The scatter plots for the correlation between HRV [1) low frequency (upper row), 2) high frequency (middle row) and 3) ASDNN (lower row)] and hemoglobin and cardiac T2*.

<p>A: whole model of multiple linear regression analysis; B: the correlation between HRV and cardiac T2*; C: the correlation between HRV and hemoglobin. ASDNN, the average of the standard deviation of all R-R intervals for all 5-minute segments in the 24-hour recordings.</p

Baseline clinical and laboratory characteristics according to the mean serum ferritin during the past 5 years.

<p>Baseline clinical and laboratory characteristics according to the mean serum ferritin during the past 5 years.</p

Heart Rate Variability for Early Detection of Cardiac Iron Deposition in Patients with Transfusion-Dependent Thalassemia

<div><p>Background</p><p>Iron overload cardiomyopathy remains the major cause of death in patients with transfusion-dependent thalassemia. Cardiac T2* magnetic resonance imaging is costly yet effective in detecting cardiac iron accumulation in the heart. Heart rate variability (HRV) has been used to evaluate cardiac autonomic function and is depressed in cases of thalassemia. We evaluated whether HRV could be used as an indicator for early identification of cardiac iron deposition.</p><p>Methods</p><p>One hundred and one patients with transfusion-dependent thalassemia were enrolled in this study. The correlation between recorded HRV and hemoglobin, non-transferrin bound iron (NTBI), serum ferritin and cardiac T2* were evaluated.</p><p>Results</p><p>The median age was 18 years (range 8–59 years). The patient group with a 5-year mean serum ferritin >5,000 ng/mL included significantly more homozygous β-thalassemia and splenectomized patients, had lower hemoglobin levels, and had more cardiac iron deposit than all other groups. Anemia strongly influenced all domains of HRV. After adjusting for anemia, neither serum ferritin nor NTBI impacted the HRV. However cardiac T2* was an independent predictor of HRV, even after adjusting for anemia. For receiver operative characteristic (ROC) curve analysis of cardiac T2* ≤20 ms, only mean ferritin in the last 12 months and the average of the standard deviation of all R-R intervals for all five-minute segments in the 24-hour recording were predictors for cardiac T2* ≤20 ms, with area under the ROC curve of 0.961 (p<0.0001) and 0.701 (p = 0.05), respectively.</p><p>Conclusions</p><p>Hemoglobin and cardiac T2* as significant predictors for HRV indicate that anemia and cardiac iron deposition result in cardiac autonomic imbalance. The mean ferritin in the last 12 months could be useful as the best indicator for further evaluation of cardiac risk. The ability of serum ferritin to predict cardiac risk is stronger than observed in other thalassemia cohorts. HRV might be a stronger predictor of cardiac iron in study populations with lower somatic iron burdens and greater prevalence of cardiac iron deposition.</p></div

Receiver operative characteristic (ROC) curve analysis of the mean ferritin in the last 12 months (A) and ASDNN (B) for predictors of the cardiac T2* ≤20 ms.

<p>ASDNN, the average of the standard deviation of all R-R intervals for all 5-minute segments in the 24-hour recordings.</p

Graphing display comparing the time domains of HRV (SDNN, SDANN, ASDNN and rMSSD) according to cardiac T2*.

<p>SDNN, the standard deviation of all normal sinus R-R intervals in the entire 24-hour recording; SDANN, the standard deviation of all average normal sinus R-R intervals for all 5-minute segments in the 24-hour recordings; ASDNN, the average of the standard deviation of all R-R intervals for all 5-minute segments in the 24-hour recordings; rMSSD, the root mean square of the mean of the squared differences of two consecutive R-R intervals in the 24-hour recordings. *—p<0.05 vs. cardiac T2*<20 ms; #—p<0.05 for cardiac T2*>20 ms vs. normal controls.</p

The correlations between HRV parameters and mean hemoglobin during the last 12 months, mean serum ferritin during the last 12 months, mean serum ferritin during the past 5 years, maximum serum ferritin during the past 5 years, NTBI and cardiac T2^*.

<p>The correlations between HRV parameters and mean hemoglobin during the last 12 months, mean serum ferritin during the last 12 months, mean serum ferritin during the past 5 years, maximum serum ferritin during the past 5 years, NTBI and cardiac T2^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0164300#t003fn002" target="_blank">*</a>}.</p

Heart Rate Variability as an Alternative Indicator for Identifying Cardiac Iron Status in Non-Transfusion Dependent Thalassemia Patients

<div><p>Background</p><p>Iron-overload cardiomyopathy is a major cause of death in thalassemia patients due to the lack of an early detection strategy. Although cardiac magnetic resonance (CMR) T2* is used for early detection of cardiac iron accumulation, its availability is limited. Heart rate variability (HRV) has been used to evaluate cardiac autonomic function and found to be depressed in thalassemia. However, its direct correlation with cardiac iron accumulation has never been investigated. We investigated whether HRV can be used as an alternative indicator for early identification of cardiac iron deposition in thalassemia patients.</p><p>Methods</p><p>Ninety-nine non-transfusion dependent thalassemia patients (23.00 (17.00, 32.75) years, 35 male) were enrolled. The correlation between HRV recorded using 24-hour Holter monitoring and non-transferrin bound iron (NTBI), hemoglobin (Hb), serum ferritin, LV ejection fraction (LVEF), and CMR-T2* were determined.</p><p>Results</p><p>The median NTBI value was 3.15 (1.11, 6.59) μM. Both time and frequency domains of HRV showed a significant correlation with the NTBI level, supporting HRV as a marker of iron overload. Moreover, the LF/HF ratio showed a significant correlation with CMR-T2* with the receiver operating characteristic (ROC) curve of 0.684±0.063, suggesting that it could represent the cardiac iron deposit in thalassemia patients. HRV was also significantly correlated with serum ferritin and Hb.</p><p>Conclusions</p><p>This novel finding regarding the correlation between HRV and CMR-T2* indicates that HRV could be a potential marker in identifying early cardiac iron deposition prior to the development of LV dysfunction, and may be used as an alternative to CMR-T2* for screening cardiac iron status in thalassemia patients.</p></div

The correlations between HRV parameters and other clinical parameters in non-transfusion dependent thalassemia (NTDT) patients.

<p>*<i>P</i> < 0.05.</p><p>^†<i>P</i> < 0.01.</p><p>^‡<i>P</i> < 0.001</p><p>The correlations between HRV parameters and other clinical parameters in non-transfusion dependent thalassemia (NTDT) patients.</p