Stroke-heart syndrome – cardiac complications in ischemic stroke patients

Introduction

Heart disease increases the risk of ischemic stroke. At the same time, patients who have had a stroke are at increased risk of developing cardiac complications, both immediately after the stroke and in the subacute and chronic phases. These complications significantly worsen the prognosis of patients. However, their pathophysiology has not yet been accurately elucidated, therapeutic options are limited, and therefore their study has received increased attention in recent years [1,2].

Patients after a first ischaemic stroke who have no history of cardiac disease are at a 25-fold higher risk of developing major cardiovascular complications in the first 30 days after stroke compared to those who have not suffered a stroke [3]. For newly identified cardiac complications in the first 30 days after stroke, a research group from the Center for Stroke Research Berlin introduced the term stroke-heart syndrome in 2018 (Table 1). The term stroke-induced cardiac injury is then used to summarize the pathophysiological mechanisms. According to this concept, not only traditional vascular risk factors underlie these early complications, but other mechanisms may also be involved that arise as a consequence of brain tissue damage during stroke. These include autonomic dysregulation or local and systemic inflammatory responses [2,4-6].

The aim of this review is to highlight cardiac complications in patients with ischemic stroke and to describe the current knowledge about their pathophysiological basis, including the new concept of stroke-heart syndrome.

Clinical manifestations

A total of 10-20% of patients experience severe cardiac complications in the first days and weeks after an acute stroke [1,7-9]. These complications include acute coronary syndrome (ACS) and acute myocardial involvement, which is documented by troponin dynamics. Furthermore, some patients manifest left atrial or ventricular dysfunction, including Takotsubo syndrome, and severe arrhythmias or sudden cardiac death may be noted. These events are associated with more severe neurological disability and are the second most common cause of death in the subacute period after stroke [1,5,6].

Myocardial impairment

The most sensitive indicator of myocardial involvement -⁠ regardless of its aetiology -⁠ is an increase in cardiac troponin (cTn). Myocardial impairment is defined as the detection of a cTn value above the 99th percentile of the upper reference limit (Figure 1). However, to distinguish between acute and chronic myocardial impairment, it is important to assess the dynamics of cTn. Impairment is considered acute if there is an increase or decrease in cTn values. If the value is stationary, the disability is considered chronic [10].

Using highly sensitive methods, 30-60% of patients may experience an elevation of cTn above the laboratory reference limit [5,11]. According to a meta-analysis of twenty studies with a total of 9,779 patients, elevated cTn levels are associated with an increased risk of death during hospitalization and during long-term follow-up [12]. Even a mild elevation of cTn can be prognostically significant. In the TRELAS study, in a cohort of 1 016 stroke patients, a cTn level above 16 ng/l (using a highly sensitive cut-off methodology of < 14 ng/l) was associated with more severe outcome neurological deficit (modified Rankin Scale [mRS] ≥ 2) at dimissis [5].

According to the AHA/ASA guidelines from 2019, the initial troponin level should be determined in patients with acute stroke [13], but due to the frequency of its elevation, interpretation is not easy. To differentiate between acute and chronic myocardial involvement, it is important to assess cTn dynamics. The differential diagnosis of acute myocardial involvement in patients with stroke including stroke-heart syndrome is presented in Table 2 [6].

Acute coronary syndrome

Although general diagnostic criteria apply for the diagnosis of ACS (Table 3), its recognition can be difficult in patients with acute stroke, especially in patients with impaired consciousness or aphasia [4,10]. According to data from a Canadian registry, 2.3% of patients with acute stroke experienced an acute myocardial infarction while still hospitalized. The mortality rate of these patients was 56.4% at one year (compared to 21.9% in patients who did not have an acute myocardial infarction) [14]. Significant atherosclerotic involvement of the coronary arteries is detected by coronary angiography in 51% percent of patients with stroke and cTn elevation [15]. When coronary angiography was indicated not only when cTn was positive but also when ACS was clinically suspected, coronary artery atherosclerosis occurred in 76% of patients with CMP [16]. Insular cortex lesions were more common in patients with suspected ACS and absence of coronary artery atherosclerosis. Thus, insular cortex lesions could cause cardiac symptomatology independently of coronary artery atherosclerosis [16].

The treatment of ACS in patients depends on the type of stroke. Decisions about invasive procedures must be individualized. Patients at high risk of bleeding complications will be treated mainly conservatively. Coronary angiography is indicated in patients with acute CMP only when the diagnosis of acute myocardial infarction is almost certain and when it puts the patient at greater risk than ongoing CMP. Although coronary angiography is associated with the administration of heparin, which may increase the risk of haemorrhagic transformation of the infarct, it may be safe in selected patients with acute CMP. If coronary intervention is decided, the risk of bleeding can be reduced, for example, by the use of drug eluting stents or drug coated balloons [6,16].

Left ventricular dysfunction

A number of echocardiographic studies have demonstrated the occurrence of left ventricular dysfunction (including the rare Takotsubo syndrome) in patients with acute stroke. However, studies are methodologically inconsistent and the incidence of left ventricular dysfunction detection varies between 1.8-30%. In the absence of information on previous cardiac history or previous echocardiographic examination, the detection of preexisting cardiac disease cannot be excluded [6]. When patients with mild left ventricular dysfunction (ejection fraction 35-50%) and a preexisting diagnosis of heart failure are included in the study, left ventricular dysfunction is detected in 30% of patients [17]. In contrast, severe left ventricular dysfunction has been reported in other studies in only 7.8% or even only 1.8% of patients with acute stroke [18,19]. Left ventricular dysfunction may or may not be accompanied by cTn elevation [19].

In patients with acute heart failure, diuretics are indicated, inotropics should be considered if there are signs of hypoperfusion, and vasopressors are indicated if their administration has no effect. If the condition progresses to pulmonary oedema (dyspnoea, respiratory failure, increased work of breathing) additional oxygen is administered and vasodilators if blood pressure is high [20].

Takotsubo syndrome is a reversible form of left ventricular dysfunction that can manifest clinically as ACS. It is characterized by echocardiographic findings of disturbed apical and mid-left ventricular kinetics, the shape of which resembles the octopus catching vessel in Japan. Diagnostic criteria state that the triggering factor may be emotional stress, but also neurological or psychiatric disease [21]. According to registry data, after intense emotional trauma, acute neurological illness is even the most common trigger of Takotsubo syndrome [22]. The pathophysiology is not precisely elucidated; in addition to sympathetic activation and catecholamine washout, structural and functional disruption of the limbic system and its integration with the autonomic nervous system may play a role [23].

In the acute phase, in hemodynamically unstable patients are given inotropic therapy. An alternative to catecholamines, which according to some studies are associated with up to 20% mortality, may be the administration of levosimendan. In stable patients, betablockers may be administered, and anticoagulation should be considered because of the high risk of thrombus formation [24].

Severe arrhythmias and sudden cardiac death

Severe arrhythmias, i.e., those requiring evaluation by a physician and, if indicated, treatment, are seen in 20-30% of patients admitted to an ischemic or hemorrhagic stroke unit with continuous ECG monitoring for 24-72 h. Tachyarrhythmias (TF above 120 or 130/min) are more common than bradyarrhythmias (TF below 40 or 45/min). Arrhythmias were more common in elderly patients with more severe neurological impairment [25-27].

Among the most serious arrhythmias in the acute stage are ventricular arrhythmias, which can result in circulatory arrest. According to an analysis of data from the Florida registry containing 215,150 patients hospitalized with ischemic and hemorrhagic stroke, the incidence of ventricular arrhythmias was observed in 2% of patients; these patients had a 75% higher risk of mortality during hospitalization [28].

Detection of atrial fibrillation is essential in patients with ischemic stroke. According to the Framingham study, atrial fibrillation increases the risk of ischaemic stroke fivefold [29], and anticoagulation therapy can reduce this risk by up to two-thirds [30,31]. According to a meta-analysis of 50 studies with 11 685 patients after ischemic stroke or transient ischemic attack, newly diagnosed atrial fibrillation is present in 23.7% of patients, of whom 12.8% are still hospitalized, and the overall prevalence of atrial fibrillation in the population of patients after stroke is estimated at 39% [32]. Newly detected atrial fibrillation is often paroxysmal, where episodes of less than 30 s duration are recorded, and is associated with a lower risk of recurrent stroke than known atrial fibrillation. It tends to be captured in patients with a lower prevalence of cardiovascular comorbidities and is more common in patients with lesions in the insular cortex [33]. It has been suggested that these lesions may lead to the disruption of the central autonomic network and the development of a systemic inflammatory response, thereby causing arrhythmia [34,35].

In patients with atrial fibrillation, anticoagulation, preferably with direct anticoagulants (DOAK), should be initiated according to the CHA2DS2-VASc clinical score. Frequency control is an integral part of treatment. Rhythm control using cardioversion, antiarrhythmic drugs or catheter ablation may be indicated to improve quality of life [36].

Sudden cardiac death in patients with stroke is reported as a manifestation of stroke-heart syndrome [4]. However, it can only be established with certainty when an autopsy is performed [37]. Due to methodological differences in the studies conducted , precise data on its incidence are lacking [1]. Excessive sympathetic activation has been implicated in the pathophysiology of sudden cardiac death, which can result in heart failure and malignant arrhythmias [38].

Oligosymptomatic cardiac abnormalities

In addition to the above mentioned clinically and prognostically serious complications, oligosymptomatic cardiac abnormalities are detected in some patients by ancillary investigative methods -⁠ e.g. elevation of specific biomarkers or ECG changes.

Up to 90% of patients have abnormal findings on ECG -⁠ most commonly ST segment changes, prolonged QTc interval or changes in T wave morphology, especially inversion [39]. Deep T wave inversions (more than 5 mm) in at least four precordial leads are called cerebral T waves in the foreign literature and are more frequently found in patients with ischemic stroke [40]. These changes may be only transient, with the highest incidence immediately after the ict. For example, the QTc interval was elevated in 65.2% of patients on admission, but in only 26.1% after 48 h. Furthermore, these subclinical changes on the ECG have been shown to correlate with mRS on diminished function and with long-term mortality after stroke [41,42].

Sometimes it can be difficult to determine whether these are new, ictal changes or signs of pre-existing cardiac involvement. In a group of patients with ischaemic and haemorrhagic ictus and subarachnoid haemorrhage in whom an ECG was available before the onset of neurological involvement, new ECG abnormalities were found in 75% of cases [43]. In another study, after excluding patients with known cardiac disease, ECG changes were found in 32% of patients [39].

Pathophysiology of stroke-heart syndrome

The pathophysiology of stroke-heart syndrome is not yet precisely understood. While the association of cardiovascular disease with nervous system disease is well established, the impact of nervous system involvement on the development of cardiovascular disease has received increased attention only in the last two decades [44].

According to several studies, a higher incidence of cardiac complications (e.g., myocardial involvement or arrhythmias) is associated with more extensive ictus or lesions in specific regions of the CNS, such as the brainstem or insula [35,45,46]. The association between CNS involvement and cardiac complications has also been described in animal models, where cardiac dysfunction correlated with the degree of insular involvement or extent of ictus [47,48]. On the basis of these studies, it has been suggested that stroke-heart syndrome may arise as a consequence of autonomic dysregulation that occurs after damage to brain structures that are part of the so-called central autonomic network [2,6].

Experimental studies also point to the role of the immune system and the local and systemic inflammatory response in the pathophysiology of stroke-heart syndrome. A systemic inflammatory response and subsequent infiltration of immune cells into the heart have been reported in animal models of cardiac involvement resulting from ischemia-reperfusion injury. When splenectomy was performed, the inflammatory response was attenuated and myocardial function improved [48,49]. The local inflammation of brain tissue that occurs after neuronal death and the subsequent activation of microglia and production of proinflammatory cytokines and chemokines have also been pointed out [6,50]. The immune response to ischemic insult and the subsequent development of systemic inflammation have also been discussed in patients with stroke [51]. Thus, it appears that the inflammatory response may be another mechanism contributing to the development of cardiac complications in patients with CMP [2,6,52].

In addition, the rise in catecholamine levels, which causes cardiac hypertrophy and ischemia and is traditionally associated with Takotsubo syndrome, seems to be involved in the pathophysiology of stroke-heart syndrome [2,53,54].

Conclusion

Cardiac complications in patients with stroke can be only subclinical or, on the contrary, very severe, significantly worsening the prognosis of patients. According to the new concept of stroke-heart syndrome, some of the complications arise as a direct consequence of acute brain tissue damage in acute stroke. Despite the growing interest in this issue and new findings in its pathophysiology, specific therapeutic approaches are still lacking. Theoretically, the use of beta-blockers or drugs from the group affecting the renin-angiotensin-aldosterone system to modulate the sympathetic nervous system, and anti-inflammatory treatments such as colchicine or statins to influence endothelial function have been proposed. However, double-blind clinical trials have not yet been performed, and thus there are insufficient data to recommend these drugs [2,4].

In the early diagnosis and treatment of cardiac complications in patients with acute stroke, the recognition of these complications by the attending physician -⁠ neurologist -⁠ and, in indicated cases, a more detailed cardiological examination is essential in routine clinical practice.

Financial support

The work was supported by the University Research Centres of Charles University program No. UNCE/MED/002, Cooperatio 38 Neuroscience of Charles University and 260648/SVV/2023.

Conflict of interest

The authors declare that they have no conflict of interest in relation to the subject of the study.

Table 1. Definition and clinical manifestations of Stroke-heart syndrome according to [2].

Table 2. Differential diagnosis of acute myocardial involvement in patients with stroke (according to [6]).

The key is the exclusion of myocardial infarction type 1, in the differential diagnosis is stroke-heart syndrome manifesting e.g. as myocardial infarction type 2, when there is a disproportion between the need and supply of oxygen e.g. during tachyarrhythmia, or as "pure" neurogenic myocardial involvement.