced HF and left ventricular assist devices (LVADs) are limited. This meta-analysis aimed to evaluate the impact of EBCR on the functional ability of LVAD patients by comparing the corresponding outcome indicators between the EBCR and ST groups. PubMed, Embase, Clinical Trials, and Cochrane Library databases were searched for studies assessing and comparing the effects of EBCR and standard therapy (ST) in patients following LVAD implantation. Using pre-defined criteria, appropriate studies were identified and selected. Data from selected studies were extracted in a standardized fashion, and a meta-analysis was performed using a fixed-effects model. The protocol was registered on INPLASY (202340073). In total, 12 trials involving 477 patients were identified. The mean age of the participants was 52.9 years, and 78.6% were male. The initiation of EBCR varied from LVAD implantation during the index hospitalization to 11months post-LVAD implantation. The median rehabilitation period ranged from 2weeks to 18months. EBCR was associated with improved peak oxygen uptake (VO2) in all trials. Quantitative analysis was performed in six randomized studies involving 214 patients (EBCR: n = 130, ST: n = 84). EBCR was associated with a significantly high peak VO2 (weighted mean difference [WMD] = 1.64mL/kg/min; 95% confidence interval [CI], 0.20-3.08; p = .03). Similarly, 6-min walk distance (6MWD) showed significantly greater improvement in the EBCR group than in the ST group (WMD = 34.54m; 95% CI, 12.47-56.42; p = .002) in 266 patients (EBCR, n = 140; ST, n = 126). Heterogeneity was low among the included trials. None of the included studies reported serious adverse events related to EBCR, indicating the safety of EBCR after LVAD implantation. This study demonstrated that EBCR following LVAD implantation is associated with greater improvement in functional capacity compared with ST as reflected by the improved peak VO2 and 6MWD values. Considering the small number of patients in this analysis, further research on the clinical impact of EBCR in LVAD patients is warranted.

Correlates of Plasma NT-proBNP/Cyclic GMP Ratio in Heart Failure With Preserved Ejection Fraction: An Analysis of the RELAX Trial.

Phosphodiesterases degrade cyclic GMP (cGMP), the second messenger that mediates the cardioprotective effects of natriuretic peptides. High natriuretic peptide/cGMP ratio may reflect, in part, phosphodiesterase activity. Correlates of natriuretic peptide/cGMP in patients with heart failure with preserved ejection fraction are not well understood. Among patients with heart failure with preserved ejection fraction in the RELAX (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure With Preserved Ejection Fraction) trial, we examined (1) cross-sectional correlates of circulating NT-proBNP (N-terminal pro-B-type natriuretic peptide)/cGMP ratio, (2) whether selective phosphodiesterase-5 inhibition by sildenafil changed the ratio, and (3) whether the effect of sildenafil on 24-week outcomes varied by baseline ratio. In 212 subjects, NT-proBNP/cGMP ratio was calculated at randomization and 24 weeks. Correlates of the ratio and its change were examined in multivariable proportional odds models. Whether baseline ratio modified the sildenafil effect on outcomes was examined by interaction terms. Higher NT-proBNP/cGMP ratio was associated with greater left ventricular mass and troponin, the presence of atrial fibrillation, and lower estimated glomerular filtration rate and peak oxygen consumption. Compared with placebo, sildenafil did not alter the ratio from baseline to 24 weeks (P=0.17). The effect of sildenafil on 24-week change in peak oxygen consumption, left ventricular mass, or clinical composite outcome was not modified by baseline NT-proBNP/cGMP ratio (P-interaction >0.30 for all). Among patients with heart failure with preserved ejection fraction, higher NT-proBNP/cGMP ratio associated with an adverse cardiorenal phenotype, which was not improved by selective phosphodiesterase-5 inhibition. Other phosphodiesterases may be greater contributors than phosphodiesterase-5 to the adverse phenotype associated with a high natriuretic peptide/cGMP ratio in HFpEF. clinicaltrials.gov. Identifier: NCT00763867.

Myocardial Metabolism in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and now accounts for half of all heart failure cases. This rise is largely attributed to growing rates of obesity, hypertension, and diabetes. Despite its prevalence, the pathophysiological mechanisms of HFpEF are not fully understood. The heart, being the most energy-demanding organ, appears to have a compromised bioenergetic capacity in heart failure, affecting all phenotypes and aetiologies. While metabolic disturbances in heart failure with reduced ejection fraction (HFrEF) have been extensively studied, similar insights into HFpEF are limited. This review collates evidence from both animal and human studies, highlighting metabolic dysregulations associated with HFpEF and its risk factors, such as obesity, hypertension, and diabetes. We discuss how changes in substrate utilisation, oxidative phosphorylation, and energy transport contribute to HFpEF. By delving into these pathological shifts in myocardial energy production, we aim to reveal novel therapeutic opportunities. Potential strategies include modulating energy substrates, improving metabolic efficiency, and enhancing critical metabolic pathways. Understanding these aspects could be key to developing more effective treatments for HFpEF.

Characterizing diabetic cardiomyopathy: baseline results from the ARISE-HF trial

BackgroundDiabetic cardiomyopathy (DbCM) is a form of Stage B heart failure (HF) at high risk for progression to overt disease. Using baseline characteristics of study participants from the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) Trial we sought to characterize clinical characteristics of individuals with findings consistent with DbCM.MethodsAmong study participants meeting inclusion criteria, clinical characteristics, laboratory testing, imaging, Kansas City Cardiomyopathy Questionnaire (KCCQ), Physical Activity Scale of the Elderly (PASE) and cardiopulmonary exercise testing (CPET) results were tabulated. Cluster phenogroups were identified.ResultsAmong 691 study participants (mean age 67.4 years; 50% were female), mean duration of type 2 diabetes mellitus (T2DM) was 14.5 years. The median (Q1, Q3) N-terminal pro-B type natriuretic peptide and high sensitivity cardiac troponin T were 71 (35, 135) ng/L and 9 [6, 12] ng/L. The most common echocardiographic abnormalities were reduced global longitudinal strain in 25.3% and impaired diastolic relaxation in 17.7%. Despite rather well-preserved KCCQ scores the average PASE score was markedly impaired at 155 accompanied by an average maximal oxygen consumption of 15.7 mL/Kg/minute on CPET. In K-means clustering, 4 phenogroups were identified including a higher-risk group with more advanced age, greater elevation of cardiac biomarkers, and more prevalent evidence for diastolic dysfunction and left ventricular hypertrophy.ConclusionsBaseline data from the ARISE-HF Trial provide clinical characterization of individuals with T2DM and features of stage B HF, and may help clarify the diagnosis of DbCM.Trial RegistrationARISE-HF, NCT04083339.

Abstract 12149: Vericiguat May Improve Conduit Vessel Function and Exercise Functional Capacity in Heart Failure With Reduced Ejection Fraction

Background: The treatment of heart failure with reduced ejection fraction (HFrEF) has advanced considerably in recent years with the advent of novel agents; however, limitations, such as blood pressure and renal dysfunction, limit the number of patients who can benefit from this treatment in practice. Vericiguat, a novel heart failure treatment, has been found to be efficacious in patients with HFrEF while maintaining a good safety profile. Unfortunately, its mechanisms remain largely unknown. Objective and Methods: A total of 11 patients with HFrEF who were determined to be inadequately treated underwent right heart catheterization, echocardiography, flow-mediated dilatation (FMD) testing, 6-min walking distance (6MWD) test, and blood sampling at a median interval of 70 ± 13 days before and after vericiguat treatment. Results: Participating patients were 73 ± 9.3 years old with a mean of 2.5 repeated heart failure hospitalizations, ejection fraction (EF) of 31.2% ± 8.7%, BNP of 328.7 ± 282, and New York Heart Association classification of mostly II. No significant changes in systolic blood pressure or pulse rate were observed before and after vericiguat introduction (115 ± 64 vs. 105 ± 52 mmHg and 70 ± 5 vs. 75 ± 12 bpm; P = 0.533 and 0.960, respectively). No significant changes in the mean pulmonary artery pressure and pulmonary artery wedge pressure were also observed before or after drug administration (19 ± 5 vs. 17 ± 10 mmHg and 7 ± 5 vs. 9 ± 3 bpm; P = 0.177 and 0.240 respectively). However, cardiac output was significantly increased and vascular resistance was significantly decreased after vericiguat treatment (4.0 ± 1.0 vs. 4.3 ± 1.1 L/min and 1719 ± 462 vs. 1467 ± 377 dynes·sec·cm-5; P = 0.016 and 0.002, respectively). FMD test results improved significantly after treatment (4.5 ± 5% vs. 8.1± 8%: P = 0.027), with the 6MWD increasing significantly by 42 m (311 ± 100 vs. 353 ± 50 m; P = 0.035). BNP also decreased significantly, whereas eGFR remained unchanged (317 ± 274 vs. 221.5 ± 200 pg/mL and 51.7 ± 21 vs. 51.5 ± 25.3 mL/min/1.73 m 2 ; P = 0.015 and 0.967, respectively). Conclusion: Vericiguat may improve exercise tolerance by improving vascular endothelial function and cardiac output.

Abstract 13795: Reduced Fetuin-A Levels Are Associated With Exercise Intolerance in Patients With Heart Failure and Predict the Risk of Adverse Outcomes

Background: Impaired exercise tolerance is a feature of heart failure (HF) and predicts adverse outcomes in patients with HF. Hepatokines are proteins synthesized and secreted by the liver, which regulate systemic metabolisms of peripheral tissues. However, the clinical impact of hepatokines on exercise capacity has not been well understood. Aims: Our objective was to investigate the relevance of a hepatokine, Fetuin-A, in relation to exercise capacity in HF. Methods and Results: We conducted a prospective study involving 120 consecutive hospitalized patients (mean 57.3 years old, 75.0% male) with HF who underwent cardiopulmonary exercise testing. The serum concentration of Fetuin-A was measured by an enzyme-linked immunosorbent assay. Patients with impaired exercise tolerance (peak oxygen uptake (VO 2 ) &lt; 14.0 mL/kg/m) exhibited lower Fetuin-A levels than those without ( Figure A ). Correlation analysis revealed that Fetuin-A was positively correlated with peak VO 2 and negatively correlated with minute ventilation to carbon dioxide production ratio and its slope. We then followed up patients and found 12 composites of cardiac events that included 5 cardiac death and 7 worsening HF. Based on classification and regression tree to determine the cut-off of Fetuin-A, Kaplan-Meier analysis revealed that patients with lower Fetuin-A levels (&lt; 22.2 ng/mL) and impaired exercise tolerance had the highest risk of cardiac events ( Figure B ). In a multivariable Cox proportional hazard model, the presence of both lower Fetuin-A and exercise intolerance was independently associated with an increased risk of cardiac events (hazard ratio, 18.8; P = 0.009). Conclusions: Reduced Fetuin-A levels were associated with exercise intolerance in patients with HF, and those with decreased levels of both Fetuin-A and peak VO 2 were at the highest risk of adverse outcomes.

Statistical analysis plan for a randomized controlled trial examining pedometer-based walking intervention in patients with heart failure with reduced ejection fraction: the WATCHFUL trial

BackgroundPhysical activity is an effective management strategy for heart failure with reduced ejection fraction, but patients’ compliance is challenging. Walking is a suitable form of physical activity due to its convenience and sustainability, and it can potentially improve functional capacity in heart failure patients.ObjectivesThe WATCHFUL trial aims to determine whether a pedometer-based walking intervention combined with face-to-face sessions and regular telephone contact improves functional capacity in heart failure patients.MethodsThe WATCHFUL trial is a 6-month multicenter, parallel-group, randomized, controlled, superiority trial with a 6-month follow-up. A total of 202 patients were recruited for the trial. The primary analysis will evaluate the change in distance walked during the 6-min walk test from baseline to 6 months based on the intention-to-treat population; the analysis will be performed using a linear mixed-effect model adjusted for baseline values. Missing data will be imputed using multiple imputations, and the impact of missing data will be assessed using a sensitivity analysis. Adverse events are monitored and recorded throughout the trial period.DiscussionThe trial has been designed as a pragmatic trial with a scalable intervention that could be easily translated into routine clinical care. The trial has been affected by the COVID-19 pandemic, which slowed patients’ recruitment and impacted their physical activity patterns.ConclusionsThe present publication provides details of the planned statistical analyses for the WATCHFUL trial to reduce the risks of reporting bias and erroneous data-driven results.Trial registrationClinicalTrials.gov (identifier: NCT03041610, registered: 3/2/2017).

Distinct Impact of Noncardiac Comorbidities on Exercise Capacity and Functional Status in Chronic Heart Failure

BackgroundNoncardiac comorbidities (NCCs) are common in patients with heart failure (HF), but how they jointly affect exercise capacity and functional status is relatively unexplored. ObjectivesThis study sought to investigate the cumulative effects of NCC on exercise capacity and functional status in chronic HF. MethodsBaseline NCC-status was assessed in HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), IRONOUT-HF (Oral Iron Repletion Effects on Oxygen Uptake in Heart Failure), NEAT-HFpEF (Nitrate’s Effect on Activity Tolerance in Heart Failure With Preserved Ejection Fraction), INDIE-HFpEF (Inorganic Nitrite Delivery to Improve Exercise Capacity in HFpEF), and RELAX-HFpEF (Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) trials, and relations with peak Vo2 and 6-minute walk test (6MWT), Kansas City Cardiomyopathy Questionnaire (KCCQ), and all-cause death were determined according to HF type (with reduced vs preserved ejection fraction). Cluster analysis of the different NCCs was performed. ResultsA total of 2,777 patients were evaluated (mean age: 60 ± 13 years; median NCC burden in HF with preserved vs reduced ejection fraction: 3 [IQR: 2-4] vs 2 [IQR: 1-3]; P < 0.001). Obesity played a more important role in HF with preserved ejection fraction in limiting peak Vo2 and 6MWT. There was a progressive decline in peak Vo2, 6MWT, and KCCQ with increasing NCC burden. Cluster analysis revealed 3 NCC clusters: cluster 1: predominance of stroke and cancer; cluster 2: predominance of chronic kidney disease and peripheral vascular disease; and cluster 3: predominance of obesity and diabetes. Patients in cluster 3 had the worst peak Vo2, 6MWT, and KCCQ despite having the lowest N-terminal pro–B-type natriuretic peptide and exhibited diminished response to aerobic exercise training (peak Vo2Pinteraction = 0.045); however, it had similar risk for all-cause death as cluster 1, whereas cluster 2 had higher risk of death than cluster 1 (HR: 1.60 [95% CI: 1.25-2.04]; P < 0.001). ConclusionsNCC type and burden have a significant and cumulative effect on exercise capacity, occur in clusters, and are associated with clinical outcomes in patients with chronic HF.