Guidelines on heart failure (HF) define iron deficiency (ID) as a serum ferritin <100 ng/mL or, when 100-299 ng/mL, a transferrin saturation (TSAT) <20%. Inflammation (common in HF) may hinder ...interpretation of serum ferritin.
This study sought to investigate how different definitions of ID affect its prevalence and relationship to prognosis in ambulatory patients with chronic HF.
Prevalence, relationship with patients' characteristics, and outcomes of various ID definitions were evaluated among patients with HF referred to a regional clinic (Hull LifeLab) from 2001 to 2019.
Of 4,422 patients with HF (median age 75 years range: 68-82 years, 60% men, 32% with reduced left ventricular ejection fraction), 46% had TSAT <20%, 48% had serum iron ≤13 μmol/L, 57% had serum ferritin <100 ng/mL, and 68% fulfilled current guideline criteria for ID, of whom 35% had a TSAT >20%. Irrespective of definition, ID was more common in women and those with more severe symptoms, anemia, or preserved ejection fraction. TSAT <20% and serum iron ≤13 μmol/L, but not guideline criteria, were associated with higher 5-year mortality (HR: 1.27; 95% CI: 1.14-1.43; P < 0.001; and HR: 1.37; 95% CI: 1.22-1.54; P < 0.001, respectively). Serum ferritin <100 ng/mL tended to be associated with lower mortality (HR: 0.91; 95% CI: 0.81-1.01; P = 0.09).
Different definitions of ID provide discordant results for prevalence and prognosis. Definitions lacking specificity may attenuate the benefits of intravenous iron observed in trials while definitions lacking sensitivity may exclude patients who should receive intravenous iron. Prespecified subgroup analyses of ongoing randomized trials should address this issue.
Filamentous inclusions made of hyperphosphorylated tau are characteristic of numerous human neurodegenerative diseases, including Alzheimer’s disease, tangle-only dementia, Pick disease, argyrophilic ...grain disease (AGD), progressive supranuclear palsy, and corticobasal degeneration. In Alzheimer’s disease and AGD, it has been shown that filamentous tau appears to spread in a stereotypic manner as the disease progresses. We previously demonstrated that the injection of brain extracts from human mutant P301S tau-expressing transgenic mice into the brains of mice transgenic for wild-type human tau (line ALZ17) resulted in the assembly of wild-type human tau into filaments and the spreading of tau inclusions from the injection sites to anatomically connected brain regions. Here we injected brain extracts from humans who had died with various tauopathies into the hippocampus and cerebral cortex of ALZ17 mice. Argyrophilic tau inclusions formed in all cases and following the injection of the corresponding brain extracts, we recapitulated the hallmark lesions of AGD, PSP and CBD. Similar inclusions also formed after intracerebral injection of brain homogenates from human tauopathies into nontransgenic mice. Moreover, the induced formation of tau aggregates could be propagated between mouse brains. These findings suggest that once tau aggregates have formed in discrete brain areas, they become self-propagating and spread in a prion-like manner.
Women who develop gestational hypertension have evidence of elevated muscle sympathetic nerve activity (MSNA) in early pregnancy, which continues to rise after diagnosis. Exercise has been shown to ...play a preventative role in the development of gestational hypertension and has been shown to reduce resting and reflex MSNA in nonpregnant populations. We sought to investigate whether aerobic exercise affected the sympathetic regulation of blood pressure between the second and third trimesters of pregnancy.
We conducted a randomized controlled trial of structured aerobic exercise (n = 31) compared with no intervention (control, n = 28) beginning at 16-20 wk and continuing until 34-36 wk of gestation (NCT02948439). Women in the exercise group were prescribed aerobic activity at 50%-70% of their heart rate reserve, on 3-4 d·wk-1 for 25-40 min with a 5-min warm-up and 5-min cool-down (i.e., up to 160 min total activity per week). At preintervention and postintervention assessments, data from ~10 min of quiet rest and a 3-min cold pressor test were analyzed to determine sympathetic nervous system activity and reactivity.
MSNA was obtained in 51% of assessments. Resting MSNA burst frequency and burst incidence increased across gestation (main effect of gestational age, P = 0.002). Neurovascular transduction was blunted in the control group (P = 0.024) but not in exercisers (P = 0.873) at the postintervention time point. Lastly, MSNA reactivity during the cold pressor test was not affected by gestational age or exercise (P = 0.790, interaction).
These data show that exercise attenuates both the rise in MSNA and the blunting of neurovascular transduction. This may partially explain the lower risk of developing gestational hypertension in women who are active during their pregnancies.
In Alzheimer’s disease, neurofibrillary tangle pathology appears to spread along neuronal connections, proposed to be mediated by the release and uptake of abnormal, disease-specific forms of ...microtubule-binding protein tau MAPT. It is currently unclear whether transfer of tau between neurons is a toxic gain-of-function process in dementia or reflects a constitutive biological process. We report two entry mechanisms for monomeric tau to human neurons: a rapid dynamin-dependent phase typical of endocytosis and a second, slower actin-dependent phase of macropinocytosis. Aggregated tau entry is independent of actin polymerization and largely dynamin dependent, consistent with endocytosis and distinct from macropinocytosis, the major route for aggregated tau entry reported for non-neuronal cells. Anti-tau antibodies abrogate monomeric tau entry into neurons, but less efficiently in the case of aggregated tau, where internalized tau carries antibody with it into neurons. These data suggest that tau entry to human neurons is a physiological process and not a disease-specific phenomenon.
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•Extracellular tau protein enters human neurons by endocytosis and micropinocytosis•Aggregated tau enters human neurons primarily by endocytosis•Tau antibodies reduce uptake and are carried into neurons by tau•Findings suggest that tau uptake is dependent on carrier proteins or receptors
In contrast with predictions that transfer of the microtubule-associated protein tau between neurons is a toxic gain-of-function process in dementia, Evans et al. show that healthy human neurons efficiently take up both normal and aggregated tau, by distinct but overlapping uptake mechanisms.
Aims
For patients with heart failure (HF) and iron deficiency (ID), randomized trials suggest that intravenous (IV) iron reduces hospitalizations for heart failure (HHF), but uncertainty exists about ...the effects in subgroups and the impact on mortality. We conducted a meta‐analysis of randomized trials investigating the effect of IV iron on clinical outcomes in patients with HF.
Methods and results
We identified randomized trials published between 1 January 2000 and 5 November 2022 investigating the effect of IV iron versus standard care/placebo in patients with HF and ID in any clinical setting, regardless of HF phenotype. Trials of oral iron or not in English were not included. The main outcomes of interest were a composite of HHF and cardiovascular death (CVD), on HHF alone and on cardiovascular and all‐cause mortality. Ten trials were identified with 3373 participants, of whom 1759 were assigned to IV iron. IV iron reduced the composite of recurrent HHF and CVD (rate ratio 0.75, 95% confidence interval CI 0.61–0.93; p < 0.01) and first HHF or CVD (odds ratio OR 0.72, 95% CI 0.53–0.99; p = 0.04). Effects on cardiovascular (OR 0.86, 95% CI 0.70–1.05; p = 0.14) and all‐cause mortality (OR 0.93, 95% CI 0.78–1.12; p = 0.47) were inconclusive. Results were similar in analyses confined to the first year of follow‐up, which was less disrupted by the COVID‐19 pandemic. Subgroup analyses found little evidence of heterogeneity for the effect on the primary endpoint, although patients with transferrin saturation <20% (OR 0.67, 95% CI 0.49–0.92) may have benefited more than those with values ≥20% (OR 0.99, 95% CI 0.74–1.30) (heterogeneity p = 0.07).
Conclusion
In patients with HF and ID, this meta‐analysis suggests that IV iron reduces the risk of HHF but whether this is associated with a reduction in cardiovascular or all‐cause mortality remains inconclusive.
In a meta‐analysis of ten randomized controlled trials (RCTs) including AFFIRM‐AHF and IRONMAN of over 3000 patients with heart failure (HF) and iron deficiency (ID), compared to standard care/placebo, intravenous (IV) iron reduced the primary outcome of recurrent hospitalisations for heart failure (HHF) and cardiovascular mortality (CVM) by 25%. The effect was mainly driven by a reduction in HHF with the effect on CVM being inconconclusive. Created in BioRender.com. Additional icons provided from
http://icon‐library.com/icon/heart‐disease‐icon‐3.html.html Heart Disease Icon #293840. CI, confidence interval; CVM, cardiovascular mortality; HF, heart failure; HHF, hospitalization for heart failure; I, iron deficiency; IV, intravenous/interval variable; OR, odds ratio; RCT, randomized controlled trial; RR, risk rate; SE, standard error; SoC, standard of care.
Aims
Iron deficiency (ID) and anaemia are common in heart failure; less is known about changes over time.
Methods and results
We investigated prevalence, incidence and resolution of ID and anaemia in ...906 patients with chronic heart failure (median age 73 (65–79) years, 70% men, 51% with heart failure with reduced ejection fraction) 1 year apart. ID was defined as serum iron ≤13 µmol/L and anaemia as haemoglobin <13.0 g/dL for men or <12.0 g/dL for women. FAIR‐HF criteria for ID were also considered. At baseline, 10% had anaemia without ID, 23% had ID without anaemia, 20% had both, and 47% had neither. Percentages changed little over 1 year, but 157 (30%) patients had new‐onset ID, 104 (16%) new‐onset anaemia, whilst ID resolved in 173 (44%) and anaemia in 63 (23%). Compared to those who remained iron replete (iron >13 µmol/L), mortality was higher in those with persistent or incident ID at 1 year hazard ratio (HR) 1.81 (1.23–2.67), and HR 1.40 (0.91–2.14), respectively in multivariable models (P = 0.02). Compared to persistent ID, resolution of ID was associated with a lower mortality HR 0.61 (0.44–0.86); P = 0.004. Changes in ID defined by FAIR‐HF criteria were not similarly associated with mortality. Anaemia was associated with a poor outcome even if it resolved.
Conclusions
The prevalence and incidence of ID and anaemia are high in chronic heart failure but so is the rate of resolution. Persistent or incident ID, defined by a serum iron ≤13 µmol/L, is associated with higher mortality and resolution of ID with lower mortality.
Longitudinal data from 906 patients with chronic heart failure. Over 1 year most patients (70%) have or develop iron deficiency (ID), anaemia or both. Compared to those with either persistent ID or anaemia, only those who recovered from ID (achieving a serum iron >13 µmol/L) had lower all‐cause mortality at 4 years, with transferrin saturation (TSAT) showing a similar trend. CI, confidence interval; HR, hazard ratio.
The prevalence of anaemia and iron deficiency and their prognostic association with cardiovascular disease have rarely been explored at population level.
National Health Service records of the ...Greater Glasgow region for patients aged ≥50 years with a broad range of cardiovascular diagnoses were obtained. During 2013/14, prevalent disease was identified and results of investigations collated. Anaemia was defined as haemoglobin <13 g/dL for men or <12 g/dL for women. Incident heart failure, cancer and death between 2015 and 2018 were identified.
The 2013/14 dataset comprised 197 152 patients, including 14 335 (7%) with heart failure. Most (78%) patients had haemoglobin measured, especially those with heart failure (90%). Of those tested, anaemia was common both in patients without (29%) and with heart failure (prevalent cases in 2013/14: 46%; incident cases during 2013/14: 57%). Ferritin was usually measured only when haemoglobin was markedly depressed; transferrin saturation (TSAT) even less often. Incidence rates for heart failure and cancer during 2015-18 were inversely related to nadir haemoglobin in 2013/14. A haemoglobin of 13-15 g/dL for women and 14-16 g/dL for men was associated with the lowest mortality. Low ferritin was associated with a better prognosis and low TSAT with a worse prognosis.
In patients with a broad range of cardiovascular disorders, haemoglobin is often measured but, unless anaemia is severe, markers of iron deficiency are usually not. Low haemoglobin and TSAT, but not low ferritin, are associated with a worse prognosis. The nadir of risk occurs at haemoglobin 1-3 g/dL above the WHO definition of anaemia.
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