Several studies have shown that elevated serum ferritin level is associated with a higher risk of coronary artery disease. Recently, it has been shown that high serum ferritin levels in men are independently correlated with an increased risk of cardiovascular mortality. This study aimed to investigate the possible correlation between the initial serum ferritin level and in-hospital mortality in patients presenting with ST-elevation myocardial infarction (STEMI).
This retrospective cohort study included 890 patients who presented with acute STEMI and underwent successful primary percutaneous coronary intervention (PPCI) according to the standard techniques during the period from 1 May 2020 to 1 May 2021. At the time of admission, an initial serum ferritin level was measured in all patients. Comparison between initial ferritin levels was made between two groups: died and survived. Propensity matching was performed to exclude confounding factors effect.
Forty-one patients had in-hospital mortality. There was no significant difference between both groups regarding baseline clinical characteristics. Initial serum ferritin levels were higher in deceased patients, even after propensity matching.
In conclusion, even after propensity matching, initial ferritin levels were significantly higher in patients who died after being admitted for STEMI.
Introduction
Ferritin is an essential protein in iron metabolism that reflects body iron homeostasis and is considered a biomarker for inflammation. The clinical significance of serum ferritin levels resides in its strong correlation with adverse outcomes in the general population and patients with various pathological conditions. In this regard, both low and high ferritin values were associated with all-cause mortality in some general population studies.1 Regarding cardiovascular morbidity and mortality, different studies showed that a high serum ferritin level is associated with a higher rate of all-cause and cardiovascular mortality.2,3 Besides all-cause and cardiovascular mortality, ferritin was also linked to a higher burden of cardiovascular risk factors, including metabolic syndrome. A recent meta-analysis that analysed 14 studies observed a higher risk of metabolic syndrome in patients with increased serum ferritin.4 The correlation between ferritin levels and the risk of ischaemic heart disease is still debatable. One study did not observe any correlation between ferritin and coronary heart disease or stroke during long-term follow-up (17 years), while in another study, a more than five-fold higher risk of acute myocardial infarction (AMI) in patients with ferritin values above 200 µg/L was found.5,6 This study aimed to investigate the correlation between initial ferritin levels and in-hospital mortality in patients presenting with STEMI.
Method
This study was a retrospective observational cohort analysis of all patients admitted to a tertiary-level hospital with acute STEMI between 1 May 2020 to 1 May 2021 who underwent primary percutaneous coronary intervention (PPCI) according to the standard techniques. Baseline clinical and laboratory measures were documented. Exclusion criteria included patients with a previous history of anaemia or on any supplemental iron therapy, patients with a previous history of PCI or coronary artery bypass grafting (CABG), patients with a concomitant diagnosis of sepsis, and/or COVID-19 infection. Initial serum ferritin level was measured in all patients at the time of admission.
Statistical analyses were performed using IBM SPSS software version 22 (SPSS Inc., Chicago, IL, USA) and its related materials. Categorical data are presented as frequency and percentages while continuous data are presented as a mean and standard deviation for normally distributed variables or as a median and interquartile range for non-normally distributed variables. A p value of less than 0.05 was considered significant. Propensity matching was done to exclude the effect of any confounding factors. Matching included age, gender, and cardiovascular risk factors, as well as the left ventricular ejection fraction.
The study protocol was approved by the medical ethics committee of the hospital and, as it was a retrospective observational cohort study, there was no need for informed consent. The study is compatible with the Declaration of Helsinki.
Results
The study included 890 patients with acute STEMI, 41 patients died (4.61%). Patients were divided into two groups, those who survived (n=849) and who died (n=41). Baseline patient clinical characteristics of both groups are illustrated in table 1.
Table 1. Comparison between both groups regarding baseline clinical and laboratory characteristics
| Survived (N=849) |
Died (N=41) |
p value | |
|---|---|---|---|
| Mean age ± SD, years | 59.3 ± 13 | 60.5 ± 12.2 | 0.56 |
| Male sex, n (%) | 636 (74.9) | 29 (70.7) | 0.55 |
| Anterior STEMI, n (%) | 670 (78.9) | 30 (73.2) | 0.38 |
| Inferior STEMI, n (%) | 153 (18) | 11 (26.8) | 0.16 |
| Lateral STEMI, n (%) | 17 (2) | 0 (0) | 0.36 |
| Posterior STEMI, n (%) | 9 (1.1) | 0 (0) | 0.5 |
| Diabetes mellitus, n (%) | 466 (54.9) | 22 (53.7) | 0.88 |
| Hypertension, n (%) | 634 (74.7) | 30 (73.2) | 0.83 |
| Smoking, n (%) | 556 (65.5) | 25 (61) | 0.55 |
| Mean ejection fraction ± SD, % | 45 ± 12 | 44 ± 15 | 0.61 |
| Mean pain to balloon ± SD, minutes | 120.1 ± 65 | 115.3 ± 62 | 0.64 |
| Killip class I–II, n (%) | 645 (76) | 31 (75.6) | 0.95 |
| Killip class III–IV, n (%) | 204 (24) | 10 (24.4) | 0.95 |
| Mechanical complications, n (%) | 16 (1.9) | 2 (4.9) | 0.18 |
| Post-PCI TIMI flow I–II, n (%) | 130 (15.3) | 8 (19.5) | 0.47 |
| Post-PCI TIMI flow III–IV, n (%) | 719 (84.7) | 33 (80.5) | 0.47 |
| Mean haemoglobin ± SD, g/dL | 12.8 ± 1.1 | 12.8 ± 1.5 | 1 |
| Mean serum creatinine ± SD, mg/dL | 0.7 ± 1.1 | 0.85 ± 0.8 | 0.39 |
| Mean platelet count ± SD, 103/ml3 | 250 ± 114 | 231 ± 93 | 0.29 |
| Mean serum ferritin ± SD, ng/ml | 255 ± 286 | 457 ± 361 | 0.0004* |
| *p<0.05, significant Key: PCI = percutaneous coronary intervention; SD = standard deviation; STEMI = ST-elevation myocardial infarction; TIMI = thrombolysis in myocardial infarction |
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Comparing baseline clinical characteristics between both groups, no statistically significant difference was noted. Initial serum ferritin level was 457 ± 361 ng/ml in those who survived and 255 ± 286 ng/ml in those who died, which was statistically significant (p=0.004). After propensity matching of both groups, this difference was still significant (p=0.039) (table 2).
Table 2. Comparison between both groups after propensity matching
| Survived (N=849) |
Died (N=41) |
p value | |
|---|---|---|---|
| Mean age ± SD, years | 60.3 ± 12.5 | 60.5 ± 12.2 | 0.64 |
| Male sex, n (%) | 29 (70.7) | 29 (70.7) | 1 |
| Anterior STEMI, n (%) | 30 (73.2) | 30 (73.2) | 1 |
| Inferior STEMI, n (%) | 11 (26.8) | 11 (26.8) | 1 |
| Lateral STEMI, n (%) | 0 (0) | 0 (0) | 1 |
| Posterior STEMI, n (%) | 0 (0) | 0 (0) | 1 |
| Diabetes mellitus, n (%) | 22 (53.7) | 22 (53.7) | 0.88 |
| Hypertension, n (%) | 30 (73.2) | 30 (73.2) | 0.83 |
| Smoking, n (%) | 25 (61) | 25 (61) | 0.55 |
| Mean ejection fraction ± SD, % | 44 ± 14 | 44 ± 15 | 1 |
| Mean pain to balloon ± SD, minutes | 116 ± 63 | 115.3 ± 62 | 0.96 |
| Mean haemoglobin ± SD, g/dL | 12.8 ± 1.3 | 12.8 ± 1.5 | 1 |
| Mean serum creatinine ± SD, mg/dL | 0.86 ± 0.9 | 0.85 ± 0.8 | 0.96 |
| Mean platelet count ± SD, 103/ml3 | 233 ± 99 | 231 ± 93 | 0.93 |
| Mean serum ferritin ± SD, ng/ml | 311 ± 261 | 457 ± 361 | 0.039* |
| *p<0.05, significant Key: SD = standard deviation; STEMI = ST-elevation myocardial infarction |
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Discussion
Data from our retrospective observational study showed that higher serum ferritin levels were associated with increased in-hospital mortality in patients presented with acute STEMI undergoing PPCI. Results from population-based studies, including 8,988 individuals, revealed a stepwise correlation between increasing concentrations of ferritin and the risk of premature mortality.3 Specifically, serum ferritin levels ≥600 μg/L, compared with <200 μg/L, were associated with higher cardiovascular mortality (adjusted hazard ratio 1.5, 95% confidence interval [CI] 1.1 to 2.0).3 A large meta-analysis of 35,799 individuals from three Danish population-based studies revealed a stepwise increase in the risk of atrial fibrillation with increasing levels of ferritin, particularly with ferritin ≥600 μg/L, without significant effect modification by gender.4 However, subgroup analyses based on gender only showed statistically significant stepwise association in men. Another population-based study comprising 5,471 individuals showed that men in the highest ferritin quartile, without major comorbidities, had a higher risk of cardiovascular mortality; however, the significance was not seen in women.2 These results suggest a sex-specific association between circulating ferritin levels and cardiovascular morbidity/mortality.
Being an acute-phase reactant protein, ferritin plays a role in both acute and chronic inflammatory conditions.7 Hepatic synthesis of ferritin is upregulated, mainly by interleukin-6, to sequester free iron in serum, thereby reducing iron availability to bacteria and cancer cells.7 Free intracellular iron is associated with hydroxyl radical production and oxidative stress via Fenton/Haber-Weiss reactions.8 These detrimental reactions are prevented by rapid sequestration of free cytosolic iron by ferritin, rendering it redox-inactive.9
Serum ferritin levels are increased in the setting of preclinical ischaemia/reperfusion (I/R) injury models, including intestines and kidneys.9,10 Data from an in-vivo study conducted in mice subjected to transient cerebral I/R injury showed that higher serum ferritin levels, which reflected higher body iron stores, were associated with worse ischaemic damage and haemorrhagic transformation.11 However, the levels of serum ferritin did not change following acute ischaemic induction in a study of mice with brain I/R injury.11
Recent evidence suggests that impaired iron homeostasis and lipid peroxidation are associated with a programmed cell death known as ferroptosis.8 Ferroptosis has been postulated to associate with many pathological conditions, including I/R injury, stroke, neurodegenerative diseases, and cancers.8 Excessive iron levels not only increase oxidative stress, but also cellular susceptibility to ferroptosis inducers.12 Administration of iron was associated with impaired ejection fraction and cardiac output, together with increased lipid peroxide levels, following cardiac I/R injury in rabbits. This detrimental effect was effectively mitigated by giving an iron chelator, deferoxamine.13
A limitation of the study is its retrospective nature. The study included a relatively large number of patients. Although the number of patients who died was small, after propensity matching, the ferritin level difference was still significant.
Conclusion
Our study showed that serum ferritin levels were significantly higher in patients presenting with acute STEMI undergoing PPCI who had in-hospital mortality compared with survivors. It is unknown whether elevated ferritin levels were a result of acute inflammation following I/R injury, hence more severe myocardial damage, or a reflection of excessive baseline iron levels in those patients. Further studies are required to elucidate whether the causal relationship exists and a clear cut-off value.
Key messages
- Ferritin is an essential protein in iron metabolism that reflects body iron homeostasis and is considered a biomarker for inflammation
- Serum ferritin levels are associated with adverse outcomes in the general population and various pathological conditions. Both low and high ferritin values were associated with all-cause mortality in some general population studies
- Different studies showed that a high serum ferritin level was associated with a higher rate of all-cause and cardiovascular mortality. Besides all-cause and cardiovascular mortality, ferritin was also linked to a higher burden of cardiovascular risk factors, including metabolic syndrome
- This current report shows that ferritin levels were significantly higher in patients presenting with acute ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) who had in-hospital mortality compared with survivors
Conflicts of interest
None declared.
Funding
None.
Study approval
The study protocol was approved by the medical ethics committee with approval number 2021/112/9392 and, as it was a retrospective observational cohort study, the committee waived the need for informed consent. The study is compatible with the Declaration of Helsinki.
References
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