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PubMed2026

Molecular Pathways, Target Landscape, and Translational Models in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a substantial global health burden and the greatest unmet medical need for cardiovascular diseases. It is marked by pronounced clinical heterogeneity and complex multi-system pathophysiology with limited therapeutic options. Progress in developing effective therapeutics is constrained by the inadequacy of experimental models to fully recapitulate the multifactorial nature of the disease. Recent evidence underscores the significant involvement of inflammatory, oxidative, and mitochondrial pathways in the pathogenesis of HFpEF, with non-coding RNAs and epigenetic regulation serving as crucial modulators and prospective therapeutic targets. This review maps the HFpEF target landscape, while critically assessing the mechanistic contributions, translational fidelity, and limitations of existing in vivo and in vitro models. Further, advances are noted among the in vitro technologies, including human cardiac organoids and engineered heart tissues integrated with high-throughput multi-omics and computational modeling, enabling in-depth examination of HFpEF mechanisms. Finally, we underscore the necessity of integrative, systems-level approaches and multi-marker strategies to enhance translational relevance, improve risk stratification, and accelerate development of mechanism-based therapies. Collectively, this review supports phenotypic-guided and mechanism-informed therapeutic development for HFpEF, and provides a roadmap for next generation model development and therapeutic innovation.

Humans↗
PubMed2006

The treatment of heart failure with preserved ejection fraction ("diastolic heart failure").

Unlike heart failure with a low ejection fraction, there is no evidence-based treatment for heart failure with preserved ejection fraction which improves clinical outcomes. Indeed, the only evidence for any treatment effect comes from small studies with verapamil where this drug increased exercise capacity and reduced a heart failure score. Large trials are presently underway which are examining the effect of treatment with an ACE inhibitor, ARB and aldosterone antagonist in patients with heart failure and preserved ejection fraction.

Adrenergic beta-Antagonists↗
PubMed2026

GPER stimulation attenuates mitochondrial dysfunction and cardiac dysfunction in ovariectomized mice with heart failure with preserved ejection fraction (HFpEF).

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is prevalent among postmenopausal women and is strongly linked to estrogen deficiency. G-protein coupled estrogen receptor (GPER) mediates non-genomic estrogen signalling and exerts cardiovascular protective effects. Its role in the pathogenesis of HFpEF remains unclear. This study aimed to explore whether GPER activation could attenuate mitochondrial dysfunction and cardiac damage in ovariectomized (OVX) mice with HFpEF. METHODS: Circulating GPER levels were measured in postmenopausal women with HFpEF and healthy controls. A correlation analysis was performed to assess the associations between GPER and cardiac function. Female C57BL/6J mice underwent ovariectomy and were fed with high-fat diet and l-NAME to induce HFpEF. Mice were treated with the GPER agonist G-1 for 4 weeks. Cardiac function, histological changes, oxidative stress, mitochondrial function and mitophagy were evaluated in vivo and in vitro. RESULTS: Serum GPER levels were significantly higher in postmenopausal women with HFpEF and correlated with NT-proBNP and E/e'. In OVX mice with HFpEF, GPER expression was up-regulated, and G-1 improved diastolic function, reduced myocardial hypertrophy and oxidative stress. Importantly, G-1 restored mitochondrial ATP production, normalized mitochondrial dynamics and promoted mitophagy in vivo and in vitro. These effects were associated with activation of the AMPK/ULK1 pathway. Inhibition of AMPK diminished the protective effects of G-1 in cardiomyocytes. CONCLUSIONS: GPER agonist G-1 ameliorated mitochondrial dysfunction, promoted mitophagy and alleviated cardiac diastolic dysfunction in OVX mice with HFpEF, partially through the AMPK/ULK1 pathway, indicating GPER as a therapeutic target for postmenopausal women with HFpEF.

AMPK/ULK1 signalling pathway↗
PubMed2006

Comparison of morbidity in women versus men with heart failure and preserved ejection fraction.

Patients with heart failure (HF) and preserved ejection fraction (HF-PEF) constitute up to 30% to 50% of patients with HF, and HF-PEF affects women more often than men. Not much is known about the role of gender in the clinical presentation, symptoms, or disease severity of HF-PEF or about the contribution of these differences to gender differences in morbidity and mortality in patients with HF-PEF. This study examined gender differences in clinical presentation, hospitalization, and mortality in patients with HF-PEF (ejection fraction > or = 50%) enrolled in the ancillary arm of the Digitalis Investigation Group trial. Time-to-event analysis was performed using Cox proportional-hazards modeling. The study cohort included 719 patients (378 men, 341 women). At baseline, compared with men, women were older and had greater clinical severity of HF, as evidenced by worse New York Heart Association functional class, more frequent symptoms and signs of HF, and more treatment with diuretics. Ischemia was identified as the primary cause of HF in 46% of women and 56% of men (p = 0.01). During a median follow-up of 39 months, crude mortality was similar in women and men (24.6% and 24.3%, p = 0.93), but more women were hospitalized for HF (26.7% vs 15.9%, p <0.001). After adjustment for baseline differences, female gender was an independent predictor of lower mortality (hazard ratio 0.59, 95% confidence interval 0.43 to 0.82), but HF hospitalization rates were similar between men and women (hazard ratio 1.09, 95% confidence interval 0.77 to 1.53). In conclusion, although the clinical manifestations of HF appear to be more severe in women with HF-PEF, after adjustment for baseline clinical differences, HF hospitalizations are not increased and survival expectancy is better for women compared with men.

Aged↗
PubMed2006

Trends in prevalence and outcome of heart failure with preserved ejection fraction.

BACKGROUND: The prevalence of heart failure with preserved ejection fraction may be changing as a result of changes in population demographics and in the prevalence and treatment of risk factors for heart failure. Changes in the prevalence of heart failure with preserved ejection fraction may contribute to changes in the natural history of heart failure. We performed a study to define secular trends in the prevalence of heart failure with preserved ejection fraction among patients at a single institution over a 15-year period. METHODS: We studied all consecutive patients hospitalized with decompensated heart failure at Mayo Clinic Hospitals in Olmsted County, Minnesota, from 1987 through 2001. We classified patients as having either preserved or reduced ejection fraction. The patients were also classified as community patients (Olmsted County residents) or referral patients. Secular trends in the type of heart failure, associated cardiovascular disease, and survival were defined. RESULTS: A total of 6076 patients with heart failure were discharged over the 15-year period; data on ejection fraction were available for 4596 of these patients (76 percent). Of these, 53 percent had a reduced ejection fraction and 47 percent had a preserved ejection fraction. The proportion of patients with the diagnosis of heart failure with preserved ejection fraction increased over time and was significantly higher among community patients than among referral patients (55 percent vs. 45 percent). The prevalence rates of hypertension, atrial fibrillation, and diabetes among patients with heart failure increased significantly over time. Survival was slightly better among patients with preserved ejection fraction (adjusted hazard ratio for death, 0.96; P=0.01). Survival improved over time for those with reduced ejection fraction but not for those with preserved ejection fraction. CONCLUSIONS: The prevalence of heart failure with preserved ejection fraction increased over a 15-year period, while the rate of death from this disorder remained unchanged. These trends underscore the importance of this growing public health problem.

Aged↗
PubMed2025

Study Protocol for HeartMagic: A&#xa0;Prospective Observational Cohort Characterizing Subtypes of Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Heart failure (HF) is a life-threatening syndrome with significant morbidity and mortality. Although evidence-based drug treatments have effectively reduced morbidity and mortality in HF with reduced ejection fraction (EF), few therapies have been demonstrated to improve outcomes in HF with preserved EF. This may be caused by the existence of several HF with preserved EF subtypes that each need different treatments. There is therefore an unmet need for a comprehensive approach to subtype patients with HF with preserved EF. This protocol details the approach employed in the HeartMagic (Heart Failure Studied With a Machine Learning, Genomics, and Imaging Combination) study to address this gap. METHODS: This prospective multicenter observational cohort study will include 500 consecutive patients with HF with preserved EF at 2 Swiss university hospitals, along with 50 age-matched patients with HF with reduced EF and 50 healthy controls. In addition to routine clinical workup, participants undergo genomic, transcriptomic, and metabolomic analyses, and the anatomy, composition, and function of the heart are quantified by comprehensive echocardiography and magnetic resonance imaging. Quantitative magnetic resonance imaging is also applied to characterize the kidney. The primary outcome is a composite of 1-year cardiovascular mortality or rehospitalization. Machine learning-based multimodal clustering will be employed to identify distinct HF with preserved EF subtypes. Statistical analysis will include group comparisons, survival analysis, and integrative multimodal clustering combining clinical, imaging, ECG, genomic, transcriptomic, and metabolomic data to identify and validate HF with preserved EF subtypes. CONCLUSIONS: The integration of comprehensive magnetic resonance imaging with extensive genomic and metabolomic profiling in this study will result in an unprecedented panoramic view of HF with preserved EF and help distinguish functional subgroups, which may provide a basis for personalized therapies.

Aged↗
PubMed2003

Clinical features and contemporary management of patients with low and preserved ejection fraction heart failure: baseline characteristics of patients in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme.

AIMS: To describe the clinical characteristics and contemporary treatment of a broad spectrum of patients with chronic heart failure (CHF) randomised in the Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) programme, consisting of three component studies comparing placebo to candesartan. METHODS AND RESULTS: CHARM Alternative, CHARM Added and CHARM Preserved enrolled 2028 low left ventricular ejection fraction (LVEF) ACE inhibitor intolerant patients, 2548 low LVEF ACE inhibitor treated patients and 3025 preserved LVEF patients, respectively. Patients in CHARM Preserved were more often female. The proportion of women in CHARM Preserved was 40% compared to 32% in CHARM Alternative and 21% in CHARM Added. Patients in CHARM Preserved were also more often hypertensive than in the other two trials (64% vs. 50% and 48%, respectively). Symptoms and signs (with the exception of a third heart sound) were similar in all three patient groups. Beta-blockers were used in over half of patients in all three groups. Digoxin and spironolactone were used less frequently and calcium antagonists more frequently in CHARM Preserved. Spironolactone was used most frequently in CHARM Alternative, i.e. in ACE inhibitor intolerant patients. CONCLUSIONS: The CHARM Programme provides the largest and most detailed comparison to date of patients low- and preserved-LVEF CHF. It also describes the causes of ACE-inhibitor intolerance in a large cohort of patients and the other treatment which these patients receive.

Adrenergic beta-Antagonists↗
PubMed2026

CTRP9 ameliorates heart failure with preserved ejection fraction by regulating lipid metabolism.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major clinical challenge, with cardiac lipotoxicity emerging as a key driver of disease progression. Despite CTRP9&#x2019;s role in lipid metabolism and cardioprotective properties, its therapeutic potential in HFpEF remains unexplored. This study aimed to investigate whether CTRP9 ameliorates HFpEF by regulating cardiac lipid metabolism and to identify the underlying molecular mechanisms. METHODS: In the established two-hit HFpEF mouse model (induced by a high-fat diet and L-NAME), the mice were treated with either CTRP9 or saline. Cardiac function was evaluated by echocardiography, while hypertrophy, fibrosis, and lipid accumulation were assessed using histology and molecular assays. Proteomic sequencing was further employed to identify downstream targets of CTRP9. RESULTS: CTRP9 treatment significantly improved diastolic function and attenuated cardiac hypertrophy and fibrosis in HFpEF mice. Myocardial lipid accumulation was substantially reduced, accompanied by enhanced fatty acid oxidation. Proteomic analysis identified GPD1 as a key downstream target upregulated by CTRP9. Cardiac-specific knockdown of GPD1 partly abolished the therapeutic benefits of CTRP9. CONCLUSION: Our data suggest that CTRP9 ameliorates HFpEF through GPD1-mediated regulation of cardiac lipid metabolism, identifying the CTRP9-GPD1 axis as a promising therapeutic target for HFpEF.

Animals↗
PubMed2006

Outcome of heart failure with preserved ejection fraction in a population-based study.

BACKGROUND: The importance of heart failure with preserved ejection fraction is increasingly recognized. We conducted a study to evaluate the epidemiologic features and outcomes of patients with heart failure with preserved ejection fraction and to compare the findings with those from patients who had heart failure with reduced ejection fraction. METHODS: From April 1, 1999, through March 31, 2001, we studied 2802 patients admitted to 103 hospitals in the province of Ontario, Canada, with a discharge diagnosis of heart failure whose ejection fraction had also been assessed. The patients were categorized in three groups: those with an ejection fraction of less than 40 percent (heart failure with reduced ejection fraction), those with an ejection fraction of 40 to 50 percent (heart failure with borderline ejection fraction), and those with an ejection fraction of more than 50 percent (heart failure with preserved ejection fraction). Two groups were studied in detail: those with an ejection fraction of less than 40 percent and those with an ejection fraction of more than 50 percent. The main outcome measures were death within one year and readmission to the hospital for heart failure. RESULTS: Thirty-one percent of the patients had an ejection fraction of more than 50 percent. Patients with heart failure with preserved ejection fraction were more likely to be older and female and to have a history of hypertension and atrial fibrillation. The presenting history and clinical examination findings were similar for the two groups. The unadjusted mortality rates for patients with an ejection fraction of more than 50 percent were not significantly different from those for patients with an ejection fraction of less than 40 percent at 30 days (5 percent vs. 7 percent, P=0.08) and at 1 year (22 percent vs. 26 percent, P=0.07); the adjusted one-year mortality rates were also not significantly different in the two groups (hazard ratio, 1.13; 95 percent confidence interval, 0.94 to 1.36; P=0.18). The rates of readmission for heart failure and of in-hospital complications did not differ between the two groups. CONCLUSIONS: Among patients presenting with new-onset heart failure, a substantial proportion had an ejection fraction of more than 50 percent. The survival of patients with heart failure with preserved ejection fraction was similar to that of patients with reduced ejection fraction.

Aged↗
PubMed2006

[Characteristics of heart failure with preserved ejection fraction: results of the Chilean national registry of heart failure, ICARO].

BACKGROUND: Heart failure (HF) with preserved ejection fraction (EF) is a condition of growing interest due to its high prevalence and difficult management. AIM: To evaluate the clinical profile of patients hospitalized with HF and preserved EF in Chilean hospitals. MATERIAL AND METHODS: Prospective registry of 15 centers. Among 649 patients hospitalized in functional class III and IV, an echocardiogram was performed to 353. Preserved EF was defined quantitatively as an EF >50%. RESULTS: Out the 353 patients, 45% presented an EF >50%. Mean age in patients with EF >50 and -50% was 66+/-13 and 67+/-13 years, respectively. Among patients with HF and EF >50%, the proportion of women was higher (73.7 and 36.3%, p <0.001), the proportion of patients with a history of hypertension (76.8 and 65.5%, p <0.05) and the presence of atrial fibrillation was also higher (62.3 and 47.8%, p <0.01) and a history of myocardial infarction was lower (17.1 and 29.5%, p <0.05). The diastolic diameter of the left ventricle was significantly lower in HF with preserved EF (51.0+10 and 63.5+10 mm respectively, p <0.001). No differences in the length of hospital stay and mortality were observed between HF with depressed and preserved EF. Female gender was an independent predictor for the presence of HF with preserved EF (Odds ratio: 2.62; confidence intervals: 1.1-6.1). CONCLUSIONS: HF and preserved EF is common among hospitalized patients, particularly in women and subjects with a history of hypertension and atrial fibrillation. Hospitalization length and mortality were similar in patients with either preserved or depressed EF.

Aged↗
PubMed2004

Comparison of outcomes of white versus black patients hospitalized with heart failure and preserved ejection fraction.

Black patients who have heart failure (HF) may have a larger proportion of HF with preserved ejection fraction (PEF) than white patients because of the greater prevalence and severity of hypertension and left ventricular hypertrophy in blacks. However, studies have not systematically evaluated differences by race in patients who have HF-PEF compared with those who have systolic HF (SHF). Therefore, we examined baseline characteristics and long-term outcomes in patients who had HF-PEF compared with those who had SHF, with an emphasis on variation by race, in a biracial cohort of patients treated within the Veterans Health Administration health care system. In a cohort of 448 patients (192 blacks and 256 whites) hospitalized with HF, 27% had HF-PEF. The proportion of HF-PEF was similar in black (25%) and white (29%) patients (p = 0.4). Among patients who had SHF, black patients were younger, had lower prevalences of atrial fibrillation and diabetes, and had less co-morbidities than white patients, whereas there were no significant differences in these variables by race in patients who had HF-PEF. However, among patients who had SHF or HF-PEF, blacks had a lower prevalence of coronary disease, higher systolic and diastolic blood pressures, and higher serum levels of creatinine than white patients. In addition, mortality and readmission rates for HF did not differ by race among patients who had HF-PEF. Overall, patients who had HF-PEF had a high morbidity rate (30% patients were readmitted for HF in </=6 months) and a high mortality rate (44% at 3 years), despite the use of angiotensin-converting enzyme inhibitors by 66% of patients at discharge. This underscores the importance of evaluating other agents for the treatment of patients who have HF-PEF.

Aged↗
PubMed2026

Subphenogroups of acute heart failure with preserved ejection fraction: comprehensive proteomics and pathway analysis.

BACKGROUND: Heterogeneity of heart failure with preserved ejection fraction (HFpEF) results in significant challenges for treatment development. Identifying and characterising distinct HFpEF phenogroups may aid in tailoring therapeutic strategies for these patients. The objective of this study was to assess proteomic patterns of HFpEF phenogroups identified through a machine-learning-based clustering model, with the aim of uncovering specific biological pathways associated with each phenogroup. METHODS: This study represents a post-hoc analysis of the ongoing Prospective mUlticenteR obServational stUdy of patIenTs with Heart Failure with preserved Ejection Fraction (PURSUIT-HFpEF) study, which is a multicentre prospective observational study of hospitalised patients with acute decompensated HFpEF. Of the overall cohort (N=1238), this study analysed 198 patients with HFpEF with available proteomics data. These patients were classified into four phenogroups using the machine-learning-based clustering model. The SomaScan assay V.4.1 was used to measure levels of >7000 plasma proteins, and subsequent pathway analysis was conducted to determine the biological differences among the phenogroups. RESULTS: We identified four distinct phenogroups: Phenogroup 1 ('rhythm trouble'), Phenogroup 2 ('ventricular-arterial uncoupling'), Phenogroup 3 ('low output and systemic congestion') and Phenogroup 4 ('systemic failure'). The proteomics revealed distinct protein expression profiles among the phenogroups, with ribonuclease 4, tax1-binding protein 1, regenerating islet-derived protein 3-gamma and alpha-1-antichymotrypsin being the most significant markers to specific identified phenogroups. Pathway analysis suggested differences in immune response, autonomic activation, cellular homeostasis and tissue repair mechanisms across the phenogroups. CONCLUSIONS: Using a comprehensive plasma proteomics approach, our study identified distinct proteomic profiles of HFpEF phenogroups, which in turn suggest specific underlying biological processes. These profiles suggest the involvement of inflammatory activation, tissue injury and regenerative responses, immune modulation and systemic stress signalling as key components of HFpEF pathophysiology. TRIAL REGISTRATION NUMBER: UMIN-CTR ID: UMIN000021831.

Humans↗
PubMed2003

Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved ejection fraction: implications for systolic and diastolic reserve limitations.

BACKGROUND: Heart failure with preserved ejection fraction (HF-nlEF) is common in aged individuals with systolic hypertension and is frequently ascribed to diastolic dysfunction. We hypothesized that such patients also display combined ventricular-systolic and arterial stiffening that can exacerbate blood pressure lability and diastolic dysfunction under stress. METHODS AND RESULTS: Left ventricular pressure-volume relations were measured in patients with HF-nlEF (n=10) and contrasted with asymptomatic age-matched (n=9) and young (n=14) normotensives and age- and blood pressure-matched controls (n=25). End-systolic elastance (stiffness) was higher in patients with HF-nlEF (4.7+/-1.5 mm Hg/mL) than in controls (2.1+/-0.9 mm Hg/mL for normotensives and 3.3+/-1.0 mm Hg/mL for hypertensives; P<0.001). Effective arterial elastance was also higher (2.6+/-0.5 versus 1.9+/-0.5 mm Hg/mL) due to reduced total arterial compliance; the latter inversely correlated with end-systolic elastance (P=0.0001). Body size and stroke volumes were similar and could not explain differences in ventricular-arterial stiffening. HF-nlEF patients also displayed diastolic abnormalities, including higher left ventricular end-diastolic pressures (24.3+/-4.6 versus 12.9+/-5.5 mm Hg), caused by an upward-shifted diastolic pressure-volume curve. However, isovolumic relaxation and the early-to-late filling ratio were similar in age- and blood pressure-matched controls. Ventricular-arterial stiffening amplified stress-induced hypertension, which worsened diastolic function, and predicted higher cardiac energy costs to provide reserve output. CONCLUSION: Patients with HF-lnEF have systolic-ventricular and arterial stiffening beyond that associated with aging and/or hypertension. This may play an important pathophysiological role by exacerbating systemic load interaction with diastolic function, augmenting blood pressure lability, and elevating cardiac metabolic demand under stress.

Adult↗
PubMed2026

Combined high-fat, high-sucrose diet and streptozotocin treatment induces cardiometabolic heart failure with preserved ejection fraction in mice.

Diabetes is associated with an increased incidence of heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms are poorly understood. A shortage of mouse models reflecting the diverse HFpEF pathophysiology contributes to this inadequate understanding of disease mechanisms. We conducted a comprehensive analysis of a nongenetic, inducible type 2 diabetes mellitus (T2DM) mouse model about its suitability as a preclinical model of cardiometabolic, diabetes-induced HFpEF. T2DM was induced in C57Bl/6 mice by a high-fat/high-sucrose diet and a low-dose streptozotocin (DIO-STZ). Cardiac function was assessed in vivo by echocardiography and left ventricular catheterization and in vitro using the isolated perfused heart. Structural, molecular, and bioenergetic disturbances were analyzed by immunohistochemistry, RNA-seq, qPCR, Western blot, and extracellular flux analysis of myocardial tissue. Blood glucose, fatty acids, and ketone body levels were elevated, and insulin levels were reduced in DIO-STZ compared with chow. DIO-STZ mice showed an HFpEF phenotype with reduced cardiac output, end-diastolic volume, and increased filling pressure. No differences in myocardial fibrosis or in vitro stiffness were detected between DIO-STZ and chow. RNA-Seq pointed toward disturbances in lipid and ketone metabolism. Extracellular flux analysis revealed increased fatty acid oxidation capacity without differences in glucose metabolism. No general mitochondrial dysfunction was observed, but a reduced capacity for &#x3b2;-hydroxybutyrate oxidation. The diabetic DIO-STZ mouse model showed a pronounced functional HFpEF phenotype with underlying mechanisms that remarkably differ from other HFpEF models, making the DIO-STZ model a relevant extension of the range of HFpEF mouse models, especially for investigating molecular mechanisms or therapeutic interventions in diabetes-associated HFpEF.NEW & NOTEWORTHY Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome whose pathophysiological mechanisms are incompletely understood, potentially due to a lack of preclinical models reflecting the broad range of pathophysiological aspects. We describe a diabetic DIO-STZ mouse model showing a pronounced HFpEF with underlying mechanisms that remarkably differ from other HFpEF models, making this model a relevant extension of the range of HFpEF models, especially for investigating molecular mechanisms or therapeutical interventions in diabetes.

Animals↗
PubMed2026

Downregulation of Trpv4 and Klf2 in brain microvessels is associated with the progression of neurovascular dysfunction and cognitive impairment in a model of heart failure with preserved ejection fraction.

Vascular cognitive impairment (VCI) shares major risk factors with heart failure with preserved ejection fraction (HFpEF), including obesity, diabetes and hypertension. Yet VCI research often relies on single-stimulus models, whereas patients experience combined risk factors. We therefore assessed cerebrovascular and cognitive phenotypes in an HFpEF model and investigated underlying mechanisms. Male Lean and Obese ZSF1 rats underwent longitudinal assessments of blood pressure, glucose, cardiac function and behavioural performance. Cerebral blood flow and neurovascular coupling were assessed by laser speckle contrast imaging. White matter integrity, blood-brain barrier (BBB) permeability and vascular density were analyzed by (immuno)histochemistry. Cortical microvessels were isolated for transcriptomic profiling, and selected targets were validated using multiplex in-situ hybridization. Obese rats exhibited neurovascular uncoupling and impaired short- and long-term memory and spatial learning, accompanied by brain atrophy and reduced myelin. BBB permeability increased at 22-23&#x2009;weeks and vascular density at 34-35&#x2009;weeks in Obese versus Lean rats. Transcriptomic analysis of brain microvessels revealed altered processes related to angiogenesis, vasoreactivity, immune mechanisms and vascular remodelling, with consistent downregulation of Trpv4 and Klf2. Obese ZSF1 rats develop progressive neurovascular dysfunction associated with HFpEF onset and reduced Trpv4 and Klf2 expression in cerebral microvessels, two key vasoprotective genes.

Diastolic dysfunction↗
PubMed2006

[Medical treatment of heart failure with preserved left ventricular ejection fraction].

Diastolic heart failure (i.e., heart failure with preserved systolic function) accounts for 30%-50% of all cases of heart failure. Prognosis is almost as poor as with systolic heart failure. Currently, the only requirements for diagnosis are that strict clinical criteria for heart failure are satisfied and that the left ventricular ejection fraction is preserved (i.e., greater than 40%-50%), although in the future measurement of brain natriuretic peptides could be useful. Because of a lack of evidence from large clinical trials, with the exception of the CHARM study which showed that candesartan slightly reduced the hospital readmission rate, therapy is based on the identification and treatment of the causal condition (e.g., hypertension or coronary heart disease), heart rate control, and relief of congestion. Thus, combination treatment with low-dose diuretics, bradycardiac antihypertensives (e.g., beta-blockers or calcium antagonists), and angiotensin antagonists currently seems to be the best therapeutic approach.

Heart Failure↗
PubMed2026

Risk prediction in patients with heart failure with preserved ejection fraction: the LIFE-Preserved model.

BACKGROUND AND AIMS: Heart failure (HF) with preserved ejection fraction (HFpEF) constitutes a heterogeneous disease with varying prognosis. Given the rising incidence of HFpEF, accurate risk prediction for these patients is needed to identify high-risk individuals, who may benefit the most from preventive treatments. The LIFE-Preserved model was developed and validated for the prediction of individual short-term and lifetime risk for HF hospitalization or cardiovascular (CV) death in patients with HFpEF. METHODS: LIFE-Preserved was derived in 20 332 patients aged 40-90 years with a left ventricular ejection fraction &#x2265; 50% from the Swedish HF Registry. Cause- and sex-specific Cox models were derived to predict the risk of HF hospitalization or CV death using 14 routinely available predictors. Use of age as the timescale allowed for predictions beyond the maximum follow-up duration in the derivation data, adjusted for competing risks. External validation was performed in two trials (EMPEROR-Preserved and TOPCAT-Americas) and three registries (NHS England Secure Data Environment, Veterans Affairs, and HF-Particles). Model performance was assessed by discrimination and calibration. RESULTS: During a median follow-up of 1.8 years (interquartile range .6-4.2, maximum 19 years), 9341 first HF hospitalizations or CV deaths (46%) were observed in Swedish HF Registry. External validation included data from 28 062 patients with HFpEF [9930 (35%) first HF hospitalizations or CV deaths]. Pooled C-statistics were .714 (95% confidence interval .652-.775) in trials and .658 (95% confidence interval .599-.717 in registries, with adequate calibration in all external validation sources. Performance was similar in men and women. An interactive calculator of the LIFE-Preserved model has been made available here. CONCLUSIONS: The LIFE-Preserved model enables prediction of short-term and lifetime risk of HF hospitalization or CV death in patients with HFpEF. The model could serve as a tool to identify high-risk HFpEF patients, guiding clinical management and shared decision-making.

Humans↗