The incidence and influencing factors of prolonged QTc interval in patients with HBV-ACLF.

doi:10.21203/rs.3.rs-2576638/v1

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The incidence and influencing factors of prolonged QTc interval in patients with HBV-ACLF.

https://doi.org/10.21203/rs.3.rs-2576638/v1

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Background

Although a large number of studies have shown that QTc interphase prolongation is common in patients with cirrhosis, there are few studies on the relationship between QTc interphase prolongation and Acute-on-Chronic liver (ACLF) patients in China. In addition, the cause of liver failure that our country causes are different from abroad. This paper attempts to discuss the incidence and potential risk factors of QTc interphase prolongation of HBV-ACLF patients in China.

Methods

A retrospective analysis was performed on the clinical data of 206 HBV-ACLF patients admitted to our study from January 2016 to December 2021 and 94 healthy controls during the same period. The heart rate (HR) and QT interval of 12-lead electrocardiogram (ECG) of patients after admission were collected, and the corrected QTc interval was calculated by Bazett formula. According to the QTc interval > 440milliseconds, patients were divided into extended group.

Results

Among 206 HBV-ACLF patients, 68 cases (33%) showed prolonged QTc interval, which was significantly different from 3 cases (3.19%) in the healthy control group (P < 0.001). Univariate analysis showed that RBC, CHOL, CRE, K, FIB, Ascites, HBV-DNA and Child–Pugh class had statistical significance (P < 0.05), and binary logistic regression analysis showed that K, CRE, HBV-DNA and Ascites (P < 0.05) were the independent influencing factors for the prolonged QTc interval in HBV-ACLF patients.

Conclusions

In this study, it was found that the incidence of QTc interval prolongation was about 33% in HBV-ACLF patients. K, CRE, HBV-DNA and Ascites are independent factors influencing the prolonged QTc interval in patients with HBV-ACLF.

Acute-on-chronic liver failure

Hepatitis B virus

QTc interval

Incidence

Influence factor

Severity of illness

Liver failure is the most serious form of liver injury caused by many factors such as virus, alcohol, drugs and ischemia-reperfusion^{1, 2}. Liver failure has become one of the most important disease burden in the world due to its high cost and poor prognosis. It is also the difficulty of clinical treatment and the hotspot of research at present. The most common type of liver failure in China is Acute-on-chronic liver failure (ACLF), in which Hepatitis B virus-related ACLF accounts for more than 80% of the total ACLF^{3, 4}.

One or more organ failure caused by liver failure is also one of the reasons for higher mortality of liver failure. In recent years, the concept of cirrhotic cardiomyopathy has been proposed, which is defined as chronic cardiac insufficiency with diastolic relaxation and/or systolic dysfunction, and electrophysiological abnormalities such as QTc interval prolongation. And it has been found by epidemiology that the probability of developing cirrhotic cardiomyopathy is as high as 50%⁵. Prolongation of QTc interval was found to be the most common ECG manifestation of cirrhosis. Currently, there have been reports of malignant arrhythmia and sudden cardiac death caused by prolongation of QTc interval in patients with cirrhosis, and it has been found that prolongation of QTc interval is associated with mortality of advanced liver disease^{6, 7}. In addition to being a potential risk factor for ventricular arrhythmia, prolonged QTc interval may also be an electrophysiological marker of cirrhotic cardiomyopathy^{8, 9}.

However, most foreign studies focus on the prolonged QTc interval in cirrhosis. It is known that alcoholic disease is the main cause of cirrhosis abroad, and hepatitis B cirrhosis is the main cause of cirrhosis in China. The results of foreign studies are not applicable to China. However, there are few studies on the incidence and influencing factors of QTc prolongation in ACLF patients in China. This study mainly discussed the incidence and independent influencing factors of QTc prolongation in ACLF patients in China.

Object of study

This study was a single-center retrospective case-control study. A total of 206 HBV-ACLF patients admitted to the Department of Infection, the First Affiliated Hospital of Xi 'an Jiaotong University from January 2016 to December 2021 were collected. All the included patients meet the diagnostic criteria of chronic plus acute liver failure in the 2018 edition of Guidelines for Diagnosis and Treatment of Liver Failure, and 94 healthy control patients were collected during the same period. Exclusion criteria: 1. Patients with ACLF caused by other causes other than hepatitis B virus were excluded; 2. Patients with chronic cardiovascular diseases such as arrhythmia and heart failure were excluded; 3. Exclude patients with metabolic diseases complicated with hypertension, diabetes, thyroid and other diseases that are likely to cause cardiovascular diseases; 4. Excluded patients using drugs affecting the QTc interval, and excluded patients without ECG examination after admission; 5. Patients with an interval of ≥ 7 days between ECG and blood sampling after admission were excluded. A total of 206 ACLF patients finally meet the study criteria, among which 68 patients with prolonged QTc interval occurred as the case group, and 138 patients without prolonged QTc interval occurred as the control group (Fig. 1). The study design was approved by the Ethics Committee of Xi 'an Jiaotong University (XJTU1AF2018LSL-002), in accordance with the Declaration of Helsinki, and all participants signed written informed consent.

Research method

The HR and QT interval of 12-lead ECG after admission were collected, and the corrected QTc interval was calculated by using the internationally accepted Bazett formula (QTc = QT/√RR, RR = 60/HR)¹⁰.According to QTc interval > 440ms, they were divided into extended group and non-extended group ≤ 440ms¹¹. The baseline characteristics consisted of number of patients analyzed, age, sex, etiology of chronic acute liver failure, hepatic encephalopathy(HE), ascites, and laboratory tests (i.e., red blood count (RBC),white blood count (WBC),hemoglobin (HGB), aspartate aminotransferase (AST), alanineaminotransferase(ALT),totalcholesterol(CHOI),albumin(ALB),creatinine(CRE),potassium (K),fibrinogen(FIB),prothrombin time activity(PTA),Child–Pugh class/score(CTP), model for end-stage liver diseases (MELD) score.

Statistical analysis

IBM SPSS Statistics V.26.0 was used to analyze the data. χ² test was used for comparison between counting data groups, t-test was used for normal continuous variables, represented by mean ± standard deviation, non-normal continuous variables were used for non-parametric tests of two independent samples, represented by median (lower quarter-upper quater), and P < 0.05 was considered to be statistically significant.

A total of 403 patients were diagnosed with chronic acute liver failure,197 cases were excluded because they did not meet the study criteria. In summary, 206 cases were included in our study. The baseline characteristics of eligible patients are shown in Table 1. There were 177 male patients (85.92%).

Table 1

Baseline characteristics.
Variables	All patients
	Number of patients(n)	Mean ± SD or frequency(percentage)	Median(Range)
Sex(male/female)	206	177/29
HBV-DNA(positive/negative)	206	189/17
Ascites(positive/negative)	206	110/96
Hepatic encephalopathy(positive/negative)	206	35/171
Age(years)	206	42.58 ± 11.07	42(34～50.25)
RBC(10¹²/L)	206	4.03 ± 0.77	4.01(3.52～4.4.54)
WBC(10⁹/L)	206	6.32 ± 3.01	5.69(4.42～7.52)
HGB(g/L)	206	128.48 ± 21.33	128(116～144)
AST (U/L)	206	363.18 ± 401.28	191(93.50～530.25)
ALT (U/L)	206	558.43 ± 730.19	249(87.50～675.75)
CHOI(mmol/L)	206	2.44 ± 0.88	2.33(1.81～2.86)
ALB(g/L)	206	32.55 ± 4.99	32.20(29.48～36.13)
CRE(umol/L)	206	65.51 ± 34.56	60(49.75～69)
K(mmol/L)	206	3.84 ± 0.57	3.78(3.50～4.23)
FIB (g/L)	206	1.53 ± 0.57	1.51(1.12～1.82)
PTA(%)	206	38.47 ± 16.55	35.60(27～46.25)
Child–Pugh class (A/B/C)	206	3/66/137
MELD score	206	18.84 ± 6.32	18.11(15.39～22)

We compared the rate of QTc prolongation in 206 HBV-ACLF patients with 94 healthy controls (Table 2). Results showed that among 206 patients, 68 patients had prolonged QTc interval, with an incidence of 33%. And the incidence of prolonged QTc interval was significantly higher in HBV-ACLF patients than in healthy controls.

Table 2

Comparison of the incidence of prolonged QTc between HBV-ACLF patients and healthy controls
group	count	• Incidence of prolonged QTc interval(%)	P value
Healthy control group	94	3/94(3.19%)	< 0.001
HBV-ACLF group	206	68/262(33%)	< 0.001

The collected data were divided into two groups according to whether the QTc interval was prolonged or not (QTc > 440 was divided into the extended group and the non-extended group ≤ 440), and then univariate analysis was performed on the prolongation of QTc interval. Results showed that HBV-DNA, Ascites, RBC, CHOI, CRE, K, FIB and Child–Pugh class difference in the two groups in the statistical (Table 3).

Table 3

Comparative data of HBV-ACLF patients.
Variables	QTc prolongation(QTc > 440)			No QTc prolongation (QTc ≤ 440)			P value
	Number of patients(n)	Mean ± SD or Frequency (percentage)	Median (Range)	Number of patients (n)	Mean ± SD or Frequency (percentage)	Median (Range)	P value
Sex (male/female)	68	59/9		138	118/20		0.807
HBV-DNA(positive/negative)	68	58/10		138	131/7			0.018
Ascites(positive/negative)	68	45/23		138	65/73		0.01
HE(positive/negative)	68	10/58		138	25/113		0.54
Age (years)	68	41.84 ± 10.31	41.50(34.50～50)	138	42.95 ± 11.45	42.50(33～51)	0.703
RBC(10¹²/L)	68	3.86 ± 0.80	3.97(3.14～4.42)	138	4.11 ± 0.75	4.03(3.67～4.65)	0.024
WBC(10⁹/L)	68	6.38 ± 3.07	5.76(4.33～7.90)	138	6.29 ± 2.99	5.64(4.42～7.48)	0.708
AST (U/L)	68	304.30 ± 401.96	178.50(75.75～367.25)	138	392.20 ± 399.21	212.50(100.25～576.25)	0.079
ALT (U/L)	68	438.05 ± 649.01	185(58～517.75)	138	617.74 ± 762.29	276(91.75～844.75)	0.051
CHOI(mmol/L)	68	2.18 ± 0.84	2.03(1.64～2.51)	138	2.57 ± 0.87	2.53(2～3.02)	＜0.001
ALB(g/L)	68	31.59 ± 4.66	31.60(28.58～34.85)	138	33.03 ± 5.09	32.80(29.68～37.45)	0.051
CRE( umol/L)	68	58.97 ± 23.70	58(47.25～65)	138	68.73 ± 38.48	61(50.75～74.25)	0.042
K(mmol/L)	68	3.63 ± 0.58	3.65(3.30～3.94)	138	3.94 ± 0.84	3.86(3.57～4.28)	＜0.001
PTA(%)	68	35.74 ± 13.24	34.05(26.93～40.57)	138	39.82 ± 17.85	37.85(27～50.25)	0.149
FIB(g/L)	68	1.37 ± 0.45	1.36(0.98～1.73)	138	1.61 ± 0.61	1.57(1.17～1.93)	0.006
Child–Pugh class (A/B/C)	68	0/12/56		138	3/54/81		0.001
MELD score	68	19.60 ± 4.49	18.95(16.79～21.58)	138	18.47 ± 7.04	17.47(14.68～22.09)	0.058

The statistically significant data analyzed in Table 3 were analyzed by binary logistic regression again, and the final results showed that K, CRE, HBV-DNA and Ascites were independent influencing factors for the prolonged QTc interval in patients with HBV-ACLF and the prediction accuracy was high 71.4%. (Table 4).

Table 4

Logistic regression analysis of independent influencing factors related to QTc interval prolongation
Variables	β	P	OR	95%CI
K	-1.354	＜0.001	0.258	0.130–0.513
CRE	-0.017	0.019	0.983	0.970–0.997
HBV-DNA	-1.310	0.041	0.270	0.077–0.946
Ascites	0.870	0.043	2.388	1.028–5.543

The results of binary logic were drawn into the deep forest map as follows (Fig. 2). It can be clearly seen from the figure that ascites is an independent risk factor for prolonged QTc interphase, while K, CRE and HBV-DNA are independent protective factors for prolonged QTc interphase.

It is known to all, this is the first study to research the incidence and influencing factors of prolonged QTc interval of patients with HBV-ACLF in China. Our study found that the incidence of QTc prolongation was significantly higher in ACLF patients than in normal subjects (33% vs 3.19% p < 0.001).

In their study, Danish researchers found a prolonged QTc interval in 37% of cirrhotic patients, compared with 5.9% in the control group¹². In a recently published study of 1268 cirrhotic patients in China, the rate of QTc prolongation was 38.2%¹¹. In contrast, the QTc interval elongation rate in our study was 33%.

The length of QTc interval is affected by physiological conditions, such as age, sex, and QTc interval tends to be longer in the elderly and female population. However, liver disease has been found to eliminate gender differences in most cirrhosis studies^{13, 14}. This is consistent with our findings that gender is not a factor influencing the prolongation of QTc in HBV-ACLF patients (Table 3). Most studies support an association between cirrhosis severity (Child-Pugh grade or MELD) and QTc prolongation, but there are also studies demonstrating that disease severity is not a factor in QTc prolongation, which is consistent with our findings^15–17. Finally, our study found that K, CRE, HBV-DNA and Ascites were independent factors influencing the prolongation of QTc interphase^{l7, 18}. The latest study found that total cholesterol is a factor affecting the prolongation of QTc interval in pregnant women¹⁹. In our study, total cholesterol was statistically significant in the univariate analysis, but it was not an independent factor affecting the QTc interval after the final binary logistic regression analysis. The reasons are analyzed as follows.

Bile acid is synthesized in liver cells and is the main metabolite of cholesterol pathway. Clinically, liver diseases are usually accompanied by abnormal metabolism of bile acid. In chronic acute liver failure, the value of bile acid increases exponentially. It was found that bile acids can exert cytotoxic effects by activating nuclear receptors such as Farnitol X receptor (FXR) and membrane receptor Takeda G protein-coupled receptor 5 (TGR5), which can lead to prolonged QTc interval, cardiac hypertrophic, myocardial apoptosis and cardiac hemodynamic abnormalities^{5, 20}.

In conclusion, total cholesterol may affect QTc interphase and myocardial cell function through bile acid, and bile acid has been found to be an indicator of liver disease severity and a predictor of adverse outcomes²¹. In our study did not find the influence factors of bile acid is extended between the QTc, we speculate that because at present we measured serum total bile acid is the floorboard of the type of cholesterol metabolite, including a variety of bile acid classification, through the different structure of bile acid can be divided into the hydrophobic and hydrophilic bile acid, and the hydrophobic bile acid has cytotoxicity, It can lead to cardiac dysfunction and prolongation of QTc interval^22–24.Hydrophilic bile acids reduce cytotoxicity by increasing the number of hydroxyl groups and can antagonize or even reverse the toxic effects of hydrophilic bile acids on liver and heart. Ursodeoxycholic acid (UDCA), a well-known and commonly used drug for the treatment of cholestatic liver disease, was one of the total bile acids that reversed myocardial damage when injected into a cholestatic mouse model²⁵. In order to study the relationship between bile acids and QTc interval or heart, it is necessary to analyze the bile acids in total bile acids, which has been performed in mouse cardiomyocytes, but has been rarely studied in humans. This study provides a new approach for further research on the molecular mechanism of how liver failure affects the heart.

It is well known that various types of potassium channels exist in cardiomyocytes and affect the action potential of cardiomyocytes. Recent studies have found that systemic inflammation can affect the prolongation of QTc interphase through the change of K ion channel expression mediated by cytokines²⁶. In addition, a large number of studies have shown that the serum K ion in patients with prolonged QTc interval is significantly lower than that in patients without prolonged QTc interval. One possible explanation is that changes in heart rate and QRS duration correlate with changes in serum electrolyte concentration, which is consistent with our study results^{27, 28}. In Sherif et al. 's study, it was found that every 1mmol/L increase in serum K concentration could lead to a 16ms decrease in QTc interphase²⁹.

Clinically, when patients with hepatitis develop liver failure, there will be decreased total cholesterol, increased total bile acid, secondary renal insufficiency resulting in increased creatinine, and electrolyte disorder, which are all indicators of disease severity, reflecting the correlation between prolonged QTc interval and disease severity of liver failure in HBV-ACIF population³⁰. In our study, it showed a significant negative correlation between QTc interval and serum CRE level (p < 0.019; Table 4), where the higher serum the CRE level, the longer the QTc interval with no sex difference. Which is consistent with our study results³¹.

In addition, because our study population is chronic acute liver failure caused by hepatitis B, we want to explore whether positive hepatitis B virus has an impact on the prolongation of QTc interval. We collect hepatitis B virus test of the included study population, and mark the results beyond the test limit as positive, otherwise as negative. After statistical analysis, it is concluded that, HBV positive status is also an independent factor for prolonged QTc interphase. This is the first time to explore the relationship between HBV virus and QTc interphase. However, in our study showed a significant but discrepant negative correlation between HBV-DNA and QTc interval (p = 0.041; Table 4), where the HBV-DNA negative but the longer the QTc interval. We hypothesized that this difference might be related to the use of antiviral drugs among the patients, but unfortunately, this study failed to collect the information of antiviral drugs included in the patients.

Finally, studies have shown that ascites is an independent risk factor for prolonged QTc interval, which is consistent with our findings (p = 0.043; Table 4)^{11, 32}.

In conclusion, because QT interval measurement is simple, noninvasive, and repeatable, it can be used as an indicator of HBV-ACIF disease severity. This study can guide clinicians to pay more attention to patients with prolonged QTc, improve the related factors leading to prolonged QTc in time, and prevent patients from having serious arrhythmias that may lead to adverse outcomes.

To our knowledge, this is the first study to examine the prevalence and influencing factors of prolonged QTc interval in HBV-ACLF patients. From our study, we know that the prevalence of prolonged QTc is common in patients with chronic plus acute liver failure. Therefore, more studies are needed to investigate the mechanisms of QTc prolongation in HBV-ACLF patients. In addition, K, CRE, HBV-DNA and Ascites were the independent influencing factors for the prolonged QTc interval in HBV-ACLF patients. Therefore, in the process of clinical treatment of such patients, if the patient is found to have ascites, total cholesterol, renal insufficiency and low potassium, corresponding preventive measures should be taken, such as timely correction of electrolyte disturbance, timely treatment of ascites, protection of kidney function and avoid the use of QTc interval prolapse drugs.

There are some limitations to our study. First of all, the number of collected was limited, and some clinical parameters did not reach statistical significance, which may affect the results of the study. In addition, we did not obtain echocardiographic information for each patient, and QTc interphase should be combined with echocardiography to comprehensively evaluate the impact on the patient's heart. In addition, our study was a cross-sectional study, and we did not record baseline electrocardiograms before patients did not have liver failure to further interpret our findings. Therefore, future studies hope to dynamically observe the changes of QTc interval in such patients. Finally, due to our incomplete follow-up work, the relationship between the rate of QTc interval prolongation and mortality in these patients needs to be further explored. Therefore, our next research work hopes to answer these questions.

QTc: QT interval corrected by heart rate

ACLF: Acute-on-Chronic liver

HBV: hepatitis B virus

ECG: electrocardiogram

RBC: red blood count

HGB: hemoglobin

WBC: white blood count

AST: aspartate transaminase

ALT: alanine aminotransferase

CHOI: total cholesterol

CRE: creatinine

PTA: prothrombin time activity

ALB: albumin

K: potassium

FIB: fibrinogen

CTP: Child–Pugh class

MELD: Model for End-Stage Liver Diseases

SD: standard deviation.

OR: Odds ratio

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgements

Thank you to all the patients who participated in the study and to the National Natural Science Foundation for your support.

Funding

This study was supported by the National Natural Science Foundation of China, No. 82070641.

Contribution

Rou Zhang, Heng Gao and Mengjun Fu were responsible for project design, data analysis and paper writing. Juan Li, Mimi Zhou, YaLi Feng and JinFeng Liu participated in collecting data and modifying the paper. YingRen Zhao and Yingli He is responsible for writing ideas, directing the writing and finalizing the article. All authors contributed substantially to the project, read and approved the manuscript, and accepted responsibility for the content of the manuscript.

Ethics declarations

Ethics approval and consent to participate

The study design was approved by the Ethics Committee of Xi'an Jiaotong University (XJTU1AF2018LSL-002), in accordance with the Declaration of Helsinki, and all participants signed written informed consent.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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The incidence and influencing factors of prolonged QTc interval in patients with HBV-ACLF.

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