AIMS:To describe exercise haemodynamics across cardiac damage stages and evaluate the incremental prognostic impact of cardiac damage stage and exercise-induced pulmonary hypertension (exPHT) in patients with symptomatic moderate aortic stenosis (AS) and asymptomatic severe AS. METHODS AND RESULTS:A total of 436 consecutive patients with ≥ moderate AS (74 ± 10 years, 32% women, 56% severe AS) underwent cardiopulmonary exercise testing with echocardiography. The primary endpoint was heart failure (HF) death and HF hospitalizations. Cardiac damage stage was 0 in 93 patients, 1 (LV damage) in 135, 2 (LA/mitral damage) in 135, and 3-4 (pulmonary vasculature/tricuspid or RV damage) in 73. Higher stages were associated with worse exercise capacity and haemodynamics. Over a median follow-up of 37 months, 65 patients met the primary endpoint. After adjustment for age, AS severity, and aortic valve replacement, cardiac damage stage and exPHT were independently associated with HF outcomes [HR per stage increase 1.51 (1.26-1.82); P < 0.001; exPHT HR 2.36 (1.10-5.07); P = 0.03]. exPHT improved risk stratification in early-stage disease (stages 1-2), conferring an approximately five-fold higher risk of HF events in patients with exPHT [HR 4.45 (1.58-12.59); P < 0.01]. CONCLUSION:In patients with ≥ moderate AS and discordant symptoms, cardiac damage stage and exPHT independently refined HF risk stratification. ExPHT provides incremental prognostic value in early damage stages (1-2), representing over half of the cohort, supporting a stepwise approach of routine damage staging with selective with exPHT assessment with exercise echocardiography in this subgroup to guide more personalized management and potentially optimize AVR timing.

Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease characterized by exercise intolerance. Defining pathophysiologically distinct subgroups allows more personalized therapy, but efforts mainly relied on resting examinations. This study aimed to define HFpEF phenotypes based on exercise limitations using combined cardiopulmonary exercise testing with stress echocardiography. Methods A total of 913 patients with HFpEF were recruited from 4 third‐line centers and divided into derivation (n=623) and validation cohorts (n=290). Unsupervised graph‐based clustering of 61 cardiopulmonary exercise testing with stress echocardiography variables was used to identify HFpEF exercise phenotypes. Pathophysiological characteristics, exercise capacity, and clinical outcomes were compared between phenotypes. Results In the derivation cohort, cluster analysis identified 5 distinct HFpEF exercise phenotypes characterized by specific exercise responses: mild diastolic dysfunction (phenotype 1), impaired peripheral oxygen extraction (phenotype 2), right ventricular‐pulmonary artery uncoupling (phenotype 3), reduced left ventricular systolic reserve (phenotype 4), and chronotropic incompetence (phenotype 5). The composite outcome of all‐cause death and unplanned cardiovascular hospitalization differed significantly across phenotypes, with phenotypes 2 (hazard ratio [HR], 1.76 [95% CI, 1.07–2.91]), 4 (HR, 2.15 [95% CI, 1.27–3.65]), and 5 (HR, 2.19 [95% CI, 1.33–3.61]) showing higher rates of the primary combined outcome compared with phenotype 1. All phenotypes were replicated in the validation cohort. Conclusions Deep phenotyping of the exercise response in patients with HFpEF revealed 5 distinct phenogroups with marked differences in pathophysiology, exercise performance, and clinical outcomes. This subclassification may support more personalized therapeutic strategies and improve risk stratification in HFpEF.

INTRODUCTION:Remodelling of the left atrium (LA) and left ventricle (LV) occurs in response to pathological and physiological stimuli, yet their inter-dependence is often overlooked in clinical practice. The left atrioventricular ratio (LA:LV)-the ratio of maximal LA end-systolic volume (LAESV) to LV end-diastolic volume (LVEDV)-may offer valuable context for distinguishing physiological from pathological cardiac remodelling. METHODS AND RESULTS:This study evaluated LA:LV, assessed via echocardiography, and cardiorespiratory fitness assessed as peak oxygen uptake (VO2peak) in a multi-centre international cohort spanning the cardiorespiratory fitness spectrum. Exercise capacity in healthy participants was categorized by VO2 peak quartiles, and cardiac structural differences were analysed. Among 2943 adults (1600 healthy, 1343 pathology), healthy individuals had a median LA:LV of 0.49 [0.38, 0.61], consistent with LVEDV being roughly twice the LAESV. Pathology revealed higher LA:LV ratios [0.53 (0.38-0.75), P < 0.001], with marked elevations amongst AF [0.60 (0.45-0.78)] and HFpEF [0.70 (0.51-0.88)]-a 30% increase vs. healthy adults. The highest indexed LA volumes occurred in the highest VO₂ peak quartile [Q4: 36 (28-46) mL/m²], while the LA:LV ratio was highest in Q1 [0.53 (0.42-0.69)]. Among participants with elevated LAVi (≥34 mL/m²), concordance with elevated LA:LV ratio (≥0.75) varied markedly by fitness level: ∼60% in Q1-Q2 vs. only 7% in Q4, highlighting the importance of fitness context when interpreting LA enlargement. CONCLUSION:The LA:LV ratio effectively discriminates between adaptive and maladaptive atrial remodelling. LA:LV is typically ∼0.5. Lower ratios correlate with higher functional capacity and physiological remodelling, whereas ratios ≥0.75 may indicate pathological remodelling and warrant consideration of atrial pathology.

BACKGROUND AND AIMS:In patients with unexplained dyspnea, heart failure with preserved ejection fraction (HFpEF) is a frequent cause. Diagnostic scores estimate HFpEF probability, but their prognostic role and clinical applicability in this population remain uncertain. This study evaluated the association of HFpEF scores with structural remodeling, functional limitation, and clinical outcomes. METHODS:This multicenter cohort study included 2,535 patients with unexplained dyspnea who underwent combined cardiopulmonary exercise testing and echocardiography. HFpEF probability was assessed using H₂FPEF, HFA-PEFF, and HFpEF-ABA scores, with patients stratified into risk categories. RESULTS:Higher scores correlated with adverse ventricular and atrial remodeling, impaired exercise capacity, and higher pulmonary pressures, both at rest and during exercise. Intermediate and high-risk categories for HFA-PEFF, H₂FPEF, and HFpEF-ABA scores showed significantly elevated hazard ratios versus the low-risk group: HFA-PEFF (HR 2.62 95%CI 1.56-4.40, p<0.001 and 5.49 95%CI 2.82-10.67, p=0.005), H₂FPEF (HR 2.74 95%CI 1.35-5.89, p<0.001 and 6.21 95%CI 2.86-13.5, p<0.001), and HFpEF-ABA (HR 1.28 95%CI 0.57-2.86, p=0.549 and 2.50 95%CI 1.02-6.14, p=0.046), all p<0.001. Event rates increased stepwise across score categories, reaching 10 per 100 patient-years in the high-score groups. Score performance differed, particularly in the elderly, women, and those with atrial fibrillation. Incorporating echocardiographic parameters, particularly resting pulmonary pressure, improved HFpEF-ABA prognostic accuracy. In the NT-proBNP subgroup, functional criteria and NT-proBNP remained independent predictors for outcome. CONCLUSIONS:HFpEF diagnostic scores reflect the structural and functional disease burden as well as clinical risk in unexplained dyspnea. These scores are complementary and may enhance risk stratification.

Exercise intolerance is a clinical hallmark of heart failure with preserved ejection fraction (HFpEF) that confers high morbidity and predicts mortality. The mechanisms underlying exercise intolerance in HFpEF are diverse and often include compound deficits in multi-organ reserve capacity that culminate in marked functional limitations. This review describes aetiologies of exercise intolerance in HFpEF, tools to quantify relative physiologic deficits unmasked during exercise, and insights gained from interventional trials that have aimed to augment exercise capacity in HFpEF. The domain-based phenotyping approach described highlights the value of comprehensive phenotyping of both cardiac and extra-cardiac reserve capacity to advance understanding of how to deploy individualized interventions to bolster exercise tolerance in HFpEF.

AIMS:To develop and externally validate an artificial intelligence (AI)-driven model to predict effort intolerance (i.e., peak oxygen uptake [VO₂] <16 mL/kg/min) in patients at risk or with established heart failure (HF). METHODS:We enrolled a consecutive sample of adults referred for dyspnea or suspected HF. The derivation cohort (Pisa, Italy) included 1,333 participants - 351 with reduced (<50%, HFrEF), 371 with preserved (≥50%, HFpEF) left ventricular ejection fraction (LVEF), and 611 with cardiovascular risk factors and/or structural heart disease without overt HF (Stages A-B); the external validation cohort (Hasselt, Belgium) included 1,101 participants. All participants underwent clinical evaluation, laboratory test, rest echocardiography, and cardiopulmonary exercise testing. RESULTS:A neural network including age, sex, body mass index (BMI), haemoglobin, left ventricular systolic mitral annulus tissue velocity (LV S'), systolic pulmonary artery pressure (sPAP), and β-blocker therapy achieved the best discrimination (AUC 0.86±0.01 in derivation; 0.76±0.06 in validation). A simplified four-variable AI-VO₂ score (BMI, haemoglobin, LV S', sPAP) showed good performance (AUC 0.79±0.05) and independently predicted HF hospitalization or all-cause death (adjusted HR 1.06 per point; 95% CI 1.03-1.10) in the derivation cohort. External validation confirmed the predictive and prognostic performance (AUC 0.73±0.02; unadjusted HR 1.18 per point, 95% CI 1.13-1.24). Score-based risk strata (<10, low; 10-13, intermediate; >13, high) showed a significant prognostic gradient (log-rank χ² = 36.8, p<0.001). CONCLUSION:The AI-VO₂ score is a clinically interpretable, externally validated tool for identifying patients with effort intolerance and adverse outcomes across the HF spectrum, supporting personalized risk stratification and management.

BACKGROUND:Secondary or functional mitral regurgitation (FMR) of atrial origin is prevalent in heart failure with preserved ejection fraction (HFpEF) and portends a worse clinical course. Unlike ventricular FMR, it lacks evidence-based treatment and is often overlooked. Sacubitril-valsartan may provide benefit in this HFpEF phenotype. OBJECTIVE:To assess the impact of sacubitril-valsartan on exercise hemodynamics in patients with HFpEF and atrial FMR. METHODS:This multicenter, prospective, randomized, open-label trial with blinded endpoint assessment enrolls patients with stable HFpEF and at least moderate FMR documented within 1 year prior to enrollment. Participants are randomly assigned to sacubitril-valsartan plus standard medical therapy or to standard therapy alone, consisting of a mineralocorticoid receptor antagonist and a sodium-glucose cotransporter-2 inhibitor. Cardiopulmonary exercise testing with echocardiography is performed at baseline and after 6 months, with interval 24-hour home blood pressure monitoring to ensure blood pressure control in both arms. The primary endpoint is the change in exercise-induced pulmonary hypertension, assessed by the change in the mean pulmonary arterial pressure to cardiac output slope. This slope reflects total pulmonary resistance driven by both pre- and postcapillary factors, capturing key HFpEF features, including myocardial properties, vascular remodeling and the overall impact of (dynamic) atrial FMR. Secondary endpoints include changes in FMR severity, peak oxygen consumption, natriuretic peptide levels, left atrial size and function, and patient-reported outcomes. Prespecified adverse events include hypotension, renal failure, hyperkalemia, and angioedema. CONCLUSION:The PRAISE-MR (Sacubitril-Valsartan in Heart Failure with Preserved Ejection Fraction and Secondary Mitral Valve Regurgitation) trial will evaluate whether sacubitril-valsartan, an angiotensin receptor neprilysin inhibitor, is beneficial in patients with HFpEF and atrial FMR.

Abstract Background Peak oxygen consumption (VO₂) is a prognostic indicator in heart failure (HF), but cardiopulmonary exercise testing (CPET) has limited feasibility. Purpose To develop an AI-driven model to predict effort intolerance (i.e., VO₂<16 mL/kg/min) in patients across HF spectrum. Methods The model was derived in a cohort of 1,333 subjects - 351 with reduced (<50%, HFrEF), 371 with preserved (>50%, HFpEF) left ventricular ejection fraction (LVEF), 611 with cardiovascular risk factors or structural heart disease without HF (Stages A–B) - and externally validated in a cohort of 1,101 subjects. All participants underwent laboratory test, rest echocardiography, CPET. Results A neural network including age, sex, body mass index (BMI), haemoglobin, systolic mitral annulus tissue velocity (S’), systolic pulmonary artery pressure (sPAP), and β-blocker therapy achieved good discrimination (AUC 0.86±0.01 in derivation; 0.76±0.06 in validation). A simplified AI-VO₂ score (BMI, haemoglobin, LV S’, sPAP) showed good performance (AUC 0.79±0.05) and predicted HF hospitalization or all-cause death (adjusted HR 1.06 per point; 95% CI 1.03–1.10) in the derivation cohort. External validation confirmed the performance (AUC 0.73±0.02; unadjusted HR 1.18 per point, 95% CI 1.13–1.24). Conclusion The AI-VO₂ score could identify patients with effort intolerance and adverse outcomes in HF spectrum.AI Vo2 scoreFor image description, please refer to the figure legend and surrounding text.Survival analysisFor image description, please refer to the figure legend and surrounding text.

Abstract Background Exercise-induced pulmonary hypertension, characterized by mean pulmonary artery pressure over cardiac output slope (mPAP/CO slope) > 3mmHg/L/min is associated with worse outcome in greater than moderate primary mitral regurgitation (PMR). However, the prognostic value of right ventricle to pulmonary artery coupling (RVPAc) is unknown. Purpose Assess the prognostic value of RVPAc; determine the additional value of exercise over rest RVPAc and compare these findings to the mPAP/CO slope. Methods The single center study included consecutive patients with greater than moderate PMR, no/discordant symptoms, left ventricular ejection fraction >60% and absence of concomitant valvular disease greater than moderate or permanent atrial fibrillation (AF) referred to simultaneous CPET and exercise echocardiography (CPET-echo). A thorough echocardiographic assessment of right ventricle (RV) systolic function and RVPAc (TAPSE/sPAP, ratio of tricuspid annular plane systolic excursion over systolic pulmonary artery pressure) was performed using a dedicated RV window. mPAP and CO were obtained by Doppler echocardiography. Primary outcome was the composite of cardiovascular mortality, unplanned cardiovascular hospitalization and new AF episodes. Results A total of 159 consecutive patients (64±11 years, 59% men) were included. The event-free survival rate was 84% at 1 year and 78% at 2 years. Patients who fulfilled the primary combined endpoint had significantly larger left atrium indexed volumes (LAVi), lower left atrial strain and strain rate at rest and strain at intermediate exercise, lower absolute and normalized peak oxygen uptake (VO2peak), and a significantly higher mPAP/CO slope. They had significantly lower TAPSE, RV free wall S’ and TAPSE/sPAP. Sequentially adding intermediate or high exercise TAPSE/sPAP and percent-predicted VO2peak to the baseline predictive model (age, LAVi, mitral regurgitation grade and TAPSE/sPAP at rest) significantly improved the area under the curve (AUC) of the baseline logistic regression model (AUC: 0.71 vs. 0.80 and 0.71 vs. 0.81, p<0.05, respectively), with LAVi and TAPSE/sPAP at intermediate or high exercise remaining as significant independent variables (although coupling assessment at high exercise technically less feasible). Replacing exercise TAPSE/sPAP with mPAP/CO yields models with comparable accuracy (Figure 1). Exercise TAPSE/sPAP <0,6 was related to a higher event rate (Figure 2) Conclusion Decreased rest or exercise TAPSE/sPAP are single point measures of RVPAc, associated with adverse outcome in patients with greater than moderate PMR and no or discordant symptoms. Exercise TAPSE/sPAP has independent additional value over rest TAPSE/sPAP in predicting adverse events, with a similar accuracy as mPAP/CO slope. Exercise TAPSE/sPAP represents a potential alternative to mPAP/CO slope in this population, being readily available and simpler to adopt in clinical practice.

OBJECTIVE:Atrial fibrillation (AF) is a common comorbidity in patients with heart failure with preserved ejection fraction (HFpEF) that contributes to increased morbidity and mortality. We sought to evaluate the impact of AF on key HFpEF features, including exercise tolerance (peak oxygen uptake, VO2peak) hemodynamic responses, and peripheral oxygen extraction (a-vO2diff). METHODS:Patients referred to a multidsciplinary clinic for evaluation of unexplained dyspnea and diagnosed with HFpEF after a comprehensive clinical and hemodynamic evaluation were stratified on the basis of whether they were in persistent/permanent AF (AFPersist; n = 86), paroxysmal AF (AFParox; n = 328), or sinus rhythm (SR; n = 274). Cardiopulmonary exercise testing with simultaneous echocardiography was applied to assess the VO2peak, a-vO2diff, and exercise hemodynamics. Groups were compared using analysis of covariance with adjustment for age, sex, body mass index, and the presence of hypertension and diabetes. RESULTS:Compared with patients in SR or with AFParox, patients with HFpEF and AFPersist had a lower VO2peak (1.3-2.4 mL/kg/min lower, P < .001). This coincided with lower peak exercise cardiac output (CO, 0.6-1.2 L/min lower), secondary to a lesser stroke volume (14-17 mL lower, P < .001), and a smaller left ventricular end-diastolic volume (15-18 mL lower, P < .001) that tended to decrease during exercise. In contrast, there was no impact of AF status on peak exercise a-vO2diff, mean pulmonary artery pressure or the mean pulmonary artery pressure/CO slope. CONCLUSIONS:Patients with HFpEF and AFPersist have a lower VO2peak secondary to decreased CO, SV, and reduced end-diastolic volume reserve. Rhythm control strategies may therefore be pivotal in optimizing exercise performance and clinical outcomes in patients with HFpEF and AF.

Background The impact of pulmonary vein isolation (PVI) using pulsed field ablation (PFA) on left atrial (LA) function remains incompletely understood. Objective To compare the effects of PVI performed with PFA vs radiofrequency ablation (RFA) on LA mechanical function in patients with paroxysmal atrial fibrillation (PAF), using serial echocardiographic strain analysis. Methods In this prospective, single-center study, patients undergoing a first-time PVI for PAF with either RFA or PFA were included. All participants underwent transthoracic echocardiography with 2-dimensional speckle tracking analysis at 3 time points: at baseline (immediately before ablation), in the acute phase (immediately after ablation), and in the chronic phase (3 months post-ablation). LA reservoir strain (LASr) and LA contraction strain (LASct) were assessed as primary parameters of LA mechanical function. Results A total of 59 patients were analyzed (RFA: 28; PFA: 31). In the PFA group, LASr and LASct decreased significantly in the acute phase (LASr: 26.5 ± 5.8% to 22.9 ± 6.6%, P = .010; LASct: 12.2 ± 3.6% to 8.6 ± 3.1%, P < .001). At 3-month follow-up, LASr had recovered to baseline levels (25.8 ± 7.9%, P = .531), while LASct remained significantly reduced (10.9 ± 4.3%, P = .031). In contrast, no significant changes in LASr or LASct were observed in the RFA group at any time point. Conclusion PVI using PFA is associated with acute LA stunning, with persistent impairment in contractile function at 3 months despite recovery of reservoir function. These findings suggest subtle, lasting alterations in atrial mechanics not observed with RFA.