Heart Failure With Preserved Ejection Fraction Patient Research Articles

HeartMate 3 for Heart Failure with Preserved Ejection Fraction: In Vitro Hemodynamic Evaluation and Anatomical Fitting.

Heart failure with preserved ejection fraction (HFpEF) constitutes approximately 50% of heart failure (HF) cases, and encompasses different phenotypes. Among these, most patients with HFpEF exhibit structural heart changes, often with smaller left ventricular cavities, which pose challenges for utilizing ventricular assist devices (VADs). A left atrial to aortic (LA-Ao) VAD configuration could address these challenges, potentially enhancing patient quality of life by lowering elevated mean left atrial pressure (MLAP). This study assessed the anatomical compatibility and left atrial unloading capacity using a simulated VAD-supported HFpEF patient. A HeartMate3-supported HFpEF patient in an LA-Ao configuration was simulated using a cardiovascular simulator. Hemodynamic parameters were recorded during rest and exercise at seven pump flow rates. Computed tomography scans of 14 HFpEF (NYHA II-III) and six heart failure with reduced ejection fraction patients were analysed for anatomical comparisons. HFpEF models were independently assessed for virtual anatomical fit with the HM3 in the LA-Ao configuration. Baseline MLAP was reduced from 15 to 11mmHg with the addition of 1L/min HM3 support in the rest condition. In an exercise simulation, 6L/min of HM3 support was required to reduce the MLAP from 29 to 16mmHg. The HM3 successfully accommodated six HFpEF patients without causing interference with other cardiac structures, whereas it caused impingement ranging from 4 to 14mm in the remaining patients. This study demonstrated that the HM3 in an LA-Ao configuration may be suitable for unloading the left atrium and relieving pulmonary congestion in some HFpEF patients where size-related limitations can be addressed through pre-surgical anatomical fit analysis.

Nonpharmacological Approaches to Managing Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a common subtype of heart failure marked by impaired left ventricular diastolic function and decreased myocardial compliance. Given the limited availability of evidence-based pharmacological treatments for HFpEF, there is a growing interest in nonpharmacological interventions as viable therapeutic alternatives. This review aims to explore the pathophysiology of HFpEF and present recent advancements in nonpharmacological management approaches, encompassing noninvasive therapies, invasive procedures and targeted treatments for comorbidities. An extensive literature review was undertaken to identify and synthesize emerging nonpharmacological treatment options for HFpEF, assessing their potential to enhance patient outcomes. Nonpharmacological strategies, such as vagus nerve stimulation, percutaneous pulmonary artery denervation, renal denervation, transcatheter insertion of atrial shunts and pericardial resection, demonstrate promising potential for alleviating HFpEF symptoms and improving patient prognosis. Moreover, addressing comorbidities, such as hypertension and diabetes, may offer additional therapeutic benefits. These cutting-edge techniques, in conjunction with well-established exercise therapies, pave the way for future research and clinical applications in the field. Nonpharmacological interventions hold promise for advancing HFpEF patient care and fostering a deeper understanding of these treatment approaches, which will facilitate new clinical applications and contribute to the development of more targeted therapies.

Diagnosis of heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF) currently causes about half of the heart failure related hospitalizations. With the aging of the population and increasing prevalence of risk factors and comorbidities, such as arterial hypertension, diabetes mellitus and obesity, HFpEF prevalence is expected to increase as well. With regards to quality of life, overall morbidity, and mortality, HFpEF patients have a similarly adverse prognosis as patients with heart failure with reduced ejection fraction. The leading symptoms of exertional dyspnea and exercise intolerance with concomitant clinical signs of heart failure should, therefore, prompt diagnostic tests to exclude or confirm HFpEF. Considering the main pathophysiological mechanisms, echocardiography is crucial to non-invasively identify signs of left ventricular (LV) hypertrophy, impaired myocardial relaxation, and elevated filling pressures. Elevated NT-proBNP may furthermore indicate increased LV wall stress and volume overload. If the results of these investigations are inconclusive, parameters of elevated filling pressures can be measured invasively by right or left heart catheterization. High pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) may confirm a HFpEF diagnosis. Ongoing studies are investigating potential distinct phenotypes within the HFpEF patient group.

Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction.

Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model. Using a panel of 20 candidate CH driver genes and a variant allele fraction cutoff of 0.5%, ultradeep error-corrected sequencing identified CH in a cohort of 81 patients with HFpEF (mean age, 71±6 years; ejection fraction, 63±5%) and 36 controls without a diagnosis of HFpEF (mean age, 74±7 years; ejection fraction, 61.5±8%). CH was also evaluated in a replication cohort of 59 individuals with HFpEF. Compared with controls, there was an enrichment of TET2-mediated CH in the HFpEF patient cohort (12% versus 0%, respectively; P=0.02). In the HFpEF cohort, patients with CH exhibited exacerbated diastolic dysfunction in terms of E/e' (14.9 versus 11.7, respectively; P=0.0096) and E/A (1.69 versus 0.89, respectively; P=0.0206) compared with those without CH. The association of CH with exacerbated diastolic dysfunction was corroborated in a validation cohort of individuals with HFpEF. In accordance, patients with HFpEF, an age ≥70 years, and CH exhibited worse prognosis in terms of 5-year cardiovascular-related hospitalization rate (hazard ratio, 5.06; P=0.042) compared with patients with HFpEF and an age ≥70 years without CH. To investigate the causal role of CH in HFpEF, nonconditioned mice underwent adoptive transfer with Tet2-wild-type or Tet2-deficient bone marrow and were subsequently subjected to a high-fat diet/L-NAME (Nω-nitro-l-arginine methyl ester) combination treatment to induce features of HFpEF. This model of Tet2-CH exacerbated cardiac hypertrophy by heart weight/tibia length and cardiomyocyte size, diastolic dysfunction by E/e' and left ventricular end-diastolic pressure, and cardiac fibrosis compared with the Tet2-wild-type condition. CH is associated with worse heart function and prognosis in patients with HFpEF, and a murine experimental model of Tet2-mediated CH displays greater features of HFpEF.

Medical Costs of Chronic Kidney Disease and Type 2 Diabetes Among Newly Diagnosed Heart Failure Patients With Reduced, Mildly Reduced, and Preserved Ejection Fraction

The economic burden of heart failure (HF) is enormous, but studies of HF costs typically consider the disease to be a single entity. We sought to distinguish the medical costs for patients with HF with reduced ejection fraction (HFrEF), mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). We identified 16,516 adult patients with an incident HF diagnosis and an echocardiogram from 2005 to 2017 in the electronic medical record of Kaiser Permanente Northwest. Using the echocardiogram nearest to the first diagnosis date, we classified patients with HFrEF (ejection fraction [EF] ≤40%), HFmrEF (EF 41% to 49%), or HFpEF (EF ≥50%). We calculated annualized inpatient, outpatient, emergency, pharmaceutical medical utilization and costs and total costs in $2,020, adjusted for age and gender using generalized linear models, with further analysis of the effects of co-morbid chronic kidney disease (CKD) and type 2 diabetes (T2D). For all HF types, 1 in 5 patients were affected by both CKD and T2D, and costs were significantly higher when both co-morbidities were present. Total per-person costs were significantly higher for HFpEF ($33,740, 95% confidence interval $32,944 to $34,536) than HFrEF ($27,669, $25,649 to $29,689) or HFmrEF ($29,484, $27,166 to $31,800), driven by in- and outpatient visits. Across HF types, visits approximately doubled with the presence of both co-morbidities. Due to greater prevalence, HFpEF accounted for the majority of total and resource-specific treatment costs of HF, regardless of the presence of CKD and/or T2D. In summary, the economic burden was greater per HFpEF patient and was further amplified by co-morbid CKD and T2D. HFpEF accounted for the large majority of total HF costs, underscoring the need to implement effective treatments.

Abstract 12212: Heart Failure With Preserved Ejection Fraction: A Cardiologist Disorder or a Nephrologist Problem? Analysis From a Largely Hispanic Population

Introduction: Heart failure with preserved ejection fraction (HFpEF) has been recognized as a multisystem process and chronic kidney disease (CKD) plays a central role in this paradigm. However, racial/ethnic variability and prevalence of CKD are not well described. Hypothesis: We hypothesize that the South Texas Hispanic patient population has a different phenotypic expression of HFpEF compared to the largely White population in the EMPEROR-Preserved trial. Methods: Consecutive HFpEF patients (total n=204) were identified from a HF population screened for a clinical trial from 2019-2020 (n=188) and inpatients with HF exacerbation during 2021 (n=16) at University Hospital. HFpEF was defined as symptomatic HF with left ventricular ejection fraction (LVEF) >40% on Echo. Clinical and lab variables were collected ±1 year from Echo date. Race/ethnicity was self-reported. CKD was identified from the problem list. Rates were compared with EMEPROR-Preserved trial’s HFpEF population which was largely White. Results: Of 204 HFpEF patients, 9 were Black, 14 were from other races, and due to small size were excluded from the analysis. Majority of the study population were Hispanics (130 of 181, 72%). LVEF was 40-50% in 31% of the study population. Table 1 demonstrates characteristics by EMPEROR population, and Hispanics and non-Hispanic Whites (NHW) in our analysis. Of significance, our population was younger, had DM2, CAD, CKD, and obesity at higher rates, and AFib and BNP at lower rates as compared to EMPEROR population. The differences in Hispanics and NHW were unremarkable except more HTN and lower eGFR in Hispanics. Conclusions: Hispanic patients with HFpEF have more frequent diabetes, CKD and CAD as compared to White population in EMPEROR-Preserved trial. In context of this observation and recent success of newer agents as empagliflozin, a multispecialty integrative approach is strongly warranted for management of HFpEF patient population.

Cost-Effectiveness of Adding Empagliflozin to Standard Treatment for Heart Failure with Preserved Ejection Fraction Patients in China.

Heart failure is a worldwide health problem and is the leading cause of hospitalization in older patients. Heart failure with preserved ejection fraction (HFpEF) accounts for about 38% of heart failure cases. The latest EMPEROR-Preserved study shows that empagliflozin can reduce the risk of hospitalization in HFpEF, but whether empagliflozin is cost-effective in HFpEF in a Chinese setting remained uninvestigated. A simulation of lifetime horizon for a 72-year-old HFpEF patient was conducted using a Markov model. The primary outcome was incremental cost-effectiveness ratio (ICER), expressed as incremental costs per quality-adjusted life-year (QALY). Three times the per capita GDP of China was set as the willingness-to-pay (WTP) threshold. Empagliflozin was considered cost-effective if the ICER was below the WTP threshold, otherwise it would be regarded as not cost-effective. One-way sensitivity and probabilistic sensitivity analysis (PSA) were used to assess uncertainty. After a simulation of lifetime horizon, a 72-year-old HFpEF patient is expected to have an expected QALY of 4.80 in the empagliflozin group, and 4.67 QALY with standard treatment. The costs of empagliflozin and standard treatment are 34,987 (US$5423) and 27,027 (US$4189) Chinese Yuan (CNY), respectively, with an ICER of 63,746 (US$9881)/QALY, lower than the WTP threshold. One-way sensitivity and PSA show that our results are robust. In Chinese HFpEF patients, adding empagliflozin to standard treatment is cost-effective, but studies based on real-world data are needed.

Cardiac contractility modulation therapy improves health status in patients with heart failure with preserved ejection fraction: a pilot study (CCM-HFpEF).

This pilot study aimed to assess the potential benefits of cardiac contractility modulation (CCM) in patients with heart failure with preserved ejection fraction (HFpEF). This was a prospective, multicentre, single-arm, pilot study of CCM therapy in patients with HFpEF and New York Heart Association (NYHA) class II or III. Echocardiographic parameters were measured by an echo core laboratory to determine study eligibility. After CCM device implantation, patients were followed for 24 weeks. Overall, 47 patients (mean age 74.3 ± 4.4 years, 70.2% female) were enrolled, with left ventricular ejection fraction of 59 ± 4.4%, 63.8% with hypertension, 46.8% with atrial fibrillation, 40.4% with diabetes, 31.9% with at least one heart failure hospitalization in the prior year, 61.7% in NYHA class III, and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score of 48.9 ± 21.7. The primary efficacy endpoint (mean change in the KCCQ overall summary score) improved by 18.0 ± 16.6 points (p < 0.001) and there was an event-free rate of 93.6% for the primary safety endpoint (device- and procedure-related complications), as adjudicated by an independent physician committee. This pilot study demonstrates that the benefits of CCM may extend to the HFpEF patient population. The significant improvement in health status observed, with no obvious impact on safety, suggests that utilization of CCM for patients with HFpEF could prove to be promising.

Exercise training for prevention and treatment of older adults with heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most rapidly increasing form of HF, occurs primarily in older women, and is associated with high rates of morbidity, mortality, and health care expenditures. In the highest age decile (≥90 years old), nearly all patients with HFpEF. As our understanding of the disease has grown in the last few years, we now know that HFpEF is a systemic disorder influenced by aging processes. The involvement of this broad collection of abnormalities in HFpEF, the recognition of the high frequency and impact of noncardiac comorbidities, and systemic, multiorgan involvement, and its nearly exclusive existence in older persons, has led to the recognition of HFpEF as a true geriatric syndrome. Most of the conventional therapeutics used in other cardiac diseases have failed to improve HFpEF patient outcomes significantly. Several recent studies have evaluated exercise training (ET) as a therapeutic management strategy in patients with HFpEF. Although these studies were not designed to address clinical endpoints, such as HF hospitalizations and mortality, they have shown that ET is a safe and effective intervention to improve peak oxygen consumption, physical function, and quality of life in clinically stable HF patients. Recently, a progressive, multidomain physical rehabilitation study among older adults showed that it is feasible in older patients with acute decompensated HF who have high frailty and comorbidities and showed improvement in physical function. However, the lack of Centers for Medicare and Medicaid Services coverage can be a major barrier to formal cardiac rehabilitation in older HFpEF patients. Unfortunately, insistence upon demonstration of mortality improvement before approving reimbursement overlooks the valuable and demonstrated benefits of physical function and life quality.

Linking diastolic function to cardiac exercise performance in heart failure with preserved ejection fraction: a virtual patient study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NWO-ZonMw Background The relative impact of left ventricular (LV) diastolic dysfunction (LVDD) and impaired left atrial (LA) function on cardiac exercise performance (CEP) in heart failure with preserved ejection fraction (HFpEF) remains largely unknown Purpose To elucidate the relative effects of LVDD and impaired LA function on hemodynamics at rest and on cardiac performance during exercise by performing virtual HFpEF patient simulations. Methods Using a well-validated cardiovascular system model (CircAdapt), impaired LV relaxation was simulated by increasing the rate of myocardial relaxation (tau) from 35 to 65 ms. To study the effect of moderate and sever LV myocardial stiffness increase, LV end-diastolic elastance was increased from 0.15 mmHg/ml to 0.60 mmHg/ml and 2.00 mmHg/ml, respectively. In each simulation, LV diastolic function at rest (cardiac output (CO) and heart rate (HR) of 5.1 l/min and 70 bpm, respectively) was assessed using LV ejection fraction (LVEF), mitral E/A ratio, maximum LA volume (LAV), and mean left atrial (LA) pressure (mLAP). To investigate the relative effect of these cardiac abnormalities on exercise capacity, CO and HR were gradually increased using a fixed CO-HR relationship until mLAP exceeded a threshold pressure of 35 mmHg, which was assumed to be a physiological limit of exercise intensity. Results Simulations showed that regardless of the modelled LV and LA function, LVEF was preserved (&amp;gt;50%). Impaired LV relaxation function was associated with decreased E/A-ratio and a small increase in mLAP at rest, regardless of LA function. Increased LV passive stiffness resulted in increased E/A-ratio, LA dilation and markedly elevated mLAP at rest, regardless of LA function (Figure: top-left). Impaired LA function resulted in reduced A-peak velocity, and increased E/A–ratio, LAV and mLAP at rest regardless of LV function (Figure: top-right) Exercise simulations showed that increased LV passive stiffness exerts a stronger exercise-limiting effect than impaired LV relaxation function, in particular when LA function is impaired (Figure: bottom). Conclusions Through simple and well-controlled variations in LV and LA function, we were able to simulate virtual HFpEF patients with a wide range of LVDD severities at rest, preserved LVEF, and reduced cardiac exercise performance. In general, our simulations suggest that increased LV passive stiffness, rather than impaired LV relaxation function, reduces exercise tolerance, especially in the presence of LA dysfunction. Abstract Figure. Simulating rest &amp; exercise hemodynamics

Increased myocardial stiffness more than impaired relaxation function limits cardiac performance during exercise in heart failure with preserved ejection fraction: a virtual patient study.

The relative impact of left ventricular (LV) diastolic dysfunction (LVDD) and impaired left atrial (LA) function on cardiovascular haemodynamics in heart failure with preserved ejection fraction (HFpEF) is largely unknown. We performed virtual patient simulations to elucidate the relative effects of these factors on haemodynamics at rest and during exercise. The CircAdapt cardiovascular system model was used to simulate cardiac haemodynamics in wide ranges of impaired LV relaxation function, increased LV passive stiffness, and impaired LA function. Simulations showed that LV ejection fraction (LVEF) was preserved (>50%), despite these changes in LV and LA function. Impairment of LV relaxation function decreased E/A ratio and mildly increased LV filling pressure at rest. Increased LV passive stiffness resulted in increased E/A ratio, LA dilation and markedly elevated LV filling pressure. Impairment of LA function increased E/A ratio and LV filling pressure, explaining inconsistent grading of LVDD using echocardiographic indices. Exercise simulations showed that increased LV passive stiffness exerts a stronger exercise-limiting effect than impaired LV relaxation function does, especially with impaired LA function. The CircAdapt model enabled realistic simulation of virtual HFpEF patients, covering a wide spectrum of LVDD and related limitations of cardiac exercise performance, all with preserved resting LVEF. Simulations suggest that increased LV passive stiffness, more than impaired relaxation function, reduces exercise tolerance, especially when LA function is impaired. In future studies, the CircAdapt model can serve as a valuable platform for patient-specific simulations to identify the disease substrate(s) underlying the individual HFpEF patient's cardiovascular phenotype.

Stem Cell Therapy for Chronic and Advanced Heart Failure.

The purpose of this review is to discuss recent advances in the field of cell therapy in patients with heart failure with reduced ejection fraction (HFrEF) of ischemic (iCMP) and nonischemic (dCMP) etiology, heart failure with preserved ejection fraction (HFpEF), and in advanced heart failure patients undergoing mechanical circulatory support (LVAD). In HFrEF patients (iCMP and dCMP cohorts), autologous and/or allogeneic cell therapy was shown to improve myocardial performance, patients' functional capacity, and neurohumoral activation. In HFpEF patient population, the concept of cell therapy in novel and remains largely unexplored. However, initial data are very encouraging and suggest at least a similar benefit in improvements of myocardial performance (also diastolic function of the left ventricle), exercise capacity, and neurohumoral activation. Recently, cell therapy was explored in the sickest population of advanced heart failure patients undergoing LVAD support also showing a potential benefit in promoting myocardial reverse remodeling and recovery. In the past decade, several cell therapy-based clinical trials showed promising results in various chronic and advanced heart failure patient cohorts. Future cell treatment strategies should aim for more personalized therapeutic approaches by defining optimal stem cell type or their combination, dose, and delivery method for an individual patient adjusted for patient's age and stage/duration of heart failure.

Research Priorities for Heart Failure With Preserved Ejection Fraction: National Heart, Lung, and Blood Institute Working Group Summary.

Heart failure with preserved ejection fraction (HFpEF), a major public health problem that is rising in prevalence, is associated with high morbidity and mortality and is considered to be the greatest unmet need in cardiovascular medicine today because of a general lack of effective treatments. To address this challenging syndrome, the National Heart, Lung, and Blood Institute convened a working group made up of experts in HFpEF and novel research methodologies to discuss research gaps and to prioritize research directions over the next decade. Here, we summarize the discussion of the working group, followed by key recommendations for future research priorities. There was uniform recognition that HFpEF is a highly integrated, multiorgan, systemic disorder requiring a multipronged investigative approach in both humans and animal models to improve understanding of mechanisms and treatment of HFpEF. It was recognized that advances in the understanding of basic mechanisms and the roles of inflammation, macrovascular and microvascular dysfunction, fibrosis, and tissue remodeling are needed and ideally would be obtained from (1) improved animal models, including large animal models, which incorporate the effects of aging and associated comorbid conditions; (2) repositories of deeply phenotyped physiological data and human tissue, made accessible to researchers to enhance collaboration and research advances; and (3) novel research methods that take advantage of computational advances and multiscale modeling for the analysis of complex, high-density data across multiple domains. The working group emphasized the need for interactions among basic, translational, clinical, and epidemiological scientists and across organ systems and cell types, leveraging different areas or research focus, and between research centers. A network of collaborative centers to accelerate basic, translational, and clinical research of pathobiological mechanisms and treatment strategies in HFpEF was discussed as an example of a strategy to advance research progress. This resource would facilitate comprehensive, deep phenotyping of a multicenter HFpEF patient cohort with standardized protocols and a robust biorepository. The research priorities outlined in this document are meant to stimulate scientific advances in HFpEF by providing a road map for future collaborative investigations among a diverse group of scientists across multiple domains.

Heartbeat: oxygen transport close to and far from the ventricle in heart failure

In patients with heart failure with reduced ejection fraction, impaired oxygen delivery to peripheral muscles is blunted due to left ventricular systolic dysfunction with a reduced stroke volume reserve during...

Iron Deficiency Anemia and Heart Failure Hospitalizations: Insight from National Inpatient Sample Data

Introduction Iron deficiency anemia (IDA) is a common comorbidity among patients with heart failure (HF). There is ongoing data suggesting the importance of balanced iron homeostasis amongst patients with HF. However, little is known about the clinical impact of IDA in patients with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF). Hypothesis The aim of this study was to assess the impact of IDA on HF hospitalizations by HF subtype, i.e. HFpEF and HFrEF. Methods We queried the National Inpatient Sample (NIS), Health Care and Utilization Project (HCUP) database from 2008 to 2014 for patients ≥ 18 years old with a primary discharge diagnosis of HF based on the Clinical Classifications Software code 108. Patients were further stratified to HFpEF using ICD-9 codes 428.3x and HFrEF using ICD-9 codes 428.2x, and 428.4x. IDA was identified using ICD-9 codes 280.1, 280.9, and 280.8. Primary outcome of interest was length of stay (LOS) and total hospital charges by HF subtypes. Secondary outcome was readmission score estimated using Elixhauser-based comorbidities by HF subtypes. Multivariable- adjusted regression models were used to examine the impact of IDA on outcomes. Hospital trend weights were accounted in all models. All analyses were performed using SAS 9.4. Results A total of 1,684,227 patients with primary diagnosis of HFpEF (mean age 76±13, 64% female) and 2,675,477 patients with primary diagnosis of HFrEF (mean age 71±15, 41% female) were identified and included in the study. Prevalence of IDA was significantly higher among patients with HFpEF as compared to HFrEF (6.1 vs. 4.6%, p Conclusions Prevalent IDA is associated with significantly longer hospital stay, higher total hospital charges, and increased likelihood of readmission in both HFpEF and HFrEF patient populations. Parallel clinical results in both HFpEF and HFrEF implicate a potential benefit of addressing IDA in all HF patients regardless of subtype.

Heart failure with preserved ejection fraction: the missing pieces in diagnostic imaging.

Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent phenotype affecting over half of today's heart failure patients. With no proven therapy and no universally accepted diagnostic guideline, many HFpEF patients continue to be misdiagnosed or underdiagnosed at the early stages until the disease has progressed much further along. It is extremely difficult to diagnose the HFpEF patient, because they have a normal ejection fraction and present with non-specific symptoms such as dyspnea or exercise intolerance. To provide greater specificity, the current diagnostic criteria mandate the presence of diastolic dysfunction, where myocardial relaxation is impaired and ventricular filling pressure is elevated as a result of a hypertrophic and stiff heart. Unfortunately, diastolic dysfunction reflects late-stage structural and functional changes and offers a very narrow window, if at all, for successful intervention. In this article, we review the imaging modalities used in the current diagnostic workflow for assessing HFpEF. We also describe the most up-to-date insight into its pathophysiological basis, which attributes systemic inflammation driven by comorbidities as the initiator of disease. With this extramyocardial perspective, we provide our recommendation on new imaging targets that extend beyond the heart to enable early, accurate diagnosis of HFpEF and allow an opportunity for treating this fatal condition.

Estrogen Contributions to Microvascular Dysfunction Evolving to Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a syndrome involving microvascular dysfunction. No treatment is available yet and as the HFpEF patient group is expanding due to the aging population, more knowledge on dysfunction of the cardiac microvasculature is required. Endothelial dysfunction, impaired angiogenesis, (perivascular) fibrosis and the pruning of capillaries (rarefaction) may all contribute to microvascular dysfunction in the heart and other organs, e.g., the kidneys. The HFpEF patient group consists mainly of post-menopausal women and female sex itself is a risk factor for this syndrome. This may point toward a role of estrogen depletion after menopause in the development of HFpEF. Estrogens favor the ratio of vasodilating over vasoconstricting factors, which results in an overall lower blood pressure in women than in men. Furthermore, estrogens improve angiogenic capacity and attenuate (perivascular) fibrosis formation. Therefore, we hypothesize that the drop of estrogen levels after menopause contributes to myocardial microvascular dysfunction and renders post-menopausal women more vulnerable for heart diseases that involve the microvasculature. This review provides a detailed summary of molecular targets of estrogen, which might guide future research and treatment options.

Heterogeneous Metabolic Response to Exercise Training in Heart Failure with Preserved Ejection Fraction.

The prevalence of heart failure with preserved ejection fraction (HFpEF) is constantly increasing and no evidence-based pharmacological treatment option is available. While exercise training (ET) improves diastolic function, its metabolic mechanisms in HFpEF are unclear. We assessed the metabolic response to 12 weeks of ET in patients with HFpEF by performing a post hoc analysis of the EX-DHF-P trial (ISRCTN86879094). Plasma concentrations of 188 endogenous metabolites were measured in 44 ET and 20 usual care (UC) patients at baseline and 3-months follow-up. Metabolic differences between ET and UC from baseline to follow-up were compared and differential responses to ET were examined by random forest feature selection. ET prevented the increase of acetylornithine and carnitine as well as the decrease of three glycerophospholipids. After ET, two opposite metabolic response clusters were identified. Cluster belonging was associated with perceived well-being at baseline and changes in low-density lipoprotein but not with cardiorespiratory, ventilatory or echocardiographic parameters. These two ET-induced metabolic response patterns illustrate the heterogeneity of the HFpEF patient population. Our results suggest that other biological parameters might be helpful besides clinical variables to improve HFpEF patient stratification. Whether this approach improves response prediction regarding ET and other treatments should be explored.

Trying to Stay Afloat: Reducing Heart Failure Hospitalizations Among Heart Failure with Preserved Ejection Fraction Patients by Utilization of an Outpatient Heart Failure Bridge Clinic

Background Heart failure with preserved ejection fraction (HFpEF) constitutes half of heart failure (HF) hospitalizations today, and is expected to be the prevalent form of hospitalized HF by the year 2020. There is limited data to date on the utilization of outpatient, nurse practitioner-managed diuresis clinics in the chronic outpatient management of the HFpEF patient population. Methods This was an observational study of HFpEF patients seen in the Johns Hopkins HF Bridge Clinic (HFBC) for intravenous (IV) furosemide administration from May 2014 to July 2016. Results Over the study period, 90 unique patients with HFpEF were seen in the HFBC for IV diuresis, 55 (61%) of whom were initially referred after a HF hospitalization ( Table 1 ). Among the 90 patients, there were a total of 664 visits including 197 visits at which IV furosemide was given. The number of visits per patient was highly variable, ranging from a single visit to 57 visits, with a mean of 14 (SD 14) visits per patient. The median percent of visits in which patients received IV diuresis was 29% (IQR 30%). Mean IV furosemide dose was 125 mg (SD 43 mg). Additionally, there were 24 (12%) visits at which metolazone was given, 132 (67%) visits at which potassium was given, and 103 (52%) visits at which magnesium was given. There were 101 (51%) oral diuretic dose titrations made during the diuretic clinic visits. The mean post IV diuretic urine output was 675 ± 412 mL and weight decreased by 0.68 ± 0.60 kg. There was no significant change reported in blood pressure, renal function, or electrolytes post-diuresis. Of the 197 IV diuresis visits, 12 (6%) resulted in need for further management with an emergency department visit or direct admission from clinic and 142 (72%) remained out of the hospital for over 30 days following the IV diuresis visit. Conclusion We describe successful outpatient management of HFpEF patients via a comprehensive, nurse practitioner-managed diuresis clinic. HFpEF patients constitute a growing proportion of hospitalized HF, and strategies to successfully manage their HF in the outpatient setting may have significant implications in reduction of healthcare utilization.

Baseline Characteristics of Patients With Heart Failure and Preserved Ejection Fraction in the PARAGON-HF Trial.

To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), β-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464-1610), and structural heart disease. PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.