Diagnosis and Treatment of Iron Deficiency in Heart Failure: OFICSel study by the French Heart Failure Working Group.

AIMS: Iron deficiency (ID) occurs in about 50% of patients with heart failure (HF). The European Society of Cardiology (ESC) recommends ID diagnostic testing in newly diagnosed patients with HF and during follow-up, with intravenous iron supplementation (IS) only recommended in patients with HF with reduced ejection fraction (HFrEF). This study aimed to assess prevalence, clinical characteristics, and application of ESC guidelines for ID and IS in patients with HF in the real-life clinical setting. METHODS AND RESULTS: The French transversal multicentre OFICSel registry (300 cardiologists) conducted in 2017 included patients hospitalized for HF at least once in the previous 5 years. Diverse adult patients were eligible including inpatients and outpatients and those with acute and chronic HF. Data were collected from cardiologists and patients using study-specific surveys. Data included demographic and clinical data, as well as HF and ID management data. Overall, 2822 patients, mainly male (69.3%) with a median age of 69 years (interquartile range 58-78), were included. A total of 1075 patients (38.1%) were tested for ID, with 364 (33.9%) diagnosed. Of these, 168 (46.2%) received IS: 128 (76.2%) intravenous IS and 40 (23.8%) oral. Among the 201 patients with HFrEF diagnosed with ID, 99 (49.3%) received IS: 79 (79.8%) intravenous IS and 20 (20.2%) oral. CONCLUSIONS: In clinical practice, only one-third of patients with HF had a diagnostic test for ID. In patients with ID with HFrEF, only 39.3% received intravenous IS as recommended. Thus, in general, cardiologists should be encouraged to follow the ESC guidelines to ensure optimal treatment for patients with HF.

sST2 adds to the prognostic value of Gal-3 and BNP in chronic heart failure.

Background: The soluble form of the IL-33 receptor (sST2) and Galectin-3 (Gal-3) are fibrosis biomarkers with prognostic value in heart failure (HF). We investigated the prognostic capacity of sST2 when combined with Gal-3, and determined if the prognostic utility of sST2 is affected by mineralocorticoid receptor antagonist (MRA) therapy.Methods: sST-2 and Gal-3 were measured in 101 stable chronic HF (CHF) patients receiving MRA therapy and compared to 97 BNP and cardiovascular risk factor matched patients not treated with MRA. sST2 and Gal-3 levels were measured to determine the relationship with all-cause mortality at 6-year follow-up.Results: ROC curve cut-off points were defined as sST2 = 36.3 ng/mL, Gal-3 = 17.8 ng/mL, and BNP = 500 pg/mL, and had 6-year mortality hazard ratios (HR) of 7.3, 6.6 and 5.4, respectively. The combination of an elevated sST2 and Gal-3 had a HR = 4.4 [95% CI 1.9-8.9]. Combining sST2 and Gal-3 to a clinical model relevant for CHF prognosis allowed a significant reclassification of 1-year adverse outcome risk, even when BNP was included. Finally, prognostic prediction by sST2 was unaffected by MRA treatment.Conclusion: Simultaneous sST2 and Gal-3 elevation is associated with poorer prognosis compared to either alone, regardless of BNP levels, and the prognostic capacity of sST2 is independent of MRA therapy.

Insulin-like Growth Factor Binding Protein 2 predicts mortality risk in heart failure.

BACKGROUND: Insulin-like Growth Factor Binding Protein 2 (IGFBP2) showed greater heart failure (HF) diagnostic accuracy than the "grey zone" B-type natriuretic peptides, and may have prognostic utility as well. OBJECTIVES: To determine if IGFBP2 provides independent information on cardiovascular mortality in HF. METHODS: A retrospective study of 870 HF patients from 3 independent international cohorts. Presentation IGFBP2 plasma levels were measured by ELISA, and patients were followed from 1 year (Maastricht, Netherlands) to 6 years (Atlanta, GA, USA and Toulouse, France). Multivariate analysis, Net Reclassification Improvement (NRI) and Integrated Discrimination Improvement (IDI) were performed in the 3 cohorts. The primary outcome was cardiovascular mortality. RESULTS: In multivariate Cox proportional hazards analysis, the highest quartile of IGFBP2 was associated with mortality in the Maastricht cohort (adjusted hazard ratio 1.69 (95% CI, 1.18-2.41), p = 0.004) and in the combined Atlanta and Toulouse cohorts (adjusted hazard ratio 2.04 (95%CI, 1.3-3.3), p = 0.003). Adding IGFBP2 to a clinical model allowed a reclassification of adverse outcome risk in the Maastricht cohort (NRI = 18.7% p = 0.03; IDI = 3.9% p = 0.02) and with the Atlanta/Toulouse patients (NRI of 40.4% p = 0.01, 31,2% p = 0.04, 31.5% p = 0,02 and IDI of 2,9% p = 0,0005, 3.1% p = 0,0005 and 4,2%, p = 0.0005, for a follow-up of 1, 2 and 3 years, respectively). CONCLUSION: In 3 international cohorts, IGFBP2 level is a strong prognostic factor for cardiovascular mortality in HF, adding information to natriuretic monitoring and usual clinical markers, that should be further prospectively evaluated for patients' optimized care.

Increased mean aliphatic lipid chain length in left ventricular hypertrophy secondary to arterial hypertension: A cross-sectional study.

About 77.9 million (1 in 4) American adults have high blood pressure. High blood pressure is the primary cause of left ventricular hypertrophy (LVH), which represents a strong predictor of future heart failure and cardiovascular mortality. Previous studies have shown an altered metabolic profile in hypertensive patients with LVH. The goal of this study was to identify blood metabolomic LVH biomarkers by H NMR to provide novel diagnostic tools for rapid LVH detection in populations of hypertensive individuals. This cross-sectional study included 48 hypertensive patients with LVH matched with 48 hypertensive patients with normal LV size, and 24 healthy controls. Two-dimensional targeted M-mode echocardiography was performed to measure left ventricular mass index. Partial least squares discriminant analysis was used for the multivariate analysis of the H NMR spectral data. From the H NMR-based metabolomic profiling, signals coming from methylene (-CH2-) and methyl (-CH3) moieties of aliphatic chains from plasma lipids were identified as discriminant variables. The -CH2-/-CH3 ratio, an indicator of the mean length of the aliphatic lipid chains, was significantly higher (P < 0.001) in the LVH group than in the hypertensive group without LVH and controls. Receiver operating characteristic curve showed that a cutoff of 2.34 provided a 52.08% sensitivity and 85.42% specificity for discriminating LVH (AUC = 0.703, P-value < 0.001). We propose the -CH2-/-CH3 ratio from plasma aliphatic lipid chains as a biomarker for the diagnosis of left ventricular remodeling in hypertension.

The prognostic value of plasma galectin-3 in chronic heart failure patients is maintained when treated with mineralocorticoid receptor antagonists.

OBJECTIVE: Galectin-3 (Gal-3) is considered as a myocardial fibrosis biomarker with prognostic value in heart failure (HF). Since aldosterone is a neurohormone with established fibrotic properties, we aimed to investigate if mineralocorticoid receptor antagonists (MRAs) would modulate the prognostic value of Gal-3. METHODS: The IBLOMAVED cohort comprised 427 eligible chronic HF patients (CHF) with echocardiography and heart failure biomarkers assessments (BNP). After propensity score matching CHF patients for cardiovascular risk factors, to form balanced groups, Gal-3 levels were measured at baseline in plasma from patients treated with MRAs (MRA-Plus, n=101) or not (MRA-Neg, n=101). The primary end point was all-cause mortality with a follow-up of 3 years. RESULTS: Gal-3 in plasma from these patients were similar with median values of 14.0 ng/mL [IQR, 9.9-19.3] and 14.4 ng/mL [IQR, 12.3-19.8] (P = 0.132) in MRA-Neg and MRA-Plus, respectively. Patients with Gal-3 ≤17.8 ng/mL had an HR of 1 (reference group) and 1.5 [0.4-5.7] in MRA-Neg and MRA-Plus, respectively (p=0.509). Patients with Gal-3 ≥ 17.8 ng/mL had an HR of 7.4 [2.2-24.6] and 9.0 [2.9-27.8] in MRA-Plus and MRA-Neg, respectively (p=0.539) and a median survival time of 2.4 years [95%CI,1.8-2.4]. Multivariate Cox proportional hazard analysis confirmed that MRA and the interaction term between MRA treatment and Gal-3 >17.8 ng/mL were not factors associated with survival. CONCLUSIONS: MRA treatment did not impair the prognostic value of Gal-3 assessed with a 17.8 ng/mL cut off. Gal-3 levels maintained its strong prognostic value in CHF also in patients treated with MRAs. The significance of the observed lack of an interaction between Gal-3 and treatment effect of MRAs remains to be elucidated.

Benefits of cardiac rehabilitation in heart failure patients according to etiology: INCARD French study.

We investigated the impact of heart failure (HF) etiology on the outcome of cardiac rehabilitation (CR) assessed by functional and clinical parameters. Treatment of chronic HF requires multidisciplinary approaches with a recognized role for CR. INCARD is a French study aimed at evaluating the benefits of sustainable CR in coronary (C) and noncoronary patients (NC) treated and educated during a 24-month period of follow-up. Prospective, monocentric patients with HF underwent inpatient physical training followed by a home-based program. Evaluations were performed at inclusion, discharge, 3 months after discharge, and subsequently every 6 months over the 24 months of outpatient rehabilitation.A total of 147 HF patients with left ventricular ejection fraction (LVEF) <40 were admitted to the CR center, 63 accepted to join INCARD (29 C and 34 NC). Although the C participants C having both an echocardiographic LVEF and an initially lower peak VO2, inpatient rehabilitation improved all functional parameters. Only NC showed an improved LVEF during the first 3 months of outpatient-follow-up. The main outcome of the outpatient rehabilitation was a trend toward stabilization of clinical and laboratory parameters with no significant difference between C and NC. This study confirms the benefits of initial HF inpatient rehabilitation and encourages prolonged outpatient monitoring. The results on functional parameters suggest exercise training should be conducted regardless of the HF etiology.

Apolipoprotein O is mitochondrial and promotes lipotoxicity in heart.

Diabetic cardiomyopathy is a secondary complication of diabetes with an unclear etiology. Based on a functional genomic evaluation of obesity-associated cardiac gene expression, we previously identified and cloned the gene encoding apolipoprotein O (APOO), which is overexpressed in hearts from diabetic patients. Here, we generated APOO-Tg mice, transgenic mouse lines that expresses physiological levels of human APOO in heart tissue. APOO-Tg mice fed a high-fat diet exhibited depressed ventricular function with reduced fractional shortening and ejection fraction, and myocardial sections from APOO-Tg mice revealed mitochondrial degenerative changes. In vivo fluorescent labeling and subcellular fractionation revealed that APOO localizes with mitochondria. Furthermore, APOO enhanced mitochondrial uncoupling and respiration, both of which were reduced by deletion of the N-terminus and by targeted knockdown of APOO. Consequently, fatty acid metabolism and ROS production were enhanced, leading to increased AMPK phosphorylation and Ppara and Pgc1a expression. Finally, we demonstrated that the APOO-induced cascade of events generates a mitochondrial metabolic sink whereby accumulation of lipotoxic byproducts leads to lipoapoptosis, loss of cardiac cells, and cardiomyopathy, mimicking the diabetic heart-associated metabolic phenotypes. Our data suggest that APOO represents a link between impaired mitochondrial function and cardiomyopathy onset, and targeting APOO-dependent metabolic remodeling has potential as a strategy to adjust heart metabolism and protect the myocardium from impaired contractility.

Blood signature of pre-heart failure: a microarrays study.

BACKGROUND: The preclinical stage of systolic heart failure (HF), known as asymptomatic left ventricular dysfunction (ALVD), is diagnosed only by echocardiography, frequent in the general population and leads to a high risk of developing severe HF. Large scale screening for ALVD is a difficult task and represents a major unmet clinical challenge that requires the determination of ALVD biomarkers. METHODOLOGY/PRINCIPAL FINDINGS: 294 individuals were screened by echocardiography. We identified 9 ALVD cases out of 128 subjects with cardiovascular risk factors. White blood cell gene expression profiling was performed using pangenomic microarrays. Data were analyzed using principal component analysis (PCA) and Significant Analysis of Microarrays (SAM). To build an ALVD classifier model, we used the nearest centroid classification method (NCCM) with the ClaNC software package. Classification performance was determined using the leave-one-out cross-validation method. Blood transcriptome analysis provided a specific molecular signature for ALVD which defined a model based on 7 genes capable of discriminating ALVD cases. Analysis of an ALVD patients validation group demonstrated that these genes are accurate diagnostic predictors for ALVD with 87% accuracy and 100% precision. Furthermore, Receiver Operating Characteristic curves of expression levels confirmed that 6 out of 7 genes discriminate for left ventricular dysfunction classification. CONCLUSIONS/SIGNIFICANCE: These targets could serve to enhance the ability to efficiently detect ALVD by general care practitioners to facilitate preemptive initiation of medical treatment preventing the development of HF.