Significant aortic stenosis associated with poorer functional outcomes in patients with acute ischaemic stroke undergoing endovascular therapy

Abstract

Background and aim

Bi-directional feedback mechanisms exist between the heart and brain, which have been implicated in heart failure. We postulate that aortic stenosis may alter cerebral haemodynamics and influence functional outcomes after endovascular thrombectomy for acute ischaemic stroke. We compared clinical characteristics, echocardiographic profile and outcomes in patients with or without aortic stenosis that underwent endovascular thrombectomy for large vessel occlusion acute ischaemic stroke.

Methods

Consecutive acute ischaemic stroke patients with anterior and posterior circulation large vessel occlusion (internal carotid artery, middle cerebral artery and basilar artery) who underwent endovascular thrombectomy were studied. Patients were divided into those with significant aortic stenosis (aortic valve area <1.5 cm²) and without. Univariate and multivariate analyses were employed to compare and determine predictors of functional outcomes measured by modified Rankin scale at three months.

Results

We identified 26 (8.5%) patients with significant aortic stenosis. These patients were older (median age 76 (interquartile range 68–84) vs. 67 (interquartile range 56–75) years, p = 0.001), but similar in terms of medical comorbidities and echocardiographic profile. Rates of successful recanalisation (73.1% vs. 78.0%), symptomatic intracranial haemorrhage (7.7% and 7.9%) and mortality (11.5% vs. 12.6%) were similar. Significant aortic stenosis was independently associated with poorer functional outcome (modified Rankin scale >2) at three months (adjusted odds ratio 2.7, 95% confidence interval 1.1–7.5, p = 0.048), after adjusting for age, door-to-puncture times, stroke severity and rates of successful recanalisation.

Conclusion

In acute ischaemic stroke patients managed with endovascular thrombectomy, significant aortic stenosis is associated with poor functional outcome despite comparable recanalisation rates. Larger cohort studies are needed to explore this relationship further.

Introduction

Heart–brain interactions have been extensively characterised in patients with heart failure. These interactions are believed to be bi-directional.¹ Worsening cardiac function may have adverse effects on cerebral structure and functional capacity, whilst neuronal signals can also lead to cardiac dysfunction.² Beyond heart failure, these interactions may exist in other pathological conditions.

Aortic stenosis (AS) is the most common valvular heart disease with an increasing burden globally.^3,4 Options for AS therapy have also been rapidly advancing, with transcatheter aortic valve replacement being a viable alternative to surgical aortic valve replacement.^5,6 As AS progresses, patients may experience complications such as congestive cardiac failure, ventricular arrhythmias and atrial fibrillation.⁷ In addition to these complications, acute ischaemic stroke (AIS) may also be an important but under-recognised complication of AS.⁸ Rates of stroke may vary from 5.6 to 21.8 per 1000 patient-years in severe AS.⁸ Previously, AIS has been reported to be associated with mortality in patients with severe AS.⁹

Whilst the association between AS and stroke is clear, the underlying pathophysiological mechanisms are myriad. It is uncertain whether patients with significant AS have different responses to recanalisation therapy for stroke. A small single-centre study demonstrated that the presence of valvular heart disease (in particular aortic valve disease) has increased rates of death in patients with AIS or transient ischaemic attack.¹⁰ Although, endovascular therapy (EVT) has become the standard of care in large vessel occlusion (LVO) AIS,¹¹ factors associated with better functional outcomes (and lower complication rates) have been the subject of debate in previous studies.^12,13 Similar to the heart–brain interactions in cardiac failure, we hypothesise that the presence of significant AS may influence functional outcomes among AIS patients receiving EVT. We explored this association in our patient cohort.

Methods

From January 2014 to March 2019, 303 consecutive AIS patients who underwent EVT and had a transthoracic two-dimensional echocardiogram evaluation within six months of the index stroke event were included. All patients selected for EVT had LVO on computed tomography angiography at AIS presentation were 18 years or older, had a National Institute of Health Stroke Scale (NIHSS) ≥6, and were assessed by a neurologist prior to EVT. All patients had a good functional baseline of modified Rankin scale (mRS) 0–2. The severity of stroke at presentation was assessed with the NIHSS.¹⁴ Radiological scores such as the ASPECTS and clot burden score were also calculated for each patient.^15,16 Other baseline demographic and clinical parameters were recorded. Successful recanalisation was defined as a modified Thrombolysis in Cerebral Infarction (mTICI) scale of ≥2b.^17,18

Significant AS was defined as either moderate or severe AS, with an aortic valve area (AVA) <1.5 cm², measured on echocardiography in accordance with the American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines.^19,20 Left ventricular geometry determined by left ventricular mass index (LVMI) and relative wall thickness (RWT). The cut-off for LVMI was 116 g/m² for males and 104 g/m² for females. The cut-off for RWT was 0.43 for both sexes. If RWT and LVMI were both below the cut-off points, then the patient had normal LV geometry. Patients with high LVMI but RWT < 0.43 were defined as eccentric hypertrophy. Patients with high RWT but LVMI below the cut-offs were defined as having concentric remodelling. If both LVMI and RWT were above the cut-offs, then the patient was identified as concentric hypertrophy.²¹

Patients were divided into two groups: those with or without significant AS. The two groups were compared for their demographics, risk factors, clinical characteristics and echocardiographic parameters. Functional outcomes were determined by the mRS at three months after AIS.²² An mRS of >2 was considered a poor functional outcome. Other outcome measures included mortality and symptomatic intracranial haemorrhage (SICH) defined as presence of blood on neuroimaging and an increase in NIHSS score by at least four points within 72 h of stroke onset.

Appropriate bivariate analyses were performed to compare the two groups for their demographics, risk factors, clinical characteristics, echocardiographic parameters and functional outcomes. These included Student’s t-tests for continuous variables and Pearson’s Chi-square test (or Fisher’s exact test where appropriate) for categorical variables. Mann–Whitney U test was used to compare variables that were not normally distributed. Statistically significant variables were entered into the multivariable binary logistic regression model to identify independent predictors of poor functional outcomes. Ordinal shift analyses were employed to compare functional outcomes by various mRS categories in both groups. A p-value of less than 0.05 was considered significant. All data analysis was performed on SPSS version 20.0 (SPSS, Inc., Chicago, Illinois). This study was approved by the institutional review board from the National Healthcare Group Domain-Specific Review Board prior to its conduct.

Results

Of the 303 patients studied, 26 (8.5%) had significant AS (AVA < 1.5 cm²). These patients had a mean AVA of 0.94 ± 0.33 cm², with a mean pressure gradient across the aortic valve of 25.8 ± 13.0 mmHg and a mean transaortic peak velocity of 325 ± 86 cm/s. None of the patients in the group without significant AS had mild AS. Furthermore, all of the patients with significant AS had tricuspid aortic valves with calcific degenerative AS. There were no patients identified with congenital bicuspid aortic valves or rheumatic heart disease (there was also no one with concomitant mitral stenosis).

The patients with significant AS were older (median age 76 (interquartile range (IQR) 68–84) vs. 67 (IQR 56–75) years, p = 0.001) but had similar prevalence of hypertension, diabetes mellitus and hyperlipidaemia, ischaemic heart disease and congestive cardiac failure. There was a non-significant higher prevalence of atrial fibrillation in the significant AS group (61.5% vs. 47.7%, p = 0.176) (Table 1).

Table 1.

Baseline characteristics of patients with and without significant aortic stenosis (AS, aortic valve area <1.5 cm²) undergoing endovascular therapy for acute ischaemic stroke.

Parameter	Significant AS (AVA < 1.5 cm2, n = 26)	No AS (n = 277)	p-Value
Clinical profile
Median age (years, interquartile range)	76 (IQR 68–84)	67 (IQR 56–75)	0.001
Male gender, n (%)	11 (42.3)	156 (56.3)	0.170
Hypertension, n (%)	18 (69.2)	196 (70.6)	0.885
Diabetes mellitus, n (%)	6 (23.1)	76 (27.6)	0.622
Hyperlipidaemia, n (%)	14 (53.8)	153 (55.1)	0.899
Ischaemic heart disease, n (%)	9 (34.6)	59 (21.3)	0.121
Congestive cardiac failure, n (%)	5 (20.0)	30 (10.9)	0.180
Atrial fibrillation, n (%)	16 (61.5)	132 (47.7)	0.176
Median door-to-puncture time (min, interquartile range)	162 (IQR 131–378)	119 (IQR 90–143)	0.060
Median time to recanalisation (min, interquartile range)	28 (IQR 25–45)	35 (IQR 17–65)	0.270
Mean systolic blood pressure on arrival (mmHg, SD)	160.6 (±27.1)	152.3 (±28.5)	0.155
Mean diastolic blood pressure on arrival (mmHg, SD)	81.9 (±19.9)	85.8 (±20.3)	0.358
NIHSS (median score, interquartile range)	20 (IQR 15–24)	19 (IQR 14–23)	0.244
Median ASPECTS score (interquartile range)a	8 (IQR 7–10)	9 (IQR 7–9)	0.663
Median clot burden scorea (interquartile range)	6 (IQR 4–7)	6 (IQR 4–8)	0.912
Median modified Rankin score at baseline	0 (IQR 0–1)	0 (IQR 0–1)	0.064
Location of occlusion			0.969
Basilar	5 (19.2%)	42 (15.2%)
CICA	0 (0%)	7 (2.5%)
Tandem	1 (3.8%)	14 (5.1%)
TICA	3 (11.5%)	36 (13.0%)
M1	13 (50.0%)	146 (52.7%)
M2	4 (15.4%)	32 (11.5%)
Echocardiographic profile
End-diastolic volume index (ml/m2)	67.5 (±27.8)	63.4 (±23.1)	0.394
Left ventricular ejection fraction (%)	63.9 (±11.6)	60.1 (±15.4)	0.224
Left ventricular mass index (g/m2)	113.0 (±33.7)	103.9 (±33.1)	0.186
End-systolic wall stress	66.5 (±25.4)	76.9 (±34.5)	0.134
Left atrial volume index (ml/m2)	29.0 (10.3)	32.3 (±11.1)	0.791
LV morphology			0.106
Normal LV morphology	7 (26.7%)	142 (51.2%)
Eccentric hypertrophy	5 (20.0%)	33 (12.0%)
Concentric remodelling	4 (13.3%)	32 (11.5%)
Concentric hypertrophy	10 (40.0%)	70 (25.4%)
Outcomes
Successful recanalisation (mTICI ≥ 2b), n (%)	19 (73.1)	216 (78.0)	0.567
SICH, n (%)	2 (7.7)	22 (7.9)	0.964
Poor functional outcome at three months (mRS > 2), n (%)	20 (76.9)	156 (56.3)	0.042
Mortality at three months	3 (11.5%)	35 (12.6%)	0.372

^aOnly applicable to anterior circulation large vessel occlusions.

At presentation, the patients in the AS group also did not differ significantly from those without AS in terms of the blood pressure, door-to-puncture time or the time taken for recanalisation. Stroke severity at presentation measured by NIHSS (median score 20 (IQR 15–24) vs. 19 (IQR 14–23), p = 0.244) was also comparable between the two groups. On imaging, the ASPECTS and clot burden scores were similar between the groups (Table 1).

Regarding echocardiographic parameters, the most common LV morphology in the significant AS group was concentric hypertrophy (40.0%), which was seen in only 25.4% of patients without significant AS (Table 1). LV ejection fraction was preserved in both groups (63.9 ± 11.6 vs. 60.1 ± 15.4%, p = 0.224), and there were no significant differences in the LVMI or the left atrial volume index.

Successful recanalisation (mTICI ≥ 2) was comparable between the groups (73.1% vs. 78.0%, p = 0.567) but higher proportion of patients with significant AS achieved poor functional outcomes at three months (mRS > 2, 76.9% vs. 56.3%, p = 0.042) in the patients with significant AS (Table 1). Mortality and SICH did not differ between the two groups. On multivariable logistic regression analysis, significant AS remained an independent predictor of poor functional outcomes, after adjusting for age, door-to-puncture times, NIHSS and rate of successful recanalisation (adjusted odds ratio 2.7, 95% confidence interval 1.1–7.5, p = 0.048) (Table 2). Distribution of mRS scores at three months between the AS and non-AS group are illustrated in Figure 1. An unfavourable shift in the mRS was observed in the significant AS group (p = 0.042).

Table 2.

Multivariable analysis to determine independent predictors of poor functional outcomes at three months (mRS > 2) in acute ischaemic stroke patients with significant aortic stenosis, following endovascular therapy.

Parameter	Adjusted odds ratio (95% confidence interval)	p-Value
Age >50 years	2.6 (1.3–5.1)	0.008
NIHSS >18	4.1 (2.4–6.8)	<0.001
Successful recanalisation (mTICI ≥ 2b)	0.4 (0.2–0.7)	0.002
Door-to-puncture time (min)	1.0 (0.9–1.1)	0.191
Significant AS (AVA < 1.5 cm2)	2.7 (1.1–7.5)	0.048

Figure 1.

Ordinal shift analyses between significant AS and no AS groups in terms of mRS categories (odds ratio 1.37, 95% confidence interval 1.08–1.72, p = 0.042).

Discussion

Our study found that significant AS is associated with poor functional outcome in AIS patients with LVO, despite comparable EVT recanalisation rates to patients without significant AS. Heart–brain interactions have been implicated in the pathophysiological processes that lead to progression of the disease.²³ Cardiac diseases have been linked to AIS through alterations in cerebral haemodynamics and impairment of cognitive function.^24,25

Several factors may contribute to the high prevalence of AS in stroke patients. Both AS and AIS share common risk factors including older age, smoking and hyperlipidaemia.²⁶ In addition, AS is associated with the development of atrial fibrillation, a strong risk factor for AIS.²⁷ Furthermore, several studies have reported that calcification of the valve was an independent risk factor for AIS, even in the absence of atrial fibrillation.^28,29

The association of poor functional outcomes in AIS patients with concomitant significant AS is multifactorial. Indeed, it was important to note that the development of AIS and AS both share common and similar risk factors. However, there may have been several important other contributory mechanisms to account for the poorer prognosis of AIS in patients with concomitant AS.

First, successful recanalisation may not lead to successful reperfusion of the cerebral ischaemic penumbra in some patients.³⁰ More specifically, in patients with significant AS, the fixed obstruction of the left ventricular outflow tract may reduce cardiac output and limit cerebral reperfusion despite successful recanalisation.³¹

Second, there may also be increased peripheral vascular resistance in patients with AS. Patients with calcific degenerative AS often also have heavily calcified arteries and arterioles that result in vascular resistance and lower vasomotor reactivity. In the context of AIS, this may reduce the chances of successful reperfusion.^32,33

Third, in addition to the alterations in cerebral haemodynamics and older age, concomitant significant AS may affect recovery from AIS due to reduced effort tolerance during rehabilitative physiotherapy.^34–36 Accordingly, in our study, significant AS remained independently associated with poor outcomes even after adjusting for age, stroke severity and rate of successful recanalisation. This is important since majority of our patients had preserved left ventricular ejection fraction. However, we did not record effort tolerance in our cohort.

Finally, AS was also associated with the development of AF, which may contribute to poorer outcomes in AIS. Although we did not find any significant difference in the prevalence of atrial fibrillation, patients with significant AS have higher risk of developing atrial fibrillation and left ventricular dysfunction, which are important risk factors for recurrent AIS.^37,38

Although we demonstrated important associations and interactions between AS and poor functional outcomes in acute ischaemic stroke patients undergoing EVT, it was not clear if this association also extended to patients who underwent intravenous thrombolysis, or for those managed conservatively. Major surgery such as valve replacement has often been avoided in patients with a stroke and may be associated with higher risk of perioperative mortality and recurrent stroke.^39,40 However, it remains unclear if early transcatheter valve replacement intervention would significantly improve cerebral haemodynamics, improving reperfusion rates and improving effort tolerance to improve cooperation with post-stroke rehabilitation and thereby lead to better functional outcomes. In fact, despite the peri-procedural stroke risk following transcatheter valve replacement, the procedure has been showing to lower the long-term incidence of stroke in patients with AS.⁴¹

Certain limitations of our study need to be acknowledged. First, despite a modest sample size, it is a single-centre study, and its retrospective nature carries the inherent limitations. It was subjected to lead-time bias where subjects may have been studied at varying time points along the natural history of AS. Second, we did not record whether significant AS in our patient cohort was symptomatic and limited their effort tolerance to rehabilitative physiotherapy. All our patients had calcific degenerative AS and were not able to compare outcomes in AS of different aetiology.

Third, we excluded patients where echocardiography was performed beyond six months of AIS. Echocardiography also only obtained a median of 42 (IQR 5–108) days from the AIS. It was not always possible to obtain the transthoracic two-dimensional echocardiogram evaluation during the patient’s admission due to logistical limitations. Fourth, we did not observe any significant differences in the prevalence of SICH and mortality between patients with and without significant AS. However, we observed only small numbers of these adverse outcomes, which may have limited the reliability of the findings.

Furthermore, patients who suffered from stroke peri-procedurally or perioperatively were not specifically studied. Although perioperative and peri-procedural stroke has been described to be relatively common with aortic valve replacement, it had not been the focus of this study.⁴² Finally, we had only studied patients with a good functional baseline prior to the study (median mRS at baseline 0 (IQR 0–1)), which did not differ significantly between the groups. Our study was not sufficiently large to include baseline mRS in the multivariable analysis. Nevertheless, we believe that our findings are exploratory and hypothesis generating. Further larger and prospective studies are important to evaluate for other potential confounders in the relationship between AS and poor functional outcomes.

Conclusions

Concomitant significant AS may be present in about 10% of LVO acute ischaemic stroke patients undergoing EVT and is significantly associated with poor functional outcomes. Further studies are recommended to evaluate this association and validate our findings.