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.

Patients with acute neurological disorders are susceptible to experience cardiac complications such as acute myocardial infarction, heart failure, arrhythmias, or cardiac arrest [1][2][3][4][5][6] . Takotsubo syndrome (TTS) is an emerging cardiovascular condition and represents an acute heart failure syndrome, which prototypically affects elderly women after a preceding triggering event 7 . Due to left ventricular recovery within weeks after the acute event it was widely anticipated that TTS is a self-limiting and rather benign cardiac condition. However, recent studies demonstrated that TTS is accompanied by similar mortality rates as acute myocardial infarction 8,9 . The underlying pathophysiological mechanisms of TTS have not been elucidated yet, but there is convincing evidence from brain imaging studies that altered physiological function within the brain heart axis might play a pivotal role 10,11 . A cross-sectional study based on national inpatient sample data has shown that 0.06% of hospitalization for primary acute neurological disorders are complicated by TTS and that incidence rates of TTS diagnosis among patients with acute neurological disorders have gradually increased during the entire study period 12  www.nature.com/scientificreports/ disorders preceded the TTS event ( Fig. 1). TTS was diagnosed within 2 days after neurological symptoms in 87.3% of patients (Fig. 2). Patients' characteristics are summarized in Table 1. Patients in the Neuro-TTS group were younger (63.7 ± 15.2 years vs. 67.5 ± 12.4 years, P < 0.001) and less often female (82.6% vs. 90.9%, P = 0.001) compared to TTS controls. Neuro-TTS patients had less often cardiac symptoms including chest pain or dyspnea. While there was no difference with regard to the frequency of the classical apical ballooning pattern (66.5% vs. 70.5%, P = 0.27), Neuro-TTS patients showed more often the basal TTS variant (3.7% vs. 1.0%, P = 0.011) on echocardiography or left ventriculography. Patients in the Neuro-TTS group had higher heart rate (91.8 ± 27.6 bpm vs. 86.9 ± 21.5 bpm, P = 0.022) and lower left ventricular ejection fraction (37.4 ± 11.9% vs. 41.0 ± 11.7%, P < 0.001) compared to TTS controls. Troponin at admission levels were comparable between Neuro-TTS and TTS controls, while troponin peak values were nearly twice as high in the Neuro-TTS group compared to TTS controls [33.91 (11.50-65.75) vs. 17.35 (6.47-41.00), factor increase of upper limit of normal, P < 0.001]. Furthermore, brain natriuretic peptide on admission as well as corresponding peak values were higher in the Neuro-TTS group indicating a greater degree of myocardial injury in the Neuro-TTS group.
Clinical spectrum of neurological disorders. Of the 161 patients with neurological disorders, the most common neurological disorders were seizures (N = 64, 39.8%; Fig. 1, Table 2), intracranial hemorrhage (N = 48, 29.8%, Fig. 1, Table 3) and cerebral ischemia (N = 43, 26.7%, Fig. 1, Table 4). Transient global amnesia was identified in 4 patients, posterior reversible encephalopathy syndrome (PRES) in 4 patients, migraine or headache disorders in 3 patients, intracranial tumor with progressive aphasia upon presentation in 1 patient, and Wernicke encephalopathy in 1 patient (Supplementary Table 1). The proportion of males was significantly higher in patients with intracranial hemorrhage than in patients with seizures or cerebral ischemia, and patients with intracranial hemorrhage and seizures were younger than patients with cerebral ischemia (Table 5 and Supplementary Fig. 1). Left ventricular ejection fraction was more reduced in patients with intracranial hemorrhage, while left ventricular end-diastolic pressure was substantially higher compared to patients with seizures and cerebral ischemia. Characteristics of patients stratified by neurologic disorders are summarized in Table 5. The prevalence of seizure/epilepsy and subarachnoid hemorrhage seems to be higher in the InterTAK Registry than in the general population using data Global Burden of Disease statistics 20 , while numbers of ischemic stroke and intracerebral hemorrhage were similar in both cohorts ( Supplementary Fig. 2).

Characteristics of patients with seizures.
Of the 64 patients who had TTS secondary to seizures, 18 had status epilepticus (STESS > 2 points in 44.4%), 26 had generalized onset seizures, 7 had focal onset seizures, and 13 had unknown onset seizures (Table 2). A history of seizure was identified in 22 patients and 17 patients were on antiepileptic drug treatment prior to TTS event. Structural underlying brain lesions were present in 37 patients (data available in N = 62) and involved the right hemisphere in 22 (59.5%) patients. Seizures were considered acute symptomatic in 20 patients, including patients with SAH (N = 2), ischemic stroke (N = 3), and PRES (N = 3). Younger age and lower predominance of females seemed to be more pronounced after status  Of the 150 patients included in the analysis median time from neurological disorders to TTS was 0 (IQR 0-1) days. Notably, time from neurological disorder to TTS was less than 2 days in 87.3% of cases. In 62% of cases the neurologic event and TTS were diagnosed on the same day, while 38% of patients were already hospitalized for the underlying neurologic conditions and TTS diagnosed during the clinical course. Numbers in boxes are the number of patients diagnosed with neurological disorders on the respective day. X-axis: days from neurological event to TTS. Y-axis: different types of neurological disorders triggering TTS. 7 patients with overlap of 2 acute neurological conditions and were excluded (2 with focal onset seizure and ischemic stroke, 2 with generalized onset seizure and PRES, 1 with status epilepticus and PRES, 1 with status epilepticus and SAH, and 1 with generalized onset seizure and SAH). In 4 cases the exact time of onset of neurological disorders was unknown (1 patient with subarachnoid hemorrhage, 1 patient with ischemic stroke, 1 patient with unknown onset seizure, and 1 patient with left frontal lobe tumor with progressive aphasia). IQR Interquartile range, PRES Posterior reversible encephalopathy syndrome, SAH Subarachnoid hemorrhage, TTS Takotsubo syndrome. www.nature.com/scientificreports/ cardiovascular causes of death were substantially higher in Neuro-TTS group than in TTS controls (82.1% vs. 47.8%, P = 0.005, Supplementary Fig. 3). On multivariable logistic regression the presence of acute neurological disorders (OR 3.20, 95% C.I. 1.93-5.33, P < 0.001) was associated with increased in-hospital mortality (Fig. 3).
10-year outcome analysis demonstrated increased MACCE (32.3% vs. 15.5%, P < 0.001) and mortality (24.8% vs. 10.0%, P < 0.001) rates in TTS patients with neurological disorders, while recurrence rates were not statistically significant different in the neuro-TTS group and in TTS controls (2.5% vs. 3.1%, P = 0.66, Table 1). Moreover, we conducted a 10-year landmark analysis with a landmark set at 30-days. Landmark analysis showed substantially higher mortality within the 30 days after admission in patients with neurological disorders. After the landmark including only patients alive 30 days after TTS, patients with neurological disorders showed substantially higher long-term mortality compared to TTS controls without neurological disorders (P = 0.020, Supplementary Fig. 4).  www.nature.com/scientificreports/

Discussion
The present study based on data from the InterTAK Registry demonstrates that neurological disorders are common triggering factors of TTS. TTS patients with neurological disorders exhibit a distinct clinical profile including younger age, lower female predominance, and less clinically apparent cardiac symptoms at presentation. Furthermore, patients with neurological disorders have more pronounced myocardial injury as reflected by markedly elevated cardiac biomarkers and more impaired left ventricular ejection fraction compared to patients without neurological disease. Seizures, intracerebral hemorrhage, and ischemic stroke constitute the most common neurological disorders preceding TTS. The presence of cardiac disorders is frequently observed after neurological disorders and is linked to a high burden of morbidity and mortality [1][2][3][4] . Cardiac complications after acute neurological disorders comprise a wide spectrum ranging from benign ECG alterations, cardiac biomarker abnormalities, myocardial disorders, left ventricular dysfunction, malignant arrhythmias to sudden cardiac death 1,2,6,21 . The link between TTS and neurovascular events was underscored more than two decades ago. For instance, the first version of the Mayo Clinic Diagnostic Criteria excluded the presence of neurologic disorders for diagnosis of TTS 22 . Instead the term neurogenic stunned myocardium was frequently found in the literature to describe myocardial dysfunction after acute neurological injury especially after subarachnoid hemorrhage 23,24 . Over the last years, the interplay of the brain and heart has gained growing interest in the medical community and TTS is now acknowledged as a cardiac consequence of acute neurological events 2,6,25-27 . While the understanding of the precise pathomechanisms

Hemodynamics-mean ± SD (N)
Heart rate-beats/min 98.9 ± 28.6 (N  www.nature.com/scientificreports/ underlying TTS development remain incomplete, there is evidence that autonomic imbalance with excessive catecholamine release and increased cardiomyocyte response to catecholamines infer the pathophysiology [28][29][30] . Levels of catecholamines are reported to be 4 times higher in TTS than in patients with myocardial infarction even three to five days after hospital admission, and over 30 times higher than normal resting values 29 . The plasma half-lives of epinephrine and norepinephrine are approximately 1-3 min 31 . Thus, the maximum catecholamine levels at symptom onset will be substantially higher than any measurement taken on hospital admission considering an onset-to-door time of at least 30 min 32 . Prolonged elevation of circulating catecholamines for several hours has also been reported after acute neurological disorders such as seizures and stroke 33,34 . Cardiovascular functions are controlled by a complex network of cortical and subcortical forebrain regions (including the amygdala, the insula, the hippocampus, as well as lateral and mesial frontal regions) 1,2,35 .     www.nature.com/scientificreports/ Neuro-imaging studies on TTS patients have demonstrated altered function of brain regions which are responsible for autonomic regulation 10 .
In our cohort, one out of 15 TTS patients had a preceding acute neurological disorder as the underlying triggering factor. The prevalence of seizure/epilepsy and subarachnoid hemorrhage in our study population seems to be higher than in the general population using data from Global Burden of Disease statistics, while numbers of ischemic stroke and intracerebral hemorrhage were similar in both cohorts 20 . Elderly women after an emotional triggering factor (e.g. death of a beloved one) have historically been considered as the high-risk population for TTS. This is in contrast to patients with TTS after neurological disorders who are younger and more frequently male than expected. It has been suggested that TTS development depends on the degree of sympathetic stimulation 36 . This could explain the atypical clinical profile of TTS patients with neurological disorders. It may be speculated that younger individuals and males may require a more intense trigger with greater sympathetic stimulation, while only a mild trigger with low sympathetic stimulation might be sufficient to provoke TTS in elderly. The way acute neurological disorders affect the function of the central autonomic network differs among neurological disorders. In seizures and status epilepticus there is paroxysmal stimulation of the autonomic nervous system and in SAH there is an early intense sympathetic stimulation, which directly affects the hypothalamus pituitary-adrenal axis via the amygdala-insular complex. The presence of ischemic stroke lesions, on the other hand, mainly leads to loss of function or network dysfunction.
TTS secondary to seizures occurred most often after generalized onset (i.e., bilateral tonic-clonic), unknown onset motor seizures or focal to bilateral tonic-clonic seizures. In these seizure types, it has been shown that the postictal phase is dominated by sympathetic overactivation and increased heart rate with parasympathetic suppression 37,38 . In contrast, focal unaware seizures (complex partial seizures), which were rather uncommon in our cohort, were associated with ictal asystole or bradycardia 39 . Moreover, we observed that nearly 60% of structural brain lesions in patients with TTS secondary to seizures involved the right hemisphere, which may be of interest as right hemispheric lesions may promote susceptibility to autonomic dysfunction [40][41][42] .
Observational studies have demonstrated that TTS secondary to SAH occurs in approximately 10-15% of patients and that severity of SAH according to Hunt and Hess Scale can predict the occurrence of cardiac dysfunction 24,43 . This corroborates the findings of the present study as virtually all patients had severe SAH as reflected by low GCS and high Hunt and Hess Scale. Interestingly, more than half of registered SAH cases were related to ruptured anterior communicating artery aneurysms.
In our study, 36% of patients with ischemic stroke had involvement of the insular cortex. Insular cortex damage has been associated with increased sympathetic nervous system activity and cardiovascular system dysregulations including arrhythmias or myocardial injury 42,44,45 . Moreover, previous studies investigating TTS secondary to ischemic stroke have suggested that hemispheric lesions and especially insular cortex involvement may promote TTS occurrence 46,47 . Median NIHSS in these series was 16, which was higher than observed herein. Thus, our results indicate that TTS secondary to ischemic stroke may also be observed in patients with overall lower stroke severity. In our cohort, TTS has been diagnosed early after SAH, while after subdural/epidural hematoma TTS has been seen after a median of 3 days. Clinical severity was substantially higher in patients with SAH or intracerebral hemorrhage than in patients with subdural or epidural hematoma. Therefore, it can be likely that clinical disease severity of the underlying neurological disorder might impact time onset of TTS.
Patients with neurological disorders had a higher prevalence of the basal TTS phenotype. The basal TTS form constitutes a relatively rare morphological TTS variant and has been linked to neurological disorders such as SAH 8,48 . Furthermore, it has been suggested that the left ventricular apex is spared out after neurological disorders 49 . However, our findings challenge the concept of left ventricular apical-sparing as we have identified the apical TTS form in more than two-thirds of TTS patients with primary neurological disorders.
TTS secondary to neurological disorders was associated with increased rates of adverse events and in-hospital mortality. After controlling for major confounders, the presence of acute neurological disorders was associated with increased in-hospital mortality. This again highlights the importance to consider TTS patients with primary acute neurological conditions as a high-risk population despite younger age and less pre-existing cardiovascular risk factors.
Although TTS has gained heightened awareness during the last years, it likely remains an underdiagnosed and underreported disorder. Especially in patients with acute neurological diseases, TTS may remain clinically silent. Classical clinical symptoms of TTS such as chest pain or dyspnea were less often documented in the Neuro-TTS group compared with TTS controls. In addition, patients with neurological disorders had an unfavorable clinical course and therefore it might be even considered to actively screen for elevation of cardiac biomarkers and signs of heart failure. Therefore, a rise in sensitive biomarkers of myocardial disorders or dysfunction (i.e. cardiac troponin or BNP, respectively) should prompt cardiac evaluation. Additionally, prolonged clinical monitoring and non-invasive cardiac investigations should be considered and treatment with catecholamines or QT-prolonging drugs should be avoided if possible given the putative involvement in the pathogenesis.
We have shown that acute neurological disorders ranging from benign to life-threatening can provoke TTS. TTS patients with neurological disorders have substantial rates of adverse events. Outcome analysis demonstrated increased mortality in the first 30 days after the TTS event in patients with neurological disorders. The increased mortality rates within the first 30 days are likely driven by the underlying neurological state and TTS adding a secondary hit. Our findings emphasize the need of a standardized cardiac work-up in patients with acute neurological disorders to avoid underdiagnosing of TTS. The considerable rates of adverse events in patients with neurological disorders and TTS should prompt neurologist to heightened awareness of the syndrome.