Academic Editors: Brian Tomlinson and Takatoshi Kasai
Background: Patients with ischemic stroke are vulnerable to heart
failure with preserved ejection fraction (HFpEF) because these conditions share
common risk factors. Although evaluation of the ascending aorta, aortic arch, and
proximal descending thoracic aorta is an essential step to determine the source
of the causative embolism, the relationship between the degree of aortic atheroma
and left ventricular (LV) diastolic function has not been extensively
investigated. Methods: We analyzed the transesophageal and transthoracic
echocardiography in ischemic stroke patients. Patients with previous coronary
artery disease, valvular heart disease of more than moderate degree, and an LV
ejection fraction of less than 50% were excluded. The relationships between the
grade of the aortic atheroma, aortic stiffness indexes, and diastolic functional
indexes were evaluated. Results: In 295 patients, the atheroma grade was
significantly correlated with aortic stiffness index, ratio of mitral annular and
inflow velocities (E/e’), left atrial volume index, and LV diastolic elastance.
With further adjustment for age, hypertension, diabetes, estimated glomerular
filtration rate, left atrial volume index, and LV mass index, the significance of
the atheroma grade was attenuated. In the subgroup analysis, the atheroma grade
was significantly and independently related to E/e’ in women (
Patients who undergo ischemic stroke are vulnerable to heart failure with preserved ejection fraction (HFpEF) because they have common risk factors, such as hypertension, diabetes, arrhythmia, dyslipidemia, old age, and obesity [1]. These two diseases have the same pathophysiological pathway. Arterial stiffness is the most important component of increased systolic and pulse pressure and is a major cause of diverse cardiovascular complications [2]. It can also be a possible risk factor for both atherosclerosis and heart failure with diastolic dysfunction, and thoracic aortic atherosclerosis is considered an intensive risk factor for embolic stroke [3, 4].
Evaluation of the ascending aorta (AA), aortic arch, and proximal descending thoracic aorta (pDTA) using transesophageal echocardiography (TEE) is an essential test for determining the presence of embolism in patients with ischemic stroke [5, 6], and the degree of aortic atheroma is known to be related to increased aortic stiffness and decreased aortic distensibility [7]. Although a significant relationship has been recognized between aortic stiffness and left ventricular (LV) diastolic function, the connection between the degree of aortic atheroma and LV diastolic function has not been extensively investigated. Previous studies showed that there were significant sex differences in cause, presentation and prognosis of ischemic stroke [8]. In addition, women are more vulnerable to HFpEF though impaired ventricular-arterial coupling [9, 10]. Therefore, it needs to reveal any sex differences in contributors to prognosis in patients with ischemic stroke.
The aim of this article was to examine the correlation between the severity of aortic atheroma as an indicator of aortic stiffness and parameters that imply LV diastolic dysfunction in a group of patients who were diagnosed with ischemic stroke. Since it is known that there are sex differences in the association between arterial stiffness and LV diastolic function [9], we also examined whether gender differences exist in the relation between aortic atheroma and diastolic dysfunction. The mid-term prognostic value of aortic atheroma and stiffness was also evaluated.
We collected consecutive data of patients treated from January 2006 to May 2019
in a tertiary hospital, who were diagnosed with ischemic stroke or transient
ischemic attack (TIA) and underwent transthoracic echocardiography (TTE) and TEE
simultaneously with the aim of identifying the focus of embolic stroke or TIA
Ischemic stroke or TIA was diagnosed based on the presence of neurologic deficits
and findings obtained using brain computed tomography or magnetic resonance
imaging. Neurologic deficits were identified by an expert in the neurology
department at the time of diagnosis in the hospital. Among the patients with
ischemic stroke or TIA, only those who met the following criteria performed TEE
as follows: (1) relatively young age as under 65, (2) age
After discharge from the hospital, the patients were scheduled to visit the outpatient clinic regularly for at least 3 months. The primary endpoint was a composite of hospitalization due to heart failure, acute myocardial infarction or acute coronary syndrome, ischemic stroke or TIA, and death from any cause. Heart failure hospitalization was defined based on symptoms of dyspnea of at least New York Heart Association Class III, as well as the need for diuretics or vasodilators, and evidence of pulmonary edema or pleural effusion on chest radiograph. If a patient had more than one clinical outcome, the first event was included in the primary outcome analysis.
Standard 2-dimensional and Doppler measurements were conducted based on
recommended guidelines [11]. LV ejection fraction, left atrial (LA) volume index
(mL/m
On TEE examination, the location and grade of the aortic atheroma were measured
using the guidelines provided by the American Society of Echocardiography [15].
Grade 1, intimal thickness
Continuous variables are expressed as mean
Of the 295 patients (mean age, 58.0
Total | Men | Women | p value | ||
(n = 295) | (n = 209) | (n = 86) | |||
Ischemic stroke, n (%) | 283 (95.9) | 201 (96.2) | 82 (95.3) | 0.745 | |
Transient ischemic attack, n (%) | 12 (4.1) | 8 (3.8) | 4 (4.7) | ||
Age, years | 58.0 |
57.3 |
59.9 |
0.154 | |
Body surface area, m |
1.77 |
1.84 |
1.59 |
||
Systolic blood pressure, mmHg | 134.2 |
134.5 |
133.3 |
0.655 | |
Diastolic blood pressure, mmHg | 81.6 |
82.7 |
79.0 |
0.049 | |
Pulse pressure, mmHg | 52.6 |
51.9 |
54.3 |
0.271 | |
Hypertension, n (%) | 168 (56.9) | 121 (57.9) | 47 (54.7) | 0.609 | |
Diabetes mellitus, n (%) | 66 (22.4) | 49 (23.4) | 17 (19.8) | 0.491 | |
Dyslipidemia, n (%) | 128 (43.4) | 95 (45.5) | 33 (38.4) | 0.265 | |
Atrial fibrillation, n (%) | 44 (14.9) | 35 (16.7) | 9 (10.5) | 0.169 | |
Previous MI, n (%) | 7 (2.4) | 4 (1.9) | 3 (3.5) | 0.419 | |
Previous stroke, n (%) | 37 (12.5) | 23 (11.0) | 14 (16.3) | 0.214 | |
Smoking, n (%) | 91 (30.8) | 76 (36.4) | 15 (17.4) | 0.001 | |
Medications, n (%) | |||||
RAAS blockers | 106 (35.9) | 78 (37.3) | 28 (32.6) | 0.438 | |
Beta-blockers | 46 (15.6) | 40 (19.1) | 6 (7.0) | 0.009 | |
CCB | 93 (31.5) | 63 (30.1) | 30 (34.9) | 0.426 | |
Diuretics | 40 (13.6) | 28 (13.4) | 12 (14.0) | 0.899 | |
Statin | 245 (83.1) | 177 (84.7) | 68 (79.1) | 0.242 | |
Antiplatelet agents | 254 (86.1) | 180 (86.1) | 74 (86.0) | 0.986 | |
Anticoagulants | 81 (27.5) | 60 (28.7) | 21 (24.4) | 0.453 | |
Laboratory data | |||||
Hemoglobin, g/dL | 14.2 |
14.7 |
12.8 |
||
Hematocrit, % | 41.8 |
43.3 |
38.3 |
||
eGFR, mL/min | 92.7 |
92.4 |
93.4 |
0.657 | |
Total cholesterol, mg/dL | 174.3 |
174.6 |
173.5 |
0.844 | |
Brain lesion | 0.686 | ||||
Left side, n (%) | 111 (37.6) | 82 (39.2) | 29 (33.7) | ||
Right side, n (%) | 108 (36.6) | 72 (34.4) | 36 (41.9) | ||
Bilateral, n (%) | 41 (13.9) | 28 (13.4) | 13 (15.1) | ||
Cerebellum, n (%) | 16 (5.4) | 12 (5.7) | 4 (4.7) | ||
Undefined, n (%) | 19 (6.4) | 15 (7.2) | 4 (4.7) | ||
MI, myocardial infarction; RAAS, renin-angiotensin-aldosterone system; CCB, calcium channel blocker; eGFR, estimated glomerular filtration rate. |
Total | Male | Female | p value | |||
(n = 295) | (n = 209) | (n = 86) | ||||
TEE findings | ||||||
Presence of visible atheromatous plaques, n (%) | 132 (44.7) | 99 (47.4) | 33 (38.4) | 0.158 | ||
Atheroma grade | 0.654 | |||||
1 | 163 (55.3) | 110 (52.6) | 53 (61.6) | |||
2 | 52 (17.6) | 38 (18.2) | 14 (16.3) | |||
3 | 41 (13.9) | 30 (14.4) | 11 (12.8) | |||
4 | 33 (11.2) | 26 (12.4) | 7 (8.1) | |||
5 | 6 (2.0) | 5 (2.4) | 1 (1.2) | |||
Indexed annulus diameter, mm/m |
11.4 |
11.3 |
11.8 |
0.011 | ||
Indexed SOV diameter, mm/m |
18.8 |
18.5 |
19.6 |
0.001 | ||
Indexed STJ diameter, mm/m |
15.3 |
15.0 |
15.9 |
0.001 | ||
Indexed AA diameter, mm/m |
18.7 |
18.2 |
20.0 |
|||
Indexed pDTA-D |
14.6 |
14.4 |
14.9 |
0.081 | ||
Indexed pDTA-D |
13.8 |
13.7 |
14.1 |
0.183 | ||
TTE findings | ||||||
LV ejection fraction, % | 64.9 |
64.4 |
65.9 |
0.050 | ||
LA volume index, mL/m |
30.3 |
31.1 |
28.2 |
0.085 | ||
LV mass index, g/mL | 90.0 |
92.4 |
84.2 |
0.001 | ||
E, m/s | 0.74 |
0.74 |
0.73 |
0.746 | ||
e’, m/s | 0.07 |
0.07 |
0.07 |
0.034 | ||
E/e’ | 10.8 |
10.4 |
11.8 |
0.003 | ||
LV diastolic elastance, 1/mL | 0.17 |
0.16 |
0.20 |
|||
Dense mitral annular calcification, n (%) | 26 (8.8) | 12 (5.7) | 14 (16.3) | 0.004 | ||
Aortic distensibility, mm/mmHg | 0.12 |
0.12 |
0.13 |
0.094 | ||
Aortic stiffness index, kPa | 11.3 |
11.5 |
11.0 |
0.601 | ||
Effective arterial elastance, mmHg/mL | 1.84 |
1.78 |
1.99 |
0.002 | ||
Total arterial compliance, mL/mmHg | 1.38 |
1.41 |
1.27 |
0.033 | ||
TTE, transthoracic echocardiography; TEE, transesophageal echocardiography; SOV, sinus of Valsalva; STJ, sinotubular junction; AA, ascending aorta; pDTA, proximal descending thoracic aorta; LV, left ventricular; LA, left atrial; E, early diastolic mitral inflow velocity; e’, early diastolic mitral annular velocity. |
A total of 132 patients (44.7%) had visible aortic atheromatous plaques. Among
them, the grade of atheroma had a similar distribution, except for grade 5.
Fifty-eight patients (44%) had aortic atheroma only at the aortic arch, 40
patients (30%) at both the aortic arch and pDTA, and 28 patients (21%) had
aortic atheroma only at the pDTA. Six patients (5%) had aortic atheroma in the
lesion, including the ascending aorta (Fig. 1). There was no difference in the
distribution of atheroma grades between both sexes. The female group had higher
dimensions of the aortic root when indexed according to body surface area. Women
had higher effective arterial elastance (1.99
Grade distribution of aortic atheroma and location of ischemic stroke. More than 50% of the patients are classified as grade 1 (163 patients, 55%). Fifty-eight patients (44%) have aortic atheroma only at the aortic arch, 40 patients (30%) at both the aortic arch and DTA, and 28 patients (21%) only at the DTA. DTA, descending thoracic aorta.
The patients with any atheroma (higher than grade 1) had higher aortic stiffness
index (14.5
Relationship between the grade of atheroma and aortic stiffness index, E/e’, and LV diastolic elastance (A–C), and LA volume index (D–F) using univariate simple linear regression. The grade of atheroma is significantly related to aortic stiffness index (A), E/e’ (B), and LV diastolic elastance (C). Among several aortic parameters, the atheroma grade (D) and aortic distensibility (E) are significantly relevant to LA volume index, but aortic stiffness index are not (F). LA, left atrial; LV, left ventricular.
Total | Male | Female | |||||
(n = 295) | (n = 209) | (n = 86) | |||||
p value | p value | p value | |||||
For E/e’ | |||||||
Atheroma grade | 0.028 | 0.595 | 0.000 | 0.998 | 0.181 | 0.032 | |
Aortic stiffness index | –0.004 | 0.945 | –0.050 | 0.459 | 0.128 | 0.181 | |
Age | 0.304 | 0.221 | 0.007 | 0.330 | 0.027 | ||
Hypertension | 0.187 | 0.001 | 0.211 | 0.001 | 0.056 | 0.571 | |
Diabetes mellitus | 0.144 | 0.004 | 0.163 | 0.006 | 0.175 | 0.049 | |
eGFR, per mL/m |
0.039 | 0.535 | –0.052 | 0.495 | 0.118 | 0.326 | |
LA volume index, mL/m |
0.200 | 0.210 | 0.001 | 0.204 | 0.036 | ||
LV mass index, g/m |
0.150 | 0.005 | 0.200 | 0.002 | 0.130 | 0.199 | |
For LA volume index | |||||||
Atheroma grade | 0.030 | 0.624 | 0.032 | 0.673 | –0.023 | 0.811 | |
Aortic stiffness index | –0.038 | 0.621 | –0.099 | 0.301 | 0.086 | 0.504 | |
Aortic distensibility | –0.002 | 0.979 | –0.050 | 0.615 | 0.232 | 0.107 | |
Age | 0.237 | 0.003 | 0.153 | 0.106 | 0.693 | ||
Hypertension | –0.031 | 0.619 | –0.046 | 0.543 | –0.077 | 0.502 | |
Diabetes mellitus | 0.029 | 0.605 | 0.015 | 0.827 | 0.025 | 0.811 | |
eGFR, per mL/m |
–0.016 | 0.822 | –0.109 | 0.210 | 0.323 | 0.020 | |
LV mass index, g/m |
0.297 | 0.251 | 0.406 | ||||
eGFR, estimated glomerular filtration rate; LA, left atrial; LV, left ventricular. |
During a mean follow-up of 2.9
Kaplan–Meier analysis for composite outcomes according to the grade of aortic atheroma as 1, 2, 3, and at least 4. There is no difference in clinical outcome (log rank p = 0.976). The subgroups based on sex differences also show no difference in clinical outcomes (men, log rank p = 0.965, women, log rank p = 0.951).
Total | Male | Female | |||||||
(n = 295) | (n = 209) | (n = 86) | |||||||
HR | 95% CI | p value | HR | 95% CI | p value | HR | 95% CI | p value | |
Age | 1.00 | 0.97–1.03 | 0.947 | 1.01 | 0.97–1.04 | 0.796 | |||
Hypertension | |||||||||
Diabetes mellitus | |||||||||
eGFR | 0.99 | 0.97–1.01 | 0.418 | 0.99 | 0.96–1.01 | 0.987 | |||
E/e’ | |||||||||
LA volume index | 1.01 | 0.99–1.03 | 0.368 | 1.07 | 1.02–1.12 | 0.008 | |||
LV mass index | 1.01 | 0.98–1.04 | 0.596 | ||||||
Aortic stiffness index | 1.02 | 0.98–1.07 | 0.249 | 1.03 | 0.98–1.09 | 0.194 | |||
Atheroma grade | |||||||||
LV diastolic elastance | 38.34 | 0.82–1783.57 | 0.063 | 76.73 | 0.42–14005.24 | 0.102 | |||
Effective arterial elastance | 1.14 | 0.45–2.94 | 0.780 | ||||||
Total Arterial Compliance | |||||||||
eGFR, estimated glomerular filtration rate; LA, left atrial; LV, left ventricular. |
The principal results of the study are as follows: (1) The presence and degree of aortic atheroma in ischemic stroke or TIA patients were significantly correlated with aortic stiffness index, E/e’, LV diastolic elastance, and LA volume index. (2) The grade of aortic atheroma in women was independently related to E/e’. (3) The LA volume index, which reflects diastolic function, was independently associated with poor prognosis in patients, especially in women. These findings imply that aortic atheroma is a potential risk factor for HFpEF through ventricular-vascular interactions and should be managed appropriately to restrain the aggravation of heart failure.
Our study demonstrated that the grade of aortic atheroma was significantly associated with the index of aortic stiffness, E/e’, and LA volume index, which reflects LV diastolic dysfunction. Although it is well known that aortic atheroma is associated with aortic stiffness and the degree of aortic stiffness is related to LV diastolic dysfunction [3, 7], no correlations have been reported in previous studies that directly investigated the correlation between the grade of aortic atheroma and LV diastolic dysfunction. Till date, in patients with ischemic stroke, the presence and degree of aortic atheroma has been demonstrated to be a possible source of embolic events. However, our study revealed that the grade of aortic atheroma was significantly associated with diastolic dysfunction. Atherosclerotic plaque is not only a potential source of embolism in patients with ischemic stroke, but can also be considered as an afterload index that reflects arteriosclerosis. Therefore, treatment that reduces arterial stiffness through prohibition of the renin-angiotensin-aldosterone system as well as statin and antiplatelet treatment should be considered.
In our study, the grade of aortic atheroma was independently correlated with LV
diastolic dysfunction, which was represented by E/e’ in women (
In our study, a total cardiovascular event occurred in 14% of patients during
the mid-term follow-up duration. Among the whole study population, the LA volume
index, as an important index of diastolic function, was an independent poor
prognosticator (HR: 1.07, 95% CI: 1.02–1.12, p = 0.008). However, the
indices related to aortic atheroma or stiffness were not independently related to
the LA volume index, regardless of sex differences. In a previous study, an
increased LA volume index in HFpEF patients was associated with poor prognosis
[23] and the results revealed that patients with a higher LA volume index (
There are some considerable limitations in this study. First, this was a retrospective study and there were no available data on regular follow-up echocardiographic exams to distinguish the changes in vascular hemodynamics after the diagnosis of ischemic stroke. Second, there are limitations in the accurate measurement of the grade of aortic atheroma, especially in patients with atheroma located at the proximal aortic arch, which is difficult to access using TEE. Third, the mid-term follow-up duration was relatively short (mean 2.9 years), which might not be sufficient to evaluate the relationship between aortic atheroma and clinical prognosis. Forth, since not all patients diagnosed with ischemic stroke or TIA underwent TEE, there is a limitation in selection bias.
The severity of atheroma grade in the aorta was significantly and independently related to LV diastolic function, especially in women, and it supports previous studies regarding the higher sensitivity of ventricular-vascular interaction in women. This suggests that aortic atheroma is an index of arterial stiffness and a potential risk factor for HFpEF through ventricular-vascular interactions, especially in women.
DYK and EYC designed this research study. YHJ, KYL, ISK, JYK, PKM, and YWY contributed to the data collection, analysis, and interpretation. BKL, BKH, and HMK contributed to statistical analysis. SJR, DYK, and EYC contributed to drafting the manuscript. All authors contributed to the manuscript. All authors read and approved the final manuscript.
This study protocol was acknowledged by the Institutional Review Board of Gangnam Severance Hospital (3-2019-0241) the need for written informed consent was waived due to the study’s retrospective design.
We thank to Minjee Kim to help us for data collection and administrative work for approving IRB process.
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2019R1F1A1045911).
The authors declare no conflict of interest.