Factor In Heart Failure Research Articles

Abstract 004: Novel Serum Metabolites Associate With Diastolic Function: Evidence From the Bogalusa Heart Study

Introduction: Diastolic dysfunction is one key causal factor for heart failure with preserved ejection fraction (HFpEF). We conducted a metabolome-wide association study to identify novel diastolic function-related metabolites in relatively young and healthy adults. Hypothesis: We hypothesized that serum metabolites could predict diastolic function and thus potentially serve as biomarkers for subclinical disease. Methods: The study cohort consisted of 1,038 participants of the Bogalusa Heart Study (34.9% black, 57.3% females, aged 33.6-57.5 years). Diastolic function was assessed via 2D and tissue doppler echocardiography, and included peak early filling velocity (E), peak velocity caused by atrial contraction (A), medial mitral annular velocity (e’), left ventricular isovolumic relaxation time (IVRT), as well as deceleration time (DT). Untargeted metabolomic analysis of fasting serum samples was conducted. Multivariable-adjusted linear regression models were employed to assess the relationship of metabolites with echocardiographic measures of diastolic function. Results: Following quality control, 1202 metabolites were tested for association with E/A ratio, E/e’ ratio, IVRT, and DT. After Bonferroni correction, 9 novel metabolites, derived from amino acid, cofactor, energy, lipid, and nucleotide pathways, were significantly associated with diastolic function in blacks with nominal significance and consistent effect direction in whites (Table). Of these significant metabolites, 2 and 6 metabolites were associated with the E/A ratio and E/e’ ratio, respectively. No significant associations of metabolites with IVRT or DT were found. Fatty acid metabolism was the biological sub-pathway most represented in significant diastolic function-metabolite associations. Conclusion: The current study identified novel metabolites associated with diastolic function, suggesting that the serum metabolome, and its underlying biological pathways, may be implicated in HFpEF pathogenesis.

Abstract P378: A Novel Risk Prediction Score for Incident Heart Failure Among Patients With Diabetes

Introduction: Diabetes is a well-established risk factor for heart failure (HF). However, risk prediction models for incident HF in patients with diabetes are lacking. Accordingly, we aim to develop a novel risk-prediction model for HF in a diabetes cohort using a hybrid machine learning method for variable selection and CoxPH approach for risk prediction. Methods: We used data from the ACCORD trial that included patients with prevalent diabetes at baseline and had adjudicated HF events on follow up. The data was divided in to 80/20% training and testing (n = 6,896/1,725, respectively) and 152 baseline variables were included. A random survival forest (RSF) of 1000 trees was constructed to identify the top 20 predictors. Finally, a 5-year incident HF risk score was developed using the 9 variables selected by backward CoxPH regression. Results: The study included 8,621 participants (Mean age: 63 y, 62% male) without prevalent HF. The RSF model for incident HF with top 20 predictors derived from the training cohort had superior discrimination than the CoxPH model in the testing cohort ( C -index 0.80 vs. 0.78; P < 0.001). The top 9 variables identified included age, waist circumference, BP, serum creatinine, HDL, prior MI, prior CABG, and EKG QTC duration and T-axis. The weighted risk score based on the nine clinical variables was used to create a composite HF risk score ranging from -6 to 36. A 1-unit increment in the risk score was associated with a 27% higher risk of HF at 5 years. A graded increment in the 5-year HF incidence was noted across quintiles of the HF risk score ranging from 1.2% in the lowest to 9.8% in the highest quintile (Figure). The HF risk score demonstrated good discrimination with an overall C -index of 75.2. Conclusions: In conclusion, an RSF model in a clinical diabetes cohort outperformed conventional CoxPH in the identification of important risk factors of incident HF. Additionally, the diabetes-HF prediction model using common clinical variables demonstrated good discrimination and risk stratification in the overall cohort.

ATRIAL FIBRILLATION THERAPY AND HEART FAILURE HOSPITALIZATION IN ADULTS WITH TETRALOGY OF FALLOT

Atrial fibrillation is a known risk factor for heart failure (HF) hospitalization and mortality in patients with acquired heart disease. Although atrial arrhythmias are common in adults with tetralogy of Fallot (TOF), data about prevalence and outcomes of therapy for atrial fibrillation are very

Usefulness of systolic blood pressure combined with heart rate measured on admission to identify 1-year all-cause mortality risk in elderly patients firstly hospitalized due to acute heart failure.

Systolic blood pressure (SBP) and heart rate (HR) are well-known prognostic factors in heart failure (HF). Our objective was to assess the value of the combination of admission SBP and HR to estimate 1-year mortality risks in elderly patients admitted due to a first episode of acute HF (AHF). During a 36-month period, we retrospectively reviewed 901 consecutive patients aged ≥ 75 admitted because of a first episode of AHF. According to admission SBP-HR combinations, three groups were defined: "low-risk" (HR < 70bpm and SBP ≥ 140mmHg), "moderate-risk" (HR < 70bpm and SBP < 140mmHg or HR ≥ 70bmp and SBP ≥ 120mmHg), and "high-risk" (HR ≥ 70bpm and SBP < 120mmHg). We analyzed all-cause mortality using Cox mortality analysis. One-year mortality ranged from 16.5% for patients in the low-risk group to 50% for those in the high-risk group (p < 0.0001). Multivariate Cox regression for 1-year mortality showed hazard risk (HzR) ratios, compared to that (HzR 1) of the low-risk reference group, of 1.759 (95% CI 1.035-2.988, p = 0.037) for moderate-risk, and 3.171 (95% CI 1.799-5.589, p = 0.0001) for high-risk group. Prior use of a high number of chronic therapies (HzR 1.045), lower admission diastolic BP (HzR 0.986) and higher admission serum potassium values (HzR 1.534) were also significantly associated with mortality. In elderly population firstly hospitalized due to AHF, the simple combined admission measurement of SBP and HR predicts higher risk for 1-year all-cause mortality.

Cardiotrophin as a prognostic factor in heart failure.

Cardiotrophin as a prognostic factor in heart failure.

Improvement of Left Ventricular Ejection Fraction and Pulmonary Hypertension Are Significant Prognostic Factors in Heart Failure with Reduced Ejection Fraction Patients.

BACKGROUNDWe evaluated long-term prognosis according to improvement of pulmonary hypertension (PH) and left ventricular ejection fraction (LVEF) in patients with heart failure with reduced ejection fraction (HFrEF) and PH.METHODSWe included all consecutive patients with HFrEF and PH who had a baseline and follow-up echocardiographic examinations from September 2011 to March 2017. PH was defined as maximal velocity of tricuspid regurgitation (TR Vmax) over 3.0 m/s, and LVEF improvement was defined as LVEF change ≥ 15% from the baseline echocardiography. Primary outcome was 5-year major adverse cardio-cerebrovascular events (MACCE).RESULTSWe analyzed 271 patients. Mean LVEF was 28±8% and TR Vmax was 3.4±0.4 m/s. On follow-up, 183 (68%) showed improvement of LVEF, and 165 (61%) demonstrated improvement of PH. We classified patients into 4 groups according to improvement of PH and LVEF; group 1 (both improvement, 134 patients), group 2 (PH improvement only, 31 patients), group 3 (LVEF improvement only, 49 patients) and group 4 (no improvement, 57 patients). Group 4 had older age, higher incidence of myocardial infarction and aggravation of pre-existing HF. During the follow-up (31±20 months), 27% died and 40.8% experienced MACCE. Group 4 had the worst survival (HR=4.332, 95% CI=2.396-7.833, p<0.001), and group 3 had increased MACCE rate (HR=2.030, 95% CI=1.060-3.888, p=0.033) compared with group 1. Group 2 had similar long-term clinical events (HR=1.085, 95% CI=0.458-2.571, p=0.853) to group 1.CONCLUSIONSIn patients with HFrEF and PH, persistence of PH and no LVEF improvement was associated with the worst long-term outcome.

A12770 Analysis of risk factors of heart failure in patients with acute coronary syndrome

A12770 Analysis of risk factors of heart failure in patients with acute coronary syndrome

Simplified plasma essential amino acid-based profiling provides metabolic information and prognostic value additive to traditional risk factors in heart failure.

In heart failure (HF), metabolic disturbances represent functional perturbations in peripheral tissues and also predict patient outcomes. This study developed a simplified essential amino acid-based profile and tested whether it could improve prognostication. Plasma essential amino acids and lipidomics were measured on 1084 participants. The initial cohort included 94 normal controls and 599 patients hospitalized due to acute/decompensated HF. The validation cohort included 391 HF patients. Patients were followed for composite events (death/HF related re-hospitalization) and were categorized into three groups: high risk type 1 (leucine ≥145μM and phenylalanine ≥ 88.9μM), high risk type 2 (leucine < 81.2μM), and low risk (other). Types 1 and 2 were associated with higher event rates [hazard ratio (95% confidence intervals) = 1.88 (1.27-2.79) and 7.71 (4.97-11.9), respectively, p < 0.001]. Compared to the low-risk group, both types of high-risk patients were older and had lower blood pressure and estimated glomerular filtration rates, but higher B-type natriuretic peptides (BNP). In addition, type 1 was associated with more incompletely metabolized lipids in the blood; type 2 patients had lower body mass indexes, rates of using guideline-based medications, and levels of cholesterol, hemoglobin, and albumin. The prognostic value of types 1 and 2 remained significant after adjusting for age, BNP and other risk factors. The value of using high-risk types for prognosis was confirmed in the validation cohort. In conclusion, simplified essential amino acid-based profiling identified two high-risk populations and provided metabolic information and prognostic value additive to traditional risk factors.

Copeptin as a prognostic biomarker in acute myocardial infarction

BackgroundCopeptin - the C-terminal section of vasopressin precursor - is a novel biomarker, that has been shown to be a useful prognostic factor in heart failure, ischemic stroke and in acute myocardial infarction (MI) but with restricted population and follow-up in ST-segment elevation MI (STEMI) setting. We evaluated in this study the hypothesis that copeptin measured on admission is an independent predictor of one-year all-cause mortality after a STEMI. MethodsCopeptin was measured immediately on arrival in the catheterization laboratory in a cohort of unselected STEMI patients and was compared to the peak of cardiac troponin I as a prognosis marker. One-year follow-up was performed. ResultsWe included 401 STEMI patients (77% of men, mean age 64 ± 14 years) treated by primary percutaneous coronary intervention. Copeptin on admission was significantly higher in patients who died during the one-year follow-up than in survivors (154.8 pmol/L; IQR [63.9–304.8] vs 30.3 pmol/L; IQR [10.8–93.5]); p < 0.0001). There was an increase in mortality at one year from the lowest to the highest quartile of copeptin. After Cox regression analysis, copeptin was an independent predictor of death at one year (adjHR 3.1, 95% CI [1.5–6.2], p = 0.001). When compared to the peak value of cardiac troponin I, copeptin measured on admission had a better prognostic value to predict one-year mortality (AUC of 0.74 vs 0.60, p = 0.022). ConclusionCopeptin measured on admission is a reliable and independent prognostic biomarker of one-year mortality in acute myocardial infarction patients.

Excess risk of hospitalisation for heart failure among people with type 2 diabetes

Aims/hypothesisType 2 diabetes is an established risk factor for heart failure, but age-specific data are sparse. We aimed to determine excess risk of heart failure, based on age, glycaemic control and kidney function in comparison with age- and sex-matched control individuals from the general population.MethodsIndividuals with type 2 diabetes registered in the Swedish National Diabetes Registry 1998–2012 (n = 266,305) were compared with age-, sex- and county-matched control individuals without diabetes (n = 1,323,504), and followed over a median of 5.6 years until 31 December 2013.ResultsWe identified 266,305 individuals with type 2 diabetes (mean age 62.0 years, 45.3% women) and 1,323,504 control individuals. Of the individuals with type 2 diabetes and control individuals, 18,715 (7.0%) and 50,157 (3.8%) were hospitalised with a diagnosis of heart failure, respectively. Comparing individuals with diabetes with those in the control group, men and women with type 2 diabetes who were younger than 55 years of age had HRs for hospitalisation for heart failure of 2.07 (95% CI 1.73, 2.48) and 4.59 (95% CI 3.50, 6.02), respectively, using analyses adjusted for socioeconomic variables and associated conditions. Younger age, poorer glycaemic control and deteriorating renal function were all associated with increased excess risk of heart failure in those with type 2 diabetes compared with the control group. However, people with diabetes who were ≥75 years and without albuminuria or with good glycaemic control (HbA1c ≤52 mmol/mol [≤6.9%]) had a similar risk of hospitalisation for heart failure as control individuals in the same age group.Conclusions/interpretationMen and women aged <55 years with type 2 diabetes are at markedly elevated excess risk of heart failure. The excess risk declined with age, but persisted even with good glycaemic control. However, among those who were 75 years and older, diabetic individuals with well controlled glucose levels or without albuminuria had a risk of heart failure that was on a par with individuals without diabetes.

Abstract 585: CDK8 Activity-dependent Regulation of Heart Disease

Pathological cardiac hypertrophy represents a major risk factor for heart failure (HF). The hypertrophic response is orchestrated in part through transcriptional alterations that ultimately modify cardiac function. Mediator is a multiprotein complex that coordinates signal dependent transcription factors with basal transcriptional machinery including RNA polymerase II and general transcription factors. Transcriptional regulation by Mediator complex can be modified by the association of the Mediator complex kinase submodule with the core complex. Cyclin-dependent kinase 8 (CDK8) is a kinase present in the submodule that has been demonstrated to have a complex role in transcriptional regulation through a number of mechanisms involving both transcriptional activation and inhibition. Our lab has demonstrated that CDK8 expression is upregulated in murine HF models as well as in failing human hearts. In addition, cardiac CDK8 over-expression promotes transcriptional remodeling that results in dilated cardiomyopathy suggesting that CDK8 inhibition may represent a novel pharmacological target. This study utilizes CDK8 kinase inhibitor, Senexin A, which is being evaluated as an anti-cancer chemotherapeutic agent. Here, we demonstrate that Senexin A inhibits kinase activity in an in vitro neonatal rat cardiomyocyte (NRCM) model resulting in reduced cardiomyocyte hypertrophy as well as a reduction in expression of specific cardiomyocyte hypertrophy markers. These studies demonstrate a role for CDK8 activity in transcriptional regulation of genes associated with pathological cardiac remodeling that drives cardiac hypertrophy and ultimately HF.

Exercise intolerance among survivors of childhood cancer exposed to cardiotoxic therapy: Identification of survivors at increased risk through myocardial strain and ejection fraction.

10565Background: Exercise intolerance is an established risk factor for heart failure and death in the general population. Exercise capacity and factors associated with intolerance have not been ex...

Abstract P162: The Association Between Hypertension and Incident Heart Failure by Race and Gender

Background: Hypertension is a major risk factor for heart failure (HF), but associations of hypertension with HF may vary by race and gender. Objective: To assess race and gender differences in the association between hypertension and incident HF hospitalization in the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Methods: REGARDS participants without suspected baseline HF (n = 25,759) were followed from study entry in 2003-2007 through 2014 with adjudication of incident HF hospitalizations (n = 855). Hypertension was defined as systolic or diastolic blood pressure ≥ 140/90 mmHg or self-reported antihypertensive medication use. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CIs) for the association between hypertension and HF hospitalization in subgroups separately by race or gender, with each subgroup model adjusted for race, gender, age, income, region of residence, health insurance, body mass index, smoking, history of coronary heart disease, diabetes, reduced estimated glomerular filtration rate, total cholesterol, statin use, physical activity, perceived stress, and depressive symptoms. Results: The mean age of the population was 64.5 years, 40.0% were black and 55.0% were female. The prevalence of hypertension was 57.1% and more common among blacks (69.3%) compared to whites (48.9%) but similar among males (56.5%) and females (57.6%). Over a median follow-up of 8.4 years, incidence rates for HF hospitalization were 4.19, 4.46, 5.14 and 4.29 per 1,000 person-years for whites, blacks, males and females, respectively. After multivariable adjustment, the association between hypertension and HF was stronger among blacks versus whites (HR 2.28 vs HR 1.50, p-interaction=0.04) and similar among males and females (HR 1.61 vs HR 1.83, p-interaction=0.19). ( Figure ) Conclusion: Hypertension may be a stronger risk factor for incident HF among blacks versus whites. This finding may be due to disparities in hypertension severity, control, or duration.

Toll-like receptor expression and apoptosis morphological patterns in female rat hearts with takotsubo syndrome induced by isoprenaline

AimsToll-like receptors (TLR) and apoptosis were indicated as important factors in heart failure. Our aim was to characterize the morphological pattern of apoptosis, TLR2, TLR4, and TLR6 expression in female rat hearts in the model of takotsubo syndrome (TTS). Main methods60 Sprague-Dawley female rats were treated with a single dose of 150 mg/kg b.wt. of isoprenaline (ISO) or 0.9% NaCl (controls). Hearts were collected 24, 48, 72 h and 7 days post-ISO injection. 32/60 hearts were used in immunohistopathological studies and 28/60 in real time. Key findingsApoptosis was observed 24 h post-ISO in cardiomyocytes, 24, 48, 72 h and 7 days post-ISO in infiltrating inflammatory cells, 7 days post-ISO in endothelial cells of vessels. Diffuse TLR4CD68 (CD68, a macrophage marker) and TLR6CD68 positive cells and TLR2, TLR4, TLR6 mononuclear cells were observed in both acute and recovery phase of TTS. In the foci located in the neighborhood of damaged (necrotic/apoptotic) cardiomyocytes in TTS, high (strong) protein expression of TLR2 (TLR2high) was observed: 24, 48, 72 h post-ISO; TLR4high – 48 and 72 h post-ISO; TLR6high – 48 h post-ISO. Whereas in cardiomyocytes of remote myocardium: TLR2high – 72 h post-ISO; TLR4high – 24 and 72 h post-ISO; TLR6high – 24 h post-ISO. TLR2 mRNA was down-regulated 48 and 72 h post-ISO whereas TLR4 up-regulated 7 days post-ISO. SignificanceThe expression pattern of apoptosis and TLR differs in the course of TTS in comparison with the control rats. We hypothesize that innate immunity and apoptosis may play a crucial role in TTS pathophysiology.

Heart Failure Prediction Models using Big Data Techniques

Big Data technologies have a great potential in transforming healthcare, as they have revolutionized other industries. In addition to reducing the cost, they could save millions of lives and improve patient outcomes. Heart Failure (HF) is the leading death cause disease, both nationally and internally. The Social and individual burden of this disease can be reduced by its early detection. However, the signs and symptoms of HF in the early stages are not clear, so it is relatively difficult to prevent or predict it. The main objective of this research is to propose a model to predict patients with HF using a multi-structure dataset integrated from various resources. The underpinning of our proposed model relies on studying the current analytical techniques that support heart failure prediction, and then build an integrated model based on Big Data technologies using WEKA analytics tool. To achieve this, we extracted different important factors of heart failure from King Saud Medical City (KSUMC) system, Saudi Arabia, which are available in structured, semi-structured and unstructured format. Unfortunately, a lot of information is buried in unstructured data format. We applied some pre-processing techniques to enhance the parameters and integrate different data sources in Hadoop Distributed File System (HDFS) using distributed-WEKA-spark package. Then, we applied data-mining algorithms to discover patterns in the dataset to predict heart risks and causes. Finally, the analyzed report is stored and distributed to get the insight needed from the prediction. Our proposed model achieved an accuracy and Area under the Curve (AUC) of 93.75% and 94.3%, respectively.

Whole exome analyses to examine the impact of rare variants on left ventricular traits in African American participants from the HyperGEN and GENOA studies.

Left ventricular (LV) hypertrophy, highest in prevalence among African Americans, is an established risk factor heart failure. Several genome wide association studies have identified common variants associated with LV-related quantitative-traits in African Americans. To date, however, the effect of rare variants on these traits has not been extensively studied, especially in minority groups. We therefore investigated the association between rare variants and LV traits among 1,934 African Americans using exome chip data from the Hypertension Genetic Epidemiology Network (HyperGEN) study, with replication in 1,090 African American from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. We used single-variant analyses and gene-based tests to investigate the association between 86,927 variants and six structural and functional LV traits including LV mass, LV internal dimension-diastole, relative wall thickness, left atrial dimension (LAD), fractional shortening (FS), and the ratio of LV early-to-late transmitral velocity (E/A ratio). Only rare variants (MAF <1% and <5%) were considered in gene-based analyses. In gene-based analyses, we found a statistically significant association between potassium voltage-gated channel subfamily H member 4 (KCNH4) and E/A ratio (P=8.7*10-8 using a burden test). Endonuclease G (ENDOG) was associated with LAD using the Madsen Browning weighted burden (MB) test (P=1.4*10-7). Neither gene result was replicated in GENOA, but the direction of effect of single variants in common was comparable. G protein-coupled receptor 55 (GPR55) was marginally associated with LAD in HyperGEN (P=3.2*10-5 using the MB test) and E/A ratio in GENOA, but with opposing directions of association for variants in common (P=0.03 for the MB test). No single variant was statistically significantly associated with any trait after correcting for multiple testing. The findings in this study highlight the potential cumulative contributions of rare variants to LV traits which, if validated, could improve our understanding of heart failure in African Americans.

GW28-e1056 The Valosin-Containing Protein Attenuates Chronic Pressure Overload-induced Cardiac Remodeling and Heart Failure via Activating mTORC2 Pathway

The pressure overload induced cardiac hypertrophy is a key risk factor for heart failure. However, the mechanism involved remains largely unknown. We previously showed that overexpression of valosin-containing protein (VCP) promotes cardiomyocytes survival in vitro . Here we tested the hypothesis

Contribution of central and peripheral factors at peak exercise in heart failure patients with progressive severity of exercise limitation

BackgroundA reduced cardiac output (CO) response during exercise is a major limiting factor in heart failure (HF). Oxygen consumption (VO2) is directly proportional to CO. Peripheral mechanisms via arteriovenous oxygen difference (Δ(a-v)O2) play a pivotal role in chronic HF. We hypothesized a weak correlation between peak VO2 and peak CO with a greater Δ(a-v)O2 variability in most severe HF. MethodsWe analyzed 278 HF patients (NYHA II–III) who performed maximal cardiopulmonary exercise test with non-invasive CO measurement by inert gas rebreathing. ResultsMedian peakVO2, CO and Δ(a-v)O2 were 0.96 (0.78–1.28) L/min, 6.3 (5.1–8.0) L/min and 16.0 (14.2–18.0) mL/100mL respectively, with a linear relationship between VO2 and CO: CO=5.3×VO2+1.13 (r2=0.705, p<0.001). Patients were grouped according to exercise limitation. Group 1 (101 patients) peakVO2<50% pred: peakVO2 0.80 (0.67–0.94) L/min, peakCO 5.6 (4.7–6.5) L/min, peakΔ(a-v)O2 14.8 (12.9–17.1) mL/100mL. Group 2 (89 patients) peakVO2≥50–<65% pred: peakVO2 1.02 (0.84–1.29) L/min, peakCO 6.4 (5.1–8.0) L/min, peakΔ(a-v)O2 16.7 (15.0–18.5) mL/100mL. Group 3 (88 patients) peakVO2≥65% pred: peakVO2 1.28 (0.93–1.66) L/min, peakCO 8.0 (6.2–9.7) L/min, peakΔ(a-v)O2 16.8 (14.6–18.3) mL/100mL. A peakVO2 and peakCO linear relationship was observed in Group 1 (r2=0.381, p<0.001), Group 2 (r2=0.756, p<0.001) and Group 3 (r2=0.744, p<0.001). ConclusionsWith worsening HF we observed a progressive reduction of peak CO and peak VO2. However in most compromised patients also peripheral mechanisms play a role as indicated by reduced Δ(a-v)O2.

P6223Restless legs syndrome is an independent risk factor for heart failure with preserved ejection fraction

P6223Restless legs syndrome is an independent risk factor for heart failure with preserved ejection fraction

P3451Iron deficiency as risk factor for heart failure and myocardial dysfunction in a male general population sample during 21-years follow-up

P3451Iron deficiency as risk factor for heart failure and myocardial dysfunction in a male general population sample during 21-years follow-up