Disease Progression In Heart Failure Research Articles

Association of diuretic requirement and right heart failure post-LVAD implantation

Diuretic responsiveness is associated with heart failure disease progression. Among patients with advanced heart failure, we hypothesized that decreased diuretic responsiveness and higher diuretic requirement is a correlate of progressive right ventricular dysfunction and may help to risk stratify patients undergoing LVAD evaluation. We performed a single-center, retrospective analysis of 147 patients undergoing LVAD implantation between 2014 and 2018. The primary outcome was early RHF or death during the index hospital stay. Patients were stratified by tertiles of preoperative 24-hour diuretic dose within 72 hours of surgery. The incidence of early RHF was higher in the highest dose group (66.0%) compared to the medium (41.3%) and low-doses groups (23.5%) (p<0.001). Each 40mg increase in IV furosemide dose was associated with a 6% increase in the risk of RHF, after adjusting for other known risk factors. The median ICU length of stay was 2 days longer for patients in the highest compared to low-dose group (7 vs. 5 days, p=0.02). Mortality within 14 days post-op was numerically higher although not significantly different between the highest dose group and the low-dose group (12.0% vs. 5.9%, p=0.55). 6-month survival across diuretic dose tertiles was also not statistically different (p=0.40). We concluded that higher preoperative diuretic dose is associated with risk of early RHF following LVAD surgery. These data furthermore support the role of progressive right ventricular dysfunction on development of cardiorenal disease and diuretic resistance.

Proteomic Associations of Adverse Outcomes in Human Heart Failure.

Identifying novel molecular drivers of disease progression in heart failure (HF) is a high-priority goal that may provide new therapeutic targets to improve patient outcomes. The authors investigated the relationship between plasma proteins and adverse outcomes in HF and their putative causal role using Mendelian randomization. The authors measured 4776 plasma proteins among 1964 participants with HF with a reduced left ventricular ejection fraction enrolled in PHFS (Penn Heart Failure Study). Assessed were the observational relationship between plasma proteins and (1) all-cause death or (2) death or HF-related hospital admission (DHFA). The authors replicated nominally significant associations in the Washington University HF registry (N=1080). Proteins significantly associated with outcomes were the subject of 2-sample Mendelian randomization and colocalization analyses. After correction for multiple testing, 243 and 126 proteins were found to be significantly associated with death and DHFA, respectively. These included small ubiquitin-like modifier 2 (standardized hazard ratio [sHR], 1.56; P<0.0001), growth differentiation factor-15 (sHR, 1.68; P<0.0001) for death, A disintegrin and metalloproteinase with thrombospondin motifs-like protein (sHR, 1.40; P<0.0001), and pulmonary-associated surfactant protein C (sHR, 1.24; P<0.0001) for DHFA. In pathway analyses, top canonical pathways associated with death and DHFA included fibrotic, inflammatory, and coagulation pathways. Genomic analyses provided evidence of nominally significant associations between levels of 6 genetically predicted proteins with DHFAand 11 genetically predicted proteins with death. This study implicates multiple novel proteins in HF and provides preliminary evidence of associations between genetically predicted plasma levels of 17 candidate proteins and the risk for adverse outcomes in human HF.

Abstract P3084: Neutrophil Expansion And Netosis Are Essential For Adverse Left Ventricular Remodeling And Dysfunction In Chronic Ischemic Heart Failure

Chronic inflammation contributes significantly to disease progression in heart failure (HF) with the expansion and adverse activation of macrophages, dendritic cells, and T cells in the failing heart. Neutrophils play a well-known role in the initial acute immune response to myocardial infarction (MI), however, whether and how they contribute to inflammation and adverse LV function and remodeling in chronic ischemic HF is unknown. We tested the hypothesis that activated neutrophils are required for tissue remodeling and disease progression in HF in mice studied 4 and 8 weeks after MI during established ischemic HF (vs sham). CD11b + Ly6G + neutrophils were expanded in peripheral blood (PB), heart, spleen and bone marrow 8 w post-MI. Neutrophils in the failing heart were localized to the MI border zone and augmented in remote zone myocardium by immunofluorescent staining. CXCL1 and CXCL5 expression was increased in the failing heart, consistent with chemotactic signals for myocardial neutrophil recruitment. Plasma from HF mice elicited greater chemotaxis in naïve neutrophils (vs naïve plasma) by time-lapse video microscopy. Further, PB neutrophils from HF mice exhibited significantly increased neutrophil extracellular trap (NET) production, with concomitant increase in plasma NETs (histone-DNA complexes) in HF mice. The direct pathological impact of NETs was demonstrated by intramyocardial injection of isolated NETs into naïve hearts mimicking HF with decreased EF, LV dilation, and fibrosis. Finally, the in vivo role of neutrophils in chronic HF (4 and 8 w post-MI) was determined via depletion studies using genetic (Ly6G-diptheria toxin receptor mice) and antibody (1A8) based approaches. Neutrophil depletion significantly improved LV EF and reduced end systolic and diastolic volumes. 1A8 treated HF mice also exhibited reduced remote zone fibrosis. The necessity of NETosis in HF development was confirmed using neutrophil and myeloid – specific PAD4 deletion where the decline in LV EF and increase in volumes in HF were attenuated. In conclusion , neutrophil expansion and NETosis are important contributors to chronic inflammation in HF and play an obligatory role in the development of LV dysfunction and remodeling in ischemic cardiomyopathy.

Left Atrial Myopathy in Heart Failure With Preserved Ejection Fraction.

The left atrium (LA) plays an important role in facilitating left ventricular (LV) filling by acting as a reservoir, passive conduit, and active booster pump, as well as a regulator of blood volume through A-type natriuretic peptide secretion in response to stimulation by mechanical stretch of the cavity. LA myopathy has emerged as one of the most important non-LV contributors to disease progression in heart failure with preserved ejection fraction (HFpEF). LA dysfunction is common in HFpEF and is associated with more severe pulmonary vascular disease and right ventricular dysfunction, and increases the risk of incident atrial fibrillation or atrial functional mitral regurgitation, leading to limitations in cardiac output reserve and reduced exercise capacity. LA deformation assessed by 2-dimensional speckle-tracking echocardiography is useful for estimating abnormal hemodynamics or exercise capacity, discriminating HFpEF from non-cardiac dyspnea and is an independent predictor of adverse outcome in HFpEF. Thus, interventions directly targeting LA myopathy may improve outcomes in HFpEF with LA myopathy. This review provides information regarding the physiology of the LA in patients with HFpEF and discusses the importance of evaluation of LA function, management issues, and future directions through ongoing trials of medical interventions.

Remote Patient Monitoring for Patients with Heart Failure: Sex- and Race-based Disparities and Opportunities.

Remote patient monitoring (RPM), within the larger context of telehealth expansion, has been established as an effective and safe means of care for patients with heart failure (HF) during the recent pandemic. Of the demographic groups, female patients and black patients are underenrolled relative to disease distribution in clinical trials and are under-referred for RPM, including remote haemodynamic monitoring, cardiac implantable electronic devices (CIEDs), wearables and telehealth interventions. The sex- and race-based disparities are multifactorial: stringent clinical trial inclusion criteria, distrust of the medical establishment, poor access to healthcare, socioeconomic inequities, and lack of diversity in clinical trial leadership. Notwithstanding addressing the above factors, RPM has the unique potential to reduce disparities through a combination of implicit bias mitigation and earlier detection and intervention for HF disease progression in disadvantaged groups. This review describes the uptake of remote haemodynamic monitoring, CIEDs and telehealth in female patients and black patients with HF, and discusses aetiologies that may contribute to inequities and strategies to promote health equity.

Prognostic Implications of Left Atrial Stiffness Index in Heart Failure Patients With Preserved Ejection Fraction

BackgroundThe left atrium (LA) plays an important role in the pathophysiology and disease progression of heart failure with preserved ejection fraction (HFpEF). ObjectivesThis study sought to assess the prognostic potential of LA stiffness index in patients who have HFpEF. MethodsThis study retrospectively screened patients with elevated left ventricular end-diastolic pressure (≥16 mm Hg) and preserved ejection fraction (≥50%) between January 1, 2004, and December 31, 2019. All patients underwent left heart catheterization to measure left ventricular end-diastolic pressure. Among these, 307 patients who had suitable image quality for left peak atrial longitudinal strain (PALS) measurement were analyzed. The study population was classified into low LA stiffness (n = 178, early diastolic transmitral inflow velocity/mitral annulus early diastolic velocity [E/e′]/PALS ≤0.26) and high LA stiffness (n = 129, E/e′/PALS >0.26) according to the best LA stiffness index (E/e′/PALS) cutoff value. The primary outcome was a composite of mortality or hospitalization caused by heart failure during follow-up. ResultsLA stiffness index showed good correlations with E/e′ (r = 0.737; P < 0.001), LA volume index (r = 0.529; P < 0.001), right ventricular systolic pressure (r = 0.404; P < 0.001), and log N-terminal pro–B-type natriuretic peptide (r = 0.540; P < 0.001). LA stiffness index demonstrated better predictive performance than echocardiographic diastolic parameters did (P < 0.001). Patients with low LA stiffness had better clinical outcomes than those with high LA stiffness during a median follow-up of 6 years did (P < 0.001). In multivariable analysis, LA stiffness index was independently associated with increased risk of the composite endpoint of death or heart failure hospitalization (HR: 1.59 [95% CI: 1.01-2.51]; P = 0.044). ConclusionsIncreased LA stiffness was associated with increased risk for all-cause mortality and hospitalization caused by heart failure in patients who have HFpEF, and its prognostic role was more pronounced than that of indexes of left ventricular filling pressure.

Disease progression of heart failure in type 2 diabetes patients in Germany; a real world data analysis using health insurance claims data

Abstract Individuals with Type 2 Diabetes (T2D) show two- to four-fold increased risk of Heart failure (HF). Given the increasing T2D prevalence in Germany, researching the interaction of T2DM and HF is of high importance. HF still progresses rapidly. Left ventricular ejection fraction (LVEF) plays an important role in understanding disease progression. Commonly, LVEF is being distinguished into three categories: HF with preserved LVEF (HFpEF), HF with moderate reduced LVEF (HFmEF) and HF with reduced LVEF (HFrEF). In Germany there are no recent data on disease progression in HF especially according to LVEF categories. Purpose of this study is to a) measure how many T2DM patients acquire HF over two years; b) understand the progression of HF in these patients in a five-year follow-up; and c) visualize disease progression with Sankey plots. We used insurance claims data from German Statutory Health Insurances (SHI). As LVEF category is not included in these data, a model was used to classify patients into HFrEF or HFpEF (with omitting the HFmEF category due to better statistical performance of a binary model). The model was derived from a set of 34 proxy variables (disease coding, interventions, drug prescriptions). Selection period for T2D patients is 2013. Inclusion period was 2014–2015, follow-up 2016–2020. Baseline characteristics include demographic data, disease stage, comorbidities, and risk factors. Follow-up criteria were MACE (including hospital admission) changes in LVEF category and mortality. 173,195 individuals with T2D were identified in 2013, median age 66 yrs. 6,725 (3.88% of the overall sample) developed HF in 2014 or 2015, median age 74 yrs. As Sankey plot visualizations show, 34.4% of the patients had MACE over the course of five years; 24.5% were still alive and 9.9% died from CV-death. Further 33% died of other causes. Myocardial infarct was the most common MACE, followed by stroke (32%), hospital admission for HF (28%) and CV death (7%). 40% of patients were never admitted to a hospital over the study period. Exploratory analyses identified 5,282 HFpEF patients (78.54%) and 1,443 HFrEF patients (21.46%). Survival after 5 years in HFpEF patients was 71%, in HFrEF patients 29%. After five years 3,430 (90%) surviving patients were still in HFpEF and 399 (10%) in HFrEF. This analysis provides disease progression insights in T2D patients who developed HF in Germany. The sample is representative for the country and numbers can be extrapolated to the overall German SHI population. A significant number of patients die within 5 years of initial diagnosis. As echo diagrams are not available in German insurance claims, validity of the predicted LVEF cannot be assessed. Further research featuring real world LVEF score validation would be highly desirable. Beyond therapeutic care, digital solutions for closer monitoring of these patients may improve the outcome of these patients. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi

Prognostic relevance of left atrial function and stiffness in heart failure with preserved ejection fraction patients with and without diabetes mellitus.

BackgroundAlthough the left atrium (LA) plays a key role in the pathophysiology and disease progression of heart failure with preserved ejection fraction (HFpEF), the impact of type 2 diabetes mellitus (T2DM) on LA function and stiffness in HFpEF patients remains unclear. Furthermore, the prognostic value of different phases of LA function and stiffness is less well-established in HFpEF patients.MethodsThis study prospectively enrolled 164 HFpEF patients who were in sinus rhythm at the time of echocardiography, including 61 (37%) HFpEF patients with T2DM. LA reservoir, conduit, and pump function were assessed using two-dimensional volume indices and speckle tracking echocardiography. The LA stiffness was calculated as the ratio of early mitral inflow velocity-to-early annular tissue velocity (E/e’) and LA reservoir function. The primary end point was a combined outcome of heart failure hospitalization or death.ResultsLeft atrium reservoir function [measured by peak LA strain (LAS-peak)] and LA pump function (measured by LAS-active) remained significantly lower in the HFpEF patients with T2DM compared with those without T2DM, even after adjustment for potential confounders. In addition, the LA stiffness of HFpEF patients with T2DM was higher than those without T2DM. After a median follow-up of 13.7 months, 46 patients (28.1%) reached the composite end point. LAS-peak (hazard ratios: 0.88; 95% confidence interval: 0.81–0.95; P = 0.001) was significantly associated with the risk of heart failure hospitalization or death after adjusting for demographic and clinical characteristics, LV global longitudinal strain, E/e’, and LA volume index. In contrast, other LA function and stiffness parameters did not independently predict the risk of adverse events. Kaplan-Meier analysis showed that HFpEF patients with T2DM and low LAS-peak (<27.2%) had a significantly increased risk of heart failure-related hospitalization or death (log-rank P < 0.001).ConclusionLeft atrium reservoir and pump function are impaired, whereas LA stiffness is increased in HFpEF patients with T2DM compared with those without T2DM. LAS-peak is a powerful predictor of adverse clinical outcomes and may be crucial for risk stratification in HFpEF patients with and without T2DM.

Integrated Bioinformatics Identifies FREM1 as a Diagnostic Gene Signature for Heart Failure.

Objective This study is aimed at integrating bioinformatics and machine learning to determine novel diagnostic gene signals in the progression of heart failure disease. Methods The heart failure microarray datasets and RNA-seq datasets have been downloaded from the public database. Differentially expressed genes (DE genes) are screened out, and then, we analyze their biological functions and pathways. Integrating three machine learning methods, the least absolute shrinkage and selection operator (LASSO) algorithm, random forest (RF) algorithm, and support vector machine recursive feature elimination (SVM-RFE) are used to determine candidate diagnostic gene signals. Then, external independent RNA-seq datasets evaluate the diagnostic value of gene signals. Finally, the convolution tool CIBERSORT estimated the composition pattern of immune cell subtypes in heart failure and carried out a correlation analysis combined with gene signals. Results Under the set threshold, we obtained 47 DE genes with the most significant differences. Enrichment analysis shows that most of them are related to hypertrophy, matrix structural constituent, protein binding, inflammatory immune pathway, cardiovascular disease, and inflammatory disease. Three machine learning methods assisted in determining the potential characteristic signals Fras1-related extracellular matrix 1 (FREM1) and meiosis-specific nuclear structural 1 (MNS1). Validation of external datasets confirms that FREM1 is a diagnostic gene signal for heart failure. Immune cell subtypes of tissue specimens found T cell CD8, mast cell resting, T cell CD4 memory resting, T cell regulation (Tregs), monocytes, macrophages M2, T cell CD4 naive, macrophages M0, and neutrophils are associated with HF. Conclusion The gene signal FREM1 may be a potential molecular target in the development of HF and is related to the difference in immune infiltration of HF tissue.

The effect of telemedicine in heart failure based on frailty phenotypes

Heart failure (HF) is a disease of the elderly. In people aged>65years, it is the most common cause of rehospitalisations [1]. Nearly half of the patients diagnosed with HF will be frail (44.5%, 95% CI, 36.2%–52.8%) [2]. Not only is the prevalence of frailty high in HF patients, older persons with frailty are also at increased risk of developing new onset HF [3]. However, frailty is not only associated with the elderly as it can also occur in younger persons (aged <60 years) with HF [3]. The presence of frailty in HF patients accelerates disease progression of HF and increases their risk of rehospitalisation, mortality and functional decline at one year [4].

Visceral adiposity, muscle composition, and exercise tolerance in heart failure with preserved ejection fraction.

AimsVisceral adipose tissue (AT) promotes inflammation and may be associated with disease progression in heart failure with preserved ejection fraction (HFpEF). We characterized regional AT distribution in HFpEF patients and controls and analysed associations with co‐morbidities and exercise tolerance.Methods and resultsMagnetic resonance imaging was performed to quantify epicardial, liver, abdominal, and thigh skeletal muscle AT. We assessed New York Heart Association (NYHA) class, 6 min walk distance, and global well‐being score. Multivariable linear regression models adjusting for body surface area were used. We studied 55 HFpEF patients (41 women, mean age 67 ± 11 years) and 33 controls (21 women, mean age 57 ± 10 years). Epicardial AT (median [interquartile range] 4.6 [2.0] vs. 3.2 [1.4] mm, P < 0.001), thigh intermuscular fat (11.0 [11.5] vs. 5.0 [2.7] cm2, P < 0.001) and liver fat fraction (6.4% [6.1] vs. 4.1% [5.5], P = 0.001) were higher in HFpEF patients than controls. Women with HFpEF had higher abdominal and thigh subcutaneous AT than men. Greater thigh intermuscular fat was associated with higher blood pressure (β [SE] 0.73 [0.17], P < 0.001) and diabetes (odds ratio [95% confidence interval] 1.2 [1.0–1.5], P = 0.03). Greater thigh intramuscular fat was associated with both worse NYHA class (β [SE] 2.7 [1.0], P = 0.01) and shorter 6 min walk distance (β [SE] −4.1 [1.9], P = 0.03), and greater epicardial AT (β [SE] −0.2 [0.1], P < 0.001) and liver fat fraction (β [SE] −0.4 [0.2], P = 0.04) were associated with lower global well‐being score.ConclusionsHeart failure with preserved ejection fraction patients have increased epicardial, liver, and skeletal muscle fat compared with controls out of proportion to their increased body size, and adiposity was associated with worse NYHA class and exercise tolerance in HFpEF. These results provide the basis for further investigation into the effect of interventions to reduce regional AT distribution in relation to HFpEF symptoms and pathophysiology.

Abstract 16640: Neutrophil Expansion is Essential for Adverse Left Ventricular Remodeling and Dysfunction in Chronic Ischemic Heart Failure

Chronic inflammation contributes significantly to disease progression in heart failure (HF), and is characterized by expansion of activated macrophages, dendritic cells, and T cells in the failing heart. Neutrophils play a well-known role as the initial drivers of inflammatory response to myocardial infarction (MI), thereby providing the platform for the subsequent recruitment of macrophages and T cells. However, whether and how neutrophils contribute to inflammation and adverse LV remodeling in chronic HF are unknown. We tested the hypothesis that activated neutrophils are required for tissue remodeling and disease progression in HF. Male C57Bl/6 mice were studied 4 and 8 weeks after left coronary artery ligation during established ischemic HF (sham-operated controls). As assessed by flow cytometry, CD11b + Ly6G + neutrophils were expanded in the peripheral blood (4 w post-MI), and in the bone marrow, spleen, and heart at 8 w post-MI. Immunostaining revealed that in the failing heart, neutrophils were primarily localized to the MI border zone, but also augmented in remote zone myocardium. CXCL1 and CXCL5 chemokine expression was increased in the failing heart, consistent with chemotactic signals for myocardial neutrophil recruitment. Isolated naïve neutrophils also exhibited increased chemotaxis in response to plasma from HF mice (versus plasma from naïve mice), as assessed by time-lapse video microscopy. Moreover, blood neutrophils isolated from HF mice exhibited significantly increased neutrophil extracellular trap (NET) production as compared to control neutrophils, whereas plasma NETs (histone-DNA complexes) were increased in HF mice. Finally, the in vivo role of neutrophils in chronic HF (8 w post-MI) was determined via depletion studies using genetic (Ly6G-diptheria toxin receptor mice) and antibody (1A8) based approaches. In both models, 2 and 4 w of neutrophil depletion, respectively, significantly improved LV systolic function and reduced end systolic volume. 1A8 treated HF mice also exhibited reduced remote zone fibrosis. We conclude: neutrophil expansion and activation are important components of the chronic inflammatory response in HF, and play an obligatory role in the progression of LV remodeling in ischemic cardiomyopathy.

Abstract 15025: Visceral Adiposity and Muscle Composition in Heart Failure With Preserved Ejection Fraction and Association With Exercise Tolerance

Introduction: Visceral adipose tissue (AT) promotes inflammation and adverse metabolic changes that mediate disease progression in heart failure with preserved ejection fraction (HFpEF). Exercise intolerance is a hallmark of HFpEF, but little is known about its relation to the extent and distribution of AT. We characterized regional AT distribution in HFpEF patients and controls and analyzed associations with comorbidities and exercise tolerance. Methods: MRI was performed to quantify epicardial, liver, abdominal and thigh skeletal muscle AT. We assessed NYHA class, 6-minute walk distance (6MWD), and global well-being score (GWBS). Multivariable linear and logistic regression models were used, adjusted for age, sex, and body surface area. Results: We studied 55 HFpEF patients (41 women, mean age 67) and 33 controls (21 women, mean age 57). Epicardial AT (4.6 vs 3.2mm, p = 0.03), thigh intermuscular fat (11.0 vs 5.0cm 2 , p &lt; 0.01) and liver fat fraction (FF) (6.4% vs 4.1%, p = 0.04) were higher in HFpEF patients than controls. Women with HFpEF had higher abdominal (443.9 vs 297.3 cm 2 , p = 0.03) and thigh (228.6 vs 112.3 cm 2 , p &lt; 0.001) subcutaneous AT than men. Higher thigh intermuscular fat was associated with higher blood pressure (β [SE] 14.1 [3.3], p &lt; 0.001) and diabetes (β [SE] 2.6 [1.1], p = 0.02), and liver FF was associated with chronic kidney disease (β [SE] 1.6 [0.6], p = 0.01). Higher thigh intramuscular fat was associated with both higher NYHA class and shorter 6MWD, and higher thigh intermuscular AT FF was associated with higher NYHA class ( Table ). Higher epicardial AT and liver FF were associated with lower GWBS. Conclusions: HFpEF patients have increased epicardial, liver, and skeletal muscle fat compared to controls out of proportion to their body size, and adiposity was associated with worse exercise intolerance in HFpEF. These results provide the basis for further investigation into regional AT distribution in relation to HFpEF symptoms and pathophysiology.

Patients Report Enhanced Control Over Their Heart Failure During Ambulatory Hemodynamic Monitoring

Introduction Heart Failure (HF) undermines daily quality of life even when not severe enough to warrant hospitalization. Ambulatory pulmonary pressure-guided management decreases hospitalizations across all ranges of EF. This management improves HF symptom scores, but it is not known whether it improves health expectations and perceptions of disease control as reported directly by patients. Hypothesis Patients with prior HF hospitalization and NYHA class III symptoms will report improved health expectations and an increased sense of control over their HF disease progression. Methods Patient-reported outcomes were explored in a substudy of 286 class III CHF patients during the post-approval study for the implanted pulmonary artery pressure sensor. Patients completed validated measures of key appraisals of their cardiac disease and health expectations (e.g. 8-item Brief Illness Perception Questionnaire (BIPQ)) and the 24-item Cardiac Health Security Survey (CHSS) at baseline, 6 months and 12-month timepoints. All patients continued to receive optimal guideline directed medical therapy during ambulatory hemodynamic monitoring with a target PAD pressure of 8-20 mmHg. Results In this substudy, age was 69 ± 11 years and 62% were male, 53% with preserved ejection fraction. From the Baseline BIPQ of 46 ± 10.5, illness perception was reduced by 3.3 and 4.4 points at 6 and 12 months, respectively (p Conclusion Patient management guided by ambulatory pulmonary pressure monitoring was associated with improved patient perception of illness spanning sense of control, symptom reduction, and reduced concerns about their illness over time. The lack of change in health expectations likely reflects patient understanding regarding chronicity of HF on recommended therapies. Patients reported high levels of end user satisfaction and benefit with the hemodynamic monitoring system itself. This technology offers sustained benefits to patients beyond reduction of hospitalizations.

Release of mitochondrial DNA is associated with mortality in severe acute heart failure.

Inflammation is regarded as an important trigger for disease progression in heart failure. Particularly in severe acute heart failure, tissue hypoxia may lead to cellular damage and the release of intracellular mitochondrial DNA, which acts as an activator of the immune system due to its resemblance to bacterial DNA. It may therefore serve as a mediator of disease progression. The aim of this study was to determine circulating levels of mitochondrial DNA and its association with mortality in patients with heart failure in different presentations. Plasma levels of circulating mitochondrial DNA were measured in 90 consecutive patients with severe acute heart failure admitted to our medical intensive care unit as well as 109 consecutive chronic heart failure patients. In patients admitted to our medical intensive care unit (median age 64 (49-74) years, median NT-pro-brain natriuretic peptide 4986 (1525-23,842) pg/mL, 30-day survival 64.4%), mitochondrial DNA levels were significantly higher in patients who died within 30 days after intensive care unit admission, and patients with plasma levels of mitochondrial DNA in the highest quartile had a 3.4-fold increased risk (P=0.002) of dying independent of renal function, vasopressor use and NT-pro-brain natriuretic peptide, troponin T, lactate levels or CardShock and acute physiology and chronic health evaluation II score. However, mitochondrial DNA did not provide incremental prognostic accuracy on top of the current gold standard acute physiology and chronic health evaluation II. Patients with severe acute heart failure showed significantly higher mitochondrial DNA levels (P<0.005) as compared to patients with chronic heart failure. In these patients, mitochondrial DNA levels were associated with the New York Heart Association functional class but were not associated with outcome. The release of mitochondrial DNA into the circulation is associated with mortality in patients with severe acute heart failure but not in patients with chronic heart failure. The release of mitochondrial DNA may therefore play a role within the pathophysiology of acute heart failure, which warrants further research. However, the use of mitochondrial DNA as a biomarker for risk stratification in these patients is of limited utility.

Heart to breathe: partial ablation of rostral ventrolateral medulla catecholaminergic neurons mediates disordered breathing in volume overload heart failure rats

Heart to breathe: partial ablation of rostral ventrolateral medulla catecholaminergic neurons mediates disordered breathing in volume overload heart failure rats

TGF-β induces a heart failure phenotype via fibroblasts exosome signaling

PurposeThe mechanisms for persistent and progressive loss of myocardial function in advanced heart failure (HF) remain incompletely characterized. In the current study, we sought to determine the impact of TGF-β on fibroblasts transcriptional profiles and assess if exosomes from TGF-β treated fibroblasts could induce a heart failure phenotype in co-cultured cardiomyocytes. MethodNormal heart fibroblasts were treated with TGF-β with a final conc. of 2.5 ng/ml in serum free media. HF fibroblasts were also obtained from patients undergoing implantation of left ventricular assist devices. Exosomes were collected using three-step ultracentrifugation. Cardiomyocytes were co-cultured with exosomes from TGF-β-treated, HF and control fibroblasts. RNA was extracted from the fibroblasts, exosomes, and the cardiomyocytes for a targeted panel of genes using Ion AmpliSeq. Fibroblast function was evaluated by collagen gel contraction. ResultsFibroblasts treated with TGF-β differentially express 21 of the 140 genes in our targeted panel. These fibroblasts exhibit enhanced collagen gel contraction similar to HF fibroblasts. Fifty of these targeted genes were also differentially expressed in fibroblast exosomes. Pathway analysis of these transcriptional changes suggest hypertrophic signaling to cardiac muscle. Cardiomyocytes, co-cultured with exosomes from TGF- β treated fibroblasts or heart failure patients, differentially expressed 40 genes compared to controls. Cardiomyocytes co-cultured with exosomes of TGF-β treated fibroblasts induced a molecular phenotype similar to cardiomyocytes co-cultured with exosomes from HF fibroblasts. These changes involve contractile proteins, adrenergic receptors, calcium signaling, metabolism and cell renewal. ConclusionTGF-β induces broad transcriptional changes in fibroblasts as well as their exosomes. These exosomes induce a heart failure phenotype in cardiomyocytes. Exosome signaling from fibroblasts likely contributes to disease progression in heart failure.

P789TLR-4 expression predicts mortality in patients with acute heart failure

Abstract Background Inflammation is regarded as an important trigger for disease progression in heart failure (HF) and activation of the inflammatory system was implicated in the pathophysiology of acute heart failure (AHF). Toll-like receptors (TLRs) play an important role in acute inflammatory processes in critically ill patients by binding to pathogen associated molecular patterns (PAMP) and danger associated molecular patterns (DAMP). However, it is not known whether the expression patterns of TLRs on neutrophils and monocytes are associated with outcome in patients with severe AHF requiring intensive care unit (ICU) admission. The aim of this prospective, observational study was to analyze whether TLR-expression on monocytes or neutrophils is associated with 30-day survival in patients with severe AHF. Methods We included 84 patients with severe AHF admitted to a cardiac ICU. Blood was taken at admission and mean fluorescence activity (MFI) of TLR-2, TLR-4 and TLR-9 on monocytes and neutrophils was analyzed by flow cytometry. Results Median age was 64 (IQR 48–74) years and 76.2% of patients were male. Median NT-proBNP was 4941 (IQR 1298–12273) pg/mL and 30-day mortality was 33.3%. TLR-4 expression on monocytes in survivors (740 IQR 694–854) was significantly lower than in non-survivors (871 IQR 723–979; p&lt;0.05). TLR-2 and TLR-9 expression on monocytes and TLR expression on neutrophils was not associated with survival. TLR-4 expression on monocytes was significantly associated with survival independent of age, sex, creatinine and NT-proBNP levels. Conclusion Monocyte TLR-4 expression predicts mortality in patients admitted to a cardiac ICU for severe acute heart failure. This suggests that activation of the innate immune system by TLR-binding of DAMPS may play a significant role in critically ill acute heart failure patients.

Soluble CD74 Reroutes MIF/CXCR4/AKT-Mediated Survival of Cardiac Myofibroblasts to Necroptosis.

BackgroundAlthough macrophage migration inhibitory factor (MIF) has been demonstrated to mediate cardioprotection in ischemia/reperfusion injury and antagonize fibrotic effects through its receptor, CD74, the function of the soluble CD74 receptor ectodomain (sCD74) and its interaction with circulating MIF have not been explored in cardiac disease.Methods and ResultsCardiac fibroblasts were isolated from hearts of neonatal mice and differentiated into myofibroblasts. Co‐treatment with recombinant MIF and sCD74 induced cell death (P<0.001), which was mediated by receptor‐interacting serine/threonine‐protein kinase (RIP)1/RIP3‐dependent necroptosis (P=0.0376). This effect was specific for cardiac fibroblasts and did not affect cardiomyocytes. Gene expression analyses using microarray and RT‐qPCR technology revealed a 4‐fold upregulation of several interferon‐induced genes upon co‐treatment of myofibroblasts with sCD74 and MIF (Ifi44: P=0.011; Irg1: P=0.022; Clec4e: P=0.011). Furthermore, Western blot analysis confirmed the role of sCD74 as a modulator of MIF signaling by diminishing MIF‐mediated protein kinase B (AKT) activation (P=0.0197) and triggering p38 activation (P=0.0641). We obtained evidence that sCD74 inhibits MIF‐mediated survival pathway through the C‐X‐C chemokine receptor 4/AKT axis, enabling the induction of CD74‐dependent necroptotic processes in cardiac myofibroblasts. Preliminary clinical data revealed a lowered sCD74/MIF ratio in heart failure patients (17.47±10.09 versus 1.413±0.6244).ConclusionsThese findings suggest that treatment of cardiac myofibroblasts with sCD74 and MIF induces necroptosis, offering new insights into the mechanism of myofibroblast depletion during scar maturation. Preliminary clinical data provided first evidence about a clinical relevance of the sCD74/MIF axis in heart failure, suggesting that these proteins may be a promising target to modulate cardiac remodeling and disease progression in heart failure.

Diabetes mellitus and heart failure: insights from a toxic relationship

Diabetes mellitus and heart failure: insights from a toxic relationship