Prediction of AF in Heart Failure With Preserved Ejection Fraction: Incremental Value of Left Atrial Strain

ObjectivesThis study sought to identify the factors associated with incident atrial fibrillation (AF) in a well-characterized heart failure with preserved ejection fraction (HFpEF) population, with special focus on left atrial (LA) strain.BackgroundAF is associated with HFpEF, with adverse consequences. Effective risk evaluation might allow the initiation of protective strategies.MethodsClinical evaluation and echocardiography, including measurements of peak atrial longitudinal strain (PALS), peak atrial contraction strain (PACS), and LA volume index (LAVI), were obtained in 170 patients with symptomatic HFpEF (mean age, 65 ± 8 years), free of baseline AF. AF was identified by standard 12-lead electrocardiogram, review of relevant medical records (including Holter documentation), and surveillance with a portable single-lead electrocardiogram device over 2 weeks. Results were validated in the 103 patients with HFpEF from the Karolinska-Rennes (KaRen) study.ResultsOver a median follow-up of 49 months, incident AF was identified in 39 patients (23%). Patients who developed AF were older; had higher clinical risk scores, brain natriuretic peptide, creatinine, LAVI, and LV mass; lower LA strain and exercise capacity; and more impaired LV diastolic function. PACS, PALS, and LAVI were the most predictive parameters for AF (area under receiver-operating characteristic curve: 0.76 for PACS, 0.71 for PALS, and 0.72 for LAVI). Nested Cox regression models showed that the predictive value of PACS and PALS was independent from and incremental to clinical data, LAVI, and E/e’ ratio. Classification and regression trees analysis identified PACS ≤12.7%, PALS ≤29.4%, and LAVI >34.3 ml/m² as discriminatory nodes for AF, with a 33-fold greater hazard of AF (p < 0.001) in patients categorized as high risk. The classification and regression trees algorithm discriminated high and low AF risk in the validation cohort.ConclusionsPACS and PALS provide incremental predictive information about incident AF in HFpEF. The inclusion of these LA strain components to the diagnostic algorithm may help guide screening and further monitoring for AF risk in this population.     

Etiology-Dependent Impairment of Diastolic Cardiomyocyte Calcium Homeostasis in Heart Failure With Preserved Ejection Fraction

BackgroundWhereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca²⁺ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF.ObjectivesThis study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF.MethodsT-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca²⁺ homeostasis was studied in rat models of these conditions.ResultsHFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca²⁺ homeostasis, although diastolic Ca²⁺ removal was also reduced. In contrast, Ca²⁺ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca²⁺ impairments, including reduced sarco/endoplasmic reticulum Ca²⁺-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models.ConclusionsAlthough t-tubule disruption and impaired cardiomyocyte Ca²⁺ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca²⁺ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.     

Systolic Blood Pressure in Heart Failure With Preserved Ejection Fraction Treated With Sacubitril/Valsartan

BackgroundGuidelines recommend targeting systolic blood pressure (SBP) <130 mm Hg in heart failure with preserved ejection fraction (HFpEF) with limited data.ObjectivesThis study sought to determine the optimal achieved SBP and whether the treatment effects of sacubitril/valsartan on outcomes are related to BP lowering, particularly among women who derive greater benefit from sacubitril/valsartan.MethodsUsing 4,795 trial participants, this study related baseline and time-updated mean achieved SBP quartiles (<120, 120 to 129, 130 to 139, ≥140 mm Hg) to the primary outcome (cardiovascular death and total heart failure hospitalization), its components, myocardial infarction or stroke, and a renal composite outcome. At the 16-week visit, the study assessed the relationship between SBP change and Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS) and N-terminal pro−B-type natriuretic peptide (NT-proBNP). The study analyzed whether the BP-lowering effects of sacubitril/valsartan accounted for its treatment effects.ResultsAverage age was 73 ± 8 years, and 52% of participants were women. After multivariable adjustment, baseline and mean achieved SBP of 120 to 129 mm Hg demonstrated the lowest risk for all outcomes. Sacubitril/valsartan reduced SBP by 5.2 mm Hg (95% confidence interval: 4.4 to 6.0) compared with valsartan at 4 weeks, which was not modified by baseline SBP. However, sacubitril/valsartan reduced SBP more in women (6.3 mm Hg) than men (4.0 mm Hg) (interaction p = 0.005). Change in SBP was directly associated with change in NT-proBNP (p < 0.001) but not KCCQ-OSS (p = 0.40). The association between sacubitril/valsartan and the primary outcome was not modified by baseline SBP (interaction p = 0.50) and was similar when adjusting for time-updated SBP, regardless of sex.ConclusionsBaseline and mean achieved SBP of 120 to 129 mm Hg identified the lowest risk patients with HFpEF. Baseline SBP did not modify the treatment effect of sacubitril/valsartan, and the BP-lowering effects of sacubitril/valsartan did not account for its effects on outcomes, regardless of sex. (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)     

Long-Term Prognostic Value of Stress CMR in Patients With Heart Failure and Preserved Ejection Fraction

ObjectivesThe objectives of this study were to investigate the long-term prognostic value of inducible myocardial ischemia assessed by vasodilator stress cardiovascular magnetic resonance (CMR) in patients with HFpEF.BackgroundSome studies suggest that ischemia could play a key role in HF in patients with preserved ejection fraction (HFpEF).MethodsBetween 2008 and 2019, consecutive patients prospectively referred for stress CMR with HFpEF as defined by current guidelines, without known coronary artery disease (CAD), were followed for the occurrence of major adverse cardiovascular events (MACE), as defined by cardiovascular mortality or nonfatal myocardial infarction (MI). Secondary composite outcomes included cardiovascular mortality or hospitalization for acute HF. Cox regression analysis was performed to determine the prognostic value of inducible ischemia or late gadolinium enhancement (LGE) by CMR.ResultsAmong the 1,203 patients with HFpEF (73 ± 13 years of age; 29% males) who underwent stress CMR and completed follow-up (6.9 years interquartile range [IQR]: 6.7 to 7.7 years]), 108 experienced a MACE (9%). Kaplan-Meier analysis showed inducible ischemia and LGE were significantly associated with MACE (HR: 6.63; 95% confidence interval [CI]: 4.54 to 9.69; and HR: 2.56; 95% CI: 1.60 to 4.09, respectively; both p < 0.001) and secondary outcomes (HR: 8.40; 95% CI: 6.31 to 11.20; p < 0.001; and HR: 1.87; 95% CI: 1.27 to 2.76, respectively; p = 0.002). In multivariate analysis, inducible ischemia and LGE were independent predictors of MACE (HR: 6.10; 95% CI: 4.14 to 9.00; p < 0.001 and HR: 1.62; 95% CI: 1.06 to 2.49; p = 0.039; respectively).ConclusionsStress CMR-inducible myocardial ischemia and LGE have accurate discriminative long-term prognostic value in HFpEF patients without known CAD to predict the occurrence of MACE.     

Spironolactone in Patients With Heart Failure,Preserved Ejection Fraction,and Worsening Renal Function

BackgroundTreatment of heart failure with preserved ejection fraction (HFpEF) with spironolactone is associated with lower risk of heart failure hospitalization (HFH) but increased risk of worsening renal function (WRF). The prognostic implications of spironolactone-associated WRF in HFpEF patients are not well understood.ObjectivesThe purpose of this study was to investigate the association between WRF, spironolactone treatment, and clinical outcomes in patients with HFpEF.MethodsIn 1,767 patients randomized to spironolactone or placebo in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial)-Americas study, we examined the incidence of WRF (doubling of serum creatinine) by treatment assignment. Associations between incident WRF and subsequent risk for the primary study endpoint of cardiovascular (CV) death, HFH, or aborted cardiac arrest and key secondary outcomes, including CV death, HFH, and all-cause mortality according to treatment assignment, were examined in time-updated Cox proportional hazards models with an interaction term.ResultsWRF developed in 260 (14.7%) patients with higher rates in those assigned to spironolactone compared to placebo (17.8% vs. 11.6%; odds ratio: 1.66; 95% confidence interval: 1.27 to 2.17; p < 0.001). Regardless of treatment, incident WRF was associated with increased risk for the primary endpoint (hazard ratio: 2.04; 95% confidence interval: 1.52 to 2.72; p < 0.001) after multivariable adjustment. Although there was no statistical interaction between treatment assignment and WRF regarding the primary endpoint (interaction p = 0.11), spironolactone-associated WRF was associated with lower risk of CV death (interaction p = 0.003) and all-cause mortality (interaction p = 0.001) compared with placebo-associated WRF.ConclusionsAmong HFpEF patients enrolled in TOPCAT-Americas, spironolactone increased risk of WRF compared with placebo. Rates of CV death were lower with spironolactone in both patients with and without WRF.     

AI-Assisted Echocardiographic Prescreening of Heart Failure With Preserved Ejection Fraction on the Basis of Intrabeat Dynamics

ObjectivesThe aim of this study was to establish a rapid prescreening tool for heart failure with preserved ejection fraction (HFpEF) by using artificial intelligence (AI) techniques to detect abnormal echocardiographic patterns in structure and function on the basis of intrabeat dynamic changes in the left ventricle and the left atrium.BackgroundAlthough diagnostic criteria for HFpEF have been established, rapid and accurate assessment of HFpEF using echocardiography remains challenging and highly desirable.MethodsIn total, 1,041 patients with HFpEF and 1,263 asymptomatic individuals were included in the study. The participants’ 4-chamber view images were extracted from the echocardiographic files and randomly separated into training, validation, and internal testing data sets. An external testing data set comprising 150 patients with symptomatic chronic obstructive pulmonary disease and 315 patients with HFpEF from another hospital was used for further model validation. The intrabeat dynamics of the geometric measures were extracted frame by frame from the image sequence to train the AI models.ResultsThe accuracy, sensitivity, and specificity of the best AI model for detecting HFpEF were 0.91, 0.96, and 0.85, respectively. The model was further validated using an external testing data set, and the accuracy, sensitivity, and specificity became 0.85, 0.79, and 0.89, respectively. The area under the receiver-operating characteristic curve was used to evaluate model classification ability. The highest area under the curve in the internal testing data set and external testing data set was 0.95.ConclusionsThe AI system developed in this study, incorporating the novel concept of intrabeat dynamics, is a rapid, time-saving, and accurate prescreening method to facilitate HFpEF diagnosis. In addition to the classification of diagnostic outcomes, such an approach can automatically generate valuable quantitative metrics to assist clinicians in the diagnosis of HFpEF.     

Physical Functioning in Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent, yet interventions and therapies to improve outcomes remain limited. There has been increasing attention towards the impact of comorbidities and physical functioning (PF) on poor clinical outcomes within this population. In this review, we summarize and discuss the literature on PF in HFpEF, its association with clinical and patient-centered outcomes, and future advances in the care of HFpEF with respect to PF. Multiple PF metrics have been demonstrated to provide prognostic value within HFpEF, yet the data are less robust compared with other patient populations, highlighting the need for further investigation. The evaluation and detection of poor PF provides a potential strategy to improve care in HFpEF, and future studies are needed to understand if modulating PF improves clinical and/or patient-reported outcomes.Lay Summary• Patients with heart failure with preserved ejection fraction (HFpEF) commonly have impaired physical functioning (PF) demonstrated by limitations across a wide range of common PF metrics.• Impaired PF metrics demonstrate prognostic value for both clinical and patient-reported outcomes in HFpEF, making them plausible therapeutic targets to improve outcomes.• Clinical trials are ongoing to investigate novel methods of detecting, monitoring, and improving impaired PF to enhance HFpEF care.Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent, yet interventions and therapies to improve outcomes remain limited. As such, there has been increasing focus on the impact of physical performance (PF) on clinical and patient-centered outcomes. In this review, we discuss the state of PF in patients with HFpEF by examining the multitude of PF metrics available, their respective strengths and limitations, and their associations with outcomes in HFpEF. We highlight future advances in the care of HFpEF with respect to PF, particularly regarding the evaluation and detection of poor PF.     

Body Composition,Natriuretic Peptides,and Adverse Outcomes in Heart Failure With Preserved and Reduced Ejection Fraction

ObjectivesThe purpose of this study was to determine the relationship between body composition, N-terminal B-type natriuretic peptide (NT-proBNP) levels, and heart failure (HF) phenotypes and outcomes.BackgroundAbnormalities in body composition can influence metabolic dysfunction and HF severity; however, data assessing fat distribution and skeletal muscle (SM) size in HF with reduced (HFrEF) and preserved EF (HFpEF) are limited. Further, whether NPs relate more closely to axial muscle mass than measures of adiposity is not well studied.MethodsWe studied 572 adults without HF (n = 367), with HFrEF (n = 113), or with HFpEF (n = 92). Cardiac magnetic resonance was used to assess subcutaneous and visceral abdominal fat, paracardial fat, and axial SM size. We measured NT-proBNP in 334 participants. We used Cox regression to analyze the relationship between body composition and mortality.ResultsCompared with controls, pericardial and subcutaneous fat thickness were significantly increased in HFpEF, whereas patients with HFrEF had reduced axial SM size after adjusting for age, sex, race, and body height (p < 0.05 for comparisons). Lower axial SM size, but not fat, was significantly predictive of death in unadjusted (standardized hazard ratio: 0.63; p < 0.0001) and multivariable-adjusted analyses (standardized hazard ratio = 0.72; p = 0.0007). NT-proBNP levels more closely related to lower axial SM rather than fat distribution or body mass index (BMI) in network analysis, and when simultaneously assessed, only SM (p = 0.0002) but not BMI (p = 0.18) was associated with NT-proBNP. However, both NT-proBNP and axial SM mass were independently predictive of death (p < 0.05).ConclusionsHFpEF and HFrEF have distinct abnormalities in body composition. Reduced axial SM, but not fat, independently predicts mortality. Greater axial SM more closely associates with lower NT-proBNP rather than adiposity. Lower NT-proBNP levels in HFpEF compared with HFrEF relate more closely to muscle mass rather than obesity.     

Utility of E/e′ Ratio During Low-Level Exercise to Diagnose Heart Failure With Preserved Ejection Fraction

BackgroundE/e′ ratio during exercise is the key parameter in identifying elevated pulmonary capillary wedge pressure (PCWP), and thus heart failure with preserved ejection fraction (HFpEF). However, its diagnostic value is limited when mitral inflow or tissue velocities are fused during elevated heart rate.ObjectivesThe authors hypothesized that E/e‘ ratio during low-level (20 W) exercise (E/e′_20W) can help diagnose HFpEF.MethodsErgometric exercise stress echocardiography was performed in 215 dyspneic patients with an EF ≥50%. The authors determined the feasibility of E/e′ ratio at each stage (frequency of patients who had measurable E/e′ without E-A fusion among 215 participants) and examined whether E/e′_20W could predict normal E/e′ ratio during peak exercise (E/e′_peak ≤15). The authors also evaluated whether E/e′_20W could predict normal PCWP during exercise (PCWP <25 mm Hg) in a subset of participants (n = 45) who underwent exercise right heart catheterization.ResultsThe feasibility of the E/e′ ratio decreased from 100% at rest to 96.3% during 20-W exercise and 74.9% during peak exercise caused by E-A fusion. In patients with E/e′_peak >15, there was an increase in E/e′ ratio from rest to 20-W exercise (11.2 ± 2.1 to 16.3 ± 3.5; P < 0.0001), but it did not change significantly from 20-W exercise to peak exercise (P = 0.12). E/e′_20W predicted E/e′_peak ≤15 (AUC: 0.91; P < 0.0001) with the cutoff value of ≤12.4 showing high specificity (94%) and positive predictive value (98%). During 20-W exercise, 93% of the HFpEF patients developed PCWP ≥25 mm Hg. E/e′_20W predicted normal PCWP during exercise (AUC: 0.77; P = 0.01) with the cutoff value of ≤12.4 showing high specificity (83%).ConclusionsE/e′ ratio during low-level exercise is highly feasible and predicts normal E/e′ ratio or PCWP during peak exercise with high specificity. These data suggest that E/e′_20W could be used as an alternative to the peak exercise value to rule out HFpEF in patients with dyspnea.