Subclinical Atherosclerosis Is Associated With Incident Atrial Fibrillation

A Systematic Review and Meta-analysis

Kit Engedal Kristensen; Cille Cederholm Knage; Liv Havgaard Nyhegn; Bart A. Mulder; Michiel Rienstra; Isabelle C. Van Gelder; Axel Brandes

Disclosures

Europace. 2020;22(7):991-1000.

Conclusion

In conclusion, increased values of both cIMT and CACS are associated with higher incidence of AF. This supports the growing evidence that subclinical atherosclerosis maybe a risk factor of AF and enhances the importance of clarifying whether treatment of subclinical atherosclerosis should be part of the initiatives to prevent AF.

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Europace. 2020;22(7):991-1000. © 2020 Oxford University Press
Copyright 2007 European Heart Rhythm Association of the European Society of Cardiology (ESC). Published by Oxford University Press. All rights reserved.

Table 1. Study characteristics and baseline measurements of the studies investigating the association between carotid intima-media thickness or coronary artery calcium score and incident atrial fibrillation
	Chen et al. ¹² (ARIC)	Chen et al. ¹² (MESA)	Adamsson Eryd et al. ¹⁴	Heeringa et al. ¹¹	Losi et al. ¹⁵	O'Neal et al. ¹³	Vinter et al. ¹⁶
Trial size	13 595	6605	4846	4225	7062	6641	27 962
Follow-up (median in years)	17.8	8.5	15.3	7.5	3.0	8.5	2.9
Exclusion criteria	AF at baseline Race other than black or white	AF at baseline Physician diagnosed heart attack, angina or taking NTG, stroke or TIA Having undergone CABG, angioplasty, valve replacement, PM, or ICD implantation, any surgery on heart or arteries	History of hospitalization due to AF, HF, or MI	AF at baseline History of MI (typical, silent or non-Q-wave) Insufficient data to exclude previous MI Angina pectoris (Rose questionnaire) Not completed Rose questionnaire History of CABG or PTCA	History of AF History of CVD (MI, coronary revascularization, stroke, TIA, valvular heart disease) EF < 50% Chronic kidney disease Stage IV or V	AF at baseline CVD	History of AF History of valvular disease (mitral stenosis, mechanical prosthetic heart valve), AMI, PCI, heart surgeries (CABG), CAD Missing CACS
Recruitment	Residents of 4 communities in 4 American states, 45–64 years of age	Residents of 6 communities in 6 American states, 45–84 years of age	All men born 1923–1945 and women born 1923–1950 living in Malmö, Sweden, were invited	All residents of Ommoord district living in Rotterdam, the Netherlands, ≥55 years were invited	Hypertensive patients from 5 districts of the Campania Region, Italy	Residents of 6 communities in 6 American states 45–84 years of age	Patients, who underwent nCCT suspect CAD, identified through the WDHR, Denmark
Age (mean ± SD, years)	57.0 ± 5.7	62.0 ± 10.2	57.5 ± 6.0	M: 67.1 ± 7.8	52 ± 12	62 ± 10	56.9 ± 11.1
Age (mean ± SD, years)	57.0 ± 5.7	62.0 ± 10.2	57.5 ± 6.0	W: 68.5 ±8.8	52 ± 12	62 ± 10	56.9 ± 11.1
Gender (%)	M: 44.5	M: 47.2	M: 40	M: 37.9	M: 57	M: 47.1	M: 44.6
Gender (%)	W: 55.5	W: 52.8	W: 60	W: 62.1	W: 43	W: 52.9	W: 55.4
Baseline information obtained by	CIMT was measured bilateral by US on the posterior wall on CCA as the mean thickness in three segments: 1 cm proximal of the bulbus, the bifurcation, and the proximal ICA	CIMT was measured by US on the anterior and posterior wall on CCA and the ICA on right and left side and calculated as the mean of the maximum CIMT	CIMT was measured by US on the posterior wall of the right distal CCA as the mean thickness over a 1 cm segment proximal to the bifurcation	CIMT was measured by US on the anterior and posterior wall of the right and left CCA as the mean thickness over a 1 cm segment proximal to the bulbus	The maximum CIMT was measured by US in the right and the left, anterior and posterior wall of CCA over a 1 cm segment proximal ICA and bifurcation	CACS was measured by nCCT and determined by the Agatston score method. The total CACS was summed for LMCA, LAD, LCX, and RCA	CACS was measured by nCCT and determined by the Agatston score method. The total CACS was summed for LMCA, LAD, LCX, and RCA
Carotid plaque definition	Two of the following: - cIMT >1.5 mm - Abnormal shape - Abnormal wall texture	Mean of maximum cIMT ≥25%	Focal thickening of IMT >1.2 mm	Focal broadening of intima-media relative to adjacent segments with protrusion into lumen	IMT >1.5 mm	NA	NA
Baseline measurement	Mean ± SD (mm): 0.75 ± 0.20	Mean ± SD (mm): 0.87 ± 0.19	Median (IQR) (mm): M: 0.77 (0.68–0.87) W: 0.73 (0.66–0.82)	Mean ± SD (mm): M: 0.84 ± 0.15 W: 0.80 ± 1.14	Mean ± SD (mm): No AF group: 1.6 ± 0.7 AF group: 1.9 ± 0.8	CACS 0: 50.4% CACS 1–100: 26.3% CACS 101–300: 10.7% CACS > 300: 12.2%	CACS 0: 52.2% CACS 1–99: 25.7% CACS 100–399: 12.6% CACS: 400–999: 5.9% CACS > 1000: 3.7%
Outcome AF information obtained by	-ECG at follow-up -Hospital diagnoses -Death certificates No differentiation between AF and atrial flutter	-ECG at follow-up -Hospital diagnoses -Death certificates -MICD -Interviews No differentiation between AF and atrial flutter	-Hospital diagnoses No differentiation between AF and atrial flutter	-ECG at follow-up -Medical files from GP -Hospital diagnoses No differentiation between AF and atrial flutter	-ECG at follow-up -Hospital diagnoses Differentiation between AF and atrial flutter is not specified	-ECG at follow-up -Hospital diagnoses -Death certificates -MICD -Interviews No differentiation between AF and atrial flutter	-Discharge diagnoses from administrative registries No differentiation between AF and atrial flutter

AF, atrial fibrillation; AMI, acute myocardial infarction; CABG, coronary artery bypass grafting; CACS, coronary artery calcium score; CAD, coronary artery disease; CCA, Common carotid artery; cIMT, carotid intima-media thickness; CVD, cardiovascular disease; ECG, electrocardiogram; EF, ejection fraction; GP, general practitioner; HF, heart failure; ICA, internal carotid artery; ICD, implantable cardioverter-defibrillator; IQR, interquartile range; LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; LMCA, left main coronary artery; M, men; MI, myocardial infarction; MICD, Medicare inpatient claims data; NA, not applicable; nCCT, non-contrast computed tomography; NTG, nitroglycerine; PCI, percutaneous coronary intervention; PM, pacemaker; PTCA, percutaneous transluminal coronary angioplasty; OP, operative procedures; RCA, right coronary artery; SD, standard deviation; TIA, transient ischaemic attack; US, ultrasound; W, women; WDHR, Western Denmark Heart Registry.

Table 2. Results from the five studies investigating the association between cIMT and incident atrial fibrillation
	Chen et al. ¹² (ARIC)	Chen et al. ¹² (MESA)	Adamsson Eryd et al. ¹⁴	Heeringa et al. ¹¹	Losi et al. ¹⁵
Incidence (incident AF/1000 person years):	7.3	6.0	4.8	Not specified	6.6
Hazard ratio (95% CI)	HR: 1.29 (1.08–1.54) 5th vs. 1st quintile M: HR: 1.25 (0.96–1.63) W: HR: 1.30 (1.01–1.66)	HR: 1.94 (1.15–3.28) 5th vs. 1st quintile	HR: 1.52 (1.08–2.16) 4th vs. 1st quartile M: HR: 2.00 (1.24–3.23) W: HR: 1.08 (0.65–1.81)	HR: 1.90 (1.20–3.00) 4th vs. 1st quartile M: HR: 1.61 (0.77–3.36) W: HR: 2.14 (1.19–3.86)	HR: 1.51 (1.27–1.79) >1.5 mm cIMT vs. ≤1.5 mm cIMT
Stratified or adjusted for:	-Age -Sex -Race -Weight -Height -Systolic BP -Diastolic BP -Antihypertensive medication -Smoking -Diabetes -HF -MI	-Age -Race -Weight -Height -Systolic BP -Diastolic BP -Antihypertensive medication -Smoking -Diabetes -HF -MI	-Age -Sex -Waist circumference -Systolic BP -Antihypertensive medication -Smoking -Diabetes -LDL -HDL -Education -Physical activity -CRP	-Age -Sex -BMI -Hypertension -Systolic BP -Smoking -Diabetes -Cholesterol -LV hypertrophy -Use of cardiac medication	-Age -Sex -Systolic BP -LV mass index -Duration of hypertension -Use of cardiac medication

AF, atrial fibrillation; BP, blood pressure; CI, confidence interval; cIMT, carotid intima-media thickness; CRP, C-reactive protein; HDL, high-density lipoprotein; HF, heart failure; HR, hazard ratio; LDL, low-density lipoprotein; LV, left ventricular; M, men; MI, myocardial infarction; W, women.

Table 3. Results from the two studies investigating the association between CACS and incident atrial fibrillation
	O'Neal et al. ¹³	Vinter et al. ¹⁶
Hazard ratio (95% CI):	HR: CACS 1–100: 1.4 (1.01–2.0) CACS 101–300: 1.6 (1.1–2.4) CACS > 300: 2.1 (1.4–2.9) (Reference CACS 0) CACS as a continuous variable: Log2(CACS+1) HR: 1.1 (1.05–1.13)	HR: CACS 1–99: (0.8–1.25) CACS 100–399: 1.36 (1.06–1.74) CACS 400–999: 1.76 (1.33–2.35) CACS > 1000: 1.67 (1.2–2.34) (Reference CACS 0) CACS as a continuous variable: Log2(CACS+1) HR: 1.05 (1.03–1.08)
Stratified or adjusted for	-Age -Sex -BMI -Race -Systolic BP -Smoking -Diabetes -Income -Lipid-lowering medications -Total cholesterol -HDL-cholesterol -Aspirin -Antihypertensive -CRP -LV hypertrophy -Education	-Age -Sex -BMI -Systolic BP -Diastolic BP -Smoking -Diabetes -HF -Lipid-lowering medication Reception -Antihypertensive medication reception -Prior stroke/TIA/systemic Embolism -CABG

BMI, body mass index; BP, blood pressure; CACS, coronary artery calcium score; CABG, coronary artery bypass grafting; CI, confidence interval; CRP, C-reactive protein; HDL, high-density lipoprotein; HF, heart failure; HR, hazard ratio; LV, left ventricular; M, men; TIA, transient ischaemic attack; W, women.

Table 4. The Newcastle-Ottawa Scale for quality assessment of cohort studies evaluating the association between subclinical atherosclerosis and incident atrial fibrillation
	Chen et al. (ARIC)¹²	Chen et al. (MESA)¹²	Adamsson Eryd et al. ¹⁴	Heeringa et al. ¹¹	Losi et al. ¹⁵	O'Neal et al. ¹³	Vinter et al. ¹⁶
Selection:
(1) Representativeness of the exposed cohort	C	B*	B*	B*	B*	B*	A*
(2) Selection of the non-exposed cohort	A*	A*	A*	A*	A*	A*	A*
(3) Ascertainment of exposure	A*	A*	A*	A*	A*	A*	A*
(4) Demonstration that outcome of interest was not present at start of study	A*	A*	A*	A*	B	A*	B
Comparability
(1) Comparability of cohorts on the basis of the design or analysis	A*	A*	A*	A*	A*	A*	A*
	A*	A*	A*	B*	A*	A*	B*
Outcome
(1) Assessment of outcome	B*	B*	B*	A*	B*	B*	B*
(2) Was follow-up long enough for outcomes to occur	A*	A*	A*	A*	A*	A*	A*
(3) Adequacy of follow-up for cohorts	B*	B*	A*	B*	A*	A*	A*
Total score
Selection:	S: 3	S: 4	S: 4	S: 4	S: 3	S: 4	S: 3
Comparability:	C: 1	C: 1	C: 1	C: 2	C: 1	C: 1	C: 2
Outcome:	O: 3	O: 3	O: 3	O: 3	O: 3	O: 3	O: 3

Selection:
(1) A*: truly representative of the average adult population in the community; B*: somewhat representative of the adult population in the community; C: selected group; D: no description of the derivation of the cohort.
(2) A*: Selection of the non-intervention cohort drawn from the same community as the intervention cohort; B: drawn from a different source; C: no description of the derivation of the non-intervention cohort.
(3) A*: secure record; B*: structured interview; C: written self-report; D: no description.
(4) A*: yes; B: no.
Comparability: (A maximum of two stars can be given for Comparability).
(1) A*: study controls for age, cardiovascular disease; B*: study controls for weight, smoking, sex, diabetes, heart surgery, blood pressure.
Outcome:
(1) A*: independent blind assessment; B*: record linkage; C: self-report; D: no description.
(2) A*: yes (≥2 years); B: no (<2 years).
(3) A*: complete follow-up; all subjects were accounted for; B*: Subjects lost to follow-up were unlikely to introduce bias because small numbers were lost; ≥80% had follow-up, or description was provided of those lost; C: follow-up rate <80%, and there was no description of those lost; D: no statement.

eTable 1. Search strategy MEDLINE and Embase
1	exp arteriosclerosis/
2	Arteriosclero*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
3	exp atherosclerosis/
4	Atherosclero*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
5	exp arterial stiffness/
6	Arterial stiff*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
7	exp coronary artery disease/
8	Coronary artery disease*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
9	Carotid artery disease*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
10	exp carotid artery disease/
11	exp vascular disease/
12	Vascular disease*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
13	1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10 or 11 or 12
14	exp arterial wall thickness/
15	Arterial wall thickness.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
16	cIMT.mp.
17	Intima media thickness.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
18	Intima-media thickness.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
19	Calcium scor*.mp.
20	exp coronary artery calcium score/
21	Coronary artery calcium*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
22	14 or 15 or 16 or 17 or 18 or 19 or 20 or 21
23	exp atrial fibrillation/
24	Atrial fibrillation*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
25	Atrium fibrillation*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
26	Auricular fibrillation*.mp. [mp=title, abstract, heading word, drug trade name, original title, device manufacturer, drug manufacturer, device trade name, keyword, floating subheading word, candidate term word]
27	23 or 24 or 25 or 26
28	13 and 22 and 27

eTable 2. Search strategy Cochrane Library
1	Arteriosclero*
2	MeSH descriptor: [Arteriosclerosis] explode all trees
3	Atherosclero*
4	MeSH descriptor: [Atherosclerosis] explode all trees
5	"Arterial stiffness"
6	"Arterial stiffening"
7	MeSH descriptor: [Vascular Stiffness] explode all trees
8	"Coronary artery disease"
9	"Coronary artery diseases"
10	MeSH descriptor: [Coronary Artery Disease] explode all trees
11	"Carotid artery disease"
12	"Carotid artery diseases"
13	MeSH descriptor: [Carotid Artery Diseases] explode all trees
14	"Vascular disease"
15	"Vascular diseases"
16	MeSH descriptor: [Vascular Diseases] explode all trees
17	#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16
18	"Arterial wall thickness"
19	cIMT
20	"Intima media thickness"
21	MeSH descriptor: [Carotid Intima-Media Thickness] explode all trees
22	"Coronary artery calcium"
23	"Calcium score"
24	"Calcium scoring"
25	#18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25
26	"Atrial fibrillation"
27	"Atrial fibrillations"
28	MeSH descriptor: [Atrial Fibrillation] explode all trees
29	"Atrium fibrillation"
30	"Atrium fibrillations"
31	"Auricular fibrillation"
32	"Auricular fibrillations"
33	#27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33
34	#17 AND #26 AND #34

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