Markers of Iron Metabolism and Outcomes in Patients with Heart Failure: A Systematic Review
Abstract
:1. Introduction
2. Methods
2.1. Data Source/Search Strategy
2.2. Study Selection
2.3. Study Classification
- All-Cause Mortality
- HF hospitalization
- Functional Capacity/Quality of Life
- Additional Adverse Outcomes
2.4. Study Quality/Data Synthesis
2.5. Risk of Bias
3. Results
3.1. All-Cause Mortality
3.2. Heart Failure Hospitalization
3.3. Exercise/Functional Capacity and Quality of Life
3.4. Additional Adverse Outcomes
4. Discussion
4.1. Iron Metabolism and Mortality
4.2. Iron Metabolism and Heart Failure Hospitalizations
4.3. Iron Metabolism and Other Outcomes
4.4. Future Directions
5. Limitations
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AKI | Acute renal injury |
BNP | Brain natriuretic peptide |
CRS | Cardiorenal syndrome |
ESC | European Society of Cardiology |
HF | Heart failure |
HFmrEF | Heart failure with midrange ejection fraction |
HFpEF | Heart failure with preserved ejection fraction |
HFrEF | Heart failure with reduced ejection fraction |
ID | Iron deficiency |
IV | Intravenous |
LVEF | Left ventricular ejection fraction |
QoL | Quality of life |
STfR | Soluble transferrin receptor |
TSAT | Transferrin saturation |
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Author (Year) | N | LVEF (%) | Mean Age (Years) | Male (%) | Follow-Up Period (Days) | Study Type | ID Criteria | Anemia Excluded (Yes/No) | Biomarker(s) | Outcomes | Association of Iron Metabolism Markers with Outcomes |
---|---|---|---|---|---|---|---|---|---|---|---|
Jankowska (2010) [20] | 546 | 26 ± 7 | 55 ± 11 | 88 | 731 ± 350 (mean) | P | ESC definitions | No | Ferritin TSAT | Mortality: 28% in 2 years | ↑ morality or HT w/ID, based on ferritin and TSAT (HR 1.58, 95% CI 1.14–2.17, p < 0.01) |
Okonko (2011) [25] | 157 | 32 ± 9 | 71 ± 12 | 72 | 743 (median) | P | TSAT <20% | No | TSAT | Mortality: 17% in 2 y | ↑ mortality w/TSAT <20% (HR 3.38; 95% CI 1.48−7.72; p = 0.004) |
Jankowska (2013) [35] | 321 | 31 ± 9 | 61 ± 11 | 84 | 1095 (endpoint) | P | N/A | No | Hepcidin | Mortality: 24% in 3 years | ↑ mortality w/Serum hepcidin ≤31 ng/mL (HR 2.89, 95%CI 1.63–5.05, p < 0.001) |
Klip (2013) [4] | 1506 | 33 ± 14 | 64 ± 13 | 74 | 701 (median) | P | ESC definitions | Yes (Hg < 8−10 g/dL based on cohort) | Ferritin TSAT | Mortality: 29.2% in 2 years | ↑ morality w/ID, based on ferritin and TSAT (HR 1.42, 95%CI 1.14−1.77, p = 0.002) |
Jankowska (2014) [33] | 165 | 33 ± 13 | 65 ± 12 | 81 | 323 ± 94 (mean) | P | (a) Hepcidin <14.5 ng/mL; (b) sTfR ≥1.59 mg/L; (c) ESC definitions | No | Hepcidin sTfR | Mortality in low hepcidin AND high sTfR: 41% in 1 year | ↑ morality w/Low Hepcidin <7.84 ng/mL and High sTfR >2.78 mg/L (HR = 6.16, 95% CI = 2.70–14.04, p < 0.001) |
Grote Beverborg (2018) [26] | 387 | 30.4 ± 9.3 | 66.8 ± 13.4 | 68 | 746 (endpoint) | P | ESC definitions | No | Iron TSAT | Mortality: 25% in 1.5 years | ↑ mortality w/serum iron ≤13 µmol/L (HR 2.39; 95% CI 1.13–5.04; p = 0.022); ↑ mortality w/TSAT <20% (HR 2.78; 95% CI 1.22–6.34, p = 0.015); Ferritin <100 ng/mL not significantly associated w/mortality (HR 1.54; 95% CI 0.45–5.52) |
Nakano (2018) [9] | 578 | 39 (median) | 78 (median) | 61 | 365 (endpoint) | P | ESC definitions | No | Ferritin | Mortality: 11% in 1 year | ↑ adverse events w/Ferritin <100 μg/L (HR 1.50, 95% CI 1.02–2.21, p = 0.040); FID with neutral effect (HR 0.73, 95% CI 0.39–1.34, p = 0.31) |
Ambrosy (2020) [30] | 4103 | 35% with LVEF > 50% | 79.2 ± 7 | 51 | 365 (endpoint) | P | ESC definitions | No | TSAT | Mortality and HF Hospitalization: 16.7 per 100 person-years | ↑ mortality w/TSAT < 20% compared to ferritin <100 ng/mL (aHR 1.42, 95% CI:1.20–1.68) and ferritin 100–300 ng/mL (aHR 1.18, 95% CI:1.00–1.38) |
Kurz (2020) [28] | 2223 | 34 ± 15 | 57.2 ± 14.7 | 72 | 2068 (median) | P | ESC definitions | No | TSAT | Mortality: 8% in 5.6 years | ↑ mortality, HT, VAD implant w/TSAT < 20% (HR 0.608, 95% CI 0.498–0.741, p < 0.001) Neutral Effect when comparing ferritin levels 100–300 μg/L vs. <100 μg/L (HR 0.857, 95% CI 0.643–1.144, p = 0.298) |
Gentil (2020) [27] | 108 | 28.1 ± 9.2 | 59.5 ± 14.1 | 52.8 | 857.5 (median) | P | ESC definitions | No | TSAT | Mortality: 29% in 2.3 years | ↑ mortality w/TSAT < 20% (HR = 2.3; 95% CI: 1.11–4.85, p = 0.026); Ferritin < 100 μg/L was not related to mortality (Log-rank test, p = 0.439) |
Sierpinski (2020) [34] | 791 | 28 ± 8 | 58 ± 11 | 84 | 1095 (endpoint) | P | based on ROC for ferritin, TSAT, sTfR | No | sTfR | Mortality: 34% in 3 years | ↓ Survival Rate w/sTfR ≥ 1.25 mg/L: (Z = 4.03, p < 0.001) |
Fitzsimons (2021) [29] | 1563 | 38 * | 65.6 * | 72 | 730 (endpoint) | P | ESC definitions | No | TSAT Ferritin | Mortality: 19% in 2 years | ↑ mortality w/TSAT < 20% (HR 1.95, CI 95% 1.52−2.51, p < 0.01): ESC definitions had inferior effect (HR 1.21, CI 95% 0.95–1.53, p = 0.12) |
Palau (2021) [31] | 1701 | 51.7% with LVEF > 50% | 76 (median) | 56 | 30 (endpoint) | P | ESC definitions | No | TSAT | Mortality: 6% in 1 month | ↑ adverse outcomes w/TSAT, exponentially higher if TSAT < 10% (HR 1.75, CI 95% 1.08–2.83; p = 0.024); Ferritin levels, even <54 ug/L, without higher risk (HR 0.97, CI 95% 0.63–1.50; p = 0.906) |
Ueda (2021) [36] | 615 | 46.7 ± 16.0 | 74.3 ± 12.0 | 57 | 976 (mean) | P | ESC definitions | No | Iron | Mortality: 25% in 2.7 years | ↑ adverse outcomes w/serum iron ≤ 64 µg/dL (irrespective of ferritin/Hg) (HR 1.500; CI 95% 1.128–1.976; p = 0.0044) |
Fitzsimons (2022) [21] | 788 | 36% with LVEF ≥ 50% | 70.0 * | 69 | 1460 (endpoint) | P | (1) sTfR ≥ 1.59 mg/L, (2) sTfR ≥ 1.76 mg/L (3) ESC definitions (4) TSAT < 20% | No | sTfR TSAT | Mortality and HF hospitalizations: 54% in 4 years | ↑ mortality w/sTfR > 1.76 mg/L in HFpEF (HR 1.84, 95% CI 1.23–2.75); ↑ mortality w/sTfR > 1.59 mg/L regardless LVEF (HR 1.45, 95% CI 1.13–1.86); ↑ mortality w/TSAT < 20% in HFpEF (HR, 1.69, 95% CI 1.10–2.59); ESC definitions were not associated with mortality (HR 1.19, 95% CI 0.77–1.85) |
Masini (2022) [32] | 4422 | 41% with LVEF ≥ 50% | 75 (median) | 60 | 1490 (median) | P | most accurate biomarker of iron status (ferritin, TSAT, iron) | No | Iron TSAT | Mortality: 34.5% in 5 years | ↑ mortality w/TSAT < 20%(HR: 1.27; 95% CI: 1.14−1.43; p < 0.001); ↑ mortality w/Serum Iron ≤13 μmol/(HR: 1.37; 95% CI: 1.22−1.54; p < 0.001); Serum ferritin < 100 ng/mL insignificantly associated with lower mortality (HR: 0.91; 95% CI: 0.81−1.01; p = 0.09) |
Author (Year) | N | LVEF (%) | Mean Age (Years) | Male (%) | Follow-Up Period (Days) | Study Type | ID Criteria | Anemia Excluded (Yes/No) | Biomarker(s) | Outcomes | Association of Iron Metabolism Markers with Outcomes |
---|---|---|---|---|---|---|---|---|---|---|---|
Núñez (2016) [11] | 626 | 52.1% with LVEF >50% | 73.4 ± 10.4 | 52 | 30 (endpoint) | P | ESC definitions | No | Ferritin | HF Hospitalization: 16.5% in 30 days | ↑ HF Hospitalization w/ferritin < 100 µg/L (sHR 1.72; 95% CI 1.13–2.60, p = 0.011); FID not related to the risk of readmission (HR 0.87; 95% CI 0.46–1.62, p = 0.652) |
Nakano (2018) [9] | 578 | 39 (median) | 78 (median) | 61 | 365 (endpoint) | P | ESC definitions | No | Ferritin | HF Hospitalization: 19% in 1 year | ↑ Adverse events w/Ferritin < 100 μg/L (HR 1.50, 95% CI 1.02–2.21, p = 0.040) FID with neutral effect (HR 0.73, 95% CI 0.39–1.34, p = 0.31) |
Ambrosy (2020) [30] | 4103 | 35% with LVEF >50% | 79.2 ± 7 | 51 | 365 (endpoint) | P | ESC definitions | No | TSAT | HF admission plus mortality: 16.7 per 100 person-years | ↑ HF Hospitalization w/TSAT < 20% for ferritin <100 ng/mL (aHR 1.40, 95% CI 1.16–1.70) and 100–300 ng/mL (aHR 1.24, 95% CI 1.01–1.52) |
Fitzsimons (2021) [29] | 1563 | 38 * | 65.6 * | 72 | 730 (endpoint) | P | ESC definitions OR TSAT< 20% | No | TSAT | Death/HF hospitalization: 43% in 2 years | ↑ Adverse events w/TSAT < 20% (HR 1.19, CI 1.01–1.41, p = 0.03) ESC definitions not a predictor of hospitalization (HR 1.11, CI 95% 0.92–1.33, p = 0.28) |
Ueda (2021) [36] | 615 | 46.7 ± 16.0 | 74.3 ± 12.0 | 57 | 976 (mean) | P | ESC definitions | No | Iron | HF hospitalization: 29% in 2.7 years | ↑ Adverse events w/Serum iron ≤ 64 µg/dL, irrespective of ferritin/Hg (HR 1.500; 95% CI 1.128–1.976; p = 0.0044) |
Author (Year) | N | LVEF (%) | Mean Age (Years) | Male (%) | Follow-Up Period (Days) | Study Type | ID Criteria | Anemia Excluded (Yes/No) | Biomarker(s) | Outcomes | Association of Iron Metabolism Markers with Outcomes |
---|---|---|---|---|---|---|---|---|---|---|---|
Jankowska (2011) [37] | 443 | 26 ± 7 | 54 ± 10 | 90 | -- | P | ESC definitions | No | Ferritin | Functional Capacity | ↓ VO2 and higher VE/VCO2 slope with serum ferritin (p < 0.05); ESC definitions associated with reduced peak VO2 (β = −0.14, p < 0.01 p < 0.05) and higher VE-VCO2 slope (β = 0.14, p < 0.01 p < 0.05) |
Okonko (2011) [25] | 157 | 32 ± 9 | 71 ± 12 | 72 | 743 (median) | P | TSAT < 20% | No | sTfR TSAT Ferritin | Functional Capacity Quality of Life | ↑ NYHA class with sTfR ≥1.76 mg/L (ANOVA p < 0.0001) VO2 positively correlated with TSAT (r = 0.71, p < 0.0001) and ferritin (r = 0.48, p = 0.01) levels |
Pozzo (2017) [22] | 138 | 28.1 * | 61.2 * | 48 | 1825 (mean) | P | ESC definitions | Yes (Hg < 13.0 g/dL in men or <12.0 g/dL in women) | Ferritin | Functional Capacity | ↓ performance in 6MWT (p = 0.03) and ↓ VO2 (p = 0.01) with ferritin < 100 μg/L |
Martens (2018) [38] | 1197 | 6% with LVEF > 50% | 70 ± 12 | 71 | 1004 (mean) | P | ESC definitions | No | Ferritin TSAT | Functional Capacity | ↓ VO2 with ID, based on ferritin and TSAT (p < 0.001) |
Tkaczyszyn (2018) [39] | 53 | LVEF ≤ 40 | 64 ± 10 | 100 | -- | P | ESC definitions | No | Ferritin | Functional Capacity | ↓ MIP with ferritin <100 μg/L compared to ferritin ≥100 μg/L (r = 0.42, p < 0.01) |
Bekfani (2019) [40] | 190 | 58 ± 7 | 71 ± 9 | 67.5 | -- | P | ESC definitions | No | Ferritin TSAT | Functional Capacity Quality of Life | ↓ performance in 6MWT (p = 0.008) and CPX (p = 0.03) with ID, based on ferritin and TSAT ↓ QoL(p = 0.03) with Ferritin < 100 µg/L |
Alcaide-Aldeano (2020) [23] | 447 | 62 ± 8 | 76 ± 9 | 41 | -- | P | ferritin < 100 ng/mL or TSAT < 20% | Yes (Hg less than < 8.5 g/dL) | sTfR | Functional Capacity Quality of Life | sTfR (overall mean value of 1.92) predictor of functional capacity (β = −63, p < 0.0001, R2 0.39); and QoL (β = 7.95, p < 0.0001, R2 0.14). TSAT < 20% (β = 3.32, p = 0.13, R2 0.10), ferritin (β = 0.64, p = 0.56, R2 0.10) and serum iron (β = −1.50, p = 0.47, R2 0.10) did not have a strong association to QoL |
Author (Year) | N | LVEF (%) | Mean Age (Years) | Male (%) | Follow-Up Period (Days) | Study Type | ID Criteria | Anemia Excluded (Yes/No) | Biomarker(s) | Outcomes | Association of Iron Metabolism Markers with Outcomes |
---|---|---|---|---|---|---|---|---|---|---|---|
Klip (2017) [41] | 6386 | N/A | 53.1 ± 12.0 | 50.3 | 3032 (median) | P | N/A | No | Ferritin | New onset HF | ferritin levels (median: 97 µg/L) predict new-onset HF in women only (p = 0.024). |
Yan (2020) [24] | 221 | 55.8 ± 9.1 | 68.6 ± 11.8 | 57.5 | 239 (median) | R | Low (7.6 ± 1.6), medium (11.9 ± 1.8) and high (19.4 ± 3.8 serum iron (μmol/L) | Yes | Iron | MACCE | ↑ MACCE with serum iron <7.58 μmol/L or >19.37 μmol/L compared to medium serum iron (p < 0.0001) |
Ceyhun (2021) [42] | 157 | 30.0 ± 8.1 | 63.9 ± 8.62 | 42 | N/A | R | N/A | No | Ferritin | AKI | ↑ AKI risk with BNP/ferritin, mean value 10.48 ± 2.14 (OR = 3.19; 95% CI 1.92–6.54; p = 0.001) & ferritin, mean value 86.78 ± 57.2 (OR = 0.72; 95% CI, 0.89–0.53; p = 0.028) |
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Dhaliwal, S.; Kalogeropoulos, A.P. Markers of Iron Metabolism and Outcomes in Patients with Heart Failure: A Systematic Review. Int. J. Mol. Sci. 2023, 24, 5645. https://doi.org/10.3390/ijms24065645
Dhaliwal S, Kalogeropoulos AP. Markers of Iron Metabolism and Outcomes in Patients with Heart Failure: A Systematic Review. International Journal of Molecular Sciences. 2023; 24(6):5645. https://doi.org/10.3390/ijms24065645
Chicago/Turabian StyleDhaliwal, Simrat, and Andreas P. Kalogeropoulos. 2023. "Markers of Iron Metabolism and Outcomes in Patients with Heart Failure: A Systematic Review" International Journal of Molecular Sciences 24, no. 6: 5645. https://doi.org/10.3390/ijms24065645