Evaluating Total Atherosclerosis Burden of Baroreceptor-Resident Arteries after Ischemic Cerebrovascular Disease for Identifying Patients with Heavy Coronary Atherosclerosis Burden

Abstract

Aim: The carotid sinuses and aortic arch are baroreceptor-resident arteries (BRAs) and atherosclerosis-susceptible sites of brain-supplying arteries, which would impair baroreflex-mediated blood pressure (BP) regulation and prompt coronary atherosclerosis. We sought to determine the relationship between total atherosclerosis burden (TAB) of BRAs and coronary atherosclerosis burden (AB) in patients with ischemic cerebrovascular disease (ICVD) and explore the potential contribution of BP profiles to this relationship.

Methods: In this cross-sectional analysis of patients with ICVD who simultaneously undertook computed tomography angiography and 24-hour ambulatory BP monitoring, TAB of BRAs was scored based on the atherosclerotic vessel circumference ratio of the carotid sinuses and aortic arch, while the ABs of the intracranial, cervical, aortic, and coronary arteries were scored based on stenosis severity and plaque complexity as routine.

Results: Among the 230 patients analyzed, coronary AB was significantly correlated with TAB of BRAs, independently of, and more tightly than the ABs of the intracranial, cervical, and aortic arteries, and the stenosis- and complexity-based AB of BRA-located arteries (bilateral common and extracranial internal carotid arteries and aortic arch). Both coronary AB and TAB of BRAs were negatively associated with the night-to-day BP dipping ratios, which was quite different from the relationship between intracranial AB and 24-hour BP characteristics. These findings were also true for patients with ICVD without a history of coronary artery disease.

Conclusion: Evaluating TAB of BRAs might provide a new link between atherosclerosis of brain- and heart-supplying arteries, connected partially by BP circadian rhythm. It might facilitate identifying patients with ICVD with heavy coronary AB and comprehensively managing vascular risk.

Introduction

About one-third of vascular events after ischemic cerebrovascular disease (ICVD) were of cardiovascular origin, with an annual risk of myocardial infarction reaching 1.67%¹⁾. A majority of patients (over 60%) diagnosed with ICVD also exhibited coronary atherosclerosis^{2, 3)}. Higher atherosclerosis burden (AB) of coronary arteries portended a higher risk of cardiovascular events in both the short- and long-term following ICVD^{4, 5)}. Early identification of patients with heavy coronary AB would facilitate reducing the substantial cardiovascular risk after ICVD.

Atherosclerosis develops systematically, so the regular evaluation of the atherosclerotic condition of brain-supplying arteries (intracranial, cervical, and aortic arteries) in patients with ICVD is usually conducted to indicate coronary atherosclerosis condition^{2, 3, 6)}. And there existed an unexplained phenomenon that the relationship of coronary atherosclerosis with cervical and aortic atherosclerosis seemed to be stronger than that with intracranial atherosclerosis^7-9). The interesting disparity had been largely attributed to different anatomic, physiologic, and hemodynamic characteristics among these brain-supplying arteries^{9, 10)}. But the specific mechanism underlying the tighter relationship between coronary atherosclerosis and cervical and aortic atherosclerosis remains unexplored.

We noted that the most susceptible sites to atherosclerosis in cervical and aortic arteries are the carotid sinuses and aortic arch¹¹⁾, which constitute baroreceptor-resident arteries (BRAs)¹²⁾. Atherosclerosis of the BRA would impair the baroreflex-mediated blood pressure (BP) regulation^{13, 14)}, and we had formulated a score of “total atherosclerosis burden (TAB) of BRAs” to better reflect the influence of atherosclerosis on the baroreflex¹²⁾. Different from the classic atherosclerosis score based on stenosis severity and plaque complexity, a circumference-based atherosclerosis scoring system was applied, as the baroreflex detects the stretch of BRA vessel walls with BP variations as input¹²⁾. It was found that higher TAB of BRAs was independently associated with worse BP circadian rhythm¹²⁾, while abnormal BP circadian rhythm could prompt the development of coronary atherosclerosis 10–15 years later in young adults¹⁵⁾. Thus, would TAB of BRA better identify patients with ICVD with heavy coronary AB than general atherosclerosis characteristics of brain-supplying arteries, and aid in clarifying the unexplained closer associations between coronary atherosclerosis and cervical and aortic atherosclerosis?

Aim

This study aims at determining the independent power of the TAB of BRAs in predicting coronary AB in patients with ICVD and examining whether 24-hour BP characteristics would serve as a potential link between the TAB of BRAs and coronary AB.

Methods

This cross-sectional study retrospectively analyzed a single-center prospective registry of patients with ICVD. The participants in this registry undertook computed tomography angiography (CTA) of the brain- and heart-supplying arteries if they had ≥ 3 vascular risk factors or evidence of atherosclerosis. The vascular risk factors included age ≥ 65 years, male, hypertension history, diabetes mellitus history, hyperlipidemia history, smoking, and being overweight (see below). Evidence of atherosclerosis included any atherosclerotic lesion detected by ultrasound or angiography in the coronary, aortic, cervical, intracranial, renal, and upper, and lower extremity arteries, as well as coronary artery disease history, peripheral artery disease history, coronary calcium score ＞0, and ankle-brachial index ＜0.8. Patients who needed intensive care or underwent urgent revascularization were not included in this registry for administrative reasons. All participants gave their informed consent before their inclusion. All study procedures were approved by the institutional ethics committee and performed in accordance with the Declaration of Helsinki.

Study Subjects

For this analysis, patients from January 1, 2018, to January 1, 2022 were consecutively included if they were diagnosed with ischemic stroke or transient ischemic attack with confirmation of computed tomography (CT) or magnetic resonance imaging within 30 days after the onset of symptoms, with CTA of the brain- and heart-supplying arteries, and with ambulatory blood pressure monitoring (ABPM). We excluded patients with suspected nonatherosclerotic arterial stenosis, such as arterial dissection, and vasculitis, cardio-embolism, or intracranial hemorrhage, carotid revascularization, or surgery of the aortic arch, malignant hypertension, or secondary hypertension, obstructive sleep apnea-hypopnea syndrome, administration of an adrenoceptor antagonist or agonist, hyperthyroidism, poor organ functions, ABPM recorded less than 6 days from the symptom onset of ICVD (to diminish the acute stress effects of ICVD on BP characteristics), worsening neurological conditions 3 days before the ABPM was performed, and the number of BP measurements that is ＜70% of the ABPM settings.

General Characteristics

Age, sex, history of hypertension, diabetes mellitus, hyperlipidemia, ICVD, coronary artery disease, and smoking status were collected through an interview. The patient was considered to be smoking if they were actively smoking within the last 12 months. Overweight was defined as a body mass index of ≥ 25 kg/m². All patients underwent standard blood tests and imaging examinations within 7 days after admission. The etiology of ICVD was classified according to The Trial of Org10172 in Acute Stroke Treatment criteria. The National Institute of Health stroke scale was used to assess the neurological deficit of the stroke.

Atherosclerosis Characteristics of the Intracranial, Cervical, Aortic, and Coronary Arteries

All patients underwent simultaneous CTA of brain- and heart-supplying arteries, as previously reported^{2, 16)}. In brief, a dual-source 192-slice CT scanner (Somatom Force, Siemens Healthcare, Forchheim, Germany) or a 256-row multidetector CT scanner (Revolution CT, GE Healthcare, Milwaukee, USA) was used for data acquisition. Both angiography protocols were similarly diagnostic regarding image quality. The Syngo.via workstation (Siemens Healthcare) and the GE AW4.7 workstation (GE Healthcare) were respectively used for image analysis. Two certified radiologists independently reconstructed and reviewed the images. The discrepancies were discussed to reach conclusions.

The brain- and heart-supplying arteries were divided into four arterial territories, including the intracranial, cervical, aortic, and coronary arteries. The intracranial arteries included 11 segments: bilateral intracranial carotid, intracranial vertebral, anterior cerebral, middle cerebral, posterior cerebral, and basilar arteries¹²⁾. The cervical arteries included 8 segments: bilateral common carotid, subclavian, extracranial carotid, and extracranial vertebral arteries¹²⁾. The aortic arteries included 3 segments: ascending aortic artery from the aortic root to the opening of the brachiocephalic trunk; aortic arch between the openings of the brachiocephalic trunk and the left subclavian artery; and proximal descending aortic artery from the opening of the left subclavian artery to the level of the pulmonary artery bifurcation¹⁷⁾. The coronary arteries included 15 segments: proximal, mid, and distal portions of the right coronary artery and its posterior descending branch; main left coronary artery; proximal, mid, and apical portions of the left anterior descending artery and the first and second diagonal branches; and the proximal and distal portions of the left circumflex coronary artery, and its obtuse marginal, posterolateral, and posterior descending branches¹⁸⁾.

The atherosclerotic severity in each intracranial, cervical, and coronary arterial segment was scored 0–5 points based on the degree of atherosclerotic stenosis (0, no visible stenosis; 1, 1%–24% stenosis; 2, 25%–49% stenosis; 3, 50%–69% stenosis; 4, 70%–99% stenosis; and 5, occlusion)¹⁹⁾. The percentage of arterial stenosis was quantified according to the North American Symptomatic Carotid Endarterectomy Trial method²⁰⁾ for cervical arteries, the Warfarin–Aspirin Symptomatic Intracranial Disease Study Trial method for intracranial arteries²¹⁾, and the formula {1 – [minimum lumen diameter/(average of proximal and distal reference vessel diameter)]}×100 % for coronary arteries²²⁾. The atherosclerotic severity in each aortic arterial segment was scored 0–2 points based on the complexity of atherosclerotic plaque (0, no atherosclerotic plaque; 1, a simple plaque with a thickness of ＜4 mm and without associated ulcerations or mural thrombus; 2, a complex plaque with a thickness of ≥ 4 mm or associated ulcerations or mural thrombus)²³⁾.

Finally, the ABs of the intracranial, cervical, aortic, and coronary arteries were computed by adding the stenosis- and complexity-based atherosclerosis scores of all arterial segments included in each arterial territory.

Atherosclerosis Characteristics of BRAs

BRAs belong to brain-supplying arteries located in the aortic arch, common carotid, and extracranial internal carotid arteries. The above-described stenosis- and complexity-based atherosclerosis scores of these BRA-located arterial segments were summarized as the “AB of BRA-located arteries.”

The “TAB of BRAs” specifically focuses on carotid sinuses (including six portions, i.e., bilateral distal common carotid arteries, carotid bifurcations, and origins of internal carotid arteries) and aortic arch (including four portions, i.e., aortic arteries from the opening of the brachiocephalic trunk to the opening of the left subclavian artery and the origins of the brachiocephalic trunk, left common carotid artery, and left subclavian artery). The 10 portions of BRAs were scored 0–4 points according to the percentage of vessel circumference affected by atherosclerosis on orthogonal views (0, none; 1, ＜25%; 2, 25%–49%; 3, 50%–74%; and 4, ≥ 75%). The TAB of BRAs was the sum of these scores¹²⁾.

24-hour BP Characteristics

The ABPM was performed more than 5 days after the onset of ICVD. ABPM data were obtained using the Meditech ABPM-05 device (Meditech, Hungary) at 20-minute intervals during the daytime (6:00 a.m.–10:00 p.m.) and at 40-minute intervals during the nighttime (10:00 p.m.–6:00 a.m.). The weighted means and standard deviations (SDs) of the 24-hour, daytime, and nighttime systolic and diastolic BP were recorded, respectively. The night-to-day BP dipping ratio was calculated as (daytime BP−nighttime BP)/daytime BP×100%¹²⁾.

Statistical Analysis

Statistical analyses were performed using SPSS (v26.0; IBM) and R (v4.2.2; www.r-project.org). A P value of ＜0.05 was considered statistically significant. Data were presented as mean±SD for normally distributed continuous variables, count (%) for nominal variables, and median (Q1, Q3) for abnormally distributed continuous variables and ordinal variables.

The relationship between ABs of brain-supplying arteries and coronary AB was tested by correlation analysis and linear regression models. Variables would be transformed as appropriate for the linear regression model. The β value was estimated with a 95% confidence interval. The independent power of the TAB of BRAs for indicating coronary AB would be determined by adjusting for (1) age, sex, hypertension history, diabetes mellitus history, hyperlipidemia history, smoking, and overweight; (2) age, sex, and all general characteristics and 24-hour BP characteristics potentially related to coronary AB (P＜0.1 with adjustment for age and sex); and (3) intracranial AB, cervical AB, aortic AB, and number of intracranial arterial segments with ≥ 50% stenosis, number of cervical arterial segments with ≥ 50% stenosis, number of aortic arterial segments with complex plaque, and AB of the BRA-located arteries. The adjusted R² was used to measure the proportion of explained variance for the dependent variable.

After bivariate correlation analysis between various atherosclerosis characteristics and 24-hour BP characteristics, partial correlation analysis would be performed (1) between BP variability (24-hour BP SDs and night-to-day dipping ratios) and various atherosclerosis characteristics, controlling age, sex, hypertension history, diabetes mellitus history, antihypertensive therapy when ABPM was performed (yes or no), time of ABPM after the onset of ICVD (days), and 24-hour weighted means of systolic and diastolic BP; (2) between BP levels (24-hour, daytime, and nighttime weighted means of BP) and various atherosclerosis characteristics, controlling age, sex, hypertension history, diabetes mellitus history, antihypertensive therapy when ABPM was performed (yes or no), time of ABPM after the onset of ICVD (days), and BP variability.

In the sensitivity analysis, coronary atherosclerosis condition would be measured instead by the number of coronary arterial segments with ≥ 50% stenosis, and by the presence of ≥ 50% stenosis in the left main trunk and (or) all three main coronary arteries (left anterior descending artery, left circumflex coronary artery, and right coronary artery). The analysis would be further limited to patients without a history of coronary artery disease.

According to Spearman’s rank correlation tests (simulation) based on 5000 Monte Carlo samples from the bivariate normal distribution under the alternative hypothesis using PASS software (v15.0.5; NCSS), a sample size of 194 would achieve 81% power to detect a correlation efficiency of 0.200 using a two-sided hypothesis test with a significance level of 0.050.

Results

A total of 230 patients were included in the analysis (Supplemental Fig.1). The median (Q1, Q3) age was 62 (54, 68) years, and 178 (77.4%) of these patients were male. As for the etiology of ICVD, 123 (53.5%) were due to large artery atherosclerosis, 87 (37.8%) resulted from small vessel occlusion, and 20 (8.7%) had multiple causes. There were 134 (58.3%), 79 (34.3%), and 130 (56.5%) patients with ≥ 50% atherosclerotic stenosis of the intracranial, cervical, and coronary arteries. Complex aortic plaque was present in 55 (22.9%) patients. The ABPM was performed 7 (6, 12) days after the onset of ICVD at median (Q1, Q3). Among the general characteristics, older age, male, hypertension history, diabetes mellitus history, coronary artery disease history, and elevated glycated hemoglobin levels were associated with higher coronary AB (Table 1). Among 24-hour BP characteristics, higher nighttime BP and lower night-to-day BP dipping ratios indicated higher coronary AB (Table 1).

Supplemental Fig.1. Flow chart of the patient selection

Abbreviations: ABPM, ambulatory blood pressure monitoring; BP, blood pressure; ICVD, ischemic cerebrovascular disease.

Table 1.Characteristics of patients and the associations with coronary AB

Characteristics a	Value (n = 230)	Age- and sex-adjusted β (95% CI)	P value
General characteristics
Age (year)	62 (54, 68)	0.282 (0.197–0.367)	＜0.001＊
Female	52 (22.6)	-5.442 (-7.488–-3.396)	＜0.001＊
Hypertension history	168 (73.0)	2.017 (0.156–3.879)	0.034＊
Diabetes mellitus history	86 (37.4)	2.299 (0.592–4.006)	0.009＊
Hyperlipidemia history	88 (38.3)	-0.616 (-2.333–1.100)	0.480
ICVD history	63 (27.4)	-0.003 (-1.909–1.903)	0.998
CAD history	34 (14.8)	4.180 (1.894–6.466)	＜0.001＊
Smoking	105 (45.7)	-0.887 (-2.700–0.926)	0.336
Overweight	118 (51.3)	0.358 (-1.321–2.037)	0.675
NIHSS at admission (point)	2 (1, 4)	-0.005 (-0.270–0.260)	0.970
HbA1c (mmol/L)	5.90 (5.40, 7.40)	0.771 (0.198–1.345)	0.009＊
HDL-C (mmol/L)	0.99 (0.85, 1.15)	-1.871 (-5.145–1.402)	0.261
LDL-C (mmol/L)	2.26 (1.70, 2.82)	-0.579 (-1.573–0.414)	0.252
eGFR (ml/min/1.73m2)	108.50 (103.31, 113.87)	0.093 (-0.021–0.206)	0.109
hs-CRP (mg/L)	2.30 (0.86, 4.94)	0.017 (-0.084–0.117)	0.745
Fibrinogen (g/L)	3.31 (2.88, 3.82)	0.027 (-0.482–0.535)	0.918
D-dimer (mg/L)	0.33 (0.23, 0.59)	-0.032 (-0.356–0.291)	0.845
LAA-ICVD	123 (53.5)	1.349 (-0.325–3.023)	0.114
Anti-hypertensive therapy b	148 (64.3)	1.121 (-0.619–2.861)	0.206
24-hour BP characteristics
24-hour weighed mean of SBP (mmHg)	138.7 (129.0, 153.8)	0.030 (-0.018–0.078)	0.213
24-hour weighed mean of 24-hour DBP (mmHg)	78.6 (72.8, 86.8)	0.044 (-0.040–0.128)	0.305
Daytime weighed mean of SBP (mmHg)	139.0 (130.0, 154.9)	0.022 (-0.026–0.070)	0.364
Daytime weighed mean of DBP (mmHg)	79.8 (72.8, 87.0)	0.031 (-0.053–0.115)	0.472
Nighttime weighed mean of SBP (mmHg)	137.5 (123.0, 150.8)	0.054 (0.010–0.097)	0.016＊
Nighttime weighed mean of DBP (mmHg)	77.4 (69.7, 84.5)	0.076 (-0.003–0.155)	0.060
24-hour SBP SD (mmHg)	13.3 (11.7, 16.0)	0.025 (-0.208–0.258)	0.835
24-hour DBP SD (mmHg)	9.6 (8.0, 11.1)	0.099 (-0.218–0.417)	0.539
SBP night-to-day dipping ratio (%)	2.7±8.2	-0.157 (-0.258–-0.056)	0.003＊
DBP night-to-day dipping ratio (%)	4.1±8.7	-0.101 (-0.197–-0.005)	0.039＊
Atherosclerosis characteristics
Coronary AB (point)	9 (3, 15)	–	–
Number of coronary segments with ≥ 50% stenosis	1 (0, 3)	3.323 (3.078–3.569)	＜0.001＊
Intracranial AB (point)	9 (4, 13)	0.202 (0.081–0.323)	0.001＊
Number of intracranial segments with ≥ 50% stenosis	1 (0, 2)	0.471 (-0.042–0.984)	0.072
Cervical AB (point)	4 (2, 8)	0.467 (0.272–0.662)	＜0.001＊
Number of cervical segments with ≥ 50% stenosis	0 (0, 1)	0.914 (0.002–1.826)	0.049＊
Aortic AB (point)	1 (0, 2)	0.761 (0.067–1.456)	0.032＊
Number of aortic segments with complex plaque	0 (0, 0)	0.606 (-0.716–1.928)	0.367
AB of BRA-located arteries (point)	3 (2, 5)	0.780 (0.484–1.076)	＜0.001＊
TAB of BRAs (point)	6 (1, 14)	0.452 (0.352–0.552)	＜0.001＊

^a Data were presented as mean±SD for normally distributed continuous variables, count (%) for nominal variables, and median (Q1, Q3) for abnormally distributed continuous variables and ordinal variables.

^b Taking antihypertensive drugs when the ambulatory BP monitoring was performed.

^＊P value ＜0.05 was considered statistically significant.

Abbreviations: AB, atherosclerosis burden; BP, blood pressure; BRAs, baroreceptor-resident arteries; CAD, coronary artery disease; CI, confidence interval; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; ICVD, ischemic cerebrovascular disease; LAA, large-artery atherosclerotic ischemic stroke; LDL-C, low-density lipoprotein cholesterol; NIHSS, National Institute of Health stroke scale; SBP, systolic blood pressure; SD, standard derivation; TAB, total atherosclerosis burden.

The Independent Value of TAB of BRAs for Predicting Coronary AB

Various atherosclerosis characteristics of brain-supplying arteries were all significantly related to coronary AB, while the correlation coefficient was the highest between TAB of BRAs and coronary AB (Table 2). The TAB of BRA demonstrated significant indicative power for coronary AB, independent of age, sex, vascular risk factors, and 24-hour BP characteristics (Table 2). The adjusted R²s of linear regression models would decrease if the TAB of BRAs was replaced by the other atherosclerosis characteristics of brain-supplying arteries (Table 2).

Table 2.Independent relationship between various atherosclerosis characteristics of brain-supplying arteries and coronary AB

Atherosclerosis characteristics of brain-supplying arteries	Spearman correlation coefficient (P value)	Adjusted β (95% CI) a	Adjusted R2 a	Adjusted β (95% CI) b	Adjusted R2 b
Intracranial AB	0.303 (＜0.001)	0.195 (0.064–0.326)＊	0.249	0.140 (0.013–0.266)＊	0.283
Number of intracranial segments with ≥ 50% stenosis	0.146 (＜0.001)	0.364 (-0.166–0.894)	0.226	0.225 (-0.293–0.743)	0.270
Cervical AB	0.502 (＜0.001)	0.448 (0.251–0.645)＊	0.284	0.398 (0.197–0.599)＊	0.315
Number of cervical segments with ≥ 50% stenosis	0.284 (＜0.001)	0.867 (-0.037–1.772)	0.232	0.691 (-0.205–1.586)	0.275
Aortic AB	0.335 (＜0.001)	0.632 (-0.069–1.334)	0.231	0.340 (-0.367–1.046)	0.270
Number of aortic segments with complex plaque	0.231 (＜0.001)	0.412 (-0.917–1.741)	0.221	-0.062 (-1.376–1.252)	0.267
AB of BRA-located arteries	0.515 (＜0.001)	0.741 (0.442–1.039)＊	0.296	0.683 (0.379–0.988)＊	0.327
TAB of BRAs	0.616 (＜0.001)	0.453 (0.349–0.556)＊	0.416	0.415 (0.309–0.522)＊	0.424

^a Each atherosclerosis characteristic of brain-supplying arteries was entered into a linear regression model for predicting coronary AB with adjustments for age, sex, hypertension history, diabetes mellitus history, hyperlipidemia history, smoking, and overweight.

^b Each atherosclerosis characteristic of brain-supplying arteries was entered into linear regression model for predicting coronary AB with adjustments for age, sex, and all general characteristics and 24-hour BP characteristics potentially related to coronary AB (P＜0.1 with adjustment for age and sex, including hypertension history, diabetes mellitus history, coronary artery disease history, glycated hemoglobin level, nighttime weighted means of systolic and diastolic BP, systolic and diastolic night-to-day BP dipping ratios).

^＊P value ＜0.05 was considered statistically significant.

Abbreviations: AB, atherosclerosis burden; BP, blood pressure; BRAs, baroreceptor-resident arteries; CI, confidence interval; TAB, total atherosclerosis burden.

With adjustments for various atherosclerosis characteristics of intracranial, cervical, and aortic arteries, as well as the AB of BRA-located arteries, the TAB of BRAs remained significantly associated with coronary AB (Table 3). However, except for intracranial AB, the other atherosclerosis characteristics of brain-supplying arteries became statistically unrelated to coronary AB when TAB of BRAs was simultaneously entered into the linear regression models (data not shown). The proportion of explained variance for coronary AB remarkably increased when the TAB of BRAs was added to the other atherosclerosis characteristics of brain-supplying arteries as covariates (Table 3).

Table 3.Value of the TAB of BRAs for predicting coronary AB independent of the other atherosclerosis characteristics of brain- supplying arteries

Models a	Adjusted β (95% CI) of TAB of BRAs	Adjusted R2
Intracranial AB	–	0.070
Intracranial AB + TAB of BRAs	0.495 (0.401–0.589)＊	0.366
Number of intracranial segments with ≥ 50% stenosis	–	0.014
Number of intracranial segments with ≥ 50% stenosis + TAB of BRAs	0.518 (0.425–0.612)＊	0.350
Cervical AB	–	0.164
Cervical AB + TAB of BRAs	0.536 (0.406–0.667)＊	0.349
Number of cervical segments with ≥ 50% stenosis	–	0.038
Number of cervical segments with ≥ 50% stenosis + TAB of BRAs	0.567 (0.462–0.671)＊	0.357
Aortic AB	–	0.076
Aortic AB + TAB of BRAs	0.575 (0.462–0.688)＊	0.355
Number of aortic segments with complex plaque	–	0.024
Number of aortic segments with complex plaque + TAB of BRAs	0.565 (0.464–0.667)＊	0.359
AB of BRA-located arteries	–	0.191
AB of BRA-located arteries + TAB of BRAs	0.528 (0.389–0.667)＊	0.349
Atherosclerosis scores of BRA-located arteries (5 variables) b	–	0.201
Atherosclerosis scores of BRA-located arteries (5 variables) b + TAB of BRAs	0.542 (0.390–0.693)＊	0.343

^a Linear regression model with different sets of covariates for predicting coronary AB.

^b The BRA-located arteries included four cervical segments (bilateral common carotid and extracranial internal carotid arteries) and one aortic segment (aortic arch). The atherosclerosis scores of them were stenosis- and complexity-based as routine.

^＊P value ＜0.05.

Abbreviations: AB, atherosclerosis burden; BRAs, baroreceptor-resident arteries; CI, confidence interval; TAB, total atherosclerosis burden.

The Relationship of 24-hour BP Characteristics with TAB of BRAs and Coronary AB

In the bivariate correlation analysis between various atherosclerosis characteristics and 24-hour BP characteristics, coronary AB was positively associated with nighttime weighted means of systolic BP and was negatively associated with systolic and diastolic night-to-day BP dipping ratios. This pattern was quite similar to the relationship between the TAB of BRAs and 24-hour BP characteristics. In contrast, AB of intracranial arteries, which constituted the baroreceptor-free part of brain-supplying arteries, had no statistically significant relationship with night-to-day BP dipping ratios. Higher intracranial AB was significantly related to higher 24-hour, daytime, and nighttime weighted means of systolic and diastolic BP (Fig.1).

Fig.1. Spearman correlation analysis between 24-hour BP characteristics and atherosclerosis of brain-and heart-supplying arteries

^＊P value ＜0.05 ^＊＊P value ＜0.01

Abbreviations: AB, atherosclerosis burden; BP, blood pressure; BRAs, baroreceptor-resident arteries; DBP, diastolic blood pressure; SBP, systolic blood pressure; SD, standard deviation; TAB, total atherosclerosis burden.

After controlling age, sex, hypertension history, diabetes mellitus history, antihypertensive therapy when ABPM was performed (yes or no), time of ABPM after the onset of ICVD (days), and 24-hour weighted means of BP, the systolic night-to-day BP dipping ratio was still negatively associated with both coronary AB and TAB of BRAs. However, the nighttime weighted mean of systolic BP had no statistically significant relationship with coronary AB or TAB of BRAs after adjustments. In contrast, intracranial AB was independently related to the 24-hour, daytime, and nighttime weighted means of systolic BP (Table 4). In addition, the AB of BRA-located arteries measured by arterial stenosis and plaque complexity showed no independent associations with night-to-day BP dipping ratios (Table 4).

Table 4.Partial correlation analysis between 24-hour BP characteristics and atherosclerosis of brain-and heart-supplying arteries

24-hour BP characteristics a	Intracranial AB	Coronary AB	TAB of BRAs	AB of BRA-located arteries
24-hour weighted means of SBP b	0.235 (＜0.001＊)	0.043 (0.524)	0.070 (0.296)	0.113 (0.093)
24-hour weighted means of DBP b	0.133 (0.048＊)	0.054 (0.421)	-0.071 (0.291)	-0.093 (0.166)
Daytime weighted means of SBP b	0.234 (＜0.001＊)	0.051 (0.447)	0.069 (0.305)	0.112 (0.096)
Daytime weighted means of DBP b	0.135 (0.045＊)	0.058 (0.387)	-0.085 (0.206)	-0.101 (0.135)
Nighttime weighted means of SBP b	0.229 (0.001＊)	0.036 (0.590)	0.059 (0.378)	0.104 (0.123)
Nighttime weighted means of DBP b	0.120 (0.073)	0.047 (0.484)	-0.087 (0.196)	-0.111 (0.099)
SBP night-to-day dipping ratio c	-0.081 (0.230)	-0.180 (0.007＊)	-0.189 (0.005＊)	-0.109 (0.107)
DBP night-to-day dipping ratio c	-0.098 (0.145)	-0.132 (0.050)	-0.126 (0.061)	-0.077 (0.253)
24-hour weighted means of SBP d	0.171 (0.011＊)	0.030 (0.659)	0.043 (0.521)	0.048 (0.479)
24-hour weighted means of DBP d	0.081 (0.230)	0.027 (0.686)	-0.097 (0.150)	-0.132 (0.050)
Daytime weighted means of SBP d	0.146 (0.030＊)	0.005 (0.936)	0.005 (0.938)	0.019 (0.774)
Daytime weighted means of DBP d	0.057 (0.397)	0.005 (0.937)	-0.136 (0.043＊)	-0.158 (0.019＊)
Nighttime weighted means of SBP d	0.199 (0.003＊)	0.115 (0.088)	0.129 (0.056)	0.101 (0.133)
Nighttime weighted means of DBP d	0.124 (0.065)	0.095 (0.157)	-0.022 (0.743)	-0.078 (0.245)
24-hour SBP SD c	0.119 (0.077)	0.012 (0.864)	0.011 (0.873)	0.100 (0.136)
24-hour DBP SD c	0.113 (0.094)	0.048 (0.479)	0.041 (0.547)	0.070 (0.303)

^a The associations with various atherosclerosis characteristics of brain-and heart-supplying arteries were presented as partial correlation coefficient (P value).

^b Partial correlation analysis controlling age, sex, hypertension history, diabetes mellitus history, antihypertensive therapy when ABPM was performed (yes or no), time of ABPM after the onset of ICVD (days), systolic and diastolic night-to-day BP dipping ratios.

^c Partial correlation analysis controlling age, sex, hypertension history, diabetes mellitus history, antihypertensive therapy when ABPM was performed (yes or no), time of ABPM after the onset of ICVD (days), 24-hour weighted means of systolic and diastolic BP.

^d Partial correlation analysis controlling age, sex, hypertension history, diabetes mellitus history, antihypertensive therapy when ABPM was performed (yes or no), time of ABPM after the onset of ICVD (days), systolic and diastolic BP SDs.

^＊P value ＜0.05 was considered statistically significant.

Abbreviations: AB, atherosclerosis burden; ABPM, ambulatory blood pressure monitoring; BP, blood pressure; BRAs, baroreceptor-resident arteries; DBP, diastolic blood pressure; ICVD, ischemic cerebrovascular disease; SBP, systolic blood pressure; SD, standard deviation; TAB, total atherosclerosis burden.

Sensitivity Analyses and Additional Analyses

Similar trends were maintained when coronary atherosclerosis was instead measured by the number of coronary arterial segments with ≥ 50% stenosis (Supplemental Tables 1 and 2) or by the presence of ≥ 50% stenosis in the left main trunk and (or) all three main coronary arteries (Supplemental Table 1). When the analysis was limited to patients without a history of coronary artery disease (n=196), these findings still stood (Supplemental Tables 3 and 4).

Supplemental Table 1.Independent value of the TAB of BRAs for predicting additional coronary atherosclerosis characteristics

Characteristics for adjustments a	Adjusted β (95% CI) of the TAB of BRAs b	Adjusted OR (95% CI) of the TAB of BRAs c
Age, sex, hypertension history, diabetes mellitus history, hyperlipidemia history, smoking, and overweight	0.110 (0.082–0.138)	1.123 (1.069–1.180)
Intracranial AB	0.108 (0.083–0.133)	1.119 (1.072–1.168)
Number of intracranial segments with ≥ 50% stenosis	0.114 (0.089–0.138)	1.122 (1.075–1.171)
Cervical AB	0.108 (0.074–0.143)	1.104 (1.045–1.166)
Number of cervical segments with ≥ 50% stenosis	0.121 (0.093–0.148)	1.118 (1.066–1.172)
Aortic AB	0.135 (0.105–0.165)	1.148 (1.088–1.212)
Number of aortic segments with complex plaque	0.126 (0.099–0.153)	1.136 (1.083–1.191)
AB of BRA-located arteries	0.106 (0.070–0.143)	1.116 (1.051–1.184)
Various atherosclerosis scores of BRA-located arterial segments (5 variables) d	0.118 (0.078–0.158)	1.131 (1.058–1.210)

^a Characteristics for adjustments were respectively entered into linear regression models as different sets of covariates, along with TAB of BRAs for predicting coronary AB.

^b The multivariable linear regression models were used to predict the number of coronary segments with ≥ 50% stenosis.

^c The multivariable Logistic models were used to predict the presence of coronary ≥ 50% stenosis in the left main or all three branches.

^d The BRA-located arterial segments included four cervical arterial segments (bilateral common carotid and extracranial internal carotid arteries) and one aortic arterial segment (aortic arch). The atherosclerosis scores of them were stenosis- and complexity-based as routine.

Abbreviations: AB, atherosclerosis burden; BRAs, baroreceptor-resident arteries; CI, confidence interval; OR, odd ratio; TAB, total atherosclerosis burden.

Supplemental Table 2.Correlation analysis of 24-hour BP characteristics and additional atherosclerosis characteristics of brain-and heart-supplying arteries

24-hour BP characteristics a	Number of coronary segments with ≥ 50% stenosis	Number of intracranial segments with ≥ 50% stenosis
24-hour weighted means of SBP	0.106	0.226 ＊＊
24-hour weighted means of DBP	0.006	0.058
Daytime weighted means of SBP	0.078	0.216 ＊＊
Daytime weighted means of DBP	-0.025	0.038
Nighttime weighted means of SBP	0.174 ＊＊	0.204 ＊＊
Nighttime weighted means of DBP	0.075	0.077
24-hour SBP SD	0.059	0.123
24-hour DBP SD	-0.033	0.039
SBP night-to-day dipping ratio	-0.191 ＊＊	-0.050
DBP night-to-day dipping ratio	-0.136 ＊	-0.062

^a The associations with various atherosclerosis characteristics of brain-and heart-supplying arteries were presented by Spearman correlation coefficients.

^＊ P value ＜0.05.

^＊＊ P value ＜0.01.

Abbreviations: BP, blood pressure; DBP, diastolic blood pressure; SBP, systolic blood pressure; SD, standard deviation.

Supplemental Table 3.Independent value of the TAB of BRAs for predicting coronary atherosclerosis in ICVD patients without known coronary artery disease (n = 196)

Characteristics for adjustments a	Adjusted β (95% CI) of the TAB of BRAs b	Adjusted β (95% CI) of the TAB of BRAs c	Adjusted OR (95% CI) of the TAB of BRAs d
Age, sex, hypertension history, diabetes mellitus history, hyperlipidemia history, smoking, and overweight	0.452 (0.340–0.564)	0.108 (0.079–0.138)	1.103 (1.045–1.165)
Intracranial AB	0.523 (0.422–0.623)	0.115 (0.089–0.141)	1.116 (1.065–1.169)
Number of intracranial segments with ≥ 50% stenosis	0.546 (0.447–0.646)	0.119(0.093–0.144)	1.119 (1.068–1.172)
Cervical AB	0.564 (0.429–0.699)	0.118 (0.083–0.153)	1.102 (1.039–1.170)
Number of cervical segments with ≥ 50% stenosis	0.595 (0.485–0.705)	0.128 (0.099–0.156)	1.121 (1.064–1.180)
Aortic AB	0.606 (0.485–0.727)	0.138 (0.107–0.169)	1.136 (1.071–1.2050
Number of aortic segments with complex plaque	0.598 (0.488–0.707)	0.131 (0.102–0.159)	1.133 (1.074–1.196)
AB of BRA-located arteries	0.552 (0.408–0.696)	0.112 (0.075–0.149)	1.113 (1.043–1.187)
Various atherosclerosis scores of BRA-located arterial segments (5 variables) e	0.565 (0.408–0.723)	0.120(0.079–0.161)	1.117 (1.039–1.201)

^a Characteristics for adjustments were respectively entered into linear regression models as different sets of covariates, along with TAB of BRAs, for predicting coronary AB.

^b The multivariable linear regression models were used to predict the coronary AB.

^c The multivariable linear regression models were used to predict the number of coronary segments with ≥ 50% stenosis.

^d The multivariable Logistic models were used to predict the presence of coronary ≥ 50% stenosis in the left main or all three branches.

^e The BRA-located arterial segments included four cervical arterial segments (bilateral common carotid and extracranial internal carotid arteries) and one aortic arterial segment (aortic arch). The atherosclerosis scores of them were stenosis- and complexity-based as routine.

Abbreviations: AB, atherosclerosis burden; BRAs, baroreceptor-resident arteries; CI, confidence interval; ICVD, ischemic cerebrovascular disease; OR, odd ratio; TAB, total atherosclerosis burden.

Supplemental Table 4.Correlation analysis of 24-hour BP characteristics and atherosclerosis of brain-and heart-supplying arteries in ICVD patients without known coronary artery disease (n = 196)

24-hour BP characteristics a	Intracranial AB	Number of intracranial segments with ≥50% stenosis	Coronary AB	Number of coronary segments with ≥50% stenosis	TAB of BRAs	AB of BRA-located arteries
24-hour weighted means of SBP	0.282＊＊	0.183＊	0.124	0.087	0.125	0.095
24-hour weighted means of DBP	0.120	-0.022	-0.015	-0.017	-0.145＊	-0.146＊
Daytime weighted means of SBP	0.269＊＊	0.172＊	0.089	0.060	0.084	0.080
Daytime weighted means of DBP	0.108	-0.036	-0.037	-0.040	-0.172＊	-0.158＊
Nighttime weighted means of SBP	0.285＊＊	0.167＊	0.204＊＊	0.152＊	0.214＊＊	0.133
Nighttime weighted means of DBP	0.153＊	-0.002	0.068	0.049	-0.068	-0.089
24-hour SBP SD	0.132	0.139	0.074	0.062	0.059	0.156＊
24-hour DBP SD	0.060	0.002	0.007	-0.063	-0.048	-0.001
SBP night-to-day dipping ratio	-0.080	-0.054	-0.205＊＊	-0.178＊	-0.255＊＊	-0.139
DBP night-to-day dipping ratio	-0.069	-0.045	-0.150＊	-0.127	-0.145＊	-0.092

^a The associations with various atherosclerosis characteristics of brain-and heart-supplying arteries were presented by Spearman correlation coefficients.

^＊P value ＜0.05.

^＊＊P value ＜0.01.

Abbreviations: AB, atherosclerosis burden; BP, blood pressure; BRAs, baroreceptor-resident arteries; DBP, diastolic blood pressure; ICVD, ischemic cerebrovascular disease; SBP, systolic blood pressure; SD, standard deviation; TAB, total atherosclerosis burden.

Given the close relationship between TAB of BRAs and BP dipping ratio with coronary AB, the predictive capability of combing TAB of BRAs and the BP dipping status for coronary AB was further examined. As shown in Fig.2 for predicting the presence of ≥ 50% atherosclerotic stenosis in the left main trunk and (or) all three main coronary arteries, the area under the receiver operating characteristic curve of models combining TAB of BRAs and BP dipping status (including two categories, i.e., non-dipping: night-to-day BP dipping ratio ＜10%, and dipping: night-to-day BP dipping ratios ≥ 10%) was only slightly larger than that of evaluating TAB of BRAs alone. The best cut-off value of TAB of BRAs for predicting the presence of ≥ 50% of atherosclerotic stenosis in the left main trunk and (or) all three main coronary arteries was 8.5 points (sensitivity: 76.6%, specificity: 66.1%). Among patients with both TAB of BRAs of ≥ 9 points and systolic or diastolic BP nondipping (n=86), 40.7% would have ≥ 50% of atherosclerotic stenosis in the left main trunk and (or) all three main coronary arteries. In contrast, among those with a TAB of BRAs of ＜9 points and without systolic or diastolic BP nondipping (n=21), the proportion was only 4.8%.

Fig.2. Receiver operating characteristic curves of the TAB of BRAs and BP dipping status for predicting the presence of ≥ 50% atherosclerotic stenosis in the left main trunk and (or) all three main coronary arteries

The SBPD and DBPD status were dichotomously categorized into night-to-day BP dipping ratio ＜10% (nondipping) and ≥ 10% (dipping). Abbreviations: AUC, area under receiver operating characteristic curve; BP, blood pressure; BRAs, baroreceptor-resident arteries; CI, confidence interval; DBPD, diastolic blood pressure dipping; SBPD, systolic blood pressure dipping; TAB, total atherosclerosis burden.

Discussion

Focusing on the carotid sinuses and aortic arch, which were not only hotspots of atherogenesis in cervical and aortic arteries but also arterial segments rich in baroreceptors, this study mainly discovered a strong and independent link between TAB of BRAs and coronary atherosclerosis in patients with ICVD. Furthermore, it was found that night-to-day BP dipping ratios might lay some kind of hemodynamic basis for this new link between atherosclerosis of brain- and heart-supplying arteries.

The close associations between TAB of BRAs and coronary AB demonstrated in this study might offer an insight into the long-recognized but unexplained tighter relationship of coronary atherosclerosis with atherosclerosis of the cervical and aortic arteries, in comparison to that with intracranial atherosclerosis^7-9). Although the atherosclerosis condition of BRA had not been specifically evaluated to predict coronary atherosclerosis before, there had been some hints suggesting that coronary atherosclerosis was especially associated with atherosclerosis of BRA-located arteries (bilateral common and extracranial internal carotid arteries and aortic arch) in patients with ICVD^{2, 3, 9)}, patients with chest pain²⁴⁾, and the general population²⁵⁾. More importantly, the circumference-based TAB of BRAs manifested a significant relationship with coronary AB independent of the stenosis- and complexity-based AB of BRA-located arteries, making it more plausible that the strong link between TAB of BRAs and coronary atherosclerosis condition was partially baroreflex-related and could not only be attributed to the similar susceptibility to atherosclerosis among coronary, cervical, and aortic arteries.

This idea was further validated by the close associations between coronary AB and night-to-day BP dipping ratios, given that baroreflex impairments could contribute to the genesis of abnormal BP dipping^{12, 26)}. Of note, an increase in intracranial AB was more correlated with high BP levels than lower night-to-day BP dipping ratios, suggesting that the negative correlation between coronary AB and night-to-day BP dipping ratios was not a ubiquitous phenomenon between atherosclerosis and BP circadian rhythm. In consistency, with decades of follow-up, the Coronary Artery Risk Development in Young Adults study indicated that BP variability might exert different influences on the atherosclerosis development of brain-supplying arteries and coronary arteries^{15, 27)}.

As a part of systematic atherosclerosis, the TAB of BRAs was also tightly related to intracranial AB and the AB of BRA-located arteries. However, intracranial AB and the circumference-based TAB of BRAs had no significant association independent of the stenosis- and complexity-based cervical AB or AB of BRA-located arteries (Supplemental Table 5). As for the correlation coefficient between the AB of BRA-located arteries and the TAB of BRAs, it was even higher than that between the coronary AB and TAB of BRAs (data not shown). However, the AB of BRA-located arteries was not statistically significantly associated with night-to-day BP dipping ratios (Fig.1 and Table 4). It would be intriguing to infer that TAB of BRAs and coronary AB are related in a specific way, and BP circadian rhythm might serve as a hemodynamic connection between them.

Supplemental Table 5.Independent value of the TAB of BRAs for predicting intracranial AB

Characteristics for adjustments a	Adjusted β (95% CI)	P value
Age, sex, hypertension history, diabetes mellitus history, hyperlipidemia history, smoking, and overweight	0.182 (0.066–0.299)	0.002＊
Cervical AB	-0.072 (-0.214–0.071)	0.322
Aortic AB	0.152 (0.020–0.284)	0.024＊
Coronary AB	0.113 (-0.019–0.246)	0.093
AB of BRA-located arteries	-0.047 (-0.202–0.107)	0.547
Atherosclerosis scores of BRA-located arteries
(5 variables) b	-0.087 (-0.252–0.078)	0.299

^a Linear regression model with different sets of covariates for predicting intracranial AB.

^b The BRA-located arteries included four cervical segments (bilateral common carotid and extracranial internal carotid arteries) and one aortic segment (aortic arch). The atherosclerosis scores of them were stenosis- and complexity-based as routine.

^＊P value ＜0.05.

Abbreviations: AB, atherosclerosis burden; BRAs, baroreceptor-resident arteries; CI, confidence interval; TAB, total atherosclerosis burden.

The possible explanations for this novel hemodynamic connection are bidirectional. On one hand, higher TAB of BRAs portended lower night-to-day BP dipping ratios¹²⁾, while coronary arteries might be especially susceptible to atherosclerosis when BP dipping was blunted^{15, 27)}. On the other hand, coronary atherosclerosis might impair BP regulation through the baroreflex similar to the atherosclerosis of BRA. Animal studies found that baroreceptors at the origins of the coronary circulation could elicit reflex vasodilatation, just like the feedback control from systemic arterial baroreceptors at BRAs²⁸⁾. Further research is warranted to verify the hemodynamic link between TAB of BRAs and coronary atherosclerosis and clarify the underlying mechanism. Furthermore, it should be acknowledged that night-to-day BP dipping ratios were far from the whole foundation of the associations between TAB of BRAs and coronary atherosclerosis because TAB of BRAs had a significant indicative value for coronary AB, independent of the limited set of 24-hour BP characteristics measured in this study (Table 2).

Previously, the TAB of BRAs was formulated by us to represent the impairments of atherosclerosis on baroreflex-mediated BP regulation, considering the specific circumference-based scoring methodology targeting particular arterial segments. We found strong associations between TAB of BRAs and night-to-day BP dipping ratios, independent of the general atherosclerosis condition of cervicocephalic arteries¹²⁾. In the present study, we further provided evidence that the role of TAB of BRAs in impairing baroreflex function beyond reflecting the systematic atherosclerosis condition might strengthen the unique relationship between TAB of BRAs and coronary AB. These findings have several clinical implications. At first, evaluating TAB of BRAs with regularly performed CTA of brain-supplying arteries after ICVD would efficiently facilitate determining patients with heavy coronary AB, even when there are no cardiac symptoms or medical history. The indicative value would be greater than the ABs of the intracranial, cervical, and aortic arteries. Better identifying patients with high coronary risk would be of great value to comprehensively improve the prognosis of patients with ICVD. Second, the new link between atherosclerosis of the brain- and heart-supplying arteries, along with its potential hemodynamic basis, would lead to a deeper understanding of the complicated interplay of BP and atherosclerosis. New therapeutic strategies might be developed accordingly, further promoting the health of the circulation system.

There are limitations to this hypothesis-generating study. First, this is a cross-sectional analysis based on a single-center patient registry. Only patients with ICVD with ≥ 3 vascular risk factors or evidence of atherosclerosis were eligible for our patient registry, assuming that they would have a higher risk of vascular risk and might benefit more from the early identification of heavy coronary AB. In consequence, male predominance, and the serious atherosclerosis of coronary and brain-supplying arteries in our study subjects would introduce selection biases. Furthermore, all participants were East Asians, whose atherosclerosis characteristics would be different from those of other ethnic groups. For example, they would be more susceptible to intracranial atherosclerosis. More efforts would be needed to test the robustness and generalizability of our findings. No causal inference about the relationship among TAB of BRAs, night-to-day BP dipping ratios, and coronary AB could be made without further prospective studies. Second, although CTA was one of the most accurate non-invasive imaging methods to evaluate the atherosclerosis of both brain- and heart-supplying arteries, its sensitivity, and specificity were not perfect²⁹⁾. Third, a lot of 24-hour BP characteristics could be derived from ABPM, but only the most common measurements of BP level and variability were involved in this analysis³⁰⁾. In addition, the ABPM was performed only once for 24 hours. Thus, it was quite likely that the 24-hour BP characteristics had not been fully captured in our study. Moreover, there were plenty of influencing factors on the 24-hour BP characteristics that could hardly be fully measured and controlled. Although we had adjusted for antihypertensive therapy when ABPM was performed, the specific types, and doses of antihypertensive drugs were not recorded. Fourth, the pathophysiological implications of the TAB of BRAs have not been fully determined, and better indices should be developed in the future.

Conclusion

TAB of BRAs independently predicted coronary AB in patients with ICVD, offering more indicative power than general atherosclerosis characteristics of brain-supplying arteries. This new link between the brain- and heart-supplying arteries might be partially based on the significant correlation of night-to-day BP dipping ratios with both the TAB of BRAs and coronary AB. Evaluating the TAB of BRAs would enhance the efficiency of identifying patients with ICVD with severe coronary atherosclerosis and provide new routes to improve the estimation and management of overall vascular risk after ICVD.

Acknowledgements and Notice of Grant Support

We acknowledged Sufang Xue for obtaining the patient’s consent, and Chengbei Hou for addressing the statistical issues. This work was supported by grants from the Beijing Municipal Natural Science Foundation (No. 7212049).

Conflict of Interest

None.

Footnotes

Abbreviations in the text:

AB, atherosclerosis burden

ABPM, ambulatory blood pressure monitoring

BP, blood pressure

BRAs, baroreceptor-resident arteries

CT, computed tomography

CTA, computed tomography angiography

ICVD, ischemic cerebrovascular disease

SD, standard deviations

TAB, total atherosclerosis burden

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