Lower heart rate in patients with acute heart failure: the role of left ventricular ejection fraction.

BACKGROUND: The clinical impact of heart rate (HR) in heart failure with preserved ejection fraction (HFpEF) is a matter of debate. Among those with HFpEF, chronotropic incompetence (CI) has emerged as a pathophysiological mechanism linked to the severity of the disease. In this study, we sought to evaluate whether admission heart rate in acute heart failure differs along left ventricular ejection fraction (LVEF). METHODS: We included retrospectively 3,712 consecutive patients admitted for acute heart failure (AHF) in the Cardiology department of a third level center. HR values were assessed at presentation. LVEF was assessed by transthoracic echocardiogram during the index admission and stratified into four categories: reduced ejection fraction (≤40%), mildly reduced ejection fraction (41-49%), preserved ejection fraction (50-64%) and supranormal ejection fraction (≥65%). The association between HR and LVEF was assessed by multivariate linear and multinomial regression analyses. RESULTS: The mean age of the sample was 73,9 ± 11.3 years, 1,734 (47,4%) were women, and 1,214 (33,2%), 570 (15,6%), 1,229 (33,6%) and 648 (17,7%) patients showed LVEF ≤40%, 41-49%, 50-64%, and ≥65% respectively. The median HR at admission was 95 (IQR 78-120) beats per minute and 1,653 were on atrial fibrillation (45.2%). There was an inverse relationship between HR at admission and LVEF. Lower HR was significantly associated with a higher LVEF in the whole sample (p < 0,001). This inverse relationship was found in sinus rhythm but not in patients with atrial fibrillation. CONCLUSION: HR at admission for AHF is a predictor of LVEF but only in patients with sinus rhythm.

Short-term Changes in Hemoglobin and Changes in Functional Status, Quality of Life and Natriuretic Peptides After Initiation of Dapagliflozin in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: We aimed to evaluate the effect of dapagliflozin on short-term changes in hemoglobin in patients with stable heart failure with reduced ejection fraction (HFrEF) and whether these changes mediated the effect of dapagliflozin on functional capacity, quality of life and NT-proBNP levels. METHODS: This is an exploratory analysis of a randomized, double-blinded clinical trial in which 90 stable patients with HFrEF were randomly allocated to dapagliflozin or placebo to evaluate short-term changes in peak oxygen consumption (peak VO2) (NCT04197635). This substudy evaluated 1- and 3-month changes in hemoglobin levels and whether these changes mediated the effects of dapagliflozin on peak VO2, Minnesota Living-With-Heart-Failure test (MLHFQ) and NT-proBNP levels. RESULTS: At baseline, mean hemoglobin levels were 14.3 ± 1.7 g/dL. Hemoglobin levels significantly increased in those taking dapagliflozin (1 month: + 0.45 g/dL (P = 0.037) and 3 months:+ 0.55 g/dL (P = 0.012)]. Changes in hemoglobin levels positively mediated the changes in peak VO2 at 3 months (59.5%; P < 0.001). Changes in hemoglobin levels significantly mediated the effect of dapagliflozin in the MLHFQ at 3 months (-53.2% and -48.7%; P = 0.017) and NT-proBNP levels at 1 and 3 months (-68.0%; P = 0.048 and -62.7%; P = 0.029, respectively). CONCLUSIONS: In patients with stable HFrEF, dapagliflozin caused a short-term increase in hemoglobin levels, identifying patients with greater improvements in maximal functional capacity, quality of life and reduction of NT-proBNP levels.

Sex Effect in the Decision to Perform Invasive Coronary Angiography in Patients With Chronic Coronary Syndrome After Undergoing Vasodilator Stress MRI.

BACKGROUND: Stress cardiac MRI permits comprehensive evaluation of patients with known or suspected chronic coronary syndromes (CCS). The impact of sex on the use of invasive cardiac angiography (ICA) after vasodilator stress cardiac MRI is unclear. PURPOSE: To evaluate the impact of sex on ICA use after vasodilator stress cardiac MRI. STUDY TYPE: Retrospective. POPULATION: A total of 6229 consecutive patients (age [mean ± standard deviation] 65.2 ± 11.5 years, 38.1% women). FIELD STRENGTH/SEQUENCE: A 5-T; a steady-state free-precession cine sequence; stress first-pass perfusion imaging; late enhancement imaging. ASSESSMENT: Patients underwent vasodilator stress cardiac MRI for known or suspected CCS. The ischemic burden (at stress first-pass perfusion imaging) was computed (17-segment model). STATISTICAL TESTS: Multivariate logistic regression was used to evaluate the potential differential association between ischemic burden and use of cardiac MRI-related ICA across sex. RESULTS: A total of 1109 (17.8%) patients were referred to ICA, among which there were significantly more men (762, 19.7%) than women (347, 14.6%). Overall, after multivariate adjustment, female sex was not associated with lower use of ICA (odds ratio [OR] = 0.99; confidence interval [CI] 95%: 0.84-1.18, P = 0.934). However, significant sex differences were detected across ischemic burden. Whereas women with nonischemic vasodilator stress cardiac MRI (0 ischemic segments) were less commonly submitted to ICA (OR = 0.49; CI 95%: 0.35-0.69) in patients with ischemia (>1 ischemic segment), adjusted use of ICA was more frequent in women than men (OR = 1.27; CI 95%: 1.1-1.5). DATA CONCLUSIONS: In patients with known or suspected CCS submitted to undergo vasodilator stress cardiac MRI, cardiac MRI-related ICA may be overused in men without ischemia. Furthermore, ICA referral in patients with negative ischemia resulted in greater odds of revascularization in men. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 5.

Right Heart Dysfunction and Readmission Risk Across Left Ventricular Ejection Fraction Status in Patients With Acute Heart Failure.

BACKGROUND: Right heart dysfunction (RHD) parameters are increasingly important in heart failure (HF). This study aimed to evaluate the association of advanced RHD with the risk of recurrent admissions across the spectrum of left ventricular ejection fraction (LVEF). METHODS AND RESULTS: We included 3383 consecutive patients discharged for acute HF. Of them, in 1435 patients (42.4%), the pulmonary artery systolic pressure could not be measured accurately, leaving a final sample size of 1948 patients. Advanced RHD was defined as the combination of a ratio of tricuspid annular plane systolic excursion/pulmonary artery systolic pressure of less than 0.36 and significant tricuspid regurgitation (n = 196, 10.2%). Negative binomial regression analyses were used to evaluate the risk of recurrent admissions. At a median follow-up of 2.2 years (interquartile range 0.63-4.71), 3782 readmissions were registered in 1296 patients (66.5%). Patients with advanced RHD showed higher readmission rates, but only if the LVEF was 40% or greater (P < .001). In multivariable analyses, this differential association persisted for cardiovascular and HF recurrent admissions (P value for interaction = .015 and P = .016; respectively). Advanced RHD was independently associated with the risk of recurrent cardiovascular and HF admissions if HF with an LVEF of 40% or greater (incidence rate ratio 1.64, 95% confidence interval 1.18-2.26, P = .003; and incidence rate ratio 1.73; 95% confidence interval 1.25-2.41, P = .001;respectively). In contrast, it was not associated with readmission risks if the LVEF was less than 40%. CONCLUSIONS: After an admission for acute HF, advanced RHD was strongly associated with a higher risk of recurrent cardiovascular and HF admissions, but only in patients with an LVEF of 40% or greater.

Matrix metalloproteinase-12 cleaved fragment of titin as a predictor of functional capacity in patients with heart failure and preserved ejection fraction.

OBJECTIVES: Serum levels of matrix metalloproteinase-12 cleaved fragment of titin (TIM), a novel circulatory biomarker specific for cardiac titin degradation, has emerged as a potential biomarker in cardiovascular diseases. In this work, we aimed to evaluate the association between TIM and maximal functional capacity assessed by the percentage of predicted peak exercise oxygen uptake (pp-peakVO2) in patients with heart failure and preserved ejection fraction (HFpEF). Design. In this post-hoc study, we included 46 stable symptomatic (New York Heart Association II-III) HFpEF patients enrolled in the TRAINING-HF study (NCT02638961). pp-peak-VO2 was calculated from baseline values. Baseline circulating levels of TIM were measured by competitive ELISA in serum from the TRAINING-HF patients. The independent association between TIM and pp-peakVO2 was evaluated by multivariate linear regression analysis. Results. The mean age of the sample was 73.8 ± 8.7 years, 56.5% were females, and 76.1% were on NYHA II. The medians of pp-peakVO2 and TIM were 60.9% (50.4-69.3), and 130.1 ng/mL (98.1-159.5), respectively. The median of NT-proBNP was 912 pg/mL (302-1826). pp-peakVO2 was significant and inversely correlated with TIM (r= -41, p = .005). In multivariate analysis, after adjusting for NYHA class, hypertension, body mass index, and glomerular filtration rate, higher TIM was significantly associated with lower pp-peak VO2 (p = .029). Conclusions. In this sample of stable and symptomatic HFpEF patients, higher serum levels of TIM identified patients with worse functional status.

Inspiratory Muscle Function and Exercise Capacity in Patients With Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by impaired exercise capacity resulting from dyspnea and fatigue. The pathophysiological mechanisms underlying the exercise intolerance in HFpEF are not well established. We sought to evaluate the effects of inspiratory muscle function on exercise tolerance in symptomatic patients with HFpEF. METHODS AND RESULTS: A total of 74 stable symptomatic patients with HFpEF and New York Heart Association class II-III underwent a cardiopulmonary exercise test between June 2012 and May 2016. Inspiratory muscle weakness was defined as maximum inspiratory pressure (MIP) <70% of normal predicted values. Pearson correlation coefficient and multivariate linear regression analysis were used to assess the association between percent of predicted MIP (pp-MIP) and maximal exercise capacity [measured by peak oxygen uptake (peak VO2) and percent of predicted peak VO2 (pp-peak VO2)]. Thirty-one patients (42%) displayed inspiratory muscle weakness. Mean (standard deviation) age was 72.5 ± 9.1 years, 53% were women, and 35.1% displayed New York Heart Association class III. Mean peak VO2 and pp-peak VO2 were 10 ± 2.8 mL•min•kg and 57.3 ± 13.8%, respectively. The median (interquartile range) of pp-MIP was 72% (58%-90%). pp-MIP was not correlated with peak VO2 (r = -0.047, P = .689) nor pp-peak VO2 (r = -0.078, P = .509). Furthermore, in multivariable analysis, pp-MIP showed no association with peak VO2 (ß coefficient = 0.01, 95% confidence interval -0.01 to 0.03, P = .241) and pp-peak VO2 (ß coefficient = -0.00, 95% confidence interval -0.10 to 0.10, P = .975). CONCLUSIONS: In symptomatic elderly patients with HFpEF, we found that pp-MIP was not associated with either peak VO2 or pp-peak VO2.

Unraveling the Mechanisms Behind Exercise Intolerance and Recovery in Long COVID.

BACKGROUND: Patients suffering from long COVID may exhibit autonomic dysregulation. However, the association between autonomic dysregulation and exercise intolerance and the impact of therapeutic interventions on its modulation remains unclear. This study investigated the relationship between heart rate recovery at the first minute (HRR1), a proxy for autonomic imbalance, and exercise intolerance in patients with long COVID. Additionally, the study aimed to assess the effects of a 12-week home-based inspiratory muscle training program on autonomic modulation in this patient population. METHODS: This study is a post hoc subanalysis of a randomized trial in which 26 patients with long COVID were randomly assigned to receive either a 12-week inspiratory muscle training program or usual care alone (NCT05279430). The data were analyzed using Pearson's correlation and linear mixed regression analysis. RESULTS: The mean age was 50.4 ± 12.2 years, and 11 (42.3%) were women. Baseline HRR1 was significantly correlated with maximal functional capacity (peakVO2) (r = 0.402, P = .041). Patients with lower baseline HRR1 (≤22 bpm) exhibited higher resting heart rates and lower peakVO2. Inspiratory muscle training led to a more substantial increase in peakVO2 in patients with lower HRR1 at baseline (P = .019). Additionally, a significant improvement in HRR1 was observed in the IMT group compared to the usual care group after 12-week (Δ +9.39, 95% CI = 2.4-16.4, P = .010). CONCLUSION: Lower baseline HRR1 is associated with exercise intolerance in long COVID patients and may serve as a valuable criterion for identifying individuals likely to benefit more from a home-based inspiratory muscle training program.

Exercise training response according to baseline ferrokinetics in heart failure with preserved ejection fraction: A substudy of the TRAINING-HF trial.

BACKGROUND: Iron deficiency (ID) is associated with impaired functional capacity in patients with heart failure (HF), even in those with preserved ejection fraction (HFpEF). This study aimed to evaluate the effect of baseline ferrokinetics on peak oxygen consumption (peakVO2) improvement after a 12-week physical therapy programme in patients with stable HFpEF. METHODS: This study is a post-hoc sub-analysis of a randomized clinical trial in which 59 stable patients with HFpEF were randomized to receive a 12-week programme of inspiratory muscle training (IMT), functional electrical stimulation (FES), IMT + FES or usual care (UC) to evaluate change in peakVO2 (NCT02638961). Serum ferritin and transferrin saturation (TSAT) determinations were assessed at baseline. ID was defined as ferritin <100 ng/mL and/or TSAT <20% if ferritin was within 100-299 ng/mL. We used a linear mixed regression model to analyse between-treatment changes in peakVO2 across ferrokinetics status at 12 and 24 weeks. RESULTS: The mean age was 74 ± 9 years, and 36 (61%) had ID. The mean of peakVO2 was 9.9 ± 2.5 mL/kg/min. The median of ferritin and transferrin saturation (TSAT) was 91 (50-181) ng/mL and 23% (16-30), respectively. A total of 52 patients completed the trial (13 patients per arm). Compared with those patients on UC, patients allocated to any of the active arms showed less improvement in peak VO2 when they showed ID (P-value for interaction <0.001), lower values of ferritin (P-value for interaction <0.001), or TSAT (P-value for interaction <0.001). CONCLUSIONS: Ferrokinetics status plays an essential role in modifying the aerobic capacity response to physical therapies in patients with HFpEF. Further studies are required to confirm these findings.

Effect of paced heart rate on quality of life and natriuretic peptides for stage B or C heart failure with preserved ejection fraction: A secondary analysis of the myPACE trial.

AIM: Emerging evidence suggests a beneficial effect of higher heart rates in some patients with heart failure with preserved ejection fraction (HFpEF). This study aimed to evaluate the impact of higher backup pacing rates in HFpEF patients with preexisting pacemaker systems that limit pacemaker-mediated dyssynchrony across left ventricular (LV) volumes and LV ejection fraction (LVEF). METHODS AND RESULTS: This is a post-hoc analysis of the myPACE clinical trial that evaluated the effects of personalized accelerated pacing setting (myPACE) versus standard of care on changes in Minnesota Living with Heart Failure Questionnaire (MLHFQ) score, N-terminal pro-brain natriuretic peptide (NT-proBNP), pacemaker-detected activity levels, and atrial fibrillation (AF) burden in patients with HFpEF with preexisting pacemakers. Between-treatment comparisons were performed using linear regression models adjusting for the baseline value of the exposure (ANCOVA design). This study included 93 patients with pre-trial transthoracic echocardiograms available (usual care n = 49; myPACE n = 44). NT-proBNP levels and MLHFQ scores improved in a higher magnitude in the myPACE group at lower indexed LV end-diastolic volumes (iLVEDV) (NT-proBNP-iLVEDV interaction p = 0.006; MLHFQ-iLVEDV interaction p = 0.068). In addition, personalized accelerated pacing led to improved changes in activity levels and NT-proBNP, especially at higher LVEF (activity levels-LVEF interaction p = 0.009; NT-proBNP-LVEF interaction p = 0.058). No evidence of heterogeneity was found across LV volumes or LVEF for pacemaker-detected AF burden. CONCLUSIONS: In the post-hoc analysis of the myPACE trial, we observed that the benefits of a personalized accelerated backup pacing on MLHFQ score, NT-proBNP, and pacemaker-detected activity levels appear to be more pronounced in patients with smaller iLVEDV and higher LVEF.

Noncardiovascular morbidity and mortality across left ventricular ejection fraction categories following hospitalization for heart failure.

INTRODUCTION AND OBJECTIVES: Noncardiovascular events represent a significant proportion of the morbidity and mortality burden in patients with heart failure (HF). However, the risk of these events appears to differ by left ventricular ejection fraction (LVEF) status. In this study, we sought to evaluate the risk of noncardiovascular death and recurrent noncardiovascular readmission by LVEF status following an admission for acute HF. METHODS: We retrospectively assessed a cohort of 4595 patients discharged after acute HF in a multicenter registry. We evaluated LVEF as a continuum, stratified in 4 categories (LVEF ≤ 40%, 41%-49%, 50%-59%, and ≥ 60%). Study endpoints were the risks of noncardiovascular mortality and recurrent noncardiovascular admissions during follow-up. RESULTS: At a median follow-up of 2.2 [interquartile range, 0.76-4.8] years, we registered 646 noncardiovascular deaths and 4014 noncardiovascular readmissions. After multivariable adjustment including cardiovascular events as a competing event, LVEF status was associated with the risk of noncardiovascular mortality and recurrent noncardiovascular admissions. When compared with patients with LVEF ≤ 40%, those with LVEF 51%-59%, and especially those with LVEF ≥ 60%, were at higher risk of noncardiovascular mortality (HR, 1.31; 95%CI, 1.02-1,68; P=.032; and HR, 1.47; 95%CI, 1.15-1.86; P=.002; respectively), and at higher risk of recurrent noncardiovascular admissions (IRR, 1.17; 95%CI, 1.02-1.35; P=.024; and IRR, 1.26; 95%CI, 1.11-1.45; P=.001; respectively). CONCLUSIONS: Following an admission for HF, LVEF status was directly associated with the risk of noncardiovascular morbidity and mortality. Patients with HFpEF were at higher risk of noncardiovascular death and total noncardiovascular readmissions, especially those with LVEF ≥ 60%.

ß-Blocker Withdrawal and Functional Capacity Improvement in Patients With Heart Failure With Preserved Ejection Fraction.

Importance: Increasing the patient's heart rate (HR) has emerged as a therapeutic option in patients with heart failure with preserved ejection fraction (HFpEF). However, the evidence is conflicting, and the profile of patients who benefit most from this strategy remains unclear. Objective: To assess the association of ß-blocker treatment withdrawal with changes in the percentage of predicted peak oxygen consumption (VO2) across indexed left ventricular diastolic (iLVEDV) and indexed left ventricular systolic volumes (iLVESV), and left ventricular ejection fraction (LVEF) in patients with HFpEF and chronotropic incompetence. Design, Setting, and Participants: This post hoc analysis was conducted using data from the investigator-blinded multicenter, randomized, and crossover clinical trial, PRESERVE-HR, that took place from October 1, 2018, through December 31, 2020, to investigate the short-term effects (2 weeks) of ß-blocker withdrawal on peak oxygen consumption (peak VO2). Patients with stable HFpEF (New York Heart Association functional class II to III) receiving treatment with ß-blocker and chronotropic incompetence were included. Intervention: Participants in the PRESERVE-HR trial were randomized to withdraw vs continue with ß-blocker treatment. After 2 weeks, they were crossed over to receive the opposite intervention. This crossover randomized clinical trial examined the short-term effect of ß-blocker withdrawal on peak VO2. Main Outcomes and Measures: The primary outcome was to evaluate the association between ß-blocker withdrawal and short-term changes in percentage of peak VO2 across iLVEDV, iLVESV, and LVEF in patients with HFpEF and chronotropic incompetence treated with ß-blocker. Results: A total of 52 patients (mean age, 73 [SD, 13] years; 60% female) were randomized. The mean resting HR, peak HR, peak VO2, and percentage of peak VO2 were 65 (SD, 9) beats per minute (bpm), 97 (SD, 15) bpm, 12.4 (SD, 2.9) mL/kg per minute, and 72.4% (SD, 17.7%), respectively. The medians (minimum-maximum) of iLVEDV, iLVESV, and LVEF were 44 mL/m2 (IQR, 19-82), 15 mL/m2 (IQR, 7-32), and 64% (IQR, 52%-78%), respectively. After stopping ß-blocker treatment, the median increase in peak HR was plus 30 bpm (95% CI, 25-35; P < .001). ß-Blocker cessation was differentially associated with change of percentage of peak VO2 across the continuum of iLVESV (P for interaction = .02), indicating a greater benefit in those with lower iLVESV. Conclusions and Relevance: In this study, results showed that in patients with HFpEF and chronotropic incompetence receiving treatment with ß-blocker, lower iLVESV may identify those with a greater short-term improvement in maximal functional capacity after stopping ß-blocker treatment. Further studies are warranted for further investigation. Trial Registration: ClinicalTrials.gov (NCT03871803).

High-sensitivity C-reactive protein and risk of clinical outcomes in patients with acute heart failure.

Inflammation is relevant in the pathogenesis and progression of heart failure (HF). Previous studies have shown that elevated high-sensitivity C-reactive protein (hsCRP) are associated with greater severity and may be associated with adverse outcomes. In this study, we sought to evaluate the prognostic role of hsCRP in a non-selected cohort of patients with acute HF. We prospectively included a multicenter cohort of 3,395 patients following an admission for acute HF. HsCRP levels were evaluated during the first 24 h following admission. Study endpoints were the risks of all-cause mortality, CV-mortality, and total HF readmissions. The mean age was 74.2 ± 11.2 years and 1,826 (53.8%) showed a left ventricular ejection fraction (LVEF) ≥ 50%. Median hsCRP was 12.9 mg/L (5.4-30 mg/L). Over a median follow-up of 1.8 (0.6-4.1) years, 1,574 (46.4%) patients died, and 1,341 (39.5%) patients were readmitted for worsening HF. After multivariable adjustment, hsCRP values were significantly and positively associated with a higher risk of all-cause and CV mortality (p = 0.003 and p = 0.001, respectively), as well as a higher risk of recurrent HF admissions (p < 0.001). These results remained consistent across important subgroups, such as LVEF, sex, age, or renal function. In patients with acute HF, hsCRP levels were independently associated with an increased risk of long-term death and total HF readmissions.

Being fit in the COVID-19 era and future epidemics prevention: Importance of cardiopulmonary exercise test in fitness evaluation.

Endurance and resistance physical activity have been shown to stimulate the production of immunoglobulins and boost the levels of anti-inflammatory cytokines, natural killer cells, and neutrophils in the bloodstream, thereby strengthening the ability of the innate immune system to protect against diseases and infections. Coronavirus disease 19 (COVID-19) greatly impacted people's cardiorespiratory fitness (CRF) and health worldwide. Cardiopulmonary exercise testing (CPET) remains valuable in assessing physical condition, predicting illness severity, and guiding interventions and treatments. In this narrative review, we summarize the connections and impact of COVID-19 on CRF levels and its implications on the disease's progression, prognosis, and mortality. We also emphasize the significant contribution of CPET in both clinical evaluations of recovering COVID-19 patients and scientific investigations focused on comprehending the enduring health consequences of SARS-CoV-2 infection.

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.

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

AIMS: 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. METHODS AND RESULTS: 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). CONCLUSIONS: 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.

Effect of exercise training in patients with chronotropic incompetence and heart failure with preserved ejection fraction: Training-HR study protocol.

BACKGROUND: Chronotropic incompetence (ChI) is linked with diminished exercise capacity in heart failure with preserved ejection fraction (HFpEF). Although exercise training has shown potential for improving functional capacity, the exercise modality associated with greater functional and chronotropic response (ChR) is not well-known. Additionally, how the ChR from different exercise modalities mediates functional improvement remains to be determined. This study aimed to evaluate the effect of three different exercise programs over current guideline recommendations on peak oxygen consumption (peakVO2) in patients with ChI HFpEF phenotype. METHODS AND RESULTS: In this randomized clinical trial, 80 stable symptomatic patients with HFpEF and ChI (NYHA class II-III/IV) are randomized (1:1:1:1) to receive: a) a 12-week program of supervised aerobic training (AT), b) AT and low to moderate-intensity strength training, c)AT and moderate to high-intensity strength training, or d) guideline-based physical activity and exercise recommendations. The primary endpoint is 12-week changes in peakVO2. The secondary endpoints are 12-week changes in ChR, 12-week changes in quality of life, and how ChR changes mediate changes in peakVO2. A mixed-effects model for repeated measures will be used to compare endpoint changes. The mean age is 75.1 ± 7.2 years, and most patients are women (57.5 %) in New York Heart Association functional class II (68.7 %). The mean peakVO2, percent of predicted peakVO2, and ChR are 11.8 ± 2.6 mL/kg/min, 67.2 ± 14.7 %, and 0.39 ± 0.16, respectively. No significant baseline clinical differences between arms are found. CONCLUSIONS: Training-HR will evaluate the effects of different exercise-based therapies on peakVO2, ChR, and quality of life in patients with ChI HFpEF phenotype. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT05649787).

Differential sex-related effect of left ventricular ejection fraction trajectory on the risk of mortality and heart failure readmission following hospitalization for acute heart failure: A longitudinal study.

AIMS: There is limited information on the sex-specific longitudinal changes of left ventricular ejection fraction (LVEF) after an acute heart failure (AHF) hospitalization. We aimed to investigate whether LVEF trajectories over time and their impact on mortality and AHF readmission rates differ between men and women. METHODS AND RESULTS: We conducted a retrospective sex-specific analysis of longitudinal LVEF measurements (n = 9581) in 3383 patients with an index hospitalization for AHF in a single tertiary-level hospital. Statistical techniques suited for longitudinal data analysis were used. The mean age of the sample was 73.8 ± 11.2 years, and 47.9% were women. The mean LVEF was 49.4 ± 15.3%. At a median follow-up of 2.58 years (interquartile range 0.77-5.62), we registered 2197 deaths (64.9%) and 2597 AHF readmissions in 1302 (38.5%) patients. The longitudinal analysis showed that women had consistently higher LVEF values throughout the follow-up with both trajectories characterized by an early peak-approximately at 1 year-followed by decreasing values in men but a plateau in women. Multivariate between-sex comparisons across LVEF categories revealed that women had lower rates of AHF readmissions when LVEF ≤40%. On the contrary, women displayed an excess risk of AHF readmissions when LVEF >60%. A trend in the same direction was found for cardiovascular and all-cause mortality. CONCLUSION: Sex was a significant factor in determining the follow-up trajectory of LVEF and predicting differences in outcomes after an AHF admission. The findings suggest that women have a higher risk of AHF readmissions at higher LVEF values, while men have a higher risk at lower LVEF values. For all-cause and cardiovascular mortality, the same direction of the association was inferred but they were not significant.

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

Background: 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. Methods: 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 (<60 ml/min/1.73 m2 versus ≥60 ml/min/1.73 m2). Results: The mean age of the sample was 73.2 ± 10.5 years and 56.4% were female. The median of peak VO2 was 11.0 ml/kg/min (interquartile range 9.0-13.0). A total of 67 (50.4%) patients had an eGFR <60 ml/min/1.73 m2. 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 ≥60 ml/min/1.73 m2, higher NT-proBNP identified patients with poorer maximal functional capacity. In individuals with eGFR <60 ml/min/1.73 m2, NT-proBNP was not significantly associated with peak VO2 [ß = 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). Conclusions: 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.

A model-driven transformation approach for the modelling of processes in clinical practice guidelines.

Clinical Practice Guidelines (CPGs) include recommendations aimed at optimising patient care, informed by a review of the available clinical evidence. To achieve their potential benefits, CPG should be readily available at the point of care. This can be done by translating CPG recommendations into one of the languages for Computer-Interpretable Guidelines (CIGs). This is a difficult task for which the collaboration of clinical and technical staff is crucial. However, in general CIG languages are not accessible to non-technical staff. We propose to support the modelling of CPG processes (and hence the authoring of CIGs) based on a transformation, from a preliminary specification in a more accessible language into an implementation in a CIG language. In this paper, we approach this transformation following the Model-Driven Development (MDD) paradigm, in which models and transformations are key elements for software development. To demonstrate the approach, we implemented and tested an algorithm for the transformation from the BPMN language for business processes to the PROforma CIG language. This implementation uses transformations defined in the ATLAS Transformation Language. Additionally, we conducted a small experiment to assess the hypothesis that a language such as BPMN can facilitate the modelling of CPG processes by clinical and technical staff.