Iron Deficiency in Heart Failure Patients and Benefits of Iron Replacement on Clinical Outcomes Including Comorbid Depression.

BACKGROUND: Iron deficiency and depression are prevalent comorbidities in the setting of heart failure. Both conditions are associated with poorer patient outcomes including mortality, hospitalisation and quality of life. Iron replacement has come to the fore as a means to improve patient outcomes. This review aims to assess the current literature regarding the benefits of iron supplementation for iron deficient heart failure patients including potential improvements in depression. METHODS AND RESULTS: The databases of Medline, EMBASE, the Cochrane library of systematic reviews, Central Register of Controlled Trials, PubMed, Web of Science and ClinicalTrials.gov were searched for studies with relevant patient outcomes. A total of 18 studies were identified and included in the review. In essence, intravenous iron was found to be beneficial for New York Heart Association (NYHA) classification, quality of life measures, heart failure (HF) hospitalisation and aerobic capacity. Oral iron however was not beneficial. Research surrounding intravenous iron improving cardiovascular mortality, time to first hospitalisation and changes in depression status is lacking. CONCLUSIONS: Further research is required to elucidate the advantages of intravenous iron for iron deficient heart failure patients on their depression, mortality and first admission to hospital. Consensus is required regarding which form of iron and the treatment regime that should be adopted for future clinical guidelines.

Insulin-like growth factor-1 directly affects cardiac cellular remodelling via distinct pathways.

BACKGROUND: Studies of insulin-like growth factor 1 (IGF-1) as a novel therapy for the treatment of cardiovascular diseases have proven promising. However, elevated IGF-1 levels have also been associated with poor patient outcomes in heart failure with reduced ejection fraction. IGF-1 therapy has additionally been shown to not be beneficial in the percutaneous coronary intervention setting. Although IGF-1 activation of the PI3K/Akt and ERK1/2 pathways have been demonstrated as cardioprotective, other cellular mechanisms have not been fully investigated. METHODS: Neonatal rat cardiac myocytes (NCMs) and fibroblasts (NCFs) were isolated from 1 to 2-day old pups using enzymatic digestion. NCMs and NCFs were pre-treated with IGF binding protein 6, inhibitors for the PI3K/Akt Wortmannin, ERK1/2 U0126, Rho Associated Protein Kinase (ROCK) GSK576371, Apoptosis Signal-regulating Kinase-1 (ASK-1) G2261818A, and p38MAPK RWJ67657 pathways before stimulation with IGF-1 for 62 and 50 h, respectively. Cardiac myocyte hypertrophy and fibroblast collagen synthesis were determined by 3H-leucine and 3H-proline incorporation, respectively. RESULTS: IGF-1 dose-dependently stimulated NCM hypertrophy and NCF collagen synthesis.Treatment with IGFBP6 and the kinase inhibitors, Wortmannin, U0126, GSK576371, G2261818A and RWJ67657 significantly inhibited IGF-1 stimulated NCM hypertrophy and NCF collagen synthesis. CONCLUSION: This study is the first to demonstrate that IGF-1 treatment in NCMs and NCFs activates the ROCK, ASK-1 and p38MAPK pathways. Future research may be guided by consideration of the PI3K/Akt and ERK1/2 pathways potentially increasing collagen synthesis, and the utilisation of a biased agonist to reduce activation of the ROCK, ASK-1 and p38MAPK pathways to maximise cardioprotective benefit whilst mitigating risks.

AFC1 Compound Attenuated MI/R-Induced Ventricular Remodeling via Inhibiting PDGFR and STAT Pathway.

Background: Effective interventions to improve the outcome of patients subjected to myocardial ischemia reperfusion (MI/R) are urgent in clinical settings. Tanshinone IIA (TSA) is reported to attenuate myocardial injury and improve ventricular remodeling post MI/R. Here, we evaluated the efficacy of AFC1 compound that is similar to TSA structure in murine MI/R models. We found that AFC1 had a comparable effect of improving murine cardiac function after MI/R while it was superior to TSA in safety profile. Administration of AFC1 reduced reactive oxygen species (ROS) production, inflammatory cells infiltration, and the expression of platelet derived growth factor receptors (PDGFR) in infarcted myocardium. Treatment with AFC1 also attenuated MI/R-induced cardiac remodeling and contributed to the recovery of cardiac function. Additionally, AFC1 reversed the elevation of PDGFR expression induced by PDGF-AB in both neonatal rat cardiomyocytes (NCMs) and neonatal rat cardiac fibroblasts (NCFs) and suppressed PDGF-AB induced NCM hypertrophy via STAT3 pathway and NCF collagen synthesis through p38-MAPK signaling in vitro. Similarly, AFC1 may contribute to the recovery of cardiac function in mice post MI/R via suppressing STAT signaling. Our results confirmed that AFC1 exerts anti-hypertrophic and anti-fibrotic effects against MI/R-induced cardiac remodeling, and suggest that AFC1 may have a promising potential in improving the outcome of patients who suffered from MI/R.