Progression Of Heart Failure With Preserved Ejection Fraction Research Articles

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.

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.

Prognostic Role of Dynamic CZT Imaging in Heart Failure With Preserved Ejection Fraction.

The objective of the study was to evaluate the prognostic role of myocardial flow reserve (MFR) and myocardial blood flow (MBF) estimates obtained with dynamic cadmium-zinc-telluride (CZT) imaging in the development and progression of heart failure with preserved ejection fraction (HFpEF) in patients with nonobstructive coronary artery disease (CAD) during a 12-month follow-up period. A total of 112 patients (70 men; median age of 62.5 [57.0; 69.0] years) with nonobstructive coronary artery disease were enrolled in the study. Dynamic CZT-SPECT, echocardiography, and coronary CT angiography studies were performed baseline. Distribution of patients was performed by adverse events: group 1 comprised patients with adverse outcomes (n = 25), and group 2 comprised those without it (n = 87). Based on receiver operating characteristic analysis, the levels of MFR ≤1.62 (area under the curve [AUС], 0.884; Р < 0.001), stress-MBF ≤1.35 mL/min per gram (AUС, 0.750; Р < 0.001), and NT-proBNP ≥760.5 pg/mL (AUС, 0.764; Р = 0.001) were identified as cutoff values to predict adverse outcomes. Univariate analysis revealed that type 2 diabetes mellitus ( P = 0.044), the levels of MFR ≤1.62 ( P = 0.014), stress-MBF ≤1.35 mL/min per gram ( P = 0.012), NT-proBNP ≥760.5 pg/mL ( P = 0.018), and diastolic dysfunction ( P = 0.009) were potential risk factors for the development and progression of HFpEF. Multivariate analysis demonstrated that the values of NT-proBNP ≥760.5 pg/mL (odds ratio, 1.87; 95% confidence interval, 1.17-3.62; P = 0.027) and MFR ≤1.62 (odds ratio, 2.801; 95% confidence interval, 1.19-6.55; P = 0.018) were independent predictors of adverse outcomes. Our data suggest that reduced MFR ≤1.62 obtained with dynamic CZT imaging and overexpression of NT-proBNP ≥760.5 pg/mL can individuate patients at high risk of development and progression of HFpEF during a 12-month follow-up period, independently of baseline clinical parameters and imaging variables.

Prognostic value of myocardial flow reserve in patients with heart failure with preserved ejection fraction

Aim. To study the prognostic value of myocardial blood flow (MBF) and myocardial flow reserve (MFR) parameters in patients with heart failure with preserved ejection fraction (HFpEF) and non-obstructive coronary artery disease (CAD) in risk stratification of HFpEF progression during a 12-month follow-up.Materials and methods. The study included 58 patients with non-obstructive CAD and HFpEF (LVEF 62 [58; 66]%). Dynamic CZT-SRECT was used to evaluate MFR and MBF at rest (rest-MBF) and stress (stress-MBF). NT-proBNP levels were determined by the enzyme immunoassay. Diastolic dysfunction parameters were measured using 2D transthoracic echocardiography. Left ventricular systolic global longitudinal strain (GLS) was assessed using 2D speckle tracking.Results. After a 12-month follow-up, the patients were retrospectively divided into 2 groups: group 1 (n = 11) included patients with an unfavorable course of HFpEF, group 2 (n = 47) encompassed patients with a favorable course of the disease. In group 1, the level of NT-proBNP was 3.8 times higher than in group 2 (284.5 [183.42; 716.73] and 1,071.4 [272.4; 2,168.1] pg / ml, respectively). MFR values in group 1 were lower by 45.4%(p &lt; 0.001) than in group 2 (1.19 [0.86; 1.55] vs. 2.18 [1.7; 2.55], respectively). In group 1, rest-MBF levels were higher by 23.6% (p = 0.046) and stress-MBF was lower by 28.2% (p = 0.046) than in group 2. The multivariate regression analysis revealed that NT-proBNP levels (odds ratio (OR) 3.23; p = 0.008), GLS (OR 2.27; p = 0.012), and MFR (OR 8.09; p &lt; 0.001) were independent predictors of adverse outcomes in HFpEF. Based on the ROC analysis, MFR levels ≤ 1.62 (AUC = 0.827; p &lt; 0.001), GLS ≤–18 (AUC = 0.756; p = 0.002), and NT-proBNP≥ 760.5 pg / ml (AUC = 0.708; p = 0.040) may be considered as markers of adverse outcomes. However, the combined determination of NT-proBNP and MFR had a greater significance (AUC 0.935; p &lt; 0.001) in risk stratification compared with the monomarker model, while the addition of GLS did not increase the significance of the analysis.Conclusion. Levels of NT-proBNP, GLS, and MFR may be used as non-invasive markers of an adverse course of HFpEF in patients with non-obstructive CAD, while the combined determination of NT-proBNP and MBF increases the prognostic value of the analysis.

Diet modification reverses diastolic dysfunction in rats with heart failure and preserved ejection fraction.

Dahl Salt-Sensitive (DSS) rats develop heart failure with preserved ejection fraction (HFpEF) when fed a high-salt (8 % NaCl) diet. Hypertension-induced inflammation and subsequent ventricular fibrosis are believed to underlie the development of HFpEF. We investigated the role of diet modification in the progression of HFpEF using male DSS rats, fed either a high-salt diet from7 weeks of age to induce HFpEF, ora normal-salt (0.3% NaCl) diet as controls. After echocardiographic confirmation of diastolic dysfunction at 14-15 weeks of age along with HF manifestations, the HFpEF rats were randomly assigned to either continue a high-salt diet or switch to a normal-salt diet for an additional 4 weeks. HFpEF rats with diet modification showed improved diastolic function (reduced E/E' ratio in echocardiogram), increased functional capacity (increased treadmill exercise distance), and reduced pulmonary congestions (lung/body weight ratio), compared to high-salt-fed HFpEF rats. Systolic blood pressure remained high (~200 mmHg), and ventricular hypertrophy remained unchanged. Ventricular arrhythmia inducibility (100 % inducible) and corrected QT interval (on ECG) did not change in HFpEF rats after diet modification. HFpEF rats with diet modification showed prolonged survival and reduced ventricular fibrosis (Masson's trichrome staining) compared to high-salt-fed HFpEF rats. Hence, the modification of diet (from high-salt to normal-salt diet) reversed HFpEF phenotypes without affecting blood pressure or ventricular hypertrophy.

Mechano-energetic defects in heart failure

Heart failure is characterized by defects in excitation-contraction coupling, energetic deficit and oxidative stress. The energy for cardiac contraction and relaxation is provided in mitochondria, whose function is tightly regulated by excitation-contraction coupling in cardiac myocytes. In heart failure with reduced ejection fraction (HFrEF), alterations in the ion balance in cardiac myocytes impair mitochondrial Ca2+ uptake, which is required for activation of the Krebs cycle, causing an energetic deficit and oxidative stress in mitochondria. Recent clinical studies suggest that in heart failure with preserved ejection fraction (HFpEF), in stark contrast to HFrEF, hypercontractility often occurs as an attempt to compensate for apathological increase in systemic and pulmonary vascular resistance. This hypercontractility increases cardiac energy and oxygen demands at rest and reduces the contractile, diastolic and coronary reserves, preventing an adequate increase in cardiac output during exercise. Moreover, increased contractility causes long-term maladaptive remodeling processes due to oxidative stress and redox-sensitive prohypertrophic signaling pathways. As overweight and diabetes, particularly in the interplay with hemodynamic stress, are important risk factors for the development of HFpEF, interventions targeting metabolism in particular could ameliorate the development and progression of HFpEF.

The NO-cGMP-PKG Axis in HFpEF: From Pathological Mechanisms to Potential Therapies.

Heart failure with preserved ejection fraction (HFpEF) accounts for almost half of all heart failure (HF) cases worldwide. Unfortunately, its incidence is expected to continue to rise, and effective therapy to improve clinical outcomes is lacking. Numerous efforts currently directed towards the pathophysiology of human HFpEF are uncovering signal transduction pathways and novel therapeutic targets. The nitric oxide-cyclic guanosine phosphate-protein kinase G (NO-cGMP-PKG) axis has been described as an important regulator of cardiac function. Suppression of the NO-cGMP-PKG signalling pathway is involved in the progression of HFpEF. Therefore, the NO-cGMP-PKG signalling pathway is a potential therapeutic target for HFpEF. In this review, we aim to explore the mechanism of NO-cGMP-PKG in the progression of HFpEF and to summarize potential therapeutic drugs that target this signalling pathway.

The double-hit protocol induces HFpEF and impairs myocardial ubiquitin-proteasome system performance in FVB/N mice.

Heart failure with preserved ejection fraction (HFpEF) is a leading cause of death and disability, with its prevalence surpassing that of heart failure with reduced ejection fraction. Obesity and hypertension are often associated with HFpEF. HFpEF can be modeled through simultaneous metabolic and hypertensive stresses in male C57BL/6N mice provoked by a combination treatment of a high-fat diet (HFD) and constitutive nitric oxide synthase inhibition by Nω-nitro-L-arginine methyl-ester (L-NAME). Ubiquitin-proteasome system (UPS) dysfunction was detected in many forms of cardiomyopathy, but whether it occurs in HFpEF remains unknown. We report successful modeling of HFpEF in male FVB/N mice and, by taking advantage of a transgenic UPS reporter mouse, we have detected myocardial UPS functioning impairment during HFpEF, suggesting a pathogenic role for impaired protein degradation in the development and progression of HFpEF.

Advances in extracardiac mechanisms for heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is a syndrome with highly heterogeneous clinical symptoms, and its incidence has been increasing in recent years. Compared with heart failure with reduced ejection fraction (HFrEF), HFpEF has a worse prognosis. Traditional therapies targeting the internal mechanisms of the heart show limited or inefficacy on HFpEF, and new therapeutic targets for HFpEF are expected to be found by focusing on the extracardiac mechanisms. Recent studies have shown that cardiopulmonary pathophysiological interaction exacerbates the progression of HFpEF. Hypertension, systemic vascular injury, and inflammatory response lead to coronary microvascular dysfunction, myocardial hypertrophy, and coronary microvascular remodeling. Acute kidney injury affects myocardial energy production, induces oxidative stress and catabolism of myocardial protein, which leads to myocardial dysfunction. Liver fibrosis mediates heart injury by abnormal protein deposition and inflammatory factors production. Skeletal muscle interacts with the sympathetic nervous system by metabolic signals. It also produces muscle factors, jointly affecting cardiac function. Metabolic syndrome, gut microbiota dysbiosis, immune system diseases, and iron deficiency promote the occurrence and development of HFpEF through metabolic changes, oxidative stress, and inflammatory responses. Therefore, the research on the extracardiac mechanisms of HFpEF has certain implications for model construction, mechanism research, and treatment strategy formulation.