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Introduction: Heart failure (HF) with preserved ejection fraction (HFpEF) is now the predominant HF subtype, largely driven by the syndemic of physical inactivity and overweight/obesity in an aging population. Deranged skeletal muscle energetics and regional ectopic adipose depots are key cardiometabolic pathways in the pathogenesis of HFpEF, both of which may be favorably modified by 1-2 hours/week of resistance exercise (RE). However, its association with HFpEF risk has not been thoroughly examined. We investigated the association between midlife RE behaviors and incident HFpEF in the Atherosclerosis Risk in Communities (ARIC) study. Hypothesis: Participation in RE at midlife is inversely associated with the risk of incident HFpEF. Methods: Our exposure (RE)—including weightlifting and bodyweight resistance exercises—was assessed using the validated Baecke questionnaire and reported weekly RE duration was averaged across Visits 1 and 3 (1987-1995). We dichotomized averaged RE as 0 hr/wk (‘No RE’, reference) and >0 hr/wk (‘Any RE’). Our outcome (incident HFpEF) was identified through committee-adjudicated HF hospitalizations (January 1, 2005 to December 31, 2023) using medical chart abstraction. Participants with prevalent HF, death, or loss to follow-up before January 1, 2005 were excluded. We constructed Cox regression models to evaluate the association between midlife RE and incident HFpEF. Model 1 adjusted for age, sex, race, field center, education, smoking status, alcohol consumption, and non-RE physical activity. Given that adiposity may lie on the causal pathway, waist-height ratio (WHtR; both measured in cm) was added in Model 2. Results: 10,751 Black and White participants (803 incident HFpEF cases) were analyzed over a median follow-up time of 14.4 years (mean±SD Visit 1 age, 53.3±5.6 years; average Visit 1 and 3 WHtR, 0.58±0.08; 24.7% Black; 57.4% female). 1,217 participants (11.3%) reported engaging in RE at Visits 1 and/or 3, with a median duration of 0.84 hr/wk (IQR, 0.50-1.61). Compared to No RE, the fully adjusted hazard ratio (HR) for Model 1 for Any RE was: 0.78 (95% CI, 0.61-1.00, P = 0.05). The association was attenuated after adjustment for WHtR: HR = 0.84 (0.65-1.07, P = 0.16). Conclusion: Participation in RE at midlife is associated with a 22% lower risk of incident HFpEF. To inform public health and clinical guidelines, further studies are needed to clarify the role of RE in HFpEF prevention.

Abstract Aims Chronic kidney disease (CKD) is common in patients with heart failure (HF) with preserved ejection fraction (HFpEF), and its presence is associated with more severe echocardiographic abnormalities and poorer outcomes through unclear mechanisms. CKD-associated endothelial dysfunction, inflammation, and activation of profibrotic pathways could worsen pulmonary vascular disease (PVD) in HFpEF, but such relationships have not been explored. Methods Consecutively evaluated patients with HFpEF undergoing invasive haemodynamic cardiopulmonary exercise testing were stratified by baseline kidney function to characterize potential differences in pulmonary vascular loading, haemodynamics, cardiopulmonary reserve, and outcomes based upon the presence and severity of kidney dysfunction. Results Of 925 patients with HFpEF, 319 (34.5%) had estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2. Patients with more severe kidney dysfunction were older and more likely to have diabetes, atrial fibrillation, and hypertension. At rest, reduced kidney function was associated with lower haemoglobin, higher biventricular filling pressures, and lower cardiac output, but the severity of kidney dysfunction was most conspicuously associated with worsening PVD, evidenced by increasing pulmonary arterial (PA) pressures due to marked increases in pulmonary vascular resistance (PVR) as kidney dysfunction progressed (median [IQR] 1.3 [0.86, 1.88] to 2.8 [2.0, 3.8] WU from eGFR ≥ 90 to eGFR < 30, P < .001), along with progressively lower PA compliance (PAC, 4.7 [3.6, 5.8] to 2.2 [1.8, 3.4] ml/mmHg from eGFR ≥ 90 to eGFR < 30, P < .001). With exercise, differences in the severity of PVD became even more striking, with more severe elevation in PA pressures and PVR, and lower PA compliance, leading to lower transmural left-sided distending pressures, with no difference in exertional PA wedge pressure. Patients with worse kidney dysfunction displayed the most dramatic cardiac output limitations with exercise, which along with more severe anaemia and markedly reduced O2 delivery, caused marked impairment in aerobic capacity. Worsening kidney function was associated with a striking gradient of increased risk of a composite of all-cause death and HF hospitalization [ranging from HR 2.38 (95% CI 1.01–5.59) for eGFR 60–90 to HR 16.77 (95% CI 6.65–42.28) for eGFR < 30 (vs. reference eGFR ≥ 90)]. Conclusions Kidney dysfunction in patients with HFpEF is characterized by more severe PVD at rest and with exercise, leading to reduced cardiac output reserve, impaired exercise capacity, and increased risk for adverse events. Further study is warranted to better understand causal relationships between CKD and PVD, and determine whether novel therapies to improve kidney function might target these impairments to improve clinical status.

BACKGROUND: The metabolic mechanisms underlying right ventricular (RV) dysfunction are poorly understood, particularly outside of group 1 pulmonary hypertension (PH). We aimed to identify metabolites and pathways associated with RV systolic function and explored whether associations differed by pulmonary vascular resistance, PH group 1 status, and sex. METHODS: We analyzed data from the multicenter PVDOMICS (Pulmonary Vascular Disease Phenomics) cohort. RV systolic function metrics included fractional area change (echo), global longitudinal strain (echo), and ejection fraction (cardiac magnetic resonance). We used linear regression adjusted for age, sex, body mass index, and PH group to assess associations between metabolites and RV function. Pathway enrichment analyses were used to identify pathways significantly associated with RV function. Interaction terms were assessed to determine whether metabolite associations were modified by pulmonary vascular resistance, group 1 PH status, or sex. Least absolute shrinkage and selection operator regression was used to develop metabolite-based scores for RV function, and prognostic performance was assessed. RESULTS: There were 979 participants with plasma metabolomics and RV function data. Linear regression identified 170 metabolites that were significantly associated with all 3 RV metrics. Androgenic steroid, gamma-glutamyl amino acid, polyamine, vitamin A, fatty acid, and sterol pathways are most strongly associated with RV systolic function. Two metabolites interacted with group 1 PH status, and 6 interacted with pulmonary vascular resistance. Four androgenic steroids are associated more strongly with RV systolic function in women compared with men. Metabolite-based scores were prognostically equivalent to RV systolic function metrics and less accurate than REVEAL Lite 2 scores. CONCLUSIONS: We provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Novel links to vitamin A and glutathione metabolites were observed. We detected few metabolites that associated with RV systolic function differentially by group 1 PH status or degree of pulmonary vascular resistance elevation. Androgenic steroids may associate more strongly with RV systolic function in women compared with men.

Abstract Aims We aimed to assess regression and development rates of ≥moderate secondary mitral regurgitation (MR) and tricuspid regurgitation (TR) in patients with heart failure and reduced ejection fraction (HFrEF) receiving contemporary guideline-directed medical therapy (GDMT). Methods Patients with a <1 year diagnosis of HFrEF with mildly (40% ≤ EF < 50%) or moderately (<40%) reduced EF enrolled in GDMT titration programme 2019–2024 were identified. Regression rates of ≥moderate MR/TR to ≤mild and development rates of incident ≥moderate MR/TR were calculated. Results Among 844 patients [median age 64; 68% men; 26% mildly reduced EF; 24% New York Heart Association (NYHA) Class III/IV], 28% had ≥moderate MR and 14% had ≥moderate TR. Over median 7.1 months, 171 (75%) patients with ≥moderate MR and 87 (75%) of patients with ≥moderate TR experienced regression to no/mild MR and TR, respectively. Conversely, over median 13 months, incident ≥moderate MR and TR developed in 5% and 6%, respectively, of patients with no/mild baseline MR and TR. Number of GDMT medications at follow-up was less in patients who did not have MR/TR regression (vs who did) and in patients who developed MR/TR (vs who did not). Patients with NYHA Class I/II received a similar number of GDMT and had a similar rate of MR and TR regression and development vs patients with NYHA Class III/IV. However, patients with mildly reduced EF received less GDMT medications vs patients with moderately reduced EF and experienced less MR regression. Conclusion In patients with a recent diagnosis of HFrEF receiving contemporary GDMT, the majority with ≥moderate secondary MR and TR achieved regression of MR/TR, and the minority without significant baseline MR/TR developed ≥moderate regurgitation at follow-up.

BACKGROUND: With pulmonary hypertension (PH), a pulmonary artery wedge pressure (PAWP)>15 mm Hg is used to diagnose left heart dysfunction, but some patients with adjudicated group 1 PH demonstrate PAWP>15 mm Hg. The primary objective of the study was to evaluate group 1 PH with high PAWP>15 mm Hg. METHODS: Patients with adjudicated group 1 PH from PVDOMICS between 2016 and 2019 were separated into high PAWP(>15 mm Hg) or normal PAWP and compared with adjudicated combined pre- and postcapillary (Cpc) PH related to heart failure with preserved ejection fraction (HFpEF). Participants underwent dynamic right heart catheterization and metabolomics. Findings were validated in 3 independent cohorts with adjudicated group 1 PH (validation cohorts 1 and 2 with exercise right heart catheterization and validation cohort 3 with resting right heart catheterization). RESULTS: Of 325 patients with group 1 PH (73% women, mean age 53.0±14.3 years), 15% (n=48) had high PAWP. Group 1 PH+high PAWP demonstrated greater obesity, left ventricular hypertrophy ( P <0.0002), left ventricular strain impairment ( P <0.0001), and decreased left ventricular compliance ( P <0.0001) compared with group 1 PH+normal PAWP, with changes comparable to Cpc-PH HFpEF (n=75). Compared with Cpc-PH HFpEF, left atrial function was better in group 1 PH+high PAWP with lower PAWP V wave, higher left atrial compliance, and left atrial ejection fraction ( P <0.0001 for all). Metabolomics demonstrated little difference between group 1 PH with high versus normal PAWP but large differences between group 1 PH+high PAWP versus Cpc-PH HFpEF (100 metabolites altered at false discovery rate P <0.05). Elevated PAWP was also observed in 18% of group 1 PH in the validation cohort 1 (n=402), with exercise PAWP response intermediately abnormal in group 1 PH+high PAWP relative to Cpc-PH HFpEF and group 1 PH+normal PAWP (interaction P <0.0001). Elevated PAWP was similarly observed in 22% and 19% of group 1 PH in validation cohorts 2 (n=55) and 3 (n=787), respectively. CONCLUSIONS: Approximately 1 in 5 adjudicated patients with group 1 PH has elevation in resting PAWP despite severe pulmonary vascular dysfunction and metabolomics consistent with traditionally defined group 1 PH. Despite resting PAWP elevation, these patients with group 1 PH were metabolomically and biologically distinct from Cpc PH HFpEF, with better left atrial function and diastolic reserve during exercise. These data emphasize the limitations of using resting PAWP alone to separate group 1 PH from HFpEF and call for development of more integrated clinical diagnostic criteria.

Background Patients with atrial fibrillation (AF) often complain of dyspnea, raising the question that symptoms could be related to unrecognized heart failure (HF) with preserved ejection fraction (HFpEF). Methods We used the HFpEF‐age, body mass index and history of AF algorithm to estimate the probability of undiagnosed HFpEF in CABANA (Catheter Ablation vs. Antiarrhythmic Drug Therapy), and its interaction with catheter ablation on quality of life (QOL). Probable HFpEF was defined as patient‐reported dyspnea with HFpEF‐age, body mass index and history of AF probability≥75%. Absence of dyspnea or HFpEF‐age, body mass index and history of AF probability<75% was considered to reflect patients without HFpEF. The effect of randomization to catheter ablation on QOL (Mayo Atrial Fibrillation‐Specific Symptom Inventory questionnaire and EuroQol‐5 Dimension‐3 Level score) was assessed using mixed models. Results Of participants without known HF, 70% (n=1225) had probable HFpEF and the remaining 30% (n=522) did not. Those with probable HFpEF had worse New York Heart Association class, EuroQol‐5 Dimension‐3 Level score, Mayo Atrial Fibrillation‐Specific Symptom Inventory severity, and Mayo Atrial Fibrillation‐Specific Symptom Inventory frequency scores ( P <0.0001 for all), with higher risk of HF hospitalization (hazard ratio [HR], 2.19 [95% CI, 1.11–4.31], P =0.01). Ablation resulted in greater improvement in EuroQol‐5 Dimension‐3 Level and Mayo Atrial Fibrillation‐Specific Symptom Inventory severity/frequency scores in probable HFpEF (interactions P =0.005, P =0.05, and P =0.04 respectively). In probable HFpEF, catheter ablation was associated with lower risk of cardiovascular hospitalization (HR, 0.78 [95% CI, 0.66–0.92], P =0.003, interaction P =0.03) but not HF hospitalization (HR, 0.94 [95% CI, 0.55–1.64], P =0.84). Conclusions Nearly three quarters of CABANA participants had potentially undiagnosed HFpEF, with worse QOL and risk of HF hospitalization. Catheter ablation in probable HFpEF resulted in greater improvement in QOL, but residual QOL impairment and HF risk remained elevated despite ablation. These data reinforce the importance of diligent consideration of HFpEF among patients with symptomatic AF to ensure optimal use of foundational treatments for HF.

Abstract Background Approximately one-third of patients with heart failure and preserved ejection fraction (EF) (HFpEF) have exercise-induced left atrial hypertension (EILAH), characterized by normal pulmonary capillary wedge pressure (PCWP) at rest, but with pathologic PCWP elevation during exercise. It has been proposed that EILAH may represent an early stage of HFpEF that progresses to resting LA hypertension (RELAH) over time, but this has never been shown. Purpose This observational study aimed to investigate the natural history of patients with EILAH, evaluating patients who underwent multiple invasive hemodynamic evaluations over time. Methods Consecutively-evaluated patients with HFpEF and EILAH (PCWP&lt;15 mmHg at rest and ≥25 mmHg during exercise) who underwent subsequent invasive hemodynamic testing were identified. Prevalence and characteristics of transition to RELAH (PCWP≥15 mmHg at rest) were evaluated. Results Of 659 patients with EILAH, 84 underwent repeat invasive hemodynamic evaluations over a median follow-up of 1.81 (IQR 0.48-3.40) years (55 female, mean age 66 years). Of this group, 33 (39%) patients changed to RELAH and 51 (61%) remained EILAH. Patients with change to RELAH experienced greater increase in NT-proBNP (+16.6%; 95% CI: 7.1% to 26.0%, P&lt;0.001), decreased left ventricular EF (-6.1%, 95% CI: -9.7 to -2.5, P=0.001), right ventricular (RV) global longitudinal strain (-4.5%, 95% CI: -8.8 to -0.3, P=0.037), RV free wall longitudinal strain (-7.3%, 95% CI: -13.1 to -1.6, P=0.013) and worsening tricuspid regurgitation (15% vs 2%, P=0.025) compared to those with no change (Figure 1). Upon invasive hemodynamic at rest, patients with change to RELAH experienced an increase in right atrial pressure (RAP) (+4.4 mmHg, 95% CI: 2.6 to 6.1, P&lt;0.001) and mean pulmonary artery (PA) pressure (+6.6 mmHg, 95% CI: 4.2 to 9.0, P&lt;0.001) (Figure 1). At the baseline, there were no significant differences in the exercise-induced increases in PCWP, mean PAP, and RAP between the two groups from rest to peak exercise (Figure 2). However, at the final evaluation, patients with change to RELAH displayed a greater increase in PCWP, mean PAP, and RAP during exercise as compared to those who remained EILAH (Figure 2). Of characteristics at the index evaluation, history of atrial fibrillation (OR 3.73; 95% CI 1.09-12.8, P=0.036), and lower resting PA compliance (OR 0.49; 95% CI 0.24-0.99, P=0.048) were independently associated with the transition to RELAH after adjusting the duration from baseline to final examination. Conclusions Approximately 40% of patients with HFpEF that first present with EILAH to RELAH, suggesting that EILAH can be considered an earlier form of HFpEF. History of atrial fibrillation and reduced PA compliance are associated with progression to RELAH, suggesting that interventions to address atrial myopathy and pulmonary vascular disease may be effective to attenuate or prevent this transition.

Abstract Background Left atrial pressure (LAP) is clinically estimated by the occluded pulmonary artery (PA) pressure (PA wedge pressure, PAWP), which should equalize with downstream LAP. Early studies reported the potential for PAWP to exceed LAP, but the frequency and clinical significance of this finding is unclear. Purpose This study aimed to investigate the hemodynamic characteristics, physiologic determinants, and prognostic impact of patients with PAWP exceeding LAP. Method Patients who underwent right heart catheterization (RHC) for diagnosis or treatment with PAWP and simultaneous measurement of LAP were identified. Patients were divided into two groups based on differences in PAWP and LAP. Pulmonary capillary pressure (Pc) was measured using the PA occlusion technique. Pulmonary vascular resistance (PVR) was then partitioned into upstream PVRa ([mean PA pressure (PAP)-Pc]/cardiac output [CO]) and downstream PVRv ([Pc-PAWP]/CO), with each expressed as a percentage of PVR. Results 675 patients underwent RHC with transseptal puncture allowing measurement of both PAWP and LAP simultaneously. A strong correlation and agreement between PAWP and LAP were demonstrated (r=0.92, P&lt;0.001; bias +0.5 mmHg), but 310 patients (46%) displayed PAWP exceeding LAP by at least 1 mmHg (mean difference 3±2 mmHg). Patients with PAWP exceeding LAP displayed higher mean PAP (Figure 1A) and PVR calculated using LAP as the downstream pressure (PVR-LA: 2.10 [1.13-3.53] vs 3.38 [2.19-5.66] WU, P&lt;0.001). PAWP was significantly higher in patients with PAWP exceeding LAP, although there was no significant difference in LAP between the groups (Figure 1B-C). PA compliance, which does not rely on either PAWP or LAP for calculation, was significantly lower in patients with PAWP exceeding LAP (2.7 [1.8-4.0] vs 2.1 [1.5-3.0] mL/mmHg, P&lt;0.001, Figure 1D). The difference between PAWP and LAP was significantly correlated with mean PAP (r=0.32, P&lt;0.001, Figure 1E). In 63 patients where Pc could be measured, those with PAWP exceeding LAP showed a higher Pc and greater pulmonary venous (vs arterial) distribution of PVR (Figure 1F-H). Over 5.4 (IQR 1.7-10.2) years, the composite outcome of all-cause death or heart failure hospitalization occurred in 326 patients (48%). Patients with PAWP exceeding LAP had a higher risk of the composite outcome than those without (log-rank P&lt;0.001, Figure 2). Patients with PAWP exceeding LAP had 37% greater risk of composite outcome than those without (hazard ratio 1.37, 95% CI 1.09-1.73; P=0.008) after adjusting for age, sex, hemoglobin, moderate or greater mitral regurgitation, and tricuspid regurgitation, LAP, and mean PAP. Conclusions While PAWP is a robust surrogate for LAP, the former commonly exceeds the latter, and patients with PAWP exceeding LAP have more severe pulmonary vascular disease, greater capillary hypertension and venous involvement, and a higher risk for adverse outcomes.