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Association of Subclinical Coronary Artery Disease and Ischemic Stroke Caused by Cervical or Intracranial Atherosclerosis

Article Information

Ana Luíza Vieira de Araújo1, Raul Dias dos Santos Filho2, Marcio Sommer Bittencourt3, Roberto Nery Dantas Junior4, Carlos André Oshiro5, Cesar Higa Nomura4, Edson Bor-Seng Shu5, Marcelo de Lima Oliveira5, Claudia da Costa Leite6, Maria da Graça Morais Martin6, Maramelia Miranda Alves7, Gisele Sampaio Silva8, Victor Marinho Silva5, Adriana Bastos Conforto1*

1Department of Neurology, Clinical Hospital, University of Sao Paulo, Neurology Clinical Division, Hospital Israelita Albert Einstein, Instituto Israelita de Ensino e Pesquisa, Sao Paulo, Brazil

2Heart Institute, University of Sao Paulo, Medical School Hospital, Hospital Israelita Albert Einstein, Academic Research Organization, Sao Paulo, Brazil

3Center for clinical and epidemiological research, University Hospital, University of Sao Paulo, Sao Paulo, Brazil

4Heart Institute, University of Sao Paulo, Medical School Hospital, Sao Paulo, Brazil

5Department of Neurology, Clinical Hospital, University of Sao Paulo, Neurology Clinical Division, Sao Paulo, Brazil

6Department of Radiology, Clinical Hospital, University of Sao Paulo, Sao Paulo, Brazil

7Department of Neurology and Neurosurgery, Federal University of Sao Paulo, Sao Paulo, Brazil

8Department of Neurology and Neurosurgery, Federal University of Sao Paulo, Hospital Israelita Albert Einstein, Academic Research Organization, Sao Paulo, Brazil

*Corresponding author: Adriana Bastos Conforto, Clinical Hospital, University of Sao Paulo, Neurology Clinical Division, Hospital Israelita Albert Einstein, Instituto Israelita de Ensino e Pesquisa, Sao Paulo, Brazil

Received: 16 November 2020; Accepted: 24 November 2020; Published: 08 January 20201

Citation: Ana Luíza Vieira de Araújo, Raul Dias dos Santos Filho, Marcio Sommer Bittencourt, Roberto Nery Dantas Junior, Carlos André Oshiro, Cesar Higa Nomura, Edson Bor-Seng Shu, Marcelo de Lima Oliveira, Claudia da Costa Leite, Maria da Graça Morais Martin, Maramelia Miranda Alves, Gisele Sampaio Silva, Victor Marinho Silva, Adriana Bastos Conforto. Association of Subclinical Coronary Artery Disease and Ischemic Stroke Caused by Cervical or Intracranial Atherosclerosis. Cardiology and Cardiovascular Medicine 5 (2021): 17-31.

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Abstract

Background: Coronary calcium score (CAC) is a marker of coronary atherosclerosis. We compared CAC scores in patients with ischemic stroke (IS) caused by large-artery atherosclerosis (Groupathero) to a control group (Groupcontrol), in multiethnic subjects without history of symptomatic coronary artery disease (CAD).

Methods: In this cross-sectional study, subjects in Groupathero (n=80) had at least one symptomatic stenosis ≥ 50% in the carotid or vertebrobasilar territories. Groupathero included two subgroups: stenosis in either cervical or intracranial arteries (GroupExtraorIntra), and in at least one cervical and one intracranial artery (GroupExtra&Intra). Subjects in Groupcontrol (n=40) had no history of stroke or stenosis ≥ 50% in cervical or intracranial arteries. Frequencies of CAC ≥ 100 and CAC > 0 were compared between the groups and subgroups by bivariate logistic regressions. Multivariate analyses were also performed.

Results: Rates of CAC ≥ 100 were not significantly different between Groupathero and Groupcontrol but were significantly greater in GroupExtra&Intra when compared to Groupcontrol (OR 4.67; 1.21-18.04; p = 0.025). CAC > 0 was significantly more frequent in Groupathero (85%) than Groupcontrol (OR, 4.19; 1.74-10.07; p = 0,001). In multivariate analyses, “Groupathero” and “GroupExtra&Intra” was significantly and independently associated with CAC.

Conclusions: The frequency of coronary calcification was higher in subjects with atherothrombotic stroke without symptoms of coronary disease than in controls with similar vascular risk factors. In patients with stroke, the burden of subclinical CAD was significantly higher in those with cervical and intracranial atherosclerosis.

Keywords

Atherosclerotic ischemic stroke; Coronary calcium score; Subclinical coronary artery disease

Atherosclerotic ischemic stroke articles; Coronary calcium score articles; Subclinical coronary artery disease articles; Coronary atherosclerosis articles; Cervicocephalic atherosclerosis articles

Article Details

1. Introduction

Unlike myocardial infarction that is caused by atherosclerosis in more than 90% of the cases [1], only about 25% of ischemic strokes (IS) are attributable to atherosclerosis [2-4]. Classiflcation systems based on results of clinical, neuroimaging and laboratory tests aim to determine the most likely etiology of stroke or whether the cause cannot be determined. A diagnosis of “evident large-artery atherosclerosis” can be made if severity of the stenosis is ≥ 50% in intracranial or cervical arteries that supply the territory affected by the stroke and other causes of stroke are excluded [5]. In addition to affecting different segments of arteries that supply the brain, atherosclerosis can involve different vascular beds. Patients with IS may have polyvascular disease with concomitant coronary (20%) or peripheral artery disease (22%) [6-8]. Asymptomatic coronary artery stenosis ≥ 50% was reported in 18-20% of French patients with noncardioembolic IS and associated with increased risk of death [9, 10].

Besides the presence of stenosis or plaques, atherosclerosis in coronary arteries can be indirectly estimated by the coronary calcium score (CAC). Large prospective studies have established CAC as an excellent noninvasive predictor of atherosclerotic cardiovascular risk currently available [11-13]. CAC is a surrogate of atherosclerosis plaque burden and is independently associated with the risk of myocardial infarction or mortality [14-16]. In a meta-analysis that included 27,622 patients with no previous manifestation of cardiovascular disease, the presence of CAC > 0 indicated a relative risk of 4.3 of major coronary events [17]. In the MESA study, the annual frequencies of cardiovascular events in asymptomatic subjects were: CAC zero, 0.4%; CAC 1-100, 0.8% and CAC > 100, 2.4% [18]. Detrano et al. 2008 reported (n=6,722) that CAC scores between 101 and 300 were associated with an 8-fold increase in the risk of any coronary event. The risk was increased almost 10-fold in those with CAC above 300 [16]. Until now, no studies about subclinical coronary artery disease (CAD) assessed with CAC were performed in patients with IS speciflcally attributed to atherosclerosis.

The main goal of this study was to evaluate CAC scores in subjects with IS caused by atherosclerosis (Groupathero) compared to controls (Groupcontrol) in multiethnic subjects in Brazil. We hypothesized that the frequency of CAC ≥ 100 and > 0, as well as absolute CAC scores would be higher in Groupathero than in Groupcontrol. In addition, we expected that patients with symptomatic cervical and intracranial stenosis ≥ 50% due to atherosclerosis (GroupExtra&Intra) would have a greater extent of subclinical CAD than patients with symptomatic, exclusively cervical or intracranial stenosis ≥ 50% (GroupExtraorIntra).

2. Methods

2.1 Study design and participants

In this cross-sectional study, patients were recruited from two outpatient stroke clinics at Hospital das Clínicas/São Paulo University and São Paulo Hospital/São Paulo Federal University between September 2015 and March 2018. Controls with comparable age and sex distribution were recruited from non-consanguineous companions of patients. The protocol was approved by the Institutional Review Board (protocol number 1.175.113) and all patients provided written informed consent.

2.2 Eligibility criteria

Subjects aged 45 to 80 years were included. History of coronary heart disease or pathologic Q waves on the electrocardiogram were exclusion criteria. Speciflc criteria for patients with atherosclerosis (Groupathero) and controls (Groupcontrol) are listed below.

2.3 Atherosclerosis group (Groupathero)

2.3.1 Inclusion criteria: IS in the internal carotid artery or vertebrobasilar territory in the past 15 years, conflrmed by computerized tomography (CT) or magnetic resonance imaging; stenosis ≥ 50% in cervical, intracranial, or both segments of these arteries, diagnosed by computed tomography angiography, magnetic resonance angiography (MRA) or digital subtraction angiography within 6 months post-stroke.

2.3.2 Exclusion criteria: High- or medium-risk source of cardiac embolism according to the Causative Classiflcation System of Ischemic Stroke (CCS) [5, 19]; stroke etiology other than atherosclerosis according to CCS; another IS in a large-artery territory, in the absence of ≥ 50% stenosis in an artery supplying that territory.

2.3.3 Groupathero was divided in two subgroups: GroupExtraorIntra (stenosis ≥ 50% in either a cervical or an intracranial artery supplying the territory affected by IS) and GroupExtra&Intra: Stenosis ≥ 50% in at least one cervical and at least one intracranial artery.

2.4 Controls (Groupcontrol)

2.4.1 Inclusion criteria: Age and sex comparable to those of subjects in Groupathero.

2.4.2 Exclusion criteria: History of transient ischemic attack (TIA) or stroke; stenosis ≥ 50% in a cervical or intracranial artery diagnosed by MRA or transcranial Doppler and cervical Doppler.

2.5 Characteristics of the subjects

Demographic data, history of hypertension, diabetes, hypercholesterolemia, Ankle-brachial Index < 0.9, smoking and metabolic syndrome were assessed. Deflnitions are shown in Supplementary flle 1. Use of antihypertensive, antidiabetic, antiplatelet drugs and statins was also registered. Results of routine laboratory exams from Groupathero were retrieved from electronic records. Tests were ordered for controls and patients if no blood work-up had been performed within 6 months prior to enrollment.

Cardiovascular risk was estimated by the Pooled Cohort Equations (PCE), a well-established, global measure of vascular risk, according to the 2013 ACC/AHA recommendations [20]. This quantitative risk assessment method predicts the 10-year risk of developing a flrst cardiovascular event, deflned as nonfatal myocardial infarction, death from CAD, or fatal or nonfatal stroke among people with no cardiovascular disease [21, 22]. Severity of neurological impairments caused by stroke was deflned by scores in the National Institutes of Health Stroke Scale (NIHSS) [23-25] and severity of disability, by the Modifled Rankin Scale [24, 26].

2.6 Outcomes

The primary outcome was CAC ≥ 100 in the two main groups (Groupathero and Groupcontrol). The secondary outcomes were CAC > 0 and CAC absolute values in the main groups; CAC ≥ 100, CAC > 0 and absolute CAC values in subgroups (GroupExtraorIntra and GroupExtra&Intra); independent associated factors of CAC ≥ 100, CAC > 0 and CAC absolute values.

2.7 CAC

CAC was acquired by a 320-detector row CT scanner (Aquilion ONE, Canon Medical System Corporation, Otawara, Japan) at the Heart Institute (InCor)/University of São Paulo Medical School, São Paulo, Brazil. The protocol consisted of a prospective acquisition in inspiratory apnea, under electrocardiographic gating with the tube voltage of 120 kV, and current adjusted according to the patient's body mass index. The collimation pattern of the apparatus was 320 x 0.5 mm and the rotation speed, 0.35 s. Sequential slices with 3.0 mm spacing were obtained, which is the standard method in clinical practice, as previously described [14]. The effective radiation dose (in mSv) was calculated and controlled in all cases.

2.8 CT image analysis

The images were fully analyzed through a dedicated workstation (Aquarius, Intuition Edition, TeraRecon Inc., Version 4.4.11, California, USA) by a single experienced cardiologist (RD) blinded to clinical data using the scoring system previously described by Agatston et al [14]. All subjects were categorized in CAC ≥ 100 or <100, as well as in CAC=0 or > 0.

2.9 Statistical analysis

Continuous variables are expressed as mean ±standard deviation (SD), whereas categorical variables are presented as frequencies. Between-group comparisons of baseline characteristics were performed with unpaired t-tests, Mann-Whitney tests, likelihood test, chi-square tests or flsher´s exact tests, according to the nature and distribution of the data. Frequencies of CAC=0 or > 0 and CAC <100 or ≥ 100 between Groupathero and Groupcontrol, as well as between subroups GroupExtraorIntra or GroupExtra&Intra and Groupcontrol, were compared with bivariate logistic regression. Odds Ratios (OR) and 95% confldence intervals (95%CI) were calculated.

The sample size was not formally estimated because no preliminary data were available. Multiple logistic regression was performed to identify independent associated factors of CAC ≥ 100 or CAC > 0. In Model 1, the independent variables were Pooled Cohort Equations (PCE) and Groupathero (Model 1). In addition, in Model 2, we calculated “PCEwithout statin use” for statin users by estimating the likely LDL-C level in the absence of statin use as previously described [LDL-C level+(30% x LDL-C level)] [27]. This analysis was performed because there is evidence that statin therapy may influence CAC development [28]. The independent variables were PCEwithout statin use and Groupathero.

Comparisons of absolute CAC values between groups were performed with the Mann-Whitney test and between GroupExtraorIntra, GroupExtra&Intra and Groupcontrol, with the Kruskal-Wallis test. Post hoc analyses were made with Dunn's multiple comparisons. We also evaluated absolute calcium scores as a continuous variable, using the base-10 logarithm of the sum of the coronary calcium score plus 1 (log10 [CAC+1]). The addition of 1 to the calcium score before logarithmic transformation was performed so that patients with a calcium score of zero could be included in the analysis as previously described [16]. A p-value <0.05 was considered statistically signiflcant. The tests were performed using SPSS for Windows version 22.0.

3. Results

3.1 Characteristics of the subjects

flgure 1 shows the flowchart of inclusion. Table 1 shows the baseline characteristics of the subjects in Groupathero (n=80) and in Groupcontrol (n=40). In Groupathero, the median modifled Rankin score was 2 (range, 0-5); the median NIHSS at the time of inclusion, 1.5 (0-16) and the median time from stroke onset, 2 years (0-11.5). More than half (55%) of the patients were assessed within the flrst-year post-stroke and 32.5%, within 2-5 years. There were no signiflcant differences between groups in relation to age, sex, diagnoses of hypertension, diabetes mellitus, smoking, metabolic syndrome or estimated cardiovascular risk according to PCE. Hyperlipidemia, family history of stroke, abnormal ankle-brachial index, use of antiplatelet drugs, statins, antidiabetic and antihypertensive drugs were more frequent in Groupathero than in Groupcontrol.

3.2 Outcomes

3.2.1 Primary outcome: 3.2.1.1 CAC ≥ 100 in main groups CAC ≥ 100 was present in 46.3% (n= 37) subjects in Groupathero and 32.5% (n= 13) in Groupcontrol (OR, 1.79; 95%CI 0.81-3.96; p=0.152). Table 2 shows results of univariate subgroup analyses. CAC ≥ 100 were signiflcantly more frequent in GroupExtra&Intra than in patients in Groupcontrol. There were no differences between proportions of CAC ≥ 100 in GroupExtra&Intra and in GroupExtraorIntra.

3.2.2 Secondary outcomes: 3.2.2.1 CAC > 0 in main groups and in subgroups CAC > 0 was found in 85% (n= 68) subjects in Groupathero and 57.5% (n=23) in Groupcontrol (OR, 4.19; 95% CI 1.74-10.07; p=0.001). Table 2 shows results of subgroup analyses. CAC > 0 was signiflcantly more frequent in GroupExtraorIntra or GroupExtra&Intra than inGroupcontrol.

3.2.2.2 Absolute CAC values in main groups and in subgroups

CAC scores were signiflcantly higher in Groupathero

(median, 75.4; range: 0-2766.1) compared to Groupcontrol (median, 11.7; range: 0-2153.7) (p=0.024). CAC absolute values were signiflcantly greater in GroupExtra&Intra (median 109.51; range: 0-2766) and in GroupExtraorIntra (median 56.26; range: 0-1817) than in Groupcontrol (p=0.028), but post-hoc analysis did not show signiflcant differences between GroupExtraorIntra and Groupcontrol (p=0.194), GroupExtra&Intra and Groupcontrol (p=0.075) or GroupExtraorIntra compared to GroupExtra&Intra (p=0.308).

3.2.2.3 Independent associated factors of CAC ≥ 100, CAC > 0 and CAC absolute values

In multiple logistic regression, the variable “Groupathero” was independently associated with CAC > 0 and Log (CAC +1) (Table 3). flgure 2 shows subgroup analyses of CAC absolute values. Only GroupExtra&Intra was signiflcantly associated with Log (CAC +1) (confldence interval, CI, 0.40-3.43; p=0.013). The results of Model 2 are shown in the Supplementary Table 1. The results of multivariate analyses, with calculated “PCEwithout statin use” for statin users, were similar to those obtained in Model 1.

fortune-biomass-feedstock

flgure 1: flow diagram. CAD: coronary artery disease; TIA: transient ischemic attack.

Characteristic

Groupathero

(n=80)

Groupcontrol

(n=40)

p-value

Age (y)

64.5 ± 7.6

64.2 ± 6.3

0.817b

Education (y)

6.8 ± 4.7

6.8 ± 4.9

0.766c

Male sex (%)

67.5

55

0.180a

Ethnic group (%)

     

Black

44.4

47.5

0.302d

White

53.8

50

 

Asian

3.8

2.5

 

Hypertension (%)

87.5

75

0.083a

Diabetes (%)

45

42.5

0.795a

Hyperlipidemia (%)

100

70

<0.001e

Family history of stroke (%)

51.2

20

0.001a

Pooled Cohort Equations risk (%)

20.2 ± 16.3

22.1 ± 15.3

0.794b

Smoking (%)

15

12.5

0.923a

Ankle-brachial Index < 0.9 (%)

29

5

0.002a

Metabolic Syndrome (%)

47.5

50

0.796a

Antiplatelet agents (%)

92.5

17.5

< 0.001a

Statins (%)

97.5

40

< 0.001a

Anti-diabetic medications (%)

28.7

12.5

0.047a

Values represent mean ± SD (standard deviation); Y= years. aChi-square test, bTeste t-Student; cTeste Mann-Whitney, dLikelihood test, eflsher.

Table 1: Characteristics of the subjects.

Subgroups

CAC ≥ 100 n (%)

OR (95% CI)

p-value

CAC > 0 (n, %)

OR (95% CI)

p-value

Groupcontrol

13 (32.5)

1

 

23 (57.5)

1

 

GroupExtraorIntra

28 (41.8)

1.49 (0.66-3.39)

0.34

56 (83.6)

3.76 (1.53-9.26)

0.004

GroupExtra&Intra

9 (69.2)

4.67 (1.21-18.04)

0.025

12 (92.3)

8.87(1.05-74.95)

0.045

OR, odds ratio; CI, confldence interval; CAC, coronary artery calciflcation scores; OR calculated using bivariate logistic regression.

Table 2: Comparisons in rates of coronary calcium scores (CAC) ≥ 100 or > 0 between Groupcontrol, GroupExtraorIntra or GroupExtra&Intra.

CAC 100a

Model 1

OR (95% CI)

p-value

PCE

1.026 (1.002-1.052)

0.035

Groupathero

1.769 (0.787-3.975)

0.167

CAC > 0b

Model 1

OR (95% CI)

p-value

PCE

1.026 (0.994-1.06)

0.108

Groupathero

4.229 (1.735 – 10.305)

0.002

Log (CAC +1)c

Model 1

Coefflcient (95%CI)

p-value

PCE

0.039 (0.012-0.066)

0.005

Groupathero

1.021 (0.097-1.945)

0.030

aMultiple logistic regression: dependent variables, presence of coronary calcium scores (CAC) ≥ 100; Independent variables, scores in pooled cohort equations and group (Groupathero or Groupcontrol). bMultiple logistic regression: dependent variables, presence of coronary calcium scores (CAC) ≥ 0 Independent variables, scores in pooled cohort equations and group (Groupathero or Groupcontrol). cLinear regression: dependent variable, logarithm of sum (absolute coronary calcium scores + 1). Independent variables, scores in pooled cohort equations and group (Groupathero or Groupcontrol). OR, odds ratio. CI, confldence interval. CAC, coronary artery calciflcation scores. PCE, pooled cohort equations.

Table 3: Multivariate analyses.

fortune-biomass-feedstock

flgure 2: Linear Regression of log (CAC+1) between subgroups (Groupcontrol, GroupExtraorIntra, GroupExtra&Intra). * indicates the statistically signiflcant difference in reference to the control group. NS indicates non-statistically signiflcant difference.

4. Discussion

We report, for the flrst time, a signiflcantly greater presence and burden of subclinical coronary atherosclerosis in individuals with IS caused by cervicocephalic atherosclerosis than in controls. The frequency of more extensive CAC (CAC ≥ 100) was higher in Groupathero than in Groupcontrol but this was not statistically signiflcant. Interestingly, CAC ≥ 100 was signiflcantly more frequent in the subgroup with a greater extension of atherosclerosis (GroupExtra&Intra) but not in the subgroup with atherosclerosis restricted to intra- or extracranial arteries (GroupExtraorIntra). We found that 85% of the patients in Groupathero had CAC > 0 despite absence of CAD symptoms. CAC > 0 was signiflcantly greater in either GroupExtraorIntra or GroupExtra&Intra than in controls. Therefore, IS due to atherosclerosis must be considered as a red flag to reinforce secondary prevention measures, not only to prevent IS recurrence but also to decrease global cardiovascular risk. Antiplatelet and statins are recommended to patients with IS caused by atherosclerosis according to current guidelines. Acknowledgment of a greater risk of death due to MI in these patients than subjects with similar risk factors without a history of IS, despite the absence of coronary symptoms, may strengthen the drive for adherence to treatment in patients with IS caused by atherosclerosis. Multivariate analysis showed an independent association of stroke caused by atherosclerosis (Groupathero) with higher values of CAC. This indicates that patients with IS caused by atherosclerosis have a greater risk of cardiovascular events or all-cause mortality than controls with comparable estimated vascular risk [17].

Multivariate analysis also showed an independent association of GroupExtra&Intra with higher values of CAC. Therefore patients with more extensive cervicocephalic atherosclerosis may be at greater risk of subclinical coronary atherosclerosis and therefore greater future risk of coronary events, compared with those with either cervical or intracranial atherosclerosis. This greater risk could point to a need for a more detailed assessment of these patients for CAD, since many patients after stroke have physical disabilities that could mask the onset of anginal symptoms related to mobility and delay the diagnosis of obstructive CAD [29, 30]. In addition, our results suggest the possibility of using more aggressive treatment measures for these very high-risk subgroups, such as the use of PSCK9 inhibitors in patients with stroke due to cervicocephalic atherosclerosis [31-34]. Future clinical trials are needed to conflrm this hypothesis. To our knowledge, this is the flrst study that compared CAC in patients with IS caused speciflcally by large-artery atherosclerosis, without known CAD, and controls. Prior studies investigated rates of subclinical CAD with coronary computed tomography angiography (CCTA) in patients with IS of diverse etiologies [35, 36] or non-cardioembolic stroke [9, 10]. In Japanese patients with IS not caused by cardiac embolism or symptomatic carotid artery disease, without symptoms of CAD, absolute CAC scores were signiflcantly higher than in controls, suggesting a greater risk of MI or death. Yet, other causes of stroke were not excluded in this study [37].

In the present study, the Groupcontrol included subjects recruited from non-consanguineous companions of patients in order to limit the difference between patients and controls to the “stroke” status rather than exposure to risk factors due to differences in lifestyle or access to health services. Of interest, controls were found to be at high risk of further atherosclerotic coronary events, comparable to those of patients, according to PCE scores. Despite this high-risk proflle, subjects in the control group were signiflcantly less likely to use medications to treat hypertension, diabetes or dyslipidemia. This flnding may reflect the poor control of risk factors likely caused by underdiagnosis of hypertension, diabetes and hyperlipidemia in asymptomatic subjects in low- and middle-income countries like Brazil [38].

This study has some limitations. It has limited power for the comparison of rates of CAC ≥ 100 between Groupathero and controls. A multicenter study would be advisable to test the hypothesis that the rate of CAC ≥ 100 is signiflcantly greater in Groupathero than in controls, suggesting an even greater risk of cardiovascular events than CAC > 0. Also, inclusion of time from stroke in Grupoathero, up to 15 years, might lead to bias. Over the years there might be progression of coronary calciflcation, as well as worsening of control of cardiovascular risk factors. However, it is unlikely that this may have biased our results because: flrst, more than half of the patients were assessed within the flrst year and less than 15%, more than flve years post-stroke. Second, PCE scores were comparable between subjects with IS and controls. Third, the use of medications to control risk factors was found to be greater in the stroke group than in the control group. This could make the flnding of greater CAC scores in the stroke group, compared to controls, less likely. Despite this, we found that the “stroke status” was an independent predictor of CAC > 0 and hence, greater cardiovascular risk. Fourth, multivariate analysis (Model 2), with “PCEwithout statin use” for statin users (estimation of the likely LDL-C level in the absence of statin use) showed the same results compared to Model 1, in which the independent variables were PCE and Groupathero.

5. Conclusion

The frequency of coronary calciflcation was higher in subjects with atherothrombotic stroke without symptoms of coronary disease than in controls with similar vascular risk factors. In patients with stroke, the burden of subclinical CAD was signiflcantly higher in those with cervical and intracranial atherosclerosis. Atherothrombotic stroke should be considered a red flag for subclinical coronary atherosclerosis.

Acknowledgments

We thank Prof. Marc Chimowitz for considerable comments and suggestions.

Funding

This research was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (grant 14/03950-2). RDS is a recipient of a scholarship from the Conselho Nacional de Pesquisa e Desenvolvimento Tecnologico (CNPq) grant #303734/2018-3. ABC is a recipient of a scholarship from the Conselho Nacional de Pesquisa e Desenvolvimento Tecnologico (CNPq) grant #303070/2019-6. MSB is a recipient of a scholarship from the Conselho Nacional de Pesquisa e Desenvolvimento Tecnologico (CNPq) grant #310255/2018-0.

Conflicts of Interest

RDS has received honoraria related to consulting, research and or speaker activities from: Amgen, Aché, Astra Zeneca, Esperion, Kowa, Merck, Novo-Nordisk, PTC, Pflzer, and Sanofl/Regeneron.

MSB has received speaker fees from GE healthcare.

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Supplementary Material

Supplementary Document 1

Deflnitions of variables.

  • (a) Hypertension: reported in the medical record or current use of antihypertensive, or physical examination, according to guidelines of the Brazilian Society of Cardiology. (http://departamentos.cardiol.br/dha/vidiretriz/06-cap02.pdf)
  • (b) Diabetes mellitus or fasting hyperglycemia: reported in the medical record or current use of medications to control blood glucose or altered fasting glucose testes or two-hour tolerance test. (http://www.diabetes.org.br/images/2015/area-restrita/diretrizes-sbd-2015.pdf)
  • (c) Dyslipidemia: diagnosis and current treatment or result of total cholesterol and fractions. (http://publicacoes.cardiol.br/consenso/2013/V_Diretriz_Brasileira_de_Dislipidemias.pdf)
  • (d) Smoking: information written on the medical record or referred by the patient. Note how many packs / year (packs / day x years of smoking, remembering that 1 pack has 20 cigarettes).
  • (e) Family history of stroke or coronary artery disease: written on the patient record or referred to by the patient.
  • (f) Ankle / brachial index: quotient between the highest ankle systolic pressure and the brachial systolic pressure. The ankle / brachial index below 0.90 is indicative of peripheral obstructive arterial disease. (http://www.jvascbr.com.br/vol4_n4_supl4.pdf)
  • (g) Metabolic syndrome: diagnosed when a patient has at least 3 of the following 5 conditions:

 

  • • Fasting glucose ≥100 mg/dL (or receiving drug therapy for hyperglycemia)
  • • Blood pressure ≥130 or ≥ 85 mm Hg (or receiving drug therapy for hypertension)
  • • Triglycerides ≥150 mg/dL (or receiving drug therapy for hypertriglyceridemia)
  • • HDL-C <40 mg/dL in men or <50 mg/dL in women Waist circumference ≥102 cm in men or ≥88 cm in women;

 

CAC 100a

   

Model 2

OR (CI)

P-value

PCE without statin

1.025 (1.002 – 1.049)

0.035

Groupathero

1.754 (0.781 - 3.942)

0.174

CAC > 0b

Model 2

OR (CI)

P-value

PCE without starting

Groupathero

1.029 (0.997 – 1.061)

4.203 (1.72 – 10.271)

0.074

0.002

Log (CAC +1)c

   

Model 2

Coefflcient (CI)

P-value

PCE without statin

Groupathero

0.039 (0.013-0.065)

1.006 (0.084-1.928)

0.004

0.033

aMultiple logistic regression: dependent variables, presence of coronary calcium scores (CAC) ≥ 100; Independent variables, scores in pooled cohort equations without statin and group (Groupathero or Groupcontrol). bMultiple logistic regression: dependent variables, presence of coronary calcium scores (CAC) ≥ 0 Independent variables, scores in pooled cohort equations and group (Groupathero or Groupcontrol). cLinear regression: dependent variable, logarithm of sum (absolute coronary calcium scores + 1). Independent variables, scores in pooled cohort equations and group (Groupathero or Groupcontrol). OR,odds ratio. CI, confidence interval. CAC, coronary artery calcification scores. PCE, pooled cohort equations.

Supplementary Table 1: Multivariate analyses with PCE without statin (Model 2).

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