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Coronary Calcium Score and Stratification of Coronary Artery Disease Risk in Patients with Atherosclerotic and Non-Atherosclerotic Ischemic Stroke

Abstract

Background

Ischemic Stroke (IS) and Coronary Artery Disease (CAD) frequently coexist and share atherosclerotic disease risk factors. According to the American Heart Association, IS subtypes may be considered CAD risk equivalents, but the evidence for non-atherosclerotic IS is uncertain. Additionally, the Coronary Calcium Score (CCS) is an accurate marker to address CAD risk; however, CCS distribution between IS subtypes is not well characterized.

Objectives

To compare the CCS between atherosclerotic and non-atherosclerotic IS groups; and to determine which covariates were associated with high CCS in IS.

Methods

This cross-sectional design included all patients with IS, 45 to 70 years of age at the time of the stroke, consecutively admitted to a rehabilitation hospital between August 2014 and December 2016, without prevalent CAD. All patients underwent CT scanning for CCS measurement. CCS≥100 was considered a high risk for CAD, with a significance level of p<0.05.

Results

From the 244 studied patients (mean age 58.4±6.8 years; 49% female), 164 (67%) had non-atherosclerotic etiology. The proportions of CCS≥100 were similar between the atherosclerotic and the non-atherosclerotic groups (33% [n=26] x 29% [n=47]; p= 0.54). Among all IS patients, only age ≥60 years was independently associated with CCS≥100 (OR 3.5; 95%CI 1.7-7.1), accounting for hypertension, dyslipidemia, diabetes, sedentarism, and family history of CAD.

Conclusion

Atherosclerotic IS did not present a greater risk of CAD when compared to non-atherosclerotic IS according to CCS. Only age ≥60 years, but not etiology, was independently associated with CCS≥100.

Stroke; Coronary Artery Disease; Calcium Signaling; Dyslipidemias; Hypertension; Diabetes Mellitus

Resumo

Fundamento

O acidente vascular encefálico isquêmico (AVEi) e a doença arterial coronariana (DAC) coexistem frequentemente e compartilham fatores de risco para doença aterosclerótica. Segundo a American Heart Association , os subtipos de AVEi podem ser considerados equivalentes de risco para DAC, mas a evidência para o AVEi não-aterosclerótico não está bem definida. Além disso, o escore de cálcio coronário (CAC) é um marcador preciso para estimar o risco de DAC. Entretanto, a distribuição do CAC pelos subtipos de AVEi ainda não foi bem caracterizada.

Objetivos

Comparar o CAC entre os grupos de AVEi ateroscleróticos e não ateroscleróticos, e determinar quais covariáveis estão associadas a CAC alto no AVEi

Métodos

Em um estudo transversal, incluímos todos os pacientes com AVEi, com idades entre 45 a 70 anos no momento do acidente vascular, consecutivamente admitidos em um hospital de reabilitação entre agosto de 2014 e dezembro de 2016, sem DAC prevalente. Todos os pacientes passaram por tomografia computadorizada (TC), para medir o CAC. CAC≥100 foi considerado alto risco de DAC. O nível de significância foi p<0,05.

Resultados

Dos 244 pacientes estudados (média de idade de 58,4±6,8 anos; 49% do sexo feminino), 164 (67%) apresentavam etiologia não-aterosclerótica. As proporções de CAC≥100 foram semelhantes entre os grupos ateroscleróticos e não-ateroscleróticos (33% [n=26] x 29% [n=47]; p= 0,54). Entre todos os pacientes com AVEi, apenas os de idade ≥60 anos foram associados independentemente a CAC≥100 (RC 3,5; 95% IC 1,7-7,1), ajustado para hipertensão, dislipidemia, diabetes, sedentarismo, e histórico familiar de DAC.

Conclusão

O AVEi aterosclerótico não apresentou risco maior de DAC quando comparado ao AVEi não-aterosclerótico de acordo com o CAC. Apenas a faixa etária ≥60 anos – mas não a etiologia - foi associada independentemente a CAC≥100. (Arq Bras Cardiol. 2020; 115(6):1144-1151)

Acidente Vascular Encefalico; Doença da Artéria Coronariana; Sinalização do Cálcio; Dislipidemias; Hipertensão; Diabetes Mellitus

Introduction

Ischemic Stroke (IS) and Coronary Artery Disease (CAD) are the leading causes of mortality worldwide.11. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics’2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146-603. Sciacca RR, Rundek T, Sacco RL, Elkind MS V. Recurrent stroke and cardiac risks after first ischemic stroke: the Northern Manhattan Study. Neurology. 2006;66(5):641-6. The estimated simultaneous prevalence of both diseases could be as high as 70%, with any degree of CAD.22. Yoo J, Yang JH, Choi BW, Kim YD, Nam HS, Choi HY, et al. The frequency and risk of preclinical coronary artery disease detected using multichannel cardiac computed tomography in patients with ischemic stroke. Cerebrovasc Dis. 2012;33(3):286-94. Additionally, the absolute risk of myocardial infarction is 2.2% per year in patients who had IS or transient ischemic attack,33. Touzé E, Varenne O, Chatellier G, Peyrard S, Rothwell PM, Mas JL. Risk of myocardial infarction and vascular death after transient ischemic attack and ischemic stroke: a systematic review and meta-analysis. Stroke. 2005;36(12):2748-55. and the risk of fatal cardiac events is approximately twice the risk of recurrent fatal stroke at 5 years after surviving stroke.44. Dhamoon MS, Siacca RR, Rundek T, Sacco RL, Elkind MS V. Recurrent stroke and cardiac risks after first ischemic stroke: The Northern Manhattan Study. Neurolgy. 2006;66(5):641-6.

This close relationship between IS and CAD may be explained by similar pathophysiology and risk factors for atherosclerosis in both diseases, like systemic arterial hypertension, dyslipidemia, and smoking, which share preventive and therapeutic goals. According to the American Heart Association and the American Stroke Association, IS subtypes may be considered CAD risk equivalents, but the evidence for non-atherosclerotic IS is uncertain.55. Lackland DT, Elkind MSV, D’Agostino Sr R, Dhamoon MS, Goff Jr DC, Higashida RT, et al. Inclusion of stroke in cardiovascular risk prediction instruments : a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43(7):1998-2027.

Large artery atherosclerosis is a frequent IS etiology, ranging from 9% to 24% of overall IS cases, alternating with cardioembolic and small vessel disease subtypes as the most prevalent IS causes,66. Arsava EM, Helenius J, Avery R, Sorgun MH, Kim GM, Pontes-Neto OM, et al. Assessment of the predictive validity of etiologic stroke classification. JAMA Neurol. 2017;74(4):419-26. , 77. Krishnamurthi RV, Barker-Collo S, Parag V, Parmar P, Witt E, Jones A, et al. Stroke incidence by major pathological type and ischemic subtypes in the Auckland Regional Community Stroke Studies: changes between 2002 and 2011. Stroke. 2018;49(1):3-10. depending on the cohort characteristics and risk factor distribution.88. Kolominsky-Rabas PL, Weber M, Gefeller O, Neundoerfer B, Heuschmann PU. Epidemiology of Ischemic stroke subtypes according to TOAST criteria: incidence, recurrence, and long-term survival in ischemic stroke subtypes: a population-based study. Stroke. 2001;32(12):2735-40. , 99. Schulz UGR, Rothwell PM. Differences in vascular risk factors between etiological subtypes of ischemic stroke: Importance of population-based studies. Stroke. 2003;34(8):2050-9. However, it is not well established whether non-atherosclerotic subtypes of IS are under the same level of CAD risk as atherosclerotic IS. Additionally, undiagnosed coronary atherosclerosis in IS patients varies in prevalence and severity. Angiographic coronary stenosis of greater than 50% is present in 26% of the patients with IS and no known history of CAD.1010. Amarenco P, Lavallée PC, Labreuche J, Ducrocq G, Juliard JM, Feldman L, et al. Prevalence of coronary atherosclerosis in patients with cerebral infarction. Stroke. 2011;42(1):22-9. Alternatively, using the coronary calcium score (CCS) as a non-invasive risk stratification strategy, the prevalence of CAD in IS can be as high as 70%, in whom approximately one quarter are under a very high risk (CCS>400).1111. Iwasaki K, Haraoka K, Hamaguchi T, Imamura T, Kawada S, Hamaguchi T, et al. Prevalence of subclinical coronary artery disease in ischemic stroke patients. J Cardiol. 2015;65(1):71-5.

Therefore, this study aimed to cross-sectionally compare the CCS between atherosclerotic and non-atherosclerotic IS, as a marker of CAD risk. In addition, this study determined which covariates were associated with high CCS in IS, other then etiology. We therefore hypothesized that coronary calcium would be higher in atherosclerotic IS than in IS from other etiologies, serving as a valuable screening tool for risk stratification in IS.

Methods

This cross-sectional design included all patients with a diagnosis of IS, 45 to 70 years of age, at the time of the neurologic event, admitted consecutively at Brasília Unit of the Sarah Network of Rehabilitation Hospitals between August 2014 and December 2016. Patients with previous diagnosis of CAD were excluded, given that our target population was at-risk individuals and not with established disease. All patients signed the informed consent form prior to study enrollment. This study was approved by the institution’s Ethics Committee.

IS was confirmed by clinical evaluation and an image method. Stroke etiology was classified by two independent neurologists, using a computerized system based on the Stop Stroke Study Causative Classification System (SSS-CCS) Trial of ORG 10172 in Acute Stroke Treatment (TOAST) available on line.1212. Massassuchets General Hospital HMS. Causative Classification System For Ischemic Stroke; 2019. [acesso em 10 jun 2019]. Disponível em: https://ccs.mgh.harvard.edu/ccs_title.php.
https://ccs.mgh.harvard.edu/ccs_title.ph...
, 1313. Ay H, Benner T, Arsava EM, Furie KL, Singhal AB, Jensen MB, et al. A computerized algorithm for etiologic classification of ischemic stroke: the causative classification of stroke system. Stroke. 2007;38(11):2979-84. Disagreements were resolved by a third independent neurologist. For this analysis, all non-atherosclerotic etiologies were adjudicated in one group for logistic regression.

Etiological investigation included transthoracic echocardiography, chest radiograph, EKG, neuroimaging (MRI or CT), non-invasive intracranial vascular studies (magnetic resonance angiography, computed tomography angiography, and transcranial Doppler). If necessary, transesophageal echocardiography and 24-hour Holter monitoring were performed. Other exams were also requested upon clinical evaluation, such as complete blood count, renal function, screening for endemic diseases (HIV, syphilis, and Chagas’ disease). In selected patients, thrombophilia (antithrombin III, protein C and S deficiency, search for antiphospholipid syndrome, prothrombin and factor V of Leiden mutations and homocysteine levels) was also investigated.

Coronary calcium score

All patients underwent CCS determination. A prospective axial image of the heart was acquired using multidetector computed tomography cuts of 3mm, synchronized with the EKG. Three models of CT scanners were used: Siemens Sensation 64, Siemens Perspective 128, and Siemens Definition. The images were analyzed in the Siemens Syngo Calcium Scoring software and the radiologists were blinded to the stroke etiology. Semiautomatic analysis of calcified plaques was performed with electronic identified images with more than 3 adjacent pixels with density greater than 130 Hounsfield Units.1414. Agatston AS, Janowitz FWR, Hildner FJ, Zusmer NR, Viamonte M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15(4):827-32. High risk was defined as a CCS≥100, considered as a prognostically validated cut-off.1515. Budoff MJ, Young R, Burke G, Carr JJ, Detrano RC, Folsom AR, et al. Ten-Year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA). Eur Heart J. 2018;39(25):2401-8. As a sensitivity analysis, the distribution of the lowest risk, defined as a CCS=0 between both IS groups, was also compared.

Characterization of the studied variables

Study variable were defined as follows:

Systemic Arterial hypertension: systolic arterial pressure more than 140 mmHg, diastolic arterial pressure more than 90 mmHg; use of antihypertensive drug.

Dyslipidemia: LDL more than 160 mg/dL or use of lipid-lowering agent.

Diabetes mellitus: fasting blood glucose more than 126 mg/dL or use of hypoglycemic agent and/or insulin.

Sedentary life style: less than 150 minutes of moderate exercise per week.

Obesity: body mass index more than 30 kg/m2

Family history of premature CAD: first degree relatives with a diagnosis of CAD of < 50 years old in men and of < 65 years old in women.

Smoking: self-reported current use of cigarettes for at least one year or cessation of smoking for less than five years.

Modified Rankin Scale: used to measure the degree of disability or dependence in one’s daily activities. This was calculated by one neurologist upon rehabilitation program admission.1818. Wolfe C, Taub N, Woodrow E, Burney PG. Assessment of scales of disability and handicap for stroke patients. Stroke. 1991;22(10):1242-4.

10 year atherosclerosis cardiovascular disease (ASCVD) estimation risk: the pooled cohort equations was used to estimate the risk of coronary events in 10 years, classified as: low risk (<5%), borderline risk (5-7.4%), intermediate risk (7.5-19.9%), high risk (≥ 20%).1919. American College of Cardiology. ASCVD Risk Estimator Plus; 2019. [acesso em 10 jun 2019]. Disponível em: http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/content/news/.
http://tools.acc.org/ASCVD-Risk-Estimato...

Statistical analysis

Categorical variables are presented as count with proportion or as continuous variables as mean ± SD or median (25-75thpercentile). Kolmogorov-Smirnov normality test was used to verify the distribution. To address the main objective, atherosclerotic and non-atherosclerotic groups were compared using the chi-square test for categorical variables, and the independent samples t test or Mann-Whitney U test, as appropriate, for continuous variables.

To address our secondary objective, a multivariate logistic regression model was used to investigate the covariates associated with a higher CAD risk, represented as a CCS≥100. The dependent variable was CCS dichotomized between ≥100 and <100. The candidate covariates to be tested as independents in the final model were considered on the basis of clinical evidence, information available in the literature and univariate analysis; in this case, the decision criterion was a p-value < 0.20. Thus, the final multivariate model included age >60years, hypertension, dyslipidemia, diabetes, sedentarism, and family history of premature CAD. The overall accepted level of significance was p < 0.05. Analyses were conducted in SPSS 20.

Results

From a total of 269 eligible patients, 25 did not attend further evaluations, resulting in a final sample of 244 patients for analysis. No silent myocardial infarction was suspected after enrollment according to patient medical history, EKG, and echocardiography. The atherosclerotic group frequency was 33% (n=80), without a significant age difference compared to the non-atherosclerotic group ( Table 1 ), who were also admitted slightly later. Gender distribution between groups was also similar (49% of female gender for both). Considering the main cardiovascular risk factors, no difference was found in the hypertension, dyslipidemia, diabetes, sedentarism, and obesity rates. On the other hand, the rates of smoking and family history of premature CAD were higher in the atherosclerotic group. Although the ASCVD score was higher for atherosclerotic IS, the median ASCVD for each group was >7.5% and <20%; therefore, both were classified as an intermediate risk. A greater median CCS was observed in atherosclerotic IS patients; however, with no statistical difference when compared to non-atherosclerotic IS patients.

Table 1
– Clinical characteristics of the Study Sample

To define the etiology, 87% of the patients underwent magnetic resonance imaging and 13% only a computed tomography. Neurologists disagreed in seven cases (3%), requiring the evaluation of a third neurologist. Atherosclerotic IS etiology was the most prevalent, followed by 74 (30%) due to cardio-aortic embolism, 37 (15%) caused by small artery occlusion, 14 (6%) due to other causes, and 39 (16%) of undetermined causes. As a group, there were 164 (67%) non-atherosclerotic cases. Among the 80 cases of atherosclerotic etiology, 18 (23%) were due to intracranial atherosclerosis. Atherosclerotic and non-atherosclerotic IS showed similar proportions of patients with CCS ≥ 100. Similarly, those with CCS zero also had equivalent proportions between groups ( Figure 1 ).

Figure 1
– Prevalence of coronary calcium score (CCS) categories in atherosclerotic and non-atherosclerotic groups.

As dichotomized IS etiology did not discriminate CCS ≥ 100, other potential contributors were analyzed. Considering clinically defined variables and those statistically different in the univariate analysis ( table 2 ), 6 variables entered the final adjusted model: age (dichotomized in ≥60 and <60 years old), hypertension, dyslipidemia, smoking, diabetes, and family history of premature CAD. Accounting for all those covariates, only age ≥60 years remained independently associated with CCS ≥100 ( Table 3 ).

Table 2
– Clinical and demographic characteristics from the overall ischemic stroke patients, by the higher coronary calcium score (CCS) cut-off point
Table 3
– Measures of association between clinical covariates and higher risk CCS (≥ 100), in final adjusted multivariate model, from the overall ischemic stroke patients.

Discussion

Our results showed that one third of stroke patients presented atherosclerotic etiology, closely followed by cardio-aortic embolism. We found that the coronary calcium score was similarly distributed between atherosclerotic and non-atherosclerotic IS, given no clinical or statistical differences were observed in the Agatston score or in the proportion of patients within a higher CAD risk, estimated by a CCS≥100. Among other potential contributors, only current smoking and family history of premature CAD could differentiate those with atherosclerotic IS when compared to non-atherosclerotic etiology– with approximately twice higher frequency for both characteristics in atherosclerotic IS.

Although ASCVD estimated risk was greater in the atherosclerotic IS group, as compared to the non-atherosclerotic IS group, both were classified in the intermediate risk stratum. Considering that the ASCVD equation potentially overestimates the risk, CCS could potentially improve the individual risk stratification.2020. Mortensen MB, Fuster V, Muntendam P, Mehran R, Baber U, Sartori S, et al. A simple disease-guided approach to personalize ACC/AHA-recommended statin allocation in elderly people: the BioImage Study. J Am Coll Cardiol. 2016;68(9):881-91.

Differently from our hypothesis, the risk according to CCS strata was similar between atherosclerotic and non-atherosclerotic IS. The proportion (approximately one third) of patients with a high CAD risk (CCS≥100) was similar for both groups. Interestingly, this finding was also true amongst patients with the lowest CAD risk (CCS zero), similarly distributed between the IS groups. Given that CCS categories did not distinguish IS etiologies, we tried to identify other potential contributors associated with CCS≥100. After accounting for clinically relevant covariates, only patients with 60 years or more had a higher likelihood of having a CCS ≥ 100 (OR 3.52; 95% CI 1.72-7.18). Age is a well-known risk factor for CAD, and its association with increasing CCS is in agreement with other authors who have demonstrated it in larger cohorts.2121. Greenland P, Blaha MJ, Budoff MJ, Erbel R, Watson KE. Coronary calcium score and cardiovascular risk. J Am Coll Cardiol. 2018;72(4):434-47.

CCS is a well-defined marker of CAD, which accurately reveals - with a low dose of radiation - an atherosclerotic burden in coronary arteries,2424. Yeboah J, Young R, McClelland RL, Delaney JC, Polonsky TS, Dawood FZ, et al. Utility of nontraditional risk markers in atherosclerotic cardiovascular disease risk assessment. J Am Coll Cardiol. 2016;67(2):139-47. and has a robust prognostic value.2525. Mitchell JD, Paisley R, Moon P, Novak E, Villines TC. Coronary artery calcium and long-term risk of death, myocardial infarction, and stroke: the Walter Reed Cohort Study. JACC Cardiovasc Imaging. 2018;11(12):1799-1806. An absolute increase in CCS is proportional to coronary event rates.2525. Mitchell JD, Paisley R, Moon P, Novak E, Villines TC. Coronary artery calcium and long-term risk of death, myocardial infarction, and stroke: the Walter Reed Cohort Study. JACC Cardiovasc Imaging. 2018;11(12):1799-1806. , 2626. Valenti V, Ó Hartaigh B, Heo R, Cho I, Schulman-Marcus J, Gransar H, et al. A 15-year warranty period for asymptomatic individuals without coronary artery calcium: a prospective follow-up of 9715 individuals. JACC Cardiovasc Imaging. 2015;8(8):900-9. Given some variation in the absolute CCS score, considering different cohorts, and a non-normal distribution, classifying patients within strata improves generalizability and clinical application.1717. Budoff MJ, Nasir K, McClelland RL, Detrano R, Wong N, Blumenthal RS, et al. Coronary calcium predicts events better with absolute calcium scores than age-sex-race/ethnicity percentiles - the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol. 2009;53(4):345-52. , 2727. Detrano R, Guerci AD, Carr JJ, Bild DE, Burke G, Folsom AR, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N Engl J Med. 2008;358(13):1336-45. Therefore, CCS≥100 Agatston units are associated with a significantly higher CAD risk,1515. Budoff MJ, Young R, Burke G, Carr JJ, Detrano RC, Folsom AR, et al. Ten-Year association of coronary artery calcium with atherosclerotic cardiovascular disease (ASCVD) events: the multi-ethnic study of atherosclerosis (MESA). Eur Heart J. 2018;39(25):2401-8. while CCS of zero predicts a very low long term risk of CAD.2626. Valenti V, Ó Hartaigh B, Heo R, Cho I, Schulman-Marcus J, Gransar H, et al. A 15-year warranty period for asymptomatic individuals without coronary artery calcium: a prospective follow-up of 9715 individuals. JACC Cardiovasc Imaging. 2015;8(8):900-9. As we showed, CCS keeps its ability to assess individual cardiovascular risk in stroke patients regardless of whether the IS etiology is atherosclerotic or not.

Regarding the shared clinical characteristics between IS and CAD, we expected that the atherosclerotic IS group would have a greater risk of CAD. However, our hypothesis was not confirmed. The similar CAD risk profile between the atherosclerotic and non-atherosclerotic IS groups can be attributed to a very high frequency – in both etiological groups – of traditional risk factors for atherosclerotic vascular diseases: ≥70% for arterial hypertension, dyslipidemia, and sedentary lifestyle. Moreover, the smoking and diabetes rates in our sample (32% and 28%, respectively) were higher than the prevalence observed in the Brazilian population: 15% for smoking and 9% for diabetes.2828. Brasil. Ministério da Saúde. DATASUS; 2015. [acesso em 1 nov 2017]. Disponível em: www.datasus.gov.br.
www.datasus.gov.br...
These findings and the relatively low mean age in this study, may reflect the poor control of modifiable risk factors indistinctively present in stroke survivors, irrespective of the etiology.

Emphasizing the close relationship between CAD and IS, Rivera et al. showed that, in autopsy studies, coronary plaques were present in 72% of patients with fatal stroke, in whom approximately 27% showed evidence of silent myocardial infarction. Interestingly, coronary atherosclerosis and myocardial infarction were prevalent regardless of the stroke subtypes.2929. Gongora-Rivera F, Labreuche J, Jaramillo A, Steg PG, Hauw JJ, Amarenco P. Autopsy prevalence of coronary atherosclerosis in patients with fatal stroke. Stroke. 2007;38(4):1203-10.

The relationship between extracranial atherosclerosis and CAD is well established.3030. Baber U, Mehran R, Sartori S, Schoos MM, Sillesen H, Muntendam P, et al. Prevalence, impact, and predictive value of detecting subclinical coronary and carotid atherosclerosis in asymptomatic adults: the BioImage Study. J Am Coll Cardiol. 2015;65(11):1065-74. However, this association with intracranial atherosclerosis is controversial3131. Conforto AB, Leite CC, Nomura CH, Bor-Seng-Shu E, Santos RD. Is there a consistent association between coronary heart disease and ischemic stroke caused by intracranial atherosclerosis? Arq Neuro-Psiquiatr. 2013;71(5):320-6. and seems to be less frequently associated with IS,3232. Wong LKS. Global burden of intracranial atherosclerosis. Int J Stroke. 2006;1(3):158-9. at least in the Brazilian population. Intracranial atherosclerosis is known to be more prevalent in the Asian population,3232. Wong LKS. Global burden of intracranial atherosclerosis. Int J Stroke. 2006;1(3):158-9. but it was described to be as high as 50% among male African Americans as well.3333. Qiao Y, Suri FK, Zhang Y, Liu L, prevalence and risk for intracranial atherosclerosis in a US community-based population. JAMA Cardiol. 2017;2(12):1341-8. We observed intracranial atherosclerosis in 23% of atherosclerotic IS cases. In our study, we used the SSS-CCS algorithm, which includes intracranial and extracranial atherosclerotic disease in the same atherosclerotic etiologic group; therefore, it could have been less restrictive, but also less discriminative for the association we aimed to define.

The low frequency of cryptogenic stroke can be attributed to the high quality of investigation and the use of SSS-CCS algorithm that standardized the etiologic classification, also leading to a low rate of disagreement among neurologists. Even with the exclusion of patients with prior CAD, the rate of 30% of stroke caused by cardio-aortic embolism is in part due to the presence of 11% of patients with Chagas’ cardiomyopathy. Chagas’s disease is a common clinical condition in Latin America, whose main mechanisms for stroke are embolism due to the presence of left ventricular apex aneurysm, severe systolic dysfunction, and atrial fibrillation.3434. Nunes MCP, Barbosa MM, Rocha MOC. Peculiar aspects of cardiogenic embolism in Gottesman R, Alonso A, et al. Racial differences in patients with Chagas’ cardiomyopathy: a transthoracic and transesophageal echocardiographic e from the multi-ethnic study of atherosclerosis. JAMA Cardiol. 2017;2(12):1332-40. study. J Am Soc Echocardiogr. 2005;18(7):761-7.

Our study has several limitations. First, considering that our facility is a rehabilitation center, admittance criteria may somehow bias overall IS frequency estimation. Some patients with delayed admittance may have a limited diagnostic precision of IS etiology. Patients with lacunar stroke were less prevalent than in the literature, which could likely be explained by frequently lower rehabilitation demands in this subgroup. In contrast, patients with severe neurologic limitations with a narrow rehabilitation potential are less frequently admitted, and for similar reasons, clinically unstable patients (treating an ongoing infection; with surgical demands; with decompensated endocrine-metabolic conditions) were not admitted for rehabilitation purposes. Although this could have included less severe coronary atherosclerosis, this was a common inclusion criterion for both groups. Second, this is a single center study and the sample size is relatively small, but CCS≥100 prevalence among IS survivors is consistent with other authors’ reports (30-45%).3535. Hur J, Lee KH, Hong SR, Suh YJ, Hong YJ, Lee HJ, et al. Prognostic value of coronary computed tomography angiography in stroke patients. Atherosclerosis. 2015;238(2):271-7. , 3636. Beigneux Y, Sablayrolles JL, Varenne O, Mas JL, Calvet D. Coronary artery calcium score improves the prediction of occult coronary artery stenosis in ischemic stroke patients. J Am Heart Assoc. 2016;5(11):e003770. Third, we expected a CCS≥100 proportion of 15 percentage points lower in the non-atherosclerotic IS group based on an arbitrary clinical observation, which is in agreement with our hypothesis; however, upon concluding the study, a 4 percentage points difference was observed ( Figure 1 ), which could have limited the power to detect between group differences regarding our main question.

The strength of this work is providing information on CAD risk according to CCS in stroke survivors from a Brazilian population and particularly in the non-atherosclerotic IS group, to which evidence is scarcer. According to the American Heart Association and American Stroke Association, the atherosclerotic IS population should be considered a high risk group for CAD, where preventive strategies should be adequately addressed; however, stroke is more heterogeneous than CAD, particularly within the non-atherosclerotic IS subtypes, where traditional risk factors and associated outcomes are less well determined.55. Lackland DT, Elkind MSV, D’Agostino Sr R, Dhamoon MS, Goff Jr DC, Higashida RT, et al. Inclusion of stroke in cardiovascular risk prediction instruments : a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43(7):1998-2027. Etiologies known not to be associated with a high risk for CAD, such as patent foramen ovale and cervical artery dissection, more frequent in younger patients, can be underrepresented in non-atherosclerotic IS groups, and could have been in our sample as well. Given the lower level of evidence to consider non-atherosclerotic IS as CAD risk equivalent, prognostic validation is still necessary; therefore, generalization should be interpreted cautiously. Data on this gap was provided in this study, showing that CCS can be used to address individual CAD risk in IS, showing similar risk profiles between atherosclerotic and non-atherosclerotic subtypes, at least in our population, given the high frequency of traditional CVD risk factors. It is important to note that even though CCS was not able to discriminate IS etiologies in our analysis, it does improve the individual risk stratification for CAD in the general population,3232. Wong LKS. Global burden of intracranial atherosclerosis. Int J Stroke. 2006;1(3):158-9. even in high-risk patients,3737. Malik S, Zhao Y, Budoff M, Nasir K, Blumenthal RS, Bertoni AG, et al. Coronary artery calcium score for long-term risk classification in individuals with type 2 diabetes and metabolic syndromefrom the multiethnic study of atherosclerosis. JAMA.2017;2(12):1332-40 whose applicability seems to be preserved for ischemic stroke patients as well, regardless of etiology.

Conclusions

In the studied population, ischemic stroke of atherosclerotic etiology did not present a greater risk of CAD when compared to non-atherosclerotic ischemic stroke according to CCS. Age equal to or over 60 years was the only variable associated with CCS ≥ 100. In ischemic stroke survivors, CCS should be considered for individual risk stratification for CAD, even in non-atherosclerotic etiologies.

Referências

  • 1
    Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics’2017 update: a report from the American Heart Association. Circulation. 2017;135(10):e146-603. Sciacca RR, Rundek T, Sacco RL, Elkind MS V. Recurrent stroke and cardiac risks after first ischemic stroke: the Northern Manhattan Study. Neurology. 2006;66(5):641-6.
  • 2
    Yoo J, Yang JH, Choi BW, Kim YD, Nam HS, Choi HY, et al. The frequency and risk of preclinical coronary artery disease detected using multichannel cardiac computed tomography in patients with ischemic stroke. Cerebrovasc Dis. 2012;33(3):286-94.
  • 3
    Touzé E, Varenne O, Chatellier G, Peyrard S, Rothwell PM, Mas JL. Risk of myocardial infarction and vascular death after transient ischemic attack and ischemic stroke: a systematic review and meta-analysis. Stroke. 2005;36(12):2748-55.
  • 4
    Dhamoon MS, Siacca RR, Rundek T, Sacco RL, Elkind MS V. Recurrent stroke and cardiac risks after first ischemic stroke: The Northern Manhattan Study. Neurolgy. 2006;66(5):641-6.
  • 5
    Lackland DT, Elkind MSV, D’Agostino Sr R, Dhamoon MS, Goff Jr DC, Higashida RT, et al. Inclusion of stroke in cardiovascular risk prediction instruments : a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012;43(7):1998-2027.
  • 6
    Arsava EM, Helenius J, Avery R, Sorgun MH, Kim GM, Pontes-Neto OM, et al. Assessment of the predictive validity of etiologic stroke classification. JAMA Neurol. 2017;74(4):419-26.
  • 7
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  • Study Association
    This study is not associated with any thesis or dissertation work.
  • Sources of Funding . There were no external funding sources for this study.

Publication Dates

  • Publication in this collection
    18 Jan 2021
  • Date of issue
    Dec 2020

History

  • Received
    06 Sept 2019
  • Reviewed
    26 Nov 2019
  • Accepted
    26 Nov 2019
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