Heart Failure With A Preserved Ejection Fraction Research Articles

Clinical and proteomic profiles of chronic kidney disease in heart failure with reduced and preserved ejection fraction

BackgroundChronic kidney disease (CKD) is prevalent and related to poor clinical outcomes in patients with heart failure (HF). The pathophysiology of CKD in HF with a reduced ejection fraction (HFrEF) and HF with a preserved ejection fraction (HFpEF) is not well defined. In this study we compared clinical and proteomic profiles of CKD between patients with HFrEF and HFpEF. MethodsWe included 478 patients of the Scottish BIOSTAT-CHF cohort, of which 246 had HFrEF and 232 had HFpEF. CKD was defined as an eGFR <60 mL/min/1.73m2. We compared HFrEF-patients with CKD to HFpEF-patients with CKD using logistic- and Cox-regression. We performed a differential expression analysis using 6376 proteins. ResultsThe prevalence of CKD was 36 % and 32 % in patients with HFpEF and HFrEF, respectively. CKD patients were on average 7 years older. BMI, higher NT-proBNP, ACE-inhibitors, HDL-cholesterol and Stroke were associated with CKD- patients with HFrEF. In HFpEF, CKD was associated with MRA-use and higher platelet count. CKD was associated with increased risk of death or heart failure hospitalization (HR 1.82, p < 0.001), with similar effect in HFrEF and HFpEF. The pattern of differentially expressed proteins between patients with and without CKD was similar in both HF-groups. ConclusionClinical profiles related to CKD- patients with HFrEF were different from CKD-patients with HFrEF. CKD was associated with an increased risk of death or heart failure hospitalization, which was not different between HFpEF and HFrEF. Patterns of circulating proteins were similar between CKD-patients with HFpEF and HFrEF, suggesting no major differences in CKD-pathophysiology.

#957 The immunometabolic profile of human peritoneal macrophages during peritoneal dialysis and its relation to systemic cardiovascular effects

Abstract Background and Aims Patients with end-stage kidney disease (ESKD) treated with peritoneal dialysis (PD) exhibit a high risk of heart failure (HF). This largely concerns HF with a preserved ejection fraction (HFpEF). Uremic toxins, oxidative stress and systemic inflammation related to ESKD contribute to this HFpEF phenotype, which may be aggravated by the daily administration of glucose-rich PD-fluids. These induce insulin resistance and formation of advanced glycaemic end products, resulting in microvascular injury and arteriosclerosis. A hallmark of HFpEF is the presence of profibrotic cardiac macrophages that aggravate fibrosis. In the peritoneum, the non-physiological high glucose concentrations trigger local oxidative stress, fibrosis and inflammation, processes alike those seen in HFpEF. While the role of macrophages in HFpEF is established, the involvement of human peritoneal macrophages (HPMs) in PD-induced peritoneal injury is largely unknown. We hypothesize that HPMs, chronically exposed to the glucose-rich fluids, exhibit an inflammation-driven immunometabolic profile. This may contribute to cardiovascular (CV)-risk in PD-treated patients. We present preliminary results on the isolation of HPMs from PD effluent (PDE) and a detailed protocol to establish the immunometabolic profile of HPMs. These profiles will subsequently be related to cardiac function (left ventricular global longitudinal strain (LV-GLS), an echocardiographic measure of HFpEF) and parameters of systemic inflammation. Method In 15 adult PD-treated patients we will prospectively perform cardiac echography, draw a blood sample and collect PDE for HPM isolation. To obtain control HPMs a peritoneal saline flush will be collected from 5 adult patients with non-metastasized colon cancer during a routine diagnostic laparoscopy. HPMs will be isolated from the PDE and saline by centrifugation, followed by freezing for storage. We compared fresh and thawed cells of a PDE-sample to evaluate the impact of storage on HPM phenotype and functionality, respectively using flow cytometry and measurement of IL-6 production, with and without a lipopolysaccharide (LPS) challenge. In-depth HPM characterization will be performed by measuring glucose and lactate, conducting metabolic flux analysis, assessing glycolysis and mitochondrial characteristics using Seahorse®, and employing cytometry to evaluate reactive oxygen species and metabolic fuel preference. A phenotypical profile will be established using fluorescent probes and antibodies. To assess functionality, HPMs will be exposed in vitro to “M1” and “M2” inducers and we will use human monocyte-derived macrophages from healthy adult controls as a comparison. We will relate the immunometabolic, phenotypical and functional HPM characteristics to LV-GLS, blood cytokine (obtained with Bio-Plex multiplex) and blood immune profiles (obtained with cytometry) in PD-treated patients. Furthermore, we will compare the HPM characteristics of the PD-treated patients with the control group. Results Preliminary results of 6 patients show that we can isolate HPMs from the PDE with a yield of &amp;gt;5M cells. The phenotype and functionality of HPMs was evaluated both directly after isolation and after a freeze-thaw cycle. Flow cytometry showed high percentages of CD14+HLA-DR+CD64+ macrophages in both fresh and biobanked HPMs. IL-6 production was observed in both fresh and biobanked HPMs even without LPS-stimulation (Figure). Conclusion By successfully isolating and storing HPMs from the easily accessible PDE, we optimized the conditions to assess their immunometabolic characteristics. The proposed protocol not only aims to provide valuable insights into HPM phenotype and functionality, but also allows us to relate these to cardiac function and systemic inflammation. With this strategy, we aim to gain insight in the immunometabolic effects of PD on peritoneal immune cells and how these relate to CV-effects.

Update: Heart Failure with Preserved Ejection Fraction

Heart failure with a preserved ejection fraction (HFpEF) is a multifaceted disease entity. Confirming the diagnosis as well as tailoring the most appropriate therapy remains an ongoing challenge. The 2021 heart failure guidelines of the European Society of Cardiology (ESC) suggested a simplified diagnostic approach, and the guideline update provided in 2023 gave recommendations regarding pharmacotherapy based on recent evidence. Further, the Heart Failure Association (HFA) and the European Heart Rhythm Association of the ESC jointly proposed a scheme how to classify HFpEF patients into phenogroups of distinct pathophysiology that may benefit from individually targeted treatment. Regarding HFpEF originating from secondary causes, e.g. M. Fabry, amyloidosis or hypertrophic cardiomyopathy, there are emerging therapeutic options with the potential to substantially improve the physical capacity, quality of life and prognosis in these patients. The here presented update gives an overview on the recent advances in the area of HFpEF.

Plain language summary of the EMPEROR-Preserved study looking at the effect of empagliflozin in patients with heart failure with preserved ejection fraction, with and without diabetes.

The EMPEROR-Preserved study looked at the effects of empagliflozin in participants with heart failure with a preserved ejection fraction (HFpEF). This is when the lower left part of the heart (left ventricle) squeezes normally or near normally but does not fill with enough blood between heartbeats. Therefore, not enough blood is pumped around the body. For this study, HFpEF was defined as a condition in which more than 40% of blood in the left ventricle was pumped around the body. When researchers started the EMPEROR-Preserved study, there was no treatment for HFpEF. Also, researchers did not know if empagliflozin was more or less effective in people with and without diabetes, a condition where there are high levels of sugar (glucose) in the blood. This study included participants with HFpEF with and without diabetes to see if empagliflozin had a positive effect on the heart compared with a placebo (a pill that looked like empagliflozin but did not contain any active medication). Nearly 50% of participants had diabetes. The researchers looked at: How many people needed to be hospitalized for heart failure (HF) or died from conditions that affect the heart and blood vessels (cardiovascular disease) If peoples' kidneys worked less over time (the decline in kidney function) The side effects of empagliflozin. Empagliflozin reduced the risk of either being hospitalized for HF or dying from cardiovascular disease. The decrease in this risk was due to fewer hospitalizations for HF. This was true regardless of whether or not participants had diabetes. Empagliflozin also slowed the decline in kidney function, regardless of whether the participant had diabetes, but the effect was larger in participants with diabetes. There were no differences in side effects in participants taking empagliflozin or placebo, and the results were similar regardless of whether or not participants had diabetes. The results showed that treatment with empagliflozin reduced the risk of hospitalization for HF and there were no major side effects in participants with HFpEF, regardless of whether or not they had diabetes.

Abstract 17940: Effects of Continuous Accelerated Pacing on Clinical Outcomes in Patients With Heart Failure With Preserved Ejection Fraction: Three Year Follow Up of the myPACE Randomized Clinical Trial

Background: Heart failure with a preserved ejection fraction (HFpEF) is prevalent and has few evidence-based therapies. In a trial of HFpEF patients with specialized pacemakers, an accelerated personalized pacing rate averaging 75 bpm (myPACE) improved quality of life, NT-proBNP, physical activity, and atrial fibrillation burden compared with the standard lower rate setting of 60bpm (usual care). The one-year myPACE trial was not powered for clinical outcomes, but most patients elected to remain on their assigned treatment. Methods: The myPACE study was a single-center, blinded, randomized controlled trial that enrolled patients from June 2019 to November 2020. In this per-protocol analysis of clinical events over a 3-year follow-up, we included trial participants who remained on their assigned heart rate after study completion. The outcome of this analysis is a composite of the first clinical event (urgent visit or hospitalization for heart failure or atrial fibrillation, unstable angina or myocardial infarction, stroke, and death). Events were obtained by chart review and adjudicated by two blinded investigators. A Kaplan-Meier event-free survival plot and a log-rank test evaluated differences between the two treatment arms. Results: Of the 100 myPACE trial participants, most (40/48 myPACE and 48/52 usual care) remained on their assigned heart rate over a median (IQR) of 3.3 (2.6, 3.7) years after enrollment. The median (IQR) age was 75(69-80), and 45% were female. Accelerated personalized pacing was associated with reduced adverse clinical outcomes by about 60 percent. The Kaplan-Meier event-free survival plot for the composite of clinical events is shown in the Figure. Conclusions: In a per-protocol clinical event analysis of the extended myPACE study, those who continued the myPACE accelerated pacing protocol had fewer adverse clinical events than those with a lower rate setting of 60 bpm.

Evidence of impaired functional sympatholysis in patients with heart failure with preserved ejection fraction.

Exercising muscle blood flow is reduced in patients with heart failure with a preserved ejection fraction (HFpEF), which may be related to disease-related changes in the ability to overcome sympathetic nervous system (SNS)-mediated vasoconstriction during exercise, (i.e., "functional sympatholysis"). Thus, in 12 patients with HFpEF (69 ± 7 yr) and 11 healthy controls (Con, 69 ± 4 yr), we examined forearm blood flow (FBF), mean arterial pressure (MAP), and forearm vascular conductance (FVC) during rhythmic handgrip exercise (HG) at 30% of maximum voluntary contraction with or without lower-body negative pressure (LBNP, -20 mmHg) to increase SNS activity and elicit peripheral vasoconstriction. SNS-mediated vasoconstrictor responses were determined as LBNP-induced changes (%Δ) in FVC, and the "magnitude of sympatholysis" was calculated as the difference between responses at rest and during exercise. At rest, the LBNP-induced change in FVC was significantly lesser in HFpEF compared with Con (HFpEF: -9.5 ± 5.5 vs. Con: -21.0 ± 8.0%; P < 0.01). During exercise, LBNP-induced %ΔFVC was significantly attenuated in Con compared with rest (HG: -5.8 ± 6.0%; P < 0.05) but not in HFpEF (HG: -9.9 ± 2.5%; P = 0.88). Thus, the magnitude of sympatholysis was lesser in HFpEF compared with Con (HFpEF: 0.4 ± 4.7 vs. Con: -15.2 ± 11.8%; P < 0.01). These data demonstrate a diminished ability to attenuate SNS-mediated vasoconstriction in HFpEF and provide new evidence suggesting impaired functional sympatholysis in this patient group.NEW & NOTEWORTHY Data from the current study suggest that functional sympatholysis, or the ability to adequately attenuate sympathetic nervous system (SNS)-mediated vasoconstriction during exercise, is impaired in patients with heart failure with preserved ejection fraction (HFpEF). These observations extend the current understanding of HFpEF pathophysiology by implicating inadequate functional sympatholysis as an important contributor to reduced exercising muscle blood flow in this patient group.

De Novo Lipogenesis-Related Monounsaturated Fatty Acids in the Blood Are Associated with Cardiovascular Risk Factors in HFpEF Patients.

De novo lipogenesis (DNL)-related monounsaturated fatty acids (MUFAs) in the blood are associated with incident heart failure (HF). This observation's biological plausibility may be due to the potential of these MUFAs to induce proinflammatory pathways, endoplasmic reticulum stress, and insulin resistance, which are pathophysiologically relevant in HF. The associations of circulating MUFAs with cardiometabolic phenotypes in patients with heart failure with a preserved ejection fraction (HFpEF) are unknown. In this secondary analysis of the Aldosterone in Diastolic Heart Failure trial, circulating MUFAs were analysed in 404 patients using the HS-Omega-3-Index® methodology. Patients were 67 ± 8 years old, 53% female, NYHA II/III (87/13%). The ejection fraction was ≥50%, E/e' 7.1 ± 1.5, and the median NT-proBNP 158 ng/L (IQR 82-298). Associations of MUFAs with metabolic, functional, and echocardiographic patient characteristics at baseline/12 months follow-up (12 mFU) were analysed using Spearman's correlation coefficients and linear regression analyses, using sex/age as covariates. Circulating levels of C16:1n7 and C18:1n9 were positively associated with BMI/truncal adiposity and associated traits (dysglycemia, atherogenic dyslipidemia, and biomarkers suggestive of non-alcoholic-fatty liver disease). They were furthermore inversely associated with functional capacity at baseline/12 mFU. In contrast, higher levels of C20:1n9 and C24:1n9 were associated with lower cardiometabolic risk and higher exercise capacity at baseline/12 mFU. In patients with HFpEF, circulating levels of individual MUFAs were differentially associated with cardiovascular risk factors. Our findings speak against categorizing FA based on physicochemical properties. Circulating MUFAs may warrant further investigation as prognostic markers in HFpEF.

Blood Immune Cell Alterations in Patients with Hypertensive Left Ventricular Hypertrophy and Heart Failure with Preserved Ejection Fraction.

(1) Background: Chronic inflammation and fibrosis are key players in cardiac remodeling associated with left ventricular hypertrophy (LVH) and heart failure with a preserved ejection fraction (HFpEF). Monocytes and T-helpers (Th) are involved in both pro-inflammatory and fibrotic processes, while regulatory T-cells (Treg) could be considered to suppress chronic inflammation in the hypertrophied myocardium. We aimed to estimate the relationship between the frequencies of circulating CD4+ T-cell and monocyte subpopulations and the variables of left ventricular (LV) diastolic function in patients with LVH depending on the presence of HFpEF. (2) Methods: We enrolled 57 patients with asymptomatic hypertensive LVH (n = 21), or LVH associated with HFpEF (n = 36). A clinical assessment and echocardiographs were analyzed. CD4+ Treg, activated Th (Th-act), and monocyte (classical, intermediate, and non-classical) subpopulations were evaluated via direct immunofluorescence and flow cytometry. (3) Results: Patients with HFpEF had a lower Treg/Th-act ratio (p = 0.001). Though asymptomatic patients and patients with HFpEF were comparable in terms of both the total monocyte number and monocyte subsets, there were moderate correlations between intermediate monocyte count and conventional and novel echocardiographic variables of LV diastolic dysfunction in patients with HFpEF. (4) Conclusions: In patients with LVH, the clinical deterioration (transition to HFpEF) and progression of LV diastolic dysfunction are probably associated with T-cell disbalance and an increase in intermediate monocyte counts.

Association of perivascular fat attenuation on computed tomography and heart failure with preserved ejection fraction.

Heart failure with a preserved ejection fraction (HFpEF) is associated with chronic inflammation. We aimed to investigate the association between pericoronary adipose tissue attenuation (PCATA) on coronary computed tomography angiography as a novel noninvasive marker of pericoronary inflammation and the presence of HFpEF. This retrospective study included 607 outpatients (median age, 65years; 50% male) who underwent both echocardiography and coronary computed tomography angiography. Patients with obstructive coronary artery disease were excluded from this study. PCATA was compared between patients with and without HFpEF, which was diagnosed according to the Heart Failure Association (HFA)-PEFF score. PCATA was assessed at the proximal 40-mm segments of all three major coronary arteries on coronary computed tomography angiography. Patients with HFpEF had higher PCATA in all coronary arteries compared to the control participants: left anterior descending artery (LAD), -65.2±6.9 Hounsfield units (HU) vs. -68.1±6.7 HU; left circumflex artery (LCX), -62.7±6.8 HU vs. -65.4±6.6 HU; and right coronary artery (RCA), -63.6±8.5 HU vs. -65.5±7.7 HU (P<0.01). Multivariate logistic regression analysis, including conventional risk factors, revealed that PCATA per standard deviation in the LAD (odds ratio [OR], 1.449; 95% confidence interval [CI], 1.152-1.823), LCX (OR, 1.634; 95% CI, 1.283-2.081), and RCA (OR, 1.388; 95% CI, 1.107-1.740) were independently associated with HFpEF. The association between PCATA and HFpEF was mostly consistent across various patient clinical characteristics. The left ventricular mass and left atrial volume index showed a mild correlation with LAD-PCATA (ρ=0.13 [P<0.01] and ρ=0.24 [P<0.01]) and LCX-PCATA (ρ=0.16 [P<0.01] and ρ=0.23 [P<0.01]). High PCATA score was significantly associated with the presence of HFpEF. Our results suggest that inflammation in the pericoronary artery adipose tissue is one of the underlying mechanisms of HFpEF.

PS-B02-3: FGF23 EXACERBATES CARDIAC FIBROSIS IN DOCA-SALT HYPERTENSIVE MICE THROUGH LOCALLY ABNORMAL VITAMIN D METABOLISM

Backgrounds: Fibroblast growth factor 23 (FGF23) is associated with cardiovascular disease in patients with chronic kidney disease (CKD), but the mechanisms underlying the effect of FGF23 on cardiac function remain to be investigated. Herein, we studied the effect of continuous intravenous (CIV) FGF23 loading in a deoxycorticosterone acetate (DOCA)-salt mouse model that has mild CKD and hypertension, and heart failure with a preserved ejection fraction (HFpEF). Design and method: Wild type male mice (n = 16) were allocated randomly to four groups: normal control (NC), vehicle-treated DOCA-salt mice (V), FGF23-treated DOCA-salt mice (F), and FGF23 and calcitriol-treated DOCA-salt mice (C). The DOCA-salt mice received agents by CIV for ten days via an infusion mini-pump, uninephrectomized, and cardiac changes were evaluated in these mice. Results: DOCA-salt mice that received FGF23 showed a marked increase in serum FGF23 (249 pg/mL in V, 1416 pg/mL in F, and 1261 pg/mL in C) than NC (51 pg/mL). Echocardiography in these DOCA-salt mice revealed HFpEF. These mice also showed exacerbation of myocardial fibrosis area (7.0% in V, 13.2% in F, and 3.8% in C) concomitant with an inverse and significant correlation with Cyp27b1 expression (r = -0.79, P &lt; 0.01). Calcitriol treatment attenuated the FGF23-induced cardiac fibrosis (F vs. C, P &lt; 0.01) and improved diastolic function (early-to-atrial wave ratio in doppler echocardiography, 0.7 in F vs. 2.0 in C; P &lt; 0.01) via inhibition of transforming growth factor (TGF)-beta signaling. Protein expression levels of TGF-beta was significantly higher in F (1.32-fold to NC; P &lt; 0.01) than in NC, and significantly lower in C (0.96-fold to NC; P &lt; 0.05) than in F. This effect was independent of systemic and local FGF23 levels. Conclusions: These results suggest that CIV FGF23 loading induced cardiac fibrosis concomitantly with locally abnormal vitamin D metabolism, and this might have contributed to HFpEF progression in the DOCA-salt mice model. Thus, cardiac toxicity of FGF23 may be partly due to vitamin D inactivation in cardiac tissue. Calcitriol has cardioprotective effects by mediating TGF-beta signaling, independently of local and systemic FGF23 levels.

One size fits all: The story of SGLT2 inhibitors in heart failure

EMPEROR-Preserved and DELIVER have ushered in a new era for thetreatment of heart failure with a preserved ejection fraction (HFpEF). In this commentary, we compare the characteristics and findings of these two trials and assess their implications for the broader management of the heart failure syndrome.

Heart failure with a preserved ejection fraction and the EMPEROR-Preserved Trial: a review of how we got here.

Heart failure with a preserved ejection fraction (HFpEF), previously known as diastolic heart failure, was first recognized more than 50years ago. In spite of all the advances in the knowledge of HFpEF, important questions remain, namely the fact that no therapy has been shown to improve outcomes in these patients. The EMPEROR-Preserved Trial, a trial on the use of empagliflozin on patients with HFpEF, published in October 2021, was the first trial to ever show a change in outcomes in these patients. This article reviews the history of HFpEF and the problems related to its definition and diagnosis over time, and critically reviews the results of the EMPEROR-Preserved Trial in light of these.

Carotid Baroreflex Responsiveness in Patients with Heart Failure with a Preserved Ejection Fraction

The carotid baroreflex (CBR) plays an important role in blood pressure regulation by modulating heart rate (HR) and vasomotor tone. In humans, CBR function can be investigated non‐invasively using the variable pressure neck collar, which alters carotid sinus transmural pressure through application of positive and negative pressure within the neck chamber. Using this technique, derangements in CBR function have been identified in a variety of patient populations, but whether patients with heart failure with a preserved ejection fraction (HFpEF) suffer from disease‐related changes in CBR responsiveness has yet to be determined. We evaluated beat‐to‐beat changes in HR and mean arterial pressure (MAP) in response to 5‐sec pulses of neck pressure (NP, +40 Torr) and neck suction (NS, ‐80 Torr) to simulate carotid hypotension and hypertension, respectively in 5 patients with HFpEF (69±3 yrs and BMI: 38±4) and 4 healthy, older controls (68±2 yrs and BMI: 26±3). Resting HR was lower in patients with HFpEF compared to control subjects (77±7 vs. 68±6 bpm, respectively; p&lt;0.005), while MAP was similar between groups (88±2 vs. 88±5mmHg, HFpEF vs controls). Following NP, a disease‐related decrement in CBR responsiveness was evident, with diminished changes in HR (2±1 vs 9±1 bpm, HFpEF vs controls, p=0.041) and MAP (4±2 vs 8±1 mmHg, p=0.095) in the HFpEF group. Similarly, changes in both HR (‐6±1 vs ‐8±1 bpm, HFpEF vs controls, p=0.21) and MAP (‐5±1 vs ‐8±1 mmHg, HFpEF vs controls, p=0.16) in response to carotid hypertension provoked by NS were reduced in patient with HFpEF. Though preliminary in nature, these initial findings appear to indicate a decline in carotid baroreflex‐mediated cardiac and vasomotor control in patients with HFpEF that is likely to contribute significantly to autonomic nervous system dysregulation in this patient group.

Obesity and heart failure with preserved ejection fraction: pathophysiology and clinical significance

Obesity is a risk factor for heart failure and cardiovascular disease. Of particular note, over 80% of patients with heart failure with a preserved ejection fraction (HFpEF) are overweight or obese. In this study, we aimed to review the association between obesity and HFpEF. Obese patients with HFpEF exhibit a distinct phenotype. In addition to impaired left ventricular (LV) diastolic function and high filling pressures, obese patients with HFpEF possess other factors that cause elevated LV filling pressure, such as a greater dependence on plasma volume expansion, aggravated pericardial restraint, and increased ventricular interaction. Obesity can contribute to HFpEF through hemodynamic, neurohormonal, inflammatory, and mechanical mechanisms. An increased amount of body fat can induce plasma volume expansion, resulting in chamber remodeling, pericardial restraint, and ultimately elevations in LV filling pressure. Obesity can mediate the activation of sympathetic nervous system signaling and the renin-angiotensin-aldosterone system. These unique pathophysiological characteristics of individuals with both obesity and HFpEF suggest that obesity with HFpEF can be considered a specific phenotype. Future research is expected to clarify effective treatment modalities for obesity-related HFpEF.

Transthoracic echocardiography indices as a biomarker in patients with embolic stroke of undetermined source

BackgroundEmbolic stroke of undetermined source (ESUS) refers to a nonlacunar, nonatherosclerotic infarct in the absence of cardioembolic source or other specific causes of stroke. The presence of ESUS strokes indicates that the conventional risk factors cannot fully account for the pathogenesis of stroke. It is very important to detect useful biomarkers of the risk of ESUS for appropriate 2ry prevention.ResultsThe present study showed significant increase in left ventricular hypertrophy (LVH) measured by left ventricular mass index and increased left atrial volume index, measuring left atrial dilatation, among ESUS patients.ConclusionsPatients with ESUS tended to have Echocardiographic features of heart failure with a preserved ejection fraction (HFpEF) as LVH and left atrial dilatation. Therefore, they should be considered as biomarkers for cardioembolic cerebrovascular accidents with the consideration of anticoagulation with new oral anticoagulants as a primary preventive measure.

Phenotypic characterization of primary cardiac fibroblasts from patients with HFpEF.

Heart failure is a leading cause of hospitalizations and mortality worldwide. Heart failure with a preserved ejection fraction (HFpEF) represents a significant clinical challenge due to the lack of available treatment modalities for patients diagnosed with HFpEF. One symptom of HFpEF is impaired diastolic function that is associated with increases in left ventricular stiffness. Increases in myocardial fibrillar collagen content is one factor contributing to increases in myocardial stiffness. Cardiac fibroblasts are the primary cell type that produce fibrillar collagen in the heart. However, relatively little is known regarding phenotypic changes in cardiac fibroblasts in HFpEF myocardium. In the current study, cardiac fibroblasts were established from left ventricular epicardial biopsies obtained from patients undergoing cardiovascular interventions and divided into three categories: Referent control, hypertension without a heart failure designation (HTN (-) HFpEF), and hypertension with heart failure (HTN (+) HFpEF). Biopsies were evaluated for cardiac myocyte cross-sectional area (CSA) and collagen volume fraction. Primary fibroblast cultures were assessed for differences in proliferation and protein expression of collagen I, Membrane Type 1-Matrix Metalloproteinase (MT1-MMP), and α smooth muscle actin (αSMA). Biopsies from HTN (-) HFpEF and HTN (+) HFpEF exhibited increases in myocyte CSA over referent control although only HTN (+) HFpEF exhibited significant increases in fibrillar collagen content. No significant changes in proliferation or αSMA was detected in HTN (-) HFpEF or HTN (+) HFpEF cultures versus referent control. Significant increases in production of collagen I was detected in HF (-) HFpEF fibroblasts, whereas significant decreases in MT1-MMP levels were measured in HTN (+) HFpEF cells. We conclude that epicardial biopsies provide a viable source for primary fibroblast cultures and that phenotypic differences are demonstrated by HTN (-) HFpEF and HTN (+) HFpEF cells versus referent control.

Study of the Correlation Between the Ratio of Diastolic to Systolic Durations and Echocardiography Measurements and Its Application to the Classification of Heart Failure Phenotypes.

BackgroundThis study aimed to investigate the correlation between the ratio of diastolic to systolic durations (D/S) and echocardiographic parameters of patients with chronic heart failure (CHF) and evaluate whether the D/S can be used as a supplementary biomarker for the classification of heart failure (HF) phenotypes.MethodsIn total, 122 CHF patients with a left ventricular ejection fraction (LVEF) <40%, 40%≤LVEF<50%, or ≥50% were categorized as having HF with a reduced ejection fraction (HFrEF) (N=32), HF with a mid-range ejection fraction (HFmrEF) (N=21) or HF with a preserved ejection fraction (HFpEF) (N=69), respectively. All patients underwent echocardiography for assessment of nineteen structural and functional echocardiographic parameters and digital phonocardiography for the measurement of D/S. Spearman correlation was used to analyse the associations between the D/S and echocardiographic parameters. Multivariate logistic regression analysis was performed to examine the associations between the D/S and HF phenotypes, and receiver operating characteristic (ROC) curve analysis was employed to evaluate the predictive value of the D/S in the classification of HF phenotypes.ResultsThe D/S values of patients with HFrEF, HFmrEF and HFpEF were 1.32±0.06, 1.44±0.11 and 1.54±0.08, respectively, which were significantly different (All P<0.05). A close correlation between the D/S and LVEF was found (r=0.777, P<0.001). The multivariate analysis indicated that the D/S was an independent risk factor for CHF phenotypes (OR=4.927, 95% CI 2.532–9.587; P<0.001). The area under the ROC curve for distinguishing between HFmrEF and HFpEF using the D/S was 0.764 (95% CI 0.707–0.845; P < 0.001) and that for distinguishing between HFmrEF and HFrEF using the D/S was 0.821 (95% CI 0.755–0.882; P < 0.001).ConclusionThe D/S was significantly associated with LVEF, and as LVEF decreased, the D/S tended to decrease, which could also serve as a noninvasive supplementary indicator for detecting systolic and diastolic dysfunction.

Endothelial-Mesenchymal Transition in Heart Failure With a Preserved Ejection Fraction: Insights Into the Cardiorenal Syndrome.

The management of clinical heart failure with a preserved ejection fraction (HFpEF) is often complicated by concurrent renal dysfunction, known as the cardiorenal syndrome. This, combined with the notable lack of evidence-based therapies for HFpEF, highlights the importance of examining mechanisms and targetable pathways in HFpEF with the cardiorenal syndrome. HFpEF was induced in mice by uninephrectomy, infusion of d-aldosterone (HFpEF; N=10) or saline (Sham; N=8), and given 1% NaCl drinking water for 4 weeks. Renal fibrosis and endothelial-mesenchymal transition (endo-MT) were evident once HFpEF developed. Human aortic endothelial cells were treated for 4 days with 10% serum obtained from patients with chronically stable HFpEF with the cardiorenal syndrome (N=12) and compared with serum-treated human aortic endothelial cells from control subjects (no cardiac/renal disease; N=12) to recapitulate the in vivo findings. Kidneys from HFpEF mice demonstrated hypertrophy, interstitial fibrosis (1.9-fold increase; P<0.05) with increased expression of endo-MT transcripts, including pdgfrβ (platelet-derived growth factor receptor β), snail, fibronectin, fsp1 (fibroblast-specific protein 1), and vimentin by 1.7- (P=0.004), 1.7- (P=0.05), 1.8- (P=0.005), 2.6- (P=0.001), and 2.0-fold (P=0.001) versus Sham. Immunostaining demonstrated co-localization of CD31 and ACTA2 (actin α2) in kidney sections suggesting evidence of endo-MT. Similar to the findings in HFpEF mice, comparable endo-MT markers were also significantly elevated in human aortic endothelial cells treated with serum from patients with HFpEF compared with human aortic endothelial cells treated with serum from control subjects. These translational findings demonstrate a plausible role for endo-MT in HFpEF with cardiorenal syndrome and may have therapeutic implications in drug development for patients with HFpEF and concomitant renal dysfunction.

Aldosterone dysregulation predicts the risk of mortality and rehospitalization in heart failure with a preserved ejection fraction.

Serum aldosterone is associated with cardiac remodeling, which contributes to morbidity and mortality in heart failure (HF); however, the prognostic value of aldosterone in HF with a preserved ejection fraction (HFpEF) is unclear. We used liquid chromatography-tandem mass spectrometry to quantify serum aldosterone in 873 patients with HFpEF in a Registry Study of Biomarkers for HF. The retrospective study was conducted at Beijing Anzhen Hospital from May 2017 to October 2019. The primary endpoint was a composite of all-cause mortality and rehospitalization for HF. Aldosterone concentrations in patients with and without events were 124.22 pmol L-1 (interquartile range (IQR): 48.62-256.20) and 96.33 pmol L-1 (IQR: 37.33-215.76), respectively (P=0.023). Aldosterone independently predicted all-cause mortality (adjusted hazard ratio (aHR), 1.55; 95% confidence interval (95%CI), 1.06-2.27; P=0.024) and the primary endpoint (aHR, 1.43; 95%CI, 1.11-1.85; P=0.006). Patients with high aldosterone concentrations were at higher risk of concentric remodeling (adjusted odds ratio (aOR), 1.45; 95% CI, 1.03-2.04; P=0.034). Patients with high aldosterone and B-type natriuretic peptide concentrations were at a higher risk of the primary endpoint (hazard ratio (HR), 1.85; 95%CI, 1.29-2.66; P=0.001). We conclude that elevated aldosterone is associated with a risk of rehospitalization with HF and all-cause mortality in patients with HFpEF.

Meta-analysis of the Usefulness of Catheter Ablation of Atrial Fibrillation in Patients With Heart Failure With Preserved Ejection Fraction

Catheter ablation improves clinical outcomes in atrial fibrillation (AF) patients with heart failure (HF) with reduced ejection fraction (HFrEF). However, the role of catheter ablation in HF with a preserved ejection fraction (HFpEF) is less clear. We performed a literature search and systematic review of studies that compared AF recurrence at one year after catheter ablation of AF in patients with HFpEF versus those with HFrEF. Risk ratio (RR; where a RR <1.0 favors the HFpEF group) and mean difference (MD; where MD <0 favors the HFpEF group) 95% confidence intervals (CI) were measured for dichotomous and continuous variables, respectively. Six studies with a total of 1,505 patients were included, of which 764 (51%) had HFpEF and 741 (49%) had HFrEF. Patients with HFpEF experienced similar recurrence of AF 1 year after ablation on or off antiarrhythmic drugs compared with those with HFrEF (RR 1.01; 95% CI 0.76, 1.35). Fluoroscopy time was significantly shorter in the HFpEF group (MD -5.42; 95% CI -8.51, -2.34), but there was no significant difference in procedure time (MD 1.74; 95% CI -11.89, 15.37) or periprocedural adverse events between groups (RR 0.84; 95% CI 0.54,1.32). There was no significant difference in hospitalizations between groups (MD 1.18; 95% CI 0.90, 1.55), but HFpEF patients experienced significantly less mortality (MD 0.41; 95% CI 0.18, 0.94). In conclusion, based on the results of this meta-analysis, catheter ablation of AF in patients with HFpEF appears as safe and efficacious in maintaining sinus rhythm as in those with HFrEF.