Heart Failure With Preserved Ejection Fraction Subjects Research Articles

Clinical characteristics and long-term outcomes of patients with heart failure with supra-normal ejection fraction: data from LECRA-HF registry

Abstract Background Heart failure with preserved ejection fraction (HFpEF) remains insufficiently characterized subgroup of HF with increasing prevalence and limited treatment options. Relationship between clinically assessed left ventricular ejection fraction (LVEF) and survival showed that LVEF ≥65% is associated with higher mortality. Therefore, a novel category of heart failure with supra-normal left ventricular ejection fraction (HFsnEF) was introduced in 2019. However, clinical characteristics and long-term outcomes of HFsnEF patients remain insufficiently elucidated. Purpose We sought to characterize Polish HFsnEF patients and to provide their long-term mortality in comparison to HFpEF. Methods Of 1186 patients enrolled in the single-center Lesser Poland Cracovian Heart Failure (LECRA-HF) Registry between 2009 and 2019 and hospitalized due to HF decompensation 261 (22%) of them were those with LVEF ≥50%. 40 (15.3%) of them were classified as HFsnEF (LVEF ≥65%) and the remaining 221 (84.7%) as HFpEF. The data including patients’ demography, anthropometric measurements, cardiovascular risk factors, prior cardiological treatment and other comorbidities were collected. The long-term follow-up of all-cause mortality was obtained from the Polish National Death Registry. Results HFsnEF patients were less frequently hypertensive (75 vs 88.2%, P=0.026) and had higher baseline LVEF (65 [65-70] vs 55 [50-60] %, P<0.001) than HFpEF subjects. Furthermore, HFsnEF patients presented lower INR (1.1 [1-1.6] vs 1.3 [1.1-1.9], P=0.027) and total protein level (57 [25-63] vs (65.2 [60.2-69.9] g/L, P=0.008) on admission. HFsnEF patients were less frequently treated on discharge with mineralocorticoid receptor antagonists (25 vs 46.2%, P=0.013) as well as loop diuretics (60 vs 76%, P=0.017). The Kaplan-Meier analysis showed that all-cause mortality is higher in HFsnEF than in HFpEF (65.0 vs 55.2%, P=0.044, Figure 1). The independent predictors of long-term mortality were age and diagnosis of HFsnEF (HR 1.037, 95% CI 1.018-1.056 and HR 1.665, 95% CI 1.063-2.608, respectively). Conclusions Our findings indicate that every seventh Polish patient admitted with HFpEF could be classified as HFsnEF. Baseline characteristics of HFsnEF patients are different than HFpEF. Simultaneously, the HFsnEF diagnosis is associated with lower long-term survival.

The prothrombotic state in patients with type 2 diabetes mellitus and ischemic heart failure: an association with endothelial dysfunction

Abstract Background Heart failure (HF) is associated with a substantial prothrombotic state and an increased risk of thromboembolism, regardless of the presence of atrial fibrillation (AF). Although oral anticoagulation in HF with known AF is recommended, there is no conclusive evidence supporting clinical benefits of chronic anticoagulation in HF subjects without AF. Other factors enhancing prothrombotic state, often concomitant with HF, are type 2 diabetes mellitus (T2D) and coronary artery disease (CAD). T2D as well as CAD are independently associated with a hypercoaguability due to multiple mechanisms including endothelial dysfunction and oxidative stress. Dysfunction of endothelium was observed in patients with HF, however a little is known about its influence on prothrombotic state in a very high risk HF population. Purpose This study aimed to investigate whether the prothrombotic state in patients with T2D, CAD, and HF, depends on the left ventricular ejection fraction (LVEF) or endothelial function. Methods We assessed 54 patients with stable chronic HF, CAD, and T2D. Based on the echocardiography examination 28 of them were those with HF with reduced ejection fraction (HFrEF) and 26 of them were classified as HF with preserved ejection fraction (HFpEF) according to current guidelines. Fibrin clot density reflected by clot permeability (Ks) and thrombin generation were evaluated. Endothelial function was determined in flow-mediated (FMD) and nitroglycerin-mediated dilatation (NMD) tests of the brachial artery. Results Subjects in both groups were comparable in terms of cardiovascular risk factors except for lower glomerular filtration rate (GFR) by 18.1%. HFrEF patients had lower Ks by 20.3%, along with higher endogenous thrombin potential (ETP) by 18.9% and maximum thrombin level (Peak) by 24.1% as compared with HFpEF. While there were no differences in FMD and NMD between subjects, we found negative correlations of NMD with ETP and Peak (r=-0.448, P=0.001; r=-0.304, P=0.034, respectively). Moreover, the proportion of NMD and FMD along with GFR and LVEF were also significantly associated with both thrombogram parameters (<0.01 for all). By the multivariate analysis of the whole population, NMD, LVEF, low-density lipoprotein and GFR were independent predictors of ETP (R2=0.530, P<0.001) while NMD, LVEF, and GFR predicted Peak levels (R2=0.327, P=0.002). Conclusion We showed for the first time that patients with ischemic etiology of HFrEF and T2D presented altered fibrin clot properties and enhanced thrombin generation compared to HFpEF subjects. It might be hypothesized that endothelial dysfunction induced by T2D could intensify hypercoagulability in patients with HF.Figurę 1

Safety and efficacy of adaptive atrial pacing regulated by blood pressure during low-level exercise: a proof-of-concept study.

Despite half of all heart failure patients suffering from heart failure with preserved ejection fraction (HFpEF), treatment options are limited. This study aims to compare safety and efficacy of standard pacemaker programming (DDD or DDDR) and a novel pacing algorithm PressurePace™ (BaroPace Inc, Issaquah, WA, USA) which modulates atrial pacing rate based on blood pressure (BPAP). This prospective, randomized, double-blind, non-significant risk proof of concept study was conducted at two large cardiology clinics in Los Angeles, California, USA. Subjects underwent two modified Bruce protocol graded treadmill exercise tests in which pacemaker programming was randomized to either standard programming (DDD or DDDR), or BPAP at least 1week apart. Physiological measurements of heart rate (HR), and systolic and diastolic blood pressure (BP) were collected at 2min intervals. During the BPAP treadmill test, the pacemaker activity sensor was disabled. The PressurePace algorithm instructed the pacemaker technician to modify or leave unchanged the atrial pacing rate based on these BP measurements. Subjects and clinical staff were blinded to pacemaker programming, only the pacemaker technician was unblinded. Ten subjects with HFpEF associated with hypertension who also had permanent dual-chamber pacemakers, previously implanted for standard clinical indications, participated in the study. Mean age was 70.1±6.8 years, left ventricular ejection fraction of 54.8±1.9%. Exercise duration increased in all 10 subjects, when paced in the BPAP mode compared with standard pacemaker programming, showing a mean increase of 117s (26%, P=0.0016). The algorithm could adjust HR at each 2min interval. The majority of subjects (60%) had their atrial pacing rate increased an average of 20% at t=2min. In the remaining 40% of subjects, the algorithm instructed HR to be unchanged. In two subjects, the pacing rate was not increased until t=6min. In contrast, subjects programmed to DDDR experienced an average of 45% increase in atrial pacing rate at t=2min. In the post-treadmill recovery period, SBP was higher for subjects who underwent BPAP. This difference in SBP was most pronounced immediately post-treadmill and diminished as subjects progressed through the 30min recovery period. Statistical significance was achieved at t=0, 20, and 30min post-treadmill. An increase in exercise duration was reported in HFpEF subjects using a pacing algorithm that modulated HR based on BP compared with standard programming. These encouraging results form the basis for a larger, randomized cross-over trial to confirm these initial observations, further characterize the safety, efficacy, and possible mechanisms of action in both acute and longer-term treatment.

Obesity and heart failure with preserved ejection fraction.

Aim: To perform an overall assessment of heart failure with preserved ejection fraction (HFpEF) adults with central obesity. Materials and Methods: We enrolled HFpEF patients with central obesity (n =73, mean age 52.4 ± 6.3 years) and without obesity (n =70, mean age 51.9 ± 7.1 years) and compared with an age-matched healthy subjects who had not suffered from HF (n = 69, mean age 52.3 ± 7.5 years). Physical examination, routine laboratory tests such as fasting blood glucose, fasting insulin, insulin resistance (HOMA) index, serum lipids, haemoglobin, creatinine, ALT, AST, uric acide, hs CRP, TSH, N-terminal proB-type natriuretic peptide (NT-proBNP) and standard transthoracic echocardiogram (2D and Doppler) examinations were performed and assessed. Results: The average values of diastolic blood pressure (DBP), glucose and lipid profiles, uric acide, hs CRP were found to be significantly higher among obese patients with HFpEF than non-obese. Despite more severe symptoms and signs of HF, obese patients with HFpEF had lower NT-proBNP values than non-obese patients with HFpEF (129±36.8 pg/ml, 134±32.5 pg/ml vs 131±30.4 pg/ml, 139±33.8 pg/ml respectively; p < 0.05). However, it was found that patients with high central (visceral) adiposity have more pronounced obesity-related LV diastolic dysfunction, lower E/e' ratio, lower mitral annular lateral e' velocity, an increased LV diastolic dimension and LV mass index. Compared with non-obese HFpEF and control subjects, obese patients displayed greater right ventricular dilatation (base, 35±3.13 mm, 36±4.7 mm vs 33±2.8 mm, 34±3.2 mm and 29±5.3 mm, 30±3.9 mm; length, 74±5 mm, 76±8 mm vs 67±4 mm, 69±6 mm and 60±3 mm, 61±5 mm respectively; p < 0.05), more right ventricular dysfunction (TAPSE 16±2 mm, 15±3 mm vs 17±2 mm, 17±1 mm and 19±2 mm, 20±3 mm respectively; p < 0.05). Conclusions: Obese patients with HFpEF have higher diastolic BP, atherogenic dyslipidemia, insulin resistance index values and greater systemic inflammatory biomarkers, despite lower NT-proBNP values, which increase the risk of cardiovascular events in future. Echocardiography examination revealed not only significant LV diastolic dysfunction, but also displayed greater RV dilatation and dysfunction.

Construction and validation of a risk prediction model for 3- and 5-year new-onset atrial fibrillation in HFpEF patients.

Patients with heart failure (HF) with preserved ejection fraction (HFpEF) are more prone to atrial fibrillation (AF) compared to those with heart failure with reduced ejection fraction (HFrEF). Nevertheless, a risk prediction model for new-onset atrial fibrillation (NOAF) in HFpEF patients remains a notable gap, especially with respect to imaging indicators. We retrospectively analyzed 402 HFpEF subjects reviewed at the Affiliated Hospital of Qingdao University from 2017 to 2023. Cox regression analysis was performed to screen predictors of NOAF. A nomogram was constructed based on these factors and internally validated through the bootstrap resampling method. A performance comparison between the nomogram and the mC2HEST score was performed. Out of the 402 participants, 62 (15%) developed atrial fibrillation. The risk factors for NOAF were finally screened out to include age, chronic obstructive pulmonary disease (COPD), hyperthyroidism, renal dysfunction, left atrial anterior-posterior diameter (LAD), and pulmonary artery systolic pressure (PASP), all of which were identified to create the nomogram. We calculated the bootstrap-corrected C-index (0.819, 95% CI: 0.762-0.870) and drew receiver operator characteristic (ROC) curves [3-year areas under curves (AUC) = 0.827, 5-year AUC = 0.825], calibration curves, and clinical decision curves to evaluate the discrimination, calibration, and clinical adaptability of the six-factor nomogram. Based on two cutoff values calculated by X-tile software, the moderate- and high-risk groups had more NOAF cases than the low-risk group (P < 0.0001). Our nomogram showed better 3- and 5-year NOAF predictive performance than the mC2HEST score estimated by the Integrated Discriminant Improvement Index (IDI) and the Net Reclassification Index (NRI) (P < 0.05). The nomogram combining clinical features with echocardiographic indices helps predict NOAF among HFpEF patients.

Abstract 16269: Heart Failure With Preserved Ejection Fraction and Sudden Cardiac Death in the General Population

Background: Published data indicate that 50% of individuals with heart failure and reduced ejection fraction (HFrEF) suffer sudden cardiac death (SCD), however the burden of SCD in heart failure with preserved ejection fraction (HFpEF) remains inconclusive. Aim: Determine the prevalence of HFpEF in a community-based cohort of SCD. Methods: We prospectively identified cases with out-of-hospital SCD in a large metro area of the US Northwest (Pop. 1 million, 2002-2017) and determined HF status prior to SCD based on review of clinical records. Heart failure was subdivided into HFpEF (EF≥50%), HFmrEF (EF 40%-50%), and HFrEF (EF≤40%). In addition, since HFpEF is often underdiagnosed, we evaluated a modified H2FPEF algorithm for the identification of HFpEF among our SCD cohort with unknown HF subtypes. The score was comprised of clinical variables including age, BMI, atrial fibrillation, hypertension, and myocardial infarction. Score accuracy was assessed using receiver operating characteristic (ROC) analysis comparing known HFpEF from clinical records and echocardiography versus non-HF subjects. Next, the score was used to identify missing HFpEF cases within the HF and SCD population. Results: Among 4,683 total SCD cases, 1,013 (22%) had a clinical history of HF. Prevalence of HF sub-types was 42% for HFpEF, 19% for HFmEF and 39% for HFrEF cases. An algorithm score of 5 or greater differentiated HFpEF subjects from non-HF subjects with an AUC of 0.68 (p &lt; 0.01). The algorithm was then deployed on cases with an unknown heart failure subtype and an additional 117 HFpEF subjects were identified. The adjusted total prevalence of HFpEF was 542 subjects (53%) in the SCD the cohort with HF. Conclusion: At least 40% of the SCD cases with HF carry a diagnosis of HFpEF, and our estimates suggest the prevalence may be as high as 53%. Ultimately, these findings highlight the need to develop effective options for primary prevention of SCD in HFpEF patients.

Dietary Interventions in Heart Failure with Preserved Ejection Fraction (HFpEF): a systematic scoping review and meta-analysis

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Evelyn Trust. Background Pharmacotherapies have improved outcomes for patients with Heart Failure with reduced Ejection Fraction (HFrEF), but less so for patients with HFpEF. Limited treatments results in substantial burden at personal, clinical and economic levels. Diet has been implicated in the pathogenesis and prognosis of HFpEF, as such, dietary manipulation has the potential to be a useful management strategy. Purpose The aim of the scoping review was to establish which nutritional interventions have so far been tested in patients with HFpEF and establish how the dietary manipulation was achieved. The aim of the meta-analysis was to quantify the effects of interventions tested to determine whether there is evidence to support specific dietary recommendations in patients with HFpEF. Methods Key word searches were performed in five bibliographic databases to identify randomised or controlled studies of dietary interventions conducted in HFpEF or mixed heart failure (HF) samples. Study characteristics were summarised according to PICO (population, intervention, comparator, outcome) categories and intervention complexity was assessed. Studies included in the meta-analysis were appraised for bias and the quality of the body of evidence was assessed via the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) framework. Results Twenty-five different interventions reported across 31 papers were identified. Only ten (40%) were conducted exclusively in HFpEF subjects. Studies employing highly tailored prescribed methods were most common (n=12, 48%). Dietary supplementation (n=10, 40%) and dietary pattern manipulations (n=3, 12%) were less represented. Seventeen studies were considered for meta-analysis; all but one were judged to be at high risk of bias. There was moderate quality evidence that caloric restriction led to clinically meaningful improvements in blood pressure and body weight. There was moderate quality evidence carbohydrate restriction resulted in meaningful reductions in blood pressure. There was very low quality evidence protein supplementation improved blood pressure and body weight and moderate quality evidence for clinically meaningful improvements in function. Conclusions Very few dietary interventions have been tested in HFpEF specifically. Most interventions tested were complex at the patient level, which may not be suitable for the older, multi-morbid patients who typify HFpEF. Results of meta-analyses performed were not of sufficient quality to make generalised conclusions. Some interventions delivered clinically meaningful changes that may be important to patients, therefore, clinicians could draw on these findings to inform personalised care plans and treatment goals.

SEPTAL AND LEFT ATRIAL VOLUME INDEX AS PREDICTORS FOR HFPEF AMONGST TYPE 2 DIABETES MELLITUS PATIENTS

Objective: The aim of this study is to determine the prevalence and determination of risk factors of heart failure with preserved ejection fraction (HFpEF) diagnosed based on the consensus recommendation from the Heart Failure Association (HFA) and European Society of Cardiology (ESC) 2019 in type 2 diabetes mellitus (T2DM) patients in Malaysia. Design and method: We conducted a cross sectional study on patients with T2DM of more than 18 years old that were under Hospital UiTM follow-up from December 2021 until May 2021 (6 month). The participants were chosen via simple random sampling. Data's on demographic data, comorbid profile, symptoms and clinical examination including vitals sign, chemical profile and proceed with echocardiography and NTproBNP test to diagnosed HFpEF. Results: 201 diabetic patients were recruited and screened for HFpEF. 40 patients were confirmed with the diagnosis of HFpEF. Mean age was 61 ± 5.4 years. A significant difference in mean septal e’ was found between diabetic patients with HFpEF (5.5 ± 1.5 cm/s) and non-heart failure subjects (7.6 ± 1.0 cm/s)(p&lt;0.001, 95% CI -2.40,-1.49). There was also significant difference in mean left atrial volume index (LAVI) between diabetic patients with HFpEF (35.5 ± 1.5 ml/m2) and non-heart failure subjects (28.6 ± 1.0 ml/m2)(p&lt;0.001, 95% CI -2.50,-1.33). A stepwise increase in cortisol level corresponding to NTproBNP was observed(p&lt;0.061). Basal septal hypertrophy was seen in 30% of HFpEF diabetic patients (p&lt;0.081). Multiple linear regression analysis revealed septal e’ and LAVI as independent predictors of HFpEF in diabetic patients (r2 = 0.249, p&lt;0.001). Conclusions: One fifth of diabetic population had HFpEF and specific echocardiography parameters including septal e’ and LAVI were predictors for HFpEF. Emerging early imaging and chemical biomarkers for HFpEF such as basal septal hypertrophy and cortisol should be further studied.

SERCA2a Agonist Effects on Cardiac Performance During Exercise in Heart Failure With Preserved Ejection Fraction

BackgroundImpaired ventricular relaxation influences left ventricular pressures during exercise in heart failure with preserved ejection fraction (HFpEF). Sarco/endoplasmic reticulum calcium-adenosine triphosphatase (SERCA2a) facilitates myocardial relaxation by increasing calcium reuptake and is impaired in HFpEF. ObjectivesThis study sought to investigate the effects of istaroxime, a SERCA2 agonist, on lusitropic and hemodynamic function during exercise in patients with HFpEF and control subjects. MethodsEleven control subjects (7 male, 4 female) and 15 patients with HFpEF (8 male, 7 female) performed upright cycle exercise with right-sided heart catheterization. Participants received istaroxime (0.5 μg/kg/min) or saline placebo (single-blind, crossover design). Cardiac output, pulmonary capillary wedge pressure (PCWP), and diastolic function were measured at rest and during submaximal exercise. In an exploratory analysis (Hedge's g), 7 patients with HFpEF received higher-dose istaroxime (1.0 μg/kg/min). End-systolic elastance (Ees) was calculated by dividing systolic blood pressure (SBP) × 0.9 by end-systolic volume (ESV) (on 3-dimensional echocardiography). ResultsPatients with HFpEF had higher PCWP (25 ± 10 mm Hg vs 12 ± 5 mm Hg; P < 0.001) and lower tissue Doppler velocities during exercise. Istaroxime (0.5 μg/kg/min) had no effect on resting or exercise measures in patients with HFpEF or control subjects. Control subjects had a larger increase in Ees (Δ 1.55 ± 0.99 mm Hg/mL vs Δ 0.86 ± 1.31 mm Hg/mL; P = 0.03), driven by lower ESV. Comparing placebo and istaroxime 1.0 μg/kg/min during exercise, PCWP during the 1.0 μg/kg/min istaroxime dose was slightly lower (Δ 2.2 mm Hg; Hedge's g = 0.30). There were no effects on diastolic function, but there were increases in SBP and s′, suggesting a mild inotropic effect. ConclusionsLow-dose istaroxime had no effect on cardiac filling pressure or parameters of relaxation in patients with HFpEF during exercise. Higher doses of istaroxime may have been more effective in reducing exercise PCWP in patients with HFpEF. (Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a; NCT02772068)

Reflex Sympathetic Vasoconstriction And Functional Sympatholysis In Patients With Heart Failure With Preserved Ejection Fraction.

INTRODUCTION: Vascular impairments resulting in blood flow limitations to exercising muscle likely contribute to marked exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF). Blood flow to exercising muscle is modulated by the interaction of sympathetic nervous system (SNS)-mediated vasoconstriction and factors related to muscle contraction that counteract this vasoconstriction, so-called “functional sympatholysis”. While there is emerging evidence for SNS overactivity during exercise in patients with HFpEF, functional sympatholysis has not been assessed in this patient group. PURPOSE: To determine the effect of SNS-mediated vasoconstriction on exercising muscle blood flow and the efficacy of functional sympatholysis in HFpEF vs. age-matched control (CON) subjects. METHODS: 4 CON (2 male, 70 ± 2 yrs) and 5 Class II/III patients with HFpEF (2 male, 70 ± 4 yrs) participated in this study. Forearm blood flow (FBF, ultrasound Doppler), mean arterial blood pressure (MAP, Finometer), and forearm vascular conductance (FVC) were evaluated at rest and during rhythmic handgrip exercise (30% maximum voluntary contraction, 3-min bout, 1 Hz) before and after SNS activation evoked by lower body negative pressure (LBNP -20 mmHg). Hemodynamic changes (%Δ) in response to LBNP at rest and during exercise were compared between groups, and the magnitude of functional sympatholysis was calculated as the difference between LBNP-induced %Δ FVC from rest to exercise. RESULTS: At rest, %Δ FBF in response to LBNP was similar between CON vs. HFpEF (-24 ± 4% vs. 17 ± 5%), while %Δ FVC was significantly greater in CON vs. HFpEF (-23 ± 4% vs. -10 ± 3%, P < 0.05). During exercise, LBNP reduced FBF (-1 ± 2% vs. -6 ± 3%) and FVC (-1 ± 3% vs. -6 ± 3%) to a similar degree between groups. However, the magnitude of sympatholysis was significantly greater in CON vs. HFpEF (-23 ± 4% vs. -3 ± 4%, P < 0.05). LBNP-induced changes in MAP were not different between CON vs. HFpEF at rest (-1 ± 2% vs. -3 ± 1%) or during exercise (0 ± 2% vs. 1 ± 2%). CONCLUSION: These data suggest impaired functional sympatholysis in HFpEF, indicating that SNS-mediated vasoconstriction may contribute to blood flow limitations underpinning exercise intolerance in HFpEF

Pressure Overload Activates DNA-Damage Response in Cardiac Stromal Cells: A Novel Mechanism Behind Heart Failure With Preserved Ejection Fraction?

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterized by impaired left ventricular (LV) diastolic function, with normal LV ejection fraction. Aortic valve stenosis can cause an HFpEF-like syndrome by inducing sustained pressure overload (PO) and cardiac remodeling, as cardiomyocyte (CM) hypertrophy and fibrotic matrix deposition. Recently, in vivo studies linked PO maladaptive myocardial changes and DNA damage response (DDR) activation: DDR-persistent activation contributes to mouse CM hypertrophy and inflammation, promoting tissue remodeling, and HF. Despite the wide acknowledgment of the pivotal role of the stromal compartment in the fibrotic response to PO, the possible effects of DDR-persistent activation in cardiac stromal cell (C-MSC) are still unknown. Finally, this novel mechanism was not verified in human samples. This study aims to unravel the effects of PO-induced DDR on human C-MSC phenotypes. Human LV septum samples collected from severe aortic stenosis with HFpEF-like syndrome patients undergoing aortic valve surgery and healthy controls (HCs) were used both for histological tissue analyses and C-MSC isolation. PO-induced mechanical stimuli were simulated in vitro by cyclic unidirectional stretch. Interestingly, HFpEF tissue samples revealed DNA damage both in CM and C-MSC. DDR-activation markers γH2AX, pCHK1, and pCHK2 were expressed at higher levels in HFpEF total tissue than in HC. Primary C-MSC isolated from HFpEF and HC subjects and expanded in vitro confirmed the increased γH2AX and phosphorylated checkpoint protein expression, suggesting a persistent DDR response, in parallel with a higher expression of pro-fibrotic and pro-inflammatory factors respect to HC cells, hinting to a DDR-driven remodeling of HFpEF C-MSC. Pressure overload was simulated in vitro, and persistent activation of the CHK1 axis was induced in response to in vitro mechanical stretching, which also increased C-MSC secreted pro-inflammatory and pro-fibrotic molecules. Finally, fibrosis markers were reverted by the treatment with a CHK1/ATR pathway inhibitor, confirming a cause-effect relationship. In conclusion we demonstrated that, in severe aortic stenosis with HFpEF-like syndrome patients, PO induces DDR-persistent activation not only in CM but also in C-MSC. In C-MSC, DDR activation leads to inflammation and fibrosis, which can be prevented by specific DDR targeting.

Atrial fibrillation is an independent risk factor for heart failure hospitalization in heart failure with preserved ejection fraction.

Atrial fibrillation (AF) is a common comorbid condition in heart failure with preserved ejection fraction (HFpEF). The effect of AF on heart failure (HF) exacerbation in HFpEF has not been well described. This study investigated how AF modifies the clinical trajectory of HFpEF patients after hospitalization for decompensated HF. We stratified HFpEF subjects by AF diagnosis and performed longitudinal analysis to compare risk for HF hospitalization after index hospitalization for decompensated HF. All-cause mortality, 30day all-cause readmissions, and response to inpatient diuresis were also evaluated. Of 90 subjects enrolled, 35.6% (n=32) had AF. Subjects with AF were older (72.5 vs. 60.5years; P<0.01), more often male (46.9% vs. 24.1%; P=0.03), and had greater left atrial diameter (4.9 vs. 3.8cm; P<0.01) compared with those without AF. Subjects with AF had a higher risk for HF hospitalization than their counterparts without AF (P=0.02); this relationship remained significant following multivariable competing risk regression with propensity score weighting (hazard ratio 2.53, P=0.04 and hazard ratio 2.91, P=0.04, with overlap and inverse probability weighting, respectively). Although having AF appeared to increase the risk of all-cause hospital readmission within 30days of discharge (37.5% vs. 17.5%; P=0.036), this relationship failed to remain significant following propensity score adjustment for clinical covariates. Atrial fibrillation is an independent risk factor for HF rehospitalization in HFpEF. Further understanding of the interplay between AF and HFpEF will be critical to guide the selection of appropriate rhythm management strategies in this population.

Effects of Hypertrophic and Dilated Cardiac Geometric Remodeling on Ejection Fraction.

Background: Both heart failure (HF) with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) can present a wide variety of cardiac morphologies consequent to cardiac remodeling. We sought to study if geometric changes to the heart during such remodeling will adversely affect the ejection fraction (EF) parameter’s ability to serve as an indicator of heart function, and to identify the mechanism for it. Methods and Results: A numerical model that simulated the conversion of myocardial strain to stroke volume was developed from two porcine animal models of heart failure. Hypertrophic wall thickening was found to elevate EF, while left ventricle (LV) dilation was found to depress EF when myocardial strain was kept constant, causing EF to inaccurately represent the overall strain function. This was caused by EF being calculated using the endocardial boundary rather than the mid-wall layer. Radial displacement of the endocardial boundary resulted in endocardial strain deviating from the overall LV strain, and this deviation varied with LV geometric changes. This suggested that using the epi- or endo-boundaries to calculate functional parameters was not effective, and explained why EF could be adversely affected by geometric changes. Further, when EF was modified by calculating it at the mid-wall layer instead of at the endocardium, this shortcoming was resolved, and the mid-wall EF could differentiate between healthy and HFpEF subjects in our animal models, while the traditional EF could not. Conclusion: We presented the mechanism to explain why EF can no longer effectively indicate cardiac function during cardiac geometric changes relevant to HF remodeling, losing the ability to distinguish between hypertrophic diseased hearts from healthy hearts. Measuring EF at the mid-wall location rather than endocardium can avoid the shortcoming and better represent the cardiac strain function.

Impaired Right Atrial Reserve Function in Heart Failure with Preserved Ejection Fraction

Patients with heart failure with preserved ejection fraction (HFpEF) have multiple cardiac reserve limitations during exercise. However, no data are available regarding right atrial (RA) reserve capacity in HFpEF. The aim of this study was to determine the association of RA reserve impairments with right ventricular function and exercise capacity in HFpEF and to explore its diagnostic value. Patients with HFpEF (n=89) and control subjects without heart failure (n=108) underwent bicycle exercise echocardiography. RA reservoir, conduit, and booster pump strain at rest and during exercise were measured using speckle-tracking echocardiography. In a subset, simultaneous expired gas analysis was performed to measure peak oxygen consumption. At rest, RA reservoir strain was lower in patients with HFpEF than control subjects (27.0±17.1% vs 38.6±17.1%, P<.0001), while RA conduit and booster pump strain were similar between groups. During peak exercise, patients with HFpEF displayed marked reserve limitations in RA reservoir and booster pump function compared with control subjects, and the differences remained significant even after adjusting for confounding factors. During peak exercise, RA reservoir and booster pump strain were correlated with right ventricular systolic function. Lower RA booster pump strain during exercise was also weakly associated with lower cardiac output (r=0.34, P<.0001) and reduced peak oxygen consumption (r=0.47, P<.0001). RA reservoir strain during exercise had incremental diagnostic value to differentiate patients with HFpEF from control subjects over the established HFpEF diagnostic algorithms and left-sided strain parameters. Limitations in RA reservoir and booster pump function during exercise are present in patients with HFpEF, and the severity is associated with right ventricular systolic reserve, poor cardiac output, and depressed exercise capacity. Exercise RA strain assessment may help in the diagnosis of HFpEF.

Mechanical dispersion of left ventricle and left atrial reservoir strain are both superior to global longitudinal strain to predict exercise capacity in heart failure with preserved ejection fraction

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Fundação Adib Jatene Background/Introduction: Peak oxygen uptake (peak VO2) measures cardiovascular fitness and is a valuable diagnostic and prognostic marker in patients with heart failure with preserved ejection fraction (HFpEF). Measurement of peak VO2, however, requires specialized equipment and expert supervision, limiting its routine use by practicing clinicians. Strain curves obtained by speckle tracking echocardiography (STE) can provide different parameters of myocardial mechanics such as the Global Longitudinal Strain (GLS), which is the most robust STE feature for clinical practice. Notwithstanding, there is conflicting data on whether the GLS is associated with peak VO2 in HFpEF subjects. Moreover, few studies have addressed the relationship between peak VO2 and other interesting deformation parameters such as the left atrial (LA) reservoir strain or the left ventricular mechanical dispersion (MD). Purpose The present study aimed to examine the utility of the myocardial mechanics as assessed by STE in predicting peak VO2 in patients with HFpEF. Methods From an ongoing prospective cohort of 189 subjects, we sampled subjects with different HFpEF stages. All patients underwent cardiopulmonary exercise testing (CPX) and a 2D-STE (LV GLS, MD, LA reservoir strain, LA conduit strain, and LA contraction strain) obtained by a blinded examinator. The missing data was handled by complete case analysis approach. We excluded subjects who had atrial fibrillation/flutter, severe COPD, STE with poor tracking quality, CPX with respiratory exchange rate (RER) &amp;lt; 1. The Spearman"s correlation was calculated, and the 95% CI were estimated. Finally, an estimative of the STE features importance to predict peak VO2 &amp;lt; 20mL/Kg/min was done using the function "xgb.importance()" from machine learning model XGBoost in R software. XGBoost is a variant of Gradient Boosting Method that uses ensembles of decision trees. Results We obtained 74 subjects (23 without evidence of heart disease, 23 with pre-heart failure and 28 with HFpEF). The MD presented the highest correlation with peak VO2 (Rho=-0.48; p-value &amp;lt; 0.001) followed by LA reservoir strain (Rho = 0.40; p-value &amp;lt; 0.001), LA conduit strain (Rho= –0.36; p-value &amp;lt; 0.001) and LA contraction (Rho= –0.30 p-value &amp;lt; 0.004) as shown in Figure 1. However, no correlation was found between GLS and peak VO2 (Rho= –0.07 p-value &amp;lt; 0.5) (Figure 2A). The feature importance score (Figure 2B) showed the MD as the best relative contribution for VO2 prediction (gain= 0.34) superior to LA reservoir strain (gain = 0.25). GLS presented contribution (gain = 20) superior to LA conduit strain (gain =10) and LA contraction strain (gain = 0.08). Conclusion Left ventricular mechanical dispersion and left atrial reservoir strain obtained with STE were better predictors of peak VO2 than GLS in patients with different HFpEF stages and may be helpful in risk stratification and diagnosis. Abstract Figure 1 Abstract Figure 2

Prevalence and Prognostic Significance of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction

BackgroundThe pathophysiological and clinical significance of microvascular dysfunction (MVD) in patients with heart failure with preserved ejection fraction (HFpEF) remains uncertain. ObjectivesThe aim of this study was to use cardiovascular magnetic resonance to: 1) quantify coronary microvascular function; 2) examine the relationship between perfusion and fibrosis; and 3) evaluate the impact of MVD and fibrosis on long-term clinical outcomes. MethodsIn a prospective, observational study, patients with HFpEF and control subjects underwent multiparametric cardiovascular magnetic resonance (comprising assessment of left ventricular volumetry, perfusion, and fibrosis [focal by late gadolinium enhancement and diffuse by extracellular volume]). The primary endpoint was the composite of death or hospitalization with heart failure. ResultsOne hundred and one patients with HFpEF (mean age 73 ± 9 years, mean ejection fraction 56% ± 5%) and 43 control subjects (mean age 73 ± 5 years, mean ejection fraction 58% ± 5%) were studied. Myocardial perfusion reserve (MPR) was lower in patients with HFpEF versus control subjects (1.74 ± 0.76 vs 2.22 ± 0.76; P = 0.001). MVD (defined as MPR <2.0) was present in 70% of patients with HFpEF (vs 48% of control subjects; P = 0.014). There was no significant linear correlation between MPR and diffuse fibrosis (r = −0.10; P = 0.473) and no difference in MPR between those with and without focal fibrosis (mean difference −0.03; 95% CI: −0.37 to 0.30). In the HFpEF group, during median follow-up of 3.1 years, there were 45 composite events. MPR was independently predictive of clinical outcome following adjustment for clinical, blood, and imaging parameters (1 SD increase: HR: 0.673 [95% CI: 0.463 to 0.978; P = 0.038]; HR: 0.694 [95% CI: 0.491 to 0.982; P = 0.039]; and HR: 0.690 [95% CI: 0.489 to 0.973; P = 0.034], respectively). ConclusionsMVD is highly prevalent among patients with HFpEF and is an independent predictor of prognosis. The lack of correlation between MVD and fibrosis may challenge the assertion of a direct causal link between these entities. (Developing Imaging and Plasma Biomarkers in Describing Heart Failure With Preserved Ejection Fraction [DIAMONDHFpEF]; NCT03050593)

Pathophysiological and diagnostic importance of fatty acid-binding protein 1 in heart failure with preserved ejection fraction

Elevated intracardiac pressure at rest and/or exercise is a fundamental abnormality in heart failure with preserved ejection fraction (HFpEF). Fatty acid-binding protein 1 (FABP1) is proposed to be a sensitive biomarker for liver injury. We sought to determine whether FABP1 at rest would be elevated in HFpEF and would correlate with echocardiographic markers of intracardiac pressures at rest and during exercise. In this prospective study, subjects with HFpEF (n = 22) and control subjects without HF (n = 23) underwent resting FABP1 measurements and supine bicycle exercise echocardiography. Although levels of conventional hepatic enzymes were similar between groups, FABP1 levels were elevated in HFpEF compared to controls (45 [25–68] vs. 18 [14–24] ng/mL, p = 0.0008). FABP1 levels were correlated with radiographic and blood-based markers of congestion, hemodynamic derangements during peak exercise (E/e’, r = 0.50; right atrial pressure, r = 0.35; pulmonary artery systolic pressure, r = 0.46), reduced exercise cardiac output (r = − 0.49), and poor exercise workload achieved (r = − 0.40, all p < 0.05). FABP1 distinguished HFpEF from controls with an area under the curve of 0.79 (p = 0.003) and had an incremental diagnostic value over the H2FPEF score (p = 0.007). In conclusion, FABP1 could be a novel hepatic biomarker that associates with hemodynamic derangements, reduced cardiac output, and poor exercise capacity in HFpEF.

Prognostic value of pulmonary transit time by cardiac magnetic resonance in patients with heart failure with preserved ejection fraction

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): National Institute for Health Research Leicester Cardiovascular Biomedical Research Centre Background Quantifying pulmonary transit time (PTT) from cardiac magnetic resonance (CMR) first pass perfusion imaging is a novel technique for the evaluation of haemodynamic congestion in heart failure. Previous studies have demonstrated that PTT is prolonged in patients with heart failure with reduced ejection fraction (HFrEF) and that it provides independent prognostic information in this patient group. However, the potential diagnostic and prognostic roles of PTT assessment in patients with heart failure with preserved ejection fraction (HFpEF) remain to be established. Aim To compare PTT in healthy controls and in patients with HFpEF, and to determine the prognostic value of PTT in HFpEF. Methods In a prospective, observational study, HFpEF and age-matched control subjects underwent multi-parametric CMR at 3-Tesla, comprising quantitative left ventricular volumetric assessment using a standard steady-state free precession (SSFP) pulse sequence, and first-pass perfusion imaging at rest using a T1-weighted segmented inversion recovery gradient echo sequence (following injection of 0.04mmol/kg of contrast). PTT was calculated as the time interval between the peaks of signal intensity curves in the right and left ventricular blood pools (defined on the basal slice of the rest perfusion images). The primary endpoint was the composite of death or hospitalisation with heart failure. Results 88 HFpEF patients (age 73 ± 9 years, 51% male, EF 56.4 ± 5.6%) and 40 controls (age 73 ± 5 years, 43% male, EF 58.5 ± 4.7%) were studied. PTT was comparable in HFpEF patients (7.7 ± 3.8s) and in healthy controls (7.5 ± 1.8, p = 0.69). Normalised to cardiac cycle lengths, PTT remained comparable in HFpEF patients and healthy controls (8.5 ± 4.0 cardiac cycles versus 7.8 ± 1.6 cardiac cycles, respectively, p = 0.19). In the HFpEF group, during median follow-up of 3.4 years, there were 38 events (25 hospitalisations with heart failure, 13 deaths); a significant relationship between survival and PTT was not demonstrated (HR 1.06 [0.99,1.14] for a one-unit increase, p = 0.098). Conclusion In HFpEF, PTT is not prolonged compared with PTT in healthy subjects. Unlike in HFrEF, PTT does not appear to be diagnostically or prognostically significant in HFpEF. Figure 1: Graph showing signal intensity curves in the right (red) and left (green) ventricular blood pools Figure 2: Kaplan-Meier plot showing comparable rates of the composite endpoint in patients with PTT greater/less than median PTT (8 cardiac cycles)

Multimodality assessment of heart failure with preserved ejection fraction skeletal muscle reveals differences in the machinery of energy fuel metabolism.

AimsSkeletal muscle (SkM) abnormalities may impact exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF). We sought to quantify differences in SkM oxidative phosphorylation capacity (OxPhos), fibre composition, and the SkM proteome between HFpEF, hypertensive (HTN), and healthy participants.Methods and resultsFifty‐nine subjects (20 healthy, 19 HTN, and 20 HFpEF) performed a maximal‐effort cardiopulmonary exercise test to define peak oxygen consumption (VO2, peak), ventilatory threshold (VT), and VO2 efficiency (ratio of total work performed to O2 consumed). SkM OxPhos was assessed using Creatine Chemical‐Exchange Saturation Transfer (CrCEST, n = 51), which quantifies unphosphorylated Cr, before and after plantar flexion exercise. The half‐time of Cr recovery (t1/2, Cr) was taken as a metric of in vivo SkM OxPhos. In a subset of subjects (healthy = 13, HTN = 9, and HFpEF = 12), percutaneous biopsy of the vastus lateralis was performed for myofibre typing, mitochondrial morphology, and proteomic and phosphoproteomic analysis. HFpEF subjects demonstrated lower VO2,peak, VT, and VO2 efficiency than either control group (all P < 0.05). The t1/2, Cr was significantly longer in HFpEF (P = 0.005), indicative of impaired SkM OxPhos, and correlated with cycle ergometry exercise parameters. HFpEF SkM contained fewer Type I myofibres (P = 0.003). Proteomic analyses demonstrated (a) reduced levels of proteins related to OxPhos that correlated with exercise capacity and (b) reduced ERK signalling in HFpEF.ConclusionsHeart failure with preserved ejection fraction patients demonstrate impaired functional capacity and SkM OxPhos. Reductions in the proportions of Type I myofibres, proteins required for OxPhos, and altered phosphorylation signalling in the SkM may contribute to exercise intolerance in HFpEF.

Mathematical Modeling of Delayed Relaxation in Heart Failure with Preserved Ejection Fraction (HF‐pEF)‐ an Effect or a Cause?

The pathophysiological mechanisms underlying heart failure with preserved ejection fraction (HF-pEF) remain incompletely understood. One proposed hypothesis is that prolonged pressure decay of left ventricle during isovolumic relaxation, due to loss of enhancement of the ventricle, may lead to elevation of left ventricular end-diastolic pressure (LVEDP) and a reduction in stroke volume in HF-pEF subjects. However, while impaired relaxation is commonly observed in HF-pEF, it is unclear whether it is a contributing cause of HF-pEF or perhaps a consequence of other impairments. We sought to evaluate whether direct impairment in cardiac relaxation can contribute to a state of HF-pEF using a mathematical modeling approach. We utilized an existing mathematical model of cardio-renal hemodynamics in which a rectified sinusoidal twitch shape function drives left ventricular contraction and relaxation. To evaluate the effect of impaired relaxation, we altered the falling side of the twitch shape function so that isovolumetric relaxation time (IVRT) increased from 100 ms to 150 ms. In addition, we also evaluated the effect of delayed relaxation coupled with other ventricular changes associated with HF-pEF, including increased ventricular stiffness. Our simulations showed that when IVRT was increased, left ventricular pressure (LV pressure) fell more slowly during diastole. However, there was minimal effect on LVEDP. Pulmonary venous pressure also fell more slowly during diastole, and the peak pulmonary venous pressure during systole was slightly increased. Ejection fraction (EF) was minimally changed. The simulated presence of hypertension, hypertrophy, and/or increased cardiac stiffness did not impact the effect of slowed relaxation. While experimental validation is needed, our simulations suggest that impaired relaxation alone may not be a primary cause for increased preload experienced by many HF-pEF patients. It is possible that delayed relaxation is a consequence of other contributing mechanisms (e.g. impaired bioenergetics, calcium handling, or fibrosis which may impact ventricle stiffness and contractility) rather than a direct cause for elevated LV preload. While impaired relaxation had minimal effect on LVEDP, the small increases in peak pulmonary venous pressure and slower fall during diastole could impact pulmonary and atrial function in HF-pEF.