Association of High-Sensitivity Troponin I with Cardiac and Cerebrovascular Events in Patient after Ischemic Stroke Open Access

Cardiovascular events after ischemic stroke are frequent observations in clinical practices [1, 2]. Patients with ischemic stroke can be prone to cardiac injury, particularly because of the advanced age at which strokes generally occur, the prevalence of cardiac comorbidities, and vascular risk factors. Importantly, cardiovascular complications after ischemic stroke are associated with a poor prognosis [3]. Therefore, the early recognition and risk stratification of cardiovascular diseases in patients with ischemic stroke are necessary; however, this is a challenging issue. Current guidelines on the early management of stroke recommend measuring cardiac troponin in all patients with suspected stroke [4]. Cardiac troponin specifically indicates myocardial injury; thus, elevated levels of troponin are widely used for the diagnosis of acute myocardial infarction (MI) [5]. The recent introduction of high-sensitive cardiac troponin (hs-cTn) assays has allowed the detection of previously undetectable levels of cardiac troponin in various clinical situations that do not exhibit acute cardiac injury. Elevated hs-cTn levels are highly specific in the early diagnosis of acute MI [6], and have been associated with the presence of subclinical structural heart disease or incident atrial fibrillation in general populations [7, 8]. In patients with ischemic stroke, hs-cTn elevation has been observed without concomitant acute MI [9‒12] and related to an increased risk of death or cardiovascular events [11, 12]. However, limited data exist regarding the association of hs-cTn with cardiovascular outcomes in patients after ischemic stroke, and the prognostic role of hs-cTn has not been established conclusively [13‒15]. Therefore, we aimed to explore the prognostic role of high-sensitivity cardiac troponin on cardiac and cerebrovascular outcomes in patients with ischemic stroke.

Between August 2014 and July 2017, 1,506 patients with acute-stage ischemic stroke were polled consecutively in a single-center registry at Konkuk University Medical Center, Seoul, Korea. Inclusion criteria were as follows: (1) patients admitted for a primary diagnosis of cerebral infarction with rapid-onset focal neurologic symptoms lasting at least 24 h within 7 days of onset, (2) 18 years of age or older, or (3) patients evaluated for high-sensitivity cardiac troponin I (hs-TnI) level at the time of admission for ischemic stroke. Exclusion criteria were as follows: (1) patients undergoing primary percutaneous coronary intervention (PCI) or urgent coronary artery bypass grafting (CABG) surgery during index admission with ischemic stroke, (2) patients with no follow-up visit after ischemic stroke, or (3) patients with insufficient clinical or laboratory data on initial evaluation and follow-up visit. A total of 1,019 patients were included in the final analysis. This observational study had no influence on patient treatment because of its retrospective design, and therapies were always provided at the discretion of attending physicians. The Institutional Review Board of Konkuk Medical Center approved the study protocol (KUH1010848) and waived the requirement for informed consent.

All patients underwent a complete baseline history survey, physical and neurologic examination, 12-lead electrocardiogram (ECG), and laboratory exam on admission. Clinical data, including demographic characteristics, conventional risk factors for stroke, medical comorbidities, reperfusion therapy, and the National Institutes of Health Stroke Scale (NIHSS) were obtained from the registered data. Cardiac troponin I was assessed using the ARCHITECT STAT High-Sensitive Troponin I immunoassay on an ARCHITECT i2000SR immunoassay analyzer (Abbott Diagnostics, Chicago, IL, USA). The limit of detection was 1.9 ng/L. The 99th percentile upper reference limit (URL) was defined as 20.7 ng/L for men and 16.1 ng/L for women. The study populations were categorized into two groups according to hs-TnI level of 99th percentile URL; patients with below 99th percentile URL of hs-TnI were allocated in non-elevated hs-TnI group and patients with at/above 99th percentile URL of hs-TnI were in elevated hs-TnI group. Coronary artery disease (CAD) was assessed using computed tomography coronary angiography or conventional coronary angiography and the decision on whether to evaluate CAD and choice of evaluation modality was left to cardiology consultants. CAD was defined as the presence of significant stenosis (≥50% luminal diameter narrowing) in at least one vessel in the coronary artery. Echocardiographic profiles were measured at an echocardiographic laboratory (Konkuk University Medical Center, Seoul, South Korea) according to a protocol established by the American Society of Echocardiography. Clinical, laboratory, and outcome data were collected by a trained study coordinator using a standardized case report form in registry data. Additional information was obtained by further inquiry into medical records, if necessary.

The primary outcome was major adverse cardiac and cerebrovascular event (MACCE), composite of all-cause death, readmission caused by stroke, heart failure (HF), or coronary revascularization during follow-up. Secondary outcomes were all-cause death, readmission caused by stroke, HF, and coronary revascularization during follow-up. Stroke causing readmission was defined as readmission with a primary diagnosis of cerebral infarction with rapid-onset focal neurologic symptoms lasting at least 24 h. HF causing readmission was defined as readmission with a primary diagnosis of HF based on major and minor clinical criteria described by the Framingham Heart Study [16]. Coronary revascularization causing readmission was defined as readmission with any PCI or CABG procedure during follow-up. Reperfusion therapy was defined as intravenous tissue plasminogen activator or intra-arterial reperfusion therapy or both. Renal insufficiency was defined as an estimated glomerular filtration rate lower than 60 mL/min/1.73 m² at initial presentation.

To compare baseline variables between the non-elevated hs-TnI and elevated hs-TnI group, continuous variables were compared using Student’s t test or Wilcoxon rank-sum test when applicable. Results were presented as mean ± standard deviation. Categorical data were analyzed using the χ² test. Cumulative event rates were estimated for clinical outcomes by the Kaplan-Meier method and were compared using log-rank tests. Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the incidence of clinical outcomes during follow-up between two groups. Multivariate Cox proportional hazard regression was performed to determine independent risk factors of all-cause mortality by adding significant variables (p < 0.05) into univariate models. Statistical analyses were performed with SPSS version 20.0 (IBM, SPSS, Chicago, IL, USA). All tests were two-tailed, and p < 0.05 was considered statistically significant.

Among 1,506 patients enrolled in the registry, 1,076 patients underwent hs-TnI evaluation at the time of acute ischemic stroke admission. Of these, 57 patients were excluded: 12 patients underwent primary PCI or urgent CABG surgery during index hospitalization with ischemic stroke, 18 patients had insufficient clinical or laboratory data at initial evaluation and follow-up visit, and 27 patients had no follow-up visit after ischemic stroke. Finally, 1,019 patients were eligible for the analysis and 708 patients were non-elevated hs-TnI group (<99th percentile URL of hs-TnI) and 311 patients were elevated hs-TnI group (≥99th percentile URL of hs-TnI). The median value of hs-TnI was 6.0 ng/L (25th percentile 2.3 ng/L, 75th percentile 30.8 ng/L) in overall population, 3.1 ng/L (25th percentile 1.9 ng/L, 75th percentile 6.8 ng/L) in non-elevated hs-TnI group and 112.0 ng/L (25th percentile 37.3 ng/L, 75th percentile 644.4 ng/L) in elevated hs-TnI group. The baseline characteristics are shown in Table 1. The patients with elevated hs-TnI group were older, had higher initial NIHSS, and had greater burden of medical comorbidity compared to the non-elevated hs-TnI group. In echocardiographic parameters, patients with elevated hs-TnI group were associated with low left ventricular ejection fraction, high left atrial volume index, and high E/e’. Among the study populations, 708 patients underwent coronary artery evaluation: 675 patients were evaluated with computed tomography coronary angiography, 80 patients were evaluated with convention coronary angiography, and 47 patients were evaluated with both. In 708 patients underwent coronary artery evaluation, 173 patients (24.4%) had CAD, and patients with elevated hs-TnI group have the higher prevalence of CAD compared to the non-elevated hs-TnI group (Table 1).

The overall median follow-up period was 22.5 (interquartile range: 5.0–38.8) months. Table 2 demonstrates the clinical outcomes of the study population and compare unadjusted and adjusted HRs between the non-elevated hs-TnI and elevated hs-TnI group. There was a higher risk of MACCE (adjusted HR: 3.12; 95% CI: 2.33–4.17; p < 0.01), all-cause death (adjusted HR: 4.15; 95% CI: 2.47–6.99; p < 0.01) and coronary revascularization causing readmission (adjusted HR: 3.12; 95% CI: 1.41–6.90; p < 0.01), HF causing readmission (adjusted HR: 2.76; 95% CI: 1.38–5.51; p < 0.01), and stroke causing readmission (adjusted HR: 1.73; 95% CI: 1.07–2.78; p = 0.02) in elevated hs-TnI group, compared to non-elevated hs-TnI group. Figure 1 demonstrates the unadjusted Kaplan-Meier curve depicting hazard for MACCE and all-cause mortality between two groups.

Multivariate Cox regression analysis was performed to identify predictors of MACCE during follow-up. The independent predictors of MACCE were elevated hs-TnI group and presence of CAD (Table 3).

In the present study, we investigated the association of hs-TnI elevation at ischemic stroke admission and following cardiac and cerebrovascular outcomes and explored the prognostic role of hs-TnI in patients with ischemic stroke. The results of this study can be summarized as follows: (1) patients in the hs-TnI elevation group at ischemic stroke were older and had a greater burden of medical comorbidities compared to the non-elevated hs-TnI group and had a higher risk of MACCE and all-cause mortality after ischemic stroke and (2) elevated hs-TnI group and presence of CAD were significant predictors of MACCE after ischemic stroke.

In real practice, patients with ischemic stroke frequently encountered incident cardiovascular disease or major adverse cardiovascular events, such as coronary revascularization, HF, or cardiovascular death. The risk of a major adverse cardiovascular event after ischemic stroke was a time-dependent association, highest within 30 days and decreasing but remaining significant to 1 year [17]. Accordingly, early recognition of cardiovascular events is an essential task and risk stratification is necessary after ischemic stroke. In the present study, we excluded patients undergoing primary PCI or urgent CABG during ischemic stroke admission, to reduce the hs-TnI elevation from concomitant acute MI. After exclusion, patients in the elevated hs-TnI group have a higher risk of MACCE, all-cause mortality and readmission caused by stroke, HF, or coronary revascularization after ischemic stroke, compared to the non-elevated hs-TnI group. These findings are consistent with those of previous studies; elevated cardiac troponin levels are associated with increased risk of cardiovascular events and poor prognosis in patients after ischemic stroke [11, 18, 19].

In this study, we dichotomized the study populations according to hs-cTn level of the 99th percentile URL. In previous study, similar manner was applied to define the hs-TnI elevation; there was a correlation between hs-TnI elevation and recurrent vascular events and death, and also demonstrated a dose-dependent relationship [20]. However, studies on specific level of hs-cTn associated with cardiovascular prognosis are limited. Therefore, further dedicated evaluation is necessary for specific hs-cTn levels under the 99th percentile URL related to cardiovascular outcomes in patients with ischemic stroke.

The pathophysiological mechanisms underlying the relationship between cardiac troponin and stroke are not yet fully understood. The possible explanation is that the elevation of cardiac troponin may be correlated with the individual state of hidden cardiac disease before ischemic stroke. In general populations, individuals with high cardiac troponin concentrations were associated with increased future cardiovascular disease, including CAD, ischemic stroke, and AF [21‒23]. In previous studies, algorithm for interpretation and classification of elevated cardiac troponin in patient with acute ischemic stroke was introduced [15, 24] and on-going study of Prediction of acute coronary syndrome in acute ischemic stroke (PRAISE) is focusing on identifying which patients required diagnostic and consequential therapeutic procedure [25]. In this study, large number of patients with acute ischemic stroke underwent coronary artery evaluation with CT coronary angiogram or conventional coronary angiogram. A quarter of patients with coronary evaluation had subclinical CAD and patients in the elevated hs-TnI group had higher prevalence of CAD compared to the non-elevated hs-TnI group. Furthermore, elevated hs-TnI and presence of CAD were independent predictors of MACCE. This result suggests that cardiac troponin may have a potential role in clinical decision making process of patients after ischemic stroke.

This study has several limitations. First, the study design was nonrandomized, retrospective, and observational, which may have significantly affected the results due to confounding factors. Although multivariate analysis was performed to adjust for these potential confounding factors, unmeasured variables could not be corrected. Second, although this registry consecutively included patients with ischemic stroke, one-third of patients in the registry were not evaluated for hs-TnI levels. Patients without initial hs-TnI data were excluded from the analysis. Therefore, selection bias associated with this factor is difficult to overcome. Third, serial assessment of hs-TnI was performed in very small number of patients and for the reason it was infeasible to identify dynamic change in hs-TnI over time. Fourth, despite of systematic screening of medical records, we might have missed events that were left either unreported by the patients or treated in hospitals other than the Konkuk University Medical Center. Fifth, another possible mechanism of cardiac troponin elevation in acute stroke is neurogenic catecholamine release leading to myocardial damage (so-called stroke-heart syndrome) [26]. Interestingly, the right insula cortex plays an important role within the central autonomic network, and its involvement in stroke has been associated with cardiac troponin elevation and mortality [27, 28]. Unfortunately, we were not able to collect information of neuroimaging about specific ischemic lesion patterns for analysis. However, in our registry, hs-TnI was evaluated at the time of admission for ischemic stroke and the early baseline troponin assessment reflects real practice, with daily encounters of mixed clinical presentation of ischemic stroke and other cardiac conditions.

In patients with ischemic stroke, elevated hs-TnI is independently associated with higher mortality and cardiac and cerebrovascular outcomes and may serve as a valuable prognostic factor in management after ischemic stroke. Our findings support the growing evidence that suggests hs-TnI may aid the individualized risk stratification of future cardiovascular events.

This study was approved by the Institutional Review Board of Konkuk Medical Center (KUH1010848). The Institutional Review Board of Konkuk Medical Center waived the requirement for informed consent due to the retrospective design.

The authors have no confliction of interest to declare.

No funding was received for this study.

Bum Sung Kim and Hyun-Joong Kim were involved in all stages of the manuscript including study design, data collection, drafting the paper, revising the paper, and final approval of the version to be published; Jeong-Jin Park was involved in all stages of the manuscript including study design, data collection, drafting the paper, and final approval of the version to be published. Haseong Chang and Sung Hea Kim were involved data collection, revising the paper, and data interpretation. Chang Hee Kwon and Sang-Man Chung were involved in study design, data collection, and revising the paper. Hahn Young Kim was involved in the study design, data interpretation, revising the paper, and final approval of the version to be published.

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.