Cerebral Microbleeds With Atrial Fibrillation After Ablation Therapy

doi:10.21203/rs.3.rs-924427/v1

Background: The prevalence of cerebral microbleeds (CMBs) is significantly higher in patients with atrial fibrillation (AF) than in those without AF. CMBs in patients with AF have been reported to be primarily of the lobar type, but the exact cause of this remains unknown. We investigated the possibility that hemorrhagic transformation of embolic microinfarction can account for de novo lobar CMBs.

Methods: A total of 101 patients who underwent ablation therapy for AF were prospectively registered, and 72 patients completed the assessment with MRI 6 months after catheter ablation. Brain MRI, including diffusion-weighted imaging (DWI) and susceptibility-weighted imaging (SWI), were examined at 1–3 days (baseline) and 6 months after catheter ablation. We quantitatively evaluated the spatial and temporal distribution of embolic microinfarctions and de novo CMBs.

Results: Of the 101 patients, 68 were enrolled in this study. Fifty-nine patients (86.8%) showed embolic microinfarctions on baseline DWI immediately after catheter ablation. There were 137 CMBs in SWI, and 96 CMBs were of the lobar type. Six months later, there were 208 CMBs, including 71 de novo CMBs, and 60 of 71 (84.5%) were of the lobar type. Of the 71 de novo CMBs, 56 (78.9%) corresponded exactly to the location of previous embolic microinfarctions found on baseline DWI. The platelet count was significantly lower and hematocrit/hemoglobin and Fazekas score were higher in the group with de novo CMBs than in the group without de novo CMBs.

Conclusions: De novo CMBs frequently appeared after catheter ablation therapy. Our results suggest that embolic microinfarction can cause lobar CMBs.

Neurology

Urology & Nephrology

cerebral microbleeds

atrial fibrillation

cerebral infarction

Cerebral microbleeds (CMBs) are small perivascular accumulations of hemosiderin-containing macrophages as a result of extravasation of erythrocytes from cerebral small vessels on histopathological examinations. In neuroimaging, CMBs are defined as small hypointense foci < 10 mm in diameter on magnetic resonance imaging (MRI) using T2*-weighted gradient-recalled echo or susceptibility-weighted imaging (SWI)^{1, 2, 3}. CMBs are classified into two types according to their location (deep and lobar CMBs), and histopathological analysis reveals mainly two types of vascular pathological changes, hypertensive vasculopathy and cerebral amyloid angiopathy (CAA), respectively. Strictly, the lobar CMBs are mostly considered to be caused by CAA and are found frequently in patients with Alzheimer’s disease^{4, 5}, whereas the non-lobar, deep or infratentorial, and mixed types of CMBs are considered to be due to hypertensive vasculopathy³.

Atrial fibrillation (AF) is a common arrhythmia, and its prevalence is increasing worldwide⁶. AF is associated not only with ischemic stroke, but also dementia. AF and dementia share multiple risk factors, and a meta-analysis study has revealed that there is an increased risk of dementia either with or without stroke⁷. One plausible cause of dementia with AF is the presence of cerebral infarctions⁸ and the other mechanism may be the existence of CMBs which have been suggested to be associated with cognitive dysfunction⁹.

The prevalence of CMBs is significantly higher in patients with AF than in those without AF^{4, 10, 11}, and CMBs in patients with AF have been reported to be primarily of the lobar type^{4, 12}. The underlying pathophysiology of strictly lobar CMBs in patients with AF is yet to be ascertained⁴. In a previous study, we have reported alleviation of cognitive dysfunction after performing catheter ablation in patients with AF¹³, and observed de novo appearance of CMBs in correspondence with preexisting embolic microinfarctions. To investigate the possibility that hemorrhagic transformation of embolic microinfarction can account for de novo CMBs in patients with AF, we quantitatively investigated the association between embolic microinfarctions and CMBs on brain MRI.

Study protocol

This prospective study was approved by the ethical review board of Mie University Hospital (certificate number 3,038), and all patients provided written informed consent. All methods were performed in accordance with the Declaration of Helsinki. All patients were recruited from the Department of Cardiology, Mie University Hospital between August 2018 and September 2019. We recruited 101 patients who were admitted to the hospital for AF catheter ablation ¹³.

We obtained clinical information, laboratory, and imaging data at baseline and follow-up after catheter ablation. Detailed clinical information, including age; sex; height; weight; blood pressure; heart rate; medical history, such as hypertension, hyperlipidemia, and diabetes mellitus; history of transient ischemic attack and/or stroke; and medication at baseline, was collected.

Ablation procedure

Catheter ablation was performed as described previously¹⁴. After obtaining informed consent, an electrophysiological study was performed in the post-absorptive state under light sedation. After internal jugular and femoral vein punctures, a heparin bolus (100 U/kg) was administered, and continuous infusion of heparin was provided thereafter to maintain an activated clotting time between 250 and 350 s. A diagnostic duodecapolar catheter was placed in the coronary sinus via the jugular vein. Three long sheaths were inserted through the femoral vein and introduced into the left atrium (LA) through a single trans septal puncture guided by intracardiac echocardiography. An eicosapolar circumferential catheter (Lasso 2515, Biosense Webster, Diamond Bar, CA, USA) and a multispline mapping catheter (PentaRay, Biosense Webster) were introduced into the LA through the trans septal long sheaths.

All imaging was performed using a biplane flat panel detector angiographic suite (Allura Xper FD10/10 Angio system; Philips Healthcare, Best, the Netherlands). Electroanatomical mapping was performed using the CARTO3 mapping system (Biosense Webster). Radiofrequency ablation was performed with an irrigated catheter (EZ Steer Thermocool, Biosense Webster) using 0.9% normal saline and a point-by-point technique. Extensive encircling pulmonary vein isolation (EEPVI) was performed in patients with paroxysmal AF, and entrance and exit blocks were documented in all patients using Lasso2515 and PentaRay multipolar catheters. In addition to EEPVI, patients with persistent AF received LA posterior wall isolation. Additional linear ablation was performed along the LA roof to connect the left superior pulmonary vein to the right superior pulmonary vein and linear ablation along the LA floor to connect the inferior margin of the left inferior pulmonary vein to the right inferior pulmonary vein to obtain a block into the posterior wall. A bidirectional block was confirmed across all linear ablations using differential pacing techniques. If common atrial flutter was induced by atrial tachycardia pacing, cavotricuspid isthmus line ablation was performed in patients with paroxysmal AF and persistent AF.

Magnetic resonance imaging (MRI) protocol

MRI studies were performed at 1 to 3 days (baseline) and 6 months after ablation (follow-up) with a 3T MR unit (Ingenia, Philips Medical System, The Netherlands) using a 32-channel phased-array head coil¹³. We used diffusion-weighted imaging (DWI), three-dimensional (3D) fluid-attenuated inversion recovery (3D-FLAIR), 3D double inversion recovery (3D-DIR), and 3D T1-weighted imaging (3D-T1WI) to detect microemboli^{15, 16}. Acute microinfarctions were diagnosed using DWI images, whereas chronic microinfarctions were evaluated using 3D-DIR, 3D-FLAIR, and 3D-T1WI images. SWI was used to detect CMBs.

3D-DIR parameters were as follows: FOV, 250 mm; matrix, 208 × 163; thickness, 1.3 mm; TR (ms)/TE (ms), 5,500/247; TI (ms), 2,550/450; NEX, 2; and acquisition time, 5 min 13 s.

3D-FLAIR parameters were as follows: FOV, 250 mm; matrix, 256 × 184; thickness, 1.14 mm; TR (ms)/TE (ms), 6,000/390; TI, 2,000 ms; NEX, 2; and acquisition time, 4 min 42 s.

3D-T1WI imaging used turbo-field echo sequence and the following parameters: FOV, 260 mm; matrix, 288 × 288; thickness, 0.9 mm; TR (ms)/TE (ms), 8.4/4.7; NEX, 1; FA, 10°; and acquisition time, 4 min 56 s.

SWI parameters were as follows: FOV, 230 mm; matrix, 384 × 300; thickness, 2 mm; TR (ms)/TE (ms), 31/7.2; NEX, 1; FA, 17°; and acquisition time, 4 min 52 s.

And DWI parameters: FOV, 220 mm; matrix, 112 × 168; thickness, 3 mm without gap; TR (ms)/TE (ms), 5800 /87; b value = 1,000 s/mm²; NEX, 1; three orthogonal diffusion directions; and acquisition time, 1 min 10 s.

CMBs and cortical superficial siderosis, white matter hyperintensity (WMH) and lacunar infarcts, and acute microinfarctions were evaluated using SWI, 3D-FLAIR, and DWI, respectively¹⁷. Periventricular and deep WMHs were assessed according to the Fazekas rating scale¹⁸. MRI images were thoroughly analyzed by two trained neurologists (Y.H. and N.K.) who were blinded to the clinical data.

Statistical analysis

For the analyses of the differences in demographic characteristics, the Mann-Whitney U test and the χ-square test were used. To compare the difference in medical history between the group with newly detected de novo CMBs (positive group) and the group without de novo CMBs (negative group), the χ-square test was used. To compare the difference in DWI-positive lesions and Fazekas scores between the two groups, the Mann-Whitney U test was used. Statistical analyses were performed using the Statistical Package for the Social Sciences Statistics software version 27 (IBM Corporation, Armonk, NY, USA).

Patient characteristics

A total of 101 patients underwent MRI 1 to 3 days after ablation. Six months after ablation, 72 patients underwent MRI, and 29 patients did not. Because of predetermined disqualification, four patients were excluded (Fig. 1): one with a history of ablation more than three times, and three with more than 50 CMBs.

The baseline characteristics of the patients are presented in Table 1. The median age at baseline was 69.0 ± 9.5 (range 32–86) years, and 49 patients were male (72.1%). All patients were administered oral anticoagulants. Moreover, 45 patients had hypertension (66.2%), nine had diabetes mellitus (13.2%), 28 had dyslipidemia (41.2%), and one had a history of stroke (1.5%). None of the patients had any neurological abnormality after ablation.

Table 1

Characteristics of the 68 patients with AF.
	All	De novo CMB-positive group (n= 35)	De novo CMB-negative group (n= 33)	p value
Mean age (years)	69.0 ± 9.5	67.7 ± 11.2	69.1 ± 7.4	0.980
Male sex, (n, %)	49 (72.1%)	25 (71.4%)	24 (72.7%)	0.560
Height (cm)	164.1 ± 9.2	162.8 ± 9.0	165.4 ± 9.4	0.269
Weight (kg)	65.8 ± 15.0	65.9 ± 17.5	65.7 ± 12.2	0.645
Body mass index (kg/m²)	24.3 ± 4.6	24.3 ± 5.1	24.0 ± 4.0	0.754
Current smoking (n, %)	34 (50.0%)	14 (40.0%)	20 (60.6%)	0.072
Blood pressure and Heart rate
Systolic blood pressure (mmHg)	132.8 ± 19.5	130.9 ± 20.2	134.8 ± 18.8	0.348
Diastolic blood pressure (mmHg)	77.9 ± 12.8	77.8 ± 11.9	77.9 ± 13.7	0.839
Heart rate (beat per minute)	71.9 ± 13.9	70.6 ± 13.9	73.4 ± 13.9	0.418
Past history
Hypertension (n, %)	45 (66.2%)	22 (62.9%)	23 (69.7%)	0.368
Dyslipidemia (n, %)	28 (41.2%)	13 (37.1%)	15 (45.5%)	0.327
Diabetes mellitus (n, %)	9 (13.2%)	5 (14.2%)	4 (12.1%)	0.539
history of TIA and/or stroke (n, %)	1 (1.5%)	1 (2.8%)	0 (0%)	0.515
Medication
antiplatelet (n, %)	9 (13.2%)	6 (17.1%)	3 (9.1%)	0.269
statin (n, %)	24 (35.2%)	12 (34.2%)	12 (36.4%)	0.529
Abbreviations: AF, atrial fibrillation; CMBs, cerebral microbleeds

Brain MRI findings 6 months after ablation

Figures 2 and 3 show two representative patterns of MRI findings. At baseline, DWI detected embolic microinfarcts in 59 out of 68 patients (86.8%), with a total of 392 lesions. These embolic microinfarcts were classified as the lobar (346), deep (11), and infratentorial lesions (35). CMBs were observed in 59 out of 68 patients (86.8%), with a total of 137 lesions on SWI at baseline. These CMBs were in the lobar (96), deep (19), and infratentorial areas (22). Six months later, MRI detected 208 CMBs with SWI. These were in the lobar (156), deep (24), and infratentorial (28) areas. Consequently, 71 de novo CMBs were revealed. They were in the lobar (60), deep (5), and infratentorial (6) areas. Additionally, 56 out of 71 de novo CMBs (78.9%) were located in exactly the same location as where embolic microinfarctions were found at baseline MRI (Fig. 2, Table 2).

Table 2

Number of embolic microinfarctions and CMBs at baseline and after 6 months.
	total	lobar	deep	infratentorial
embolic microinfarctions (baseline)	392	346 (88.3%)	11 (2.8%)	35 (8.9%)
CMBs (baseline)	137	96 (70.1%)	19 (13.9%)	22 (16.1%)
CMBs(after 6 months)	208	156 (75.0%)	24 (11.5%)	28 (13.5%)
de novo CMBs	71	60 (84.5%)	5 (7.0%)	6 (8.5%)
CMBs due to microinfarct	56	51 (91.1%)	1 (1.8%)	4 (7.1%)
CMBs without relation to microinfarct	15	9 (60.0%)	4 (26.7%)	2 (13.3%)
Abbreviations: AF, atrial fibrillation; CMBs, cerebral microbleeds; DWMH, deep white matter hyperintensity; PVH, periventricular hyperintensity

Imaging and laboratory characteristics of patients between the de novo CMB-positive and de novo CMB-negative groups are also shown in Tables 3. When we compared the positive and negative groups for de novo CMBs, DWI-positive lesions at baseline, especially those in the lobar area, were significantly higher in the positive group (P = .01). Furthermore, the Fazekas scores for both periventricular hyperintensity and deep white matter hyperintensity were significantly higher in the positive group than in the negative group (P < .05). Moreover, hemoglobin and hematocrit levels were significantly higher in the positive group than in the negative group (P < .05), and platelet count was significantly lower in the positive group than in the negative group (P < .01).

Table 3

MRI findings, laboratory and echocardiography findings in the 68 patients with AF.
	All	de novo CMB-positive group (n = 35)	de novo CMB-negative group (n = 33)	p value
MRI findings
Embolic microinfarctions(baseline)
Total	5.8 ± 6.9	8.1 ± 8.1	3.2 ± 4.4	0.01*
Lobar	5.1 ± 6.2	7.0 ± 7.2	3.0 ± 4.3	0.01*
Deep	0.2 ± 0.5	0.3 ± 0.6	0.1 ± 0.2	0.089
Infratentorial	0.5 ± 0.9	0.9 ± 1.1	0.2 ± 0.4	0.01*
PVH(Fazekas grade)	1.1 ± 0.9	1.3 ± 0.8	0.9 ± 0.8	0.024*
DWMH (Fazekas grade)	1.8 ± 0.9	2.1 ± 0.87	1.6 ± 0.9	0.041*
CMBs (baseline)
Total	2.0 ± 2.3	1.9 ± 1.9	2.2 ± 2.7	0.96
Lobar	1.4 ± 1.7	1.4 ± 1.6	1.4 ± 1.8	0.63
Deep	0.3 ± 0.7	0.2 ± 0.5	0.3 ± 0.9	0.91
Infratentorial	0.3 ± 0.7	0.2 ± 0.6	0.4 ± 0.7	0.21
6 months
Total	3.1 ± 2.7	3.9 ± 2.4	2.2 ± 2.7	0.01*
Lobar	2.3 ± 2.1	3.1 ± 2.1	1.4 ± 1.8	0.01*
Deep	0.4 ± 0.9	0.4 ± 0.8	0.3 ± 0.9	0.49
Infratentorial	0.4 ± 0.7	0.4 ± 0.7	0.4 ± 0.7	0.92
Cortical superficial siderosis (n)	1 (1.0%)	1 (0.3%)	0	0.52
Lacune	0.9 ± 2.0	0.8 ± 2.2	1.0 ± 1.9	0.60
Enlargement of perivascular spaces	51 (75.0%)	28 (80.0%)	23 (70.0%)	0.24
Centrum semiovale	12 (17.6%)	7 (20.0%)	5 (15.2%)	0.42
Basal ganglia	48 (70.6%)	26 (74.3%)	22 (66.7%)	0.34
Laboratory data
WBC (×10³/µL)	5.6 ± 1.7	5.4 ± 1.6	5.9 ± 1.7	0.141
RBC(×10³/µL)	445.0 ± 56.7	454.8 ± 63.5	434.6 ± 47.3	0.071
Hemoglobin (g/dl)	13.7 ± 1.6	14.1 ± 1.7	13.3 ± 1.4	0.026*
Hematocrit (%)	41.2 ± 4.6	42.4 ± 4.9	39.9 ± 4.1	0.023*
Platelet (×103/µL)	24.1 ± 18.2	19.8 ± 4.9	28.6 ± 25.1	0.003*
APTT(second)	36.9 ± 8.2	37.1 ± 7.0	36.8 ± 9.5	0.338
PT (%)	14.4 ± 3.2	14.8 ± 3.8	13.9 ± 2.5	0.397
PT-INR	1.2 ± 0.3	1.3 ± 0.4	1.2 ± 0.2	0.523
Fibrinogen (mg/dL)	271 ± 63.0	269.0 ± 63.6	274.3 ± 63.2	0.827
D-dimer (µg/mL)	0.6 ± 0.2	0.5 ± 0.01	0.62 ± 0.31	0.201
BNP (ng/mL)	82.8 ± 67.4	94.8 ± 70.5	70.0 ± 62.6	0.103
Echocardiography
SV (ml)	67.8 ± 16.7	66.0 ± 16.1	69.6 ± 17.4	0.414
LAD (mm)	41.4 ± 7.1	42.2 ± 7.6	40.6 ± 6.4	0.601
LAVI (ml/m²)	46.3 ± 17.7	47.9 ± 17.7	44.7 ± 18.0	0.318
E/e'	11.4 ± 6.3	11.7 ± 8.1	11.0 ± 3.4	0.486
CHADS₂ score	1.2 ± 1.0	1.2 ± 1.2	1.2 ± 0.8	0.555
HAS-BLED	1.2 ± 0.7	1.2 ± 0.6	1.2 ± 0.8	0.826
Abbreviations: AF, atrial fibrillation; CMBs, cerebral microbleeds; DWMH, deep white matter hyperintensity; PVH, periventricular hyperintensity; WBC, white blood cell ; RBC, red blood cell ; APTT, activated partial thromboplastin time; PT, prothrombin time : PT-INR, prothrombin time-international normalized ratio; BNP, brain natriuretic peptide; SV, stroke volume; LAD, left atrial dimension; LAVI, left atrial volume index;

In this study, we reported de novo CMBs in patients with AF after ablation therapy. First, de novo CMBs appeared in 35 (51.5%) patients 6 months after ablation therapy, and the location of almost 80% of de novo CMBs matched with the embolic microinfarctions detected on baseline MRI. Second, 84.5% of de novo CMBs were detected as the lobar type. Third, when comparing the positive and negative groups for de novo CMBs, the Fazekas score, and hemoglobin and hematocrit levels were higher in the positive group than in the negative group, while platelet count was significantly lower in the positive group than in the negative group.

This study revealed that de novo CMBs appeared after catheter ablation therapy, and most de novo CMBs were located spatially in correspondence to preceding embolic microinfarctions. Previous studies have reported a higher incidence of CMBs in patients with AF than in those without AF, and CMBs with AF were predominantly of the lobar type^{4, 11, 19}. Although anticoagulation therapy might be associated with the occurrence of CMBs^{20, 19}, the detailed pathogenesis of CMBs in patients with AF remains unclear. This study revealed a novel mechanism in that some de novo CMBs after catheter ablation were derived from embolic microinfarctions found at baseline MRI. Our previous study showed that small cortical infarctions could cause lobar CMBs, such as hemorrhagic transformation in ischemic stroke²¹. In accordance with these observation, a previous review has classified CMBs into either primary or secondary microbleeds²². Primary CMBs can be caused by the perivascular accumulation of hemosiderin-laden macrophages as a corollary of extravasated erythrocytes. Secondary CMBs may be caused by hemorrhagic transformation of microinfarction. Although our study evaluated only patients with AF after catheter ablation therapy, the present results may suggest that embolic CMBs could develop from incidentally-occurring microembolism and explain why CMBs in patients with AF are predominantly of the lobar type.

In the present study, the Fazekas score was higher in the positive group than in the negative group. Both periventricular and deep subcortical WMHs are often found on MRI in elderly people, and are a representative finding of cerebral small vessel disease²³. Periventricular and deep WMH are closely associated with CMBs²⁴. Moreover, another study has reported that CMBs are associated with recurrent stroke²⁵. Laboratory data in the present study revealed elevated hemoglobin and hematocrit values, and a decreased platelet count in the positive group compared to the negative group. A higher viscosity and fragility of hemostasis might be associated with microvascular disturbance, leading to development of CMBs.

Several studies have reported an association between AF and dementia^{7, 26, 27}. Although stroke events can increase the incidence of dementia, stroke-free patients with AF also have a higher risk of cognitive impairment and dementia^{7, 28}. The existence of more than three CMBs is reportedly associated with dementia²⁹, and, in reality, lobar CMBs are often observed in patients with AF ^{4 ,12}. Therefore, cognitive dysfunction in AF may be partially attributable to an increase in lobar CMBs. These CMBs may impair the functions of the cerebral cortex and cerebral white matter³⁰, since CMBs and cerebral microinfarcts are reportedly associated with cognitive dysfunction³¹. Recent studies have shown that treatment for AF, such as anticoagulants and ablation, can prevent cognitive decline^{32, 33, 34, 35}.

This study has some limitations. First, an MRI examination could not be performed before the ablation. Therefore, it cannot be denied that the CMBs at baseline MRI might have been affected by ablation therapy. Second, we could not compare the MRI findings of patients who underwent ablation therapy and those who did not. The incidence of CMBs in patients with AF in our study remains unclear. Moreover, we did not follow up the MRI images of patients with AF without ablation; it was not clear whether most patients with AF also had CMBs due to microinfarcts. A prospective study comparing patients with AF with and without ablation can resolve this problem. Therefore, further studies are required.

Our study showed that most de novo CMBs were derived from embolic microinfarctions and were of the lobar type after catheter ablation therapy in patients with AF. Some of the CMBs in patients with AF may have originated from incidental cerebral microinfarction.

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No competing interests reported.

Cerebral Microbleeds With Atrial Fibrillation After Ablation Therapy

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Journal Publication

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Abstract

Figures

Introduction

Patients And Methods

Results

Discussion

Conclusions

References

Additional Declarations

Status:

Journal Publication

Version 1