Heart Failure Subtypes Research Articles

Comprehensive insights into heart failure with mildly reduced ejection fraction: A critical review

Abstract This review explores the enigmatic heart failure (HF) subtype known as HF with mildly reduced ejection fraction (HFmrEF), which constitutes a significant percentage of HF cases yet remains inadequately understood. Characterized by an ejection fraction (EF) between 41% and 49%, HFmrEF poses unique challenges in diagnosis and treatment due to its intermediary nature between HF with reduced EF (HFrEF) and HF with preserved EF (HFpEF). Epidemiological data reveal variable prevalence rates influenced by demographic and regional factors, with a higher incidence associated with aging and cardiovascular comorbidities such as hypertension and diabetes. Pathophysiological insights suggest a blend of systolic and diastolic dysfunction, myocardial fibrosis, and inflammatory processes that differentiate HFmrEF from other HF categories. Diagnostic approaches currently rely on echocardiography and biomarkers such as N-terminal pro-brain natriuretic peptide, but there is a need for more precise tools. Treatment largely extrapolates from HFrEF and HFpEF protocols, yet specific evidence for HFmrEF is sparse, underscoring the necessity for targeted clinical trials. Patient outcomes, falling between those of HFrEF and HFpEF, further highlight the need for individualized management strategies. This review underscores the urgency of dedicated research to refine diagnostic criteria, optimize therapeutic regimens, and ultimately improve patient care for those with HFmrEF. Future research must focus on tailored treatments, pathophysiological clarity, and identifying specific biomarkers to advance our understanding and management of this complex condition.

Uncovering Unrecognized Heart Failure With Preserved Ejection Fraction Among Individuals With Obesity and Dyspnea.

Although heart failure with preserved ejection fraction (HFpEF) has become the predominant heart failure subtype, it remains clinically under-recognized. HFpEF diagnosis is particularly challenging in the setting of obesity given the limitations of natriuretic peptides and resting echocardiography. We examined invasive and noninvasive HFpEF diagnostic criteria among individuals with obesity and dyspnea without known cardiovascular disease to determine the prevalence of hemodynamic HFpEF in the community. Research volunteers with dyspnea and obesity underwent resting echocardiography; participants with possible pulmonary hypertension qualified for invasive cardiopulmonary exercise testing. HFpEF was defined using rest or exercise pulmonary capillary wedge pressure criteria (≥15 mm Hg or Δpulmonary capillary wedge pressure/Δcardiac output slope, >2.0 mm Hg·L-1·min-1). Among n=78 participants (age, 53±13 years; 65% women; body mass index, 37.3±6.8 kg/m2), 40 (51%) met echocardiographic criteria to undergo invasive cardiopulmonary exercise testing. In total, 24 participants (60% among the cardiopulmonary exercise testing group, 31% among the total sample) were diagnosed with HFpEF by rest or exercise pulmonary capillary wedge pressure (n=12) or exercise criteria (n=12). There were no differences in NT-proBNP (N-terminal pro-B-type natriuretic peptide; 79 [62-104] versus 73 [57-121] pg/mL) or resting echocardiography (mitral E/e' ratio, 9.1±3.1 versus 8.0±2.7) among those with versus without HFpEF (P>0.05 for all). Distributions of HFpEF diagnostic scores were similar, with the majority classified as intermediate risk (100% versus 93.75% [H2FPEF] and 87.5% versus 68.75% [HFA-PEFF (Heart Failure Association Pretest assessment, echocardiography and natriuretic peptide, functional testing, and final etiology)] in those with versus without HFpEF). Among adults with obesity and dyspnea without known cardiovascular disease, at least a third had clinically unrecognized HFpEF uncovered on invasive cardiopulmonary exercise testing. Clinical, biomarker, resting echocardiography, and diagnostic scores were similar among those with and without HFpEF. These results suggest clinical underdiagnosis of HFpEF among individuals with obesity and dyspnea and highlight limitations of noninvasive testing in the identification of HFpEF.

Pathophysiological Link and Treatment Implication of Heart Failure and Preserved Ejection Fraction in Patients with Chronic Kidney Disease.

Heart failure with preserved ejection fraction (HFpEF) results from a complex interplay of age, genetic, cardiac remodeling, and concomitant comorbidities including hypertension, obesity, diabetes, and chronic kidney disease (CKD). Renal failure is an important comorbidity of HFpEF, as well as a major pathophysiological mechanism for those patients at risk of developing HFpEF. Heart failure (HF) and CKD are intertwined conditions sharing common disease pathways; the so-called "kidney tamponade", explained by an increase in intracapsular pressure caused by fluid retention, is only the latest model to explain renal injury in HF. Recognizing the different phenotypes of HFpEF remains a real challenge; the pathophysiological mechanisms of renal dysfunction may differ across the HF spectrum, as well as the prognostic role. A better understanding of the role of cardiorenal interactions in patients with HF in terms of symptom status, disease progression, and prognosis remains essential in HF management. Historically, patients with HF and CKD have been scarcely represented in clinical trial populations. Current concerns affect the practical approach to HF treatment, and, in this context, physicians are frequently hesitant to prescribe and titrate both new and old treatments. Therefore, the extensive application of HF drugs in diverse HF subtypes with numerous comorbidities and different renal dysfunction etiologies remains a controversial matter of discussion. Numerous recently introduced drugs, such as sodium-glucose-linked transporter 2 inhibitors (SGLT2i), constitute a new therapeutic option for patients with HF and CKD. Because of their protective vascular and hormonal actions, the use of these agents may be safely extended to patients with renal dysfunction in the long term. The present review delves into the phenotype of patients with HFpEF and CKD from a pathophysiological perspective, proposing a treatment approach that suggests a practical stepwise algorithm for the proper application of life-saving therapies in clinical practice.

Iron Deficiency, Anemia, and Iron Supplementation in Patients With Heart Failure: A Population-Level Study.

Studies have shown an association between iron deficiency (ID) and clinical outcomes in patients with heart failure (HF), irrespective of the presence of ID anemia (IDA). The current study used population-level data from a large, single-payer health care system in Canada to investigate the epidemiology of ID and IDA in patients with acute HF and those with chronic HF, and the iron supplementation practices in these settings. All adult patients with HF in Alberta between 2012 and 2019 were identified and categorized as acute or chronic HF. HF subtypes were determined through echocardiography data, and ID (serum ferritin concentration <100 μg/L, or ferritin concentration between 100 and 300 μg/L along with transferrin saturation <20%), and IDA through laboratory data. Broad eligibility for 3 clinical trials (AFFIRM-AHF [Study to Compare Ferric Carboxymaltose With Placebo in Patients With Acute HF and ID], IRONMAN [Intravenous Iron Treatment in Patients With Heart Failure and Iron Deficiency], and HEART-FID [Randomized Placebocontrolled Trial of Ferric Carboxymaltose as Treatment for HF With ID]) was determined. Among the 17 463 patients with acute HF, 38.5% had iron studies tested within 30 days post-index-HF episode (and 34.2% of the 11 320 patients with chronic HF). Among tested patients, 72.6% of the acute HF and 73.9% of the chronic HF were iron-deficient, and 51.4% and 49.0% had IDA, respectively. Iron therapy was provided to 41.8% and 40.5% of patients with IDA and acute or chronic HF, respectively. Of ID patients without anemia, 19.9% and 21.7% were prescribed iron therapy. The most common type of iron therapy was oral (28.1% of patients). Approximately half of the cohort was eligible for each of the AFFIRM-AHF, intravenous iron treatment in patients with HF and ID, and HEART-FID trials. Current practices for investigating and treating ID in patients with HF do not align with existing guideline recommendations. Considering the gap in care, innovative strategies to optimize iron therapy in patients with HF are required.

Omecamtiv Mecarbil in the treatment of heart failure: the past, the present, and the future.

Heart failure, a prevailing global health issue, imposes a substantial burden on both healthcare systems and patients worldwide. With an escalating prevalence of heart failure, prolonged survival rates, and an aging demographic, an increasing number of individuals are progressing to more advanced phases of this incapacitating ailment. Against this backdrop, the quest for pharmacological agents capable of addressing the diverse subtypes of heart failure becomes a paramount pursuit. From this viewpoint, the present article focuses on Omecamtiv Mecarbil (OM), an emerging chemical compound said to exert inotropic effects without altering calcium homeostasis. For the first time, as a review, the present article uniquely started from the very basic pathophysiology of heart failure, its classification, and the strategies underpinning drug design, to on-going debates of OM's underlying mechanism of action and the latest large-scale clinical trials. Furthermore, we not only saw the advantages of OM, but also exhaustively summarized the concerns in sense of its effects. These of no doubt make the present article the most systemic and informative one among the existing literature. Overall, by offering new mechanistic insights and therapeutic possibilities, OM has carved a significant niche in the treatment of heart failure, making it a compelling subject of study.

Mkk7 Protects Against Cardiac Dysfunction in Heart Failure with Preserved Ejection Fraction

Article Mkk7 Protects Against Cardiac Dysfunction in Heart Failure with Preserved Ejection Fraction Tayyiba Azam 1, * , Hongyuan Zhang 1, Susanne S. Hille 2, Elizabeth J. Cartwright 1, Oliver J. Müller 2, and Xin Wang 1, * 1 Faculty of Biology, Medicine, and Health, University of Manchester, Oxford Road, M13 9PT, Manchester, UK 2 Department of Internal Medicine III, University of Kiel, Germany; German Centre for Cardiovascular Research (DZHK), 24105 Partner Site Hamburg/Kiel/Lübeck, Germany * Correspondence: xin.wang@manchester.ac.uk (Xin Wang); tayyiba.azam@manchester.ac.uk (Tayyiba Azam) Received: 12 June 2023 Accepted: 25 September 2023 Published: 6 March 2024 Abstract: Shifts in epidemiological patterns foretell a rapid increase in the number of patients with heart failure (HF) globally, representing a significant health and economic burden. Heart failure with preserved ejection (HFpEF) is now considered the prevailing subtype of HF, with no effective treatment available to combat this syndrome. Previous studies have highlighted the cardioprotective role of MKK7 during cardiac pathology, however, no extensive research has been performed to examine MKK7 in the context of HFpEF. This study aimed to address this shortcoming by using adeno-associated virus (AAV) 9 to overexpress MKK7 in the two-hit clinically relevant HFpEF mouse model. We report that cardiomyocyte-specific overexpression of MKK7 improved the HFpEF phenotype in mice, by impeding cardiac diastolic dysfunction and myocardial fibrosis. Mechanistically, it was found that MKK7 ameliorated ER stress by maintaining IRE1-XBP1 signalling and blunted CHOP increase in the myocardium. To summarise, MKK7 overexpression holds the ability to protect the myocardium from HFpEF associated pathologies.

Identification of Shared Signature Genes and Immune Microenvironment Subtypes for Heart Failure and Chronic Kidney Disease Based on Machine Learning.

A complex interrelationship exists between Heart Failure (HF) and chronic kidney disease (CKD). This study aims to clarify the molecular mechanisms of the organ-to-organ interplay between heart failure and CKD, as well as to identify extremely sensitive and specific biomarkers. Differentially expressed tandem genes were identified from HF and CKD microarray datasets and enrichment analyses of tandem perturbation genes were performed to determine their biological functions. Machine learning algorithms are utilized to identify diagnostic biomarkers and evaluate the model by ROC curves. RT-PCR was employed to validate the accuracy of diagnostic biomarkers. Molecular subtypes were identified based on tandem gene expression profiling, and immune cell infiltration of different subtypes was examined. Finally, the ssGSEA score was used to build the ImmuneScore model and to assess the differentiation between subtypes using ROC curves. Thirty-three crosstalk genes were associated with inflammatory, immune and metabolism-related signaling pathways. The machine-learning algorithm identified 5 hub genes (PHLDA1, ATP1A1, IFIT2, HLTF, and MPP3) as the optimal shared diagnostic biomarkers. The expression levels of tandem genes were negatively correlated with left ventricular ejection fraction and glomerular filtration rate. The CIBERSORT results indicated the presence of severe immune dysregulation in patients with HF and CKD, which was further validated at the single-cell level. Consensus clustering classified HF and CKD patients into immune and metabolic subtypes. Twelve immune genes associated with immune subtypes were screened based on WGCNA analysis, and an ImmuneScore model was constructed for high and low risk. The model accurately predicted different molecular subtypes of HF or CKD. Five crosstalk genes may serve as potential biomarkers for diagnosing HF and CKD and are involved in disease progression. Metabolite disorders causing activation of a large number of immune cells explain the common pathogenesis of HF and CKD.

Correlation between systolic blood pressure and mortality in heart failure patients with hypertension.

The correlation between systolic blood pressure (SBP) and mortality in hypertensive patients with different phenotypes of heart failure (HF) has not been adequately studied, and optimal blood pressure control targets remain controversial. To explore the link between SBP and prognosis in all or three ejection fraction (EF) phenotypes of HF patients with hypertension. We analyzed 1279 HF patients complicated by hypertension in a retrospective cohort. The SBP <130 mmHg group included 383 patients, and the SBP ≥130 mmHg group included 896 patients. The major end point was all-cause mortality. Of the 1279 study patients, with a median age of 66.0 ± 12.0 years, 45.3% were female. The proportions of the three subtypes of heart failure complicated with hypertension (HFrEF, HEmrEF, and HFpEF) were 26.8%, 29.3%, and 43.9%, respectively. During the 1-year follow-up, 223 patients experienced all-cause death, and 133 experienced cardiovascular death. Restricted cubic splines showed that the risk of all-cause and cardiovascular death increased gradually as the SBP level decreased in patients with HFrEF and HFmrEF. Furthermore, the multivariate Cox proportional hazards model revealed that SBP <130 mmHg was also associated with an increased risk of all-cause death [hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.23-5.20, P = 0.011] and cardiovascular death (HR 1.91, 95% CI 1.01-3.63, P = 0.047) in HFrEF patients. A trend toward increased risk was observed among HFmrEF patients, but it was not statistically significant. This trend was not observed in HFpEF patients. In HFrEF patients, SBP <130 mmHg was associated with an increased risk of all-cause and cardiovascular mortality. A trend toward increased risk was observed among HFmrEF patients, but not among HFpEF patients.

Atrial fibrillation and risk of adverse outcomes in heart failure with reduced, mildly reduced, and preserved ejection fraction: A systematic review and meta-analysis.

Heart failure (HF) and atrial fibrillation (AF) frequently co-exist. Contemporary classification of HF categorizes it into HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction (HFmrEF), and HF with preserved ejection fraction (HFpEF). Aggregate data comparing the risk profile of AF between these three HF categories are lacking. We conducted a systematic review and meta-analysis aimed at determining any significant differences in AF-associated all-cause mortality, HF hospitalizations, cardiovascular mortality (CV), and stroke between HFrEF, HFmrEF, and HFpEF. A systematic search of PubMed, EMBASE, and Cochrane Library databases until February 28, 2023. Data were combined using DerSimonian-Laird random effects model. A total of 22 studies comprising 248 323 patients were retained: HFrEF 123 331 (49.7%), HFmrEF 40 995 (16.5%), and HFpEF 83 997 (33.8%). Pooled baseline AF prevalence was 36% total population, 30% HFrEF, 36% HFmrEF, and 42% HFpEF. AF was associated with a higher risk of all-cause mortality in the total population with pooled hazard ratio (HR) = 1.13 (95% confidence interval [CI] = 1.07-1.21), HFmrEF (HR = 1.25, 95% CI = 1.05-1.50) and HFpEF (HR = 1.16, 95% CI = 1.09-1.24), but not HFrEF (HR = 1.03, 95% CI = 0.93-1.14). AF was associated with a higher risk of HF hospitalizations in the total population (HR = 1.29, 95% CI = 1.14-1.46), HFmrEF (HR = 1.64, 95% CI = 1.20-2.24), and HFpEF (HR = 1.46, 95% CI = 1.17-1.83), but not HFrEF (HR = 1.01, 95% CI = 0.87-1.18). AF was only associated with CV in the HFpEF subcategory but was associated with stroke in all three HF subtypes. AF appears to be associated with a higher risk of all-cause mortality and HF hospitalization in HFmrEF and HFpEF. With these findings, the paucity of data and treatment guidelines on AF in the HFmrEF subgroup becomes even more significant and warrant further investigations.

Distinguishing heart failure subtypes: the diagnostic power of different cardiac magnetic resonance imaging parameters.

The aim of this retrospective study was to explore the diagnostic potential of various cardiac parameters in differentiating between heart failure with preserved ejection fraction (HFpEF) and heart failure with mid-ranged and reduced ejection fraction (HFm + rEF), and to discern their relationship with normal cardiac function. This research encompassed a comparative analysis of heart failure subtypes based on multiple indicators. Participants were categorized into HFm + rEF, HFpEF, and control groups. For each participant, we investigated indicators of left ventricular function (LVEDVi, LVESVi, and LVEF) and myocardial strain parameters (GLS, GCS, GRS). Additionally, quantitative tissue evaluation parameters including native T1, enhanced T1, and extracellular volume (ECV) were examined.For comprehensive diagnostic performance analysis, receiver operating characteristic (ROC) curve evaluations for each parameters were conducted. HFm + rEF patients exhibited elevated LVEDVi and LVESVi and decreased LVEF compared to both HFpEF and control groups. Myocardial strain revealed significant reductions in GLS, GCS, and GRS for HFm + rEF patients compared to the other groups. HFpEF patients showed strain reductions relative to the control group. In cardiac magnetic resonance imaging (CMR) evaluations, HFm + rEF patients demonstrated heightened native T1 times and ECV fractions. Native T1 was particularly effective in distinguishing HFpEF from healthy subjects. Native T1, ECV, and myocardial strain parameters have substantial diagnostic value in identifying HFpEF. Among them, native T1 displayed superior diagnostic efficiency relative to ECV, offering critical insights into early-stage HFpEF. These findings can play a pivotal role in refining clinical management and treatment strategies for heart failure patients.

Heart failure outcomes by left ventricular ejection fraction in a contemporary region-wide patient cohort.

This study aimed to characterize a contemporary population with subtypes of incident or prevalent heart failure (HF) based on reduced (HFrEF), mildly reduced, or preserved (HFpEF) left ventricular ejection fraction (LVEF) and to assess how outcomes, healthcare, treatments, and healthcare costs vary between each subtype of incident HF. Using Swedish data from the CardioRenal and Metabolic disease Heart Failure (CaReMe HF) study, updated to cover a more recent time period, this population-based study characterized patients from Stockholm County, Sweden, with incident HF (patients with a first HF diagnosis between 1 January 2015 and 31 December 2019) or prevalent HF (patients with a first HF diagnosis before 1 January 2020). Patients with incident HF had LVEF measured by echocardiography within ±90days of their first HF diagnosis, and patients with prevalent HF within 5years prior to the index date. The 13375 patients with prevalent HF (39.2% women, mean age 73.9years) had multiple comorbidities (cardiovascular diseases, chronic kidney disease, diabetes, and cancer). These were already highly prevalent at the time of the first HF diagnosis in the 8042 patients with incident HF (40.5% women, mean age 72.3years). Patients with incident HFpEF received less specialist HF care at outpatient secondary care facilities following their first HF diagnosis than those with incident HFrEF. Patients with HFrEF had higher risks of complications and exerted a higher burden, in terms of care for and costs of HF, on the healthcare system. This study of contemporary patients with incident HF demonstrates that those with HFpEF and HFrEF differ considerably in terms of clinical presentation, prognosis, and care, highlighting a potential to improve HF outcomes.

Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction

Clonal hematopoiesis of indeterminate potential (CHIP), the age-related clonal expansion of hematopoietic stem cells with leukemogenic acquired genetic variants, is associated with incident heart failure (HF). To evaluate the associations of CHIP and key gene-specific CHIP subtypes with incident HF with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). This population-based cohort study included participants from 2 racially diverse prospective cohort studies with uniform HF subtype adjudication: the Jackson Heart Study (JHS) and Women's Health Initiative (WHI). JHS participants were enrolled during 2000 to 2004 and followed up through 2016. WHI participants were enrolled during 1993 to 1998 and followed up through 2022. Participants who underwent whole-genome sequencing, lacked prevalent HF at baseline, and were followed up for HF adjudication were included. Follow-up occurred over a median (IQR) of 12.0 (11.0-12.0) years in the JHS and 15.3 (9.0-22.0) years in the WHI. Statistical analysis was performed from June to December 2023. Any CHIP and the most common gene-specific CHIP subtypes (DNMT3A and TET2 CHIP). First incident hospitalized HF events were adjudicated from hospital records and classified as HFpEF (left ventricular ejection fraction ≥50%) or HFrEF (ejection fraction <50%). A total of 8090 participants were included; 2927 from the JHS (median [IQR] age, 56 [46-65] years; 1846 [63.1%] female; 2927 [100.0%] Black or African American) and 5163 from the WHI (median [IQR] age, 67 [62-72] years; 5163 [100.0%] female; 29 [0.6%] American Indian or Alaska Native, 37 [0.7%] Asian or Pacific Islander, 1383 [26.8%] Black or African American, 293 [5.7%] Hispanic or Latinx, 3407 [66.0%] non-Hispanic White, and 14 [0.3%] with other race and ethnicity). The multivariable-adjusted hazard ratio (HR) for composite CHIP and HFpEF was 1.28 (95% CI, 0.93-1.76; P = .13), and for CHIP and HFrEF it was 0.79 (95% CI, 0.49-1.25; P = .31). TET2 CHIP was associated with HFpEF in both cohorts (meta-analyzed HR, 2.35 [95% CI, 1.34 to 4.11]; P = .003) independent of cardiovascular risk factors and coronary artery disease. Analyses stratified by C-reactive protein (CRP) in the WHI found an increased risk of incident HFpEF in individuals with CHIP and CRP greater than or equal to 2 mg/L (HR, 1.94 [95% CI, 1.20-3.15]; P = .007), but not in those with CHIP and CRP less than 2 mg/L or those with CRP greater than or equal to 2 mg/L without CHIP, when compared with participants without CHIP and CRP less than 2 mg/L. In this cohort study, TET2 CHIP was an independent risk factor associated with incident HFpEF. This finding may have implications for the prevention and management of HFpEF, including development of targeted therapies.

Harnessing the power of RNA therapeutics in treating ischemic heart failure: the TRAIN-HEART story.

Ischemic heart disease (IHD) is one of the world's foremost killers, accounting for 16% of all deaths worldwide. IHD is the main cause of heart failure (HF), as it leads to pathological changes in the heart, improper pumping function and eventual death. Therapeutic interventions usually follow a systemic general strategy for all heart failure subtypes due to the lack of a deep understanding of the disease mechanisms. Hence, HF and IHD therapeutics need groundbreaking concepts to guide the development of a new therapeutics class that tackles the disease at a molecular level. The TRAIN-HEART consortium, a Marie Skłodowska-Curie Actions Innovative Training Network (MSCA-ITN) funded by the European Commission, was established with the goal of filling that gap and developing RNA-based cardiovascular therapeutics. Created in the context of the Horizon 2020 research and innovation program, TRAIN-HEART comprises three key work packages (WPs) focusing on the pathogenesis of heart disease (WP1), the therapeutic potential of RNA therapeutics (WP2), and the development of new efficient delivery systems (WP3). Fifteen international early stage researchers (ESRs) from multiple complementary scientific disciplines were recruited to collaborate with a network of PIs from nine academic and eight non-academic partners in various disciplines to fully harness their collective potential for the betterment of HF treatment. This article provides an overview of the benefits of being part of an MSCA-ITN, with its different training and networking opportunities, maximizing ESRs' potential and broadening collaborative research possibilities. Finally, it describes what was like to do a PhD during the COVID-19 pandemic, with all the uncertainty and concern attached to it. Luckily, TRAIN-HEART stood out as a proactive network, finding new initiatives and alternatives to promote scientific and personal development. By bringing together leading academic teams, (biotech) companies, and highly motivated researchers, TRAIN-HEART is expanding scientific horizons and accelerating future development of effective RNA-based therapies to treat IHD.

Network-based identification of diagnosis-specific trans-omic biomarkers via integration of multiple omics data

The integration of multiple omics data promises to reveal new insights into the pathogenic mechanisms of complex human diseases, with the potential to identify avenues for the development of targeted therapies for disease subtypes. However, the extraction of diagnostic/disease-specific biomarkers from multiple omics data with biological pathway knowledge is a challenging issue in precision medicine. In this paper, we present a novel computational method to identify diagnosis-specific trans-omic biomarkers from multiple omics data. In the algorithm, we integrated multi-class sparse canonical correlation analysis (MSCCA) and molecular pathway analysis in order to derive discriminative molecular features that are correlated across different omics layers. We applied our proposed method to analyzing proteome and metabolome data of heart failure (HF), and extracted trans-omic biomarkers for HF subtypes; specifically, ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM). We were able to detect not only individual proteins that were previously reported from single-omics studies but also correlated protein–metabolite pairs characteristic of HF disease subtypes. For example, we identified hexokinase1(HK1)–d-fructose-6-phosphate as a paired trans-omic biomarker for DCM, which could significantly perturb amino-sugar metabolism. Our proposed method is expected to be useful for various applications in precision medicine.

Heterogeneity in cardiorenal protection by Sodium glucose cotransporter 2 inhibitors in heart failure across the ejection fraction strata: Systematic review and meta-analysis.

Gliflozins or Sodium glucose cotransporter 2 inhibitors (SGLT2i) are relatively novel antidiabetic medications that have recently been shown to represent favorable effects on patients' cardiorenal outcomes. However, there is shortage of data on potential disparities in this therapeutic effect across different patient subpopulations. To investigate differential effects of SGLT2i on the cardiorenal outcomes of heart failure patients across left ventricular ejection fraction (LVEF) levels. Literature was searched systematically for the large randomized double-blind controlled trials with long enough follow up periods reporting cardiovascular and renal outcomes in their patients regarding heart failure status and LVEF levels. Data were then meta-analyzed after stratification of the pooled data across the LVEF strata and New York Heart Associations (NYHA) classifications for heart failure using Stata software version 17.0. The literature search returned 13 Large clinical trials and 13 post hoc analysis reports. Meta-analysis of the effects of gliflozins on the primary composite outcome showed no significant difference in efficacy across the heart failure subtypes, but higher efficacy were detected in patient groups at lower NYHA classifications (I2 = 46%, P = 0.02). Meta-analyses across the LVEF stratums revealed that a baseline LVEF lower than 30% was associated with enhanced improvement in the primary composite outcome compared to patients with higher LVEF levels at the borderline statistical significance (HR: 0.70, 95%CI: 0.60 to 0.79 vs 0.81, 95%CI: 0.75 to 0.87; respectively, P = 0.06). Composite renal outcome was improved significantly higher in patients with no heart failure than in heart failure patients with preserved ejection fraction (HFpEF) (HR: 0.60, 95%CI: 0.49 to 0.72 vs 0.94, 95%CI: 0.74 to 1.13; P = 0.04). Acute renal injury occurred significantly less frequently in heart failure patients with reduced ejection fraction who received gliflozins than in HFpEF (HR: 0.67, 95%CI: 51 to 0.82 vs 0.94, 95%CI: 0.82 to 1.06; P = 0.01). Volume depletion was consistently increased in response to SGLT2i in all the subgroups. Heart failure patients with lower LVEF and lower NYHA sub-classifications were found to be generally more likely to benefit from therapy with gliflozins. Further research are required to identify patient subgroups representing the highest benefits or adverse events in response to SGLT2i.

Identification and exploration of aging-related subtypes and distinctive role of SERPINE1 in heart failure based on single-cell and bulk RNA sequencing data.

Aging is a major risk factor for heart failure (HF) and is the leading cause of death worldwide. Currently, the nature of the relationship between aging and HF is not entirely clear. Herein, this study aimed to explore new diagnostic biomarkers, molecular typing and therapeutic strategies for HF by investigating the biological significance of aging-related genes in HF. A total of 157 differentially expressed genes (DEGs) were screened totally between HF and normal samples, and functional enrichment analysis of DEGs revealed the strong association of HF progression with aging, immune processes and metabolism. Six HF-specific aging-related genes were further identified, and a diagnostic model was developed and validated for good diagnostic efficacy. In addition, we collected blood samples from 10 normal controls and 10 HF patients for RT-qPCR analysis to verify the bioinformation. We also identified two aging-associated subtypes with distinctly different immune infiltration and metabolic microenvironment. Further single-cell sequencing analysis conducted in the study identified SERPINE1 as a key gene in HF. The distinctive role of SERPINE1 fibroblasts was revealed, including three main findings: (I) fibroblasts had a higher proportion and expression of SERPINE1 levels in HF; (II) the ligand-receptor pair MDK-LRP1 made the most contributions in high interactions with other cell types in SERPINE1 fibroblasts; and (III) SERPINE1 fibroblasts were associated with the interaction of extracellular matrix and receptor and may be regulated by the transcription factor EGR1. In conclusion, this study highlights the importance of aging-related genes in diagnosing HF and regulating immune infiltration. We also identified different HF subtypes and a potentially crucial gene, which may provide a better understanding of the molecular-level mechanisms of aging-related HF and aid in developing effective therapeutic strategies.

How Would You Manage This Patient With Heart Failure With Preserved Ejection Fraction? : Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

The proportion of patients with new-onset heart failure who have preserved rather than reduced left ventricular ejection fraction (HFpEF and HFrEF) has been increasing over recent decades. In fact, HFpEF now outweighs HFrEF as the predominant heart failure subtype and likely remains underdiagnosed in the community. This is due in part to an aging population and a rise in other risk factors for HFpEF, including obesity and associated cardiometabolic disease. Whereas the diagnosis of HFrEF is relatively straightforward, the diagnosis of HFpEF is often more challenging because there can be other causes for symptoms, including dyspnea and fatigue, and cardinal physical examination findings of elevated jugular venous pressure or pulmonary congestion may not be evident at rest. In 2022, the American College of Cardiology, the American Heart Association, and the Heart Failure Society of America published a comprehensive guideline on heart failure that included recommendations for the management of HFpEF. The use of diuretics for the management of congestion remained the only class 1 (strong) recommendation. New recommendations included broader use of sodium-glucose cotransporter-2 inhibitors (SGLT2i, class 2a), and angiotensin receptor-neprilysin inhibitors (class 2b). In 2023, the American College of Cardiology published an expert consensus decision pathway for the management of HFpEF that suggests treatment strategies based on sex assigned at birth, ejection fraction, clinical evidence of congestion, and candidacy for SGLT2i therapy. Here, 2 experts, a cardiologist and a geriatrician, discuss their approach to the diagnosis and management of HFpEF and how they would apply guidelines to an individual patient.

A meta-analysis investigating the efficacy and adverse events linked to sacubitril-valsartan in various heart failure subtypes.

Sacubitril-valsartan, an inhibitor of the angiotensin receptor neprilysin (ARNi), has been purported to exhibit superiority over angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in individuals diagnosed with heart failure. This paper gives an updated meta-analysis comparing the efficacy and safety of sacubitril-valsartan to that of standard treatment for different types of heart failure. The meta-analysis comprised a total of nine randomized controlled trials (RCTs), incorporating data from a substantial sample size of 15 939 patients. The study observed a decrease in overall mortality and mortality related to cardiovascular causes among patients in the heart failure with reduced ejection fraction (HFrEF) category who were treated with sacubitril-valsartan. However, no statistically significant variation in this outcome was seen among patients with heart failure with preserved ejection fraction and HFmrEF. Patients who were administered sacubitril-valsartan had a notably elevated likelihood of experiencing hypotension. Nevertheless, no significant disparities were observed in terms of other adverse events among the various treatment groups. Current meta-analysis provide support for use of sacubitril-valsartan in decreasing mortality in patients with HFrEF. However, more numbers of studies are required to draw a definite conclusion on other benefits associated with sacubitril-valsartan use over standard treatment of ACE inhibitors and ARBs.

Sex differences in long-term outcomes among hospitalized heart failure patients across the spectrum of ejection fraction: findings from the Get with the guidelines - heart failure registry

Abstract Background Sex differences in 5-year outcomes across heart failure (HF) ejection fraction (EF) subtypes are not well known. Purpose To assess the interaction between sex and EF for risk of long-term adverse outcomes after hospitalization with HF. Methods Patients from American Heart Association’s Get With The Guidelines – Heart Failure registry enrolled between 1/1/2006 – 12/31/2014 with age ≥ 65 years with available 5-year follow-up data, ascertained through linkage with Medicare fee-for-service Part A administrative claims, were included. HF subtypes included HF with reduced EF (HFrEF) with EF ≤ 40%, HF with mildly reduced EF (HFmrEF) with EF 41-49%, and HF with preserved EF (HFpEF) with EF ≥ 50%. Sex differences in 5-year all-cause mortality and readmission for each HF subtype were assessed using unadjusted cumulative incidence methods and adjusted Cox models. Median survival across HF subtypes was compared to median survival of U.S. adults. Results 155,670 patients (mean age 81 years, 53.4% females) were included. Male patients were younger and had a higher prevalence of prior myocardial infarction or coronary artery bypass graft surgery and were more likely to have HFrEF, while women were more likely to have history of hypertension and HFpEF. The median post-hospitalization survival of patients with HF was substantially lower than the age- and sex-specific U.S. life expectancy across each HF subtype (Figure 1).Patients with HF had high 5-year mortality rates (HFrEF male: 81.3%, female: 78.4%; HFpEF male: 80.5% vs female 79.5%). In adjusted analysis, female (vs. male) patients had a significantly lower 5-year mortality risk (HR [95%CI]: 0.89 [0.87 – 0.90], p&amp;lt;0.01) and a higher 5-year readmission risk (all-cause: 1.03 [1.02 – 1.04]), CV: 1.05 [1.04 – 1.07]), HF: 1.06 [1.04 – 1.08], p&amp;lt;0.01 for each). HF subtype modified the association between sex and 5-year outcomes (pinteraction &amp;lt;0.05 for mortality and CV and HF readmission), with the greatest risk reduction of mortality for female vs. male patients with HFrEF and the greatest risk increase of readmission (CV and HF) among female vs. male patients with HFmrEF and HFpEF (Figure 2). Conclusion Among patients with HF, the overall survival post-HF hospitalization is very low for each HF subtype. Female patients have a lower 5-year mortality risk but a higher risk of HF or CV readmission regardless of EF.Figure 1Figure 2

Contemporary insights into the epidemiology, impact and treatment of secondary tricuspid regurgitation across the heart failure spectrum

Abstract Background Tricuspid regurgitation secondary to heart failure (sTR) is common with considerable impact on survival and hospitalization rates. Currently, insights into epidemiology, impact, and treatment of sTR across the entire heart failure (HF) spectrum are lacking yet are necessary for informed health care decision-making. Purpose To investigate (i) the demographic aspects of sTR overall and according to HF subtype, (ii) the association of sTR with mortality compared to expected survival in the age and sex matched community (iii) differences in subgroups, to identify patients at increased risk of mortality and (iv) to assess treatment demand and utilization for sTR in a unique setting with a population-wide health-care plan and state-of-the-art medical facilities. Methods This population-based study included individual data from 13469 patients with HF and sTR over a 10-year period. Primary outcome measure was long-term mortality. Results Overall, heart failure with preserved ejection fraction (HFpEF) was the most frequent (57%, n = 7733) HF subtype and the burden of comorbidities was high. Severe sTR was present in 1514 patients (11%), most common among patients with reduced EF (HFrEF) (20%, n = 496). Mortality of patients with sTR was higher than expected survival of sex- and age-matched community and independent of HF subtype (moderate sTR: Hazard ratio [HR] 6.32; 95% Confidence Interval [CI] 5.88-6.80, P&amp;lt;0.00, severe sTR: HR 9.04; 95% CI 8.27-9.87, P&amp;lt;0.001). In comparison to HF and no/mild sTR patients, mortality increased for moderate sTR (HR 1.58, 95%CI 1.48-1.69, P&amp;lt;0.001) and for severe sTR (HR 2.19, 95%CI 2.01-2.38, P&amp;lt;0.001). Survival is presented in Figure 1. This effect prevailed after multivariate adjustment and was similar across all HF subtypes (Figure 2). In subgroup analysis severe sTR mortality-risk was more pronounced in younger patients (&amp;lt;70a). Moderate and severe sTR were rarely treated surgically or percutaneously (3%, n = 147), despite availability of state-of-the-art facilities and universal health care. Conclusion sTR is frequent, increasing with age and associated with excess mortality independent of left ventricular ejection fraction. Nevertheless, sTR is rarely treated surgically or percutaneously. With the projected increase in HF prevalence and population ageing the data suggest a major burden for health-care systems, that needs to be adequately addressed. Low-risk transcatheter treatment options may provide a suitable alternative.Figure 1Figure 2