Sex Differences in Outcomes of Acute Myocardial Injury After Stroke.

BACKGROUND: Sex differences in presentation, treatment, and prognosis of cardiovascular disorders are well recognized. Although an association between acute myocardial injury and mortality after ischemic stroke has been demonstrated, it is unclear whether prevalence and outcome of poststroke acute myocardial injury differ between women and men. METHODS AND RESULTS: We prospectively screened consecutive patients with acute ischemic stroke and serial high-sensitivity cardiac troponin T measurements admitted to our center. Acute myocardial injury was defined as at least 1 high-sensitivity cardiac troponin T value above the upper reference limit (14 ng/L) with a rise/fall of >20%. Rates of acute myocardial injury were also calculated using sex-specific high-sensitivity cardiac troponin T cutoffs (women upper reference limit, 9 ng/L; men upper reference limit, 16 ng/L). Logistic regression analyses were performed to evaluate the association between acute myocardial injury and outcomes. Of 1067 patients included, 494 were women (46%). Women were older, had a higher rate of known atrial fibrillation, were more likely to be functionally dependent before admission, had higher stroke severity, and more often had cardioembolic strokes (all P values <0.05). The crude prevalence of acute myocardial injury differed by sex (29% women versus 23% men, P=0.024). Statistically significant associations between acute myocardial injury and outcomes were observed in women (7-day in-hospital mortality: adjusted odds ratio [aOR], 3.2 [95% CI, 1.07-9.3]; in-hospital mortality: aOR, 3.3 [95% CI, 1.4-7.6]; modified Rankin Scale score at discharge: aOR, 1.6 [95% CI, 1.1-2.4]) but not in men. The implementation of sex-specific cutoffs did not increase the prognostic value of acute myocardial injury for unfavorable outcomes. CONCLUSIONS: The prevalence of acute myocardial injury after ischemic stroke and its association with mortality and greater disability might be sex-dependent. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03892226.

Heart rate turbulence in acute ischemic stroke.

BACKGROUND: Heart rate turbulence (HRT), an ECG-based marker of autonomic cardiac regulation, has shown high prognostic value in patients with established cardiovascular diseases, while data in patients with acute ischemic stroke are scarce. PATIENTS AND METHODS: The HRT parameters turbulence onset and turbulence slope were analyzed using Holter-ECG recordings from patients with acute ischemic stroke, consecutively enrolled in the prospective observational HEBRAS study. HRT was categorized as normal (category 0; both parameters normal), abnormal (category 1; one parameter abnormal), or severely abnormal (category 2; both parameters abnormal). Outcomes of interest were functional outcome according to modified Rankin Scale (mRS) score at 3 months, mortality at 1 year, newly detected atrial fibrillation (AF), and evidence of focal myocardial fibrosis on cardiovascular MRI. RESULTS: HRT was assessed in 335 patients in sinus rhythm (median age 69 years, 37% female, median NIHSS score 2 on admission), including 262 (78%) with normal HRT, 47 (14%) with abnormal and 26 (8%) with severely abnormal HRT. Compared with normal HRT, severely abnormal HRT was associated with increased disability [higher mRS] at 3 months (adjusted odds ratio [aOR]: 2.9, 95% confidence interval [CI]: 1.3-6.6), new AF (aOR: 3.5, 95% CI: 1.1-10.6), MRI-detected myocardial fibrosis (aOR: 5.8, 95% CI: 1.3-25.9), but not with mortality at 1 year after stroke (aOR: 3.0, 95% CI: 0.7-13.9). Abnormal HRT was not associated with the analyzed outcomes. CONCLUSIONS: Severely abnormal HRT was associated with increased disability and previously unknown cardiac comorbidities. The potential role of HRT in selecting patients for extended AF monitoring and cardiac imaging should be further investigated.

Data lake-driven analytics identify nocturnal non-dipping of heart rate as predictor of unfavorable stroke outcome at discharge.

BACKGROUND: Post-stroke heart rate (HR) and heart rate variability (HRV) changes have been proposed as outcome predictors after stroke. We used data lake-enabled continuous electrocardiograms to assess post-stroke HR and HRV, and to determine the utility of HR and HRV to improve machine learning-based predictions of stroke outcome. METHODS: In this observational cohort study, we included stroke patients admitted to two stroke units in Berlin, Germany, between October 2020 and December 2021 with final diagnosis of acute ischemic stroke or acute intracranial hemorrhage and collected continuous ECG data through data warehousing. We created circadian profiles of several continuously recorded ECG parameters including HR and HRV parameters. The pre-defined primary outcome was short-term unfavorable functional outcome after stroke indicated through modified Rankin Scale (mRS) score of > 2. RESULTS: We included 625 stroke patients, 287 stroke patients remained after matching for age and National Institute of Health Stroke Scale (NIHSS; mean age 74.5 years, 45.6% female, 88.9% ischemic, median NIHSS 5). Both higher HR and nocturnal non-dipping of HR were associated with unfavorable functional outcome (p < 0.01). The examined HRV parameters were not associated with the outcome of interest. Nocturnal non-dipping of HR ranked highly in feature importance of various machine learning models. CONCLUSIONS: Our data suggest that a lack of circadian HR modulation, specifically nocturnal non-dipping, is associated with short-term unfavorable functional outcome after stroke, and that including HR into machine learning-based prediction models may lead to improved stroke outcome prediction.

Elevation of cardiac biomarkers in stroke is associated with pathological findings on cardiac MRI-results of the HEart and BRain interfaces in Acute Stroke study.

INTRODUCTION: Cardiac biomarkers, such as high-sensitivity cardiac troponin T (hs-cTnT), are frequently elevated in ischemic stroke patients but the mechanisms underlying this elevation are insufficiently understood. We determined the presence of cardiac damage, assessed using cardiac magnetic resonance imaging (CMR), in stroke patients with elevated hs-cTnT and brain natriuretic peptide (BNP). METHODS: This is a post hoc analysis of the prospective, investigator-initiated, cross-sectional HEart and BRain interfaces in Acute Stroke (HEBRAS) study. All patients underwent the measurement of hs-cTnT and BNP as well as gadolinium-enhanced CMR in the acute phase of ischemic stroke. We performed unadjusted and adjusted logistic regression models to assess the association between hs-cTnT and BNP elevation and the presence of pathological CMR findings. RESULTS: Two hundred and thirty-three stroke patients (median age 67 years, 33% female) were included, of whom 43 (21%) had elevated hs-cTnT and 109 (47%) had elevated BNP. Hundred of the 233 (43%) patients had pathological findings on CMR had focal fibrosis as detected by late-gadolinium enhancement (LGE) in 51 (23%), left-ventricular hypertrophy (LVH) in 38 (16%), reduced LVEF in 32 (14%), and left-atrial dilatation in 34 (15%). After adjustment for potential confounders, both hs-cTnT (adjOR 5.0 (95%CI 2.1-11.7), p < 0.001) and BNP (adjOR 4.1 (95%CI 2.3-7.3), p < 0.001) were significantly associated with pathological findings on CMR. Hs-cTnT was associated with LGE, LVEF, and LVH, whereas BNP was associated with left-atrial dilatation and LVEF, LVH. CONCLUSION: Elevated cardiac biomarkers in acute stroke including CMR are strongly associated with pathological findings on CMR. In acute stroke patients, the elevation of cardiac biomarkers may identify patients who require a more thorough cardiology work-up.

Frequency, associated variables, and outcomes of acute myocardial injury according to the fourth Universal Definition of Myocardial Infarction in patients with acute ischemic stroke.

Background: Myocardial injury as indicated by elevation of cardiac troponin levels is common after acute ischemic stroke (AIS) and linked to poor outcomes. Previous studies rarely reported on serial hs-cTn measurements to distinguish whether myocardial injury is acute or chronic. Thus, little is known about frequency, associated variables, and outcome of acute myocardial injury in AIS. Methods and patients: In this single-centered observational cohort study, from 01/2019 to 12/2020, consecutive patients with neuroimaging-confirmed AIS <48 h after symptom onset, and serial troponin measurements within the first 2 days after admission (Roche Elecsys®, hs-cardiac troponin T) were prospectively registered. Acute myocardial injury was defined according to the fourth Universal Definition of Myocardial Infarction (troponin above the upper reference limit and rise/fall>20%). Outcomes of interest were in-hospital mortality and unfavorable functional status at discharge (modified Rankin Scale >1). Results: Out of 1067 analyzed patients, 25.3% had acute myocardial injury, 40.4% had chronic myocardial injury and 34.3% had no myocardial injury. Older age, higher stroke severity, thrombolytic treatment, and impaired kidney function were independently associated with acute myocardial injury. In-hospital mortality was higher in patients with acute myocardial injury than in those without (13% vs 3%, adjusted OR, 2.9% [95% CI, 1.6-5.5]). Compared with no myocardial injury, both acute and chronic myocardial injury were associated with unfavorable functional status at discharge (adjusted OR, 1.6 [95% CI, 1.1-2.5] and OR, 1.7 [95% CI, 1.2-2.4], respectively). Conclusions: A quarter of patients with AIS have evidence of acute myocardial injury according to the fourth Universal Definition of Myocardial Infarction. The strong association with in-hospital mortality highlights the need for clinical awareness and future studies on underlying mechanisms.

Clinical correlates and prognostic impact of neurologic disorders in Takotsubo syndrome.

Cardiac alterations are frequently observed after acute neurological disorders. Takotsubo syndrome (TTS) represents an acute heart failure syndrome and is increasingly recognized as part of the spectrum of cardiac complications observed after neurological disorders. A systematic investigation of TTS patients with neurological disorders has not been conducted yet. The aim of the study was to expand insights regarding neurological disease entities triggering TTS and to investigate the clinical profile and outcomes of TTS patients after primary neurological disorders. The International Takotsubo Registry is an observational multicenter collaborative effort of 45 centers in 14 countries (ClinicalTrials.gov, identifier NCT01947621). All patients in the registry fulfilled International Takotsubo Diagnostic Criteria. For the present study, patients were included if complete information on acute neurological disorders were available. 2402 patients in whom complete information on acute neurological status were available were analyzed. In 161 patients (6.7%) an acute neurological disorder was identified as the preceding triggering factor. The most common neurological disorders were seizures, intracranial hemorrhage, and ischemic stroke. Time from neurological symptoms to TTS diagnosis was ≤ 2 days in 87.3% of cases. TTS patients with neurological disorders were younger, had a lower female predominance, fewer cardiac symptoms, lower left ventricular ejection fraction, and higher levels of cardiac biomarkers. TTS patients with neurological disorders had a 3.2-fold increased odds of in-hospital mortality compared to TTS patients without neurological disorders. In this large-scale study, 1 out of 15 TTS patients had an acute neurological condition as the underlying triggering factor. Our data emphasize that a wide spectrum of neurological diseases ranging from benign to life-threatening encompass TTS. The high rates of adverse events highlight the need for clinical awareness.

Cardiomyocyte Injury Following Acute Ischemic Stroke: Protocol for a Prospective Observational Cohort Study.

BACKGROUND: Elevated cardiac troponin, which indicates cardiomyocyte injury, is common after acute ischemic stroke and is associated with poor functional outcome. Myocardial injury is part of a broad spectrum of cardiac complications that may occur after acute ischemic stroke. Previous studies have shown that in most patients, the underlying mechanism of stroke-associated myocardial injury may not be a concomitant acute coronary syndrome. Evidence from animal research and clinical and neuroimaging studies suggest that functional and structural alterations in the central autonomic network leading to stress-mediated neurocardiogenic injury may be a key underlying mechanism (ie, stroke-heart syndrome). However, the exact pathophysiological cascade remains unclear, and the diagnostic and therapeutic implications are unknown. OBJECTIVE: The aim of this CORONA-IS (Cardiomyocyte injury following Acute Ischemic Stroke) study is to quantify autonomic dysfunction and to decipher downstream cardiac mechanisms leading to myocardial injury after acute ischemic stroke. METHODS: In this prospective, observational, single-center cohort study, 300 patients with acute ischemic stroke, confirmed via cerebral magnetic resonance imaging (MRI) and presenting within 48 hours of symptom onset, will be recruited during in-hospital stay. On the basis of high-sensitivity cardiac troponin levels and corresponding to the fourth universal definition of myocardial infarction, 3 groups are defined (ie, no myocardial injury [no cardiac troponin elevation], chronic myocardial injury [stable elevation], and acute myocardial injury [dynamic rise/fall pattern]). Each group will include approximately 100 patients. Study patients will receive routine diagnostic care. In addition, they will receive 3 Tesla cardiovascular MRI and transthoracic echocardiography within 5 days of symptom onset to provide myocardial tissue characterization and assess cardiac function, 20-min high-resolution electrocardiogram for analysis of cardiac autonomic function, and extensive biobanking. A follow-up for cardiovascular events will be conducted 3 and 12 months after inclusion. RESULTS: After a 4-month pilot phase, recruitment began in April 2019. We estimate a recruitment period of approximately 3 years to include 300 patients with a complete cardiovascular MRI protocol. CONCLUSIONS: Stroke-associated myocardial injury is a common and relevant complication. Our study has the potential to provide a better mechanistic understanding of heart and brain interactions in the setting of acute stroke. Thus, it is essential to develop algorithms for recognizing patients at risk and to refine diagnostic and therapeutic procedures. TRIAL REGISTRATION: Clinicaltrials.gov NCT03892226; https://www.clinicaltrials.gov/ct2/show/NCT03892226. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/24186.

Neurological update: use of cardiac troponin in patients with stroke.

Cardiac troponin is a specific and sensitive biomarker to identify and quantify myocardial injury. Myocardial injury is frequently detected after acute ischemic stroke and strongly associated with unfavorable outcomes. Concomitant acute coronary syndrome is only one of several possible differential diagnoses that may cause elevation of cardiac troponin after stroke. As a result, there are uncertainties regarding the correct interpretation and optimal management of stroke patients with myocardial injury in clinical practice. Elevation of cardiac troponin may occur as part of a 'Stroke-Heart Syndrome'. The term 'Stroke-Heart Syndrome' subsumes a clinical spectrum of cardiac complications after stroke including cardiac injury, dysfunction, and arrhythmia which may relate to disturbances of autonomic function and the brain-heart axis. In this review, we provide an up-to-date overview about prognostic implications, mechanisms, and management of elevated cardiac troponin levels in patients with acute ischemic stroke.

Association Between High-Sensitivity Cardiac Troponin and Risk of Stroke in 96 702 Individuals: A Meta-Analysis.

Background and Purpose- Our study aim was to estimate risk of incident stroke based on levels of hs-cTn (high-sensitivity cardiac troponin), a specific biomarker indicating myocardial injury, in the general population, patients with atrial fibrillation, and patients with previous stroke. Methods- Embase, PubMed, and Web of Science were searched until March 14, 2019 to identify relevant articles. Randomized controlled trials and cohort studies assessing the risk of incident stroke based on hs-cTn were eligible. Pooled adjusted hazard ratios including 95% CI were calculated using a random-effects model due to study heterogeneity per population, coding of hs-cTn (categorical/continuous data), per hs-cTn subunit (T or I), for low risk of bias, and for all-cause and ischemic stroke separately. Results- We included 17 articles with 96 702 participants. In studies conducted in the general population (n=12; 77 780 participants), the pooled adjusted hazard ratio for incident stroke was 1.25 (CI, 1.10-1.40) for high versus low hs-cTn (as defined by included studies) during an average follow-up of 1 to 20 years (median 10). When categorical data were used, this was increased to 1.58 (CI, 1.26-1.90). The results were robust when accounting for stroke classification (all-cause stroke/ischemic stroke), hs-cTn subunit, risk of bias, and coding of hs-cTn. In patients with atrial fibrillation (4 studies; 18 725 participants), the pooled adjusted hazard ratio for incident stroke was 1.95 (CI, 1.29-2.62) for high versus low hs-cTn. Due to lack of data (one study, 197 participants), no meta-analysis could be performed in patients with previous stroke. Conclusions- This meta-analysis suggests that hs-cTn can be regarded as a risk marker for incident stroke, with different effect size in different subgroups. More research about the association between hs-cTn and incident stroke in high-risk populations is needed, especially in patients with history of ischemic stroke.

Effects of Anodal Transcranial Direct Current Stimulation and Serotonergic Enhancement on Memory Performance in Young and Older Adults.

In the absence of effective therapies for dementia and its precursors, enhancing neuroplasticity by means of non-invasive brain stimulation such as anodal transcranial direct current stimulation (atDCS) might be a promising approach to counteract or delay the onset of cognitive decline, but effect sizes have been moderate so far. Previous reports indicate that increasing serotonin levels may enhance atDCS-induced neuroplasticity. However, evidence for serotonergic modulation of atDCS effects on memory is still lacking. Here, we conducted a double-blind, randomized, sham-/placebo-controlled trial to investigate the impact of a selective serotonin reuptake inhibitor (SSRI; single dose of 20 mg citalopram) and atDCS over the right temporoparietal cortex (1 mA, 20 min) on memory formation. Twenty young and 20 older subjects completed an object-location learning task in each of the four conditions: sham+placebo, sham+SSRI, atDCS+placebo, and atDCS+SSRI. Outcome measures were performance in immediate (primary outcome) and delayed cued recall. While we found an SSRI effect, but no statistically significant effect of atDCS on immediate recall scores, young and older adults benefited most from the combined application (comparisons: atDCS+SSRI>atDCS+placebo and atDCS+SSRI>sham+placebo). Thus, our data provide evidence that atDCS improves memory formation if serotonergic neurotransmission is enhanced simultaneously. Further studies are needed to assess whether these findings extend to clinical populations with memory impairment and translate into clinically relevant improvements after long-term serotonergic enhancement and repeated stimulation.