Original ArticleHyperglycemia Predicts AF in STEMIs Acta Cardiol Sin 2012;28:279-285

Arrhythmia and Electrophysiology Hyperglycemia Increases New-Onset Atrial in Patients with Acute ST-Elevation

Hong-Pin Hsu,1 Yu-Lan Jou,1 Tao-Cheng Wu,2,3 Ying-Hwa Chen,2,3 Shao-Song Huang,2,3 Yenn-Jiang Lin,2,3 Li-Wei Lo,2,3 Yu-Feng Hu,2,3 Ta-Chuan Tuan,3 Shih-Lin Chang2,3 and Shih-Ann Chen2,3

Background: (AF) is a frequent complication of acute myocardial infarction, and is often accompanied by an increased morbidity and mortality. The aim of this study was to investigate the predictors and outcome of new-onset AF occurring after acute ST-elevation myocardial infarction (STEMI). Methods: A total of 307 patients with acute STEMI from May 2007 to June 2009 were included in our study. Of those patients, 57 patients experienced new-onset AF during their hospitalization in the coronary care unit with continuous ECG monitoring. The primary endpoint was the occurrence of AF during the hospitalization. The secondary endpoint was the all-cause mortality during a 12-month follow-up period. Results: Two hundred eighty three patients (92.2%) received revascularization during the hospitalization. The patients with new-onset AF after the acute STEMI were older, with lower diastolic blood pressure, higher initial fasting glucose, lower lipid level, and a higher incidence of history when compared to those without new-onset AF. In a multivariable analysis, the initial fasting glucose level (p = 0.025, OR = 1.007, 95% CI = 1.001~1.012) was an independent predictor of the occurrence of new-onset AF after acute STEMI. New-onset AF was associated with a higher all-cause mortality rate during the follow-up (p = 0.001). Conclusion: A higher initial fasting glucose level was an independent predictor of the occurrence of AF in patients with acute STEMI, which may be associated with a poor prognosis.

Key Words: Atrial fibrillation · Hyperglycemia · Myocardial infarction

INTRODUCTION and associated with an increased mortality and morbid- ity.1,2 Those patients with AMI who developed AF were Atrial fibrillation (AF) is the most frequently occur- at a greater risk for an acute stroke and mortality during ring supraventricular during an acute myo- their hospitalization than those without it.3 On the other cardial infarction (AMI), with an incidence of 6-21%, hand, ventricular tachyarrhythmias are also an important cause of sudden cardiac death in patients with AMI. The patients with ventricular tachyarrhythmias had higher Received: June 9, 2011 Accepted: July 13, 2012 low-density lipoprotein cholesterol (LDL-C) levels and a 1Division of Cardiology, Department of Internal Medicine, Taipei lower blood pressure on their initial arrival, suggesting 2 City Hospital; Division of Cardiology, Taipei Veterans General that dyslipidemia may impose a higher risk of develop- Hospital; 3Department of Medicine and Institute of Clinical Medicine, Cardiovascular Research Center, National Yang-Ming University ing tachyarrhythmias in the acute phase of ST-segment School of Medicine, Taipei, Taiwan. elevation myocardial infarction (STEMI).4 However, the Address correspondence and reprint requests to: Dr. Shih-Lin Chang, relationship of new-onset AF to the clinical biochemical Division of Cardiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan. Tel: 886-2-2875-7156; Fax: markers and outcome in the patients with acute STEMI 886-2-2873-5656; E-mail: [email protected] is still not fully clarified. The purpose of this study was

279 Acta Cardiol Sin 2012;28:279-285 Hong-Pin Hsu et al. to determine the predictors of the risk of developing total creatine kinase (CK) level was < 200 IU/L. new-onset AF in the clinical setting of acute STEMI, and AF was detected by the 12-lead ECGs recorded dur- to try to elucidate the relationship between new-onset ing the entire hospital course and the 24 hour continuous AF and the clinical outcome. ECG monitoring in the CCU. The ECG monitor auto- matically detected and recorded any non-sustained or sustained supraventricular and ventricular PATIENTS AND METHODS after the myocardial infarction, and the recording was further confirmed by the CCU doctor. All of the 12-lead A retrospective study was designed and we enrolled ECGs acquired during the hospitalization were con- those patients admitted to Taipei Veterans General Hos- firmed by the cardiologists. Patients who had AF epi- pital of Taiwan due to acute STEMI from May 2007 to sodes in the past were excluded from the study. June 2009. A total of 307 consecutive patients without The serum lipids, including the total cholesterol any documented AF prior to admission were included in (TC), LDL-C, high-density lipoprotein cholesterol this study based on the registration of the coronary care (HDL-C), triglyceride (TG), and fasting glucose level unit (CCU) of Taipei Veterans General Hospital. The were sampled on the morning after the day of admission, outcome within 12 months after discharge was acquired and all patients generally should fast for at least 8 hours by the medical records of the hospital and telephone before checking those biochemical data. The C-reactive communication with family members. protein (CRP) level was checked immediately upon the The patients included in this study met the following patient’s arrival at our emergency room. criteria for acute STEMI: (1) chest pain of ³ 30 minutes Hypertension was defined as a systolic blood pres- in duration; (2) electrocardiograph (ECG) showing sure (SBP) of ³ 140 mmHg and/or diastolic pressure ST-segment elevation of ³ 0.1mVintwoormoreleads; (DBP) of ³ 90 mmHg with more than two readings dur- and (3) elevated creatine kinase-MB (CK-MB) isoen- ing a resting state, according to the criteria of the Joint zymes or troponin-I within 24 hours of the chest pain. National Committee-VII (JNC-VII),6 or those who had Most of these patients were treated with a primary per- taken antihypertensive medications during their daily cutaneous coronary intervention (PCI), coronary artery life. Diabetes mellitus (DM) was defined according to the bypass graft (CABG) surgery, or medical control and American Diabetes Association criteria,7 or as those who then an elective PCI according to the guidelines pub- used oral hypoglycemic agents or insulin for blood sugar lished by the American College of Cardiology/American control. A past history of coronary artery disease (CAD) Heart Association (ACC/AHA).5 All the patients were was defined according to the results of the previous coro- initially admitted to the CCU, with follow-up cardiac nary angiography (CAG) or non-invasive stress imaging. enzyme tests and 12 lead ECGs taken every 6 hours to The left atrial (LA) diameter and left ventricular trace the ST-T change after the acute STEMI. Con- ejection fraction (LVEF) were determined by echocar- tinuous ECG, blood pressure and oximetry monitoring diography during the hospitalization. The culprit lesion were performed in all the study patients when they were was identified by correlating the coronary angiography in the CCU. The medications used during the hospital with the ST-segment elevation on the admission ECG, course, such as aspirin, clopidogrel, anticoagulants, an- and the regional wall motion abnormality in the left giotensin converting enzyme (ACE) inhibitors, angio- ventriculography. Coronary artery stenosis of > 50% in tensin receptor blockers, beta-antagonists, lipid-lower- diameter was regarded as significant. The number of dis- ing agents, and intravenous or sublingual nitroglycerin eased arteries was determined accordingly. The hemo- were all administered as recommended by the ACC/ dynamic status included the SBP, DBP, and heart rate, AHA guidelines and were continued after discharge which were recorded immediately after arrival at the from the hospital unless there was any contraindication emergency room. for the patients. The patients were transferred to an ordi- nary ward if they became hemodynamically stable, no Statistical analyses symptoms of ongoing were observed, and the Data are expressed as the mean ± standard deviation.

Acta Cardiol Sin 2012;28:279-285 280 Hyperglycemia Predicts AF in STEMIs

Chi-square and Fisher’s exact tests were used for cate- CAD into the multivariable analysis, the initial fasting gorical data. Student’s t tests were used for continuous glucose level [odds ratio (OR) = 1.007, confidence inter- data. A univariate analysis of the various clinical vari- val (CI) = 1.001~1.012, p = 0.025] was an independent ables was performed to determine the predictors of predictor of the occurrence of new-onset AF after acute new-onset AF occurring after acute STEMI. The vari- STEMI (Table 2). ables selected to be tested in the multivariate analysis After a follow-up of 12 months, the patients with (logistic regression) were those with p values of < 0.1 in new-onset AF had a higher all-cause mortality rate the univariate models. The survival rate and cumulative (39.1% vs. 16.0%, p = 0.001) (Figure 1) and a higher survival curve between the two groups were analyzed by rate of cardiovascular death (28.1% vs. 13.6%, p = 0.01) a Kaplan-Meier method and log-rank test. The compari- than those without AF. The causes of cardiovascular son of the all-cause mortality between the sinus rhythm death included recurrent myocardial infarction (2 pa- and AF groups was further adjusted by age with a Cox tients), decompensated (35 patients), and regression analysis. A p value of < 0.05 was considered ventricular arrhythmias (13 patients). The non-cardio- statistically significant. vascular deaths included septic shock (5 patients) and malignant neoplasms (2 patients). Because there was a significant difference in the age between new-onset AF RESULTS and non-AF, the age was adjusted in a Cox regression model to compare the mortality of these two groups. The Among the 307 patients admitted due to an acute all-cause mortality rate of new-onset AF during 12 STEMI, 83% were male and 17% were female. A total of months was still higher than that for non-AF (Hazard 283 patients (92.2%) received revascularization (either a ratio = 1.851, 95% CI = 1.062~3.227, p = 0.03). primary PCI, elective PCI, or CABG), including a pri- mary PCI in 250 patients (81%) during the hospitaliza- tion. Nearly half (45.3%) of the patients had a culprit le- DISCUSSION sion in the left anterior descending coronary artery, 12.1% in the left circumflex coronary artery, 33.2% in the right New onset of AF after an acute STEMI coronary artery, and 4.9% of those patients had left main A variant incidence of AF after an AMI has been re- coronary disease. Fourteen patients had no definite culprit ported in previous studies. Goldberg et al. reported that lesion due to coronary spasms. There were 57 patients the incidence of new-onset AF after AMI increased from (18.6%) that suffered from new-onset AF during the 11.3% to 14.4% during the period 1999 to 2005.2 The hospital course, and all of them had paroxysmal AF. development of new-onset AF after AMI was associated The comparison of the clinical characteristics in the with an increase in the mortality and risk of stroke dur- patients with and without new-onset AF after acute ing the hospitalization. A discordant incidence of AF STEMI is shown in Table 1. Patients with new-onset AF after AMI has been demonstrated in previous studies. had a higher incidence of a CAD history than those with- Pederson et al. found that the incidence of paroxysmal out new-onset AF. There was no significant difference in AF/ after AMI was 21%.8 In the GUSTO-I the culprit arteries between the patients with and without trial, the incidence of AF after AMI was 2.5% on admis- new-onset AF. Patients with new-onset AF had a higher sion and 7.9% after enrollment. In the GRACE trial, the mean fasting glucose level. There was a trend for the pa- incidence of new-onset AF was 6.2%. In our study, the tients with a history of DM to be associated with a higher incidence of new-onset AF after acute STEMI was about occurrence of new-onset AF compared with those without 18%, which was higher than that of some other studies it. The patients with new-onset AF had a lower incidence (5% to 15%).9-13 The different methodology in the AF of a history of hyperlipidemia with a lower triglyceride detection and varied severity of the disease may account level and total cholesterol level compared to those with- for the discrepancy in results. Continuous ECG monitor- out AF. After taking the fasting glucose, TG, and LDL-C ing was performed in all of our patients with acute levels, age, diastolic BP, TIMI score, history of DM and STEMI during the CCU admission, which differed from

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Table 1. Clinical characteristics of the patients with/without AF Sinus rhythm (n = 250) AF (n = 57) p value Age (years) 067.3 ± 14.3 75.2 ± 10.2 < 0.001 Male gender (%) 83.2 80.7 0.80 Heart rate (bpm) 082.2 ± 21.0 083.7 ± 32.0 0.77 Systolic pressure (mmHg) 130.9 ± 33.0 121.9 ± 39.8 0.11 Diastolic pressure (mmHg) 075.8 ± 18.0 069.6 ± 19.7 0.04 Killip Class 0.11 Class I, n (%) 107 (42.8%)0 18 (31.6%) Class II, n (%) 57 (22.8%) 11 (19.3%) Class III, n (%) 33 (13.2%) 07 (12.3%) Class IV, n (%) 53 (21.2%) 21 (36.8%) TIMI score 06 ± 3 08 ± 3 < 0.001 Left atrial diameter (mm) 39.2 ± 6.1 41.1 ± 6.1 0.27 LV ejection fraction (%) 044.6 ± 12.7 042.9 ± 16.3 0.63 Body mass index (Kg/m2) 25.0 ± 3.5 24.1 ± 4.2 0.41 Smoking (%) 90 (36.0%) 18 (31.6%) 0.78 HbA1C (%) 07.0 ± 1.8 06.9 ± 1.4 0.83 Triglyceride (mg/dl) 112.5 ± 96.7 081.0 ± 55.7 0.02 Total cholesterol (mg/dl) 164.3 ± 42.2 146.3 ± 40.9 0.01 Fasting glucose (mg/dl) 150.5 ± 80.4 0197.6 ± 111.4 0.01 HDL-cholesterol (mg/dl) 040.4 ± 12.4 042.5 ± 13.3 0.29 LDL-cholesterol (mg/dl) 105.6 ± 35.6 093.0 ± 35.3 0.03 C-reactive protein (mg/dl) 01.9 ± 0.2 02.6 ± 0.7 0.21 Primary PCI, n (%) 205 (82.0%)0 45 (78.9%) 0.73 Revascularization, n (%) 233 (93.2%)0 49 (86.0%) 0.13 Culprit lesion 0.10 LAD, n (%) 118 (47.6%)0 21 (36.8%) LCX, n (%) 33 (13.3%) 4 (7.0%) RCA, n (%) 76 (30.6%) 26 (45.6%) LM, n (%) 13 (5.2%)0 2 (3.5%) Hypertension, n (%) 161 (64.4%)0 42 (73.7%) 0.24 Hyperlipidemia, n (%) 86 (34.4%) 09 (15.8%) 0.01 Diabetes mellitus, n (%) 93 (37.2%) 29 (50.9%) 0.08 Coronary artery disease history, n (%) 44 (17.6%) 19 (33.3%) 0.01 Cerebral vascular disease, n (%) 35 (14.4%) 4 (7.0%) 0.23 All-cause mortality, n (%) 36 (14.4%) 21 (36.8%) 00.001 CV death, n (%) 34 (13.6%) 16 (28.1%) 0.01 AF, atrial fibrillation; CV death, cardiovascular death; HDL, high-density lipoprotein; LAD, left anterior descending artery; LCX, left circumflex artery; LDL, low-density lipoprotein; LM, left main coronary artery; LV, left ventricle; PCI, percutaneous coronary intervention; RCA, right coronary artery. the other studies, using only one episode of an ECG re- low HDL-C, which are considered to be independent cording. Moreover, the exclusion of the patients at high risk factors of AMI, are not independent risk factors of risk for AF (acute STEMI) may result in the lower inci- new-onset AF after AMI in our study.14 Previous studies dence of AF observed in some clinical trials. found an increased risk of AF in patients with DM.15-17 Koracevic et al. showed that hyperglycemia is associated Metabolic disturbance leads to a new onset of with an increased prevalence of AF and higher in- AF hospital mortality in patients after AMI (either ST- Many risk factors, such as hypertension, DM, and elevation or non-ST elevation).18 Our study further

Acta Cardiol Sin 2012;28:279-285 282 Hyperglycemia Predicts AF in STEMIs

Table 2. Univariate and multivariate analyses of the risk factors for AF Risk factor Univariate p value Multivariate p value Odds ratio 95% CI Age* < 0.001 0.206 1.034 0.982~1.088 TIMI score* < 0.001 0.383 1.117 0.871~1.432 Diastolic BP* 0.04 0.749 0.995 0.968~1.023 Fasting glucose* 0.01 0.025 1.007 1.001~1.012 LDL-cholesterol* 0.03 0.789 0.998 0.983~1.013 Total triglyceride* 0.02 0.060 0.989 0.979~1.000 Previous CAD history 0.01 0.709 0.812 0.272~2.424 Diabetes mellitus 0.08 0.646 1.295 0.430~3.894 * Continuous variable. BP, blood pressure; CAD, coronary artery disease; LDL, low-density lipoprotein; TIMI, Thrombolysis in Myocardial Infarction.

animal study, an increased diffuse fibrotic deposition was revealed on histologic examination of diabetic rats.20 Fibrosis in the left atrium plays an important role in determining the dynamics of AF, which could present as an anchor for reentrant circuits and alter the wave- front propagation, causing fractionated electrograms, wave breaks, and conduction delays and thus promoting AF perpetuation.21,22 In the present study, both the TC and TG levels ex- hibited a negative association with new-onset AF after myocardial infarction. Although the real mechanism un- derlying this phenomenon remains unclear, it has been Figure 1. Cumulative survival (all-cause mortality) in patients with suggested that hypolipidemia may cause electrophysio- and without new-onset atrial fibrillation (AF) during the 12 months logical changes that could increase the occurrence of AF. after an acute ST elevation myocardial infarction (STEMI). Annoura et al. found that the TC, TG, and HDL-C were demonstrated that hyperglycemia can predict the occur- inversely and linearly associated with the incidence of rence of new-onset AF following STEMI, with a 0.7% AF in patients.23 In an animal model study, a choles- increased risk of AF for an elevation in the blood glu- terol-fed state led to a longer effective refractory period cose level of 1 mg/dl. and shortened the conduction time of the atrium, which The reason why hyperglycemia correlates independ- resulted in an antiarrhythmic state in rabbits.23 This ently with AF after myocardial infarction is still unclear. could suggest that hypolipidemia may be associated with Chao et al. have found that patients with abnormal glu- the occurrence of AF. Although Dublin reported that cose metabolism, including those with DM and those hyperlipidemia seemed to be more common among with an impaired fasting glucose, had a lower atrial new-onset AF,24 Funk found that hyperlipidemia was a voltage and longer atrial activation time than those with negative independent predictor of AF after cardiac sur- normal glucose metabolism. The AF recurrence rate af- gery.25 Because lipid-lowering medications were often ter catheter ablation was greater in the abnormal glucose prescribed to patients with hyperlipidemia or CAD at metabolism group than in the normal glucose meta- other hospitals, even though they did not have elevated bolism group.19 The study supports the hypothesis that lipid levels, this lipid profile obtained after admission hyperglycemia results in damage to the atrial tissue, with may not truly represent a condition of hyperlipidemia. subsequent changes in the electrophysiologic properties, No previous studies have well defined the presence or which could lead to the genesis of AF. absence of hyperlipidemia as an independent predictor Oxidative stress-related atrial fibrosis in patients of AF, and the real mechanism for the negative associa- with hyperglycemia was a possible mechanism. In an tion between hyperlipidemia and AF remains unclear.

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