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Keywords:

  • MRI ;
  • transfusion;
  • MDS

The clinical impact of iron overload on morbidity and mortality in regularly transfused patients with myelodysplastic syndrome (MDS) is not clearly demonstrated. Indeed, although cardiac disease is the commonest cause of non-leukaemic deaths in low risk MDS with anaemia, it may also be a result of confounding factors in these patients, including chronic anaemia, ageing, coronary artery disease, diabetes and systemic hypertension (Malcovati et al, 2005). Cardiac assessment by T2* magnetic resonance imaging (MRI), allowing in vivo estimation of iron content, is specific for iron overload and unaffected by confounding factors. Experience in thalassaemia major patients clearly demonstrates that cardiac T2* is associated with systolic and diastolic ventricular dysfunction (Pennell, 2005). In MDS, several small studies have assessed cardiac iron overload by MRI, with controversial results. However, none of them evaluated the impact of iron overload on cardiac function (Konen et al, 2007; Di Tucci et al, 2008; Roy et al, 2011).

In order to study the clinical impact of heart iron overload, we performed a cross-sectional study in 75 consecutive regularly transfused MDS patients from six centres of the Groupe Francophone des Myélodysplasies. Cardiac T2* was assessed by MRI according to Anderson et al (2001), liver iron content (LIC) was assessed by MRI (Gandon et al, 2004), and cardiac function was determined by routine echocardiography assessment of left ventricular ejection fraction (LVEF). Cardiac iron overload was defined by a T2* ≤20 ms, and severe cardiac iron overload by T2* below 10 ms. LVEF <55% was considered abnormal and severe systolic ventricular dysfunction diagnosed if LVEF <35%. We defined three patient groups according to the total number of packed red blood cell (PRBC) units received: low (≤50), intermediate (50–150) and high (≥150). All statistical analyses were 2-tailed and performed with IBM SPSS Statistics v20 software (IBM, Armonk, NY, USA). P values <0·05 were considered statistically significant.

Patient characteristics, including World Health Organization classification of MDS and International Prognostic Scoring System (IPSS) score, are summarized in Table 1. Pre-existing cardiovascular disorder was found in 12/21, 30/37, 8/17 patients in the low, intermediate and high transfusions groups, respectively. Most patients (67/75) had low- or intermediate-1 IPSS. Median (range) serum ferritin level was 467 (150–954) μg/l at diagnosis, and 1743 (282–5000) μg/l at time of MRI study. 56/75 patients were on chelation therapy at time of MRI study (12/21, 30/37, and 14/17 in the low, intermediate and high transfusion groups, respectively), with deferasirox alone (n = 18); deferoxamine alone (n = 14); deferasirox + deferoxamine (n = 13); deferoxamine + deferiprone (n = 2). Median interval from diagnosis to MRI testing was 4·3 years (range 0·25–27 years), and the median number of PRBC units transfused was 76 (range 5–574). Cardiac MRI T2* values ranged from 6 to 74 ms (median 27). Cardiac T2* was ≤20 ms in 14 patients (18·6%), who had received a median number of 202 PRBC units since diagnosis (range 12–574). Three of them had very low T2* ≤10 ms (6, 8·5 and 10 ms, respectively) and had received 66, 290 and 396 PRBC units respectively. Hereditary haemochromatosis was excluded in the patient with T2* <20 ms who had received only 12 RBC concentrates. An inverse correlation between the number of PRBC units transfused and T2* was found (Spearman's ρ = −0·347; P = 0·002). T2* ≤20 ms was found in 1/22 (4·5%) patients in the low transfusion group, 4/37(10·8%) in the intermediate group, and 9/17 (52·9%) in the highly transfused group (Kruskall–Wallis, P = 0·0002; Fig 1A). No correlation was found between cardiac T2* and liver T2* values (Spearman's ρ = −0·06; P = 0·6), and between cardiac T2* and serum ferritin (Spearman's ρ = −0·13; P = 0·4) and age (Spearman's ρ = −0·04; P = 0·75).

Table 1. Patient characteristics
  1. WHO, World Health Organization; RA, refractory anaemia; RARS, refractory anaemia with ringed sideroblasts; RCMD(-RS), refractory cytopenia with multilineage dysplasia (with ringed sideroblasts); RAEB, refractory anaemia with excess blasts; PRBC, packed red blood cell units.

Patients75
Male/Female40/35
Diagnosis (WHO classification)
RA5
RARS35
RCMD4
RCMD-RS1
RAEB-111
RAEB-24
5q-8
Unclassified7
Age (median-range)73 (31–88)
Months on transfusion therapy (median-range)52 (2–324)
Red blood Cell units transfused (median-range)76 (5–574)
Low transfused group (PRBC ≤50)21
Intermediate transfused group (PRBC >50 and <150)37
High transfused group (PRBC ≥150)17
Serum ferritin at MRI (μg/l)1743 (282–5000)
Myocardial T2* value (milliseconds)27 (6–74)
image

Figure 1. (A) Box and Whisker plot representing median T2* (and interval interquartile) values according to transfusional burden. PRBC, packed red blood cell units. (B) proportion of patients with severe systolic ventricular dysfunction [left ventricular ejection fraction (LVEF) ≤35%] according to myocardial iron overload (T2* ≤20 ms).

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At the time of MRI analysis, LVEF was measured in 57/75 patients. Median LVEF value was 66% (range 22–88%). 13/57 (23%) patients had LVEF ≤55% and 4/57 patients (7%) had LVEF ≤35%. Three of the 4 (75%) patients with LVEF ≤35% had T2* ≤20 ms, compared with 8/53 (15%) patients with a LVEF >35% (P = 0·02 by Fisher's t-test; Fig 1B). Conversely, 3 (27%) of the 11 patients with T2* ≤20 ms studied by echocardiography had LVEF ≤35%, compared to 1/46 (2%) of the patients with T2* >20 ms (P = 0·02). Four (36%) of the 11 had LVEF ≤55%, compared to 9/46 (20%; P = 0·25). Two of the three patients with T2* ≤10 ms, (defining high cardiac iron overload) were studied by echocardiography, which showed LVEF of 42% and 32%, respectively.

Thus, in this relatively large patient series, we found cardiac iron overload (T2* ≤20 ms) in 18·2% of regularly transfused (mostly IPSS low and intermediate 1 risk) MDS patients, which was severe (T2* ≤10 ms) in 4%. Until now, cardiac iron overload had been assessed only in selected groups of highly transfused MDS patients or in small patient series (Chacko et al, 2007; Konen et al, 2007; Di Tucci et al, 2008; Roy et al, 2011; who analysed 11, 10, 27 and 43 patients, respectively). Our incidence of cardiac iron overload is very close to that (16%) reported in a group of 43 patients (Roy et al, 2011). We found an inverse correlation between the number of PRBC units transfused and cardiac T2* value, confirming in a larger MDS population the previously reported relationship between transfusional burden and cardiac iron overload (Di Tucci et al, 2008). We also studied cardiac function by echocardiography. 23% of the patients had cardiac dysfunction (LVEF ≤55%), and 7% had severe systolic ventricular dysfunction (LVEF ≤35%). The incidence of severe cardiac dysfunction was 27% in patients with T2* ≤20 ms, vs. 2% in patients with T2* >20 ms indicating that iron overload impairs systolic function in regularly transfused MDS patients. Patients with MDS are generally elderly, with cardiac comorbidities potentially leading to cardiac failure (Malcovati et al, 2011). In addition, chronic anaemia, often present in MDS, is known to induce cardiac haemodynamic changes: compensatory LV hypertrophy, higher myocardial chamber volumes, and a high–cardiac output state that can, in the long term, be detrimental and trigger or exacerbate previous heart failure (Ezekowitz et al, 2003). Our results however suggest that iron overload can be a significant aggravating factor in the pathophysiology of cardiac failure in MDS, in addition to chronic anaemia and comorbidities. We therefore recommend systematic assessment of cardiac T2* in addition to liver T2* in all regularly transfused MDS patients who have received at least 50 units of PRBC.

Acknowledgement

  1. Top of page
  2. Acknowledgement
  3. Author contributions
  4. References

We thank Noemi Roy for her help in reviewing the paper and Fatiha Chermat and from GFM for their support. No disclosure to declare.

Author contributions

  1. Top of page
  2. Acknowledgement
  3. Author contributions
  4. References

L. Pascal: data collection, performed the research, the statistical analysis and wrote the paper; O. Beyne-Rauzy: inclusion of patients; S. Brechignac: inclusion of patients; S. Marécaux: inclusion of patients; D. Vassilief: inclusion of patients; O. Ernst: contributed to MRI analysis; C. Berthon: inclusion of patients; E. Gyan inclusion of patients; M-P. Gourin: inclusion of patients; F. Dreyfus: inclusion of patients; P. Fenaux: inclusion of patients, reviewing the paper; C. Rose: inclusion of patients designed the research study, analysed the data and wrote the paper.

References

  1. Top of page
  2. Acknowledgement
  3. Author contributions
  4. References
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