Correlation between lactate dehydrogenase and QTc interval prolongation in maintenance hemodialysis patients: a cross-sectional study

Introduction

The incidence of chronic kidney disease (CKD) is increasing, and sudden cardiac death (SCD) is the leading cause of death in hemodialysis patients. The increased risk of arrhythmia is an important cause of SCD in this disease population. According to statistics, in the dialysis population, the ratio of the number of deaths caused by arrhythmia or cardiac arrest to the total number of deaths on dialysis is close to 1/3 (1). In the hemodialysis population, cardiac arrhythmias may occur during and shortly after treatment independent of traditional cardiovascular risk factors (2,3). In patients with end-stage renal disease (ESRD), QTc interval prolongation is common, but the mechanism of its prolongation has not yet been elucidated. There are relatively few clinical studies on QTc interval prolongation in patients with CKD at home and abroad. Previous studies have shown that the causes of prolonged QTc interval include drugs, myocardial ischemia, heart failure, cardiomyopathy, bradycardia, male, advanced age, inflammation, tumor, liver and kidney insufficiency, hypothyroidism, hypokalemia, hypocalcemia, hypomagnesemia, diabetes, etc. (4-7). Lactate dehydrogenase (LDH), as a myocardial marker, is significantly increased in maintenance hemodialysis (MHD) population, and LDH is associated with the mortality of MHD patients (8). So far, there has been no research on the correlation between LDH and QTc interval prolongation. This study investigated the influencing factors of QTc interval prolongation in MHD patients and the correlation between LDH and QTc interval prolongation. We present the following article in accordance with the STARD reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-22-1053/rc).

Methods

Patient

A retrospective analysis was performed between November 2012 and November 2019 in the Department of Nephrology of the Second Affiliated Hospital of Nantong University. Patients who underwent MHD for more than 3 months, the dialysis vascular access was an autogenous arteriovenous fistula, those who had a 12-lead electrocardiogram (ECG), received echocardiography, and those with complete follow-up data were included in the study. The exclusion criteria were as follows: (I) arrhythmia; (II) patients with confirmed hereditary long QTc syndrome; (III) acute coronary syndrome, cardiomyopathy, or heart valve disease; (IV) other known causes of QTc interval prolongation, or diseases or conditions such as liver disease, acute stroke, malignant tumor, hypothyroidism, application of drugs that can prolong the QTc interval, etc.; (V) the information was incomplete (Figure 1). The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of the Second Affiliated Hospital of Nantong University (approval number: 2022KT241) and individual consent for this retrospective analysis was waived.

Figure 1 Flowchart of study participant selection. MHD, maintenance hemodialysis; ECG, electrocardiogram; QTc, corrected QT.

Grouping

A 12-lead resting ECG was used to record the QTc of the subjects. QTc interval prolongation was defined according to QTc ≥450 ms in men and QTc ≥460 ms in women (9), and they were divided into the normal QTc interval group and QTc interval prolongation group.

Dialysis program

The frequency of dialysis was 3 times/week, 4 hours/time, and Duration on HD ≥3 months. The dialysate was bicarbonate dialysate, the dialyzer used was Nipro 15G, cellulose acetate membrane (area 1.5 m²) was used, the dialysate flow rate was 500 mL/min, the blood flow rate was 200–300 mL/min, and the dialysate calcium was 1.5 mmol/L, dialysate potassium was 2.0 mmol/L, anticoagulation with low molecular weight heparin.

Data collection

All study subjects were enrolled at the time when they received a 12-lead ECG in our center. Fasting blood was collected before the first dialysis every week, and the selected blood collection time and the 12-lead ECG time interval did not exceed 24 hours. The time of echocardiography and 12-lead ECG of the enrolled patients did not exceed 1 month. The following baseline data were collected: age, gender, primary disease, body mass index (BMI), duration on HD, predialysis systolic blood pressure (SBP), predialysis diastolic blood pressure (DBP), hemoglobin (Hb), alanine aminotransferase (ALT), aspartate aminotransferase (AST), LDH, albumin (Alb), serum creatinine (Scr), uric acid (UA), blood glucose (Glu), total cholesterol (TC), triacylglycerol (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), serum potassium (K), corrected calcium (Ca), serum phosphorus (P), bicarbonate (HCO₃^-), magnesium (Mg), high-sensitivity C-reactive protein (hs-CRP), parathyroid hormone (PTH), and N-terminal precursor brain natriuretic peptide (NT-proBNP). The 12-lead ECG was performed by specialists in the ECG room of our hospital, and the ECG was recorded when the patient was in a stable condition. The ECG paper speed was 25 mm/s and the standard voltage was 10 mm/mv. The corrected QT interval was calculated using the Bazett formula [QTc = QT/(RR^0.5)]. Echocardiography was performed by cardiac ultrasound specialists in our hospital using Philips EPIQ 7C, IE33 echocardiograph, with X5-1 probe/frequency 1–3 MHz, S5-1 probe/frequency 1–5 MHz, and QLAB 3DQA quantitative analysis software. The patient was instructed to lie on the left side in a calm state. Aortic diameter (AOD), left atrial diameter (LAD), ventricular septal thickness (IVS), left ventricular posterior wall thickness (LVPW), left ventricular end-diastolic diameter (LVDd), left ventricular end-systolic diameter (LVDs), Ejection fraction (EF), and left ventricular mass (LVM) were measured.

Statistical analysis

Statistical processing of data was performed with SPSS 23.0, GraphPad prism 8.0, and MedCalc 19.1 software packages. GPower3.1.9.2 was used to estimate the sample size, α=0.05 (two-sided), 95% confidence (Power =1−β), and the minimum sample size was calculated as 176 cases. Normally distributed measurement data were expressed as mean ± SD, and the t-test was used for comparisons between groups. Dialysis age, hs-CRP, PTH, and NT-proBNP were non-normally distributed data, and the logarithm (Lg) was converted to normal distribution data for analysis. At the same time, non-normally distributed measurement data were represented by M (P_1/4, P_3/4), and the non-parametric test was used for comparisons between groups. Enumeration data were expressed as percentage or frequency, and the χ² test was used for comparisons between groups. Pearson’s correlation analysis was used to analyze the correlation between relevant indicators and QTc. Relevant factors were analyzed by binary logistic regression analysis. Receiver operating characteristic (ROC) curves and the Youden index were used to evaluate the predictive effect of LDH on QTc interval prolongation in MHD patients, and the cutoff value was calculated. A difference of P<0.05 was statistically significant.

Results

Baseline information

A total of 279 patients were included in this study. Among them, there were 154 males (55.2%) and 125 females (44.8%), with an average age of 60.41±14.58 years. There were 155 cases (55.6%) in the normal QTc interval group and 124 cases (44.4%) in the QTc interval prolongation group. In the QTc interval prolongation group, the QTc was 478.31±21.64 ms. Compared with the normal QTc interval group, the proportions of males, DBP, ALT, LDH, serum potassium <4 mmol/L, P, PTH, LAD, LVDd, LVDs, and LVM in the QTc interval prolongation group were significantly higher than those in the normal QTc interval group (P<0.05). Age, Alb, corrected calcium, and EF values in the prolonged interval group were significantly lower than those in the normal group (P<0.05; Table 1).

Correlation between QTc interval and observational indicators

The results of Pearson correlation analysis showed that the QTc interval was closely related to ALT (r=0.150), LDH (r=0.386), Cr (r=0.123), P (r=0.205), LgPTH (r=0.123), LgBNP (r=0.141), LAD (r=0.245), LVDd (r=0.314), LVDs (r=0.325), and LVM (r=0.246) and were positively correlated, while Alb (r=−0.159), serum potassium (r=−0.133), corrected calcium (r=−0.166), and EF value (r=−0.263) were negatively correlated (Table 2, Figure 2).

Figure 2 Correlation analysis between LDH level and QTc interval prolongation in MHD patients. QTc, corrected QT; LDH, lactate dehydrogenase; MHD, maintenance hemodialysis.

Related factors and independent related factors of QTc prolongation

Univariate binary logistic regression analysis showed that gender, age, DBP, ALT, LDH, Alb, Ca, K<4 mmol/L, P, LAD, LVDd, LVDs, EF value, and LVM were the related factors for QTc prolongation. We included the results of single factor P<0.05 into the multivariate binary logistic regression analysis and the results showed that LDH, K<4 mmol/L, P, and LVDd were independent related factors for QTc interval prolongation (Table 3).

ROC curve of LDH in predicting QTc interval prolongation in MHD patients

To explore the predictive value of LDH for QTc interval prolongation in MHD patients, the cutoff value of LDH was determined by an ROC curve. When the cutoff level was 220 U/L, the sensitivity was 81.45%, the specificity was 59.35%, and the Youden index was 0.408 (Figure 3).

Figure 3 ROC curve of LDH in predicting QTc interval prolongation in MHD patients. AUC, area under the curve; ROC, receiver operating characteristic; LDH, lactate dehydrogenase; QTc, corrected QT; MHD, maintenance hemodialysis.

According to the cutoff value of LDH, we divided patients into the LDH ≤220 U/L group and LDH >220 U/L group, with QTc interval prolongation as the dependent variable. The risk of QTc interval prolongation in the high LDH group was 6.41 times that in the low LDH group. In the model adjusted for K<4 mmol/L + P + LVDd, the risk of QTc interval prolongation in the high LDH group was 6.34 times that of the low LDH group (Table 4).

Discussion

The QT interval on a standard 12-lead ECG represents the time from ventricular depolarization (start of Q wave) to completion of cardiac repolarization (end of T wave). The QT interval increases with the slowing of the heart rate. Therefore, when measuring, evaluating, and comparing whether there is a prolongation or shortening of the QT interval, it should be determined according to the heart rate. Most scholars use QTc to represent the heart rate-corrected QT interval. The method for calculating QTc in this study was to use the Bazett formula for correction.

MHD patients are a high-risk group for cardiovascular disease. According to the 2015 annual data report of the American Renal Data System, cardiovascular disease caused more than 40% of ESRD patient deaths, and cardiac arrhythmia and cardiac arrest accounted for about 28.0% of the deaths (10). Studies have shown that in patients with CKD or those receiving hemodialysis or peritoneal dialysis, a longer QTc interval is associated with an increased risk of death, heart failure, coronary heart disease, and sudden death (11-13). Low K low Ca, and low P are recognized risk factors for QTc interval prolongation (4,14). During hemodialysis, a rapid drop in serum calcium or potassium can lead to a prolongation of the QTc interval and an increase in QTc dispersion (15-18). In this study, there were similar results. Compared with the normal QTc interval group, the proportion of K<4 mmol/L in the QTc interval prolongation group was significantly higher than that in the normal QTc interval group. The corrected calcium in the QTc interval prolongation group was significantly lower than that in the QTc interval normal group. Serum potassium and corrected calcium were negatively correlated with QTc interval, and K<4 mmol/L was an independent related factor for QTc interval prolongation. The “Expert Consensus on Ion Management of Patients with Heart Failure in China” recommends that potassium in patients with heart failure should be controlled between 4.0–5.0 mmol/L. Even if the serum potassium is at a low normal value of 3.5–4.0 mmol/L, potassium should be supplemented appropriately. Attention should be paid to magnesium supplementation, which can reduce the risk of arrhythmia. Hypocalcemia in MHD patients is mainly caused by active vitamin D deficiency, metabolic acidosis, insufficient calcium intake, and osteodystrophy. When blood calcium is low, the influx of calcium ions into cells is slowed, and the ECG shows ST segment prolongation, normal T wave width, and total QTc interval prolongation. In addition, this study found that blood P was an independent related factor for QTc interval prolongation, which was consistent with previous literature reports (19). It shows that abnormal calcium and phosphorus metabolism in patients with CKD has a certain relationship with the prolongation of QTc interval.

In this study, LAD, LVDd, and LVM were positively correlated with QTc interval, while EF was negatively correlated with QTc interval. Furthermore, LVDd was an independent related factor for QTc interval prolongation. Cerbai et al. (20) found that compared with normal cardiomyocytes, there was a transient decrease in the expression of outward potassium current channels in cardiomyocytes with left ventricular hypertrophy. Therefore, it is considered that the prolonged action potential time of cardiomyocytes is related to this. The hypertrophic ventricle may set the stage for QTc prolongation and uneven recovery of excitability, which may increase the risk of arrhythmias in this condition (21,22). Liu et al. found that decreased left ventricular EF in CKD patients was an independent risk factor for QTc prolongation in this disease population (23). Therefore, for CKD patients with reduced cardiac function and structural heart disease, the risk of arrhythmia should be assessed carefully.

At the same time, in this study, it was found that LDH was positively correlated with QTc interval prolongation and was also an independent related factor for QTc interval prolongation, and this result was rarely found in other studies. LDH exists in the tissues and cells of the human body, with the highest content in the kidneys, and decreases in the cardiac muscle, skeletal muscle, liver, and red blood cells in turn. Conditions that lead to increased blood LDH include tissue damage, necrosis, hypoxia, hemolysis, or malignancy. Uremic patients are often accompanied by severe cardiomyopathy, and dialysis aggravates myocardial damage. The QTc interval represents the repolarization of the cardiomyocytes with the longest action potential duration, that is, M cells. Some scholars have established 2 models of lethal ventricular tachyarrhythmia (LVTA), representing LVTA caused by abnormal myocardial ion channels and myocardial ischemia (24). β-oxidation and anerobic glycolysis are enhanced, TCA is inhibited, and amino acid metabolism is disordered. As a cardiac ion channel disease, QTc interval prolongation may result in glycolysis, and LDH is one of the important enzymes in anerobic glycolysis and gluconeogenesis, and there may be a certain relationship between the two. Therefore, LDH level may be an effective indicator for the diagnosis of QTc interval prolongation.

The results of this study showed that the LDH level of MHD patients in the prolonged QTc interval group was significantly higher than that in the normal QTc interval group. Univariate and multivariate binary logistic regression analysis showed that LDH was an independent related factor for QTc interval prolongation in MHD patients. In addition, the risk ratio of QTc interval prolongation in patients with high LDH level was significantly increased. After adjusting for factors such as K<4 mmol/L, P, and LVDd, the risk of QTc interval prolongation in patients with high LDH level was still 6.34 times that of the low level group. Therefore, this study suggests that the increase of LDH level may play an important role in the pathophysiological process of QTc interval prolongation in MHD patients, and the mechanism may be related to myocardial injury and enhanced anerobic glycolysis in MHD patients.

There are some shortcomings in this study. First, this study is a single-center, retrospective analysis with a small sample size. The relationship between LDH and QTc, and whether LDH can accurately predict the occurrence of QTc interval prolongation, must be analyzed in large-scale, long-term, prospective studies for further confirmation. Second, QTc was calculated using the Bazett formula, which partially overestimates the QTc value when the patient’s heart rate is high.

In conclusion, LDH in MHD patients is closely related to QTc interval prolongation, and its mechanism may be related to myocardial injury and enhanced anerobic glycolysis in MHD patients. LDH, K<4 mmol/L, serum P, and LVDd were independent related factors for QTc interval prolongation. Monitoring related indicators can remind clinicians to intervene as soon as possible to reduce the potential risk of arrhythmia and sudden cardiac death (SCD).

Acknowledgments

Funding: The study was supported by Municipal Health Commission Fund of Nantong City, Jiangsu, China (Nos. MB2019009, MA2020004) and Nantong Science and Technology Bureau Fund (Nos. JCZ21099, JCZ21067).

Footnote

Reporting Checklist: The authors have completed the STARD reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-22-1053/rc

Data Sharing Statement: Available at https://apm.amegroups.com/article/view/10.21037/apm-22-1053/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-22-1053/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Ethics Committee of the Second Affiliated Hospital of Nantong University (approval number: 2022KT241) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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(English Language Editor: C. Betlazar-Maseh)