Early detection of cardiac involvement in thalassemia: From bench to bedside perspective

Table 1 Summary of the controversial correlation between cardiac magnetic resonance T2* and serum ferritin in thalassemia major

Population/size	Type of study	Findings	Correlation	Ref.
TM/652 patients	Prospective	Significant correlation between cardiac T2* and ferritin	/	Kirk et al[56]
		(r2 = 0.003, P = 0.04)
TM/776 patients	Retrospective	Significant relationship between cardiac R2* and ferritin	/	Marsella et al[59]
		(r = -0.359, P < 0.0001)
TM/167 patients	Prospective	Myocardial T2* was correlated with serum ferritin	/	Tanner et al[60]
		(r = -0.34, P < 0.001)
TM/19 patients, SCD/17 patients	Cross sectional	Cardiac 1/T2* was correlated with ferritin level	/	Wood et al[61]
		(r2 = 0.33, P = 0.01)
TM/106 patients	Prospective	No significant correlation between heart T2* and serum ferritin	×	Anderson et al[16]
TM/60 patients	Prospective	Serum ferritin did not correlate with cardiac iron values	×	Merchant et al[57]
TM/20 patients	Prospective	No correlation between serum ferritin and cardiac T2*	×	Kolnagou et al[58]
TM/47 patients	Retrospective	Cardiac T2* was not associated with the serum ferritin	×	Bayraktaroğlu et al[22]

TM: Thalassemia major; SCD: Sickle cell disease.

Table 2 Summary of the correlation between cardiac magnetic resonance T2* and cardiac function in thalassemia major

Population/size	Type of study	Findings	Correlation	Ref.
TM/776 patients	Retrospective	Significant correlation between LVEF and cardiac R2* (r = -0.327, P < 0.0001)	/	Marsella et al[59]
TM/106 patients	Prospective	Significant correlation of myocardial T2* below 20 ms with LVEF (r = 0.61, P < 0.0001), LVESVi (r = 0.50, P < 0.0001), and LV mass index (r = 0.40, P < 0.001)	/	Anderson et al[16]
TM/167 patients	Prospective	Significant relationship between myocardial iron and LVEF (r = 0.57, P < 0.001)	/	Tanner et al[60]
TM/67 patients	Cross sectional	Myocardial T2* related to LV diastolic function (EPFR, r = –0.20, P = 0.19; APFR, r = 0.49, P < 0.001; EPFR/APFR ratio, r = –0.62, P < 0.001)	/	Westwood et al[52]
TM/33 patients	Cross sectional	Good correlation of DT, Tei index and E/Em index with cardiac T2* values (P < 0.05, r = 0.70-0.81) and weak correlation of E/A with T2* (P < 0.05, r = -0.44)	/	Barzin et al[84]
TM/47 patients	Retrospective	Significant correlations of the myocardial T2* with LVESVi and LVEDVi (r = -0.32, P = 0.027; r = -0.29, P = 0.046, respectively)	/	Bayraktaroğlu et al[22]
TM/19 patients, SCD/17 patients	Cross sectional	Significant relationship between LVEF and myocardial T2*	/	Wood et al[61]

TM: Thalassemia major; SCD: Sickle cell disease; LVEF: Left ventricular ejection fraction; LVESVi: Left ventricular end systolic volume index; LVEDVi: Left ventricular end diastolic volume index; EPFR: Early peak filling rate; APFR: Atrial peak filling rate; DT: Deceleration time; E/Em: Early diastolic peak inflow velocity and early diastolic myocardial velocity ratio; E/A: Early and late transmittal peak flow velocity ratio.

Table 3 Comparison of various methods to evaluate cardiac iron overload in thalassemia patients

Method	Advantages	Disadvantages
Serum ferritin	Easy and available	Poor predictor of iron overload[85,86]
	Inexpensive	Nonspecific for cardiac iron
		Altered by many conditions[14]
Echocardiogram	Easy and available	Late indicator of cardiac involvement[21,23]
	Inexpensive
Liver biopsy	Total body iron estimation[32]	Invasive
		No correlation with myocardial iron deposition[33]
Myocardial biopsy		Invasive No correlation with cardiac iron status and function[34]
ECG	Easy and available	Ineffective screening parameter for cardiac iron overload[25,31]
	Inexpensive
SQUID	Standardized noninvasive index for liver iron[36]	Lack of availability, technical demands, and reproducibility
		Costly
		Application for the study of heart iron pending
NTBI	Direct parameter of freeform iron resulting in	Limited availability
	peroxidative damage[87]	No generally accepted method[48], and poor correlation
		between methods[49]
CMR T2*	Method of choice for the assessment of tissue iron deposition in last decade[51]	Costly
	Noninvasive measurement of cardiac iron deposition[50]
	Available
	High sensitivity and reproducible[50]
	Correlation with clinical outcome[16,17,56,62,63]

ECG: Electrocardiogram; SQUID: Superconducting quantum interference device; NTBI: Non-transferrin-bound iron; CMR T2*: Cardiac magnetic resonance T2*.

Table 4 Summary of heart rate variability findings from both clinical and basic studies in thalassemia

Population/size	Type of study	Findings	Ref.
34 TM patients and 20 healthy subjects	Prospective	Significantly depressed both time and frequency domain HRV parameters in TM patients	Rutjanaprom et al[20]
32 TM patients and 46 control subjects	Prospective	Significantly reduced all HRV parameters in TM patients	Kardelen et al[77]
19 TM patients and 19 healthy volunteers	Cross sectional	Significantly lower both time and frequency domain HRV parameters in the TM group	Franzoni et al[75]
100 TM patients and 60 healthy controls	Cross sectional	Lower SDNN in TM with ectopia while markedly increased LF/HF ratio in this group.	Oztarhan et al[88]
48 Thalassemia patients and 45 healthy subjects	Cross sectional	Significantly reduced time domain parameters in the thalssemia group	Gurses et al[89]
9 TM patients and 9 healthy subjects	Cross sectional	Significantly lower LF/HF ratio during tilt in TM patients than in control subjects	Veglio et al[90]
21 TM patients and 15 healthy subjects	Cross sectional	Significantly lower in all HRV parameters in TM group than in control group	Ma et al[91]
13 wildtype, 13 HbE/β thalassemia and 13 muβ+/− mice	Cross sectional	Depressed all HRV parameters in the heterozygous βglobin knockout mice (muβ+/−)	Incharoen et al[92]
810 wildtype and 810 heterozygous betaknockout mice	Prospective	Higher LF ⁄ HF ratio in thalassemic mice than those in the wild type	Kumfu et al[82]
12 wildtype and 12 heterozygous betaknockout mice	Prospective	Depressed HRV in betathalassemic mice compared to wild type	Thephinlap et al[93]

TM: Thalassemia major; HRV: Heart rate variability; SDNN: Standard deviation of all NN intervals; LF: Low frequency power; HF: High frequency power.

Table 5 Summary of the correlation between HRV and serum ferritin in thalassemia major

Population/size	Type of study	Findings	Correlation	Ref.
34 TM patients and 20 healthy subjects	Prospective	No correlations between HRV parameters and serum ferritin	×	Rutjanaprom et al[20]
19 TM patients and 19 healthy volunteers	Cross sectional	No correlation between HRV parameters and serum ferritin	×	Franzoni et al[75]
	21 TM patients and 15 healthy subjects	Cross sectional	No relationship of HRV parameters with serum ferritin	×	Ma et al[91]

TM: Thalassemia major; HRV: Heart rate variability.

Table 6 Summary of the relationship between heart rate variability and cardiac function in thalassemia major

Population/size	Type of study	Findings	Correlation	Ref.
34 TM patients and	Prospective	None of the echocardiographic parameters was correlated with HRV	×	Rutjanaprom et al[20]
20 healthy subjects
32 TM patients and	Prospective	Reduced HRV were described in TM despite no echocardiographic abnormality	×	Kardelen et al[77]
46 control subjects
19 TM patients and	Cross sectional	No correlation between HRV parameters and echocardiographic parameters	×	Franzoni et al[75]
19 healthy volunteers
20 TM patients	Prospective	Abnormal HRV in TM with no evidence of ventricular dysfunction	×	De Chiara et al[78]

TM: Thalassemia major; HRV: Heart rate variability.