Lipid Levels and New-Onset Atrial Fibrillation in Patients with Acute Myocardial Infarction

Abstract

Aim: In acute myocardial fraction (AMI) patients, the association between lipid parameters and new-onset atrial fibrillation (NOAF) remains unclear due to limited evidence.

Methods: A total of 4282 participants free from atrial fibrillation (AF) at baseline were identified in Beijing Friendship Hospital. Fasting levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured at baseline. The study population was stratified based on tertiles of lipid profile and lipid ratios. Incidence of NOAF was observed at the follow-up visits. The associations between different lipid parameters and the incidence of NOAF were assessed by multivariate Cox regression analysis.

Results: Over a median follow-up period of 42.0 months (IQR: 18.7, 67.3 months), 3.1% (N=132) AMI patients developed NOAF. After multivariable adjustment, higher TC (hazard ratios (HR): 0.205, 95% confidence intervals (CI): 0.061–0.696) levels were inversely associated with NOAF development. However, higher HDL-C (HR: 1.892, 95% CI: 1.133–3.159) levels were positively associated with NOAF development. LDL-C levels, TG levels, non-HDL-C levels, and lipid ratios showed no association with NOAF development.

Conclusion: TC levels were inversely associated with incidence of NOAF; this was mainly reflected in the subgroups of male gender and older patients (65 years or older). HDL-C levels were positively associated with incidence of NOAF; this was mainly reflected in the subgroups of male gender and younger patients (age ＜65 years). There was no significant association of NOAF with LDL-C, TG, or non-HDL-C levels.

Trial registration: Prospective registered.

Introduction

Hyperlipidemia is a common risk factor for atherosclerotic cardiovascular disease. Higher low-density lipoprotein cholesterol (LDL-C) and lower high-density lipoprotein cholesterol (HDL-C) have been confirmed to a higher risk of coronary heart disease (CHD) and other cardiovascular diseases^{1, 2)}. As the most serious kind of CHD, the morbidity of acute myocardial infarction (AMI) is obviously associated with higher lipid levels. Atrial fibrillation (AF) is the most common heart arrhythmia worldwide. Multiple risk factors of cardiovascular disease, including obesity, hypertension, diabetes mellitus (DM), and old age, can increase the incidence of AF³⁾. AF often coexists in patients with AMI and increases the risk of mortality and stroke. However, the relationship between lipid levels and the incidence of AF is less clear. As a “cholesterol paradox,” hypercholesterolemia has been associated with a lower incidence of AF. Studies have shown that low levels of LDL-C and total cholesterol (TC) have been associated with increased AF incidence^{4, 5)} and HDL-C has been inversely or not significantly associated with AF development^{4, 6-8)}. According to triglycerides (TG), no correlation was found in the previous literature^{5, 6)}. Moreover, lipid ratios such as LDL-C/HDL-C, TC/LDL-C, TC/HDL-C, and TG/HDL-C are considered useful indexes for the stratification of cardiovascular diseases^{4, 9)}. Although previous studies have shown the associations between lipid levels, lipid ratios, and AF, some inconsistencies in these conclusions suggest that further research is needed.

Therefore, for the AMI population with a high incidence of AF, we examined the prognostic significance of baseline lipid levels and lipid ratios and observed the roles based on sex and age categories of lipid parameters in the study cohort.

2.Methods

2.1. Study Population

Study subjects were identified from the database at the Cardiovascular Center of Beijing Friendship Hospital. From December 2012 to December 2020, patients with missing data pertaining to lipid levels (N=161) or those with AF or atrial flutter at baseline (N=408) were excluded. Finally, 4282 consecutive patients with AMI were enrolled in this study. AMI, including ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI), was defined as chest pain with new ST-segment changes and elevation of myocardial necrosis markers to at least twice of the upper limit of the normal range. All the AMI patients were required to go to the clinic for routine examination at the 1, 3, 6, and 12 months and then every year after discharge. This study cohort included individuals who did not meet the exclusion criteria and subsequently received ≥ 1 routine examination. All patients were followed up to December 2021 with a median follow-up of 42.0 months (IQR: 18.7, 67.3 months). The end point was incidence of new-onset AF (NOAF) during the clinical follow-up period.

The local institutional review board at our hospital approved the study protocol, and this study was in accordance with the Declaration of Helsinki.

2.2. Ascertainment of AF

NOAF diagnosis was ascertained based on the European Society of Cardiology guidelines, and all the following 12-lead electrocardiogram (ECG) criteria were met: (1) irregular R-R intervals, (2) absence of repeating P waves, and (3) irregular atrial activity¹⁰⁾. Moreover, 12-lead ECG was systematically performed at every visit and reviewed by two cardiologists and the final diagnosis of NOAF was confirmed only when both cardiologists independently confirmed the same. The incidence time of NOAF was defined as the time of the first signs of AF.

2.3. Assessment of Lipid Levels

Overnight fasting venous blood samples were drawn from the antecubital vein within 12–24 h from admission and using vacuum tubes containing EDTA for storage. Plasma was separated and measured immediately. TC and TG were both measured using the enzymatic colorimetric method, and HDL-C and LDL-C were measured by direct test method. Less than 0.1% of measured values were within 5% of the upper limit of detection. Non-HDL-C was calculated as TC minus HDL-C.

2.4. Other Data Collection and Definitions

Patient demographic information, medical and medication history, and laboratory measurements were collected and confirmed through electronic medical records. The left atrium (LA), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left ventricular ejection fraction (LVEF), and left ventricular fraction shortening (LVFS) were determined using two-dimensional echocardiography during the index hospitalization. The echocardiography was measured within 24 h from admission after the diagnosis of AMI.

2.5. Statistical Analysis

Depending on the distribution of the data, continuous variables were expressed as mean value±SD or median and interquartile range (IQR). Frequencies and percentages were used to describe categorical data. Differences between continuous and categorical variables were assessed using Student’s t-test, analysis of variance, Chi-square test, and Wilcoxon signed-rank test as appropriate.

The patients were categorized into three groups based on tertiles of lipid levels including TC, TG, LDL-C, HDL-C, and non-HDL-C. In addition, we investigated lipid levels as continuous variables. Moreover, lipid ratios including LDL-C/HDL-C, TC/LDL-C, TC/HDL-C, and TG/HDL-C scaled to 1-unit increments were included in the analysis. The cumulative incidence of NOAF was estimated by the Kaplan–Meier method. The association of baseline blood lipid levels with incidence of NOAF was determined by calculation of hazard ratios (HRs) and 95% confidence intervals (CIs) with the use of Cox hazard models, after verification of the proportional hazard assumption with Schoenfeld residuals. Baseline variables that were significantly correlated with outcomes by univariate analysis and clinically relevant were entered into the multivariate model. In model 1, we adjusted for age, sex, and body mass index (BMI). In model 2, we further adjusted for estimated glomerular filtration rate (eGFR), the peak value of N-terminal pro-B-type natriuretic peptide (pNT-proBNP), the peak value of creatine kinase isoenzyme-MB (pCKMB), and the peak value of troponin I (pTNI). In model 3, we further included LA, Killip (II–IV), and chronic total occlusion (CTO). Sex and age differences were assessed with analyses of P for interaction.

All analyses were two-tailed and P value ＜0.05 was considered statistically significant. Data were analyzed using SPSS statistical package version 26.0 (SPSS Inc., Chicago, IL, USA).

3.Results

3.1. Baseline Characteristics

Table 1 shows that of the 4282 eligible patients (mean age 63.9 years, men 74.2%), more than half of them (64.5%, N=2762) were identified as having hypertension, 38.0% (N=1629) had DM, 27.4% (N=1176) had CHD, 16% (N=683) had a history of stroke, and 11.0% (N=470) had a history of myocardial infarction (MI). Compared with the AF-free group, the NOAF group showed significantly older, lower BMI, and eGFR, a higher percent of Killip II–IV at admission, and CTO after coronary angiogram. However, there were no significant differences in the medicine used before admission and during hospitalization including antiplatelet agent, angiotensin-converting enzyme inhibitor (ACEI)/ angiotensin II receptor blocker (ARB), β-blockers, statins, ezetimibe, and fibrates. AF was newly diagnosed in 132 patients, and the incidence of NOAF was 3.1%. Supplementary Fig.1 shows the incidence of NOAF in different follow-up periods.

Table 1. Clinical characteristics of patients in the NOAF and AF-free groups

	Total N = 4282	NOAF N = 132	AF-free N = 4150	P value
Male (%)	3176 (74.2)	89 (67.4)	3087 (74.4)	0.072
Age (years)	63.9±12.4	70.7±11.6	63.7±12.4	＜0.001
BMI (kg/m2)	25.5±3.7	24.3±3.4	25.5±3.7	＜0.001
SBP (mmHg)	129.1±22.0	128.2±23.7	129.1±21.9	0.656
DBP (mmHg)	73.8±12.6	72.5±13.4	73.8±12.5	0.237
Heart rate(bpm)	73 (65,83)	74 (65,82)	73 (65,83)	0.505
STEMI (%)	2134 (49.8)	70 (53.0)	2064 (49.7)	0.456
Anterior MI (%)	1073 (25.1)	33 (25.0)	1040 (25.1)	0.987
Killip II-IV (%)	1101 (25.7)	47 (35.6)	1054 (25.4)	0.008
Medical history
Hypertension (%)	2762 (64.5)	93 (70.5)	2669 (64.3)	0.147
DM (%)	1629 (38.0)	44 (33.3)	1585 (38.2)	0.258
CHD (%)	1176 (27.4)	44 (33.3)	1132 (27.3)	0.164
OMI (%)	470 (11.0)	14 (10.6)	456 (11.0)	0.890
Dyslipidemia (%)	1895 (44.3)	56 (42.4)	1839 (44.3)	0.667
Hyperthyroidism (%)	20 (0.5)	1 (2.0)	19 (0.5)	0.121
Stroke (%)	683 (16.0)	25 (18.9)	658 (15.9)	0.341
Revascularization (%)	458 (10.7)	19 (14.4)	439 (10.6)	0.163
Current/ex-smoker (%)	2667 (62.3)	76 (57.6)	2591 (62.4)	0.257
Medication used before admission
Antiplatelet agent, %	1144 (26.7)	26 (19.7)	1118 (26.9)	0.064
ACEI/ARB (%)	1054 (24.6)	38 (28.8)	1016 (24.5)	0.258
β-blockers (%)	499 (11.7)	17 (12.9)	482 (11.6)	0.656
Statins (%)	535 (12.5)	15 (11.4)	520 (12.5)	0.690
Ezetimibe (%)	11 (0.3)	0 (0)	11 (0.3)	1.000
Fibrates (%)	19 (0.4)	0 (0)	19 (0.5)	0.909
Medication used during hospitalization
Antiplatelet agent (%)	4021 (93.9)	126 (95.5)	3895 (93.9)	0.450
ACEI/ARB (%)	2762 (64.5)	86 (65.2)	2676 (64.5)	0.874
β-blockers (%)	3106 (72.5)	87 (65.9)	3019 (72.7)	0.083
Statins (%)	3741 (87.4)	114 (86.4)	3627 (87.4)	0.725
Ezetimibe (%)	100 (2.3)	1 (0.8)	99 (2.4)	0.354
Fibrates (%)	8 (0.2)	0 (0)	8 (0.2)	1.000
Laboratory values
WBC (×109/L)	7.9 (6.3,9.8)	7.3 (5.6,9.8)	7.9 (6.3,9.8)	0.151
HsCRP (mg/l)	6.5 (2.1,17.7)	6.7 (2.9,14.3)	5.7 (2.3,15.7)	0.193
eGFR (ml/min/1.73m2)	84.6 (67.3,99.5)	75.0 (56.0,93.3)	84.9 (67.6,99.7)	＜0.001
FBG (mmol/l)	5.8 (5.0,7.6)	5.9 (5.0,8.0)	5.8 (5.0,7.6)	0.621
Angiography values
LM (%)	469 (11.0)	17 (12.9)	452 (10.9)	0.472
Triple-vessel (%)	2768 (64.6)	84 (63.6)	2684 (64.7)	0.806
PCI (%)	3281 (76.6)	94 (71.2)	3187 (76.8)	0.136
CTO (%)	145 (3.4)	23 (17.4)	122 (2.9)	＜0.001
Slow flow after PCI (%)	48 (1.1)	2 (1.5)	46 (1.1)	0.662

NOAF, new-onset atrial fibrillation; BMI, body Mass Index; SBP, systolic blood pressure; DBP, diastolic blood pressure; STEMI, ST-segment elevation myocardial infraction; MI, myocardial infarction; DM, diabetes mellitus; CHD, coronary heart disease; OMI: old myocardial infarction; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; WBC, white blood cells; hsCRP, hypersensitivity C-reactive protein; eGFR, estimated glomerular filtration rate; FBG, fasting blood glucose; LM, left main trunk; PCI, percutaneous coronary intervention; CTO, chronic total occlusion.

Supplementary Fig.1. Incidence rate of NOAF during follow-up visit

NOAF, new-onset atrial fibrillation

We further evaluated the estimated infarction size by using serum peak value of creatine kinase isoenzyme-MB (pCKMB) and troponin I (pTNI) levels and left ventricular function based on echocardiography between NOAF and AF-free patients. The peak value of N-terminal pro-B-type natriuretic peptide (pNT-proBNP) was also compared in our study. We found higher pCKMB, pTnI, and pNT-proBNP in NOAF group (pCKMB: 41.4 vs. 23.0, P=0.012; pTnI: 13.4 vs. 7.2, P=0.020; pNT-proBNP: 2243.5 vs. 1335.0, P＜0.001, Table 2). From the perspective of cardiac function assessed by echocardiography, the NOAF patients were associated with larger LA, lower LVEF, and LVFS than AF-free patients (LA: 3.9 vs. 3.7, P＜0.001; LVEF: 0.60 vs. 0.61, P=0.032; LVFS: 0.32 vs. 0.33, P=0.035; Table 2). However, there were no significant differences in LVEDD, LVESD, LVEDV, and LVESV between the two groups.

Table 2. Myocardial injury markers and echocardiographic characteristics of patients in the NOAF and AF-free groups

	Total N = 4282	NOAF N = 132	AF-free N = 4150	P value
Myocardial injury markers
pCKMB (ng/ml)	23.2 (4.3, 120.0)	41.4 (6.0, 207.3)	23.0 (4.3, 117.0)	0.012
pTNI (ng/ml)	7.3 (1.1, 34.0)	13.4 (1.4, 50)	7.2 (1.1, 33.5)	0.020
pNT-proBNP (pg/ml)	1358.0 (459.8, 3943.5)	2243.5 (941.3, 8164.0)	1335.0 (452.0, 3848.5)	＜0.001
Echocardiographic values
LA (cm)	3.7 (3.4, 4.0)	3.9 (3.7, 4.3)	3.7 (3.4, 4.0)	＜0.001
LVEDD (cm)	5.2 (4.8, 5.5)	5.2 (4.8, 5.5)	5.2 (4.8, 5.5)	0.519
LVESD (cm)	3.5 (3.1, 3.9)	3.6 (3.2, 4.0)	3.5 (3.1, 3.9)	0.064
LVEDV (ml/m2)	127.2 (107.5, 147.4)	129.5 (109.0, 147.4)	126.6 (107.5, 147.4)	0.526
LVESV (ml/m2)	50.9 (38.5, 65.9)	54.4 (41.0, 70.0)	50.9 (38.2, 65.9)	0.113
LVEF	0.61 (0.53, 0.66)	0.60 (0.50, 0.64)	0.61 (0.53, 0.66)	0.032
LVFS	0.33 (0.27, 0.36)	0.32 (0.26, 0.35)	0.33 (0.27, 0.36)	0.035

NOAF, new-onset atrial fibrillation; pCKMB, peak value of creatine kinase isoenzyme-MB; pTNI, peak value of troponin I; pNT-proBNP, peak value of N-terminal pro-B-type natriuretic peptide; LA, left atrium; LVEDD, left ventricular end-diastolic dimension; LVESD, left ventricular end- systolic dimension; LVEDVI, left ventricular end-diastolic volume index; LVESDVI, left ventricular end-systolic volume index; LVEF, left ventricular ejection fraction; LVFS, left ventricular fraction shortening.

3.2. Baseline Lipid Levels and Lipid Ratios Characteristic in NOAF and AF-Free Groups

Except for baseline lipid levels, we further analyzed the association between the incidence of NOAF and blood lipid ratios frequently used for cardiovascular risk stratification in the secondary analysis. The NOAF group showed significantly lower TC, TG, non-HDL-C, LDL-C/HDL-C, TC/HDL-C, and TG/HDL-C than the AF-free group. LDL-C, HDL-C, and TC/LDL-C showed no significant difference in the two groups. For males, compared with the AF-free group, the NOAF group showed significantly lower TC, non-HDL-C, LDL-C/HDL-C, TC/HDL-C, and TG/HDL-C. For females, the lipid levels and lipid ratios showed no significant difference in the two groups (Table 3).

Table 3. Blood lipid levels and lipid ratios in the NOAF and AF-free groups

	Total	NOAF	AF-free	P value
All participants	N= 4282	N= 132	N= 4150
TC (mmol/l)	4.4 (3.7, 5.1)	4.1 (3.7, 4.9)	4.4 (3.7, 5.1)	0.048
TG (mmol/l)	1.4 (1.0, 2.0)	1.3 (0.9, 1.9)	1.4 (1.0, 2.0)	0.035
LDL-C(mmol/l)	2.6 (2.1, 3.1)	2.4 (2.0, 3.0)	2.6 (2.1, 3.1)	0.054
HDL-C (mmol/l)	1.0 (0.9, 1.2)	1.0 (0.9, 1.3)	1.0 (0.8, 1.2)	0.053
Non-HDL-C (mmol/l)	3.4 (2.7, 4.0)	3.1 (2.7, 3.9)	3.4 (2.7, 4.0)	0.018
LDL-C/HDL-C	2.6 (2.0, 3.2)	2.3 (1.9, 2.9)	2.6 (2.0, 3.2)	0.005
TC/LDL-C	1.7 (1.6, 1.8)	1.7 (1.6, 1.9)	1.7 (1.6, 1.8)	0.243
TC/HDL-C	4.3 (3.6, 5.2)	4.0 (3.4, 4.8)	4.3 (3.6, 5.2)	0.002
TG/HDL-C	1.4 (1.0, 2.1)	1.3 (0.8, 1.8)	1.4 (1.0, 2.4)	0.007
Male	N= 3176	N= 89	N= 3087
TC (mmol/l)	4.3 (3.7, 5.0)	4.0 (3.7, 4.8)	4.3 (3.7, 5.0)	0.036
TG (mmol/l)	1.4 (1.0, 2.1)	1.3 (0.9, 1.9)	1.4 (1.0, 2.1)	0.062
LDL-C(mmol/l)	2.5 (2.0, 3.0)	2.3 (2.0, 2.9)	2.5 (2.0, 3.0)	0.089
HDL-C (mmol/l)	1.0 (0.9, 1.1)	1.0 (0.9, 1.2)	1.0 (0.9, 1.1)	0.078
Non-HDL-C (mmol/l)	3.3 (2.7, 4.0)	3.0 (2.6, 3.6)	3.3 (2.7, 4.0)	0.012
LDL-C/HDL-C	2.6 (2.1, 3.2)	2.4 (1.9, 2.9)	2.6 (2.1, 3.2)	0.014
TC/LDL-C	1.7 (1.6, 1.8)	1.7 (1.6, 1.8)	1.7 (1.6, 1.8)	0.947
TC/HDL-C	4.4 (3.7, 5.3)	4.1 (3.4, 4.7)	4.4 (3.7, 5.3)	0.002
TG/HDL-C	1.5 (1.0, 2.2)	1.4 (0.8, 1.8)	1.5 (1.0, 2.2)	0.025
Female	N= 1106	N= 43	N= 1063
TC (mmol/l)	4.6 (3.9, 5.4)	4.5 (3.8, 5.3)	4.6 (3.9, 5.4)	0.421
TG (mmol/l)	1.4 (1.1, 1.9)	1.4 (0.9, 1.9)	1.4 (1.1, 1.9)	0.343
LDL-C(mmol/l)	2.7 (2.1, 3.2)	2.6 (2.0, 3.0)	2.7 (2.1, 3.2)	0.252
HDL-C (mmol/l)	1.1 (0.9, 1.3)	1.2 (0.9, 1.4)	1.1 (0.9, 1.3)	0.667
Non-HDL-C (mmol/l)	3.5 (2.8, 4.2)	3.4 (2.8, 4.0)	3.5 (2.8, 4.2)	0.464
LDL-C/HDL-C	2.4 (1.9, 3.0)	2.2 (1.9, 2.9)	2.4 (1.9, 3.0)	0.238
TC/LDL-C	1.7 (1.6, 1.9)	1.8 (1.7, 1.9)	1.7 (1.6, 1.8)	0.074
TC/HDL-C	4.2 (3.5, 5.0)	3.9 (3.5, 4.9)	4.2 (3.5, 5.0)	0.403
TG/HDL-C	1.3 (0.9, 1.9)	1.2 (0.8, 1.7)	1.3 (0.9, 1.9)	0.212

NOAF, new-onset atrial fibrillation; TC, total cholesterol; TG, triglyceride; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol. Non-HDL-C was calculated as TC minus HDL-C.

3.3. Baseline Lipid Levels, Lipid Ratios, and Risk of NOAF for all Participants

Fig.1 shows the Kaplan–Meier event curves for NOAF in different lipid levels. Supplementary Fig.2A and 2B shows the unadjusted proportions of NOAF incidence in different lipid levels and lipid ratios. The patients were categorized into three groups based on tertiles of lipid parameters including TC, TG, LDL-C, HDL-C, non-HDL-C and LDL-C/HDL-C, TC/LDL-C, TC/HDL-C, and TG/HDL-C. Supplementary Fig.2A shows that unadjusted NOAF incidences in the low (＜3.96 mmol/l), middle (3.96–4.83 mmol/l), and high (＞4.83 mmol/l) TC tertiles were 4.2%, 2.6%, and 2.5%, respectively (P=0.013), whereas incidences in the low (＜2.94 mmol/l), middle (2.94–3.80 mmol/l), and high (＞3.80 mmol/l) non-HDL-C tertiles were 4.0%, 2.7%, and 2.5%, respectively (P=0.039). In addition, the lowest TG (＜1.17 mmol/l), lowest LDL-C group (＜2.24 mmol/l), and highest HDL-C (＞1.11 mmol/l) tertiles showed a trend in association with an increased risk of NOAF (P=0.333; P=0.059; P=0.090, respectively). During a median follow-up of 42.0 months, the cumulative incidence of NOAF was higher in the lowest tertile of TC, TG, LDL-C, and non-HDL-C and the highest tertile of HDL-C. But only based on tertiles of TC and non-HDL-C, the incidence of NOAF was statistically significant (log-rank P=0.009; log-rank P=0.031, respectively).

Fig.1. Kaplan–Meier event curves for NOAF by differing lipid levels for all participants

NOAF, new-onset atrial fibrillation; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol. Non-HDL-C was calculated as TC minus HDL-C.

Supplementary Fig.2. Incidence rate of NOAF by differing lipid levels and lipid ratios for all participants

NOAF, new-onset atrial fibrillation; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol. Non-HDL-C was calculated as TC minus HDL-C.

T1 indicates lowest tertile; T2 indicates middle tertile; T3 indicates highest tertile.

^＊represent P＜0.05.

According to lipid ratios, the incidences of NOAF were higher in the lowest tertile of LDL-C/HDL-C, TC/HDL-C, and TG/HDL-C (3.9% vs. 4.0% vs. 3.8%, P＜0.05). The tertiles of TC/LDL-C did not show a significant difference in NOAF incidence (Supplementary Fig.2B).

Table 4 shows that a multivariable Cox regression analysis was conducted to determine the lipid profiles associated with the incidence of NOAF during the follow-up period. On repeat analysis using the lowest tertile as a reference, after adjusting for potential confounders, lower TC and higher HDL-C significantly increased the risk of NOAF in AMI patients. The HRs of NOAF across TC tertiles (＜3.96 mmol/L, 3.96 to 4.83 mmol/L, ＞4.83 mmol/L) were 1 (reference), 0.382 (0.177 to 0.826), and 0.205 (0.061 to 0.696), respectively (P_trend=0.024). The HRs of NOAF across HDL-C tertiles (＜0.92 mmol/L, 0.92 to 1.11 mmol/L, ＞1.11 mmol/L) were 1 (reference), 1.550 (0.968 to 2.481), and 1.892 (1.133 to 3.159), respectively (P_trend=0.047). However, there were no similar trends in TG, LDL-C, and non-HDL-C tertiles.

Table 4. HRs (95% CIs) for NOAF by tertiles of blood lipids

Tertiles of TC (mmol/l)	Tertiles1 (＜3.96)	Tertiles 2 (3.96~4.83) HR (95%CI)	P value	Tertiles 3 (＞4.83) HR (95%CI)	P value	P trend
N	1435	1435		1412
NOAF cases	60	37		35
Model 1	reference	0.418 (0.193, 0.906)	0.027	0.240 (0.071, 0.808)	0.021	0.048
Model 2	reference	0.408 (0.188, 0.885)	0.023	0.220 (0.065, 0.743)	0.015	0.036
Model 3	reference	0.382 (0.177, 0.826)	0.014	0.205 (0.061, 0.696)	0.011	0.024
Tertiles of TG (mmol/l)	Tertiles 1 (＜1.17)	Tertiles 2 (1.17~1.77) HR (95%CI)	P value	Tertiles 3 (＞1.77) HR (95%CI)	P value	P trend
N	1462	1398		1422
NOAF cases	52	43		37
Model 1	reference	1.292 (0.837, 1.996)	0.247	1.494 (0.905, 2.464)	0.116	0.271
Model 2	reference	1.279 (0.825, 1.981)	0.271	1.560 (0.939, 2.590)	0.086	0.224
Model 3	reference	1.240 (0.793, 1.940)	0.346	1.555 (0.932, 2.596)	0.091	0.240
Tertiles of HDL-C (mmol/l)	Tertiles 1 (＜0.92)	Tertiles 2 (0.92~1.11) HR (95%CI)	P value	Tertiles 3 (＞1.11) HR (95%CI)	P value	P trend
N	1500	1380		1402
NOAF cases	35	45		52
Model 1	reference	1.586 (0.999, 2.518)	0.050	1.857 (1.132, 3.047)	0.014	0.043
Model 2	reference	1.549 (0.974, 2.464)	0.065	1.813 (1.101, 2.986)	0.019	0.057
Model 3	reference	1.550 (0.968, 2.481)	0.068	1.892 (1.133, 3.159)	0.015	0.047
Tertiles of LDL-C (mmol/l)	Tertiles 1 (＜2.24)	Tertiles 2 (2.24~2.88) HR (95%CI)	P value	Tertiles 3 (＞2.88) HR (95%CI)	P value	P trend
N	1437	1426		1419
NOAF cases	57	38		37
Model 1	reference	1.159 (0.560, 2.397)	0.691	1.393 (0.490, 3.961)	0.534	0.824
Model 2	reference	1.102 (0.530, 2.293)	0.795	1.341 (0.469, 3.837)	0.584	0.851
Model 3	reference	1.052 (0.477, 2.322)	0.900	1.343 (0.456, 3.961)	0.593	0.813
Tertiles of non-HDL-C (mmol/l)	Tertiles 1 (＜2.94)	Tertiles 2 (2.94~3.80) HR (95%CI)	P value	Tertiles 3 (＞3.80) HR (95%CI)	P value	P trend
N	1439	1418		1425
NOAF cases	58	38		36
Model 1	reference	1.278 (0.565, 2.893)	0.556	1.842 (0.532, 6.382)	0.335	0.624
Model 2	reference	1.314 (0.578, 2.990)	0.515	1.919 (0.547, 6.737)	0.309	0.594
Model 3	reference	1.512 (0.642, 3.562)	0.345	2.130 (0.584, 7.772)	0.252	0.509

OAF, new-onset atrial fibrillation; TC, total cholesterol; TG, triglyceride; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol. BMI, body Mass Index; eGFR, estimated glomerular filtration rate; CTO, chronic total occlusion; pCKMB, peak value of creatine kinase isoenzyme-MB; pTNI, peak value of troponin I; pNT-proBNP, peak value of N-terminal pro-B-type natriuretic peptide; LA, left atrium. Non-HDL-C was calculated as TC minus HDL-C.

Model 1 adjusted for sex, age and BMI.

Model 2 adjusted for sex, age, BMI, eGFR, pTNI, pCKMB and pNT-proBNP.

Model 3 adjusted for sex, age, BMI, eGFR, pTNI, pCKMB, pNT-proBNP, LA, Killip II-IV and CTO.

According to lipid ratios, after multivariable adjustment, there was no association between LDL-C/HDL-C, TC/LDL-C, TC/HDL-C, or TG/HDL-C and the incidence of NOAF (Table 5).

Table 5. Blood lipid ratios and risk for development of NOAF

	Model 1		Model 2		Model 3
	HR (95%CI)	P value	HR (95%CI)	P value	HR (95%CI)	P value
LDL-C/HDL-C (per-unit increase)	0.615 (0.138, 2.737)	0.523	0.674 (0.154, 2.956)	0.601	0.664 (0.154, 2.855)	0.582
TC/LDL-C (per-unit increase)	0.323 (0.054, 1.916)	0.213	0.381 (0.066, 2.181)	0.278	0.442 (0.077, 2.549)	0.361
TC/HDL-C (per-unit increase)	1.098 (0.415, 2.902)	0.851	1.033 (0.394, 2.710)	0.947	1.081 (0.425, 2.752)	0.870
TG/HDL-C (per-unit increase)	1.022 (0.882, 1.183)	0.775	1.031 (0.892, 1.192)	0.681	1.019 (0.887, 1.171)	0.790

NOAF, new-onset atrial fibrillation; TC, total cholesterol; TG, triglyceride; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol.

Model 1 adjusted for sex, age and BMI.

Model 2 adjusted for sex, age, BMI, eGFR, pTNI, pCKMB and pNT-proBNP.

Model 3 adjusted for sex, age, BMI, eGFR, pTNI, pCKMB, pNT-proBNP, LA, Killip II-IV and CTO.

3.4. Baseline Lipid Levels, Lipid Ratios and Risk of NOAF Stratified by Sex and Age Categories

Of 4282 patients, 74.2% (N=3176) were male and 25.8% (N=1106) were female. The proportions of patients with a diagnosis of NOAF were 2.8% and 3.9%, respectively. Furthermore, 54.5% (N=2332) were aged younger than 65 years, and 45.5% (N=1950) were aged 65 years or older. The proportions of patients with a diagnosis of NOAF were 2.1% and 4.2%, respectively. There was no significant interaction with sex and age for the association between TC, TG, LDL-C, HDL-C, and non-HDL-C levels with NOAF development. Across these sex and age categories, there were no significant differences in the associations between TG, LDL-C, and non-HDL-C levels with NOAF development. After adjusting for potential confounders including sex, age, BMI, eGFR, pTNI, pCKMB, pNT-proBNP, LA, Killip II–IV, and CTO, the inverse association between TC and NOAF was mainly reflected in the subgroups of male gender (HR 0.172, 95% CI 0.036–0.808, P=0.032) and aged 65 years or older (HR 0.162, 95% CI 0.034–0.768, P=0.016). However, the positive association between HDL-C and NOAF was mainly reflected in the subgroups of male gender (HR 2.409, 95% CI 1.286–4.515, P=0.016) and aged younger than 65 years (HR 2.393, 95% CI 1.010–5.670, P =0.045). The prevalence of NOAF was not statistically significantly lower in the highest tertile for those female and aged younger than 65 years in TC levels and in the lowest tertile for female and those aged 65 years or older in HDL-C levels (Fig.2 and 3).

Fig.2. NOAF risk by tertiles of baseline lipid levels stratified by sex category

A, TC; B, TG; C, HDL-C. D, LDL-C. E, non-HDL-C. T1 indicates lowest tertile; T2 indicates middle tertile; T3 indicates highest tertile.

NOAF, new-onset atrial fibrillation; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol. Non-HDL-C was calculated as TC minus HDL-C.

Fig.3. NOAF risk by tertiles of baseline lipid levels stratified by age category

A, TC; B, TG; C, HDL-C. D, LDL-C. E, non-HDL-C. T1 indicates lowest tertile; T2 indicates middle tertile; T3 indicates highest tertile.

NOAF, new-onset atrial fibrillation; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol. Non-HDL-C was calculated as TC minus HDL-C.

Similar to the results for all patients, there was no significant interaction with sex and age for the association between LDL-C/HDL-C, TC/LDL-C, TC/HDL-C, and TG/HDL-C levels with NOAF development. No statistically significant differences in the prevalence of NOAF were observed for patients across different tertiles for LDL-C/HDL-C, TC/LDL-C, TC/HDL-C, and TG/HDL-C levels for age or sex category (Supplementary Fig.3 and Supplementary Fig.4).

Supplementary Fig.3. NOAF risk by tertiles of baseline lipid ratios stratified by sex category

A, LDL-C/HDL-C; B, TC/LDL-C; C, TC/HDL-C. D, TG/HDL-C. T1 indicates lowest tertile; T2 indicates middle tertile; T3 indicates highest tertile.

NOAF, new-onset atrial fibrillation; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol. Non-HDL-C was calculated as TC minus HDL-C.

Supplementary Fig.4. NOAF risk by tertiles of baseline lipid ratios stratified by age category

A, LDL-C/HDL-C; B, TC/LDL-C; C, TC/HDL-C. D, TG/HDL-C. T1 indicates lowest tertile; T2 indicates middle tertile; T3 indicates highest tertile.

NOAF, new-onset atrial fibrillation; TC, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol. Non-HDL-C was calculated as TC minus HDL-C.

4.Discussion

In this study cohort with AMI patients, we determined that higher levels of TC were associated with a lower prevalence of NOAF and higher levels of HDL-C were associated with a higher prevalence of NOAF after multivariable adjustments. Second, the inverse association of TC for incidence of NOAF was mainly reflected in the subgroups of male gender and older patients (65 years or older); and positive association of HDL-C for incidence of NOAF was mainly reflected in the subgroups of male gender and younger patients (age＜65 years). Third, there was no significant association observed between TG levels, LDL-C levels, non-HDL-C levels, or lipid ratios and the prevalence of NOAF in this study.

The relationship between lipid levels and the development of NOAF has been controversial. While hyperlipidemia is a well-known risk factor for cardiovascular disease, especially high LDL-C levels, and low HDL-C levels, this has not been the case for AF. AMI can induce AF through inflammation and atrial diastolic overload, whereas rapid heart rate of AF leads to an increase in oxygen demand and worsens ischemia¹¹⁾. Previous studies on lipid and AF were mostly based on the general population, and relatively few studies were in light of AMI patients whose lipid control needed more attention. In our study cohort, 3.1% (132/4282) of AMI patients developed NOAF during the median 42.0 months of follow-up period, which was higher than the NOAF incidence in the general population. The reasons were maybe as follows: (1) The advanced age in AMI patients was common in the real world; (2) high-risk factors of AF at baseline were contained and these factors were the CHD risk factors too; (3) abnormal blood electrolyte levels were more likely to occur in AMI patients; (4) stronger immune and inflammatory response participated, which had been considered as the possible reason of AF; and (5) myocardial necrosis existed and it was more likely to occur in cardiac insufficiency^12-14). For the above reasons, the association between lipid levels and NOAF in AMI patients needed to be excavated.

In our study cohort, we found a clear inverse association between TC levels with NOAF development; the result is mostly consistent with previous studies. Back in 1999, M Annoura et al.¹⁵⁾ had observed the inverse association between TC levels with paroxysmal AF development. LEE HJ et al.¹⁶⁾ still found that the highest quartile of TC had a risk reduction of AF in Korea nationwide population–based cohort of 3660385 adults, and the association also existed for males and females. The Chinese Kailuan study⁴⁾ also found the cholesterol paradox in the AF population. In our study, the highest tertile of TC, compared with the lowest tertile, showed a risk reduction of 1.7% for NOAF. Our research further expanded the research foundation of the association between TC and NOAF and confirmed that the “cholesterol paradox” still existed in patients with AMI. Throughout previous research results, several mechanisms may link TC levels and NOAF development. Firstly, the membrane-stabilizing effect of cholesterol on lipid rafts and caveolae indirectly determined the localization of ion channels including K^＋, Na^＋, and Ca^2＋ subunits, especially Kv1.5 and Kir2.1 channels, which can induce prolongation of QT interval. That was a mechanism of AF development^{17, 18)}. Furthermore, a previous study showed that cholesterol depletion also increased intracellular Ca2+ concentration and triggered a signaling cascade, culminating with contraction impairment and myofibril disruption in cardiomyocytes¹⁹⁾. Thus, these may be the reasons why the lower levels of TC in AMI patients had a higher incidence of NOAF.

The association between HDL-C and NOAF development was greatly inconsistent in previous studies. Lopez FL et al.²⁰⁾ found that no significant association of AF incidence with HDL-C or TG was observed in the US communities. A meta-analysis suggested that higher levels of HDL-C were linearly associated with a lower risk of NOAF²¹⁾. Watanabe H et al.⁶⁾ observed that deceased HDL-C was associated with an increased risk of NOAF and that the association was strong in women but was weak in men in Japanese community-based population (Niigata Preventive Medicine Study) (N=28449). In the individuals who were out of AF risk factors such as taking anti-hypertensive drugs, diabetes, and heart disease at baseline, the incidence of AF increased in low HDL-C (＜40 mg/dl), especially in women. These studies all focused on general population. The inconsistent results may be attributable to some confounding factors such as geographical, ethnic variations or differences in follow-up time. However, in our study with AMI patients, we found that high HDL-C levels were associated with high NOAF incidence and the positive association was mainly reflected in the subgroups of male gender and aged younger than 65 years; this result was different from previous studies. HDL-C had an anti-atherosclerotic effect and preserved endothelial function by ameliorating the cytotoxic effect of oxidized LDL-C, promoting cholesterol efflux from macrophages, decreasing the vessel tone of resistant coronary arteries, and then improving the myocardial blood supply^{6, 22)}. HDL-C also improved endothelial repair mediated by progenitor cells, thus decreasing the risk of cardiac and vascular remodeling. It acted both as the acceptor of cholesterol from cells and as the cholesterol carrier in the reverse cholesterol transport (RCT) pathway^{23, 24)}. In previous studies on hypertension, reduced levels of HDL-C were associated with increased left ventricular (LV) mass, LV diastolic dysfunction, and the development of heart failure^{25, 26)}. However, the mechanisms were not suitable for our result. This positive association between HDL-C and NOAF was not reported before. As the cholesterol carrier, the reduction of TC throughout the RCT pathway by promoting cholesterol efflux from macrophage may increase the incidence of NOAF. In addition, AMI may cause redistribution of blood lipids, and HDL-C may increase reactively due to its anti-inflammatory and cardiovascular protective effect in AMI condition. Furthermore, these inflammation and oxidative stress may also play critical roles in the initiation and perpetuation of AF. These may be the reasons why high HDL-C was associated with high NOAF incidence in AMI population. However, the potential mechanism was unclear and needed further exploration.

The association between TC or HDL-C levels and NOAF incidence was still statistically significant for males, which was inconsistent with previous studies^{6, 16)}. The reason was maybe that relatively few women (25.8%) were included in our study and the incidence of AF in men was higher than in women in the real world²⁷⁾. Furthermore, the result may be driven by the geographical or ethnic variations. The electrophysiological properties of the atria were different between men and women^{6, 28)}. These reasons could possibly account for these gender-related differences. The prevalence of AF increases substantially with age and age has been inversely associated with TC levels^{29, 30)}. When stratifying by age, decreasing of TC levels in older age (age ≥ 65 years) groups may partly explain the inverse association between TC levels and NOAF. However, the positive association between HDL-C and NOAF development was statistically significant in the younger age group (＜65 years). The older age group (age ≥ 65 years) had fewer patients (1950/4282) than the younger age groups. Therefore, a power reduction may have impacted the nonsignificant association between HDL-C and NOAF for the older age group. Moreover, the decreasing activity of RCT pathway with age may be a potential reason. We did not observe the association between LDL-C and NOAF development in AMI patients; it was consistent with the Framingham Heart Study⁷⁾. TG, non-HDL-C, and lipid ratios were not associated with NOAF too, which is in line with the results of this study⁴⁾.

In our study, the LVEF was almost normal after AMI in the NOAF and NOAF-free groups. The previous studies showed that the early left cardiac remodeling occurred in 2–3 weeks after AMI. Hyperemic microcirculatory resistance, no-reflow phenomenon, and infarct size were found as strong predictors for early cardiac remodeling, and the main manifestation of echocardiography was the decline of diastolic dysfunction in the early stage. Furthermore, STEMI-induced cardiac remodeling was frequently related to heart failure with reduced ejection fraction or heart failure with midrange ejection fraction, and NSTEMI-induced cardiac remodeling was rather associated with developing heart failure with preserved ejection fraction^{31, 32)}. In addition, previous studies showed that LVEF was significantly lower in patients in Killip II than in those in Killip I and patients with anterior MI had lower LVEF^33-35). In our study, there was no statistical difference in the proportion of slow flow after PCI, and patients with NSTEMI accounted for 50.2%, and about one-quarter were acute anterior MI. Patients in Killip I were 74.3%. Furthermore, echocardiography was measured within 24 h from admission after AMI. The biased choice of our population may also be one of the reasons. Therefore, the decrease in LVEF was not obvious in early stage, and LVEF was even normal in our study.

Previous studies showed that more risk factors including hypertension, DM, or obesity can increase AF development. Interestingly, we found that NOAF patients had lower BMI, and after multivariate adjustment, lower BMI was still a risk factor for NOAF. This phenomenon needs further study.

In sum, low serum levels of TC, TG, non-HDL-C, LDL-C/HDL-C, TC/HDL-C, and TG/HDL-C were found in NOAF patients, while reduced TC and increased HDL-C may cause NOAF in AMI population. Our results add to the growing literature on blood lipids, lipid ratios, and NOAF development. However, these literatures are inconsistent, and the evidence may provide a new clue and perspective for clarifying the relationship and exploring underlying mechanisms.

5. Study Limitations

First, this was a single-center study, some potential selection bias existed and lipid profiles will be different during the acute phase. Second, although many potential interfering covariables were adjusted by our models, we cannot rule out residual confounding such as thyroid hormone levels or other medications. Determination of AF was based on a 12-lead electrocardiogram when they were outpatient or rehospitalized. The data of 24-h-holter ECG, 2 weeks of ECG, and implantable devices was not collected. The manner and frequency of the evaluation for the diagnosis of AF may lead to an underestimation of the incidence of NOAF. Third, only one lipid result at admission was contained in the cohort. We did not permit examination of the lipid variability over time; high lipid variability has been associated with a higher risk of NOAF previously¹⁶⁾.

6.Conclusion

The present finding of an inverse association between TC and risk of NOAF supports the “dyslipidemia paradox,” and it was also statistically significant in subgroups of males and patients aged ≥ 65 years. Furthermore, we found that increased HDL-C levels were associated with an increased risk of developing NOAF and that the association was observed in subgroups of males and aged ＜65 years. There was no significant association of NOAF with LDL-C, TG, non-HDL-C levels, or lipid ratios.

List of Abbreviations

BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; AMI: acute myocardial infarction; CHD, coronary heart disease; OMI: old myocardial infarction; DM, diabetes mellitus; WBC, white blood cells; hsCRP, Hypersensitivity C-reactive protein; eGFR, estimated glomerular filtration rate; FBG, fasting blood glucose; TC, total cholesterol; TG, triglyceride; LDL-C, low density lipoprotein cholesterol; HDL-C, high density lipoprotein cholesterol; pCKMB, peak value of creatine kinase isoenzyme-MB; pTNI, peak value of troponin I; pNT-proBNP, peak value of N-terminal pro-B-type natriuretic peptide; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; LVEDD, left ventricular end-diastolic dimension; LVESD, left ventricular end-systolic dimension; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; LVEF, left ventricular ejection fraction; LVFS, left ventricular fraction shortening; LM, left main trunk; PCI, percutaneous coronary intervention; CTO, chronic total occlusions; NOAF, new-onset atrial fibrillation.

Funding

This study was supported by National Key R&D Program of China (2021ZD0111004), Natural Science Foundation of China (No. 82070357), Beijing Municipal Administration of Hospital Incubating Program (No. PX2018002), and Beijing Key Clinical Subject Program.

Competing Interests

The authors declare that they have no competing interests.

Ethics Approval and Consent to Participate

The study data collections were approved by the Institutional Review Board of Beijing Friendship Hospital, Capital Medical University, and written informed consent was obtained from all patients.

Consent for Publication

Not applicable.

Availability of Data and Materials

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

Authors’ Contributions

WPL contributed to the conception or design of the work. LL, XYL and XSD contributed to the acquisition, analysis, or interpretation of data for the work. HC and HWL contributed discussion and edited manuscript. LL drafted the manuscript. All authors critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work ensuring integrity and accuracy.

Acknowledgements

The authors gratefully acknowledge the contributions of all staffs who work on the Cardiovascular Center of Beijing Friendship Hospital Data Bank (CBD BANK).

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