Cardiomyocyte Injury Following Acute Ischemic Stroke: Protocol for a Prospective Observational Cohort Study (Preprint)

Abstract

BACKGROUND Elevated cardiac troponin (cTn) indicating cardiomyocyte injury is common after acute ischemic stroke (AIS) and associated with poor functional outcome. Myocardial injury is part of a broad spectrum of cardiac complications that may occur after AIS. 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, 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 (i.e., ‘Stroke-Heart-Syndrome’). However, the exact pathophysiological cascade remains unclear and diagnostic and therapeutic implications are unknown. OBJECTIVE The aim of the Cardiomyocyte injury following Acute Ischemic Stroke (CORONA-IS) study is to quantify autonomic dysfunction and to decipher downstream cardiac mechanisms leading to myocardial injury after AIS. METHODS In this prospective, observational, single-center cohort study, 300 patients with acute ischemic stroke, confirmed via cerebral MRI and presenting within 48h of symptom onset, will be recruited during in-hospital stay. Based on high-sensitivity cardiac troponin levels (hs troponinT, Gen. V, Roche Elecsys®) and corresponding to the fourth universal definition of myocardial infarction, three groups are defined (i.e. ‘no myocardial injury’ [no cTN 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 and additionally, 1) 3T cardiovascular MRI and transthoracic echocardiography within 5 days of symptom onset to provide myocardial tissue characterization and assess cardiac function, 2) 20-minute high-resolution ECG-recording for analysis of cardiac autonomic function, and 3) extensive biobanking. A follow-up for cardiovascular events will be conducted 3 and 12 months after inclusion. RESULTS After a four-month pilot phase, recruitment started in April 2019. We estimate a recruitment period of approximately three years to include 300 patients with complete CMR 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 interaction in the setting of acute stroke. This will be essential to develop algorithms for recognizing patients at risk and refine diagnostic and therapeutic procedures. CLINICALTRIAL Clinicaltrials.gov NCT03892226

TRoponin of Unknown origin in STroke evaluated by multi-component cardiac Magnetic resonance Imaging – The TRUST-MI study

“…Apart from acute thrombotic CAD, a mismatch of oxygen supply and demand is considered as a potential reason for increased troponin levels. Various other factors such as rhythm disturbances, blood pressure instabilities, respiratory failure and renal failure may also contribute to a rise in troponin levels (6). In our study, 13 out of 25 patients (52%) demonstrated (mainly focal) myocardial scars (LGE) with an overall low total volume of 5% LV mass, Tables 1, 2 and Supplementary Tables A, B.…”

“…Twenty-five complete datasets remained fully evaluable for this study. According to the fourth universal definition of myocardial infarction, patients were categorized 10.3389/fcvm.2022.989376 by their repeated troponin measurements in: (1) chronic myocardial injury (increased but stable troponin levels in terms of rise/fall ≤ 20% in serial measurements), and (2) acute myocardial injury (rise/fall of troponin > 20% in serial measurements) (6,7). Twelve healthy volunteers [5 female (42%), age 51 ± 9 years] served as a control group to define reference values for the CMR mapping sequences (T1 and T2 mapping).…”

“…Acute "dynamic" elevation of troponin (characterized by the rise or fall in repeated measurements) is present in 30-60% of the patients. Despite several theories, the exact mechanisms of myocardial injury resulting in increased troponin levels are still unknown and to date, no specific diagnostic or therapeutic algorithms are established beside general cardiology guidelines for the work-up of troponinpositive ischemic stroke patients (2,4,6,7). Significant coronary artery disease seems not to be main driver of increased troponin levels in the majority of patients (19), lowering the role of invasive coronary angiography as a "sine qua non" diagnostic 10.3389/fcvm.2022.989376 tool, and underlining the unmet need of further evaluation in these high-risk patients.…”

“…reaction. Noradrenaline seems to be a main driver of myocardial injury, damages cardiomyocytes, stimulates macrophages, and leads to activation of fibroblasts to myofibroblasts (4,6,23). Furthermore, neuronal death may result in local cerebral inflammation by activation of microglia and the production of cytokines and chemokines (4).…”

“…Another explanation may be the concept of stroke-heart syndrome (2), in which cardiac manifestations (e.g., myocardial injury, dysfunction and arrhythmia) are induced by an acute ischemic stroke, potentially mediated by autonomic function and the brain-heart axis (3)(4)(5). Beside the presence of an increased troponin level itself, dynamic changes in troponin levels are of paramount importance for the treating physicians, allowing to separate acute myocardial injury (dynamic rise/fall > 20% in serial measurements) from chronic myocardial injury (increased but stable hs-cTnI levels) (6,7). However, the reason for acute myocardial injury remains often elusive since symptoms, ECG, echocardiography or even coronary angiography might be unspecific or ambiguous (4).…”