In the New England Journal of Medicine in May 8th, 1986, a case study was published that reported a 44-year-old woman who presented to the hospital with retrosternal pain and pulmonary edema immediately after her son’s suicide [1]. Acute cardiac symptoms induced by severe emotional stress have been previously described, but this case may represent the first description of Takotsubo syndrome (TTS). The term “Takotsubo cardiomyopathy” was coined by Hikaru Sato in 1990 [2]. The name “Takotsubo” refers to the shape of a Japanese octopus trap, which resembles the morphological appearance of the heart with abnormal contractility of the left ventricle. TTS is also known as “stress cardiomyopathy” or “broken heart syndrome”, characterized by an acute and transient regional left ventricular systolic and diastolic dysfunction induced by severe emotional or physical stress. In 2018, Pelliccia proposed to replace the term “cardiomyopathy” in those patients with “syndrome” since several features of this disease (e.g., reversibility) do not fit with the concept of a cardiomyopathy [3].

In addition to emotional stress, severe brain damage is also described as a possible trigger. While ischemic stroke, cranial trauma, and intracerebral hemorrhage are less frequently encountered, aneurysmal subarachnoid hemorrhage (aSAH) is described as an immediate cause in up to 28% of the cases [4].

The appearance of a left ventricular wall motion abnormality with normal coronary arteries in patients with aSAH has been previously described [5, 6, 7, 8]

The “InterTAK Diagnostic Criteria” for the diagnosis of TTS are as follows [the corresponding “InterTAK Diagnostic Score” (points)]:

– transient left ventricular dysfunction (hypokinesia, akinesia, or dyskinesia) presenting as apical ballooning or midventricular, basal, or focal wall motion abnormalities or right ventricular involvement; the regional wall motion abnormality usually extends beyond a single epicardial vascular distribution. However, rare cases can exist where the regional wall motion abnormality is present in the myocardial territory of a single coronary artery (focal TTS)

– a trigger (emotional, physical, combined) can precede the TTS but is not obligatory [emotional trigger (24), physical trigger (13)]

– neurologic disorders (e.g., aSAH, stroke, seizures), as well as pheochromocytoma, may trigger TTS [psychiatric disorder (11), neurologic disorder (9)]

– new ECG abnormalities are present (ST-segment elevation, ST-segment depression, T-wave inversion, and QTc prolongation); rare cases exist without any ECG changes [absence of ST-segment depression (12), QTc prolongation (6)]

– levels of cardiac biomarkers (troponin and creatine kinase) are moderately elevated in most cases; significant elevation of brain natriuretic peptide is common

– significant coronary artery disease may occur in TTS

– patients have no evidence of myocarditis

– postmenopausal women are predominantly affected [female gender (25)]

An updated diagnostic algorithm for patients presenting with chest pain and/or dyspnea has been proposed by Ghadri et al. [9, 10, 11]. The “InterTAK Diagnostic Score” allows differentiation between an acute coronary syndrome and TTS. A score of $>$70 points support the diagnosis of TTS.

In a subgroup of patients, a neurological disorder is the most likely cause of TTS. Kono et al. [12] in 1994 and Lee et al. [13] in 2006 coined the terms “neurogenic stunned myocardium” and “neurogenic stress cardiomyopathy”.

The true incidence of TTS in association with aSAH is unknown. Published data suggest it occurs in 0.1–15% [14, 15], with other studies suggesting that this condition occurs less frequently [16, 17]. We encounter TTS in 4% of all aSAH patients, with a preponderance of women and a massive aSAH (Hunt and Hess IV and V). Due to the proximity of the medulla oblongata, which may play a critical role in the “brain-heart connection”, it is conceivable that ruptured aneurysms in the posterior circulation are more prone to cause TTS than those in the anterior circulation [18, 19]. This is, however, not well supported by published data.

Several reviews on this subject have recently been published [20, 21, 22].

This review sought to provide an overview of TTS accompanying aSAH and propose a treatment strategy for this combined pathology.

Although the “connection” between the brain and heart in TTS development has been previously documented, the exact pathophysiological mechanisms have not yet been clarified.

Controversy exists in the pathophysiology of TTS after aSAH, as to the effects of an increased level of plasma catecholamines (Fig. 1). This has been shown in animal models [23] and clinical studies, with a preponderance of neurogenic norepinephrine (released from the cardiac sympathetic nerve fibers) over adrenal epinephrine (released by the adrenal gland) [24]. In line with this observation is the restoration of the cardiac function (e.g., the ejection fraction (EF)), which frequently occurs during the first week after an aSAH, accompanied by a normalization of the plasma catecholamine levels [25].

Greenhoot and Reichenbach [26], Zaroff et al. [27], and Y-Hassan [28] defined TTS as an acute cardiac sympathetic disease characterized by local cardiac norepinephrine seethe, followed by cardiac sympathetic nerve terminal eruption.

Goico et al. [29] proposed various hypotheses for the pathophysiology of TTS. During an initial phase, “stress” (localized in “cognitive brain centers”) may activate a hypothalamic-pituitary-adrenal axis, resulting in an increased release of norepinephrine and epinephrine, contributing to a hyperactive sympathetic nervous system, and hyperresponsive myocardial tissue. The phenomenon of “stunned myocardium” is considered to be related to the catecholamine effect on cardiomyocytes. The stimulation of $\beta$1- and $\beta$2-adrenergic receptors are connected to the intracellular stimulatory G protein, the activation of the cyclic adenosine monophosphate (cAMP), and the protein kinase A. While epinephrine, through the $\beta$2-adrenergic receptor stimulation, has a positive inotropic effect at normal levels, it becomes a negative inotrope at abnormally increased levels via a coupling of the $\beta$2-adrenergic receptors to the intracellular inhibitory G protein. Norepinephrine has a positive inotropic effect through a $\beta$1-adrenergic receptor stimulation. The positive inotropic effect of norepinephrine-mediated $\beta$1-adrenergic receptor stimulation affects mainly the base of the left ventricle. The negative inotropic effect of excessive epinephrine-mediated $\beta$2-adrenergic receptor stimulation preferentially affects the left ventricular apex, leading to wall motion abnormalities. Microvascular dysfunction in TTS has been correlated with elevated levels of endothelin-1, plasminogen activator inhibitor-1 and von Willebrand factor.

In patients in the acute phase after aSAH, irrespective of cardiac issues, a massive sympathetic nervous activation with norepinephrine release has been reported [30]. Exogenous catecholamines are frequently required in aSAH patients during the acute phase to increase systolic arterial blood pressure to maintain cerebral perfusion. Intravenous administration of vasopressin [31], norepinephrine [32, 33], and dobutamine [34] have been described as potential TTS triggers. At pathological concentrations, catecholamines can cause $\beta$-receptor paradoxical negative inotropic effects [35]. Thus, this pathomechanism of TTS may result in cardiogenic shock.

Catecholamines act as strong vasoconstrictors of the cardiac microvasculature. Therefore myocardial stunning in TTS may be sympathetically induced and lead to microcirculatory dysfunction. The role of impaired coronary microcirculation has been discussed by several authors [36, 37, 38].

In “typical” TTS-patients, the left ventricular apex develops a wall motion abnormality. Mori et al. [39] found increased $\beta$-adrenergic receptor density and/or increased myocardial responsiveness to adenylate stimulation in apical myocardium in a canine model. Waller et al. [40] described a reverse TTS pattern with hypokinesis of the basal 2/3 of the left ventricle and a hypercontractile apex in a patient with aSAH. They suggest that variations in the density of adrenergic receptors may be responsible for this observation. Kumai et al. [41] compared 21 patients with typical and 10 patients with the reverse (basal) TTS, all related to aSAH. The patients with the reverse pattern were younger and showed higher plasma epinephrine levels. The management and prognosis, however, were essentially the same for both groups.

Ancona et al. [42] described the differences between neurogenic stunning in patients with aSAH (n = 14) and “classic” TTS (n = 22). They found a higher prevalence of women in both groups. Compared to patients with “classic” TTS, the patients with aSAH and neurogenic stunned myocardium were slightly younger (mean age 53 vs. 61 years), had no previous coronary heart disease, presented with heart failure (instead of chest pain), had no ST-segment elevation, had more T-wave inversion (64% vs. 27%), had less depressed left ventricle (LV) function, and presented less frequently with apical LV dysfunction (21% vs. 77%) and in $>$90% (vs. 45%) mid and basal LV dysfunction.

In both groups, an improved EF (mean 17%) at discharge was observed.

The diagnosis and follow-up of TTS requires extensive laboratory, electrophysiological, imaging and circulatory examinations.

Once the diagnosis of TTS is established, and the treatment is initiated, continuous monitoring of arterial blood pressure, heart rate, oxygen saturation, and central venous pressure is required. Frequent ECG, cardiac and pulmonary ultrasound examinations should be performed.

For patients with TTS and even more so for TTS triggered by aSAH, guidelines and comprehensive data from randomized trials are lacking. The current management of these patients is based on individual and institutional experience, retrospective literature analysis, and common sense. Madias recently published a comprehensive review of this subject [64].

The concurrent impact of a ruptured intracranial aneurysm (possibly with an elevated ICP), posthemorrhagic cerebral vasospasm, and TTS (possibly with heart failure) can create a therapeutic dilemma. The treatment of a ruptured aneurysm and an aSAH-triggered TTS will be discussed separately, knowing that the coordination of both therapeutic efforts is critical for success in clinical practice. Several drugs are available, together with the armamentarium of neurointensive care.

The following recommendations have found widespread acceptance [11].

– Patients with mild TTS without heart failure should be continuously monitored. Patients in the acute phase after aSAH require monitoring and treatment in an intensive care unit. Angiotensin-converting-enzyme inhibitors (ACEI), angiotensin-receptor blockers (ARB), and $\beta$-blockers are potential options. Adrenaline, noradrenaline, dobutamine, milrinone, and isoproterenol should be avoided unless milrinone is needed to treat cerebral vasospasm.

– TTS-patients with heart failure and/or pulmonary edema may receive ACEI, ARB, and $\beta$-blockers. Diuretics and nitroglycerin are indicated as long as left ventricular outflow obstruction (LVOTO) is not present.

– For patients with hypotension or cardiogenic shock with primary pump failure, levosimendan, a left ventricular assist device (LVAD, such as Impella; intra-aortic balloon pump), and venoarterial extracorporeal membrane oxygenation (VA-ECMO) are considered. In the case of LVOTO fluid replacement, short-acting $\beta$-blockers and LVAD can be indicated, while diuretics, nitroglycerin, and an intra-arterial balloon pump should be avoided unless circulatory support is necessary.

– Arrhythmias may be treated with $\beta$-blockers and temporary pacing, while QT interval prolongation drugs and $\beta$-blockers in the case of bradycardia are contraindicated.

– Left ventricular thrombus and clinically apparent emboli are indications for anticoagulation with heparin, warfarin, or novel oral anticoagulants.

At least half of the patients with full-blown TTS require intubation, inotropic and vasopressor support, and anticoagulation [65]. In the rare case of ventricular fibrillation, immediate defibrillation is required [66]. The combination of TTS with posthemorrhagic cerebral vasospasm can be challenging. A detailed description of individual therapeutic regimens for neurogenic TTS can be found in the literature [67].

In patients presenting with cardiogenic shock due to TTS, an intraaortic balloon pump insertion for counterpulsation, an Impella heart pump, or extracorporeal life support (ECLS) may help overcome the hypotensive phase [43, 68]. The redirection of the blood flow towards the head can also be used to manage posthemorrhagic vasospasm [69]. Since these procedures require heparinization, a ruptured aneurysm must first be treated.

In a recent retrospective analysis, Napierkowski et al. [70] found no reduced mortality but higher costs in patients with cardiogenic shock from TTS treated with mechanical circulatory support [70].

In patients with aSAH and TTS, early treatment of the ruptured intracranial aneurysm should be attempted to prevent recurrent hemorrhage, especially if anticoagulation is required to treat the TTS. The cardiac wall motion abnormality can be associated with left intraventricular thrombus formation [71]. Apical TTS, thrombocytosis, and elevated plasma levels of C-reactive protein, d-dimers, and troponin are considered associated risk factors [72, 73]. A left ventricular thrombus carries the risk of an embolic large intracranial vessel occlusion [74]. Anticoagulation with heparin or warfarin is the standard of care, which can only be initiated after the ruptured intracranial aneurysm has been excluded from the blood circulation [75].

Based on the individual circumstances, a variety of drugs should be considered. Many of these drugs can be administered intravenously (IV) or per os (PO). Those available as a PO variant only can be used (with some restrictions) via a nasogastric tube. Patients in the early phase after aSAH (also without TTS) frequently show a disturbance of gastrointestinal absorption. Therefore, for most patients suffering from aSAH and TTS, the IV administration of drugs is preferred.

Epidemiological studies have shown that advanced diabetes mellitus with autonomic neuropathy may have a protective effect against the occurrence of TTS and may prevent TTS-related morbidity and recurrent TTS episodes [97].

TTS patients have a higher incidence of malignancies than the age-matched general population [60].

About 50% of TTS patients present with arterial hypertension, with an incidence of 27–83% [98]. Recurrence of TTS has been described in 4% of patients with a higher prevalence of arterial hypertension in these patients (87% vs. 68%) [99].

The prognosis of patients with aSAH and TTS is mainly determined by the underlying neurovascular disorder and cerebrovascular complications [18]. In the International Takotsubo Registry, the overall mortality was 5.6% per patient-year in the long-term follow-up, and the rate of serious adverse cardiac and cerebrovascular events was 9.9% per patient-year [47]. Thus, TTS per se is infrequently the main reason for fatal outcomes [65]. A coronary intervention in aSAH patients including heparinization and antiplatelet therapy without prior diagnosis and treatment of a ruptured aneurysm may result in a re-rupture of the aneurysm [43, 100].

Predictors for a poor neurological outcome are onset with cardiac arrest [101], right ventricular involvement, and the need for inotropic support [65]. In addition, elevated cardiac troponin after aSAH is associated with an increased risk of echocardiographic left ventricular dysfunction, delayed cerebral ischemia from vasospasm, and death or poor functional outcome at discharge [16, 84].

In the International Takotsubo Registry, 18% of the enrolled patients had atypical (i.e., non-apical wall motion abnormality) TTS, and those patients had an increased incidence of a neurologic disorder as the trigger. The in-hospital mortality with atypical TTS was 3.1% [9].

Talahma et al. [16] published a series of 800 patients with aSAH. The mortality in the entire series was 15%, while 4/18 patients (22%) with aSAH and TTS eventually died.

Norberg et al. [102] enrolled 455 SAH patients in their study. Elevated values of hs-cTnT, NTproBNP, and ST-T ECG abnormalities within 72 h after the clinical aSAH onset were associated with an increased risk of death during the first three months. TTS was associated with an increased risk of cerebrovascular events.

TTS occurs in 5–10% of all aSAH patients. Female gender, age $>$60 years, and a massive SAH are considered predisposing factors. The key finding is impaired wall movement of the left ventricle (frequently basal and not apical), confirmed on echocardiography. Medical treatment is individualized and may include vasopressors, $\beta$-blockers, levosimendan, and insulin/glucose infusion. The prognosis can be improved with treatments that addresses arterial hypotension, arrhythmias, and thromboembolic events. Early treatment of the underlying ruptured aneurysm is required to prevent recurrent aSAH and allows for systemic anticoagulation in the case of intraventricular thrombus formation.

ACEI, Angiotensin-converting-enzyme inhibitors; ARB, angiotensin-receptor blockers; aSAH, aneurysmal subarachnoid hemorrhage; BNP, B-type natriuretic peptide; cAMP, cyclic adenosine monophosphate; CKMB, creatine kinase myocardial band; DSA, digital subtraction angiography; ECG, Electrocardiogram; ECLS, extracorporeal life support; EF, ejection fraction; hs-cTnT, high-sensitivity cardiac troponin T; ICP, intracranial pressure; InterTAK Registry, International Takotsubo Registry; IV, intravenous(ly); LV, left ventricle; LVAD, left ventricular assist device; LVOTO, left ventricular outflow obstruction; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PO, per os; STEMI, ST-elevation myocardial infarction; TnT, troponin T; TTS, Takotsubo syndrome; VA-ECMO, venoarterial extracorporeal membrane oxygenation.

SW—selection of the relevant references, review of the pharmacological aspects; conducting the research process, specifically performing the evidence collection from the literature. TG—drafting of the work, management and coordination responsibility for the research activity planning and execution final approval, and agreement to the accuracy of the work, review of the cardiological aspects. PB—selection and analysis of the references, review of the neuroradiological aspects, verification, whether as a part of the activity, of the overall reproducibility of results and other research outputs. AC—managing the revisions of the manuscript, including reference integration, preparation, creation and presentation of the published work, specifically visualization, final approval, and agreeing to the accuracy of the work. OG—drafting of the work, reviewing the neurosurgical aspects, development of methodology, final approval, and agreeing to the accuracy of the work. HB—selection of the relevant references, conducting the research process, specifically performing the evidence collection from the literature; preparation, creation and/or presentation of the published work by those from the original research group, specifically critical review, commentary or revision – including pre- or post-publication stages, review of the neurological aspects, drafting of the work, final approval, and agreeing to the accuracy of the work. HH—primary drafting of the manuscript, selection, analysis of the references, revisions of the manuscript; Ideas; formulation or evolution of overarching research goals and aims, oversight and leadership responsibility for the research activity planning and execution, including mentorship to the core team.

Not applicable.

We would like to express our gratitude to all those who helped us during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.

This research received no external funding.

The authors declare no conflict of interest.