Progression Of Heart Failure With Preserved Ejection Fraction Research Articles

Identification and validation of circulating microRNAs as biomarkers for heart failure with preserved ejection fraction

Abstract Background Heart failure (HF) is a syndrome due to cardiac insufficiency, manifested by excessive volume overload, increased sympathetic activity, and circulatory redistribution [1]. Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 40%-50% of the total HF events, and its development is often accompanied by various complications, including hypertension, obesity, and metabolic syndrome. Biomarker associations in heart failure with reduced ejection fraction were mostly cardiac stretch based, while many biomarkers of HFpEF are also associated with inflammation [2]. To date, treatments that effectively improve the clinical prognosis of HFpEF are relatively limited, thus HFpEF remains one of the challenges that needs to be further explored. A full understanding of the molecular mechanisms of HFpEF is essential to improve the early diagnosis, treatment and prognosis of these patients. Purpose The study aims to explore key circulating miRNAs and related molecular pathways in HFpEF patients through bioinformatics analysis and machine learning, and to further validate them using a double-hit HFpEF mouse model. Methods We downloaded HF datasets including circulating miRNA expression profiles from the GEO database. LASSO regression, SVM-RFE, Random Forest and XGboost algorithm were conducted to identify key miRNAs for diagnostic model construction. We used R software, GO, KEGG and Cytoscape to better understand the functions of key miRNA targets. Besides, the mRNA-miRNA interaction networks were predicted by starbase. We also constructed a HFpEF mouse model subjected to high fat diet and L-NAME (0.5 g/L) in drinking water to discover the correlation between the screened circulating miRNA and HFpEF. Results After differential expression analysis of the combined HFpEF dataset, we identified 37 differentially circulating miRNAs, of which 15 were down-regulated and 22 were up-regulated. Subsequently, we screened by machine learning and identified 4 key miRNAs that may be involved in the progression of HFpEF, including hsa-miR-645, hsa-miR-296-5p, hsa-miR-199b-5p, and hsa-miR-509-3-5p. We validated these miRNAs based on their expression, and the ROC plots suggest that these miRNAs may have diagnostic capability in HFpEF. The results of GO and KEGG enrichment analyses showed that the target genes of the differentiated miRNAs were mainly enriched in the MAPK signaling pathway, mTOR signaling pathway, protein processing in endoplasmic reticulum, hippo signaling pathway, cell cycle, Foxo signaling pathway, hypertrophic cardiomyopathy, dilated cardiomyopathy, and circadian rhythm. The mRNA-miRNA interaction networks suggested that TMEM135 was regulated by both has-miR-199b-5p and hsa-miR-296-5p. The RT-PCR results also suggested that miR-199b-5p was upregulated in the HFpEF mice. Conclusion We validated 4 circulating miRNAs with strong correlation to HFpEF, which provide a more reliable basis for pre-symptomatic diagnosis.

Novel method in mice to evaluate left atrial (LA) systolic contribution to left ventricular volume (LV) using pressure-volume (PV) loops

Abstract Background LA myopathy is a critically important non-LV contributor to the progression of HFpEF (heart failure with preserved ejection fraction) in patients and is associated with a severe phenotype, leading to impaired cardiac output reserve and reduced exercise capacity. In normal humans LA systole contributes ~20% of total LV filling, but with HFpEF, this contribution decreases to <16% with a greater reliance on this contribution to LV filling. Purpose We sought to investigate LA function as a critical component of cardiac function analysis by utilizing the LV pressure signal to identify and quantify the contribution of volume during LA systole to the total LV volume in mice with HFpEF. Methods Hypertension (HTN)-associated HFpEF C57BL/6J mice were subjected to chronic aldosterone infusion and 1% NaCl for 4 weeks (SAUNA model). Obesity after a high fat diet (HFD: 60% fat diet) for 16 weeks followed by the SAUNA protocol, induced HTN and obesity associated HFpEF. Blood pressure was monitored weekly. Mice were anesthetized with isoflurane, intubated, chest opened to expose the heart and allow placement of a PV catheter (Transonic) which was introduced into the LV via apical stab with a 27G needle. Calibration of the PV catheter was performed according to the manufacturer’s instructions. Atrial systole was identified using 2nd order derivative of the LV pressure signal. Contribution of LA systole was calculated using volume at the beginning of LA systole identified by the 2nd order derivative of the LV pressure signal and subtracting from the LV end diastolic volume. The % of LA systole contribution was calculated as a % of the total LV stroke volume. Data was analyzed with LabChart pro software (AD Instruments). Results SAUNA mice had normal LVEF, moderate HTN and lung congestion. PV relationships demonstrated Tau was impaired in HFpEF vs. control mice (14±1 vs. 10±0.5 ms) with a shift of the PV loop to the left (Fig. A.) In control mice, the atrial systole contributed 39± 4% to LV volume and was impaired in HFpEF mice 20± 3% a 1.95-fold reduction (P<0.01). Importantly atrial systole contribution was increased in obese mice 53±5 %. However, the combination of obesity and HTN, both common comorbidities in HFpEF, resulted in a reduced LA systole contribution by 1.43-fold to 37± 9%, (P<0.005; Fig B). Conclusion A novel method of % atrial systole from LV PV loop using 2nd order derivative to quantify the volume contribution of atrial systole to total LV stroke volume was identified in mice. LA dysfunction was present in murine HTN-associated HFpEF with/without obesity.

GLP-1 receptor agonists as promising anti-inflammatory agents in heart failure with preserved ejection fraction.

Heart Failure with Preserved Ejection Fraction (HFpEF) represents a significant challenge in modern cardiovascular medicine, characterized by diastolic dysfunction and a chronic pro-inflammatory milieu. The high prevalence of comorbidities such as diabetes, visceral obesity, and aging, which contribute to systemic inflammation, plays a pivotal role in the pathogenesis and progression of HFpEF. Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs), a class of glucose-lowering drugs, have demonstrated a wide range of pleiotropic effects that extend beyond glycaemic control. These effects include the reduction of inflammation and oxidative stress, vasodilation, decreased arterial stiffness, and a reduction in myocardial fibrosis-key factors in the pathophysiology of HFpEF. Recent evidence from the STEP-HFpEF and STEP-HFpEF-DM trials provides the first robust data supporting the efficacy of GLP-1 RAs, specifically semaglutide, in improving the quality of life in obese patients with HFpEF. These trials also demonstrated a significant reduction in C-Reactive Protein (CRP) levels, reinforcing the hypothesis that suppressing the pro-inflammatory state may yield substantial clinical benefits in this patient population. These findings suggest that GLP-1 RAs could play a crucial role in the management of HFpEF, particularly in patients with obesity, by targeting the underlying inflammatory processes and contributing to better overall cardiovascular outcomes.

The role of markers of endothelial dysfunction in the pathogenesis of coronary microvascular dysfunction in patients with non-obstructive coronary artery disease

Aim. To study the potential of non-invasive biomarkers in the diagnosis of coronary microvascular dysfunction (CMD) and prediction of the course of heart failure with preserved ejection fraction (HFpEF) in non-obstructive coronary artery disease.Materials and methods. The 12-month observational study included 118 consecutive patients (6 patients dropped out of the study due to contact loss) with non-obstructive coronary artery disease (CAD) and HFpEF (62 [59; 64]%). At the beginning of the study, serum levels of several biomarkers were assessed using the enzyme immunoassay: N-terminal pro-B-type natriuretic peptide (NT-proBNP), vascular endothelial growth factor (VEGF), and endothelin-1. Coronary flow reserve (CFR) was examined using dynamic single photon emission computed tomography. In the absence of obstructive CAD, CMD was defined as a global decrease in CFR ≤ 2. Echocardiography was used to determine parameters of hemodynamics, LV diastolic dysfunction, and myocardial stress. LV global longitudinal strain (GLS) was assessed using 2D speckle tracking.Results. The patients were divided into groups depending on the presence of CMD: group 1 included patients with CMD (n = 43), group 2 included those without it (n = 75). In patients in group 1, serum levels of endothelin-1 were 1.9 times higher (p = 0.012), levels of VEGF were 2.16 times higher (p = 0.008), and the concentration of NT-proBNP was 2.6 times higher (p = 0.004) than in patients in group 2. According to the ROC analysis, the concentrations of endothelin-1 ≥ 6.9 pg / ml (AUC = 0.711; p = 0.040) and VEGF ≥ 346.7 pg / ml (AUC = 0.756; p = 0.002) were considered as markers associated with the presence of CMD in patients with non-obstructive CAD. The multivariate regression analysis showed that only the presence of CMD (odds ratio (OR) 2.42; 95% confidence interval (95% CI) 1.26–5.85; p < 0.001) and an increase in NT-proBNP ≥ 760.5 pg / ml (OR 1.33; 95% CI 1.08–3.19; p = 0.023) were factors associated with adverse events, and their combination increased the risk of HFpEF progression by more than 3 times (OR 3.18; 95% CI 2.76–7.98; p < 0.001), whereas markers of endothelial dysfunction were not independent predictors. Conclusion. Endothelin-1 ≥ 6.9 pg / ml and VEGF ≥ 346.7 pg / ml can be used as non-invasive markers for the diagnosis of CMD. However, markers of endothelial dysfunction were not independent predictors of HFpEF progression in patients with non-obstructive CAD during 12-month follow-up.

Commonalities of platelet dysfunction in heart failure with preserved ejection fraction and underlying comorbidities.

Heart failure with preserved ejection fraction (HFpEF) is characterized by a lack of a specific targeted treatment and a complex, partially unexplored pathophysiology. Common comorbidities associated with HFpEF are hypertension, atrial fibrillation, obesity and diabetes. These comorbidities, combined with advanced age, play a crucial role in the initiation and development of the disease through the promotion of systemic inflammation and consequent changes in cardiac phenotype. In this context, we suggest platelets as important players due to their emerging role in vascular inflammation. This review provides an overview of the role of platelets in HFpEF and its associated comorbidities, including hypertension, atrial fibrillation, obesity and diabetes mellitus, as well as the impact of age and sex on platelet function. These major HFpEF-associated comorbidities present alterations in platelet behaviour and in features linked to platelet size, content and reactivity. The resulting dysfunctional platelets can contribute to further increase inflammation, oxidative stress and endothelial dysfunction, suggesting an active role of these cells in the initiation and progression of HFpEF. Recent evidence shows that reduced platelet count and elevated mean platelet volume are associated with worsening heart failure in HFpEF patients. However, the specific mechanisms by which platelets contribute to HFpEF development and progression are still largely unexplored, with only a few studies investigating platelet function in HFpEF. We discuss the limited yet significant body of research investigating platelet function in HFpEF, emphasizing the need for more comprehensive studies. Additionally, we explore the potential mechanisms through which platelets may influence HFpEF, such as their interactions with the vascular endothelium and the secretion of bioactive molecules like cytokines, chemokines and RNA molecules. These interactions and secretions may play a role in modulating vascular inflammation and contributing to the pathophysiological landscape of HFpEF. The review underscores the necessity for future research to elucidate the precise contributions of platelets to HFpEF, aiming to potentially identify novel therapeutic targets and improve patient outcomes. The evidence presented herein supports the hypothesis that platelets are not merely passive bystanders but active participants in the pathophysiology of HFpEF and its comorbidities.

A Contemporary Review on Heart Failure with Preserved Ejection Fraction: Epidemiology, Diagnosis, and Management

Heart failure with preserved ejection fraction (HFpEF) includes almost half of heart failure cases typified by a specific clinical syndrome. Despite diagnostic and management advances, HFpEF still presents a diagnostic challenge and a paucity of therapies specifically aimed at enhancing survival and improving quality of life is still lacking. This review elucidates the diagnostic complexity of HFpEF, highlighting the use of both subjective and objective criteria within algorithmic frameworks. It also examines the significant impact of comorbidities on the progression of HFpEF. Additionally, we explore the latest evidence on targeting these comorbidities therapeutically, although the benefits to mortality are still limited.

Abstract 29: Blood Pressure Phenotypes in an Interventional Study of Participants with Heart Failure with Preserved Ejection Fraction

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) affects engenders high morbidity and mortality. Hypertension is a major risk factor for HFpEF progression. We aimed to evaluate the prevalence of and factors associated with abnormal home blood pressure (BP) phenotypes in a trial cohort of individuals with hypertension and HFpEF. Methods: We evaluated baseline office and home BP measurements in 36 participants of BLOCK HFpEF, an ongoing trial of antihypertensive treatment in HFpEF (NCT04434664). Office BP was measured using a standardized approach with the average of 3 seated readings. Home BP was measured for the first 7 days of the trial, prior to initiating the intervention. Participants were asked to perform nocturnal home BP one night, taken 3 times while sleeping. We used a conservative threshold for controlled BPs, defined as office systolic BP (SBP) <140 mmHg, office diastolic BP (DBP) <90 mmHg, home daytime SBP <135 mmHg, and home daytime DBP <85 mmHg. White coat effect was defined as elevated office and controlled home BP. Masked uncontrolled hypertension was defined as controlled office and elevated home BP. Sustained hypertension was defined as controlled office and elevated home BP. Nocturnal hypertension was defined as nighttime SBP ≥120 mmHg or DBP ≥70 mmHg. Results: Of the 36 participants with home BP data, 7 (19%) had controlled hypertension, 6 (17%) had white coat effect, 6 (17%) had masked uncontrolled hypertension, and 17 (47%) had sustained hypertension. 27 participants completed nighttime home BP readings, among whom 23 (85%) had nocturnal hypertension. Of those with nocturnal hypertension, 2 (9%) had controlled hypertension based on their daytime home BPs, 3 (13%) had white coat effect, 5 (22%) had masked uncontrolled hypertension, and 13 (56%) had sustained hypertension. There was no significant difference in age, sex, race, history of atrial fibrillation, and history of diabetes mellitus across BP phenotypes. The mean number of cardiology visits in the two years before enrollment was 4.3 (SD 2.8), which did not differ across home BP phenotypes. Conclusion: Masked uncontrolled hypertension and nocturnal hypertension were common in patients enrolled in the BLOCK HFpEF trial. These home BP phenotypes cannot be determined using office BP alone. While this is a small sample, patients with HFpEF may particularly benefit from careful BP phenotyping using out-of-office monitoring, including nocturnal BP monitoring.

Abstract Tu081: T-tubule microdomains promote protective mitophagy in failing hearts

Heart failure (HF) with preserved ejection fraction (HFpEF) represents about 50% of all HF incidence, yet with limited therapeutic options. Although poorly understood, a key pathophysiology of HFpEF includes mitochondrial dysfunction and increased oxidative stress. We recently identified that abnormal remodeling of the cardiomyocyte t-tubule microdomains organized by the scaffolding protein cardiac bridging integrator 1 (cBIN1) contributes to HFpEF progression in db/db mice with type 2 diabetes, which can be rescued by cBIN1 gene therapy. In db/db mice, cBIN1 gene therapy (2x10 12 vg/kg) rescues HFpEF by normalizing t-tubule microdomains. With transmission electron microscopy imaging, here we report that t-tubule cBIN1-microdomains are in close proximity to mitochondria and can correct abnormal mitochondrial accumulation in db/db cardiomyocytes (Figure 1A-B). Oroboros and seahorse analysis indicates that reduced mitochondrial calcium retention, elevated oxidative stress, and impaired oxygen consumption in diabetic cardiomyocytes can be normalized by cBIN1 therapy (Figure 1C-E). Furthermore, proteomics analysis indicates accumulation of mitochondrial proteins in db/db cardiomyocytes can be reversed by the therapy. cBIN1-normalized mitochondrial number, proteomics, and function in db/db cardiomyocytes are associated with activation of LC3 but not changes in PGC1a, indicating increased mitophagy by the therapy. Mechanistic exploration in rat myoblast H9C2 cells indicates that FCCP stress induces mitophagy as evidenced by elevated LC3II/I ratio, which is further accumulated with autophagic flux blockade with chloroquine. Knockdown of BIN1 results in further accumulation of LC3II/I in FCCP-stressed cells (Figure 1F with quantification in the bar graph below), which is abolished by chloroquine. These data indicate that cBIN1 promotes protective mitophagy in diabetic failing hearts, suggesting its therapeutic potential for HFpEF in general.

Association of Cardiac MRI-derived Aortic Stiffness with Early Stages and Progression of Heart Failure with Preserved Ejection Fraction.

Purpose To investigate if aortic stiffening as detected with cardiac MRI is an early phenomenon in the development and progression of heart failure with preserved ejection fraction (HFpEF). Materials and Methods Both clinical and preclinical studies were performed. The clinical study was a secondary analysis of the prospective HFpEF stress trial (August 2017 through September 2019) and included 48 participants (median age, 69 years [range, 65-73 years]; 33 female, 15 male) with noncardiac dyspnea (NCD, n = 21), overt HFpEF at rest (pulmonary capillary wedge pressure [PCWP] ≥ 15 mm Hg, n = 14), and masked HFpEF at rest diagnosed during exercise stress (PCWP ≥ 25 mm Hg, n = 13) according to right heart catheterization. Additionally, all participants underwent echocardiography and cardiac MRI at rest and during exercise stress. Aortic pulse wave velocity (PWV) was calculated. The mechanistic preclinical study characterized cardiac function and structure in transgenic mice with induced arterial stiffness (Runx2-smTg mice). Statistical analyses comprised nonparametric and parametric comparisons, Spearman correlations, and logistic regression models. Results Participants with HFpEF showed increased PWV (NCD vs masked HFpEF: 7.0 m/sec [IQR: 5.0-9.5 m/sec] vs 10.0 m/sec [IQR: 8.0-13.4 m/sec], P = .005; NCD vs overt HFpEF: 7.0 m/sec [IQR: 5.0-9.5 m/sec] vs 11.0 m/sec [IQR: 7.5-12.0 m/sec], P = .01). Increased PWV correlated with higher PCWP (P = .006), left atrial and left ventricular long-axis strain (all P < .02), and N-terminal pro-brain natriuretic peptide levels (P < .001). Participants with overt HFpEF had higher levels of myocardial fibrosis, as demonstrated by increased native T1 times (1199 msec [IQR: 1169-1228 msec] vs 1234 msec [IQR: 1208-1255 msec], P = .009). Aortic stiffness was independently associated with HFpEF on multivariable analyses (odds ratio, 1.31; P = .049). Runx2-smTG mice exhibited an "HFpEF" phenotype compared with wild-type controls, with preserved left ventricular fractional shortening but an early and late diastolic mitral annulus velocity less than 1 (mean, 0.67 ± 0.39 [standard error of the mean] vs 1.45 ± 0.47; P = .004), increased myocardial collagen deposition (mean, 11% ± 1 vs 2% ± 1; P < .001), and increased brain natriuretic peptide levels (mean, 171 pg/mL ± 23 vs 101 pg/mL ± 10; P < .001). Conclusion This study provides translational evidence that increased arterial stiffness might be associated with development and progression of HFpEF and may facilitate its early detection. Keywords: MR Functional Imaging, MR Imaging, Animal Studies, Cardiac, Aorta, Heart ClinicalTrials.gov identifier NCT03260621 Supplemental material is available for this article. © RSNA, 2024.

Glucagon Receptor Antagonist for Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized. We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lepob/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts. In contrast to the post-transverse aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-transverse aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress. These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.

Estrogen and the estrogen receptor in ZSF1 rats with heart failure with preserved ejection fraction

Abstract Funding Acknowledgements None. Background Heart failure with preserved ejection fraction (HFpEF) is more prevalent in women, so declining estrogen levels after menopause may be involved in genesis of the disease. Estrogen is cardio-protective, affecting blood pressure and vasodilatation and endothelial dysfunction is discussed as HFpEF pathomechanism. However, the potential connection between HFpEF and estrogen levels remains poorly understood. The well-established HFpEF ZSF1 rat model was used to analyze endothelial dysfunction, and a pronounced imbalance of the NO synthase substrates arginine and homoarginine was observed. Of note, estrogen levels in woman are directly and positively associated to homoarginine levels. Purpose We characterized serum estrogen levels and the expression of the estrogen receptor alpha (ERα) in the hearts of female ZSF1 HFpEF rats to investigate a possible contribution of estrogen signaling in HFpEF manifestation and to evaluate the suitability of this animal model in the context of estrogen and HFpEF. Methods In total, 12 obese ZSF1 rats with HFpEF (O-ZSF1) and 12 lean healthy ZSF1 rats (L-ZSF1) at 20 weeks of age and 5 animals of either phenotype aged 32 weeks were analyzed. Further, six O-ZSF1 rats were supplemented with homoarginine (hArg) when HFpEF was manifest and were observed up to 32 weeks of age. The manifestation of HFpEF was confirmed by echocardiography and determination of NT-proBNP by ELISA. Circulating estradiol (E2) in serum was determined using ELISA. Expression of the estrogen receptor alpha was determined by Western Blot analysis in the left ventricle (LV), septum and right ventricle (RV). Results Serum estradiol levels were similar in age-matched L-ZSF1 and O-ZSF1, but were ~2-fold increased at an age of 32 weeks compared to 20 weeks (p=0.002). The canonical ERα-66kDa was very weakly expressed in all tissues. ERα-45kDa expression in the LV was lower in O-ZSF1 at an age of 20 weeks (-46%, p=0.008) and at 32 weeks (-46%, p=0.002). ERα-45kDa expression in LV was 2-fold higher than in septum and 5-fold higher than in RV in rats aged 20 weeks (p&amp;lt;0.001). In RV, no differences in ERα-45kDa expression were observed. Supplementation of O-ZSF1 with hArg reestablished the ERα-45kDa expression in the LV (p=0.005 vs. O-ZSF1 without supplementation). Conclusion The manifestation and progression of HFpEF in ZSF1 rats is accompanied by a decrease of the ERα-45kDa expression in the LV, whereas the RV is not affected. Supplementation with homoarginine normalizes ERα-45kDa expression. The ERα-45kDa isoform was found to suppress the transcriptional activity of the classical ERα-66kDa isoform and to be an acute regulator of endothelial NO synthase in response to estrogen. These results suggest that altered ERα expression in the LV may represent a novel pathomechanism in HFpEF. In combination with decreasing estrogen levels in woman, adverse consequences for NO production in the LV seem likely.

Elevated ITGA1 levels in type 2 diabetes: implications for cardiac function impairment

Aims/hypothesisType 2 diabetes mellitus is known to contribute to the development of heart failure with preserved ejection fraction (HFpEF). However, identifying HFpEF in individuals with type 2 diabetes early on is often challenging due to a limited array of biomarkers. This study aims to investigate specific biomarkers associated with the progression of HFpEF in individuals with type 2 diabetes, for the purpose of enabling early detection and more effective management strategies.MethodsBlood samples were collected from individuals with type 2 diabetes, both with and without HFpEF, for proteomic analysis. Plasma integrin α1 (ITGA1) levels were measured and compared between the two groups. Participants were further categorised based on ITGA1 levels and underwent detailed transthoracic echocardiography at baseline and during a median follow-up period of 30 months. Multivariable linear and Cox regression analyses were conducted separately to assess the associations between plasma ITGA1 levels and changes in echocardiography indicators and re-hospitalisation risk. Additionally, proteomic data for the individuals’ left ventricles, from ProteomeXchange database, were analysed to uncover mechanisms underlying the change in ITGA1 levels in HFpEF.ResultsIndividuals with type 2 diabetes and HFpEF showed significantly higher plasma ITGA1 levels than the individuals with type 2 diabetes without HFpEF. These elevated ITGA1 levels were associated with left ventricular remodelling and impaired diastolic function. Furthermore, during a median follow-up of 30 months, multivariable analysis revealed that elevated ITGA1 levels independently correlated with deterioration of both diastolic and systolic cardiac functions. Additionally, higher baseline plasma ITGA1 levels independently predicted re-hospitalisation risk (HR 2.331 [95% CI 1.387, 3.917], p=0.001). Proteomic analysis of left ventricular myocardial tissue provided insights into the impact of increased ITGA1 levels on cardiac fibrosis-related pathways and the contribution made by these changes to the development and progression of HFpEF.Conclusions/interpretationITGA1 serves as a biomarker for monitoring cardiac structural and functional damage, can be used to accurately diagnose the presence of HFpEF, and can be used to predict potential deterioration in cardiac structure and function as well as re-hospitalisation for individuals with type 2 diabetes. Its measurement holds promise for facilitating risk stratification and early intervention to mitigate the adverse cardiovascular effects associated with diabetes.Data availabilityThe proteomic data of left ventricular myocardial tissue from individuals with type 2 diabetes, encompassing both those with and without HFpEF, is available from the ProteomeXchange database at http://proteomecentral.proteomexchange.org.Graphical

Targeting HDAC6 to treat heart failure with preserved ejection fraction in mice

Heart failure with preserved ejection fraction (HFpEF) poses therapeutic challenges due to the limited treatment options. Building upon our previous research that demonstrates the efficacy of histone deacetylase 6 (HDAC6) inhibition in a genetic cardiomyopathy model, we investigate HDAC6’s role in HFpEF due to their shared mechanisms of inflammation and metabolism. Here, we show that inhibiting HDAC6 with TYA-018 effectively reverses established heart failure and its associated symptoms in male HFpEF mouse models. Additionally, in male mice lacking Hdac6 gene, HFpEF progression is delayed and they are resistant to TYA-018’s effects. The efficacy of TYA-018 is comparable to a sodium-glucose cotransporter 2 (SGLT2) inhibitor, and the combination shows enhanced effects. Mechanistically, TYA-018 restores gene expression related to hypertrophy, fibrosis, and mitochondrial energy production in HFpEF heart tissues. Furthermore, TYA-018 also inhibits activation of human cardiac fibroblasts and enhances mitochondrial respiratory capacity in cardiomyocytes. In this work, our findings show that HDAC6 impacts on heart pathophysiology and is a promising target for HFpEF treatment.

Early Renal Denervation Attenuates Cardiac Dysfunction in Heart Failure With Preserved Ejection Fraction.

The renal sympathetic nervous system modulates systemic blood pressure, cardiac performance, and renal function. Pathological increases in renal sympathetic nerve activity contribute to the pathogenesis of heart failure with preserved ejection fraction (HFpEF). We investigated the effects of renal sympathetic denervation performed at early or late stages of HFpEF progression. Male ZSF1 obese rats were subjected to radiofrequency renal denervation (RF-RDN) or sham procedure at either 8 weeks or 20 weeks of age and assessed for cardiovascular function, exercise capacity, and cardiorenal fibrosis. Renal norepinephrine and renal nerve tyrosine hydroxylase staining were performed to quantify denervation following RF-RDN. In addition, renal injury, oxidative stress, inflammation, and profibrotic biomarkers were evaluated to determine pathways associated with RDN. RF-RDN significantly reduced renal norepinephrine and tyrosine hydroxylase content in both study cohorts. RF-RDN therapy performed at 8 weeks of age attenuated cardiac dysfunction, reduced cardiorenal fibrosis, and improved endothelial-dependent vascular reactivity. These improvements were associated with reductions in renal injury markers, expression of renal NLR family pyrin domain containing 3/interleukin 1β, and expression of profibrotic mediators. RF-RDN failed to exert beneficial effects when administered in the 20-week-old HFpEF cohort. Our data demonstrate that early RF-RDN therapy protects against HFpEF disease progression in part due to the attenuation of renal fibrosis and inflammation. In contrast, the renoprotective and left ventricular functional improvements were lost when RF-RDN was performed in later HFpEF progression. These results suggest that RDN may be a viable treatment option for HFpEF during the early stages of this systemic inflammatory disease.

Prognostic Role of Myocardial Flow Reserve in Heart Failure With Preserved Ejection Fraction.

Aim To study the role of myocardial blood flow (MBF) and myocardial flow reserve (MFR) in patients with heart failure with preserved ejection fraction (HFpEF) in stratifying the risk of HFpEF progression during 12 months of follow-up.Material and methods The study included 58 patients with non-obstructive coronary artery disease and HFpEF. Concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) were measured using an enzyme-linked immunosorbent assay. MFR and MBF were determined by dynamic single-photon emission computed tomography of the myocardium.Results At 12 months, the patients were divided into two groups: group 1 (n=11) included patients with an unfavorable course of HFpEF, group 2 (n=47) included patients with a favorable course. A multivariate analysis showed that NT-proBNP concentrations (odds ratio (OR), 3.23; 95% confidence interval (CI), 1.76-6.78; p=0.008) and MFR (OR, 8.09; 95% CI, 5.12-19.98; p&lt;0.001) were independent predictors of adverse outcomes. According to ROC analysis, values of MFR ≤1.62 (area under the curve (AUC)=0.827; p&lt;0.001) and NT-proBNP ≥760.5 pg/ml (AUC=0.708; p=0.040) can be considered as markers for HFpEF progression. Furthermore, the combined measurement of NT-proBNP concentration and MFR had a higher prognostic significance (AUC, 0.954; p&lt;0.001).Conclusion Values of NT-proBNP and MFR can be used as noninvasive markers for an unfavorable course of HFpEF, and their combined measurement increases the prognostic significance.

High sensitivity cardiac troponin I in response to handgrip in women with signs and symptoms of ischemia with no obstructive coronary arteries

Abstract Background Women with signs and symptoms of ischemia and no obstructive coronary arteries (INOCA) are suspected to have myocardial ischemia, ∼10% have prior myocardial scar often in the absence of acute myocardial infarction (AMI) diagnosis and the development of heart failure with preserved ejection fraction (HFpEF) is relatively frequent. The mechanisms contributing to AMI and HFpEF progression are poorly understood in INOCA. Purpose To compare clinical, invasive, and high sensitivity cardiac troponin I (hsTnI) parameters in women with INOCA at rest and in response to isometric handgrip exercise. Methods Women with suspected INOCA underwent cannulation of the coronary sinus (CS), handgrip exercise testing and serial CS plasma sampling before, after 3 minutes of isometric handgrip stress at 30% of maximal voluntary contraction, and after 5 minutes of recovery. hsTnI was measured using a commercial immunoassay (R-PLEX, Meso Scale Discovery, Rockville, MD) and compared using t-tests. Results A total of 54 women with complete invasive data were included with a mean age of 53 ± 10 years, mean body mass index 28 ± 7 kg/m2. 20 women (37% of the cohort) had detectable CS hsTnI from baseline. Among these women, median values were elevated in response to handgrip (Figure) (baseline median 33.75 (IQR 18.12-67.75) pg/mL vs peak handgrip median 56.23 (IQR 32.84-97.83) pg/mL, signed rank p=0.0007, baseline vs recovery median 52.35 (IQR 32.59-106.27) pg/mL, signed rank p=0.0002). Conclusion Among women with INOCA, handgrip stress leads to an increase in hsTnI in more than a third, demonstrating objective evidence of myocardial injury. More work is needed to better understand contribution of coronary microvascular dysfunction to HFpEF progression.

Abstract 15172: P21 Activated Kinase 2 Mediates Cardioprotection in Heart Failure With Preserved Ejection Fraction by Modulating Endoplasmic Reticulum Stress Response

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a type of heart failure characterised by diastolic dysfunction but normal systolic function. Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of HFpEF. Previous studies have reported that P21 activated kinase 2 (Pak2) confers cardioprotection against the endoplasmic reticulum stress response. Hypothesis: Pak2 protein can potentially alleviate the adverse effects of maladaptive ER stress in HFpEF. Methods: The HFpEF model was developed by feeding C57/BL6N male mice with a high-fat diet (HFD) and a constitutive nitric oxide inhibitor, L-NAME, in drinking water for 15 weeks. Cardiac function was assessed by echocardiography and hemodynamics. Heart and lung structure was detected by H&amp;E staining and Masson staining. Electron microscopy, immunoblotting, and RNA sequencing were used to investigate the ER structure and function. Cardiomyocyte-specific Pak2 knockout (Pak2 CKO ) mice and adeno-associated virus (AAV) 9 for Pak2 overexpression were used to investigate the role of Pak2 in the heart. Results: After 15 weeks of feeding, mice on the HFD+L-NAME diet developed an HFpEF phenotype, as indicated by cardiac hypertrophy, impaired diastolic function but preserved systolic function, and pulmonary remodelling. The ER structure and the IRE1/XBP1s pathway were impaired in the cardiomyocytes of HFD+L-NAME mice. Pak2CKO mice exhibited the HFpEF phenotype at 10 weeks. In addition, Pak2 overexpression prevented diastolic dysfunction after 15 weeks and preserved the activation of the IRE1/XBP1s pathway under stress conditions. Conclusions: HFD + L-NAME diet for 15 weeks recapitulated the features of HFpEF in mice. Pak2 plays a protective role in HFpEF progression by modulating the cardiomyocyte ER stress response through the IRE1/XBP1s signaling pathway.

Abstract 14155: Handgrip Exercise Provoked High Sensitivity Cardiac Troponin I Increase in Women With No Obstructive Coronary Artery Disease: Relations to Myocardial Function

Background: Among women with signs and symptoms of ischemia and no obstructive coronary arteries (INOCA) around 10% develop heart failure with preserved ejection fraction (HFpEF). Mechanisms contributing to AMI and HFpEF progression in INOCA are poorly understood. Purpose: To characterize clinical profile and stress cardiac magnetic resonance imaging (CMRI) myocardial features of INOCA patients with and without increased troponin levels in response to handgrip exercise. Methods: Women with suspected INOCA underwent cardiac MRI and invasive coronary function testing (CFT), including coronary sinus (CS) cannulation, handgrip exercise testing, and serial CS plasma sampling before, after 3 minutes of isometric handgrip stress at 30% of maximal voluntary contraction, and after 5 minutes of recovery. High sensitivity cardiac troponin I (hsTnI) was measured using commercial immunoassay (R-PLEX, Meso Scale Discovery, Rockville, MD) and compared using t-tests. Results: A total of 51 women with complete data were included, of whom 31 (60.7%) had handgrip provoked increases in hsTnI levels from baseline, while 20 (39.2%) did not. Baseline characteristics are shown in Table. Patients with increased hsTnI levels had greater impaired global longitudinal strain rates and early diastolic strain rates (radial and circumferential) compared to those without increased hsTnI. No significant differences were observed in myocardial perfusion reserve index (MPRI). Conclusion: Women with INOCA demonstrating objective evidence of handgrip exercise provoked myocardial injury exhibit evidence of myocardial dysfunction not related to myocardial perfusion. Further prospective research is needed to understand the sequence of relations between coronary microvascular dysfunction contribution to HFpEF progression.

Development and Challenges of Pre-Heart Failure with Preserved Ejection Fraction.

Pre-heart failure with preserved ejection fraction (Pre-HFpEF) is a critical link to the development of heart failure with preserved ejection fraction (HFpEF). Early recognition and early intervention of pre-HFpEF will halt the progression of HFpEF. This article addresses the concept proposal, development, and evolution of pre-HFpEF, the mechanisms and risks of pre-HFpEF, the screening methods to recognize pre-HFpEF, and the treatment of pre-HFpEF. Despite the challenges, we believe more focus on the topic will resolve more problems.

Dapagliflozin Attenuates Heart Failure With Preserved Ejection Fraction Remodeling and Dysfunction by Elevating β-Hydroxybutyrate-activated Citrate Synthase.

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent, accounting for 50% of all heart failure patients, and is associated with significant mortality. Sodium-glucose cotransporter subtype inhibitor (SGLT2i) is recommended in the AHA and ESC guidelines for the treatment of HFpEF, but the mechanism of SGLT2i to prevent and treat cardiac remodeling and dysfunction is currently unknown, hindering the understanding of the pathophysiology of HFpEF and the development of novel therapeutics. HFpEF model was induced by a high-fat diet (60% calories from lard) + N [w] -nitro- l -arginine methyl ester ( l -NAME-0.5 g/L) (2 Hit) in male Sprague Dawley rats to effectively recapture the myriad phenotype of HFpEF. This study's results showed that administration of dapagliflozin (DAPA, SGLT2 inhibitor) significantly limited the 2-Hit-induced cardiomyocyte hypertrophy, apoptosis, inflammation, oxidative stress, and fibrosis. It also improved cardiac diastolic and systolic dysfunction in a late-stage progression of HFpEF. Mechanistically, DAPA influences energy metabolism associated with fatty acid intake and mitochondrial dysfunction in HFpEF by increasing β-hydroxybutyric acid (β-OHB) levels, directing the activation of citrate synthase, reducing acetyl coenzyme A (acetyl-CoA) pools, modulating adenosine 5'-triphosphate production, and increasing the expression of mitochondrial oxidative phosphorylation system complexes I-V. In addition, following clinical DAPA therapy, the blood levels of β-OHB and citrate synthase increased and the levels of acetyl-CoA in the blood of HFpEF patients decreased. SGLT2i plays a beneficial role in the prevention and treatment of cardiac remodeling and dysfunction in HFpEF model by attenuating cardiometabolic dysregulation.