Clinical Characteristics in Adult Congenital Heart Disease Patients With Acute Stroke　― A Retrospective Analysis ―

Abstract

Background: The number of adult congenital heart disease (ACHD) patients is rising due to advancements in surgery and medical treatment for congenital heart disease (CHD) during childhood. However, acute treatment and stroke prevention measures in ACHD patients have been insufficiently assessed. To address this insufficiency, we conducted a retrospective single-center investigation of the clinical characteristics of ACHD patients who experienced stroke.

Methods and Results: We studied adult patients with acute stroke hospitalized within 7 days of onset between January 2011 and March 2017. Among 4,837 adults with stroke, 22 (0.5%) had CHD, including 19 with ischemic stroke and 3 with intracerebral hemorrhage. Compared with the non-CHD group, the ACHD group was younger (median age 56 vs. 75 years; P<0.01), had a higher incidence of large vessel occlusion (LVO; 53 vs. 24%; P=0.01), and exhibited more favorable functional outcomes at discharge (median modified Rankin scale 2 vs. 3; P=0.03). Atrial septal defect (ASD) was the most common underlying CHD, accounting for 55% of cases.

Conclusions: ACHD patients with acute stroke were significantly younger and more frequently developed LVO compared with the general stroke population, with ASD being the most common type of CHD. Despite their favorable short-term prognosis, these characteristics must be considered to implement effective acute treatment and prevention strategies.

Central Figure

Congenital heart disease (CHD) is defined as a gross structural abnormality of the heart or intrathoracic great vessels that is actually or potentially life-threatening.¹ It is the most prevalent congenital disease, occurring in 9.1–10.8 cases per 1,000 births.^2,3 Until half a century ago, patients with CHD showed poor survival, especially those with complex CHD.^4,5 However, advances in surgery and medical treatments have improved the life expectancy of patients with complex CHD. As a result, the number of adult patients with CHD has increased,^6,7 and these CHD patients who have survived childhood are called adult CHD (ACHD) patients.

As the lifespan of ACHD patients has increased, stroke has become a focus of interest. Population-based studies showed higher risks of ischemic stroke, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage in ACHD patients compared with the same age group without CHD, and some risk factors and comorbidities associated with the development of stroke in ACHD patients have been investigated.^8–10 However, the literature on acute stroke in ACHD patients is yet to be comprehensively reviewed.

In addition, the treatment strategy for acute ischemic stroke has changed markedly over the past few decades, including reperfusion therapy such as intravenous tissue plasminogen activator (tPA) and endovascular treatment (EVT), even for patients with large vessel occlusion (LVO) whose prognosis was often previously considered poor.^11,12

As numbers of ACHD patients will further increase in the future, the potential risk and treatment of stroke in such patients should be assessed.

We aimed to clarify the risks, imaging findings, treatments, and functional outcomes of acute stroke in ACHD patients using a single-study database.

Methods

Study Design

This was a retrospective observational study conducted at a single institution. We enrolled consecutive adult patients (aged ≥18 years) with ischemic stroke and ICH admitted to National Cerebral and Cardiovascular Center and registered in the National Cerebral and Cardiovascular Center Stroke Registry within 7 days of onset between January 2011 and March 2017 (ClinicalTrials.gov no. NCT02251665).

We classified the patients into 2 groups: (1) ACHD; and (2) non-CHD. CHD was defined as heart disease present from birth, regardless of age at diagnosis¹⁰ (an isolated patent foramen ovale was not included as CHD).¹³

Data Collection

Baseline data in the ACHD and non-CHD groups were collected, and included sex, age, history of hypertension, dyslipidemia, diabetes, atrial fibrillation (AF), smoking habits, antithrombotic treatments before admission, pre-admission modified Rankin scale (mRS), National Institutes of Health Stroke Scale (NIHSS) at admission, ischemic stroke, and ICH. Cardiogenic and aortogenic sources were assessed using 12-channel electrocardiograms (ECG), 24-h Holter ECG, transthoracic echocardiography (TTE), or transesophageal echocardiography (TEE). Imaging findings included the presence of cerebral infarction, ICH, location of ischemic and hemorrhagic lesions, and LVO based on magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), digital subtraction angiography (DSA), computed tomography (CT), and CT angiography (CTA). The location of the ischemic lesion was classified as the anterior circulation (territory of internal carotid artery [ICA], anterior cerebral artery, or middle cerebral artery) and posterior circulation (territory of vertebral artery, basilar artery [BA], or posterior cerebral artery). LVO was defined as occlusion of ICA, the first (M1) or second (M2) segment of the middle cerebral artery, or BA based on MRA, DSA, or CTA. Stenosis of intra- or extracranial arteries was assessed using either ultrasonography, CTA, DSA, or MRA.

Acute treatment during hospitalization included anticoagulants, antiplatelets, tPA, EVT, and surgery. Treatment strategies were determined by the attending physicians. Functional outcomes at discharge were assessed using mRS.

In the ACHD group, the following additional data were collected. CHD data included the diagnosis, history of surgery, and whether CHD was diagnosed before or after stroke onset. Cardiac function was assessed using the New York Heart Association (NYHA) classification before admission, presence of a right-to-left shunt and shunt volume, and diameter of the hole in the atrial septal defect (ASD) by TTE or TEE. A right-to-left shunt was assessed by contrast-enhanced TEE using an agitated saline solution during the Valsalva maneuver or rest, or by TTE. Classification of the shunt size was based on the maximum number of microbubbles seen in the left atrium during the first 3 cardiac cycles after detection in the right atrium: the presence of 0 microbubbles was classified as occluded or no shunt, 1–5 as small, 6–25 as medium, and >25 as large.¹⁴ A large right-to-left shunt was also diagnosed when continuous inflow from the right atrium to the left atrium was confirmed using the color Doppler technique in TTE.

Institutional Ethical Approval

According to the standard ethical guidelines for retrospective clinical research in Japan, the requirement for informed consent was waived. This study used an opt-out approach. Ethical approval was obtained from the local ethics committee of National Cerebral and Cardiovascular Center (approval no. M23-073-13), and the study was conducted in accordance with the Declaration of Helsinki.

Statistical Analysis

The clinical characteristics were compared between patients in the ACHD and non-CHD groups. Categorical variables were tested with Pearson’s chi-square and Fisher’s exact tests. Continuous variables were compared using the Mann-Whitney U test. All statistical analyses were performed using R for macOS version 4.4.1. P values <0.05 were considered significant.

Results

The total population of this study was 4,837 patients (3,554 ischemic strokes and 1,283 ICH). There were 22 (0.5%; 19 ischemic strokes and 3 ICH) acute stroke patients in the ACHD group, and 4,815 (3,535 ischemic strokes and 1,280 ICH) in the non-CHD group. Compared with the non-CHD group, the ACHD group was younger (median age 56 vs. 75 years, respectively), had a lower prevalence of hypertension (41% vs. 80%, respectively), dyslipidemia (9% vs. 45%, respectively), and better pre-admission mRS (all P<0.05; Table 1). LVO (53% vs. 24%; P=0.01) was more common in ACHD than non-CHD patients (Figure 1). In the non-CHD group, 64 patients did not undergo imaging valuation of intracranial vessels. Of the ACHD patients developing ischemic stroke, 1 was treated with tPA and 3 with EVT, and all received anticoagulants during the acute phase. One ACHD patient with ICH underwent craniotomy and external decompression. Functional outcomes at discharge in all ACHD patients (median mRS 2 [interquartile range (IQR) 1–3]) were more favorable than those in the non-CHD group (3 [IQR 1–4]; P=0.03; Figure 2).

Table 1.

Demographics and Clinical Characteristics of the ACHD and Non-CHD Groups

	ACHD group (n=22)	Non-CHD group (n=4,815)	P value
Age (years)	56 [41–68]	75 [66–82]	<0.01
F	13 (59)	1,928 (40)	0.07
HT	9 (41)	3,831 (80)	<0.01
Dyslipidemia	2 (9)	2,187 (45)	<0.01
Diabetes	3 (14)	1,036 (25)	0.60
AF	5 (23)	1,176 (24)	1.00
Current smoker	5 (23)	921 (19)	0.28
AT before admission	6 (27)	1,916 (40)	0.28
Pre-admission mRS	0 [0–0]	0 [0–1]	0.03
Stroke			0.23
Ischemic stroke	19 (86)	3,535 (73)
ICH	3 (14)	1,280 (27)
NIHSS	8 [1–17]	6 [2–16]	0.91
Ischemic lesions			0.33
AC alone	16 (84)	2,400 (68)
PC alone	3 (16)	912 (26)
AC and PC	0	223 (6)
LVO	10 (53)	845 (24)	0.01
Acute treatment
Ischemic stroke
Anticoagulant treatment	19 (100)	2,705 (77)	0.01
Antiplatelet treatment	6 (32)	1,846 (52)	0.10
tPA	1 (5)	443 (13)	0.50
EVT	3 (16)	220 (6)	0.11
ICH
Surgery	1 (33)	24 (2)	0.06

Data are presented as median [interquartile range] or n (%). Wilcoxon signed-rank test, Pearson’s chi-square test, or Fisher’s exact test was performed. AC, anterior circulation; ACHD, adult congenital heart disease; AF, atrial fibrillation; AT, antithrombotic treatment; CHD, congenital heart disease; EVT, endovascular treatment; F, female; HT, hypertension; ICH, intracerebral hemorrhage; IQR, interquartile range; LVO, large vessel occlusion; mRS, modified Rankin scale; NIHSS, National Institutes of Health Stroke Scale; PC, posterior circulation; tPA, tissue plasminogen activator.

Figure 1.

Prevalence and location of large vessel occlusion (LVO) in the adult congenital heart disease (ACHD) and the non-congenital heart disease (CHD) groups. BA, basilar artery; ICA, internal carotid artery; M1, proximal middle cerebral artery; M2, distal middle cerebral artery.

Figure 2.

Functional outcomes at discharge between the adult congenital heart disease (ACHD) and the non-congenital heart disease (CHD) groups. mRS, modified Rankin scale.

Among all ACHD patients, ASD was the most common (55%; 12/22) CHD, as well as among ACHD patients with ischemic stroke (58%; 11/19), followed by tetralogy of Fallot and ventricular septal defect (n=2, respectively; Table 2). Three patients with ASD and 1 patient with ventricular septal defect had Eisenmenger syndrome. Nine patients had histories of surgery for CHD. CHD was initially detected after stroke onset in 6 patients, all with ASD.

Table 2.

Distribution of CHD

	All (n=22)	Ischemic stroke (n=19)	ICH (n=3)
ASD	12 (55)	11 (58)	1 (33)
TOF	2 (11)	2 (11)	0
VSD	2 (11)	1 (5)	1 (33)
TGA	1 (5)	1 (5)	0
Corrected TGA	1 (5)	1 (5)	0
Ebstein’s anomaly	1 (5)	1 (5)	0
Bicuspid aortic valve	1 (5)	1 (5)	0
DORV	1 (5)	1 (5)	0
ECD	1 (5)	0	1 (33)

Data are presented as n (%). ASD, atrial septal defect; CHD, congenital heart disease; DORV, double-outlet right ventricle; ECD, endocardial cushion defect; ICH, intracerebral hemorrhage; TGA, transposition of the great arteries; TOF, tetralogy of Fallot; VSD, ventricular septal defect.

The clinical characteristics of the ACHD patients are shown in Table 3. All strokes in the ACHD patients were first-ever events. According to the NYHA classification, 16 patients presented with class I, 2 with class II, 4 with class III, and none with class IV. Four patients with ischemic stroke used antithrombotic medications prior to admission. A right-to-left shunt was present in 9 of 16 patients with anterior circulation infarction and in 2 of 3 with posterior circulation. Among ischemic stroke patients with ASD, 9 had right-to-left shunt, with a median hole diameter of 11 mm (range 1.5–36 mm). Eight patients had a large shunt, one had a small shunt, and the remaining 2 patients with a surgical history of ASD closure had no right-to-left shunt by TEE. One of the patients with a surgical history of ASD closure had AF, and the other had ischemic stroke 3 days after ASD closure, which was caused by a mural thrombus in the ascending aorta shown by contrast-enhanced CT. Only one patient with tetralogy of Fallot had AF. The mobile thrombus at the aortic arch detected using TEE was considered to be the cause of stroke in 1 patient with a bicuspid aortic valve. Of 2 ACHD patients with ICH who had taken antithrombotic drugs prior to admission, 1 took warfarin plus aspirin, and the international normalized ratio on admission was 2.78. Cerebral abscess did not occur in any of the ACHD patients.

Table 3.

Clinical Characteristics of the ACHD Group

No.	Age (years)	Sex	Underlying CHD	History of surgery	AT before admission	Vascular risk factors	AF	NYHA classification	RL shunt	Ischemic lesions	Location of LVO	NIHSS on admission	IVtPA	MT	mRS at discharge
ACHD patients with ischemic stroke
1	21	F	ASD	No	No	No	No	I	Yes	PC	BA	7	No	No	0
2	37	F	ASD, ES	No	No	No	No	III	Yes	AC	–	1	No	No	1
3	42	F	ASD	No	WF	No	No	I	Yes	AC	–	4	No	No	2
4	55	F	ASD	No	No	No	No	I	Yes	AC	–	0	No	No	1
5	55	F	ASD	ASD closure	No	HT, diabetes	No	I	No	AC	M2	17	No	No	2
6	68	F	ASD	No	No	HT, DL	No	I	Yes	AC	–	1	No	No	2
7	68	M	ASD	No	No	HT, SM	No	I	Yes	PC	–	4	No	No	1
8	68	F	ASD, ES	No	No	No	Yes	III	Yes	AC	M2	22	No	No	2
9	69	F	ASD	ASD closure	ASA	HT, diabetes	Yes	II	No	AC	M2	0	No	No	0
10	76	F	ASD	No	No	No	No	I	Yes	AC	ICA	18	No	Yes	3
11	82	F	ASD, ES	No	No	HT, diabetes	No	III	Yes	AC	–	4	No	No	4
12	22	M	TGA	Fontan	No	No	No	I	No	AC	–	9	No	No	0
13	24	M	DORV	Fontan	No	No	No	I	No	PC	BA	1	No	No	0
14	40	F	TOF	ICR	No	No	No	I	No	AC	ICA	25	Yes	Yes	4
15	43	M	TOF	ICR	RX	SM	Yes	III	No	AC	M1	16	No	No	3
16	49	F	VSD, ES	No	No	No	No	II	Yes	AC	–	2	No	No	1
17	57	M	TGA	LVAS	WF, ASA	HT, SM	No	I	No	AC	ICA	9	No	No	3
18	62	M	Ebstein’s anomaly	No	No	No	No	I	Yes	AC	–	0	No	No	0
19	68	M	Bicuspid aortic valve	No	No	HT, SM	No	I	No	AC	ICA	13	No	Yes	1
No.	Age (years)	Sex	Underlying CHD	History of surgery	AT before admission	Vascular risk factors	AF	NYHA classification	Location of ICH	NIHSS on admission	Surgical treatment	mRS at discharge
ACHD patients with ICH
1	24	M	ECD	ICR	WF, ASA	No	Yes	I	Subcortical	16	Yes†	3
2	59	F	ASD	ASD closure	No	HT	No	I	Pontine	29	No	4
3	80	M	VSD	No	ASA	HT, SM	Yes	I	Thalamus	26	No	5

^†Craniotomy and extra decompression. ASA, aspirin; BA, basilar artery; cTGA, corrected transposition of the great arteries; DL, dyslipidemia; DORV, double-outlet right ventricle; ECD, endocardial cushion defect; ES, Eisenmenger syndrome; ICA, internal carotid artery; ICR, intracardiac repair; LVAS, left ventricular assist system; LVO, large vessel occlusion; M, male; MT, mechanical thrombectomy; M1, proximal middle cerebral artery; M2, distal middle cerebral artery; NYHA, New York Heart Association; PC, posterior circulation; RX, rivaroxaban; SM, current smoker; TGA, transposition of the great arteries; WF, warfarin. Other abbreviations as in Tables 1,2.

Discussion

This study assessed the incidence of stroke, imaging findings, treatments, and functional outcomes in ACHD patients with acute ischemic stroke and ICH. The results showed that the ACHD group with stroke was significantly younger than the non-CHD group. LVO was more common in ACHD patients with ischemic stroke compared with those without CHD. Additionally, the ACHD group exhibited more favorable functional outcomes at discharge. ASD was the most prevalent type of CHD among ACHD patients with acute stroke.

The increased life expectancy of ACHD patients has raised the associated risk of stroke, similar to the phenomenon noted in the general population. Major advancements in surgical treatment for CHD in the 1980s and 1990s have led to >95% of children with CHD reaching adulthood. However, depending on the original heart disease and type of surgery received, some serious hemodynamic abnormalities may occur later in life, necessitating medical or surgical intervention.^15–17 As of 2007, the number of ACHD patients had reached 400,000 and continues to increase in Japan.⁷ ACHD patients, who were once primarily under the care of pediatricians and cardiovascular surgeons, now face a broad range of health issues, including stroke.¹⁸

A previous cohort study with an average follow up of 20 years reports that the incidence of ischemic stroke among ACHD patients was approximately 0.5%.⁸ In this study, which analyzed a consecutive series of adult patients with stroke, the prevalence of CHD was also found to be 0.5%, a rate that appears lower than the estimated CHD prevalence of approximately 1% in the general population. However, this apparent gap may reflect several factors. First, people with severe CHD often have a high mortality rate, frequently dying at a relatively young age,¹⁹ and therefore may not survive to adulthood. Second, while the peak incidence of stroke in the general population typically occurs in older age, ACHD patients are generally younger, and there are relatively few elderly individuals with CHD. Third, recent advances in the management of CHD, including surgical and medical treatment, may have contributed to a reduction in stroke risk among this population. Taken together, these factors suggest that the relatively low prevalence of ACHD patients with stroke cannot be fully explained by a simple comparison with the prevalence in the general population. Accurate interpretation of these findings requires consideration of the natural history of CHD, age-related stroke risk, and evolving medical care.

ACHD patients were more likely to have ischemic stroke with LVO than the non-CHD population. LVO was reported to account for 24–38% of acute ischemic syndrome.^20,21 The frequency (53%) of LVO in ACHD patients with ischemic stroke in this study was higher than in these reports. The mechanism of stroke in CHD is considered to be embolism from a paradoxical embolus or in situ thrombus formation associated with arrhythmias, hyperviscosity, ventricular dilatation, or surgical intervention.²² Therefore, CHD may be an important risk factor for LVO. Prompt determination of EVT indications should be considered for ACHD patients with acute stroke.

The functional outcome at discharge of ACHD patients in this study was more favorable compared with non-CHD patients, although numbers of reports on functional outcomes in ACHD patients with stroke are limited. One population-based study showed a higher risk of death in ACHD patients 30 days after the onset of ischemic stroke compared with the general population, especially in younger patients.²³ The relatively young onset of stroke in ACHD patients may explain the better short-term functional outcomes observed in our study.

Here, ASD was the most common type of CHD among ACHD patients with ischemic stroke. It is known to be the most common CHD of ACHD patients in Japan.²⁴ The incidence of ischemic stroke has been reported to be 4.0–14% among ACHD patients with ASD.^13,25,26 Although paradoxical embolism was the most commonly considered ischemic stroke mechanism in patients with ASD, AF, which is an increasing complication in middle-aged and older adults with ASD, has also been reported to be associated with stroke mechanisms.²⁶ In this study, 9 patients had right-to-left shunts and 2 had AF. A study by Lok et al. showed that 53 ASD patients with TIA or ischemic stroke had 11 recurrent cerebrovascular ischemic events with a median follow up of 5.3 years, and the risk of recurrent stroke was higher in the open than closed ASD group.²⁷ Therefore, detection and closure of ASD may be effective in preventing recurrent stroke. However, early diagnosis of ASD can be challenging; approximately 25–30% of new cases identified only in adulthood are ASD, representing the highest rate among CHD. This is likely because the clinical course of ASD is gradual and asymptomatic in most childhood and young adulthood cases.^28,29 Also, all cases of ASD detected after stroke onset in this study were asymptomatic. Therefore, early detection and closure of patients with asymptomatic ASD can be considered to prevent stroke.

There have been very few studies on the risk of hemorrhagic stroke in ACHD patients. In a population-based study of 29,638 ACHD patients, 47 per 258,045 person-years had hemorrhagic stroke.¹⁰ In another population-based study, the annual incidences of ICH and subarachnoid hemorrhage were estimated to be 1.18 per 10,000 person-years and 0.96 per 10,000 person-years among 21,982 ACHD patients, respectively.⁹ ACHD patients were known to have a higher risk of developing hemorrhagic stroke compared with the general population in both studies. Severe non-conotruncal cardiac defects have been reported to be associated with the risk of ICH in ACHD patients.⁹ One of the ACHD patients with ICH in this study had an endocardial cushion defect, which is a non-conotruncal cardiac defect. The other 2 patients had hypertension, which is a risk for ICH. Additionally, the long-term use of antithrombotic medications by ACHD patients since childhood could also be a risk for ICH. A large population-based study is warranted to promote further research on ICH management of blood pressure and antithrombotic medications for ACHD patients.

In addition, the optimal management of antithrombotic therapy following ICH in ACHD patients remains uncertain. This issue is particularly critical in ACHD patients who require long-term anticoagulant therapy, such as those with AF. In such patients, the decision to resume antithrombotic therapy after ICH presents a significant clinical dilemma. Some studies have demonstrated that anticoagulant treatment in patients with AF is associated with a reduction in thromboembolic events and all-cause mortality.^30–32 Direct oral anticoagulants, which are associated with a lower risk of intracranial bleeding compared with warfarin, are effective for ischemic cardiovascular events even in patients with prior ICH.³³ However, emerging evidence also suggests a possible increase in the risk of recurrent ICH in this population.³⁴ Therefore, in ACHD patients with strong indications for anticoagulants, such as AF or mechanical valves, the decision to restart therapy after ICH must carefully weigh the competing risks of recurrent bleeding and thromboembolic complications. Multidisciplinary discussion and individual risk stratification remain essential until more robust, ACHD-specific evidence becomes available.

Study Limitations

There were several limitations in the present study. One major limitation is the small sample size (n=22) of ACHD patients, which limits the statistical power and generalizability of the findings. This limitation should be acknowledged when interpreting the results. Furthermore, because this was a single-center study using a stroke registry rather than the ACHD-specific registry, selection bias may have occurred. In addition, ACHD outpatients who are living far from National Cerebral and Cardiovascular Center might have stroke but were treated at other emergency hospitals. Although National Cerebral and Cardiovascular Center is a major pediatric cardiology center that concentrates on ACHD treatments, the present findings may underrepresent the broader ACHD population. To validate and generalize these results, further multicenter studies with large sample sizes and longer follow up are essential. Future studies are needed to evaluate the incidence and characteristics of stroke in all ACHD patients with long-term follow up, regardless of where they received acute stroke treatment, to provide complementary and more comprehensive insights.

Conclusions

The present study revealed several important findings. We found that ACHD patients were likely to develop ischemic stroke with LVO. Additionally, among ACHD patients with acute stroke, ASD was the most common underlying CHD. Furthermore, the short-term prognosis of ACHD patients with acute stroke was found to be more favorable than that of the general population with stroke. Last, it was a concern that ACHD patients tended to develop stroke at a much younger age than the general population. These findings highlight the need to develop prevention strategies and establish acute management for stroke in ACHD patients.

Acknowledgments

None.

Sources of Funding

This study was supported by the Japan Agency for Medical Research and Development (grant nos. JP251k0221171, and JP25lk0221186), and the Intramural Research Fund (24-B-6) for Cardiovascular Diseases of the National Cerebral and Cardiovascular Center in Japan.

Disclosures

M. Inoue reports receiving lecturer’s fees from Bayer Yakuhin, Bristol-Myers Squibb, Teijin, and Nippon Boehringer Ingelheim, not related to the submitted work. K.T. reports receiving honoraria from Daiichi-Sankyo, Otsuka, Bayer Yakuhin, Bristol-Myers-Squibb, and Janssen, not related to the submitted work. M.K. reports receiving honoraria from AstraZeneca, Bayer Yakuhin, Daiichi-Sankyo, Mitsubishi Tanabe Pharma Corporation, BMS/Pfizer, BMS/Janssen Pharmaceuticals, and Otsuka Pharmaceutical, and research support from Daiichi-Sankyo and Nippon Boehringer Ingelheim, which are not related to the submitted work.

IRB Information

Ethical approval was obtained from the local ethics committee of National Cerebral and Cardiovascular Center, Suita, Japan (approval no. M23-073-13).

Data Availability

The deidentified participant data will not be shared.

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