Heart Failure with Preserved Ejection Fraction: Mechanisms and Treatment Strategies.

Approximately half of all patients with heart failure (HF) have a preserved ejection fraction, and the prevalence is growing rapidly given the aging population in many countries and the rising prevalence of obesity, diabetes, and hypertension. Functional capacity and quality of life are severely impaired in heart failure with preserved ejection fraction (HFpEF), and morbidity and mortality are high. In striking contrast to HF with reduced ejection fraction, there are few effective treatments currently identified for HFpEF, and these are limited to decongestion by diuretics, promotion of a healthy active lifestyle, and management of comorbidities. Improved phenotyping of subgroups within the overall HFpEF population might enhance individualization of treatment. This review focuses on the current understanding of the pathophysiologic mechanisms underlying HFpEF and treatment strategies for this complex syndrome.

Impact of right ventricular reserve on exercise capacity and quality of life in patients with left ventricular assist device.

Although measuring right ventricular (RV) function during exercise is more informative than assessing it at rest, the relationship between RV reserve function, exercise capacity, and health-related quality of life (HRQoL) in patients with left ventricular assist devices (LVAD) remains unresolved. We aimed to investigate whether RV reserve assessed by the change in RV stroke work index (RVSWI) during exercise is correlated with exercise capacity and HRQoL in patients with LVAD. We prospectively assessed 24 consecutive patients with LVAD who underwent invasive right heart catheterization in the supine position. Exercise capacity and HRQoL were assessed using the 6-min walk distance (6 MWD) and peak oxygen consumption (V̇o2) in cardiopulmonary exercise testing, and the EuroQol visual analog scale (EQ-VAS), respectively. The patients were divided into two groups according to the median ΔRVSWI (change from rest to peak exercise). Patients with lower ΔRVSWI had significantly lower changes in cardiac index and absolute value of RV dP/dt than those with higher ΔRVSWI. The ΔRVSWI was positively correlated with 6 MWD (r = 0.59, P = 0.003) and peak V̇o2 (r = 0.56, P = 0.006). In addition, ΔRVSWI was positively correlated with the EQ-VAS (r = 0.44, P = 0.030). In contrast, there was no significant correlation between RVSWI at rest and 6 MWD (r = -0.34, P = 0.88), peak V̇o2 (r = 0.074, P = 0.74), or EQ-VAS (r = 0.127, P = 0.56). Our findings suggest that the assessment of RV reserve function is useful for risk stratification in patients with LVAD.NEW & NOTEWORTHY The change in right ventricular stroke work index (RVSWI) during exercise, not RVSWI at rest, was associated with exercise capacity and HRQoL. Our findings suggest that the assessment of change in RVSWI during exercise as a surrogate of RV reserve function may aid in risk stratification of patients with LVAD.

Liver stiffness assessed by magnetic resonance elastography predicts clinical outcomes in patients with heart failure and without chronic liver disease.

OBJECTIVES: Evaluation of liver stiffness (LS) by magnetic resonance elastography (MRE) is useful for estimating right atrial pressure (RAP) in patients with heart failure (HF). However, its prognostic implications are unclear. We sought to investigate whether LS measured by MRE (LS-MRE) could predict clinical outcomes in patients with HF. METHODS: We prospectively examined 207 consecutive HF patients between April 2018 and May 2021 after excluding those with organic liver disease. All patients underwent 3.0-T MRE. The primary outcome of interest was the composite of all-cause death and hospitalisation for HF. RESULTS: During a median follow-up period of 720 (interquartile range [IQR] 434-1013) days, the primary outcome occurred in 44 patients (21%), including 15 (7%) all-cause deaths and 29 (14%) hospitalisations for HF. The patients were divided into two groups according to median LS-MRE of 2.54 (IQR 2.34-2.82) kPa. Patients with higher LS-MRE showed a higher incidence of the primary outcome compared to those with lower LS-MRE (p < 0.001). Multivariable Cox regression analyses revealed that LS-MRE value was independently associated with the risk of adverse events (hazard ratio 2.49, 95% confidence interval 1.46-4.24). In multivariable linear regression, RAP showed a stronger correlation with LS-MRE (ß coefficient = 0.31, p < 0.001) compared to markers related to liver fibrosis. CONCLUSIONS: In patients without chronic liver disease and presenting with HF, elevated LS-MRE was independently associated with worse clinical outcomes. Elevated LS-MRE may be useful for risk stratification in patients with HF and without chronic liver disease. KEY POINTS: • Magnetic resonance elastography (MRE) is an emerging non-invasive imaging technique for evaluating liver stiffness (LS) which can estimate right atrial pressure. • Elevated LS-MRE, which mainly reflects liver congestion, was independently associated with worse clinical outcomes in patients with heart failure. • The assessment of LS-MRE would be useful for stratifying the risk of adverse events in heart failure patients without chronic liver disease.

Differences in blood flow dynamics between balloon- and self-expandable valves in patients with aortic stenosis undergoing transcatheter aortic valve replacement.

BACKGROUND: The differences in pre- and early post-procedural blood flow dynamics between the two major types of bioprosthetic valves, the balloon-expandable valve (BEV) and self-expandable valve (SEV), in patients with aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR), have not been investigated. We aimed to investigate the differences in blood flow dynamics between the BEV and SEV using four-dimensional flow cardiovascular magnetic resonance (4D flow CMR). METHODS: We prospectively examined 98 consecutive patients with severe AS who underwent TAVR between May 2018 and November 2021 (58 BEV and 40 SEV) after excluding those without CMR because of a contraindication, inadequate imaging from the analyses, or patients' refusal. CMR was performed in all participants before (median interval, 22 [interquartile range (IQR) 4-39] days) and after (median interval, 6 [IQR 3-6] days) TAVR. We compared the changes in blood flow patterns, wall shear stress (WSS), and energy loss (EL) in the ascending aorta (AAo) between the BEV and SEV using 4D flow CMR. RESULTS: The absolute reductions in helical flow and flow eccentricity were significantly higher in the SEV group compared in the BEV group after TAVR (BEV: - 0.22 ± 0.86 vs. SEV: - 0.85 ± 0.80, P < 0.001 and BEV: - 0.11 ± 0.79 vs. SEV: - 0.50 ± 0.88, P = 0.037, respectively); there were no significant differences in vortical flow between the groups. The absolute reduction of average WSS was significantly higher in the SEV group compared to the BEV group after TAVR (BEV: - 0.6 [- 2.1 to 0.5] Pa vs. SEV: - 1.8 [- 3.5 to - 0.8] Pa, P = 0.006). The systolic EL in the AAo significantly decreased after TAVR in both the groups, while the absolute reduction was comparable between the groups. CONCLUSIONS: Helical flow, flow eccentricity, and average WSS in the AAo were significantly decreased after SEV implantation compared to BEV implantation, providing functional insights for valve selection in patients with AS undergoing TAVR. Our findings offer valuable insights into blood flow dynamics, aiding in the selection of valves for patients with AS undergoing TAVR. Further larger-scale studies are warranted to confirm the prognostic significance of hemodynamic changes in these patients.

Left Atrial Myopathy in Heart Failure With Preserved Ejection Fraction.

The left atrium (LA) plays an important role in facilitating left ventricular (LV) filling by acting as a reservoir, passive conduit, and active booster pump, as well as a regulator of blood volume through A-type natriuretic peptide secretion in response to stimulation by mechanical stretch of the cavity. LA myopathy has emerged as one of the most important non-LV contributors to disease progression in heart failure with preserved ejection fraction (HFpEF). LA dysfunction is common in HFpEF and is associated with more severe pulmonary vascular disease and right ventricular dysfunction, and increases the risk of incident atrial fibrillation or atrial functional mitral regurgitation, leading to limitations in cardiac output reserve and reduced exercise capacity. LA deformation assessed by 2-dimensional speckle-tracking echocardiography is useful for estimating abnormal hemodynamics or exercise capacity, discriminating HFpEF from non-cardiac dyspnea and is an independent predictor of adverse outcome in HFpEF. Thus, interventions directly targeting LA myopathy may improve outcomes in HFpEF with LA myopathy. This review provides information regarding the physiology of the LA in patients with HFpEF and discusses the importance of evaluation of LA function, management issues, and future directions through ongoing trials of medical interventions.

Heart failure with preserved ejection fraction in patients with normal natriuretic peptide levels is associated with increased morbidity and mortality.

BACKGROUND: A substantial proportion of patients with heart failure (HF) with preserved ejection fraction (HFpEF) present with normal natriuretic peptide (NP) levels. The pathophysiology and natural history for this phenotype remain unclear. METHODS AND RESULTS: Consecutive subjects undergoing invasive cardiopulmonary exercise testing for unexplained dyspnoea at Mayo Clinic in 2006-18 were studied. Heart failure with preserved ejection fraction was defined as a pulmonary arterial wedge pressure (PAWP) ≥15 mmHg (rest) or ≥25 mmHg (exercise). Patients with HFpEF and normal NP [N-terminal of the pro-hormone B-type natriuretic peptide (NT-proBNP) < 125 ng/L] were compared with HFpEF with high NP (NT-proBNP ≥ 125 ng/L) and controls with normal haemodynamics. Patients with HFpEF and normal (n = 157) vs. high NP (n = 263) were younger, yet older than controls (n = 161), with an intermediate comorbidity profile. Normal NP HFpEF was associated with more left ventricular hypertrophy and worse diastolic function compared with controls, but better diastolic function, lower left atrial volumes, superior right ventricular function, and less mitral/tricuspid regurgitation compared with high NP HFpEF. Cardiac output (CO) reserve with exercise was preserved in normal NP HFpEF [101% predicted, interquartile range (IQR): 75-124%], but this was achieved only at the cost of higher left ventricular transmural pressure (LVTMP) (14 ± 6 mmHg vs. 7 ± 4 mmHg in controls, P < 0.001). In contrast, CO reserve was decreased in high NP HFpEF (85% predicted, IQR: 59-109%), with lower LVTMP (10 ± 8 mmHg) compared with normal NP HFpEF (P < 0.001), despite similar PAWP. Patients with high NP HFpEF displayed the highest event rates, but normal NP HFpEF still had 2.7-fold higher risk for mortality or HF readmissions compared with controls (hazard ratio: 2.74, 95% confidence interval: 1.02-7.32) after adjusting for age, sex, and body mass index. CONCLUSION: Patients with HFpEF and normal NP display mild diastolic dysfunction and preserved CO reserve during exercise, despite marked elevation in filling pressures. While clinical outcomes are not as poor compared with patients with high NP, patients with normal NP HFpEF exhibit increased risk of death or HF readmissions compared with patients without HF, emphasizing the importance of this phenotype.

Pulmonary vascular disease in pulmonary hypertension due to left heart disease: pathophysiologic implications.

AIMS: Pulmonary hypertension (PH) and pulmonary vascular disease (PVD) are common and associated with adverse outcomes in left heart disease (LHD). This study sought to characterize the pathophysiology of PVD across the spectrum of PH in LHD. METHODS AND RESULTS: Patients with PH-LHD [mean pulmonary artery (PA) pressure >20 mmHg and PA wedge pressure (PAWP) ≥15 mmHg] and controls free of PH or LHD underwent invasive haemodynamic exercise testing with simultaneous echocardiography, expired air and blood gas analysis, and lung ultrasound in a prospective study. Patients with PH-LHD were divided into isolated post-capillary PH (IpcPH) and PVD [combined post- and pre-capillary PH (CpcPH)] based upon pulmonary vascular resistance (PVR <3.0 or ≥3.0 WU). As compared with controls (n = 69) and IpcPH-LHD (n = 55), participants with CpcPH-LHD (n = 40) displayed poorer left atrial function and more severe right ventricular (RV) dysfunction at rest. With exercise, patients with CpcPH-LHD displayed similar PAWP to IpcPH-LHD, but more severe RV-PA uncoupling, greater ventricular interaction, and more severe impairments in cardiac output, O2 delivery, and peak O2 consumption. Despite higher PVR, participants with CpcPH developed more severe lung congestion compared with both IpcPH-LHD and controls, which was associated lower arterial O2 tension, reduced alveolar ventilation, decreased pulmonary O2 diffusion, and greater ventilation-perfusion mismatch. CONCLUSIONS: Pulmonary vascular disease in LHD is associated with a distinct pathophysiologic signature marked by greater exercise-induced lung congestion, arterial hypoxaemia, RV-PA uncoupling, ventricular interdependence, and impairment in O2 delivery, impairing aerobic capacity. Further study is required to identify novel treatments targeting the pulmonary vasculature in PH-LHD.

Blood flow dynamics with four-dimensional flow cardiovascular magnetic resonance in patients with aortic stenosis before and after transcatheter aortic valve replacement.

BACKGROUND: Pre- and post-procedural hemodynamic changes which could affect adverse outcomes in aortic stenosis (AS) patients who undergo transcatheter aortic valve replacement (TAVR) have not been well investigated. Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) enables accurate analysis of blood flow dynamics such as flow velocity, flow pattern, wall shear stress (WSS), and energy loss (EL). We sought to examine the changes in blood flow dynamics of patients with severe AS who underwent TAVR. METHODS: We examined 32 consecutive severe AS patients who underwent TAVR between May 2018 and June 2019 (17 men, 82 ± 5 years, median left ventricular ejection fraction 61%, 6 self-expanding valve), after excluding those without CMR because of a contraindication or inadequate imaging from the analyses. We analyzed blood flow patterns, WSS and EL in the ascending aorta (AAo), and those changes before and after TAVR using 4D flow CMR. RESULTS: After TAVR, semi-quantified helical flow in the AAo was significantly decreased (1.4 ± 0.6 vs. 1.9 ± 0.8, P = 0.002), whereas vortical flow and eccentricity showed no significant changes. WSS along the ascending aortic circumference was significantly decreased in the left (P = 0.038) and left anterior (P = 0.033) wall at the basal level, right posterior (P = 0.011) and left (P = 0.010) wall at the middle level, and right (P = 0.012), left posterior (P = 0.019) and left anterior (P = 0.028) wall at the upper level. EL in the AAo was significantly decreased (15.6 [10.8-25.1 vs. 25.8 [18.6-36.2]] mW, P = 0.012). Furthermore, a significant negative correlation was observed between EL and effective orifice area index after TAVR (r = - 0.38, P = 0.034). CONCLUSIONS: In severe AS patients undergoing TAVR, 4D flow CMR demonstrates that TAVR improves blood flow dynamics, especially when a larger effective orifice area index is obtained.

Prognostic value of admission serum magnesium in acute myocardial infarction complicated by malignant ventricular arrhythmias.

OBJECTIVES: Although electrolyte abnormalities are related to worse clinical outcomes in patients with acute myocardial infarction (AMI), little is known about the association between admission serum magnesium level and adverse events in AMI patients complicated by out-of-hospital cardiac arrest presenting with malignant ventricular arrhythmias (OHCA-MVA). We investigated the prognostic value of serum magnesium level on admission in these patients. METHODS: We retrospectively analyzed the data of 165 consecutive reperfused AMI patients complicated with OHCA-MVA between April 2007 and February 2020 in our university hospital. Serum magnesium concentration was measured on admission. The primary outcome was in-hospital death. RESULTS: Fifty-four patients (33%) died during hospitalization. Higher serum magnesium level was significantly related to in-hospital death (Fine & Gray's test; p < 0.001). In multivariable logistic regression analyses, serum magnesium level on admission was independently associated with in-hospital death (hazard ratio 2.68, 95% confidence interval 1.24-5.80) even after adjustment for covariates. Furthermore, the incidences of cardiogenic shock necessitating an intra-aortic balloon pump (p = 0.005) or extracorporeal membrane oxygenation (p < 0.001), tracheal intubation (p < 0.001) and persistent vegetative state (p = 0.002) were significantly higher in patients with higher serum magnesium level than in those with lower serum magnesium level. CONCLUSIONS: In reperfused AMI patients complicated by OHCA-MVA, admission serum magnesium level might be a potential surrogate marker for predicting in-hospital death.

Clinical Phenogroups in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) accounts for more than one-half of patients with heart failure. Effective treatment of HFpEF has not been established, largely because of the complexities and heterogeneity in the phenotypes of HFpEF. Categorizing patients based on clinical and pathophysiologic phenotype may provide more targeted and efficacious therapies. Despite this clinical need, there is no consensus on how to categorize patients with HFpEF into phenogroups. Possible metrics include the presence or absence of specific comorbidities that influence pathophysiology, imaging, hemodynamics, or other biomarkers. This article describes currently recognized phenotypes of HFpEF and potential treatment strategies.

18F-FDG uptake of the right ventricle is an important predictor of histopathologic diagnosis by endomyocardial biopsy in patients with cardiac sarcoidosis.

BACKGROUND: The aim of this study was to determine whether right ventricle (RV) 18F-fluorodeoxyglucose (FDG) uptake can predict positive findings of endomyocardial biopsy (EMB) in patients with cardiac sarcoidosis (CS). METHODS: 70 consecutive patients with clinically diagnosed CS who had undergone FDG PET were registered in the present study. Patients without EMB (n = 42) were excluded. Ultimately, 28 patients were studied. EMB samples were obtained from the RV septum. We evaluated the FDG uptake on six segments (RV, left ventricle anterior, septal, lateral, inferior, and apex). RESULTS: Positive EMB was found in six patients (21%). Patients were divided into two groups according to positive (n = 12 [43%]) or negative (n = 16 [57%]) RV FDG uptake. Patients with positive RV FDG uptake had a significantly higher frequency of positive EMB than those without (42% vs. 6%, P = 0.024). On the other hand, there was no EMB-predictive value for the FDG uptakes in the other five segments, the cardiac metabolic volume, total lesion glycolysis, left ventricular ejection fraction, or any electrocardiogram findings. CONCLUSIONS: FDG uptake of the RV but no other heart segment was associated with positive EMB in CS patients. The presence of RV FDG uptake could improve the rate of positive EMB up to 42% in patients with CS.

Differential Prognostic Impact of Atrial Fibrillation in Hospitalized Heart Failure Patients With Preserved Ejection Fraction According to Coronary Artery Disease Status　- Report From the Japanese Nationwide Multicenter Registry.

BACKGROUND: Atrial fibrillation (AF) is an important prognostic determinant in heart failure (HF) with preserved ejection fraction (HFpEF). However, it is unclear which HFpEF phenotypes are affected by AF in terms of long-term clinical outcomes because HFpEF is a heterogeneous syndrome with comorbidities such as coronary artery disease (CAD). In this study we determined the differential prognostic significance of AF in HFpEF patients according to CAD status.Methods and Results:Data for 408 hospitalized HFpEF patients enrolled in the Japanese Heart Failure Syndrome with Preserved Ejection Fraction Nationwide Multicenter Registry were analyzed. Patients were divided into 4 groups according to the presence of AF and CAD. The primary outcome was the composite of all-cause death and HF rehospitalization. The incidence of adverse events was higher in the AF-non-CAD than non-AF-non-CAD group (P=0.004). On multivariable Cox regression analysis with prespecified confounders, AF-non-CAD was significantly associated with an increased risk of adverse events than non-AF-non-CAD (adjusted HR, 1.91; 95% CI: 1.02-3.92) regardless of the type of AF. In contrast, risk was comparable between the AF-CAD and non-AF-CAD groups (adjusted HR, 1.24; 95% CI: 0.64-2.47). CONCLUSIONS: In HFpEF patients without CAD, AF was independently related to adverse events, indicating that intensive management of AF would have more beneficial effects particularly in HFpEF patients without CAD.

Long-term Prognostic Significance of Admission Tricuspid Regurgitation Pressure Gradient in Hospitalized Patients With Heart Failure With Preserved Ejection Fraction: A Report From the Japanese Real-World Multicenter Registry.

BACKGROUND: Doppler-estimated peak systolic tricuspid regurgitation pressure gradient (TRPG) is a representative noninvasive parameter for evaluating pulmonary artery systolic pressure, which can be a determinant of adverse outcomes in chronic heart failure with preserved ejection fraction (HFpEF). However, the prognostic implications of TRPG at admission for hospitalized patients with HFpEF are undetermined. METHODS AND RESULTS: We examined 469 consecutive hospitalized patients with decompensated HFpEF (left ventricular ejection fraction ≥ 50%) who underwent TRPG measurement at admission in our HFpEF multicenter registry. The primary outcome of interest was all-cause death. Admission TRPG was significantly correlated with estimated pulmonary capillary wedge pressure and left atrial dimension (r = 0.24, P < 0.001 and r = 0.21, P < 0.001, respectively). During a median follow-up period of 748 (IQR 540-820) days, 83 patients died. Higher TRPG was significantly associated with higher mortality compared to lower TRPG (log-rank; P = 0.007). Multivariable analysis revealed that elevated TRPG was an independent determinant of mortality (HR 1.02, 95% CI 1.01-1.04, P = 0.008) after adjustment for prespecified confounders and renal function. CONCLUSIONS: Elevated TRPG at admission was an independent determinant of mortality in hospitalized patients with HFpEF, indicating that TRPG at admission could be a useful marker for risk stratification in these patients.

Comparison of Mortality Prediction Models on Long-Term Mortality in Hospitalized Patients With Acute Heart Failure　- The Importance of Accounting for Nutritional Status.

BACKGROUND: The ideal mortality prediction model (MPM) for acute heart failure (AHF) patients would have sufficient and stable predictive ability for long-term as well as short-term mortality. However, published MPMs for AHF predominantly predict short-term mortality up to 90 days, and their prognostic performance for long-term mortality remains unclear. Methods and Results: We analyzed 609 AHF patients in a prospective registry from January 2013 to May 2016. We compared the prognostic performance for long-term mortality among 8 systematically identified MPMs for AHF that predict short-term mortality up to 90 days from admission. The PROTECT 7-day model showed the highest c-index for long-term as well as short-term mortality among the studied MPMs. Sensitivity analyses revealed serum albumin and total cholesterol to be the most important variables, as dropping these variables resulted in a significant decline in c-index, when compared with other variables specific to the PROTECT 7-day model. Furthermore, significant improvements in c-index and net reclassification were observed when serum albumin or serum albumin plus total cholesterol was added to the studied MPMs, other than the PROTECT 7-day model. CONCLUSIONS: The PROTECT 7-day model demonstrated the highest predictive performance for long-term as well as short-term mortality in AHF patients among the published MPMs. Our findings indicate the importance of accounting for nutritional status such as serum albumin and total cholesterol in AHF patients when developing a MPM.

Impact of admission liver stiffness on long-term clinical outcomes in patients with acute decompensated heart failure.

Liver stiffness (LS) has been reported to be a marker of liver congestion caused by elevated central venous pressure in heart failure (HF) patients. Recent studies demonstrated that LS could be non-invasively measured by virtual touch quantification (VTQ). However, its prognostic implication in patients with acute decompensated heart failure (ADHF) is unclear. This study sought to determine whether LS measured by VTQ could be a determinant of subsequent adverse events in ADHF patients. We prospectively recruited 70 ADHF patients who underwent LS measurement by VTQ on admission in our university hospital between June 2016 and April 2018. The primary outcome of interest was the composite of all-cause mortality and worsening HF. During a median follow-up period of 272 (interquartile range 122-578) days, there were 26 (37%) events, including 5 (7%) deaths and 21 (30%) cases of worsening HF. The c-index of LS for predicting the composite of adverse events was 0.77 (95% CI 0.66-0.88), and the optimal cut-off value of LS was 1.50 m/s. Adverse events were more frequently observed in patients with high LS (≥ 1.50 m/s) compared to those with low LS (< 1.50 m/s). Multivariable Cox regression analyzes revealed that higher LS was independently associated with increased subsequent risk of adverse events after adjustment for confounders. In conclusion, high admission LS was an independent determinant of worse clinical outcomes in patients with ADHF. This finding suggests that LS on admission is useful for risk stratification of patients with ADHF.

Biatrial myopathy in heart failure with preserved ejection fraction.

AIM: Left atrial (LA) myopathy is increasingly recognized as an important phenotypic trait in heart failure (HF) with preserved ejection fraction (HFpEF). Right atrial (RA) remodelling and dysfunction also develop in HFpEF, but little data are available regarding the clinical characteristics and pathophysiology among patients with isolated LA, RA, or biatrial myopathy. METHODS AND RESULTS: Patients with HFpEF underwent invasive haemodynamic exercise testing, comprehensive imaging including speckle tracking strain echocardiography, and clinical follow-up at Mayo Clinic between 2006 and 2018. LA myopathy was defined as LA volume index >34 ml/m2 and/or LA reservoir strain ≤24% and RA myopathy by RA volume index >39 ml/m2 in men and >33 ml/m2 in women and/or RA reservoir strain ≤19.8%. Of 476 consecutively evaluated patients with HFpEF defined by invasive exercise testing with evaluable atrial structure/function, 125 (26%) had no atrial myopathy, 147 (31%) had isolated LA myopathy, 184 (39%) had biatrial myopathy, and 20 (4%) had isolated RA myopathy. Patients with HFpEF and biatrial myopathy had more atrial fibrillation, poorer left ventricular systolic and diastolic function, more severe pulmonary vascular disease, tricuspid regurgitation, ventricular interdependence and right ventricular dysfunction, and poorer cardiac output reserve with exercise. There were 94 patients with events over a median follow-up of 2.9 (interquartile range 1.4-4.6) years. Individuals with biatrial myopathy had an 84% higher risk of HF hospitalization or death as compared to those with isolated LA myopathy (hazard ratio 1.84; 95% confidence interval 1.16-2.92, p = 0.01). CONCLUSIONS: Biatrial myopathy identifies patients with more advanced HFpEF characterized by more severe pulmonary vascular disease, right HF, poorer cardiac reserve, and a greater risk for adverse outcomes. Further study is required to define optimal strategies to treat and prevent biatrial myopathy in HFpEF.