Prognostic value of three iron deficiency definitions in patients with advanced heart failure.

AIMS: There is uncertainty about the definition of iron deficiency (ID) and the association between ID and prognosis in patients with advanced heart failure. We evaluated three definitions of ID in patients referred for heart transplantation. METHODS AND RESULTS: Consecutive patients assessed for heart transplantation at a single UK centre between January 2010 and May 2022 were included. ID was defined as (1) serum ferritin concentration of <100 ng/ml, or 100-299 ng/ml with transferrin saturation <20% (guideline definition), (2) serum iron concentration ≤13 µmol/L, or (3) transferrin saturation <20%. The primary outcome measure was a composite of all-cause mortality, urgent heart transplantation or need for mechanical circulatory support. Overall, 801 patients were included, and the prevalence of ID was 39-55% depending on the definition used. ID, defined by either serum iron or transferrin saturation, was an independent predictor of the primary outcome measure (hazard ratio [HR] 1.532, 95% confidence interval [CI] 1.264-1.944, and HR 1.595, 95% CI 1.323-2.033, respectively), but the same association was not seen with the guideline definition of ID (HR 1.085, 95% CI 0.8827-1.333). These findings were robust in multivariable Cox regression analysis. ID, by all definitions, was associated with lower 6-min walk distance, lower peak oxygen consumption, higher intra-cardiac filling pressures and lower cardiac output. CONCLUSIONS: Iron deficiency, when defined by serum iron concentration or transferrin saturation, was associated with increased frequency of adverse clinical outcomes in patients with advanced heart failure. The same association was not seen with guideline definition of ID.

Effects of Intravenous Iron Replacement Therapy on Cardiovascular Outcomes in Patients with Heart Failure: A Systematic Review and Meta-Analysis.

(1) Background: Iron deficiency (ID) is an important adverse prognostic marker in patients with heart failure (HF); however, it is unclear whether intravenous iron replacement reduces cardiovascular mortality in this patient group. Here, we estimate the effect of intravenous iron replacement therapy on hard clinical outcomes following the publication of IRONMAN, the largest trial in this field. (2) Methods: In this systematic review and meta-analysis, prospectively registered with PROSPERO and reported according to PRISMA guidelines, we searched PubMed and Embase for randomized controlled trials investigating intravenous iron replacement in patients with HF and co-existing ID. The primary outcome was cardiovascular mortality and secondary outcomes were all-cause mortality, hospitalizations for HF and a combination of the primary outcome and hospitalizations for HF. (3) Results: A total of 1671 items were identified and after removal of duplicates we screened titles and abstracts of 1202 records. Some 31 studies were identified for full-text review and 12 studies were included in the final review. The odds ratio (OR) for cardiovascular death using a random effects model was 0.85 (95% CI 0.69 to 1.04) and for all-cause mortality it was 0.83 (95% CI 0.59 to 1.15). There was a significant reduction in hospitalizations for HF (OR 0.49, 95% CI 0.35 to 0.69) and the combination of hospitalizations for HF and cardiovascular death (OR 0.65, 95% CI 0.5 to 0.85). (4) Conclusions: This review supports the use of IV iron replacement reducing hospitalization rates for HF, however more research is required to determine the effect on cardiovascular mortality and to identify the patient population most likely to benefit.

Shared decision making in cardiology: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the effectiveness of interventions to improve shared decision making (SDM) in cardiology with particular focus on patient-centred outcomes such as decisional conflict. METHODS: We searched Embase (OVID), the Cochrane library, PubMed and Web of Science electronic databases from inception to January 2021 for randomised controlled trials that investigated the effects of interventions to increase SDM in cardiology. The primary outcomes were decisional conflict, decisional anxiety, decisional satisfaction or decisional regret; a secondary outcome was knowledge gained by the patients. RESULTS: Eighteen studies which reported on at least one outcome measure were identified, including a total of 4419 patients. Interventions to increase SDM had a significant effect on reducing decisional conflict (standardised mean difference (SMD) -0.211, 95% CI -0.316 to -0.107) and increasing patient knowledge (SMD 0.476, 95% CI 0.351 to 0.600) compared with standard care. CONCLUSIONS: Interventions to increase SDM are effective in reducing decisional conflict and increasing patient knowledge in the field of cardiology. Such interventions are helpful in supporting patient-centred healthcare and should be implemented in wider cardiology practice.

Iron deficiency for prognosis in acute coronary syndrome - A systematic review and meta-analysis.

BACKGROUND: Iron deficiency (ID) is an important predictor of adverse outcomes in patients with heart failure, however it is unclear whether ID also affects prognosis in patients with acute coronary syndrome (ACS). The aim of this systematic review and meta-analysis was to assess the prognostic value of iron deficiency in patients with ACS. METHODS: We searched PubMed, Web of Science, and the Cochrane library and included cohort studies of patients with ACS that were stratified by ID status. There were no restrictions on definition of ACS or ID. Studies were systematically appraised and data extracted by two independent reviewers. Meta-analysis was performed where two or more studies reported on the same pre-determined outcome measure. RESULTS: Seven studies with 2821 participants were identified, reporting a high prevalence of ID in the ACS population. Three studies reported worse long-term outcomes in the ID population, whereas short-term outcomes were heterogeneous across studies. CONCLUSIONS: Patients with ID presenting with ACS may have a worse long-term prognosis but more studies are required for confirmation. A role for ID in prognosis of patients with ACS and as a potentially treatable condition may have implication for the current management of this patient population.

Hypohydration impairs endurance performance: a blinded study.

The general scientific consensus is that starting exercise with hypohydration >2% body mass impairs endurance performance/capacity, but most previous studies might be confounded by a lack of subject blinding. This study examined the effect of hypohydration in a single blind manner using combined oral and intragastric rehydration to manipulate hydration status. After familiarization, seven active males (mean ± SD: age 25 ± 2 years, height 1.79 ± 0.07, body mass 78.6 ± 6.2, VO2peak 48 ± 7 mL·kg·min-1) completed two randomized trials at 34°C. Trials involved an intermittent exercise preload (8 × 15 min exercise/5 min rest), followed by a 15-min all-out performance test on a cycle ergometer. During the preload, water was ingested orally every 10 min (0.2 mL·kg body mass-1). Additional water was infused into the stomach via a gastric feeding tube to replace sweat loss (EU) or induce hypohydration of ~2.5% body mass (HYP). Blood samples were drawn and thirst sensation rated before, during, and after exercise. Body mass loss during the preload was greater (2.4 ± 0.2% vs. 0.1 ± 0.1%; P < 0.001), while work completed during the performance test was lower (152 ± 24 kJ vs. 165 ± 22 kJ; P < 0.05) during HYP At the end of the preload, heart rate, RPE, serum osmolality, and thirst were greater and plasma volume lower during HYP (P < 0.05). These results provide novel data demonstrating that exercise performance in the heat is impaired by hypohydration, even when subjects are blinded to the intervention.

Nucleotide Pool Depletion Induces G-Quadruplex-Dependent Perturbation of Gene Expression.

Nucleotide pool imbalance has been proposed to drive genetic instability in cancer. Here, we show that slowing replication forks by depleting nucleotide pools with hydroxyurea (HU) can also give rise to both transient and permanent epigenetic instability of a reporter locus, BU-1, in DT40 cells. HU induces stochastic formation of Bu-1(low) variants in dividing cells, which have lost the H3K4me3 present in untreated cells. This instability is potentiated by an intragenic G quadruplex, which also promotes local H2Ax phosphorylation and transient heterochromatinization. Genome-wide, gene expression changes induced by HU significantly overlap with those resulting from loss of the G4-helicases FANCJ, WRN, and BLM. Thus, the effects of global replication stress induced by nucleotide pool depletion can be focused by local replication impediments caused by G quadruplex formation to induce epigenetic instability and changes in gene expression, a mechanism that may contribute to selectable transcriptional changes in cancer.

Determinants of G quadruplex-induced epigenetic instability in REV1-deficient cells.

REV1-deficient chicken DT40 cells are compromised in replicating G quadruplex (G4)-forming DNA. This results in localised, stochastic loss of parental chromatin marks and changes in gene expression. We previously proposed that this epigenetic instability arises from G4-induced replication fork stalls disrupting the accurate propagation of chromatin structure through replication. Here, we test this model by showing that a single G4 motif is responsible for the epigenetic instability of the BU-1 locus in REV1-deficient cells, despite its location 3.5 kb from the transcription start site (TSS). The effect of the G4 is dependent on it residing on the leading strand template, but is independent of its in vitro thermal stability. Moving the motif to more than 4 kb from the TSS stabilises expression of the gene. However, loss of histone modifications (H3K4me3 and H3K9/14ac) around the transcription start site correlates with the position of the G4 motif, expression being lost only when the promoter is affected. This supports the idea that processive replication is required to maintain the histone modification pattern and full transcription of this model locus.

The role of the chemokines MCP-1, GRO-alpha, IL-8 and their receptors in the adhesion of monocytic cells to human atherosclerotic plaques.

Monocyte adhesion to the arterial endothelium and subsequent migration into the intima are central events in the pathogenesis of atherosclerosis. Previous experimental models have shown that chemokines can enhance monocyte-endothelial adhesion by activating monocyte integrins. Our study assesses the role of chemokines IL-8, MCP-1 and GRO-alpha, together with their monocyte receptors CCR2 and CXCR2 in monocyte adhesion to human atherosclerotic plaques. In an adhesion assay, a suspension of monocytic U937 cells was incubated with human atherosclerotic artery sections and the levels of endothelial adhesion were quantified. Adhesion performed in the presence of a monoclonal antibody to a chemokine, chemokine receptor or of an isotype matched control immunoglobulin, shows that antibodies to all chemokines tested, as well as their receptors, inhibit adhesion compared to the control immunoglobulins. Immunohistochemistry demonstrated the expression of MCP-1, GRO-alpha and their receptors in the endothelial cells and intima of all atherosclerotic lesions. These results suggest that all these chemokines and their receptors can play a role in the adhesion of monocytes to human atherosclerotic plaques. Furthermore, they suggest that these chemokine interactions provide potential targets for the therapy of atherosclerosis.