Predictors of Concomitant Coronary Artery Disease and Major Cardiovascular Events in Patients with Acute Ischemic Stroke
Keywords: Acute ischemic stroke, carotid intima-media thickness, coronary artery disease, Framingham Heart Study Risk Score, troponin IKey Message: A high Framingham Heart Study Risk Score, elevated troponin levels and carotid plaques may be signs of concomitant coronary artery disease in stroke patients.
Coronary artery disease (CAD) and stroke are the leading cause of death. Ischemic stroke, which accounts for 80%–85% of all cerebrovascular diseases, develops as a partial or complete occlusion of cerebral blood flow and shares the same risk factors with CAD.
The prevalence of asymptomatic CAD in patients with ischemic stroke or transient ischemic attack has been explored by either noninvasive or invasive methods and reported as 20%–25% for coronary stenosis ≥50% in patients with ischemic stroke.,, In patients with fatal stroke, the prevalence of asymptomatic CAD is even higher, with up to 80% of patients having coronary plaques and 40% having coronary stenosis ≥50%.
Cardiovascular mortality is the most common cause of mortality in stroke patients. Although stroke recurrence is the most common vascular event in short term, the deaths due to myocardial infarction doubles the deaths due to recurrent stroke., Amarenco et al. reported that the presence and extent of asymptomatic stenosis on coronary angiography were strong predictors of major vascular events within two years in nonfatal stroke patients. However, the routine imaging of coronary arteries is not recommended in stroke patients. The American Heart Association/American Stroke Association statement recommends an individual risk assessment based on Framingham Risk Score (FRS) and presence of significant carotid disease to identify stroke patients who should be referred to noninvasive testing for CAD.
The aim of the study was to explore the prevalence and predictors of concomitant CAD and short-term major cardiovascular events in ischemic stroke patients.
The investigation conformed to the principles outlined in the Declaration of Helsinki. The study was approved by local ethics committee. All participants gave written informed consent.
One hundred and fifty consecutive patients aged ≥18 years admitted with acute ischemic stroke documented by neuroimaging were invited to participate in the study. TOAST classification system was used to define the stroke subtypes. After the exclusion of patients with stroke of other determined etiology and stroke of undetermined etiology, cardioembolic stroke or atrial fibrillation (24 patients), cancer (6 patients), dementia (4 patients), hemodynamically unstable or disabling stroke (9 patients), pregnancy (2 patients), and the remaining 105 patients with either large-artery atherosclerosis (84 patients) or small-vessel occlusion (21 patients) were included.
All patients underwent a complete cardiac evaluation including patient history, physical examination, and standard 12-lead electrocardiography (ECG). Patients were evaluated for the presence of cardiovascular risk factors, including hypertension, hyperlipidemia, diabetes, renal dysfunction, and smoking status. Twenty-seven stroke patients had already documented coronary stenosis ≥50% in at least one of their coronary arteries and were accepted as CAD group. Blood samples for plasma glucose, high sensitive (hs) C-reactive protein (CRP), troponin-I, creatine kinase-MB (CK-MB), N-terminal pro-brain natriuretic peptide (NT-proBNP), creatinine, and hemoglobin levels were noted.
Framingham risk score (FRS) and 10-year risk of myocardial infarction and cardiac death were calculated for each patient (https://www.framinghamheartstudy.org/fhs-risk-functions/cardiovascular-disease-10-year-risk/). The risk was defined as low (<10%), intermediate (10%–20%), or high (>20%). Cardiovascular risks of the patients were also assessed by the American College of Cardiology (ACC) and the American Heart Association (AHA) 10-year atherosclerotic cardiovascular disease (ASCVD; http://www.cvriskcalculator.com) and Systematic Coronary Risk Evaluation (SCORE; https://www.escardio.org/Education/Practice-Tools/CVD-prevention-toolbox/SCORE-Risk-Charts) system., Patients with SCORE ≥5% or ASCVD ≥7.5% were categorized as high CV risk patients.
All patients underwent a transthoracic echocardiographic study by a Philips iE33 echocardiography device (Philips Medical Systems, Andover, MA, USA) by an experienced cardiologist within the first 3 days following acute ischemic stroke. Conventional echocardiographic measurements were performed in accordance with the recommendations of the American Society of Echocardiography guidelines.
Endothelial functions were assessed noninvasively by brachial artery ultrasonography using a Vivid 7 (GE Healthcare, Horten, Norway) ultrasound system with a 10-MHz linear transducer based on the protocols described previously by a single-blinded cardiologist in a temperature-controlled room (22°C) in the morning after a fasting period of 8–12 h. The right brachial artery was imaged above the antecubital fossa in the longitudinal plane. Upon acquisition of a clear image, the surface of skin was marked and the arm and ultrasound probe were kept in the same position during the entire study. Continuous ECG monitoring was achieved. The diameter of the brachial artery was measured from longitudinal images in which the lumen-intima interface was visualized on the anterior and posterior walls at end-diastole. The mean of three highest measurements from five consecutive cardiac cycles was taken. After baseline measurements of lumen diameter and blood flow at rest, a sphygmomanometer cuff was placed on forearm and inflated to 250 mmHg for 5 min to induce arterial occlusion. Then, the cuff was deflated and lumen diameter was estimated 1 min after deflation to assess the endothelium-dependent flow-mediated dilatation (FMD). FMD was defined as the increase in luminal diameter in the first minute of reactive hyperemia versus baseline diameter, and was recorded as both a percentage and an absolute change. The intraobserver variability for repeated measurements (the mean of the differences) was 0.00 ± 0.11 mm in our laboratory.
Carotid artery intima-media thickness (CIMT) and presence of plaque in carotid arteries were evaluated by carotid ultrasonography by the same blinded cardiologist via a commercially available Vivid 7 (GE Healthcare, Horten, Norway) ultrasound system with a 10-MHz linear transducer. Each subject was examined in the supine position in a semi-dark room. The carotid artery was investigated bilaterally and scanned at the level of the bifurcation of common carotid arteries. The image was focused on the far wall of the artery. CIMT was measured on the longitudinal views of the far wall of bilateral distal common carotid arteries (1–3 cm proximal to the carotid bifurcation) at the diastolic phase. CIMT was taken as the distance from the leading edge of first echogenic line to the leading edge of second echogenic line and expressed as the mean of six measurements (three on each side). Plaque was defined as an intima-media thickness ≥1.5 mm measured from media-adventitia interface to intima-lumen interface or a focal structure protruding into arterial lumen ≥0.5 mm or 50% of the adjacent intima-media thickness.
All patients underwent 24-h ambulatory blood pressure monitoring on the same day with echocardiography and ultrasound examinations. The device was programmed to measure blood pressure regularly every 30 min during 24-h period. The cuff was placed around the nondominant arm and patients were instructed to keep their arm still during measurements. Sleep and awake periods were assessed based on the self-information of patients and nurse charts. Nocturnal blood pressure dipping was calculated as: 100× [1–(sleep systolic blood pressure/awake systolic blood pressure)]. Patients with decreased nighttime mean systolic blood pressures ≥10% were defined as dippers while patients with <10% decrease were defined as nondippers. Reverse dipping (nocturnal rise in night-time blood pressure) and extreme dipping (nocturnal fall in night-time blood pressure >20%) are also associated with greater risk of intracranial hemorrhage and fatal stroke, silent cerebral infarct, and cerebral ischemia. The patients having reverse dipping or extreme dipping were included in the nondipper group due to the small number (3 patients). Blood pressure load was calculated as the percentage of ambulatory systolic and diastolic blood pressures that exceed 140/90 mmHg in day time (awake) and 120/80 mmHg in nocturnal (asleep) measurements.
Patients were followed 6 months for the detection of major cardiovascular events including myocardial infarction, recurrent stroke, or cardiovascular death.
Statistical analyses were performed by a statistical software (SPSS 11.0 for windows, Chicago, IL). Continuous variables were checked for normal distribution by the Kolmogorov–Smirnov test and were expressed as mean ± standard deviation. Student's t-test was used to compare the normally distributed continuous parameters while Mann–Whitney U test was used to compare the nonparametric continuous variables. Categorical variables were expressed in numbers. Pearson's Chi-square test was used to compare categorical parameters. Receiver operating characteristic (ROC) curve analysis and logistic regression analysis were performed to explore the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) with “odds ratio” (OR) and 95% confidence interval (CI) of the single and combined risk parameters to predict CAD. A P value of <0.05 was considered as statistically significant.
One hundred and five ischemic stroke patients with large-artery atherosclerosis (84 patients) or small-vessel occlusion (21 patients) were included in the study and the mean age of the patients was 64.3 ± 15.0 years and 61 patients were male. Twenty-seven of the patients (25.7%) had already documented CAD. The characteristics and laboratory parameters of the patients are shown in [Table 1]. The frequencies of hypertension, diabetes, and hyperlipidemia and mean troponin I values were significantly higher in the CAD group. Hs-CRP and NT-proBNP values were also higher in the CAD group, but the differences were not statistically significant. The mean cardiovascular risk scores are shown in [Table 2]. The stroke patients with known CAD had significantly higher FRS and ASCVD.
Conventional echocardiographic, FMD, CIMT, and ambulatory blood pressure measures are shown in [Table 3]. Stroke patients with known CAD had significantly larger left atrium and lower left ventricular ejection fraction. They had lower FMD measures and higher CIMT, but the differences were not statistically significant. However, they had significantly more carotid plaque. There were not any significant differences in ambulatory blood pressure monitoring measures between the groups other than systolic blood pressure load.
ROC analysis determined cut-off values as ≥22% for FRS, ≥11% for ACC/AHA ASCVD, ≥4% for SCORE index, ≥0.05 ng/mL for Troponin I, and ≥0.80 mm for carotid artery intima-media thickness to predict stroke patients with CAD. [Table 4] shows the sensitivity, specificity, PPV, and NPV values of single or combined parameters to predict CAD in our cohort.
During the 6 months of follow-up, 22 stroke patients (6 patients in the known CAD group and 16 patients in the non-CAD group) had experienced major cardiovascular events including myocardial infarction, recurrent stroke, or cardiovascular death. Among the six stroke patients in the known CAD group, two had developed myocardial infarction (one died, one survived) and four had recurrent stroke (one died, three survived). Among the 16 stroke patients without known CAD, seven had myocardial infarction (two died, five survived) and nine had recurrent stroke (two died, seven survived) and the characteristics of these patients are shown in [Table 5]. These patients had higher FRS and ACC/AHA ASCVD risk scores and hs-CRP measures compared to the non-CAD stroke patients without any cardiovascular event.
Since CAD and stroke share the same risk factors, it is not surprising to expect coronary atherosclerosis in a patient with stroke. Nearly 20%–40% of the stroke patients are shown to have concomitant coronary artery stenosis.,,,, In our study, the prevalence of CAD was 25.7%, which is consistent with the previous studies. Nevertheless, we might underestimate the exact prevalence of CAD in our study as we did not perform invasive or noninvasive coronary angiography to the patients during their hospitalization, which might be considered as a study limitation. Routine coronary angiography is not recommended in asymptomatic patients and even in patients with stable CAD, routine revascularization is not superior to intensive medical therapy in improving major clinical outcomes.,, Since there was no indication to perform new coronary angiography to the patients, we aimed to determine the characteristics of the stroke patients with already known CAD and identify the predictors of concomitant CAD.
One of the important findings of our study was the use of FRS and ACC/AHA ASCVD in predicting CAD in stroke patients. Stroke patients with known CAD had higher FRS and ACC/AHA ASCVD scores and the prevalence of FRS ≥20% was higher in these patients. ROC analysis determined cut-off values as ≥22% for FRS and ≥11% for ACC/AHA ASCVD with a sensitivity of 88.9% and 92.6%, respectively. Although the frequency of hypertension, diabetes, and hyperlipidemia was higher in stroke patients with known CAD, there were no significant differences in the blood pressure, glucose, and lipid measures between the groups. Therefore, instead of assessing traditional CAD risk factors individually, assessing the total CAD risk of patients through the FRS or ACC/AHA ASCVD scores might be better. Our findings were consistent with the current guideline, which recommends that stroke patients with an FRS-predicted 10-year CAD risk ≥20% should be considered for noninvasive testing for asymptomatic CAD.
Stroke patients with known CAD had lower FMD measures and higher CIMT, but the differences were not statistically significant. This might be due to the association of endothelial dysfunction with multiple cardiac risk factors. Carotid plaques were significantly more prevalent in stroke patients with CAD. Amarenco et al. showed a significant association between the presence of CAD and carotid and femoral atherosclerosis in stroke patients with either known or no known history of CAD. They reported that having both femoral and carotid artery plaques was a good predictor of the presence of CAD with a PPV of 84% and NPV of 44%. Calvet et al. showed that both FRS and the presence of at least one cervicocephalic stenosis ≥50% were significantly associated with ≥50% asymptomatic CAD and developed a 5-point score using FRS-predicted-10-year CAD risk and cervicocephalic artery stenosis to predict occult ≥50% coronary artery stenosis risk. However, in our study, the addition of carotid plaque did not add much to the predictive power of FRS or ASCVD.
In a stroke cohort, the cumulative occurrence of subsequent events including secondary stroke, acute myocardial infarction, and vascular deaths was shown to be 4.2%, 6.5%, 9.8%, and 11.8% at 0.5, 1, 2, and 3 years, respectively. In our study, during the 6 months of follow-up, 22 stroke patients (6 patients in the CAD group and 16 patients in the non-CAD group) had experienced major cardiovascular events including myocardial infarction, recurrent stroke, or cardiovascular death. The stroke patients without known CAD who had experienced major cardiovascular events had higher FRS and ASCVD risk scores and hs-CRP measures compared to the non-CAD stroke patients without any cardiovascular event. CRP was shown as an independent predictor of future cerebrovascular events and survival after acute ischemic stroke., However, only a single study explored the prognostic value of FRS in ischemic stroke and showed that higher FRS in hospitalized ischemic stroke patients was associated with death or disability at discharge.
Troponin elevation is frequently observed in ischemic stroke. Interestingly, in our study, stroke patients with known CAD had higher levels of elevated troponin I. Similar to our finding, a recent study showed that troponin elevation was associated with the previous ischemic heart disease. Troponin elevation in the acute stage of ischemic stroke is shown to be associated with both short-term and long-term mortality., However, in our study, we did not find an association between troponin I levels and short-term prognosis.
Women may differ from men in the distribution of risk factors and stroke subtype, stroke severity, and outcome. Arboix et al. found that lacunar infarction was more frequent in men and cardioembolic infarction in women and acute stroke in women was associated with high risk of death in the immediate post-stroke phase and low probability of early full neurological recovery. Similarly, different stroke types might also be associated with CAD and prognosis differently. In their review, Arboix et al. mentioned about the concerns that lacunar ischemic strokes resulting usually from occlusion of a single penetrating artery by microatheromas or lipohyalinosis and rarely from an intracranial atheromatous branch disease might not possibly be an intracranial atheromatous disease because of the failure of dual antiplatelet treatment in the secondary prevention studies. They also noted that recurrent lacunar stroke might be associated with more severe clinical features. Because of the small sample size, we could not make comparisons according to gender or stroke subtype.
The major limitation of our study was a small sample size and the study was a single-center study. Second, we might underestimate the true prevalence of CAD in our cohort as we did not perform coronary angiography and diagnosis of CAD was based on the previous medical records of coronary angiography. Another limitation was the validity of the risk assessment systems in determining the risk of stroke patients as they are mostly used to determine the risk in patients without known cardiovascular disease. Finally, our results do not apply to patients with cardioembolic stroke as these patients were excluded from the study.
The presence and extent of asymptomatic stenosis on coronary angiography are strong predictors of major vascular events in patients with nonfatal cerebral infarction. Identification of the high-risk patients with concomitant asymptomatic CAD is important in stroke patients. Guidelines recommend all ischemic stroke patients be assessed for cardiovascular risk to identify those at a greater likelihood of morbidity and mortality from asymptomatic CAD. Our study suggests stroke patients with higher FRS and troponin-I levels and carotid artery plaques might be further investigated for the presence of concomitant CAD and those with higher FRS and hs-CRP should be closely followed for subsequent cardiovascular events.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]