Heart Failure Subtypes Research Articles

Abstract 17030: Phenome-Wide Mapping of Genetic Effects Distinguishes Etiological Modules Underlying the Phenotypic Spectrum of Heart Failure

Introduction: The heart failure (HF) syndrome has been associated with multiple risk factors of which causal effects on conventional HF subtypes remain unclear. Leveraging insights from human genetics, we characterized the associations of genetic loci associated with susceptibility to HF across a wide range of risk factors and diseases to identify causal risk factors and etiological modules underlying HF subtypes. Methods: Through a genome-wide association meta-analysis in 1.9 million individuals, we identified 66 independent genetic susceptibility loci across HF subtypes. We evaluated the pleiotropic effects of these loci across 294 disease phenotypes in 400,000 UK Biobank participants. Using graph modeling, we constructed a pleiotropy network of HF loci and identified distinct etiological clusters based on the network topology. Finally, we performed cross-trait genetic colocalization, genetic correlation, and Mendelian randomization analyses to investigate the causal effects of 24 HF-related phenotypes across HF subtypes. Results: We identified 207 associations between 49 genetic susceptibility loci of HF and 79 disease phenotypes. Network analysis revealed 18 distinct etiological clusters underlying these associations (Figure A), including clusters of interlinked ischemic phenotypes, cardiac arrhythmia / cardiomyopathies, hypertension, and diabetes / obesity. Through colocalization analysis, we found 105 causal genetic variants that are shared between HF and at least one other trait at 42 loci. We observed differential patterns of genetic correlation and causal associations, for instance, type 2 diabetes were genetically correlated to all HF subtypes but not causally associated with any (Figure B). Conclusions: Genetic analysis identifies distinct etiological modules and causal risk factors underlying different forms of HF, providing insights that may inform approaches to treatment and prevention.

Abstract 17631: Diabetic Retinopathy and Risk of Heart Failure Subtypes: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: Although diabetic retinopathy is associated with higher risk of incident heart failure (HF), its associations with HF subtypes (HF with preserved ejection fraction [HFpEF] and HF with reduced ejection fraction [HFrEF]) largely remain unknown. Hypothesis: Diabetic retinopathy, a microvascular complication of hyperglycemic states, is more strongly associated with HFpEF than with HFrEF. Methods: We included 5038 ARIC participants who underwent fundus photography at Visit 3 (1993-1995), had diabetes or prediabetes, and were free of HF (mean age 60 years, 48% women, 27% Black adults). Retinopathy was graded according to the Early Treatment of Diabetic Retinopathy Study (ETDRS) grading scale, with a severity score ≥14 defining the presence of any retinopathy. We used data on incident HF hospitalization. Information on HF subtypes was only available from 2005 onwards. We used Cox regression to estimate the associations of retinopathy with incident overall HF. For HF subtypes, to account for the competing risks of HFpEF and HFrEF, we used competing risks regression analysis by the proportional sub-hazards Fine and Gray method. Results: Over a median 21.2 years of follow-up, there were 1358 HF events (461 prior to 2005 and 897 post-2005 [including 418 HFpEF and 383 HFrEF]). The presence of diabetic retinopathy conferred higher risk of overall HF (hazard ratio [HR]: 1.84, 95% confidence interval [CI]: 1.55, 2.20). Among participants with information on HF subtypes post-2005 (n= 4120), diabetic retinopathy significantly increased the risk of HFpEF (HR 1.86, 95% CI: 1.28, 2.71), but not of HFrEF (sub-HR: 0.73, 95% CI: 0.45, 1.20). An increasing severity of diabetes retinopathy was associated with increasing risks of overall HF and HFpEF. Conclusions: The presence of diabetic retinopathy signifies an excess risk of HF, primarily HFpEF. Our findings support a strong contribution of microvascular disease to the development of HFpEF.

Abstract 12069: Impact of Atrial Fibrillation on Outcomes in Patients With Heart Failure With Reduced, Mildly Reduced and Preserved Ejection Fraction. A Systematic Review and Meta-Analysis of Published Studies

Background: Atrial fibrillation (AF) is highly prevalent in patients with heart failure (HF), however the difference in outcomes between the HF sub-types is not well known. 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). With the new designation of HFmrEF, there have been studies researching the risk profile of AF in the three HF categories, however there is not yet a unifying statement on these data. Aim: Systematic review and meta-analysis aimed to determine if there are any significant differences in AF-associated all-cause mortality (primary endpoint), heart failure hospitalizations, cardiovascular mortality, and stroke (secondary endpoints) between HFrEF, HFmrEF, and HFpEF. Methods: A systematic search of PubMed, EMBASE, and Cochrane Library databases until February 28 th , 2023, identified studies reporting clinical outcomes linked to AF by HF category status. Data were combined using D+L random effects model. Results: The review included 21 studies comprising 238,107 patients. Pooled AF prevalence: 32% in HFrEF, 38% in HFmrEF, and 43% in HFpEF. AF was associated with a higher risk of all-cause mortality in HFmrEF and HFpEF only (Figure for pooled hazard ratio (HR) and 95% CI). AF 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 cardiovascular mortality in the HFpEF subcategory but was associated with stroke in all three HF subtypes. Conclusion: AF was associated with a higher risk of all-cause mortality and heart failure hospitalization in HFmrEF and HFpEF only. As treatment guidelines for AF in HFmrEF are limited, the benefit of treatments to control AF in this subgroup should be further investigated.

Abstract 12727: Liver Elasticity in Elderly Heart Failure Patient

Introduction: Liver elastography is a novel ultrasound technique assessing elasticity of liver tissue. Clinical indication of liver elastography remains unrevealed. Moreover, reports about relationship between liver stiffness and heart failure subtypes haven’t well been published. Hypothesis: We have investigated the cardio-hepatic interaction using liver elastography in heart failure subtypes. Methods: We prospectively enrolled 58 consecutive patients with heart failure admission from April 2022 to March 2023. Liver elastography, transthoracic echocardiography and blood sampling were done at the time of discharge from heart failure treatment. Results: Patients were divided into two groups according to the left ventricular ejection fraction (LVEF) of echocardiography: heart failure with reduced ejection fraction (HFrEF) group (EF ≦40%, n = 11) and non-HFrEF group (EF >40%, n = 31). The mean age of all patients was 83 ± 11 years. The mean age and the prevalence of hypertension and diabetes mellitus was higher in non-HFrEF group than in HFrEF group. The prevalence of taking sodium glucose co-transporter 2 (SGLT2) inhibitors was lower in non-HFrEF group than in HFrEF group. LV end-diastolic diameter, LV end-systolic diameter was larger in HFrEF group than in non-HFrEF group. Tricuspid regurgitation pressure gradient (TRPG) was higher in non-HFrEF group than in HFrEF group. Inferior vena cava diameter was not different between two groups. The mean values of almost liver function tests of all patients were within the normal range. eGFR was lower in non-HFrEF group than in HFrEF group. Liver elasticity was higher in non-HFrEF group than in HFrEF group (7.1 ± 2.7 vs. 5.1 ± 1.5 hPa; P=0.008) indicating liver stiffness. Pearson’s correlation coefficient showed that liver elasticity was positively correlated with the prevalence of diabetes mellitus, LVEF, TRPG, serum creatinine, aspartate aminotransferase, γ-glutamyl transpeptidase and was negatively correlated with LV end-diastolic diameter, LV end-systolic diameter. Conclusions: Liver stiffness was elevated in EF-preserved heart failure patients. Liver elasticity was correlated with parameters of congestion (TRPG) and useful for the assessment of congestion in patients with heart failure.

Abstract 12911: Life’s Essential 8 and Heart Failure: The Million Veteran Program

Background: Heart failure (HF) incidence has increased over past decades and is associated with poor quality of life, increased comorbidities, and high treatment costs. Prevention for HF warrant a major public health priority. Aim: To quantify the association of Life’s Essential 8 (LE8) score with HF. Methods: LE8 score (0-800) was developed based on the AHA guidelines among 348,311 Veterans who enrolled in the VA Million Veteran Program (MVP) (2011-2021) and free of HF at baseline. Cox proportional hazard models were used to calculate the hazard ratios (HR) with their 95% confidence intervals (CI) for first incident HF event, and HF subtypes (HF with reduced ejection fracture (HFrEF) and HF with preserved EF (HFpEF)) across categories of LE8 score. The population attributable fraction (PAF) was calculated to estimate the proportional reduction in HF events that would occur if LE8 was changed to the ideal level. Results: A total of 31,397 HF events were recorded over 1.8 million person-years of follow-up. LE8 score was negatively associated with incidence of HF, HFrEF and HRpEF, even after extensive adjustment for potential confounders ( Figure 1A ). The multivariate-adjusted HR for HF was 0.76 (95% CI: 0.73-0.78), 0.63 (0.61-0.65), 0.52 (0.50-0.54), 0.41 (0.39-0.43), 0.34 (0.32-0.36), 0.28 (0.27-0.30), and 0.23 (0.21-0.25), respectively, among Veterans whose LE8 score was 350-, 400-, 450-, 500-, 550-, 600- and ≥650, respectively, as compared to those with LE8 score <350. The PAF for HF was 7.1%, 10.3%, 15.1%, 15.8%, 17.1%, 17.5% 18.4%, and 49.1% for not ideal sleep, diet, lipid, activity, BMI, smoking, glucose/HbA1c, and blood pressure, respectively, with an estimated joint PAF of 83.2% for total HF, 79.5% for HFrEF and 90.1% for HFpEF for not ideal of any LE8 ( Figure 1B ). Conclusion: Greater adherence to a healthy LE8 lifestyle could be a key component in prevention of HF among Veterans. Assuming everyone follows a lifestyle meet ideal LE8, majority of HF cases will be prevented.

Abstract 17497: Natural History of the Left Ventricular Ejection Fraction in Heart Failure and Sudden Cardiac Death

Background: A clinical diagnosis of heart failure (HF) is associated with increased risk of sudden cardiac death (SCD), but only HF with severely reduced LV ejection fraction (HFrEF, EF ≤35%) is utilized for risk stratification. Guideline-directed medical therapy and heart disease processes may improve or reduce the LVEF. Hypothesis: There is significant variation of LVEF over time among HF patients with SCD. Methods: From a large, prospective population-based study of SCD in the Northwest US (catchment population 1 million, 2002-2018), we identified all consecutive patients with a diagnosis of HF and prior assessment of LVEF. The sub-group of patients with at least 2 prior LVEF evaluations (earliest and latest in relation to SCD) was determined. Results: A total of 1622 individuals suffered SCD with a known diagnosis of HF (65% male, age 72±14) of which 434 had 2 LVEF evaluations at least 1 yr apart prior to their SCD. At earliest evaluation, 100 (23%) had HFrEF (73% male, age 67±13), 88 (20%) had HF with moderately reduced EF (HFmrEF, 35<ef<50) (71% male, age 72±12), and 246 (57%) had hf with preserved ef (hfpef, ef≥50) (57% 72±12). comparing the earliest latest assessment of lvef, mean lvef in hfref increased by 9±14 percentage points (p<0.001) from 27±6 to 36±14; hfmref decreased over time -4±14 (p="0.003)" 43±4 39±14; hfpef -8±13, 62±7 54±14. each subtype changed substantially (mean 2.9±1.5 yrs), sizeable proportions re-classified into different subtypes (Figure). Overall, the HF LVEF subtype was unchanged in 58% and altered in 42% (p<0.001). Conclusions: Based on the LVEF, at least 40% of HF sub-types were re-classified prior to SCD and risk assessment would be variable depending on when LVEF was measured. These findings highlight the limitations of using the LVEF as the only risk predictor of SCD.

Abstract 12519: Biomarker Characterisation of Heart Failure Subtypes: A Population-Based Bioresource Linked Study

Background: Deep learning (DL)-based interpretation of echocardiographic images can help create pragmatic cohort studies to validate novel biomarkers. In this study, we have characterised biomarkers implicated in heart failure (HF) pathophysiology across the ejection fraction (EF) range in a DL-supported pragmatic cohort study. Methods: We used electronic health record data from Tayside, representing 20% of the Scottish population, between 1993 and 2021. Utilising record linkage to DL automated reading of echocardiographic DICOM images, we identified patients with HFrEF or HFpEF and patients without HF. We then linked identified patients to available plasma samples from the Go-SHARE BioBank. We analysed multi-panel biomarkers, such as NT-proBNP, high-sensitivity cardiac troponin-T (hs-cTnT), growth differentiation factor-15 (GDF-15), insulin-like growth factor-binding protein-7 (IGFBP-7), bone morphogenetic protein-10 (BMP-10), Dickkopf WNT Signaling Pathway Inhibitor-3 (DKK-3), fibroblast growth factor-23 (FGF-23), angiopoietin-2 (Ang2), and fatty acid-binding protein-3 (FABP-3), all with electrochemiluminescence immunoassays (Roche Diagnostics, Germany). Results: We identified 236 patients with HFpEF, 156 with HFrEF, and 185 patients without HF with available plasma samples from 3680 patient records linked to echocardiographic DICOMs and blood samples. Patients with HFrEF and HFpEF had significantly higher median values of hs-cTnT, GDF-15, NT-proBNP, IGFBP-7, DKK-3, and FGF-23 than controls. The diagnostic accuracy (AUC) of NT-proBNP, hs-cTnT, GDF-15, IGFBP-7, and FABP-3 was >0.8 for identifying patients with HFrEF or HFpEF from controls. DL-algorithm-based interpretation of DICOM images provided further coverage of echocardiographic parameters relevant for diagnosis of HF subtypes. All biomarkers were associated with all-cause mortality and HF-related hospitalisation during a median follow-up of 1089 days. Conclusions: In this population-based study, we demonstrated a novel approach utilising a bioresource linked to a DL-supported pragmatic study to explore biomarkers in HF and demonstrated that multiple biomarkers to have diagnostic and prognostic significance for patients with HFrEF and HFpEF.

Abstract 16269: Heart Failure With Preserved Ejection Fraction and Sudden Cardiac Death in the General Population

Background: Published data indicate that 50% of individuals with heart failure and reduced ejection fraction (HFrEF) suffer sudden cardiac death (SCD), however the burden of SCD in heart failure with preserved ejection fraction (HFpEF) remains inconclusive. Aim: Determine the prevalence of HFpEF in a community-based cohort of SCD. Methods: We prospectively identified cases with out-of-hospital SCD in a large metro area of the US Northwest (Pop. 1 million, 2002-2017) and determined HF status prior to SCD based on review of clinical records. Heart failure was subdivided into HFpEF (EF≥50%), HFmrEF (EF 40%-50%), and HFrEF (EF≤40%). In addition, since HFpEF is often underdiagnosed, we evaluated a modified H2FPEF algorithm for the identification of HFpEF among our SCD cohort with unknown HF subtypes. The score was comprised of clinical variables including age, BMI, atrial fibrillation, hypertension, and myocardial infarction. Score accuracy was assessed using receiver operating characteristic (ROC) analysis comparing known HFpEF from clinical records and echocardiography versus non-HF subjects. Next, the score was used to identify missing HFpEF cases within the HF and SCD population. Results: Among 4,683 total SCD cases, 1,013 (22%) had a clinical history of HF. Prevalence of HF sub-types was 42% for HFpEF, 19% for HFmEF and 39% for HFrEF cases. An algorithm score of 5 or greater differentiated HFpEF subjects from non-HF subjects with an AUC of 0.68 (p < 0.01). The algorithm was then deployed on cases with an unknown heart failure subtype and an additional 117 HFpEF subjects were identified. The adjusted total prevalence of HFpEF was 542 subjects (53%) in the SCD the cohort with HF. Conclusion: At least 40% of the SCD cases with HF carry a diagnosis of HFpEF, and our estimates suggest the prevalence may be as high as 53%. Ultimately, these findings highlight the need to develop effective options for primary prevention of SCD in HFpEF patients.

The Burden of Heart Failure and Its Impact on Mortality and Outcomes in Hospitalized Multiple Myeloma Patients: A Nationwide Study.

Background Multiple myeloma is a hematologic malignancy characterized by its association with a range of cardiovascular comorbidities, most notably heart failure. Our study aims to investigate the impact of heart failure on individuals who are hospitalized for multiple myeloma. Methods In this retrospective cohort study, we assembled a cohort of patients diagnosed with multiple myeloma from the National Inpatient Sample (NIS) data from 2019 to 2020. Within this study population, patients were classified according to the presence or absence of heart failure as a secondary diagnosis, with further stratification into distinct groups such as heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). The primary outcome studied was inpatient mortality. Secondary outcomes were length of stay, total hospitalization charges, acute respiratory failure, acute kidney injury, intensive care unit (ICU) admission, and mechanical ventilation. Confounders were adjusted using multivariate regression analysis. Results Among the 38,735 patients admitted with multiple myeloma, 5.6% (2,195 patients) were diagnosed with HFpEF, while 3% (1,170 patients) had HFrEF. The mortality rate was significantly higher in HFpEF patients compared to HFrEF and non-heart failure individuals (aOR: 1.68, [CI: 1.17-2.43]; P = 0.005). Length of hospital stay did not differ between these two groups; however, total hospitalization charges were more significant in the presence of heart failure versus without heart failure (coefficient: 33597; CI: 1730-65463; P = 0.04; and coefficient: 26107; CI: 5414-46800; P = 0.01 for HFrEF and HFpEF, respectively). Similarly, a significant increase in the odds of acute respiratory failure, care at the ICU, and requirement for mechanical ventilation was observed in patients with both types ofheart failure compared to those without heart failure. Conclusion HFpEF was associated with high mortality rates and greater incidence of acute kidney injury in multiple myeloma patients compared to those with HFrEF and non-heart failure counterparts. However, both heart failure subtypes were associated with heightened total hospitalization charges and the increased likelihood of encountering acute respiratory failure, admission to the ICU, and the utilization of mechanical ventilation compared to patients without heart failure.

Association of marine PUFAs intakes with cardiovascular disease, all-cause mortality, and cardiovascular mortality in American adult male patients with dyslipidemia: the U.S. National Health and Nutrition Examination Survey, 2001 to 2016

BackgroundThe relationship between marine polyunsaturated fatty acid (PUFA) intake and cardiovascular disease and mortality in dyslipidemic patients is unclear. Men with dyslipidemia have a higher risk of cardiovascular disease than women, and PUFA supplementation may be more beneficial in men.ObjectiveThe purpose of this study was to assess the relationship between different types of marine polyunsaturated fatty acids intakes and cardiovascular disease, all-cause mortality, and cardiovascular mortality in adult U.S. males with dyslipidemia.MethodsThe study ultimately included 11,848 adult men with dyslipidemia who were screened from the National Health and Nutrition Examination Survey (NHANES) between 2001 and 2016. This was linked to the 2019 National Death Index (NDI) records to establish a prospective cohort. In the study, a logistic regression model was established to assess the relationship between PUFA intake and prevalent CVD, and a Cox proportional hazards regression model was established to assess the relationship between PUFA intake and death.ResultsIn the fully adjusted models, compared with participants in the lowest tertile, participants with the highest DPA intake were associated with a lower risk of CVD (CVD: OR = 0.71, 95%CI: 0.55, 0.91; angina: OR = 0.54, 95%CI: 0.38, 0.79; stroke: OR = 0.62, 95%CI: 0.43, 0.89), but not with three subtypes of congestive heart failure, coronary heart disease, and myocardial infarction. And the highest tertile level of DPA intake can reduce all-cause mortality (HR = 0.77, 95%CI: 0.64, 0.91) and CVD mortality (HR = 0.68, 95%CI: 0.52, 0.90).ConclusionsCardiovascular disease risk, all-cause mortality, and CVD mortality were inversely associated with dietary DPA intake but not EPA and DHA intakes in U.S. male participants with dyslipidemia.

Development and Optimization of the Veterans Affairs’ National Heart Failure Dashboard for Population Health Management

BackgroundIn 2020, the Veterans Affairs (VA) health care system deployed a heart failure (HF) dashboard for use nationally. The initial version was notably imprecise and unreliable for the identification of HF subtypes. We describe the development and subsequent optimization of the VA national HF dashboard. Materials and MethodsThis study describes the stepwise process for improving the accuracy of the VA national HF dashboard, including defining the initial dashboard, improving case definitions, using natural language processing for patient identification, and incorporating an imaging-quality hierarchy model. Optimization further included evaluating whether to require concurrent ICD-codes for inclusion in the dashboard and assessing various imaging modalities for patient characterization. ResultsThrough multiple rounds of optimization, the dashboard accuracy (defined as the proportion of true results to the total population) was improved from 54.1% to 89.2% for the identification of HF with reduced ejection fraction (HFrEF) and from 53.9% to 88.0% for the identification of HF with preserved ejection fraction (HFpEF). To align with current guidelines, HF with mildly reduced ejection fraction (HFmrEF) was added to the dashboard output with 88.0% accuracy. ConclusionsThe inclusion of an imaging-quality hierarchy model and natural-language processing algorithm improved the accuracy of the VA national HF dashboard. The revised dashboard informatics algorithm has higher use rates and improved reliability for the health management of the population.

Fibroblast Growth Factor 23 and Risk of Heart Failure Subtype: The CRIC (Chronic Renal Insufficiency Cohort) Study

Heart failure (HF) is an important cause of morbidity and mortality among individuals with chronic kidney disease (CKD). A large body of evidence from preclinical and clinical studies implicates excess levels of fibroblast growth factor 23 (FGF23) in HF pathogenesis in CKD. It remains unclear whether the relationship between elevated FGF23 levels and HF risk among individuals with CKD varies by HF subtype. Prospective cohort study. A total of 3,502 participants were selected in the Chronic Renal Insufficiency Cohort study. Baseline plasma FGF23. Incident HF by subtype and total rate of HF hospitalization. HF was categorized as HF with preserved ejection fraction (HFpEF, ejection fraction [EF]≥ 50%), HF with reduced EF (HFrEF, EF<50%) and HF with unknown EF (HFuEF). Multivariable-adjusted cause-specific Cox proportional hazards models were used to investigate associations between FGF23 and incident hospitalizations for HF by subtype. The Lunn-McNeil method was used to compare hazard ratios across HF subtypes. Poisson regression models were used to evaluate the total rate of HF. During a median follow-up time of 10.8 years, 295 HFpEF, 242 HFrEF, and 156 HFuEF hospitalizations occurred. In multivariable-adjusted cause-specific Cox proportional hazards models, FGF23 was significantly associated with the incidence of HFpEF (HR, 1.41; 95% CI, 1.21-1.64), HFrEF (HR, 1.27; 95% CI, 1.05-1.53), and HFuEF (HR, 1.40; 95% CI, 1.13-1.73) per 1 standard deviation (SD) increase in the natural log of FGF23. The Lunn-McNeil method determined that the risk association was consistent across all subtypes. The rate ratio of total HF events increased with FGF23 quartile. In multivariable-adjusted models, compared with quartile 1, FGF23 quartile 4 had a rate ratio of 1.81 (95% CI, 1.28-2.57) for total HF events. Self-report of HF hospitalizations and possible lack of an echocardiogram at time of hospitalization. In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risks for all HF subtypes. Heart failure (HF) is a prominent cause of morbidity and mortality in individuals with chronic kidney disease (CKD). Identifying potential pathways in the development of HF is essential in developing therapies to prevent and treat HF. In a large cohort of individuals with CKD, the Chronic Renal Insufficiency Cohort (N=3,502), baseline fibroblast growth factor-23 (FGF23), a hormone that regulates phosphorous, was evaluated in relation to the development of incident and recurrent HF with reduced, preserved, and unknown ejection fraction. In this large multicenter prospective cohort study, elevated FGF23 levels were associated with increased risk of all HF subtypes. These findings demonstrate the need for further research into FGF23 as a target in preventing the development of HF in individuals with CKD.

Changing health related quality of life and outcomes in heart failure by age, sex and subtype

There are calls to integrate serial recordings of health related quality of life (HRQoL) into routine care, clinical trials and prognosis. Little is known about the relationship between change in HRQoL and outcomes in heart failure (HF) patients by age, sex and HF subtype. From the Swedish Heart Failure Registry (SwedeHF; 2008-2019), patients were categorised by reduced (<40%, HFrEF), mildly-reduced (40-49%, HFmrEF) and preserved (≥50%, HFpEF) ejection fraction. HRQoL was measured using Euro-QoL-5D visual analogue scale (EQ5D-vas), collected at baseline and 1-year. Baseline EQ5D-vas scores were categorised by: "best" (76-100), "good" (51-75), "bad" (26-50), and "worst" (0-25). Change in EQ5D-vas was categorised as 'no significant change' (<5 points increase/decrease); some worsening (5-9 points decrease); considerable worsening (≥10 points decrease); some improvement (5-9 points increase); considerable improvement (≥10 points increase). Associations with admission and death were estimated and interactions with patient sub-groups tested. Among 23,553 patients (median age 74 [66-81] years, 8000 [34%] female), baseline EQ5D-vas was worse in older patients, women, and those with HFpEF compared to their respective counterparts. Compared to patients with the "best" EQ5D-vas, the adjusted associations for admission for those with "good", "bad" and "worst" EQ5D-vas were, respectively: HR 1.09 (1.04, 1.14), 1.27 (1.21, 1.33) and 1.39 (1.28, 1.51). Compared to no significant change in EQ5D-vas, the adjusted estimates for admission following some improvement, considerable improvement, some worsening and considerable worsening were, respectively: HR 0.91 (0.82, 1.01), 0.75 (0.70, 0.81), 1.04 (0.92, 1.16) and 1.25 (1.16, 1.35). Results were similar amongst groups and for HF admission and death. Change in HRQoL was an independent indicator of risk of admission and death in people with all HF subtypes, irrespective of age and sex. NIHR.

Use of electronic health record data mining for heart failure subtyping

ObjectiveTo assess whether electronic health record (EHR) data text mining can be used to improve register-based heart failure (HF) subtyping. EHR data of 43,405 individuals from two Finnish hospital biobanks were mined for unstructured text mentions of ejection fraction (EF) and validated against clinical assessment in two sets of 100 randomly selected individuals. Structured laboratory data was then incorporated for a categorization by HF subtype (HF with mildly reduced EF, HFmrEF; HF with preserved EF, HFpEF; HF with reduced EF, HFrEF; and no HF).ResultsIn 86% of the cases, the algorithm-identified EF belonged to the correct HF subtype range. Sensitivity, specificity, PPV and NPV of the algorithm were 94–100% for HFrEF, 85–100% for HFmrEF, and 96%, 67%, 53% and 98% for HFpEF. Survival analyses using the traditional diagnosis of HF were in concordance with the algorithm-based ones. Compared to healthy individuals, mortality increased from HFmrEF (hazard ratio [HR], 1.91; 95% confidence interval [CI], 1.24–2.95) to HFpEF (2.28; 1.80–2.88) to HFrEF group (2.63; 1.97–3.50) over a follow-up of 1.5 years. We conclude that quantitative EF data can be efficiently extracted from EHRs and used with laboratory data to subtype HF with reasonable accuracy, especially for HFrEF.

Sex differences in long-term outcomes following acute heart failure hospitalization: Findings from the Get With The Guidelines-Heart Failure registry.

Sex differences in long-term outcomes following hospitalization for heart failure (HF) across ejection fraction (EF) subtypes are not well described. In this study, we evaluated the risk of mortality and rehospitalization among males and females across the spectrum of EF over 5 years of follow-up following an index HF hospitalization event. Patients hospitalized with HF between 1 January 2006 and 31 December 2014 from the American Heart Association's Get With The Guidelines-Heart Failure registry with available 5-year follow-up using Medicare Part A claims data were included. The association between sex and risk of mortality and readmission over a 5-year follow-up period for each HF subtype (HF with reduced EF [HFrEF, EF ≤40%], HF with mildly reduced EF [HFmrEF, EF 41-49%], and HF with preserved EF [HFpEF, EF >50%]) was assessed using adjusted Cox models. The effect modification by the HF subtype for the association between sex and outcomes was assessed by including multiplicative interaction terms in the models. A total of 155 670 patients (median age: 81 years, 53.4% female) were included. Over 5-year follow-up, males and females had comparably poor survival post-discharge; however, females (vs. males) had greater years of survival lost to HF compared with the median age- and sex-matched US population (HFpEF: 17.0 vs. 14.6 years; HFrEF: 17.3 vs. 15.1 years; HFmrEF: 17.7 vs. 14.6 years for age group 65-69 years). In adjusted analysis, females (vs. males) had a lower risk of 5-year mortality (adjusted hazard ratio [aHR] 0.89, 95% confidence interval [CI] 0.87-0.90, p < 0.0001), and the risk difference was most pronounced among patients with HFrEF (aHR 0.87, 95% CI 0.85-0.89; pinteraction [sex*HF subtype] = 0.04). Females (vs. males) had a higher adjusted risk of HF readmission over 5-year follow-up (aHR 1.06, 95% CI 1.04-1.08, p < 0.0001), with the risk difference most pronounced among patients with HFpEF (aHR 1.11, 95% CI 1.07-1.14; pinteraction [sex*HF subtype] = 0.001). While females (vs. males) had lower adjusted mortality, females experienced a significantly greater loss in survival time than the median age- and sex-matched US population and had a greater risk of rehospitalization over 5 years following HF hospitalization.

Effects of Rhythm Control for Atrial Fibrillation on Cardiac Remodeling and Valvular Regurgitation in Patients with Heart Failure.

Previous studies investigating cardiac remodeling and functional regurgitation of rhythm control for atrial fibrillation (AF) in heart failure (HF) are limited. Therefore, this study aimed to evaluate the impact of rhythm control for AF on cardiac remodeling and functional regurgitation in the spectrum of HF. Its effect on prognosis was explored. According to the treatment strategies of AF, the cohort was classified into the rhythm control and rate control groups. To further detect the implications of rhythm control on cardiac remodeling, functional regurgitation, and outcomes in HF subtypes, patients were further divided into HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction, and HF with preserved ejection fraction (HFpEF) subgroups. A total of 828 patients were enrolled, with 307 patients in the rhythm control group and 521 patients in the rate control group. Over a median follow-up time of 3.8 years, patients with rhythm control treatments experienced improvements in biatrial structure parameters, left ventricular ejection fraction, and functional regurgitation (mitral and tricuspid regurgitation) compared with rate control treatment (p < 0.05). Cox regression analysis demonstrated that rhythm control reduced the risks of all-cause mortality (HR 0.436 [95% CI, 0.218-0.871], p = 0.019) in HFpEF and HF-related admissions in HFrEF (HR 0.500 [95% CI, 0.330-0.757], p = 0.001) and HFpEF (HR 0.541 [95% CI, 0.407-0.720], p < 0.001); these associations were similar after adjusting for multiple confounders. Rhythm control therapy can be considered an appropriate treatment strategy for the management of AF in HF to improve cardiac remodeling, functional regurgitation, and prognosis.

Advance in the pharmacological and comorbidities management of heart failure with preserved ejection fraction: evidence from clinical trials.

The prevalence of heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of the total heart failure population, and with the aging of the population and the increasing prevalence of hypertension, obesity, and type 2 diabetes (T2DM), the incidence of HFpEF continues to rise and has become the most common subtype of heart failure. Compared with heart failure with reduced ejection fraction, HFpEF has a more complex pathophysiology and is more often associated with hypertension, T2DM, obesity, atrial fibrillation, renal insufficiency, pulmonary hypertension, obstructive sleep apnea, and other comorbidities. HFpEF has generally been considered a syndrome with high phenotypic heterogeneity, and no effective treatments have been shown to reduce mortality to date. Diuretics and comorbidity management are traditional treatments for HFpEF; however, they are mostly empirical due to a lack of clinical evidence in the setting of HFpEF. With the EMPEROR-Preserved and DELIVER results, sodium-glucose cotransporter 2 inhibitors become the first evidence-based therapies to reduce rehospitalization for heart failure. Subgroup analyses of the PARAGON-HF, TOPCAT, and CHARM-Preserved trials suggest that angiotensin receptor-neprilysin inhibitors, spironolactone, and angiotensin II receptor blockers may be beneficial in patients at the lower end of the ejection fraction spectrum. Other potential pharmacotherapies represented by non-steroidal mineralocorticoid receptor antagonists finerenone and antifibrotic agent pirfenidone also hold promise for the treatment of HFpEF. This article intends to review the clinical evidence on current pharmacotherapies of HFpEF, as well as the comorbidities management of atrial fibrillation, hypertension, T2DM, obesity, pulmonary hypertension, renal insufficiency, obstructive sleep apnea, and iron deficiency, to optimize the clinical management of HFpEF.

Prognostic Significance of Serum Chloride Level Reduction in Patients with Chronic Heart Failure with Different Ejection Fractions.

Little is known regarding the prognostic value of serum chloride in patients with chronic heart failure (CHF) with different ejection fractions. We sought to determine the postdischarge outcomes associated with lower serum chloride between different CHF types.We reviewed the medical records of 1221 consecutive patients with CHF admitted to the First Affiliated Hospital of Kunming Medical University from January 2017 to October 2021. After excluding patients with in-hospital death, missing follow-up data, missing serum chloride level data, or chronic dialysis therapy, 791 patients were included. Of these patients, 343 had heart failure with reduced ejection fraction (HFrEF; i.e., left ventricular ejection fraction (LVEF) < 40%), and 448 had heart failure with preserved ejection fraction (HFpEF) or heart failure with median ejection fraction (HFmrEF; HFpEF plus HFmrEF; i.e., LVEF ≥40%). Over a median follow-up of 750 days, 344 patients (43.5%) had all-cause mortality. In the univariate analysis, serum sodium and chloride were strongly associated with mortality in both HF subgroups (P < 0.0001). A multivariable model including both serum sodium and chloride showed the highly significant association between serum chloride and survival (P < 0.0001), whereas the association between serum sodium and mortality was not reported (HFpEF plus HFmrEF, hazard ratio (HR) 0.975, 95% confidence interval [CI] 0.942-1.010, P = 0.158; HFrEF, HR 1.007, 95% CI 0.966-1.051, P = 0.734). Kaplan-Meier survival curve analysis revealed a significant difference in mortality risk with decreasing chloride levels in all patients with CHF. The optimal cutoff value of chloride in predicting all-cause mortality was 102.95 mmol/L with area under the curve value of 0.76 [HR 0.760, 95% CI 0.727-0.793, P < 0.0001], sensitivity of 60.2%, and specificity of 78.3%.Lower serum chloride is an independent predictor of death in CHF, regardless of heart failure subtype.

A network medicine approach to study comorbidities in heart failure with preserved ejection fraction

BackgroundComorbidities are expected to impact the pathophysiology of heart failure (HF) with preserved ejection fraction (HFpEF). However, comorbidity profiles are usually reduced to a few comorbid disorders. Systems medicine approaches can model phenome-wide comorbidity profiles to improve our understanding of HFpEF and infer associated genetic profiles.MethodsWe retrospectively explored 569 comorbidities in 29,047 HF patients, including 8062 HFpEF and 6585 HF with reduced ejection fraction (HFrEF) patients from a German university hospital. We assessed differences in comorbidity profiles between HF subtypes via multiple correspondence analysis. Then, we used machine learning classifiers to identify distinctive comorbidity profiles of HFpEF and HFrEF patients. Moreover, we built a comorbidity network (HFnet) to identify the main disease clusters that summarized the phenome-wide comorbidity. Lastly, we predicted novel gene candidates for HFpEF by linking the HFnet to a multilayer gene network, integrating multiple databases. To corroborate HFpEF candidate genes, we collected transcriptomic data in a murine HFpEF model. We compared predicted genes with the murine disease signature as well as with the literature.ResultsWe found a high degree of variance between the comorbidity profiles of HFpEF and HFrEF, while each was more similar to HFmrEF. The comorbidities present in HFpEF patients were more diverse than those in HFrEF and included neoplastic, osteologic and rheumatoid disorders. Disease communities in the HFnet captured important comorbidity concepts of HF patients which could be assigned to HF subtypes, age groups, and sex. Based on the HFpEF comorbidity profile, we predicted and recovered gene candidates, including genes involved in fibrosis (COL3A1, LOX, SMAD9, PTHL), hypertrophy (GATA5, MYH7), oxidative stress (NOS1, GSST1, XDH), and endoplasmic reticulum stress (ATF6). Finally, predicted genes were significantly overrepresented in the murine transcriptomic disease signature providing additional plausibility for their relevance.ConclusionsWe applied systems medicine concepts to analyze comorbidity profiles in a HF patient cohort. We were able to identify disease clusters that helped to characterize HF patients. We derived a distinct comorbidity profile for HFpEF, which was leveraged to suggest novel candidate genes via network propagation. The identification of distinctive comorbidity profiles and candidate genes from routine clinical data provides insights that may be leveraged to improve diagnosis and identify treatment targets for HFpEF patients.Graphical

Sex Differences in Heart Failure: What Do We Know?

Heart failure (HF) remains an important global health issue, substantially contributing to morbidity and mortality. According to epidemiological studies, men and women face nearly equivalent lifetime risks for HF. However, their experiences diverge significantly when it comes to HF subtypes: men tend to develop HF with reduced ejection fraction more frequently, whereas women are predominantly affected by HF with preserved ejection fraction. This divergence underlines the presence of numerous sex-based disparities across various facets of HF, encompassing aspects such as risk factors, clinical presentation, underlying pathophysiology, and response to therapy. Despite these apparent discrepancies, our understanding of them is far from complete, with key knowledge gaps still existing. Current guidelines from various professional societies acknowledge the existence of sex-based differences in HF management, yet they are lacking in providing explicit, actionable recommendations tailored to these differences. In this comprehensive review, we delve deeper into these sex-specific differences within the context of HF, critically examining associated definitions, risk factors, and therapeutic strategies. We provide a specific emphasis on aspects exclusive to women, such as the impact of pregnancy-induced hypertension and premature menopause, as these unique factors warrant greater attention in the broader HF discussion. Additionally, we aim to clarify ongoing controversies and knowledge gaps pertaining to the pharmacological treatment of HF and the sex-specific indications for cardiac implantable electronic devices. By shining a light on these issues, we hope to stimulate a more nuanced understanding and promote the development of more sex-responsive approaches in HF management.