Effect of controlled reduction of body iron stores on clinical outcomes in peripheral arterial disease

doi:10.1016/j.ahj.2011.08.013

American Heart Journal

Volume 162, Issue 5, November 2011, Pages 949-957.e1

https://doi.org/10.1016/j.ahj.2011.08.013 Get rights and content

Background

Published results from a controlled clinical trial in patients with peripheral arterial disease found improved outcomes with iron (ferritin) reduction among middle-aged subjects but not the entire cohort. The mechanism of the age-specific effect was explored.

Methods

Randomization to iron reduction (phlebotomy, n = 636) or control (n = 641) stratified by prognostic variables permitted analysis of effects of age and ferritin on primary (all-cause mortality) and secondary (death, nonfatal myocardial infarction, and stroke) outcomes.

Results

Iron reduction improved outcomes in youngest age quartile patients (primary outcome hazard ratio [HR] 0.44, 95% CI 0.21-0.92, P = .028; secondary outcome HR 0.34, 95% CI 0.19-0.61, P < .001). Mean follow-up ferritin levels (MFFL) declined with increasing entry age in controls. Older age (P = .035) and higher ferritin (P < .001) at entry predicted poorer compliance with phlebotomy and rising MFFL in iron-reduction patients. Intervention produced greater ferritin reduction in younger patients. Improved outcomes with lower MFFL were found in iron-reduction patients (primary outcome HR 1.11, 95% CI 1.01-1.23, P = .028; secondary outcome HR 1.10, 95% CI 1.0-1.20, P = .044) and the entire cohort (primary outcome HR 1.11, 95% CI 1.01-1.23, P = .037). Improved outcomes occurred with MFFL below versus above the median of the entire cohort means (primary outcome HR 1.48, 95% CI 1.14-1.92, P = .003; secondary outcome HR 1.22, 95% CI 0.99-1.50, P = .067).

Conclusions

Lower iron burden predicted improved outcomes overall and was enhanced by phlebotomy. Controlling iron burden may improve survival and prevent or delay nonfatal myocardial infarction and stroke.

Section snippets

Methods

The Consort Diagram⁶ and methodological details of study protocols, informed consent, randomization and intervention, outcome ascertainment including statistical procedures and sample size calculation, and administration of this study have been reported.5, 6, 7 Institutional review boards at each participating hospital and a national institutional review board approved the protocol. Consenting patients >21 years old with stable PAD were computer randomized by age, ferritin level, high-density

Results

Of the 1,277 patients entered, 636 were randomized to iron reduction, and 641, to control. The 2 groups were comparable at entry for clinical and laboratory parameters (Table I).⁶ The average entry age, 67 ± 9 (mean ± SD) years, was identical between groups and remained constant over the 3.5 years of accrual to this study. Details on entry and follow-up ferritin levels, number of phlebotomy episodes and volumes of blood removed initially and at 6-monthly intervals, factors effecting compliance

Discussion

In the FeAST study, preplanned analyses by randomization variables including entry age and ferritin level showed significantly improved outcomes in middle-aged subjects randomized to iron reduction but not in the overall cohort.⁶ Analyses reported here demonstrate an interaction between age and both entry and MFFL that might have masked benefits of iron reduction on primary and secondary outcomes. Significantly improved outcomes were found in age quartile 1 patients (age 43-61 years) randomized

Conclusions

We postulate that iron reduction may ameliorate established vascular disease6, 11^,30, 31, 32, 33, 34, 35 and that disease prevention may be achieved by controlling presymptomatic iron burden.⁹ Low-risk ferritin levels appear to be uncommon in most free-living populations as that which exist in northern Europe⁹ and the United States,² presumably because of iron overdosing from consumption of iron-containing vitamins and minerals and processed foods adulterated with iron.9, 10, 36 Qualitative

Disclosures

This material is based on work supported by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development Cooperative Studies Program; Study no. 410.

Conflict of interest: none declared.

Acknowledgements

The authors wish to express their deep and sincere appreciation to members of the VA Cooperative Study no. 410 investigator group for their extraordinary commitment and accomplishments.

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Erythrocyte-rich thrombi related to serum iron contribute to single stent retrieval and favorable clinical outcomes in acute ischemic stroke by endovascular treatment
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Citation Excerpt :
A significant difference was observed in laboratory tests results between both groups, such as the level of serum iron (10.2 μmol/L vs 5.0 μmol/L, p < 0.001), but serum calcium (2.3 μmol/L vs 2.2 μmol/L, p = 0.564), PT (10.9 s vs 11.0 s, p = 0.590), PTA (93.00% vs 93.50%, p = 0.905), PTR (1.0 vs 1.0, p = 0.886), INR (1.0 vs 1.0, p = 0.828), APTT (30.6 s vs 32.2 s, p = 0.455), FIB (2.9 g/L vs 2.9 g/L, p = 0.379), TT (13.5 s vs 14.2 s, p = 0.114) and D-dimer (275.0 ng/L vs 175.5 ng/L, p = 0.706) showed no significant difference. However, sex difference and blood collection time directly influenced serum iron level in congruence with previous reports [11,12]. Therefore, in this study, we respectively divided all patients into two subgroups based on gender and blood collection time.
Erythrocyte-rich thrombi seem to be associated with favorable clinical outcomes of patients with AIS by endovascular treatment (EVT), as observed from previous studies. However, only few studies show whether erythrocyte-rich thrombi can be associated with favorable clinical outcomes by EVT and which factor can be related to erythrocyte-rich thrombi. This retrospective study aimed to evaluate the relationship between erythrocyte-rich thrombi and favorable clinical outcomes and further explored factors associated with erythrocyte-rich thrombi.
This study was carried out retrospectively from March 2016 to April 2019 on patients who suffered acute ischemic stroke and were treated by EVT at this stroke center. The laboratory test and clinical data were assessed for the relationship between erythrocyte-rich thrombi and favorable clinical outcomes and factors associated with erythrocyte-rich thrombi. All thrombi were divided into erythrocyte-rich thrombi group and fibrin-rich thrombi group based on the proportion of area of the predominant composition which was more than 50% in retrieved thrombi.
This retrospective study enrolled 84 patients, including 32 patients in the erythrocyte-rich thrombi group and 52 patients in the fibrin-rich thrombi group. It showed single stent retrieval (p = 0.017, adjusted OR: 4.061, 95% CI: 1.281–12.872) and favorable clinical outcomes (p < 0.001, adjusted OR: 14.648, 95% CI: 4.637–46.270) were both significantly associated with erythrocyte-rich thrombi. A significant difference in the factor associated with erythrocyte-rich thrombi was serum iron, which correlated positively with erythrocyte fraction in thrombi (p < 0.001, r: 0.452).
Erythrocyte-rich thrombi could contribute to single stent retrieval and favorable clinical outcomes by EVT, and serum iron might be the factor associated with erythrocyte-rich thrombi.
Pathophysiological significance of protein hydrophobic interactions: An emerging hypothesis
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Also, chronic inflammation has been associated with the excessive production of oxygen free radicals [38]. Another factor that has been suggested to contribute to carcinogenesis, known through its role in the hydroxyl radical production, is the iron overload [39–41]. Whatever be the mechanism, the most important fact is that the insoluble fibrin(ogen) deposits persist in the cancer tissue due to their resistance to the fibrinolytic degradation [42].
Fibrinogen is a unique protein that is converted into an insoluble fibrin in a single enzymatic event, which is a characteristic feature of fibrinogen due to its susceptibility to fibrinolytic degradation and dissolution. Although thrombosis is a result of activated blood coagulation, no explanation is being offered for the persistent presence of fibrin deposits in the affected organs. A classic example is stroke, in which the thrombolytic therapy is effective only during the first 3–4 h after the onset of thrombosis. This phenomenon can now be explained in terms of the modification of fibrinogen structure induced by hydroxyl radicals generated during the period of ischemia caused, in turn, by the blocking of the blood flow within the obstructed vessels. Fibrinogen modification involves intra-to intermolecular disulfide rearrangement induced by the reductive power of hydroxyl radicals that result in the exposition of buried hydrophobic epitopes. Such epitopes react readily with each other forming linkages stronger than the peptide covalent bonds, thus rendering them resistant to the proteolytic degradation. Also, limited reduction of human serum albumin (HSA) generates hydrophobic polymers that form huge insoluble complexes with fibrinogen. Consequently, such insoluble copolymers can be deposited within the circulation of various organs leading to their dysfunction. In conclusion, the study of protein hydrophobic interactions induced by a variety of nutritional and/or environmental factors can provide a rational explanation for a number of pathologic conditions including cardiovascular, neurologic, and other degenerative diseases including cancer.
Dysmetabolic iron overload syndrome
2016, Bulletin de l'Academie Nationale de Medecine
Une hyperferritinémie modérée est fréquente au cours du syndrome métabolique. Lorsqu’elle excède 500 μg/l, elle témoigne en règle d’un réel excès de fer décrit sous le terme d’hépatosidérose dysmétabolique (HSD), laquelle touche essentiellement l’homme d’âge mur. Le diagnostic d’HSD passe par la démonstration de l’excès hépatique de fer par la biopsie ou l’IRM. L’excès de fer n’est pas uniquement hépatique mais concerne également la rate et le tissu viscéral adipeux. Le fer adipeux semble jouer un rôle important dans le maintien et l’aggravation de l’insulino-résistance mais la preuve n’est pas faite de l’efficacité à court terme des saignées sur les paramètres du métabolisme du glucose et de l’insuline. Une prise en charge hygiéno-diététique vigoureuse et prolongée demeure, à ce jour, la seule mesure indiscutable dans l’HSD.
Mild hyperferritinemia is frequent in patients with metabolic syndrome. When exceeding 500 μg/l, it usually accounts for real iron excess and is coined as dysmetabolic iron overload syndrome (DIOS). The diagnosis of DIOS is mainly made in middle-aged males. It relies upon the demonstration of hepatic iron overload by liver biopsy or MRI. Iron excess is located not only within the liver but also within the spleen and visceral adipous tissue. Adipocytic iron is involved in maintaining or worsening insulin resistance. However, there is no definite proof of a short-term effect of iron removal by phlebotomy on glucose and insulin metabolism. Sustained modification of lifestyle and diet currently remains the only indisputable therapy in DIOS.
Une hyperferritinémie est fréquente chez les sujets présentant tout ou partie des éléments du syndrome métabolique (SMet) et des complications cardiovasculaires et hépatiques qui y sont liées. Cette « hyperferritinémie métabolique » est caractérisée par
- —
  son caractère modéré : elle est en règle comprise entre 500 et 1000 μg/l,
- —
  sa corrélation avec le degré d’insulino-résistance sous-jacent que celui-ci soit évalué par la méthode du clamp euglycémique hyperinsulinique [1], le nombre d’éléments du SMet [2] ou la diminution des taux sériques de l’adiponectine [3], [4],
- —
  sa signification pronostique : elle prédit l’installation d’un diabète [5].
L’hyperferritinémie métabolique pose des questions diagnostiques, physiopathologiques et thérapeutiques, surtout lorsqu’elle témoigne d’une réelle augmentation du stock en fer de l’organisme, prenant alors le nom d’hépatosidérose dysmétabolique (HSD) ou Dysmetabolic Iron Overload Syndrome [6], [7].
The Mediterranean Diet and Body Iron Stores
2015, The Mediterranean Diet: An Evidence-Based Approach
Adherence to a traditional Mediterranean diet has been shown to be associated with significantly lower risk of major degenerative diseases. Evidence suggests that the cumulative action of its multiple dietary components may be substantial. Lower body iron stores, induced by components of the Mediterranean diet, may be involved in its beneficial effects. Although iron is an essential nutrient, in excess it is a pro-oxidant that leads to degenerative diseases. Humans have no mechanism for excreting excess iron. Elevated iron stores can be prevented by diet or treated by phlebotomy or chelation; iron depletion has been shown to stabilize atherosclerotic plaque and decrease cancer mortality. The Mediterranean diet might be considered a low-iron available diet, that is, a diet containing a low amount of iron and one in which iron absorption inhibitors (polyphenols, phytates, and dairy products) prevail over enhancers (ascorbic acid and red meat). Over time, this dietary pattern leads to reduced iron stores.
Serum ferritin is a biomarker for liver mortality in the hemochromatosis and iron overload screening study
2015, Annals of Hepatology
Background. We identified no reports of long-term follow-up of participants in hemochromatosis screening programs. We evaluated causes of death and survival in non-C282Y homozygous Canadian participants in the primary care-based hemochromatosis and iron overload screening (HEIRS) study.
Material and methods. Initial screening (IS) included transferrin saturation (TS), serum ferritin (SF), HFE genotyping (C282Y, H63D), and health questionnaire responses. By definition, participants without C282Y or H63D had HFE wt/wt. We linked 20,306 Canadian participants to the Ontario Death Registry for dates and causes of death 9 y after IS. We computed Cox proportional hazards to identify factors with increased death risks and Kaplan-Meier curves to estimate survival of non-C282Y homozygous participants with SF ≤ 1,000 µg/L and > 1,000 µg/dL.
Results. There were 19,052 evaluable participants (IS mean age 49 y; 60% women; 93 C282Y homozygotes). There were 988 deaths. Significantly increased hazard ratios for all-cause mortality were positively associated with TS, SF, men, and C282Y homozygosity, and liver disease, diabetes, and heart failure reports. Non-C282Y homozygous participants with SF > 1,000 µg/L had lower survival than those with SF ≤ 1,000 µg/L (p < 0.0001).
Conclusions. Nine years after initial screening, non-C282Y homozygous participants and SF > 1,000 µg/L was associated with decreased survival.
Iron, oxidative stress, and the mediterranean diet
2014, American Journal of Medicine

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Clinical InvestigationPeripheral Vascular DiseaseEffect of controlled reduction of body iron stores on clinical outcomes in peripheral arterial disease

Background

Methods

Results

Conclusions

Section snippets

Methods

Results

Discussion

Conclusions

Disclosures

Acknowledgements

Lancet

Am Heart J

Ageing Res Rev

Am Heart J

Am Heart J

Am J Clin Nutr

Metabolism

J Am Coll Cardiol

J Nutr

J Nutr Biochem

Obstet Gynecol

J Am Coll Cardiol Intv

Nutr Metab Cardiovasc Dis

Arch Med Res

Am J Clin Nutr

Prospects for the prevention of free radical disease, regarding cancer and cardiovascular disease

Br Med Bull

Reduction of iron stores and cardiovascular outcomes in patients with peripheral arterial disease

JAMA

Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial

J Natl Cancer Inst

Oxidative stress, and iron and antioxidant status in elderly men: differences between the Mediterranean south (Crete) and northern Europe (Zutphen)

Eur J Cardiovasc Prev Rehabil

Clinical Investigation
Peripheral Vascular Disease
Effect of controlled reduction of body iron stores on clinical outcomes in peripheral arterial disease