Can Iron Play a Crucial Role in Maintaining Cardiovascular Health in the 21st Century?
Abstract
:1. Introduction
2. Material and Methods
3. Iron Metabolism in the Finer Details
4. Definition and Importance of Iron Deficiency
5. Iron Deficiency and Heart Failure—Litmus Papers of Inequality
6. Iron and the Heart
6.1. Iron in Heart Metabolism
6.2. Anemia in Heart Failure
6.3. Observational Studies of Iron Deficiency in Heart Failure
6.4. Interventional Studies of Iron Deficiency in Heart Failure
6.5. Iron and Treatment of Heart Failure
7. Iron and Muscle Performance
8. Iron and Obesity
9. Iron and Diabetes
10. Iron and COVID-19
11. Iron and Enviromental Pollution
12. Iron and Stress
13. Iron and Psychiatric Disorders
14. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Study Name/Author | Iagnosis | Number of Patients | Mean Age | Ferritin, Tsat and Hb | Exclusions Criteria | Nyha | Lvef | Nt-Probnp | Dosage of Iron | Duration | Effect on Hematologic Parameters | Results/Primary and Secondary End Points | Safety |
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Bolger et al. [85] | HFrEF | 16 | 68.3 ± 11.5 | Hb < 12 g/dL; ferritin <30 ng/mL; transerrin saturation <16% | Vitamin B1, Folic acid deficiency; hemoglobinopathy; ferritin > 400 ng/mL | NYHA II–III | <26 ± 13% | Not included | Iron sucrose 200 mg on days 1, 3 and 5. If ferritin < 400 ng/mL on day 12–200 mg doses on days 15 and 17 | 12 weeks | Hb 11.2 --> 12.6 g/dL; ferritin 87 --> 217 ng/mL; TSAT 16 --> 24.6% | Increased 6MW MLHF from 33 --> 19; | Well tolerated |
Toblli et al. [86] | HFrEF | 40 | A—intervetion group: 74 ± 8; B—control group: 76 ± 7 | Hb < 12,5 g/dL; ferritin < 100 ng/mL; TSAT <20% | Patients with: hemodialysis therapy; NYHA I; allergy to iron; acute bacterial infections; neoplasm; parasitism; chronic digestive disease; hypothyroidism; congenital cardiopathies; receiving iron or rhEPO in the previous 4 weeks; history of hospitalization during previous 4 weeks | NYHA II–IV | <35% | Included | Iron sucrose 200 mg weekly for 5 weeks | 25 weeks | Hb 10.3 --> 11.8 g/dL; ferritin 78.9 --> 240.4 ng/mL; TSAT: 20 --> 25% | In group B: nt-proBNP: 450.9 --> 117.5 pg/mL, CRP: 6.5 --> 2.3 mg/mL; LVEF: 28.8 --> 35.7%; NYHA 3.3 --> 2.0; MLHFQ: 59 --> 41; 6MW test 184.5 m --> 240.1 m | – |
FAIR-HF/Anker et al. [88] | HFrEF | 459 | - | Ferritin < 100 ng/mL; or Ferritin 100–299 ng/mL with TSAT <20%; Hb: 9–13.5 g/dL | Uncontrolled hipertension; Inflammation; impaired liver or renal function | NYHA II–III | <40% in NYHA I; <45% in NYHA III | Not included | 200 mg ferric carboxy- maltose | 53 weeks | The mean difference in the ferritin level between group receiving iron and those receiving placebo was: 246 ± 20 mcg/L at week 24. Hb: 5.9 ± 1.5 g/L; | Patient Global Assessment in the group receiving iron was improved with 50% of patients as compared to 28% in the pla- cebo group. 47% having NYHA I–II in the group receiving iron, as compared with 30% in the placebo group. Improvement in QoL and 6MW test in the gruop receiving iron. | No severe allergic reactions. Injection discoloration in 4 and injection-site pain in 2 patients. |
FERRIC-HF [89] | HFrEF | 35 | - | Ferritin < 100 ng/mL, or ferritin < 100–200 ng/mL with TSAT <20%; Hb < 12 g/dL anemic group | Use of Epo oraz iron; blood transfusion within the previous 30 days; history of hemochromatosis (or first relative with hemochromatosis); hypersensitivity to parental iron; history of allergic disorders; active infection, bleeding, malignancy or hemolytic anemia; decompensated heart failure; muscosceletal disease; unstable angina pectoris; obstructive cardiomyopa- thy; severe uncorrected valvular disease; uncontrolled brady- or tachyarrhytmias; immunosuppressive or renal replacement therapy; chronic liver disease | NYHA II–III | <45% | Not included | Iron sucrose 200 mg weekly until ferritin >500 ng/mL | 16 weeks | Ferritin: 151 --> 396 ng/mL; TSAT 5% --> 17%; sTfR 1.4 --> 1.3 mg/L; Hb 8 g/dL --> 9 g/dL | NYHA: 2.4 ± 0.5 --> 2.1 ± 0.5; MLHFQ score: 41 ± 22 --> 31 ± 25; Fatigue score: 6 ± 1 --> 4 ± 2; LVEF: 30 ± 7 --> 32 ± 10; Absolute pV02: 13.9 ± 2.7 --> 15.4 ± 3.5 mL/kg/min | No episodes of symp- tomatic hypotension oraz anaphylactic reactions |
CONFIRM-HF [90] | HFrEF | 304 | – | Ferritin < 100 ng/mL, or ferritin 100–299 ng/mL with TSAT <20%; Hb <15 g/dL | Uncontrolled hipertension; infection; malignancy; impaired liver or renal function | NYHA II–III | <45% | BNP > 100 pg/mL; NT-proBNP >400 pg/mL | 200 mg ferric carboxy- maltose | 52 weeks | Mean treatment effect on ferritin and TSAT in patients assigned to ferric carboxy- maltose compared to placebo was 265 ± 19 ng/mL and 8.9 ± 1.1% at week 24 and 200 ± 19 ng/mL and 5.7 ± 1.2% at 52 week. Hb: 0.6 ± 0.2 and 1.0 ± 0.2 g/dL, at weeks 24 and 52, respectively. | Increase in 6MWT distance by 18 ± 8 m in ferric carboxymal- tose group. Decrease in 6MWT distance by 16 ± 8 m in placebo group. Significant benefit in PGA and NYHA. Reduction in Fatigue score. Beneficial effect on QoL (overall KCCQ) and EQ-5D health state score. | No severe allergic reactions. Two patients experienced injection site discolouration, four patients repor- ted feeling hot. One patient reported urticaria, rash and erythema. |
EFFECT-HF [91] | HFrEF | 174 | – | Ferritin < 100 ng/mL, or ferritin 100–299 ng/mL with TSAT <20%; Hb <15 g/dL | Known sensivity to ferric carboxymaltose; history of iron overload; received erythropoiesis-stimulating agents, i.v. iron therapy and/or blood transfusions in the 6 weeks before randomization. | NYHA II–III | <45% | BNP >100 pg/mL; NT- -proBNP >400 pg/mL | 500 mg ferric carboxy- maltose 3 times | 24 weeks | Hb: 12.9 ± 1.3 g/dL --> 13.9 ± 1.3 g/dL; ferritin: 48 --> 283 ± 150 ng/mL; TSAT: 17.3% --> 27.8 ± 8% | Increase peak VO2: + 0.25 mL/min/kg for ferric carboxymaltose versus −0.34 mL/kg/min for the usual care patients (difference: 0.45 ± 0.38). 11 patients hospi- talized, no deaths occured for HF in ferric carboxymaltose group. In the standard care group: 4 patients died during the study, 5 patients were hospita- lized for worsening HF | No hypersensivity reactions, no cases of hypophosphatemia |
FERRIC-HF II [94] | HFrEF | 40 | – | Ferritin < 100 mcg/L, or 100–300 mcg/L with TSAT < 20% | History of acquired iron overload; known hemochromatosis or first degree relatives with hemachromatosis; an allergic disor- der; prior hypersensivity to iron drugs; active infection, bleeding, malignancy, hemolytic anemia, rheumatoid arthritis and myelodysplasia; AIDS; chronić liver disease; chronic lung disease; coagulopa- thy or anticoagulated for metallic valve or LV thrombus; immunosupressant use; renal dialysis; need for Epo or blood trans- fusions; unstable ungina; severe obstruc- tive lesions; uncontrolled arrhythmias; muscoloskeletal limitations | NYHA II–III | <45% if NYHA III; <40% if NYHA II | – | Iron isomaltoside 1000. The total repletion dose was calculated to the nearest multiple of 100 mg using the Ganzi formula: body weight (kg) × 2.4 × (15-patients Hb (g/dL) + 500 mg). Mean dose was 929 mg ± 320 mg | 27 weeks | Ferritin increased by 83% (327 ± 185 ng/mL) in the iron group and decreased by 24% in the placebo group. TSAT incresed by 29% (8 ± 6%) with iron and by 4% (2 ± 9%) with placebo. Hb increased by 0.4% (0.6 ± 9 g/dL) | PCr t1/2 improved (shortened) by 17% in the iron group, worse- ned by 7% in the placebo. Improved post-exercise ADP t1/2 by 45% while it leng- thened by 3% with placebo. Reduction in NYHA and post-exercise Borg dyspnea score in iron group. | 1 patient had arthralgia during the infusion; 1 noted a mild rash at the venepuncture site 1 day post-infusion; 1 had a serious adverse event-unrelated to stu- dy drug. No anaphy- lactic reactions. |
RON-HF [82] | HF | 23 | – | Ferritin < 500 ng/mL; TSAT: <20%; Hb: 9–12 g/dL | Overt bleeding; hypothyroidism; inflam- matory, neoplastic or infectious disease; serum creatinine>1.5 mg/dL; intolerance to iron; HF due alcoholic cardiomyopathy; current regular drinker of alcohol; decom- pensated HF; recent ACS, stroke or TIA; recent myocardial revascularization pro- cedures; patients in heart transplantation list; pregnant or lactating women; pre- -menopausal women that are not using any method of contraception; patients with pacemakers, implanted defibrillators or cardiac resynchronization therapy | NYHA II–IV | <40% | Not included | Group 1: iron sucrose 200 mg i.v. once a week, for 5 weeks; group 2: ferrous sulfate 200 mg orally ×3/day for 8 weeks; | 8 weeks | Ferritin increase in i.v. iron (167 ± 149 ng/mL to 293 ± 270 ng/mL) as well as in oral iron group (115 ± 141 ng/mL to 218 ± 189 ng/mL). No ferritin increment in pla- cebo group. TSAT increased in all study groups. | >20% improvement in maxi- mal oxygen consumption (V02 max) in i.v. iron from baseline. 4.36 mL/kg/min in V02max between i.v. iron and oral iron groups. 3.5 mL/kg/min intra- group increment detected in the i.v. iron group. | No data |
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Szklarz, M.; Gontarz-Nowak, K.; Matuszewski, W.; Bandurska-Stankiewicz, E. Can Iron Play a Crucial Role in Maintaining Cardiovascular Health in the 21st Century? Int. J. Environ. Res. Public Health 2022, 19, 11990. https://doi.org/10.3390/ijerph191911990
Szklarz M, Gontarz-Nowak K, Matuszewski W, Bandurska-Stankiewicz E. Can Iron Play a Crucial Role in Maintaining Cardiovascular Health in the 21st Century? International Journal of Environmental Research and Public Health. 2022; 19(19):11990. https://doi.org/10.3390/ijerph191911990
Chicago/Turabian StyleSzklarz, Michał, Katarzyna Gontarz-Nowak, Wojciech Matuszewski, and Elżbieta Bandurska-Stankiewicz. 2022. "Can Iron Play a Crucial Role in Maintaining Cardiovascular Health in the 21st Century?" International Journal of Environmental Research and Public Health 19, no. 19: 11990. https://doi.org/10.3390/ijerph191911990