Patients who have heart failure with preserved ejection fraction (HFpEF) have signs and symptoms of heart failure, yet their ejection fraction remains greater than or equal to 50 percent. Understanding the underlying cause of HFpEF is crucial for accurate diagnosis and effective treatment. This condition can be caused by multiple factors, including ischemic or nonischemic myocardial diseases. HFpEF is often associated with diastolic dysfunction. Cardiac magnetic resonance (CMR) allows for a precise examination of the functional and structural alterations associated with HFpEF through the measurement of volumes and mass, the assessment of systolic and diastolic function, and the analysis of tissue characteristics. We will discuss CMR imaging indicators that are specific to patients with HFpEF and their relation to the disease. These markers can be acquired through both established and emerging methods.

Recent clinical studies have reported that heart failure with preserved ejection fraction (HFpEF) can be divided into two phenotypes based on the range of ejection fraction (EF), namely HFpEF with higher EF and HFpEF with lower EF. These phenotypes exhibit distinct left ventricle (LV) remodelling patterns and dynamics. However, the influence of LV remodelling on various LV functional indices and the underlying mechanics for these two phenotypes are not well understood. To address these issues, this study employs a coupled finite element analysis (FEA) framework to analyse the impact of various ventricular remodelling patterns, specifically concentric remodelling (CR), concentric hypertrophy (CH), and eccentric hypertrophy (EH), with and without LV wall thickening on LV functional indices. Further, the geometries with a moderate level of remodelling from each pattern are subjected to fibre stiffening and contractile impairment to examine their effect in replicating the different features of HFpEF. The results show that with severe CR, LV could exhibit the characteristics of HFpEF with higher EF, as observed in recent clinical studies. Controlled fibre stiffening can simultaneously increase the end-diastolic pressure (EDP) and reduce the peak longitudinal strain (ell) without significant reduction in EF, facilitating the moderate CR geometries to fit into this phenotype. Similarly, fibre stiffening can assist the CH and \'EH with wall thickening\' cases to replicate HFpEF with lower EF. These findings suggest that potential treatment for these two phenotypes should target the bio-origins of their distinct ventricular remodelling patterns and the extent of myocardial stiffening.

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BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is associated with systemic inflammation, obesity, metabolic syndrome, and gut microbiome changes. Increased trimethylamine-N-oxide (TMAO) levels are predictive for mortality in HFpEF. The TMAO precursor trimethylamine (TMA) is synthesized by the intestinal microbiome, crosses the intestinal barrier and is metabolized to TMAO by hepatic flavin-containing monooxygenases (FMO). The intricate interactions of microbiome alterations and TMAO in relation to HFpEF manifestation and progression are analyzed here.
METHODS: Healthy lean (L-ZSF1, n = 12) and obese ZSF1 rats with HFpEF (O-ZSF1, n = 12) were studied. HFpEF was confirmed by transthoracic echocardiography, invasive hemodynamic measurements, and detection of N-terminal pro-brain natriuretic peptide (NT-proBNP). TMAO, carnitine, symmetric dimethylarginine (SDMA), and amino acids were measured using mass-spectrometry. The intestinal epithelial barrier was analyzed by immunohistochemistry, in-vitro impedance measurements and determination of plasma lipopolysaccharide via ELISA. Hepatic FMO3 quantity was determined by Western blot. The fecal microbiome at the age of 8, 13 and 20 weeks was assessed using 16s rRNA amplicon sequencing.
RESULTS: Increased levels of TMAO (+ 54%), carnitine (+ 46%) and the cardiac stress marker NT-proBNP (+ 25%) as well as a pronounced amino acid imbalance were observed in obese rats with HFpEF. SDMA levels in O-ZSF1 were comparable to L-ZSF1, indicating stable kidney function. Anatomy and zonula occludens protein density in the intestinal epithelium remained unchanged, but both impedance measurements and increased levels of LPS indicated an impaired epithelial barrier function. FMO3 was decreased (- 20%) in the enlarged, but histologically normal livers of O-ZSF1. Alpha diversity, as indicated by the Shannon diversity index, was comparable at 8 weeks of age, but decreased by 13 weeks of age, when HFpEF manifests in O-ZSF1. Bray-Curtis dissimilarity (Beta-Diversity) was shown to be effective in differentiating L-ZSF1 from O-ZSF1 at 20 weeks of age. Members of the microbial families Lactobacillaceae, Ruminococcaceae, Erysipelotrichaceae and Lachnospiraceae were significantly differentially abundant in O-ZSF1 and L-ZSF1 rats.
CONCLUSIONS: In the ZSF1 HFpEF rat model, increased dietary intake is associated with alterations in gut microbiome composition and bacterial metabolites, an impaired intestinal barrier, and changes in pro-inflammatory and health-predictive metabolic profiles. HFpEF as well as its most common comorbidities obesity and metabolic syndrome and the alterations described here evolve in parallel and are likely to be interrelated and mutually reinforcing. Dietary adaption may have a positive impact on all entities.

Currently, no therapy is proven to effectively improve heart failure with preserved ejection fraction (HFpEF). Although stem cell therapy has demonstrated promising results in treating ischemic heart disease, the effectiveness of treating HFpEF with human umbilical cord mesenchymal stem cells (hucMSCs) remains unclear. To answer this question, we administered hucMSCs intravenously (i.v.), either once or repetitively, in a mouse model of HFpEF induced by a high-fat diet and NG-nitroarginine methyl ester hydrochloride. hucMSC treatment improved left ventricular diastolic dysfunction, reduced heart weight and pulmonary edema, and attenuated cardiac modeling (inflammation, interstitial fibrosis, and hypertrophy) in HFpEF mice. Repeat hucMSC administration had better outcomes than a single injection. In vitro, hucMSC culture supernatants reduced maladaptive remodeling in neonatal-rat cardiomyocytes. Ribonucleic acid sequencing and protein level analysis of left ventricle (LV) tissues suggested that hucMSCs activated the protein kinase B (Akt)/forkhead box protein O1 (FoxO1) signaling pathway to treat HFpEF. Inhibition of this pathway reversed the efficacy of hucMSC treatment. In conclusion, these findings indicated that hucMSCs could be a viable therapeutic option for HFpEF.

UNASSIGNED: Heart failure with preserved ejection fraction (HFpEF) often coexists with chronic kidney disease (CKD). Exercise intolerance is a major determinant of quality of life and morbidity in both scenarios. We aimed to evaluate the associations between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and carbohydrate antigen 125 (CA125) with maximal aerobic capacity (peak VO2) in ambulatory HFpEF and whether these associations were influenced by kidney function.
UNASSIGNED: This single-centre study prospectively enrolled 133 patients with HFpEF who performed maximal cardiopulmonary exercise testing. Patients were stratified across estimated glomerular filtration rate (eGFR) categories (<60 ml/min/1.73 m2 versus ≥60 ml/min/1.73 m2).
UNASSIGNED: The mean age of the sample was 73.2 ± 10.5 years and 56.4% were female. The median of peak VO2 was 11.0 ml/kg/min (interquartile range 9.0-13.0). A total of 67 (50.4%) patients had an eGFR <60 ml/min/1.73 m2. Those patients had higher levels of NT-proBNP and lower peak VO2, without differences in CA125. In the whole sample, NT-proBNP and CA125 were inversely correlated with peak VO2 (r = -0.43, P < .001 and r = -0.22, P = .010, respectively). After multivariate analysis, we found a differential association between NT-proBNP and peak VO2 across eGFR strata (P for interaction = .045). In patients with an eGFR ≥60 ml/min/1.73 m2, higher NT-proBNP identified patients with poorer maximal functional capacity. In individuals with eGFR <60 ml/min/1.73 m2, NT-proBNP was not significantly associated with peak VO2 [β = 0.02 (95% confidence interval -0.19-0.23), P = .834]. Higher CA125 was linear and significantly associated with worse functional capacity without evidence of heterogeneity across eGFR strata (P for interaction = .620).
UNASSIGNED: In patients with stable HFpEF, NT-proBNP was not associated with maximal functional capacity when CKD was present. CA125 emerged as a useful biomarker for estimating effort intolerance in HFpEF irrespective of the presence of CKD.

UNASSIGNED: Recognition of heart failure with preserved ejection fraction (HFpEF) at an early stage in mass screening is desirable, but difficult to achieve. We examined whether the fibrosis (Fib)-4 index, a simple index of liver stiffness/fibrosis, could be used as a screening tool to select candidates requiring expert diagnostics.
UNASSIGNED: Individuals who participated in annual health checks between 2006 and 2007 in Arita-cho, Saga, Japan, with no history of cardiovascular disease and EF ≥ 50% were enrolled (total 710; 258 men; median age, 59 years).
UNASSIGNED: Participants were divided into 5 groups according to HFpEF risk: 215 (30%), 100 (14%), 171 (24%), 163 (23%), and 61 (9%) with Heart Failure Association (HFA)-PEFF scores of 0, 1, 2, 3, and 4-6 points, respectively. The highest HFpEF risk group (HFA-PEFF score, 4-6 points) showed poor prognosis for the clinical events of all-cause mortality and hospitalization for HF (log-rank test, P = .002). The Fib-4 index was correlated with HFpEF risk stratification (rs = 0.526), and increment in the Fib-4 index was independently linked to high HFpEF risk by multiple logistic regression analysis (adjusted odds ratio, 1.311; 95% confidence interval, 1.078-1.595; P = .007). The Fib-4 index stratified clinical prognosis (log-rank test, P < .001) was an independent predictor of all-cause mortality and hospitalization for HF (hazard ratio, 1.305; 95% confidence interval, 1.139-1.495; P < .001).
UNASSIGNED: The Fib-4 index can be used to select appropriate candidates for a detailed examination of HFpEF in a subclinical population.

UNASSIGNED: Approximately one-half of all heart failure (HF) consists of heart failure with preserved ejection fraction (HFpEF) or heart failure with mid-range ejection fraction (HFmrEF). Although several recent trials have investigated treatments for HFpEF/HFmrEF, there is limited insight on the long-term clinical trajectory of this population.
UNASSIGNED: The purpose of this study was to model clinical outcomes in patients with symptomatic (NYHA functional class II-IV) HFpEF/HFmrEF over 10 years.
UNASSIGNED: We developed a Markov model with stable HF, HF hospitalization, and death states to follow a cohort of patients with HFpEF/HFmrEF treated with standard of care (SoC) recommended by the American Heart Association/American College of Cardiology/Heart Failure Society of America. Population characteristics and clinical event probabilities were derived from recent phase 3 HFpEF/HFmrEF trials. We used weighted averages for control and sodium-glucose cotransporter-2 inhibitor outcomes. SoC was informed by baseline treatments reported in clinical trials.
UNASSIGNED: In a cohort of U.S. patients with HFpEF/HFmrEF treated with SoC, our model estimated 0.53 cumulative HF hospitalizations per patient over 10 years. Overall, 37% had at least 1 HF hospitalization, and 26% experienced cardiovascular death. The model estimated 6.1 years of life expectancy from age 72 and total cost of care over this time of $123,900.
UNASSIGNED: HFpEF/HFmrEF is associated with high rates of HF hospitalization and cardiovascular mortality based on contemporary clinical trials in this population. Furthermore, clinical trial results are likely to be more optimistic than real-world outcomes. Continuing to optimize care and treatment may reduce clinical burden and improve population health.

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