Natural language processing of biomedical text to map and prioritize protein-disease associations in HFpEF.

Vascular Dysfunction in Heart Failure with Preserved Ejection Fraction

H eart failure (HF) with preserved ejection fraction (HFpEF) is the most common form of HF.Approximately 90% of new HF cases in older women are HFpEF. 1 Adverse outcomes -exercise intolerance, poor quality of life, frequent hospitalizations, and reduced survival -approach those of HF with reduced EF (HFrEF).In contrast to HFrEF, the prevalence of HFpEF is increasing and its prognosis is worsening. 2Despite the strong public health importance of HFpEF, its pathogenesis is poorly understood.Our lack of understanding of HFpEF and its treatment is punctuated by the fact that 6 large, well-designed, randomized, clinical trials and several smaller ones were all neutral on their primary outcomes.The combination of high prevalence and lack of evidence-based treatments makes HFpEF a highpriority topic for research in cardiovascular disease. Article see p 550A glaring absence among HFpEF studies has been a systematic autopsy-based study.Such studies have become more difficult as autopsy rates have declined with the availability of advanced multimodality imaging and deep-tissue biopsy techniques.Despite the increasing array of modern research techniques, postmortem methods continue to be uniquely valuable because of the ability to perform comprehensive, indepth, detailed examinations of tissues and organs in humans.In this issue of Circulation, Mohammed and colleagues 3 at the Mayo Clinic fill this critical gap with the first autopsy series of HFpEF.From a tissue registry patiently accumulated over a period of 19 years, their multidisciplinary team methodically collected and comprehensively analyzed specimens, medical records, electrocardiograms, and echocardiograms from 255 individuals, including patients with premortem diagnosis of HFpEF (n=124) and HFrEF (n=27), and from age-matched case controls who died of noncardiovascular causes (n=104).Characteristics of the HFpEF patients were relatively similar to community-based reports, including advanced age and a high prevalence of common comorbidities, including hypertension, diabetes mellitus, obesity, and clinical coronary artery disease (CAD).

Jumping down the rabbit hole: unravelling the right ventricle in heart failure.

Recent evidence implicates the endothelium as a central mediator in the development of heart failure with preserved ejection fraction (HFpEF).1 Co-morbidities such as hypertension, diabetes mellitus and obesity induce an inflammatory state and reduce nitric oxide (NO) bioavailability.2 This NO shortage modulates diastolic function and ventricular stiffness and reduces peripheral vasodilatory capacity—both physiological hallmarks of HFpEF.3 Reduced NO bioavailability can be clinically measured as endothelial dysfunction. In HFpEF patients, most studies agree brachial artery endothelial function is not different from controls, but microvascular function is reduced.4 Repair of deficient endothelium is possible through endothelial progenitor cells (EPC), circulating bone marrow-derived cells that secrete vascular growth factors and are recruited rapidly by injury or exercise.5 Angiogenic T cells (TA), a subpopulation of T lymphocytes with high angiogenic properties, have been shown to help proliferate EPC and mature endothelial cells in vitro.5 Exercise training is recommended to improve aerobic capacity and quality of life in HFpEF patients,6 but the mechanisms underlying these improvements are largely unknown. In patients with heart failure and reduced ejection fraction (HFrEF), known to have severe endothelial dysfunction, levels of circulating EPC are reduced and TA are dysfunctional. The latter could be corrected by a single exercise bout.7 Data in HFpEF are lacking. We hypothesized that HFpEF patients are characterized by microvascular endothelial dysfunction, coinciding with reduced numbers of circulating EPC and TA. Also, we postulated that a single maximal exercise bout recruits EPC and TA, in analogy to HFrEF patients. Power analysis based on previous literature8 revealed that 26 patients per group would detect a difference in endothelial function with 80% power. From 2014 to 2015, we recruited ambulatory and clinically stable HFpEF patients according to criteria for an ongoing HFpEF clinical trial.9 Inclusion criteria were (i) signs or symptoms of heart failure, New York Heart Association (NYHA) class II or III; (ii) left ventricular ejection fraction ≥50%; (iii) echocardiographic E/e' ratio >15 or E/e' 8–15 and plasma brain natriuretic peptide >80 pg/mL; (iv) structured exercise <2 × 30 min per week. Additionally, we recruited age- and sex-matched healthy volunteers (HV). Volunteers were required to be sedentary, asymptomatic, free from cardiovascular disease and diabetes, and not taking cardiovascular drugs, to limit the confounding effect of co-morbidities. Cardiac structural or functional abnormalities were excluded by electrocardiogram and echocardiography. All participants provided written informed consent. This study abides to the Declaration of Helsinki and was approved by the ethics committee of the Antwerp University Hospital. Endothelial function was assessed by peripheral arterial tonometry (PAT) at the fingertip (EndoPAT, Itamar Medical, Caesarea, Israel). After 5 min of baseline measurement, a blood pressure cuff was inflated at the forearm during 5 min to 100 mmHg above systolic blood pressure, and subsequently released causing an endothelium-dependent reactive hyperaemia. Dedicated software calculated the PAT ratio and reactive hyperaemia index (RHI). A RHI below the median has been described to predict a worse prognosis in HFpEF patients.10 Exercise capacity was assessed by a symptom-limited maximal cardiopulmonary exercise test (CPET) using a ramp protocol of 20 W + 10 W/min on a bicycle ergometer (Ergoline-Schiller).11 Endothelial function was reassessed after CPET. Blood was drawn before and 10 min after CPET, and flow cytometry for EPC and TA was performed on a FACSCanto II flow cytometer (BD Biosciences). EPC were defined as CD34+KDR+CD45dim cells, TA were defined as CD3+CD31+CD184+ cells. Analysis and gating strategy have been published previously.5 Baseline comparisons were performed using Welch two-sample t-test (continuous variables), Wilcoxon rank sum test (skewed continuous variables) and Pearson's Chi-squared test (categorical variables). Spearman coefficients (rho) were used for correlations. Linear mixed models were used to analyse repeated measures data, with Holm correction for post-hoc multiple comparisons. A multiple linear regression model was used to assess determinants of peak oxygen uptake (peak VO2), NYHA class and E/e' adding all traditional cardiovascular risk factors as covariates and subsequently removing those not contributing to the analysis. A P-value of <0.05 was considered significant. All data were analysed using R v3.4.3. Healthy volunteers and HFpEF patients were well matched for age and gender (HV: 73 ± 6, HFpEF: 74 ± 7 years, P = 0.622; HV: 62%, HFpEF: 62% female, P = 1.0) Several co-morbidities were more prevalent in HFpEF patients, including hypertension (85%), hyperlipidaemia (77%), obesity (46%) and diabetes (31%, all P < 0.05). HFpEF patients were characterized by diastolic dysfunction [E/e' HV: 10.1 (9.3–11.7), HFpEF 16.5 (14.0–20.0), P < 0.001] and structural cardiac changes [left atrial volume HV: 22.9 (17.3–27.5), HFpEF 43.2 (33.5–49.4) mL/m2, P < 0.001]. Exercise capacity was reduced in HFpEF patients compared to HV [peak VO2: HV: 23.3 (21.6–29.0), HFpEF 17.5 (13.6–19.1) mL/kg/min, P < 0.001]. Baseline endothelial function was impaired in HFpEF patients: the PAT ratio was consistently lower in HFpEF patients (Figure 1A). RHI, adjusting PAT measurements for systemic effects and baseline variation, was significantly reduced (P = 0.036, Figure 1B). Likewise, the amount of circulating EPC and TA was significantly lower in HFpEF compared to HV (EPC P = 0.025; TA P = 0.047, Figure 1C and 1D). A single exercise bout decreased RHI in HV, while it did not aggravate the pre-existent endothelial dysfunction in HFpEF patients (Figure 1E and 1F). No exercise-induced changes were seen in EPC (Figure 1G), whereas circulating TA significantly increased with exercise in both groups (Figure 1H). RHI showed an inverse relation with E/e': better endothelial function predicted better diastolic function (β = −7.53, adjusted R2 = 0.20, P = 0.001, multiple linear regression corrected for age). Endothelial function was also modestly related to NYHA class and peak VO2 (rho = –0.381, P = 0.007 and rho = 0.349, P = 0.015, respectively) but these relations were lost in multiple linear regression (correcting for age, body mass index and diabetes). Higher baseline TA predicted less severe symptoms of dyspnoea assessed by NYHA class (β = −1.19·10−4, adjusted R2 = 0.40, P = 0.008, multiple linear regression corrected for body mass index and diabetes). Neither EPC nor TA were related to endothelial function (all P > 0.10). In conclusion, we report reduced baseline numbers of circulating endothelium-repairing cells parallel to microvascular endothelial dysfunction in HFpEF patients. Acute exercise recruits angiogenic TA in both HV and HFpEF patients. Endothelial function did not further aggravate after acute exercise in HFpEF patients. The effect of exercise training on endothelial function and repair in HFpEF remains to be determined, but hopes are high that unravelling the beneficial effects of exercise will eventually lead to efficient endothelium-targeting therapies in HFpEF patients. Conflict of interest: none declared.

eart failure with preserved ejection fraction (HFpEF) has been previously defined by various criteria, 1 with a common theme being the presence of preserved left ventricular ejection fraction. Defining a heart disease on the basis of a normal cardiac finding should beg the question: What is distinctly abnormal about the heart in HFpEF? Answering this question may aid in overcoming a track record of limited success to date with pharmacological approaches to HFpEF.

Study objective: Heart failure (HF) syndrome is associated with pulmonary system abnormalities that have a direct impact on mortality. Heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF) are distinct subtypes of HF with different pathophysiologies, clinical presentations, and treatment approaches. Obesity is highly prevalent in HFpEF and significantly contributes to its development. Importantly, obesity and high abdominal adiposity can have significant effects on pulmonary function. Therefore, HFpEF patients may have more pronounced pulmonary function impairment than HFrEF patients in part due to higher prevalence of upper body adiposity. Hypothesis: We hypothesized that lung volumes would be lower in patients with HFpEF compared to those with HFrEF and CTL. Further, we hypothesized that higher upper body adiposity (measured as trunk fat by dual-energy X-ray absorptiometry) would be associated with lower lung volumes in patients with HFpEF. Methods: HFpEF patients (n=26), HFrEF patients (n=26) and CTL (n=36) performed pulmonary function tests according to ATS/ERS guidelines. Total lung capacity (TLC), residual volume (RV), forced vital capacity (FVC), and forced expiratory volume in one second (FEV1) were measured and absolute and % predicted values are reported. Dual-energy X-ray absorptiometry scans quantified % trunk fat. Absolute lung volumes were compared across groups using ANCOVA with age as a covariate and % predicted lung volumes were compared using one-way ANOVA. Results: HFpEF patients were older than HFrEF patients and CTL (HFpEF: 71±9 vs. HFrEF: 65±9 vs. CTL: 63±11 yrs, both p&lt;0.05) while no differences were present among groups for sex, height, or BMI (all, p&gt;0.05). HFpEF patients had higher % trunk fat than CTL (p&lt;0.01), while no differences were present between HFrEF and HFpEF or CTL (p&gt;0.05) (HFpEF: 46±11 vs. HFrEF: 42±8 vs. CTL: 38±11%). HFpEF patients had lower FVC (HFpEF: 3.0±0.7 vs. HFrEF: 3.7±1.0 vs. CTL: 3.8±0.8 L), FEV1 (HFpEF: 2.3±0.5 vs. HFrEF: 2.8±0.8 vs. CTL: 2.9±0.6 L), TLC (HFpEF: 5.5±1.3 vs. HFrEF: 6.3±1.4 vs. CTL: 6.4±1.1 L), and % predicted TLC than CTL (all, p&lt;0.05). HFpEF and HFrEF patients had lower % predicted FVC and % predicted FEV1 than CTL (p&lt;0.05). All other pulmonary function parameters were not different among groups (p&gt;0.05). There was a negative relationship between % trunk fat and TLC for HFpEF patients (r= -0.51, p&lt;0.05). There were negative relationships between % trunk fat and FVC for CTL (r= -0.37) and HFpEF patients (r= -0.50) (both, p&lt;0.05), with statistically different y-intercepts (p&lt;0.01). There were no other significant relationships (all, p&gt;0.05). Conclusion: These findings demonstrate that patients with HF have smaller lung volumes than CTL. Further, our findings suggest that upper body adiposity may be an important contributing factor to these pulmonary system abnormalities in HFpEF. None. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

This article refers to 'Different correlates but similar prognostic implications for right ventricular dysfunction in heart failure patients with reduced or preserved ejection fraction' by S. Ghio et al., published in this issue on pages 873-879.

Cardiac Rehabilitation Has Important Benefits for Both HFpEF and HFrEF Patients

Diagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging. Intraventricular four-dimensional flow (4D flow) phase-contrast cardiovascular magnetic resonance (CMR) can assess different components of left ventricular (LV) flow including direct flow, delayed ejection, retained inflow and residual volume. This could be utilised to identify HFpEF. This study investigated if intraventricular 4D flow CMR could differentiate HFpEF patients from non-HFpEF and asymptomatic controls. Suspected HFpEF patients and asymptomatic controls were recruited prospectively. HFpEF patients were confirmed using European Society of Cardiology (ESC) 2021 expert recommendations. Non-HFpEF patients were diagnosed if suspected HFpEF patients did not fulfil ESC 2021 criteria. LV direct flow, delayed ejection, retained inflow and residual volume were obtained from 4D flow CMR images. Receiver operating characteristic (ROC) curves were plotted. 63 subjects (25 HFpEF patients, 22 non-HFpEF patients and 16 asymptomatic controls) were included in this study. 46% were male, mean age 69.8 ± 9.1years. CMR 4D flow derived LV direct flow and residual volume could differentiate HFpEF vs combined group of non-HFpEF and asymptomatic controls (p < 0.001 for both) as well as HFpEF vs non-HFpEF patients (p = 0.021 and p = 0.005, respectively). Among the 4 parameters, direct flow had the largest area under curve (AUC) of 0.781 when comparing HFpEF vs combined group of non-HFpEF and asymptomatic controls, while residual volume had the largest AUC of 0.740 when comparing HFpEF and non-HFpEF patients. CMR 4D flow derived LV direct flow and residual volume show promise in differentiating HFpEF patients from non-HFpEF patients.

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