Clinical impact of complete atrioventricular block in patients with ST‐segment elevation myocardial infarction

Abstract Complete atrioventricular block (CAVB) is a common complication of ST‐segment elevation myocardial infarction (STEMI). Although STEMI patients complicated with CAVB had a higher mortality in the thrombolytic era, little is known about the impact of CAVB on STEMI patients who underwent primary percutaneous coronary intervention (PCI). The study aimed at evaluating the clinical impact of CAVB on STEMI patients in the primary PCI era. We consecutively enrolled 1295 STEMI patients undergoing primary PCI within 24 hours from onset. Patients were divided into two groups according to the infarct location: anterior STEMI (n = 640) and nonanterior STEMI (n = 655). The outcomes were all‐cause death and major adverse cardiocerebrovascular events (MACCE) with a median follow‐up period of 3.8 (1.7–6.6) years. Eighty‐one patients (6.3%) developed CAVB. The incidence of CAVB was lower in anterior STEMI patients than in nonanterior STEMI (1.7% vs 10.7%, p < .05). Anterior STEMI patients with CAVB had a higher incidence of all‐cause deaths (82% vs 20%, p < .05) and MACCE (82% vs 25%, p < .05) than those without CAVB. Although higher incidence of all‐cause deaths was found more in nonanterior STEMI patients with CAVB compared with those without CAVB (30% vs 18%, p < .05), there was no significant difference in the incidence of MACCE (24% vs 19%). Multivariate analysis showed that CAVB was an independent predictor for all‐cause mortality and MACCE in anterior STEMI patients, but not in nonanterior STEMI. CAVB is rare in anterior STEMI patients, but remains a poor prognostic complication even in the primary PCI era.


| Study population
This was a retrospective and observational study. We evaluated consecutive STEMI patients admitted in the Hirosaki University Hospital from January 2007 to December 2016 within 24 hours of symptom onset, and had underwent primary PCI. We defined STEMI as an elevated cardiac biomarker with two of the following 1 : typical chest pain lasting >20 minutes and 2 ECG showing new ST-segment elevation ≥2 mm in at least two contiguous precordial leads or ≥ 1 mm in at least two contiguous limb leads, or newly apparent left bundle branch block. We divided patients by evaluating lesions using emergent coronary angiography as follows: (a) anterior STEMI patients with culprit in left anterior descending artery (LAD) or left main trunk and (b) nonanterior STEMI patients with culprit in right coronary artery (RCA) or left circumflex artery (LCX). We defined CAVB as complete interruption of atrioventricular (AV) conduction with dissociation of P waves and QRS complexes and the existence of junctional or ventricular escape rhythms with a rate less than the atrial rate. In this study, we considered CAVB as follows: documented CAVB in continuous cardiac monitoring in ambulances, previous hospital, or at any point during the hospitalization whether it was temporary or sustained. The Ethics Committee of our Institution approved this study.

| Data collection and follow-up
We obtained baseline clinical characteristics including previous medical history, and analyzed laboratory data at admission with electrocardiography (ECG) before PCI and during hospitalization. We assessed the left ventricular ejection fraction (LVEF) at acute phase by transthoracic echocardiography or left ventriculography during hospitalization. In this phase, we evaluated the number of diseased vessels defined as more than 75% major coronary stenosis, and judged thrombolysis in myocardial infarction (TIMI) grade flow after emergent PCI.
The primary outcome of this study was all-cause death and the secondary outcome was major adverse cardiocerebrovascular events (MACCE), defined as a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and hospitalization due to acute decompensated heart failure (ADHF). Follow-up started on the day of admission and we followed up patients until 2018 with a median follow-up period of 3.8 (1.7-6.6) years. We obtained follow-up data by reviewing our hospital records, interviewing the patients or their families by telephone, or examining the outpatient clinic records.

| Statistical analysis
We expressed continuous variables as mean ± standard deviation or median (interquartile range), and categorical variables as frequencies and percentages. We compared continuous variables using one-way analysis of variance, and calculated the statistical significance of differences using the Tukey-Kramer test. We used the Mann-Whitney U test for nonparametric variables and the chi-square analysis to compare categorical variables. We estimated primary and secondary outcomes using the Kaplan-Meier method and compared them using the

| Clinical outcomes in anterior STEMI
As shown in Table 2

| Clinical outcomes in nonanterior STEMI
Nonanterior STEMI patients with CAVB had a higher Killip classification than those without CAVB (

| Incidence of CAVB in STEMI patients
CAVB is one of the most common brady-arrhythmias in STEMI patients, especially in inferior STEMI patients. The definition of AVB are different and it is not unified in many articles. For example, AVB was defined as "advanced" or "high-degree" AVB in some studies, 5,10-13,16-20 while only CAVB was reported in others. [1][2][3][4][6][7][8][9]21,22 Moreover, monitoring timing was different whether it was recorded at admission or during hospitalization. Therefore, the frequency of AVB might be different among articles. In the present study, we focused on CAVB and showed that the incidence of CAVB was 6.3%  23 Our study included only STEMI patients, and therefore, we may have found a relatively higher incidence of CAVB in the present study.

| Impact of CAVB on clinical outcomes in STEMI patients
The association between CAVB and worse outcomes has been reported in several studies. Furthermore, they showed that among discharged patients, 5-year survival rate for patients with an anterior AMI with CAVB was lower than those without CAVB (37% vs 62%), whereas it was approximately 70% in patients with inferior AMI with CAVB. Consistent with these previous reports, our study in the era of primary PCI revealed that CAVB in nonanterior STEMI patients was also not independently associated with short-term, nor long-term mortality.
In contrast, anterior STEMI patients with CAVB had a higher mortality even in the era of primary PCI. Hreybe et al. previously showed that patients with anterior or lateral AMI were more likely to die prior to hospital discharge compared to those with an inferior or posterior AMI (11% vs 8%). 7 In the present study, the mortality among the CAVB group was substantially higher in anterior STEMI than in nonanterior STEMI (82% vs 30%, p < .05). In anterior STEMI, CAVB

| Possible mechanism of CAVB in STEMI Patients
CAVB can occur in STEMI patients with either inferior or anterior infarction, though more common in inferior STEMI patients. The mechanism of conduction disturbance in STEMI patients is different according to the location of infarction. As expected, CAVB was more frequent in nonanterior STEMI. This is due to hypoperfusion of the AV nodal artery that is mainly supplied by RCA and rarely from LCX. 5,[24][25][26][27] This is also due to occlusion of RCA that secondarily increases acetylcholine release from the inferoposterior myocardium leading to an increasing parasympathetic tonus. 24 Otherwise, CAVB is thought to be provoked by local release of potassium, adenosine, or a mixture of all the mentioned mechanisms. 5 The conduction tissue of the AV node is usually resistant to permanent damage from ischemia due to the high intracellular contents of glycogen, the complex arterial blood supply such as from the septal perforators of LAD, and the capability of nutrient and oxygen absorption supplied from adjacent venous sinusoids. 28

| Study limitations
Our study has several limitations. Firstly, we designed and performed this study in a single center. Secondly, we were unable to determine the precise onset or duration of CAVB and recovery timing from CAVB due to the retrospective nature of the study.

| CONCLUSION
Although CAVB is a rare complication in anterior STEMI patients, it remains a poor prognostic complication even in the primary PCI era.
Therefore, anterior STEMI patients with CAVB may require a more careful monitoring. Further studies are needed to determine the impact of CAVB and optimal treatment in these patients.

ACKNOWLEDGMENTS
We thank Ms. Machiko Kogawa for her excellent assistance about data collection of this study.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available on reasonable request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.