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Advances in Understanding the Pathophysiology of Lacunar Stroke : A Review

• 1 Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston
• 2 Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston
• 3 Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
• Comment & Response The Importance of Blood Pressure Gradients in the Brain : Cerebral Small Vessel Disease J. David Spence, MD JAMA Neurology

Importance   Stroke is the second leading cause of death in the world, and nearly one-third of ischemic strokes are lacunar strokes (LSs) or small subcortical infarcts. Although smaller in size, they create large problems, leaving many patients with intellectual and physical disabilities. Because there are limitations in understanding the underlying pathophysiology of LS, the development of novel therapies has been slow.

Observations   When the term lacune was described in the 1800s, its underlying pathophysiological basis was obscure. In the 1960s, C. Miller Fisher, MD, performed autopsy studies that showed that vessels supplying lacunes displayed segmental arteriolar disorganization, characterized by vessel enlargement, hemorrhage, and fibrinoid deposition. For these pathologic changes, he coined the term lipohyalinosis . Since that time, few attempts have been made to reconcile this pathologic description with modern mechanisms of cerebral small vessel disease (CSVD). During the past 6 years, progress has been made in understanding the clinical mechanisms, imaging characteristics, and genetic basis of LS.

Conclusions and Relevance   Questions persist regarding the order of events related to the initiation and progression of CSVD, how LS is related to other sequelae of CSVD, and whether LS is part of a systemic disease process. The relative roles of aging, oxidative stress, mechanical stress, genetic predisposition, and other vascular risk factors should be further studied, especially in the era of widespread antihypertensive use. Although understanding of endothelial dysfunction has increased, future work on the role of media and adventitial dysfunction should be explored. Recent advances in mapping the brain vasculome may generate new hypotheses. The investigation of new therapeutic targets, aimed at reversing CSVD processes and promoting neural repair after LS, depends upon further understanding these basic mechanisms.

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Regenhardt RW , Das AS , Lo EH , Caplan LR. Advances in Understanding the Pathophysiology of Lacunar Stroke : A Review . JAMA Neurol. 2018;75(10):1273–1281. doi:10.1001/jamaneurol.2018.1073

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Lacunar stroke: mechanisms and therapeutic implications

Affiliations.

• 1 Department of Neurology, Brown University Warren Alpert Medical School, Providence, Rhode Island, USA [email protected].
• 2 Department of Radiology, NYU Langone Health, New York, New York, USA.
• 3 Department of Neurology, NYU Langone health, New York, New York, USA.
• 4 Department of Neurology, Brown University Warren Alpert Medical School, Providence, Rhode Island, USA.
• 5 Department of Neurology, Duke Medicine, Durham, North Carolina, USA.
• 6 Department of Neurology, Columbia University Medical Center, New York, New York, USA.
• 7 Department of Neurology, University of Utah Hospital, Salt Lake City, Utah, USA.
• PMID: 34039632
• DOI: 10.1136/jnnp-2021-326308

Lacunar stroke is a marker of cerebral small vessel disease and accounts for up to 25% of ischaemic stroke. In this narrative review, we provide an overview of potential lacunar stroke mechanisms and discuss therapeutic implications based on the underlying mechanism. For this paper, we reviewed the literature from important studies (randomised trials, exploratory comparative studies and case series) on lacunar stroke patients with a focus on more recent studies highlighting mechanisms and stroke prevention strategies in patients with lacunar stroke. These studies suggest that lacunar stroke is a heterogeneous disease with various mechanisms, including most commonly lipohyalinosis and less commonly atheromatous disease and cardioembolism, highlighting the importance of a careful review of brain and neurovascular imaging, a cardiac and systemic evaluation. A better understanding of pathomechanisms of neurological deterioration may lead to investigating the utility of novel treatment strategies and optimisation of short-term antithrombotic treatment strategies to reduce the risk of neurological deterioration and prevent long-term disability in patients with lacunar stroke.

Keywords: stroke.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

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Case Study – Lacunar Strokes

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Improving Clinical Detection of Acute Lacunar Stroke

Francesco arba.

1 From the Stroke Unit, AOU Careggi, Florence, Italy (F.A.)

2 Division of Neuroimaging Sciences, Brain Research Imaging Centre, University of Edinburgh, United Kingdom (G.M., J.M.W.)

3 Brain Research Imaging Centre, SINAPSE Collaboration, United Kingdom (G.M., J.M.W.)

4 Centre for Clinical Brain Sciences, University of Edinburgh, Western General Hospital, United Kingdom (G.M., P.S., J.M.W.)

Stephen Phillips

5 Division of Neurology, Department of Medicine, Dalhousie University and Nova Scotia Health Authority, Halifax, Nova Scotia, Canada (S.P.).

Peter Sandercock

Joanna m. wardlaw, associated data.

Supplemental Digital Content is available in the text.

Background and Purpose—

We aim to identify factors associated with imaging-confirmed lacunar strokes and improve their rapid clinical identification early after symptom onset using data from the IST-3 (Third International Stroke Trial).

Methods—

We selected patients likely to have lacunar infarcts as those presenting with: Oxfordshire Community Stroke Project lacunar syndrome; a random sample with National Institutes of Health Stroke Scale (NIHSS) score <7; and recent lacunar infarct identified on imaging by IST-3 central blinded expert panel. An independent reviewer rated brain scans of this sample and classified visible infarcts according to type, size, and location. We investigated factors associated with presence of lacunar infarct on a 24 to 48 hour follow-up scan using multivariable logistic regression and calculated sensitivity and specificity of Oxfordshire Community Stroke Project alone and in combination with NIHSS score <7.

Results—

We included 568 patients (330 lacunar syndrome; 147 with NIHSS score <7; 91 with lacunar infarct on baseline imaging, numbers exclude overlaps between groups), mean (±SD) age, 73.2 (±13.6) years, 316 (56%) males, and median NIHSS score 5 (IQR, 4–8). On 24 to 48 hour scan, 138 (24%) patients had lacunar infarcts, 176 (31%) other infarct subtypes, 254 (45%) no visible infarct. Higher baseline systolic blood pressure (odds ratio, 1.01 [95% CI, 1.01–1.02]) and preexisting lacunes (odds ratio, 2.29 [95% CI, 1.47–3.57) were associated with recent lacunar infarcts. Sensitivity and specificity of lacunar syndrome was modest (58% and 45%, respectively), but adding NIHSS score <7 increased specificity (99%), positive and negative predictive values (97% and 87%, respectively).

Conclusions—

In patients presenting within 6 hours of stroke onset, adding NIHSS score <7 to Oxfordshire Community Stroke Project lacunar syndrome classification may increase specificity for identifying lacunar stroke early after stroke onset. Our findings may help selection of patients for clinical trials of lacunar stroke and should be validated externally.

Registration—

URL: http://www.controlled-trials.com/ ; Unique identifier: ISRCTN25765518.

Stroke is the leading cause of disability in the world and a frequent cause of death, with ischemic stroke representing the majority of stroke subtypes. Lacunar stroke accounts for around 20% to 30% of ischemic strokes. 1 Traditionally, lacunar stroke is thought to result from disease of a small perforating artery, with typical clinical syndromes, 2 often leaving a small hole (ie, lacune) long term in the subcortical white matter. Given their distinct physiopathology, 3 prompt identification of lacunar strokes may guide subsequent treatment and management.

The gold standard to identify acute lacunar strokes is magnetic resonance (MR) with diffusion-weighted imaging. 4 However, MR is not widely available for acute stroke assessment, and computed tomography (CT), due to its accessibility, cost, and few contraindications is routinely used for acute stroke assessment. Unfortunately, small acute infarcts can be difficult to identify on CT and diagnosing patients with lacunar infarct in the acute stroke assessment may be challenging.

According to the Oxfordshire Community Stroke Project (OCSP) classification, 5 the lacunar syndrome may be diagnosed with a combination of motor and sensory deficits, or with typical clinical syndromes (eg, dysarthria/clumsy hand). The OCSP classification has good interobserver reliability, may provide fast information about etiology and prognosis of acute stroke, and is easy to communicate among physicians. 6 , 7 However, studies showed that while OCSP classification correctly identified nonlacunar strokes subtypes, sensitivity and specificity in identifying imaging-confirmed lacunar infarcts were inconsistent, particularly in the early hours after stroke onset. 8 – 10

The IST-3 (Third International Stroke Trial) 11 was a large multicentre trial of r-tPA (recombinant tissue-type plasminogen activator) in patients aged over 18 with any subtype of acute ischemic stroke. In a subgroup of the IST-3 trial, we tested the following: (1) factors associated with lacunar infarction on 24 to 48 hours follow-up CT scan; (2) OCSP classification in identifying subsequent lacunar infarction on 24 to 48 hour follow-up CT scan; and (3) combined OCSP and National Institutes of Health Stroke Scale (NIHSS) in identifying lacunar infarction on 24 to 48 hour follow-up CT scan.

Population and Procedures

The authors declare that all supporting data are available within the article (and the Data Supplement ). IST-3 has a data access policy managed by contact with the investigators through University of Edinburgh website. We analyzed data from patients enrolled in the IST-3 trial. Briefly, IST-3 was a randomized, open-label trial of intravenous recombinant tissue-type plasminogen activator (0.9 mg/kg) versus control given within 6 hours of onset in patients with symptoms and signs of acute stroke in whom brain imaging had excluded hemorrhage or nonstroke lesions. 11 Clinical examination included NIHSS and 8 easily recognizable clinical signs. The randomization system assigned the OCSP subtype according to a validated computer algorithm using such clinical signs, independently of the clinicians OCSP clinical syndrome diagnosis, to minimize bias in the assignment of the syndrome by knowledge of the imaging appearances by the treating clinician. All patients had prerandomization brain imaging with CT or MR, and a follow-up scan was performed 24 to 48 hours after randomization in all patients. All scans were assessed by a central expert panel blinded to clinical information. 12

For the present study, we selected patients who were more likely to have a new lacunar stroke as having one or more of the following characteristics:

• Patients with clinical diagnosis of lacunar stroke syndrome (LACS) at the time of study enrolment.
• Patients with radiological diagnosis of recent lacunar infarct on the follow up (24–48 hours) scan according to the blinded expert panel ratings.
• Patients with NIHSS score <7 as stroke severity considered less likely to have a large vessel occlusion and more likely to have lacunar stroke 13 , 14 randomly selected from the 817 patients with NIHSS score <7 of whole IST-3 cohort. The selection was made manually with random patient anonymous number.

Each patient was present only once in each subgroup.

The IST-3 study was approved by local ethics committees and other regulatory bodies of all participating hospitals and institutions. All patients, or a relative if the patient lacked capacity, provided written consent.

Imaging Analysis

In this analysis, we only used CT scans. All scans had already been scored for acute stroke and prestroke changes (eg, leukoaraiosis, atrophy, old stroke lesions) by the IST-3 expert panel, masked to clinical details. For the present analysis, a stroke neurologist, trained in CT readings (Dr Arba), independently rated all the prerandomization and follow-up scans blinded to all clinical information except the affected side and identified the supposed culprit ischemic lesion, when visible. A new lacunar infarct was defined as a round or ovoid-shaped hypodensity in the supratentorial subcortical white matter with maximum axial diameter ≤20 mm, not visible on or with increased hypodensity compared with the baseline scan. Supratentorial location of lacunar infarcts was categorized into thalamic, internal capsule, lentiform nucleus, and centrum semiovale. We excluded from the present analysis infratentorial new lacunar infarcts because of reduced CT quality in the posterior fossa. Recent basal ganglia infarcts with axial diameter >20 mm were defined as striatocapsular infarcts. Other infarct types were classified according to the IST-3 classification based on arterial territories and the amount of the territory affected. 12 Two experienced neuroradiologists (Drs Wardlaw and Mair) cross-checked the neurologist’s scan readings and resolved uncertain cases.

Statistical Analysis

We described the characteristics of the study population using descriptive statistics. To test differences between groups, we used χ 2 Pearson test, Mann-Whitney U test or Kruskal-Wallis, ANOVA test as appropriate. We described differences among lacunar infarcts visible at the 24 hours scan according to lesion shape, location; and investigated factors associated with presence of lacunar infarct at the follow-up scan using multivariable logistic regression analysis adjusted for age, sex, NIHSS, and relevant variables with P <0.1 on univariable analysis. In the multivariable analysis, we considered a P value <0.05 as statistically significant.

We calculated sensitivity, specificity, positive and negative predictive values of OCSP lacunar classification in detecting visible lacunar stroke on the follow-up scan. We calculated a best scenario as the hypothetic case assuming that all patients with no lesion on the follow-up scan in fact had a lacunar infarct, and a worst scenario as the hypothetic case assuming that all patients with no lesion on the follow-up scan in fact had a nonlacunar infarct, and calculated sensitivity, specificity, positive and negative predictive values of OCSP lacunar classification (LACS) accordingly.

We therefore calculated a combined measure as follows: patients with OCSP consistent with both LACS and NIHSS score <7, scored=1, otherwise (nonlacunar OCSP or NIHSS score ≥7) scored=0. We also calculated the best scenario and the worst scenario sensitivity, specificity, positive predictive value and negative predictive values of the combined measure. Statistical analysis was carried out using SPSS for Windows (version 23.0; SPSS, Armonk, NY, IBM Corp).

From the whole IST-3 population (N=3035), we retrieved 332 patients with LACS, 92 patients with diagnosis of recent lacunar infarction on 24 to 48 hour scans according to the IST-3 expert radiological panel, and 147 (18%) randomly selected patients with NIHSS score <7 (N=817), giving a total of 571 individual patients with no overlap between the 3 groups. Three patients had no available CT scan and were therefore excluded from the analysis. This left 568 patients for the present study. A detailed flowchart of study population is shown in Figure. Overall, OCSP was as follows: total anterior circulation syndrome=35 (6%), PACS=161 (28%), LACS=330 (58%), POCS=42 (8%).

Diagram of the study population. CT indicates computed tomography; LACS, lacunar syndrome; NIHSS, National Institutes of Health Stroke Scale; OCSP, Oxfordshire Community Stroke Project; PACS, partial anterior circulation syndrome; POCS, posterior circulation syndrome; and TACS, total anterior circulation syndrome.

Characteristics of patients from each of the 3 groups are shown in Table ​ Table1. 1 . Patients with expert IST-3 radiological panel-diagnosed recent lacunar infarction had higher median NIHSS compared with LACS and random NIHSS score <7 sample (8 versus 6 versus 4; P <0.001), and more frequently presented with total anterior circulation syndrome syndrome compared with patients from the random NIHSS score <7 (26% versus 8%; P <0.001), whereas most patients with a clinical PACS syndrome were from the random NIHSS score <7 sample subgroup (76% versus 55%; P <0.001). There were no differences regarding prestroke radiological characteristics of leukoaraiosis or atrophy severity or presence of prior infarct. Among patients with LACS presentation (N=330, 58%), on the follow-up scan, 148 (45%) had no visible infarct, 80 (24%) had lacunar infarct, 102 (31%) had other infarct type. Lacunar infarct was more frequent in patients with higher NIHSS (6 for lacunar, 6 for other infarct type, 5 for no visible infarct; P <0.001), higher baseline glucose (mean, 132.9 mg/dL for lacunar; 125.6 mg/dL for other infarct type; 117.5 mg/dL for no visible infarct; P =0.021), higher systolic blood pressure (mean 165.1 mm Hg for lacunar; 151.1 mm Hg for other infarct type; 153.2 mm Hg for no visible infarct; P =0.016) and presence of preexisting lacunes (41% for lacunar; 25% and 26 % for other infarct type and no infarct, respectively, P =0.022; Data Supplement ).

Clinical and Radiological Characteristics of the Study Population According to the Subgroup

In the whole study population, we identified 138 (24%) patients with recent lacunar infarct, 176 (31%) with other infarct type, and 254 (45%) with no visible new infarct (Table ​ (Table2). 2 ). Patients with any recent infarct had higher NIHSS scores (median 6 for other infarct type and lacunar infarcts, 5 for no infarct; P <0.001), whereas those with lacunar infarct had higher baseline systolic blood pressure (mean 160.8 mm Hg for lacunar infarct, 152.1 mm Hg for other infarct type, 154.3 for no visible infarct; P =0.016) and were randomized at later times (median 285 minutes for lacunar infarct, 264 minutes for other infarct type, 267 no infarct; P =0.046). Patients with recent lacunar infarcts had less severe leukoaraiosis grade (13% versus 21%, 9% for other infarct than lacunar; P =0.004) but more frequently evidence of preexisting lacunes (44% versus 21% for other infarct type and 26% for no infarct; P <0.001). After adjustment for confounders, we found that systolic blood pressure (odds ratio [OR], 1.01 [95% CI, 1.01–1.02]) and preexisting lacunes (OR, 2.29 [95% CI, 1.47–3.57]) were associated with lacunar infarct at follow-up. In the LACS patients subgroup, higher NIHSS (OR, 1.17 [95% CI, 1.03–1.32]), baseline glucose (OR, 1.01 [95% CI, 1.00–1.02]; P =0.018), systolic blood pressure (OR, 1.02 [95% CI, 1.01–1.03]), and preexisting lacunes (OR, 1.89 [95% CI, 1.06–3.38]) were associated with presence of lacunar infarct, whereas higher NIHSS (OR, 1.32 [95% CI, 1.15–1.50]) and preexisting lacunes (OR, 3.06 [95% CI, 1.50–6.24]) were associated with presence of lacunar infarct in non-LACS patients (Table ​ (Table3 3 ).

Characteristics of Study Population According to Radiological Findings of the Independent Reviewer at the Follow-Up Scan

Multivariable Logistic Regression Showing Factors Associated With Presence of Lacunar Infarct on Follow-Up CT Scan

Among 138 patients with recent lacunar infarct, 86 (63%) had the infarct located in the basal ganglia (32 thalamus, 55 internal capsule/lentiform nuclei, 9 internal borderzone), whereas 52 (37%) in the centrum semiovale; 68 (49%) had round-shaped infarct and 70 (51%) ovoid; 97 (70%) had an axial diameter ≤15 mm and 41 (30%) an axial diameter from 15 to 20 mm ( Data Supplement ). Higher NIHSS was associated with larger lesion size; whereas patients with lesions ≤15 mm were older and more frequently had hypertension. Lacunar infarcts in the centrum semiovale had higher baseline systolic and diastolic blood pressure ( Data Supplement ). Further results in patients with subcortical versus lacunar infarcts, lacunar versus no infarct, follow-up scans of no-LACS patients and comparison of baseline factors associated with lacunar stroke in young and very old patients are shown in the Data Supplement .

LACS correctly identified 80/138 (58%) lacunar infarcts. Of the 59 (42%) remaining patients, 8 (6%) were classified as total anterior circulation syndrome, 36 as PACS (26%), 15 (11%) as POCS. Out of the 8 patients classified as total anterior circulation syndrome, 5 had old infarcts.

Table ​ Table4 4 shows sensitivity, specificity, positive predictive value and negative predictive value of LACS. Overall, accuracy of either LACS and NIHSS score <7 alone in diagnosing lacunar infarct was modest (sensitivity, 0.58; specificity, 0.45; sensitivity, 0.58; specificity, 0.31, respectively). If all patients with no visible infarct at the follow-up scan had a lacunar infarct (best scenario), positive predictive value of LACS moved from 0.27 to 0.71 and negative predictive value fall from 0.75 to 0.31; whereas if all patients with no visible infarct at the follow-up scan did not have a lacunar infarct (worst scenario), accuracy of LACS remained almost the same (positive predictive value 0.25 and negative predictive value 0.75). Similarly, sensitivity and positive predictive value of NIHSS score <7 increased with the best scenario and remained the same in the worst scenario.

Sensitivity and Specificity for Lacunar Syndrome, NIHSS Score <7, and Lacunar Score in Detecting Lacunar Infarct

A total of 79 out of 138 patients fulfilled the combined LACS+NIHSS score <7 and did have a recent lacunar infarct. In the whole study population, the combined measure showed modest sensitivity (0.55) but excellent specificity (0.99), positive and negative predictive values (0.97, 0.98, respectively), which were confirmed in the hypothetical worst scenario. Sensitivity and negative predictive value of the combined LACS+NIHSS score <7 fell to 0.20 and 0.34 in the best scenario, but specificity and positive predictive value remained excellent (0.98 and 0.97, respectively).

In this population of likely lacunar stroke selected from a large multicenter clinical trial, we found that one-fourth of patients had a relevant lacunar infarct as seen by follow-up CT scan, whereas almost a half of patients did not have imaging evidence of infarction. Higher baseline blood pressure and preexisting lacunar infarcts were associated with presence of new lacunar infarct on the follow-up CT scan. Although OCSP had poor sensitivity and specificity for detection of lacunar infarct, a combined clinical measure using LACS and NIHSS remarkably improved specificity.

Identification of lacunar stroke with plain CT is challenging and may potentially lead to false negative findings. Consistent with previous studies that showed negative CT scan in 35% and 50% of patients with lacunar stroke, 10 , 15 , 16 we found a negative CT scan in 45% of our population. In line with previous studies, 17 , 18 the characteristics of younger and older patients with lacunar infarcts were slightly different to those of the general population. We identified clinical factors associated with presence of a new lacunar lesion on follow-up CT including higher systolic blood pressure in the whole study population, NIHSS score <7, and higher blood glucose in the LACS subgroup. Similar to our results, previous studies identified systolic blood pressure as variably associated with subsequent lacunar infarction, 19 , 20 and diabetes mellitus but not baseline blood glucose was also associated with lacunar infarction. 21 Among radiological factors, preexisting lacunes were associated with a new lacunar infarction both in LACS and non-LACS populations. This is in keeping with another study that found leukoaraiosis more common in patients with lacunar strokes and silent brain infarction, 22 suggesting a common origin and risk factors of lacunar lesions throughout the brain.

Similar to previous studies, OCSP alone missed around a half of lacunar strokes investigated with CT, 15 , 23 with low sensitivity and specificity, underlining the limits of CT in diagnosing small cerebral infarcts but also the modest accuracy of OCSP. 22 , 24 On the other hand, we found that low stroke severity intended as NIHSS score <7 was not able to reliably identify lacunar strokes. However, we showed that combining clinical features assessed with OCSP and stroke severity may improve early identification of subsequent lacunar strokes. While the sensitivity of our combined measure was still modest, the specificity remarkably increased compared with LACS and NIHSS alone. In other words, with our combined clinical assessment, we were able to exclude strokes other than lacunar. Considering the limited capacity of CT scan in diagnosis of lacunar stroke, we hypothesized a worst scenario (ie, all negative follow-up scans were not lacunar strokes) and a best scenario (ie, all negative follow-up scans were lacunar strokes), and specificity of the combined measure remained the approximately same in both scenarios. This finding highlighted the importance of a careful clinical examination and assessment of acute stroke, particularly for suspected lacunar stroke subtype, since also angio-CT and perfusion CT do not provide additional information in diagnosis of lacunar infarction during the acute assessment. 25 , 26 MR could identify a greater proportion of stroke compared with CT scan; however, a significant proportion of false negative findings remains. 26 – 29 Particularly for future pragmatic trials targeted on lacunar stroke, a practical screening tool allowing reliable identification of lacunar stroke with limited use of MR imaging would be useful.

Our study has limits. The use of CT rather than MR for diagnosis of ischemic lesion may underestimate the real burden of new ischemic lesions and we probably missed useful information, although MR is not perfect in this respect 29 either, and not all the subcortical small cerebral infarcts consistent with lacunar infarcts may evolve into an established lacune. 30 , 31 However, the specificity and positive predictive value of the combined measure was excellent in the best and worse scenario, lending support to a careful clinical examination of patients with suspected lacunar stroke. As a subgroup analysis of a randomized controlled trial, we cannot exclude an effect of r-tPA, on the fate of the ischemic lesion; however, we did not find relevant differences in r-tPA use among patients with different infarct type. The NIHSS cutoff we adopted was arbitrary, although based on previously reported probability to exclude a large vessel occlusion 13 and data from a large study on lacunar strokes. 14 However, different NIHSS thresholds may be explored with statistical methods to increase sensitivity of the combined measure. Again, our results arise from a retrospective study and are therefore hypothesis generating, and need external validation in other cohorts, possibly using MR as imaging technique to identify a greater number of lacunar infarcts.

In conclusion, we showed that in patients presenting within 6 hours of symptom onset with clinical features suggestive of a lacunar stroke syndrome, systolic blood pressure and the presence of preexisting lacunes on the first CT scan were associated with an increased likelihood of detecting an acute lacunar infarct on a CT scan repeated 24 to 48 hours later. An indicator combining the clinical features of a lacunar syndrome (according to the OCSP classification) with stroke severity (defined as NIHSS score <7), increased the specificity of clinical lacunar stroke diagnosis. If validated, our results may find practical application in the diagnosis of hyperacute lacunar stroke and help select patients for clinical trials targeted at lacunar stroke.

Acknowledgments

The IST-3 (Third International Stroke Trial) collaborative group thanks all patients who participated in the study. We gratefully acknowledge the members of the trial steering committee, image reading panel, national coordinators (Appendices I and II in the Data Supplement ).

Sources of Funding

IST-3 (Third International Stroke Trial) was funded from a large number of sources (see Appendix II in the Data Supplement ) but chiefly the UK Medical Research Council (MRC G0400069 and EME 09-800-15) and the UK Stroke Association. The work was supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK, the British Heart Foundation Centre for Research Excellence Award III (RE/18/5/34216), the European Union Horizon 2020, PHC-03-15, project No 666881, ‘SVDs@Target’, the Fondation Leducq Transatlantic Network of Excellence for the Study of Perivascular Spaces in Small Vessel Disease, ref no. 16 CVD 05, and the Row Fogo Centre for Research into Ageing and the Brain, Ref No: AD.ROW4.35. BRO-D.FID3668413. Dr Sandercock received grants from UK Medical Research Council and from UK Stroke Association. Boeringher and Ingheleim donated the drug and the placebo for the pilot phase of the IST-3 study.

Disclosures

Supplementary material.

Presented in part at the European Stroke Organisation Conference, Milan, Italy, May 22–24, 2019.

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Open Access

Peer-reviewed

Research Article

Correlation between novel inflammatory markers and carotid atherosclerosis: A retrospective case-control study

Roles Conceptualization, Formal analysis, Investigation, Writing – original draft

Affiliation Department of General, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China

Roles Funding acquisition, Supervision

Roles Validation

Roles Conceptualization, Funding acquisition, Supervision, Writing – review & editing

* E-mail: [email protected] (YL); [email protected] (BQ)

• Man Liao, 
• Lihua Liu, 
• Lijuan Bai, 
• Ruiyun Wang, 
• Yun Liu, 
• Liting Zhang, 
• Jing Han, 
• Yunqiao Li, 

• Published: May 29, 2024
• https://doi.org/10.1371/journal.pone.0303869
• Peer Review
• Reader Comments

Carotid atherosclerosis is a chronic inflammatory disease, which is a major cause of ischemic stroke. The purpose of this study was to analyze the relationship between carotid atherosclerosis and novel inflammatory markers, including platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to neutrophil ratio (PNR), neutrophil to lymphocyte platelet ratio (NLPR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI), in order to find the best inflammatory predictor of carotid atherosclerosis.

We included 10015 patients who underwent routine physical examinations at the physical examination center of our hospital from January 2016 to December 2019, among whom 1910 were diagnosed with carotid atherosclerosis. The relationship between novel inflammatory markers and carotid atherosclerosis was analyzed by logistic regression, and the effectiveness of each factor in predicting carotid atherosclerosis was evaluated by receiver operating characteristic (ROC) curve and area under the curve (AUC).

The level of PLR, LMR and PNR in the carotid atherosclerosis group were lower than those in the non-carotid atherosclerosis group, while NLR, NLPR, SII, SIRI and AISI in the carotid atherosclerosis group were significantly higher than those in the non-carotid atherosclerosis group. Logistic regression analysis showed that PLR, NLR, LMR, PNR, NLPR, SII, SIRI, AISI were all correlated with carotid atherosclerosis. The AUC value of NLPR was the highest, which was 0.67, the cut-off value was 0.78, the sensitivity was 65.8%, and the specificity was 57.3%. The prevalence rate of carotid atherosclerosis was 12.4% below the cut-off, 26.6% higher than the cut-off, and the prevalence rate increased by 114.5%.

New inflammatory markers were significantly correlated with carotid atherosclerosis, among which NLPR was the optimum inflammatory marker to predict the risk of carotid atherosclerosis.

Citation: Liao M, Liu L, Bai L, Wang R, Liu Y, Zhang L, et al. (2024) Correlation between novel inflammatory markers and carotid atherosclerosis: A retrospective case-control study. PLoS ONE 19(5): e0303869. https://doi.org/10.1371/journal.pone.0303869

Editor: Elvan Wiyarta, Universitas Indonesia Fakultas Kedokteran, INDONESIA

Received: January 11, 2024; Accepted: May 1, 2024; Published: May 29, 2024

Copyright: © 2024 Liao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting information files.

Funding: The study was supported by the National Natural Science Foundation of China (Grant No.81571373, No.81601217, No.82001491), Natural Science Foundation of Hubei Province of China (Grant No. 2017CFB627), Health Commission of Hubei Province scientific research project (Grant No. WJ2021M247) and Scientific Research Fund of Wuhan Union Hospital (Grant No.2019). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Cardiovascular was always the main cause of premature death and rising healthcare costs [ 1 , 2 ]. From 1990 to 2019, the total number cardiovascular disease cases has nearly doubled globally, while the number of cases and deaths from peripheral artery disease tripled [ 3 ]. Atherosclerosis, a major pathological process in most cardiovascular diseases, which may occuar as early as childhood and remain latent in the body for a long time [ 4 ]. Early detection of arterial disease in seemingly healthy individuals focuses on the peripheral arteries, especially the carotid arteries [ 5 ]. In clinical practice, carotid atherosclerosis (CAS) is the earlier and most easily detected form of atherosclerosis. Besides, carotid atherosclerotic plaque is an independent risk factor for stroke and coronary heart disease [ 6 ]. Atherosclerosis is widely recognized as a chronic inflammatory disease of the blood vessels caused by the accumulation of low density lipoprotein cholesterol [ 7 ]. Chronic inflammation is a low-grade, non-infectious, systemic inflammatory state that is associated with age, psychology, environment, lifestyle, and the resolution of acute inflammation [ 8 ]. Chronic inflammation is associated with endothelial dysfunction, leukocyte recruitment, transformation of monocytes into macrophages and eventually into foam cells, smooth muscle cell migration and other processes [ 7 ]. Chronic inflammation is involved in the whole process of the occurrence and development of atherosclerosis and is the core of atherosclerosis.

In clinical practice, peripheral blood cell count is often used as a predictor and evaluation factor for the severity of inflammation and treatment outcome of acute inflammatory diseases, such as lung infection and sepsis. Platelet to lymphocyte ratio (PLR), neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), platelet to neutrophil ratio (PNR), neutrophil to lymphocyte platelet ratio (NLPR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) are commonly used blood cell count derived values in clinical practice, also known as novel inflammatory markers. These novel inflammatory markers have repeatedly demonstrated their potential value in the early prediction and prognosis of cardiovascular disease [ 9 – 14 ]. However, the relationship between these readily available inflammation markers and atherosclerosis, especially carotid atherosclerosis, has not yet been clear, which nedds further research to be confirmed.

Therefore, this study aimed to explore the correlation between novel inflammatory markers and CAS, in order to find a better early warning indicator of clinical carotid atherosclerosis.

Study design

This is a retrospective case-control study. All methods were carried out in accordance with relevant guidelines and regulations and no important aspects of the study have been omitted. Patients’ personal information is being kept confidentially. The study complies with the Declaration of Helsinki and the ethical approval of the study was obtained from the Ethics Committee of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology at Sep. 4 th 2023 ([2023]ID:0611). The ethics committee exempted the need for informed consent.

In this study, we included 14,115 patients who underwent routine physical examinations at our physical examination center from January 2016 to December 2019. The first time we accessed the data was on September 10, 2023. The following were the inclusion criteria for this study: (1) Age>18 years; (2) People who have underwent carotid vascular ultrasound. The exclusion criteria of participants were as follows: (1) Receiving or being receiving anti-inflammatory therapy within 6 months; (2) Critically ill patients with unstable vital signs; (3) Have received or are receiving glucocorticoid therapy within 6 months; (4) Incomplete clinical data or incomplete personal information. After screening, a total of 10015 patients were included and divided into CAS group and non-CAS group according to diagnosis.

Collected clinical data and laboratory indicators and definition of inflammatory markers

Age, gender, height, and weight of the patient at admission were obtained from the hospital electronic system, and BMI was calculated according to BMI = weight/height ^2. Proper amount of venous blood was extracted by professional nurses with nursing qualification during the fasting period and sent to the laboratory for analysis to obtain white blood cell count (WBC), neutrophil count (NC), lymphocyte count (LC), monocyte count (MC), platelet (PLT), neutrophil percentage (NP), lymphocyte percentage (LP), monocyte percentage (MP), PLR, NLR, LMR, PNR, NLPR, SII, SIRI, AISI and biochemical index, such as aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), uric acid (UA), urea nitrogen (BUN), creatinine. The estimated glomerular filtration rate (eGFR) was calculated based on the modified MDRD equation. SIRI was defined as neutrophil count*monocyte count/lymphocyte count. SII was calculated using the formula: NLR*platele. AISI was calculated using the formula: (neutrophil count*monocyte count*platelet)/lymphocyte count. NLPR was calculated using the formula: neutrophil count*100/lymphocyte count*platelet. Comorbidity, smoking history and drinking history were obtained from the patient’s personal history.

Diagnostic criteria for carotid atherosclerosis

Carotid atherosclerosis is diagnosed in one of the following situations: (1) A clear history of atherosclerosis or revascularization treatment; (2) Carotid artery ultrasound showed atherosclerotic plaque or carotid intima-media thickness of 1.0mm or more [ 5 ].

Statistical analysis

Shapiro-Wilkstest is used to test whether the continuous variables obey normal distribution, and the continuous variables with normal distribution are represented by mean ± standard deviation (SD). Continuous variables that are not normally distributed are expressed as medians with interquartile range (IQR). The categorical variable is represented by number with percentages (%). ANOVA tests (conforming to normal distribution) and Kruskal-Wallis tests (non-conforming to normal distribution) were used for the differences between of continuous data among CAS and non-CAS. Chi-square test was used to compare the difference of Categorical data between patients with CAS and non-CAS. Logistic regression analysis was used to evaluate the correlation between various inflammatory indicators and CAS after adjusting factors such as age, gender, BMI, serum biochemical indicators and clinical diagnosis and other factors. In Logistic regression analysis, forward selection method was used to identify CAS risk factors. Finally, the efficiency of each inflammatory markers to CAS was evaluated by receiver operating characteristic (ROC) curve. P<0.05 was considered to be statistically significant. All statistical analyses and diagrams were done using SPSS (version 23.0) or R language.

Clinical baseline data

A total of 10015 patients aged 18–94 were enrolled in the study, including 1910 (19.1%) in the CAS group. Table 1 shows the baseline characteristics between the two groups. There were no significant differences in BMI, PLR and dyshepatia between the two groups (P>0.05). While age, gender, WBC, NC, LC, MC, PLT, NP, LP, MP, NLR, LMR, PNR, NLPR, SII, SIRI, AISI, AST, TG, TC, HDL_C, LDL_C, BUN, creatinine, eGFR, UA, smoking history, drinking history, renaldysfuncyion, hyperuricemia, fatty liver, dyslipidemia, hypertension, diabetes and osteoporosis were significantly different between the two groups(P<0.05).

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https://doi.org/10.1371/journal.pone.0303869.t001

Relationship between novel inflammatory markers and CAS

The relationship between novel inflammation markers and CAS was observed by spline smoothing plot, shown in Fig 1 . LMR, PNR were negatively correlated with CAS, while PLR, NLR, NLPR, SII, SIRI, AISI, NLPR were positively correlated with CAS.

A non- linear relationship between novel inflammation markers and carotid atherosclerosis after adjusting for age, gender, body mass index, aspartate aminotransferase, triglyceride, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, estimated glomerular filtration rate, uric acid, hypertension, diabetes, osteoporosis, fatty liver, smoking history, drinking history. CAS, carotid atherosclerosis; PLR, platelet to lymphocyte ratio; NLR, neutrophil to lymphocyte ratio; LMR, lymphocyte to monocyte ratio; PNR, platelet to neutrophil ratio; NLPR, neutrophil to lymphocyte platelet ratio; SII, systemic immune-inflammation index; SIRI, systemic inflammation response index; AISI, aggregate index of systemic inflammation.

https://doi.org/10.1371/journal.pone.0303869.g001

Logistic regression analysis of CAS

Univariate logistic regression analysis of the relationship between inflammatory markers and CAS showed the same difference as that between the two groups. Furthermore, after adjusting for many possible confounders such as age, sex, BMI, all inflammatory markers were statistically significant (P<0.05) with CAS. These infalmmatory markers have varying effects on CAS, and the risk value of NLPR is much higher than other markers (OR = 2.35). Their CAS risk value and forest plot were shown in Fig 2 .

Model 1 adjusted for none. Model 2 adjusted for age, sex, and body mass index. Model 3 adjusted for age, gender, body mass index, aspartate aminotransferase, triglyceride, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, estimated glomerular filtration rate, uric acid, hypertension, diabetes, osteoporosis, smoking history, drinking history. Forest plot of novel inflammatory markers for carotid atherosclerosis risk after adjusting for Model 3. PLR, platelet to lymphocyte ratio; NLR, neutrophil to lymphocyte ratio; LMR, lymphocyte to monocyte ratio; PNR, platelet to neutrophil ratio; NLPR, neutrophil to lymphocyte platelet ratio; SII, systemic immune-inflammation index; SIRI, systemic inflammation response index; AISI, aggregate index of systemic inflammation.

https://doi.org/10.1371/journal.pone.0303869.g002

The efficacy of inflammatory markers to predict CAS was assessed by ROC curve. After adjusting for confounding factors, there were still statistical differences in all inflammatory markers. The ROC curve to evaluate the effectiveness of the above markers in CAS diagnosis is shown in Table 2 and Fig 3 . The AUC values of NLR, SII, SIRI, AISI and NLPR were all in the range of 0.5–0.7. The highest AUC value for NLPR recognition of CAS is 0.67. And NLPR uses the adjusted predictive value of Model 3 to identify the AUC value of CAS as 0.91. The cut-off value calculated by Youden index was that NLPR was 0.78, that the sensitivity was 65.8%, and that the specificity was 57.3%. The prevalence rate of carotid atherosclerosis was 12.4% below the cut-off, 26.6% higher than the cut-off, and the prevalence rate increased by 114.5%.

PLR, platelet to lymphocyte ratio; NLR, neutrophil to lymphocyte ratio; LMR, lymphocyte to monocyte ratio; PNR, platelet to neutrophil ratio; NLPR, neutrophil to lymphocyte platelet ratio; SII, systemic immune-inflammation index; SIRI, systemic inflammation response index; AISI, aggregate index of systemic inflammation.

https://doi.org/10.1371/journal.pone.0303869.g003

https://doi.org/10.1371/journal.pone.0303869.t002

Subgroup analyses between NLPR and CAS

In order to study the CAS risk and interaction of inflammatory markers in people with different clinicopathological characteristics. We further analyzed six subgroups of NLPR and CAS risk indicators (hyperuricemia, fatty liver, dyslipidemia, hypertension, diabetes, osteoporosis). The results showed that NLPR had the highest OR value in population without lipid metabolism abnormalities ( Table 3 ). CAS were significantly associated with NLPR in all subgroups. The interaction among subgroups revealed that NLPR had an interaction with hyperuricemia, fatty liver, dyslipidemia, hypertension, diabetes and osteoporosis, and all of these disease subgroups significantly weakened the risk of NLPR for CAS.

https://doi.org/10.1371/journal.pone.0303869.t003

Novel inflammatory markers have been proven to be closely related to various diseases, and their easy availability has important clinical value. In this cross-sectional study, we analyzed the effect of multiple inflammatory markers on CAS, where NLR, SII, SIRI, AISI, NLPR remained significant after adjusting for multiple confounding factors. At the same time, this study further evaluated the value of various inflammatory markers in predicting CAS, among which NLPR had the largest AUC value in identifying CAS risk. Compared with other inflammatory markers, NLPR has a higher value for predicting CAS which may be the best inflammatory indicator for identifying atherosclerosis.

Chronic inflammation leads to atherosclerosis and cardiovascular disease. Neutrophils are the most numerous type of white blood cell and play a major role in inflammation. Although neutrophil count is primarily used as a biomarker for acute infection and inflammation, it has also been shown to accelerate chronic inflammation [ 15 ]. Monocyte-derived macrophages are important mediators in the atherosclerotic cascade and are associated with plaque formation through infiltration into the subendothelial layer. Subsequently, uptake of LDL-C complexes leads to the formation of foam cells. In addition to plaque formation, macrophages are involved in extracellular matrix remodeling by secreting pro-inflammatory cytokines and chemokines [ 16 ]. In our study, the number of neutrophils and monocytes increased in patients with CAS compared with non-CAS patients, indicating that the higher the number of neutrophils and monocytes, the higher the incidence of CAS. In contrast, lymphocytes slow the progression of atherosclerosis [ 14 ]. Our findings were the same, with a reduced number of lymphocytes in patients with CAS, suggesting that the higher the number of lymphocytes, the lower the incidence of CAS. Platelets play two main roles in atherosclerosis: platelets directly adhere to the blood vessel wall to promote plaque formation, and platelets then release inflammatory mediators and chemokines to promote leukocyte recruitment [ 17 ]. In our results, platelet counts were reduced in patients with CAS compared to non-CAS patients. The reason for this opposite situation may be that platelets have multiple roles in the formation of atherosclerosis, and in our study, the number of platelets alone was not significantly associated with the development of carotid atherosclerosis. In subsequent binary logistic regression analysis, there was no statistical difference between platelet count and CAS risk after adjusting for confounders.

In previous studies, we found that NLR, MLR, and PLR increase the risk of arterial stiffness [ 18 ]. In recent years, LMR, PNR, NLPR, SII, SIRI, AISI and other indicators have also proved their clinical significance in cardiovascular diseases. A small sample observational study showed that the novel inflammatory markers SIRI, NLR, and LMR were associated with CAS risk in middle-aged and older men [ 9 ]. PNR have also been shown to predict mortality in patients with ischemic stroke [ 10 ]. SII was also found to be a strong independent predictor of adverse outcomes in patients with acute coronary syndromes [ 12 ]. To find the best predictors of CAS, we included these markers in a larger population study at the same time. The results showed that the NLPR had the highest accuracy in identifying the risk of CAS. NLPR is the ratio of neutrophil to lymphocyte*platelet. Initially, NLPR was found to have predictive value in tumor prognosis [ 19 , 20 ]. Subsequently, NLPR was also found to be associated with the prognosis of acute kidney injury, suppurative liver abscess, severe trauma, and COVID-19 [ 21 – 25 ]. The value of NLPR in cardiovascular disease is equally outstanding. Studies have shown that NLPR is an independent predictor of in-hospital mortality after acute type A aortic dissection [ 11 ]. A prospective cohort study found that NLPR was an independent predictor of adverse outcomes in patients with acute coronary syndrome, and patients with a higher NLRP had a higher incidence of major adverse cardiovascular events [ 26 ]. In this study, our results directly show that there is a significant correlation between NLPR and CAS, and the higher the level of NLPR, the higher the risk of CAS.

In statistical analyses of baseline characteristics, in addition to indicators of inflammation, we found a number of variables that were statistically different between the CAS and Non-CAS groups, including age, gender, AST, TG, TC, HDL_C, LDL_C, BUN, creatinine, eGFR, UA, smoking history, drinking history, renaldysfuncyion, hyperuricemia, fatty liver, dyslipidemia, hypertension, diabetes and osteoporosis. Undoubtedly, age is the number one risk factor for a wide range of chronic diseases and systemic chronic inflammatory states [ 8 ]. A significant increase in age in the CAS group was also found in our results. Some studies have shown that the incidence of atherosclerosis is higher in postmenopausal women compared to men [ 27 ]. Whereas, our results showed higher percentage of males in CAS group, which may be due to the uneven gender distribution in the total population of our medical examination, where males were significantly more than females. In addition to this, renaldysfuncyion, hyperuricaemia, fatty liver, dyslipidaemia, hypertension, diabetes, osteoporosis and history of smoking and alcohol consumption were all strongly associated with atherosclerosis [ 28 – 34 ]. And chronic inflammation can lead to cardiovascular disease, cancer, diabetes, chronic kidney disease, non-alcoholic fatty liver disease and many other diseases [ 8 ]. In our subsequent stratified analyses, we also analysed that there was a significant interaction between these diseases and NLPR, which together contributed to the development of CAS.

In this study, we evaluated the value of multiple inflammatory markers for the risk of CAS and found the best inflammatory marker that can be easily obtained to effectively identify the risk of CAS. In addition, the relatively large sample size ensures the accuracy and reliability of the results. Nevertheless, there are some limitations to this study. First, due to the cross-sectional design of the study, a causal relationship between inflammatory markers and CAS cannot be demonstrated, so more prospective studies are needed to confirm these findings. Second, because this study was a single-center study with a relatively narrow group of participants, the findings may not be well extrapolated to other populations. Finally, although we have carefully adjusted for potential confounding factors, it is difficult to rule out potential residual confounding.

Atherosclerosis is a chronic inflammatory disease of the walls of blood vessels. In this study, novel inflammatory markers have good predictive effects on carotid atherosclerosis, and NLPR has the highest predictive value. NLPR can be used as a potential predictor of carotid atherosclerosis.

Supporting information

S1 raw data..

https://doi.org/10.1371/journal.pone.0303869.s001

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