Correlation between iron stores and QTc dispersion in chronic ambulatory peritoneal dialysis patients

Abstract

Aim: We aimed to investigate the QT dispersion and corrected QT (QTc) dispersion which are suggested as the signals of ventricular arrhythmias, in patients on maintenance CAPD and to evaluate the correlation between iron stores and these electrocardiographic parameters. Materials and method: Fifty-eight patients on maintenance CAPD and 19 healthy age- and sex-matched adults without cardiac disease were included. The PD patients were divided into two groups according to whether their computerized measurements of QTc dispersion were longer than 65 ms. Results: Although QT interval was statistically significantly shorter in control group (34 ± 28 vs. 43 ± 34 ms; p < 0.05), there was no significant difference in regards to the QTc, QT dispersion and QTc dispersion between two groups. PD patients with QTc dispersion longer than 65 ms had higher levels of serum ferritin (p = 0.038) and transferrin saturation (TSAT; p = 0.022) than the others. QTc dispersion were positively correlated with ferritin (r = 0.469, p < 0.01) and TSAT (r = 0.430, p < 0.01) in CAPD patients. Conclusion: Although prolonged QTc, QT dispersion and QTc dispersion were suggested as the markers of ventricular arrhythmias we did not find any significant difference in regards to these parameters between control patients and CAPD patients. But the high body iron stores in these patients increase the risk of increased QT dispersion. The concern over iron overload in dialysis patients is not only because of its oxidative toxicity, but also its precipitation of arrhythmias, which may be measured by the surrogate marker of QTc dispersion.

• CAPD
• QTc
• QT dispersion
• QTc dispersion

Introduction

It is clearly known that cardiovascular disease (CVD) is still one of the most common causes of death in patients with end-stage renal disease (ESRD).1 Notably, not only the atherosclerotic heart diseases or cardiomyopathies but also fatal arrhythmias due to electrolyte disturbances are common in this group of patients. Interestingly, arrhythmias may also be present in patients with renal disease without any abnormalities in serum electrolyte levels. It should be emphasized that ventricular arrhythmias are shown to be associated with sudden cardiac death.2,3

The QT interval represents the time between the beginnings of the Q wave until the end of the T wave. This interval is best measured in lead II and accounts for the total duration of ventricular depolarization and repolarization on the standard 12-lead surface electrocardiography (ECG). The QT interval should be reported uncorrected and corrected for heart rate (using the Bazett formula (QTc = QT/square root of the RR). A lengthened QT interval is a biomarker for ventricular tachyarrhythmias like torsades de pointes and a risk factor for sudden death.

On the other hand, QT dispersion (QTd) is defined as the difference between the longest and shortest QT intervals (QT dispersion = QT_max − QT_min) while QTc dispersion was calculated as QT dispersion corrected by heart rate using Bazett’s formula (QTc/R-R interval in seconds) (QTc dispersion = QTc_max − QTc_min).4,5

The QT dispersion and QTc dispersion are important since their role in predicting the risk of malignant arrhythmias has been shown.6,7 The average normal value of QT dispersion in normal subjects was ≤40 ms in 13 studies and ≥40 ms in eight studies.8 Perhaps the QT dispersion in normal subjects should be ≤50 ms.9 QTd values >65 ms are associated with an increased risk of serious ventricular arrhythmias and sudden death. QTd is often elevated in patients with diabetes mellitus, left ventricular hypertrophy, myocardial infarction, familial long-QT syndrome and mitral valve prolapse.10 In many studies prolonged QT dispersion (>65 ms) is reported among hemodialysis patients.7,11,12

Iron overload in ESRD patients, resulting from repeated blood transfusion and iron supplements for achieving the optimal effect of erythropoietin, may increase the risk for cardiac death. Iron plays an important role in oxygen delivery, free radical production and immunity.13 In the heart, iron is deposited predominantly in myocardial cells, rather than in the interstitium.14,15 This leads to impaired generation and propagation of electrical impulses at the level of the myocardial membrane.15 It has been suggested that excessive intracellular iron interferes with electrical function of the heart, either by generating large amounts of free radicals or by causing selective dysfunction of Na⁺ channels.15 Aberrant function of Na⁺ and K⁺ channels contributes to the etiology of prolonged QT syndrome, ventricular tachyarrhythmias and atrial fibrillation.16 However, there are limited data regarding changes in QT dispersion and QTc dispersion in patients receiving chronic ambulatory peritoneal dialysis (CAPD).

In this study, we evaluated the association between QT dispersion, QTc dispersion and iron load, as measured by serum ferritin and transferrin saturation (TSAT) in patients undergoing peritoneal dialysis (PD).

Materials and methods

Fifty-eight adult patients with chronic renal failure who were receiving CAPD were included in the study. Patients with atrial fibrillation, bundle branch block and patients taking any drugs that can affect QT interval were excluded from the study. The control group consisted of 19 healthy age- and sex-matched adults without cardiac or renal disease. The study protocol was approved by Fatih University Ethical Committee.

Electrocardiography and serum biochemistry were performed in all cases. Serum electrolyte levels, including sodium, potassium, calcium, magnesium and phosphate were measured at the time of the ECG.

Twelve-lead ECG were recorded with a three-channel electrocardiographic recorder at a paper speed of 25 mm/s. One blinded observer manually measured the QT intervals for each lead. The QT intervals were measured from the first deflection of the QRS complex to the point of T wave offset. Three consecutive cycles in each of the 12 leads were measured and mean QT interval was calculated. Meanwhile QT dispersion was defined as the difference between the minimal and maximal QT intervals. Each QT interval was corrected by heart rate according to Bazett’s formula [QTc = QT/(R−R)1/2] and then QTc dispersion was calculated. At least nine leads in which the QT interval could be measured were required for QT dispersion calculation.

Descriptive statistics are reported as mean ± SD. Comparisons between groups were made using Student’s t-test, Mann–Whitney U test, chi-squared test and Pearson correlation tests. p < 0.05 was considered as statistically significant. All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) version 16.0 for Windows (SPSS, Chicago, IL).

Results

The mean ages were 42.1 ± 13.6 years, and 42.4 ± 14.0 years in the subjects of the CAPD and control groups, respectively. Other main clinical characteristics are demonstrated in Table 1. The underlying causes of ESRD were as follows: Hypertensive nephropathy (n = 24), diabetic nephropathy (n = 16), chronic primary glomerulonephritis (n = 4), interstitial nephritis (n = 2), polycystic kidney disease (n = 2), obstructive nephropathy (n = 1), Lupus nephritis (n = 1) and unknown (n = 8). There was no significant difference between two groups in regards to age, weight and smoking habits (Table 1).

Table 1. Demographic and laboratory data of peritoneal dialysis and control subjects.

	PD patients (n = 58)	Controls (n = 19)	p
Age (years)	42.1 ± 13.6	42.4 ± 14.0	NS
Weight (kg)	69.2 ± 13.4	70.3 ± 13.9	NS
Blood urea nitrogen (mg/dL)	140.6 ± 50.2	22.4 ± 12.4	<0.0001
Serum creatinine (mg/dL)	7.4 ± 4.2	0.8 ± 0.3	<0.0001
Sodium (mEq/L)	137.8 ± 3.3	138.1 ± 3.1	NS
Potassium (mEq/L)	4.3 ± 0.6	4.4 ± 0.6	NS
Calcium (mg/dL)	8.8 ± 1.2	9.2 ± 1.1	NS
Phosphate (mg/dL)	5.3 ± 1.8	5.0 ± 1.9	NS
Magnesium (mg/dL)	1.0 ± 0.5	1.4 ± 0.3	NS
Smoker n (%)	12 (20.6)	4 (21.0)	NS
QT interval (s)	0.43 ± 0.34	0.34 ± 0.28	0.007
QTc (s)	0.46 ± 0.36	0.38 ± 0.27	NS
QT dispersion (s)	0.51 ± 0.23	0.48 ± 0.20	NS
QTc dispersion (s)	0.62 ± 0.29	0.55 ± 0.26	NS

Although the mean QTc dispersion was not significantly different between PD patients and control subjects, PD patients had a significantly longer QT interval than the control group (0.43 ± 0.34 s vs. 0.34 ± 0.28 s, p = 0.007). There was no significant difference in regards to the QTc, QT dispersion between two groups (Table 1).

For PD patients, there were no significant correlation between QTc dispersion and hemoglobin level, electrolyte levels, albumin, TSH and duration of PD treatment (Table 2). However, higher serum ferritin and TSAT levels (but not serum iron) were significantly and positively associated with greater QTc dispersion (respectively; r = 0.469, p < 0.01; r = 0.367, p < 0.01) (Figures 1 and 2). When PD patients were grouped according to QTc dispersion of ≥65 ms (n = 25) or <65 ms (n = 33), PD patients with QTc dispersion of ≥65 ms have significantly higher serum ferritin (Figure 3) and TSAT levels than PD patients with QTc dispersion of <65 ms (552.25 ± 344.37 vs. 284.38 ± 255.87, p = 0.038; 47.18 ± 29.12 vs. 32.03 ± 24.3, p = 0.022, respectively).

Figure 1. Correlation between QTc dispersion and ferritin levels in CAPD patients.

Figure 2. Correlation between QTc dispersion and TSAT levels in CAPD patients.

Figure 3. Boxplot showed that CAPD patients who have QTcD > 65 msn, have higher ferritin levels.

Table 2. Correlation between QTc dispersion and clinical and laboratory data in PD patients.

	QTc dispersion (ms)
	r	p
Duration of peritoneal dialysis (months)	−0.040	0.785
Hemoglobin (mg/dL)	−0.117	0.383
Albumin (mg/dL)	−0.052	0.708
Sodium (mEq/L)	0.054	0.692
Potassium (mEq/L)	0.102	0.452
Magnesium (mg/dL)	0.144	0.313
Phosphate (mg/dL)	−0.062	0.664
Iron (μg/dL)	−0.113	0.395
Transferrin saturation (%)	0.512	0.002
Ferritin (ng/mL)	0.469	0.003
TSH (µIU/mL)	−0.062	0.650

Discussion

Our study demonstrates that QT interval is increased in ESRD patients undergoing as compared with control subjects. We found no significant difference between control group and CAPD patients in regards to the QTc, QT dispersion or QTc dispersion. Although the prolongation of QTc dispersion have been shown in many studies among hemodialysis patients, in literature there was not a clear data about the QTc dispersion in CAPD patients.13–16 Interestingly, we found that there is strong correlation between QTc dispersion and ferritin, TSAT in PD patients.

QT dispersion, which reflects the differences in heart dipole projections and abnormalities of T-wave loop morphology, has been proposed as a direct measure of the regional heterogeneity of myocardial repolarization, and hence was predisposed to malignant arrhythmia.10 Day et al.4 proposed the use of QT dispersion (QTd) measurement as an index of the inhomogeneity of myocardial repolarization, which could be applied as a potential prognostic tool in the detection of future ventricular tachyarrhythmic events and sudden death. Increased QTc dispersion has been associated with patchy myocardial fibrosis, resulting from myocardial ischemia, ventricular dilatation, symptomatic overactivity and neurohormonal activation.10 Among patients with end stage renal disease, ventricular arrhythmias, which are generally caused by heterogeneous myocardial repolarization, are one of the main complications that increase the mortality. Furthermore, a recent study shows that QTc dispersion is an independent predictor of cardiovascular death, and associated with arrhythmia-related death in ESRD patients.7 Rapid potassium removal, low calcium dialysate, intracellular magnesium overload, and rapid bicarbonate gain are important factors that increase QTc dispersion in dialysis patients.10 In addition to these, heart disease such as acute myocardial infarct, presence of ischemic heart disease and LVH are responsible from increased QTc dispersion.10 In our results, we have no association between QTc dispersion and heart disease, electrolytes. But, QTc dispersion correlated transferrin saturation and ferritin.

The mechanism of arrhythmia induced by iron overload was attributed to the following mechanisms in PD patients: (a) excessive intracellular iron interferes with electrical function of the heart,17,18 (b) catalyze the generation of free radicals17,19 and (c) cause selective dysfunction of Na+ channels.15,17 Furthermore, iron overload is associated with increases in myocardial apoptosis and the development of fibrosis.20–23

Large iron load in animal models may change electrical conduction, which is the earliest detectable manifestation of iron cardiac toxicity, resulting in sudden death. A high incidence of unexplained sudden death in guinea pigs in a previous study was presumably owing to arrhythmias that were observed with larger doses of iron.24 To date, only one study has been published regarding the association of iron status with QTc dispersion in ESRD patients. Wu et al.25 measured QTc dispersion along with TSAT and ferritin levels in 102 peritoneal dialysis patients and found a linear correlation between QTc with TSAT, serum iron and serum ferritin levels, as well as a direct relationship between the duration of PD therapy and magnitude of QTc dispersion.25 QT dispersion, has been proposed to be a relevant parameter for the heterogeneity of iron deposition and duration of cardiac action potential.15

In conclusion, although prolonged QTc, QT dispersion and QTc dispersion were suggested as the markers of ventricular arrhythmias especially in patients with end stage renal disease we did not find any significant difference in regards to these parameters between control patients and CAPD patients. We showed that increased transferrin saturation and ferritin were prolonged QTc dispersion suggests that iron overload may contribute to arrhythmias in these dialysis patients. The possible mechanism of QT dispersion prolongation may be cooperation between iron and the precipitation of its toxicity in cardiac muscles in ESRD patients. Iron overload, from repetitive administration of parenteral iron or blood in attempts to maintain an optimum response to erythropoietin therapy, may increase the risk for sudden cardiac death and serious arrhythmia in CAPD patients. In clinical practice, transferrin saturation and ferritin were followed regularly in CAPD patients because increased iron stores were contributed to arrhythmias especially prolonged QTc dispersion.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.