Dapagliflozin Enhances Arterial and Venous Compliance During Exercise in Heart Failure With Preserved Ejection Fraction: Insights From the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial.

BACKGROUND: Systemic arterial compliance and venous capacitance are typically impaired in patients with heart failure with preserved ejection fraction (HFpEF), contributing to hemodynamic congestion with stress. Sodium-glucose cotransporter-2 inhibitors reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. This study tested the hypothesis that Dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF. METHODS: In this secondary analysis from the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial, 37 patients with HFpEF (mean age 68 ± 9 years, women 65%) underwent invasive hemodynamic exercise testing with simultaneous echocardiography at baseline and following treatment for 24 weeks with Dapagliflozin or placebo. Radial artery pressure (BP) was measured continuously using a fluid-filled catheter with transformation to aortic pressure, central hemodynamics were measured using high-fidelity micromanometers, and stressed blood volume was estimated from hemodynamic indices fit to a comprehensive cardiovascular model. RESULTS: There was no statistically significant effect of Dapagliflozin on resting BP, but Dapagliflozin reduced systolic BP during peak exercise (estimated treatment difference [ETD], -18.8 mm Hg [95% CI, -33.9 to -3.7] P=0.016). Reduction in BP was related to improved exertional total arterial compliance (ETD, 0.06 mL/mm Hg/m2 [95% CI, 0.003-0.11] P=0.039) and aortic root characteristic impedance (ETD, -2.6 mm Hg/mL*sec [95% CI: -5.1 to -0.03] P=0.048), with no significant effect on systemic vascular resistance. Dapagliflozin reduced estimated stressed blood volume at rest and during peak exercise (ETD, -292 mm Hg [95% CI, -530 to -53] P=0.018), and improved venous capacitance evidenced by a decline in ratio of estimated stressed blood volume to total blood volume (ETD, -7.3% [95% CI, -13.3 to -1.3] P=0.020). Each of these effects of Dapagliflozin at peak exercise were also observed during matched 20W exercise intensity. Improvements in total arterial compliance and estimated stressed blood volume were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in estimated stressed blood volume during exercise (r=0.40, P=0.019). Decreases in BP were correlated with reduction in pulmonary capillary wedge pressure during exercise (r=0.56, P<0.001). CONCLUSIONS: In patients with HFpEF, treatment with Dapagliflozin improved systemic arterial compliance and venous capacitance during exercise, while reducing aortic characteristic impedance, suggesting a reduction in arterial wall stiffness. These vascular effects may partially explain the clinical benefits with sodium-glucose cotransporter-2 inhibitors in HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04730947.

Cardiac diastolic dysfunction by cigarette smoking is associated with mitochondrial integrity in the heart.

Cigarette smoking behaviors are harmful and cause one out of ten deaths due to cardiovascular disease. As population sizes grow and number of cigarette smokers increases, it is vital that we understand the mechanisms leading to heart failure in cigarette smokers. We have reported that metabolic regulation of a histone deacetylase, SIRT1, modulates cardiovascular and mitochondrial function under stress. Given this conclusion, we hypothesized that chronic cigarette smoking led to cardiovascular dysfunction via a reduction SIRT1. Mice were randomly organized into smoking or nonsmoking groups, and the smoking group received cigarette smoke exposure for 16 weeks. Following 16-week exposure, diastolic function of the heart was impaired in the smoking group as compared to sham, indicated by a significant increase in E/e'. The electrical function of the heart was also impaired in the smoking group compared to the sham group, indicated by increased PR interval and decreased QTc interval. This diastolic dysfunction was not accompanied by increased fibrosis in mouse hearts, although samples from human chronic smokers indicated increased fibrosis compared to their nonsmoker counterparts. As well as diastolic dysfunction, mitochondria from the 16-week smoking group showed significantly impaired function, evidenced by significant decreases in all parameters measured by the mitochondrial stress test. We further found biochemical evidence of a significantly decreased level of SIRT1 in left ventricles of both mouse and human smoking groups compared to nonsmoking counterparts. Data from this study indicate that decreased SIRT1 levels by cigarette smoking are associated with diastolic dysfunction caused by compromised mitochondrial integrity.

Characterization and Mortality Risk of Impaired Left Ventricular Filling in COPD.

BACKGROUND: In COPD, impaired left ventricular (LV) filling might be associated with coexisting HFpEF or due to reduced pulmonary venous return indicated by small LV size. We investigate the all-cause mortality associated with small LV or HFpEF and clinical features discriminating between both patterns of impaired LV filling. METHODS: We performed transthoracic echocardiography (TTE) in patients with stable COPD from the COSYCONET cohort to define small LV as LVEDD below the normal range and HFpEF features according to recommendations of the European Society of Cardiology. We assessed the E/A and E/e' ratios, NT-pro-BNP, hs-Troponin I, FEV1, RV, DLCo, and discriminated patients with small LV from those with HFpEF features or no relevant cardiac dysfunction as per TTE (normalTTE). The primary outcome was all-cause mortality after four and a half year. RESULTS: In 1752 patients with COPD, the frequency of small LV, HFpEF-features, and normalTTE was 8%, 16%, and 45%, respectively. Patients with small LV or HFpEF features had higher all-cause mortality rates than patients with normalTTE, HR: 2.75 (95% CI: [1.54 - 4.89]) and 2.16 (95% CI: [1.30 - 3.61]), respectively. Small LV remained an independent predictor of all-cause mortality after adjusting for confounders including exacerbation frequency and measures of RV, DLCo, or FEV1. Compared to normalTTE, patients with small LV had reduced LV filling, as indicated by lowered E/A. Yet in contrast to patients with HFpEF-features, patients with small LV had normal LV filling pressure (E/e') and lower levels of NT-pro-BNP and hs-Troponin I. CONCLUSION: In COPD, both small LV and HFpEF-features are associated with increased all-cause mortality and represent two distinct patterns of impaired LV filling This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function.

SGLT2 inhibitors are antihyperglycemic drugs that protect kidneys and the heart of patients with or without type 2 diabetes and preserved or reduced kidney function from failing. The involved protective mechanisms include blood glucose-dependent and -independent mechanisms: SGLT2 inhibitors prevent both hyper- and hypoglycemia, with expectedly little net effect on HbA1C. Metabolic adaptations to induced urinary glucose loss include reduced fat mass and more ketone bodies as additional fuel. SGLT2 inhibitors lower glomerular capillary hypertension and hyperfiltration, thereby reducing the physical stress on the filtration barrier, albuminuria, and the oxygen demand for tubular reabsorption. This improves cortical oxygenation, which, together with lesser tubular gluco-toxicity, may preserve tubular function and glomerular filtration rate in the long term. SGLT2 inhibitors may mimic systemic hypoxia and stimulate erythropoiesis, which improves organ oxygen delivery. SGLT2 inhibitors are proximal tubule and osmotic diuretics that reduce volume retention and blood pressure and preserve heart function, potentially in part by overcoming the resistance to diuretics and atrial-natriuretic-peptide and inhibiting Na-H exchangers and sympathetic tone.

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

AIMS/HYPOTHESIS: Type 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. METHODS: Blood 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. RESULTS: Individuals 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/INTERPRETATION: ITGA1 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 AVAILABILITY: The 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 .

Distinguishing pathophysiological features of heart failure with reduced and preserved ejection fraction: A comparative analysis of two mouse models.

Heart failure (HF) is a heterogeneous condition that can be categorized according to the left ventricular ejection fraction (EF) into HF with reduced (HFrEF) or preserved (HFpEF) EF. Although HFrEF and HFpEF share some common clinical manifestations, the mechanisms underlying each phenotype are often found to be distinct. Identifying shared and divergent pathophysiological features might expand our insights on HF pathophysiology and assist the search for therapies for each HF subtype. In this study, we evaluated and contrasted two new murine models of non-ischaemic HFrEF and cardiometabolic HFpEF in terms of myocardial structure, left ventricular function, gene expression, cardiomyocyte calcium handling, mitochondrial polarization and protein acetylation in a head-to-head fashion. We found that in conditions of similar haemodynamic stress, the HFrEF myocardium underwent a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation was greater in the HFpEF myocardium. We observed opposing features on calcium release, which was diminished in the HFrEF cardiomyocyte but enhanced in the HFpEF cardiomyocyte. Mitochondria were less polarized in both HFrEF and HFpEF cardiomyocytes, reflecting similarly impaired metabolic capacity. Hyperacetylation of cardiac proteins was observed in both models, but it was more accentuated in the HFpEF heart. Despite shared features, unique triggering mechanisms (neurohormonal overactivation in HFrEF vs. inflammation in HFpEF) appear to determine the distinct phenotypes of HF. The findings of the present research stress the need for further exploration of the differential mechanisms underlying each HF subtype, because they might require specific therapeutic interventions. KEY POINTS: The mechanisms underlying heart failure with either reduced (HFrEF) or preserved (HFpEF) ejection fraction are often found to be different. Previous studies comparing pathophysiological traits between HFrEF and HFpEF have been conducted on animals of different ages and strains. The present research contrasted two age-matched mouse models of non-ischaemic HFrEF and cardiometabolic HFpEF to uncover divergent and shared features. We found that upon similar haemodynamic stress, the HFrEF heart experienced a more pronounced hypertrophic and fibrotic remodelling, whereas inflammation appeared to be greater in the HFpEF myocardium. Calcium release was diminished in the HFrEF cardiomyocyte and enhanced in the HFpEF cardiomyocyte. Mitochondria were comparably less polarized in both HFrEF and HFpEF myocytes. Hyperacetylation of proteins was common to both models, but stronger in the HFpEF heart. Casting light on common and distinguishing features might ease the quest for phenotype-specific therapies for heart failure patients.

Integrated proteomic and metabolomic profiling reveals novel insights on the inflammation and immune response in HFpEF.

BACKGROUND: The precise mechanisms leading to the development of heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. In this study, an integrative approach utilizing untargeted proteomics and metabolomics was employed to delineate the altered proteomic and metabolomic profiles in patients with HFpEF compared to healthy controls. MATERIALS AND METHODS: Data were collected from a prospective cohort consisting of 30 HFpEF participants and 30 healthy controls, matched by gender and age. plasma samples were analyzed by multi-omics platforms. The quantification of plasma proteins and metabolites was performed using data-independent acquisition-based liquid chromatography-tandem mass spectrometry (LC-MS/MS) and ultrahigh-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS), respectively. Additionally, Proteomic and metabolomic results were analyzed separately and integrated using correlation and pathway analysis. This was followed by the execution of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment studies to elucidate the biological relevance of the observed results. RESULTS: A total of 46 significantly differentially expressed proteins (DEPs) and 102 differentially expressed metabolites (DEMs) were identified. Then, GO and KEGG pathway enrichment analyses were performed by DEPs and DEMs. Integrated analysis of proteomics and metabolomics has revealed Tuberculosis and African trypanosomiasis pathways that are significantly enriched and the DEPs and DEMs enriched within them, are associated with inflammation and immune response. CONCLUSIONS: Integrated proteomic and metabolomic analyses revealed distinct inflammatory and immune response pathways in HFpEF, highlighting novel therapeutic avenues.

Novel insights into the pathobiology of pulmonary hypertension in heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) is the most common cause of pulmonary hypertension (PH) worldwide and is strongly associated with adverse clinical outcomes. The American Heart Association recently highlighted a call to action regarding the distinct lack of evidence-based treatments for PH due to poorly understood pathophysiology of PH attributable to HFpEF (PH-HFpEF). Prior studies have described cardiophysiological mechanisms to explain the development of isolated postcapillary PH (ipc-PH); however, the consequent increase in pulmonary vascular (PV) resistance (PVR) may lead to the less understood and more fatal combined pre- and postcapillary PH (cpc-PH). Metabolic disease and inflammatory dysregulation have been suggested to predispose PH, yet the molecular mechanisms are unknown. Although PH-HFpEF has been studied to partly share vasoactive neurohormonal mediators with primary pulmonary arterial hypertension (PAH), clinical trials that have targeted these pathways have been unsuccessful. The increased mortality of patients with PH-HFpEF necessitates further study into viable mechanistic targets involved in disease progression. We aim to summarize the current pathophysiological and clinical understanding of PH-HFpEF, highlight the role of known molecular mechanisms in the progression of PV disease, and introduce a novel concept that lipid metabolism may be attenuating and propagating PH-HFpEF.NEW & NOTEWORTHY Our review addresses pulmonary hypertension (PH) attributable to heart failure (HF) with preserved ejection fraction (HFpEF; PH-HFpEF). Current knowledge gaps in PH-HFpEF pathophysiology have led to a lack of therapeutic targets. Thus, we address identified knowledge gaps in a comprehensive review, focusing on current clinical epidemiology, known pathophysiology, and previously studied molecular mechanisms. We also introduce a comprehensive review of polyunsaturated fatty acid (PUFA) lipid inflammatory mediators in PH-HFpEF.

Repeat administration of human umbilical cord mesenchymal stem cells improves left ventricular diastolic function in mice with heart failure with preserved ejection fraction.

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

Exploring the role of iNOS in HFpEF-Related myocardial fibrosis: Involvement of PTEN-PI3K/AKT signaling pathway.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a challenging condition to treat with myocardial fibrosis being a pivotal pathological component. Previous studies have suggested a role for inducible nitric oxide synthase (iNOS) in the progression of this condition, but the precise mechanisms remain unclear. This study aimed to investigate the role of iNOS in HFpEF-related myocardial fibrosis and identify potential therapeutic targets. METHODS: A 'two-hit' mouse model of HFpEF was established, and echocardiography, histopathology and biochemical analyses were performed. In vitro experiments were conducted in mouse cardiac fibroblasts, with iNOS overexpression and application of iNOS or phosphatidylinositol 3 kinase (PI3K) inhibitors. The iNOS-S-nitrosylated phosphatase and TENsin homolog (SNO-PTEN)-phosphorylated-protein kinase B (p-AKT) pathway was investigated, along with the effects on fibrotic markers and cell proliferation and migration. RESULTS: HFpEF mice exhibited significant cardiac dysfunction and fibrosis, with increased expression of iNOS, SNO-PTEN, and p-AKT, indicative of the activation of the iNOS-SNO-PTEN-p-AKT pathway. iNOS overexpression in mouse cardiac fibroblasts led to increased SNO-PTEN, decreased PTEN, activated phosphorylated PI3K (p-PI3K) and p-AKT, and enhanced cell proliferation and migration, as well as increased collagen I and III expression. The use of an iNOS inhibitor (L-NIL) or a PI3K inhibitor (LY294002) partially reversed these changes. CONCLUSION: Our findings suggest that the iNOS-SNO-PTEN-p-AKT pathway may play a crucial role in HFpEF-related myocardial fibrosis, with iNOS and PI3K inhibitors offering potential therapeutic benefits. These insights may pave the way for the development of effective drug therapies for HFpEF.

Long term safety and outcomes after atrial shunting for heart failure with preserved or mildly reduced ejection fraction: 5-year and 3-year follow-up in the REDUCE LAP-HF I and II trials.

BACKGROUND: There is a little evidence regarding long-term safety and efficacy for atrial shunt devices in heart failure (HF). METHODS: The REDUCE LAP-HF I (n=44) and II (n=621) trials (RCT-I and -II) were multicenter, randomized, sham-controlled trials of patients with HF and ejection fraction >40%. Outcome data were analyzed from RCT-I, a mechanistic trial with 5-year follow-up, and RCT-II, a pivotal trial identifying a responder group (n=313) defined by exercise PVR <1.74 WU and no cardiac rhythm management device with 3-year follow-up. RESULTS: At 5 years in RCT I, there were no differences in cardiovascular (CV) mortality, HF events, embolic stroke, or new-onset atrial fibrillation between groups. After 3 years in RCT II, there was no difference in the primary outcome (hierarchical composite of CV mortality, stroke, HF events, and KCCQ) between shunt and sham in the overall trial. Compared to sham, those with responder characteristics in RCT-II had a better outcome with shunt (win ratio 1.6 [95% CI 1.2-2.2], P=0.006; 44% reduction in HF events [shunt 9 vs. control 16 per 100 patient-years], P=0.005; and greater improvement in KCCQ overall summary score [+17.9±20.0 vs. +7.6±20.4], P<0.001), while non-responders had significantly more HF events. Shunt treatment at 3 years was associated with a higher rate of ischemic stroke (3.2% vs. 0%, 95% CI 2% - 6.1%, p=0.032) and lower incidence of worsening kidney dysfunction (10.7% vs. 19.3%, p=0.041). CONCLUSIONS: With up to 5 years of follow up, adverse events were low in patients receiving atrial shunts. In the responder group, atrial shunt treatment was associated with a significantly lower HF event rate and improved KCCQ compared to sham through 3 years of follow-up. CLINICALTRIALS: gov registration: NCT02600234, NCT03088033.

Long-term Changes in Body Composition and Exercise Capacity Following Calorie Restriction and Exercise Training in Older Patients with Obesity and Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Obesity combined with heart failure with preserved ejection fraction (HFpEF) is the dominant form of HF among older persons. In a randomized trial, we previously showed that a 5-month calorie restriction (CR) program, with or without aerobic exercise training (AT), resulted in significant weight and fat loss and improved exercise capacity. However, little is known regarding the long-term effects of these outcomes after a short-term (5-month) intervention of CR with or without AT in older patients with obesity and HFpEF. METHODS: Sixteen participants from either the CR or CR+AT who experienced significant weight loss ≥ 2 kg were reexamined after a long-term follow-up endpoint (28.0 ± 10.8 months) without intervention. The follow-up assessment included body weight and composition via dual-energy X-ray absorptiometry and exhaustive cardiopulmonary treadmill exercise testing. RESULTS: Compared to the 5-month time-point intervention endpoint, at the long-term follow-up endpoint, mean body weight increased +5.2 ± 4.0 kg (90.7 ± 11.2 kg vs 95.9 ± 11.9; P < 0.001) due to increased fat mass (38.9 ± 9.3 vs 43.8 ± 9.8; P < 0.001) with no change in lean mass (49.6 ± 7.1 vs 49.9±7.6; P = 0.67), resulting in worse body composition (decreased lean-to-fat mass). Change in total mass was strongly and significantly correlated with change in fat mass (r = 0.75; P < 0.001), whereas there appeared to be a weaker correlation with change in lean mass (r = 0.50; P = 0.051). Additionally, from the end of the 5-month time-point intervention endpoint to the long-term follow-up endpoint, there were large, significant decreases in VO2peak (-2.2 ± 2.1 mL/kg/min; P = 0.003) and exercise time (-2.4 ± 2.6 min; P = 0.006). There appeared to be an inverse correlation between the change in VO2peak and the change in fat mass (r = -0.52; P = 0.062). CONCLUSION: Although CR and CR+AT in older patients with obesity and HFpEF can improve body composition and exercise capacity significantly, these positive changes diminish considerably during long-term follow-up endpoints, and regained weight is predominantly adipose, resulting in worsened overall body composition compared to baseline. This suggests a need for long-term adherence strategies to prevent weight regain and maintain improvements in body composition and exercise capacity following CR in older patients with obesity and HFpEF.

Racial Differences of Cardiac Structure and Function in Heart Failure with Preserved Ejection Fraction.

Potential race differences in cardiac structure and function among patients with heart failure with preserved ejection fraction (HFpEF) are not well-understood but may have pathophysiologic and treatment implications. In this study, patients with HFpEF who self-identified as Asian (n=360), White (n=787), and Black (n=171) from three institutions underwent comprehensive transthoracic echocardiography to evaluate for potential differences. The Asian HFpEF group was oldest and the Black HFpEF group was youngest (75±12 vs. 73±13 vs. 62±12 years, p<0.0001). Women constituted the lowest proportion of patients with HFpEF among Asian individuals but were the largest among Black patients (49% vs. 56% vs. 73%, p<0.0001). Body mass index and obesity prevalence were highest in Black patients with HFpEF and were lowest in Asian patients. Black individuals with HFpEF had greater left ventricular (LV) wall thickening and concentricity, smaller LV chamber size, leftward-shifted LV end-diastolic pressure volume relationship (EDPVR) indicating greater LV stiffening, smallest left atrial (LA) volumes, and the most right ventricular dilatation. Asian individuals with HFpEF had greater LV and LA dilation, more rightward shifted LV EDPVR, and the highest arterial stiffness. In summary, we show that patients with HFpEF of Asian, Black, and White race display key differences in clinical, anthropometric, and cardiac structure-function indices, indicating that consideration of race-related differences might important to individualize treatment strategies in HFpEF.

Does Heterogeneity Exist in Treatment Associations With Renin-Angiotensin-System Inhibitors or Beta-blockers According to Phenotype Clusters in Heart Failure with Preserved Ejection Fraction?

BACKGROUND: We explored the association between use of renin-angiotensin system inhibitors and beta-blockers, with mortality/morbidity in 5 previously identified clusters of patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We analyzed 20,980 patients with HFpEF from the Swedish HF registry, phenotyped into young-low comorbidity burden (12%), atrial fibrillation-hypertensive (32%), older-atrial fibrillation (24%), obese-diabetic (15%), and a cardiorenal cluster (17%). In Cox proportional hazard models with inverse probability weighting, there was no heterogeneity in the association between renin-angiotensin system inhibitor use and cluster membership for any of the outcomes: cardiovascular (CV) mortality, all-cause mortality, HF hospitalisation, CV hospitalisation, or non-CV hospitalisation. In contrast, we found a statistical interaction between beta-blocker use and cluster membership for all-cause mortality (P = .03) and non-CV hospitalisation (P = .001). In the young-low comorbidity burden and atrial fibrillation-hypertensive cluster, beta-blocker use was associated with statistically significant lower all-cause mortality and non-CV hospitalisation and in the obese-diabetic cluster beta-blocker use was only associated with a statistically significant lower non-CV hospitalisation. The interaction between beta-blocker use and cluster membership for all-cause mortality could potentially be driven by patients with improved EF. However, patient numbers were diminished when excluding those with improved EF and the direction of the associations remained similar. CONCLUSIONS: In patients with HFpEF, the association with all-cause mortality and non-CV hospitalisation was heterogeneous across clusters for beta-blockers. It remains to be elucidated how heterogeneity in HFpEF could influence personalized medicine and future clinical trial design.

Interplay of the heart, spleen, and bone marrow in heart failure: the role of splenic extramedullary hematopoiesis.

Improvements in therapies for heart failure with preserved ejection fraction (HFpEF) are crucial for improving patient outcomes and quality of life. Although HFpEF is the predominant heart failure type among older individuals, its prognosis is often poor owing to the lack of effective therapies. The roles of the spleen and bone marrow are often overlooked in the context of HFpEF. Recent studies suggest that the spleen and bone marrow could play key roles in HFpEF, especially in relation to inflammation and immune responses. The bone marrow can increase production of certain immune cells that can migrate to the heart and contribute to disease. The spleen can contribute to immune responses that either protect or exacerbate heart failure. Extramedullary hematopoiesis in the spleen could play a crucial role in HFpEF. Increased metabolic activity in the spleen, immune cell production and mobilization to the heart, and concomitant cytokine production may occur in heart failure. This leads to systemic chronic inflammation, along with an imbalance of immune cells (macrophages) in the heart, resulting in chronic inflammation and progressive fibrosis, potentially leading to decreased cardiac function. The bone marrow and spleen are involved in altered iron metabolism and anemia, which also contribute to HFpEF. This review presents the concept of an interplay between the heart, spleen, and bone marrow in the setting of HFpEF, with a particular focus on extramedullary hematopoiesis in the spleen. The aim of this review is to discern whether the spleen can serve as a new therapeutic target for HFpEF.

Heart failure with mildly reduced and preserved ejection fraction: A review of disease burden and remaining unmet medical needs within a new treatment landscape.

This review provides a comprehensive overview of heart failure with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF), including its definition, diagnosis, and epidemiology; clinical, humanistic, and economic burdens; current pharmacologic landscape in key pharmaceutical markets; and unmet needs to identify key knowledge gaps. We conducted a targeted literature review in electronic databases and prioritized articles with valuable insights into HFmrEF/HFpEF. Overall, 27 randomized controlled trials (RCTs), 66 real-world evidence studies, 18 clinical practice guidelines, and 25 additional publications were included. Although recent heart failure (HF) guidelines set left ventricular ejection fraction thresholds to differentiate categories, characterization and diagnosis criteria vary because of the incomplete disease understanding. Recent epidemiological data are limited and diverse. Approximately 50% of symptomatic HF patients have HFpEF, more common than HFmrEF. Prevalence varies with country because of differing definitions and study characteristics, making prevalence interpretation challenging. HFmrEF/HFpEF has considerable mortality risk, and the mortality rate varies with study and patient characteristics and treatments. HFmrEF/HFpEF is associated with considerable morbidity, poor patient outcomes, and common comorbidities. Patients require frequent hospitalizations; therefore, early intervention is crucial to prevent disease burden. Recent RCTs show promising results like risk reduction of composite cardiovascular death or HF hospitalization. Costs data are scarce, but the economic burden is increasing. Despite new drugs, unmet medical needs requiring new treatments remain. Thus, HFmrEF/HFpEF is a growing global healthcare concern. With improving yet incomplete understanding of this disease and its promising treatments, further research is required for better patient outcomes.

Large animal models to study effectiveness of therapy devices in the treatment of heart failure with preserved ejection fraction (HFpEF).

Our understanding of the complex pathophysiology of Heart failure with preserved ejection fraction (HFpEF) is limited by the lack of a robust in vivo model. Existing in-vivo models attempt to reproduce the four main phenotypes of HFpEF; ageing, obesity, diabetes mellitus and hypertension. To date, there is no in vivo model that represents all the haemodynamic characteristics of HFpEF, and only a few have proven to be reliable for the preclinical evaluation of potentially new therapeutic targets. HFpEF accounts for 50% of all the heart failure cases and its incidence is on the rise, posing a huge economic burden on the health system. Patients with HFpEF have limited therapeutic options available. The inadequate effectiveness of current pharmaceutical therapeutics for HFpEF has prompted the development of device-based treatments that target the hemodynamic changes to reduce the symptoms of HFpEF. However, despite the potential of device-based solutions to treat HFpEF, most of these therapies are still in the developmental stage and a relevant HFpEF in vivo model will surely expedite their development process. This review article outlines the major limitations of the current large in-vivo models in use while discussing how these designs have helped in the development of therapy devices for the treatment of HFpEF.

Sex-specific differences in risk factors, comorbidities, diagnostic challenges, optimal management, and prognostic outcomes of heart failure with preserved ejection fraction: A comprehensive literature review.

Due to hormonal variations, heart failure with preserved ejection fraction (HFpEF) remains prevalent in women and affects almost half of the heart failure (HF) patients. Given the yearly death rate of 10-30% and the unavailability of medications targeting HFpEF, the need arises for a better understanding of the fundamental mechanisms of this syndrome. This comprehensive review explores sex-specific differences in traditional risk factors; female-specific factors that may impact HFpEF development and response to therapy, including variations in hormone levels that may occur pre- and post-menopausal or during pregnancy; and disparities in comorbidities, clinical presentation, and diagnostic challenges. Lastly, the review addresses prognostic outcomes, noting that women with HFpEF have a poor quality of life but a higher survival rate. It also discusses novel biomarkers and precision medicine, emphasizing their potential to improve early detection and personalized treatment.

Anti-bradycardia pacing-impact on patients with HFpEF: a systematic review.

Heart failure with preserved ejection fraction (HFpEF) has become an emerging concern. The protective effect of bradycardia in patients with reduced ejection fraction using beta-blockers or ivabradine does not improve symptoms in HFpEF. This review aims to assess current data regarding the impact of anti-bradycardia pacing in patients with HFpEF. A search was conducted on PubMed, ScienceDirect, Springer, and Wiley Online Library, selecting studies from 2013 to 2023. Relevant and eligible prospective studies and randomized controlled trials were included. Functional status, quality of life, and echocardiographic parameters were assessed. Six studies conformed to the selection criteria. Four were prospective studies with a total of 90 patients analyzed. Two were randomized controlled trials with a total of 129 patients assessed. The 6-min walk test (6MWT) and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) score improved in all prospective studies. My-PACE trial showed improvements in MLHFQ score (p < 0.001), significant relative lowering in NT-proBNP levels (p = 0.02), and an increased mean daily activity in the personalized accelerated pacing group compared to usual care. RAPID-HF trial proved that pacemaker implantation to enhance exercise heart rate (HR) did not improve exercise capacity and was associated with increased adverse events. HFpEF requires a more individualized approach and quality of life management. This review demonstrates that higher resting HR by atrial pacing may improve symptoms and even outcomes in HFpEF, while a higher adaptive rate during exertion has not been proven beneficial.

The prevalence of coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF): a systematic review and meta-analysis.

To date, studies on the prevalence of coronary microvascular dysfunction (CMD) in heart failure with preserved ejection fraction (HFpEF) have not been summarized and analyzed as a whole. We conducted this systematic review and meta-analysis to assess the prevalence of CMD in patients with HFpEF. The PubMed, Cochrane, and Embase databases were searched from dates of inception until May 1, 2023. The primary outcome was the prevalence of CMD in patients with HFpEF, and values of CMD prevalence were pooled using a random-effects model. In total, 10 studies involving 1267 patients, including 822 with HFpEF and 445 without HFpEF, were included. The pooled prevalence of CMD in patients with HFpEF was 71% (95% CI, 0.63-0.79). In the subgroup analysis, the prevalence of CMD was 79% (95% CI, 0.71-0.87) by invasive measurement and 66% (95% CI, 0.54-0.77) by noninvasive measurement and 67% (95% CI, 0.52-0.82) with CFR < 2.0 and 75.0% (95% CI, 0.71-0.79) with CFR < 2.5. The prevalence of endothelium-independent CMD and endothelium-dependent CMD was 62% (95% CI, 0.53-0.72) and 50% (95% CI, 0.19-0.81), respectively. The prevalence of CMD was 74% (95% CI = 0.69-0.79) and 66% (95% CI = 0.41-0.90) in prospective and retrospective studies, respectively. Compared with the control group, patients with HFpEF had a significantly lower CFR (MD = - 1.28, 95% CI = - 1.82 to - 0.74, P < 0.01) and a higher prevalence of CMD (RR = 2.21, 95% CI = 1.52 to 3.20, P < 0.01). Qualitative analysis demonstrated that CMD might be associated with poor clinical outcomes in patients with HFpEF. In conclusion, this is the first systematic review and meta-analysis of all studies reporting the prevalence of CMD in patients with HFpEF. Our study demonstrates that CMD is common in patients with HFpEF and might be associated with poor clinical outcomes in these patients. Clinicians should attach importance to CMD in the diagnosis and treatment of HFpEF. The number of studies in this field is relatively small. Therefore, more high-quality studies are needed to explore the diagnostic and prognostic value of CMD and the potential role of CMD as a therapeutic target in patients with HFpEF.