Mechanism of Stress-Induced Cardiomyopathy Complicated with Acute Cerebral Infarction

To the Editor: A 72-year-old female patient was admitted to the hospital in the morning due to “recurrent retrosternal discomfort for many years, aggravated with chest pain for 1 day.” She had a history of intermittent retrosternal chest pain for many years, which could be relieved within 10 minutes by sublingual administration of 6 pills of Suxiao Jiuxin Pills, but she had not received standardized treatment. At 1 o’clock in the early morning of the day before admission, she suddenly developed severe retrosternal stuffy pain radiating to the back, accompanied by nausea, vomiting, and profuse sweating, without other accompanying symptoms. She went to the emergency department at 06:00 am. Electrocardiogram showed that the QT interval was > 0.44 s, and the T waves in leads I, II, augmented vector left (aVL), V1-V6 were low and inverted Figure 1. On the afternoon of the first day of admission, the patient was transferred to the Department of Psycho-Cardiology, Beijing Anzhen Hospital. Multiple re-examinations of myocardial markers were conducted, and the results showed significant changes compared to those at admission Figure 2. On the third day after admission, the patient began to have a fever. The patient was given sponge baths and loxoprofen for the management of fever and associated symptoms. On the morning of hospital day 4, the patient was noted to have a recurrent fever of 38°C. Antimicrobial treatment with ceftriaxone was given to the patient. The repeat bedside echocardiogram demonstrated a decreased myocardial movement in the apex segments of the left ventricle, thrombus formation in the apex segments of the left ventricle, thrombus formation in the left ventricular apex (about 10 mm × 9 mm), left atrium enlargement (38 mm), interventricular septum thickening (13 mm), and left ventricular ejection fraction (LVEF) was 52%. This prompted the initiation of therapeutic anticoagulation with rivaroxaban 20 mg daily. On the 5th day of admission, the patient’s temperature was 37.6°C. At 07:00 pm on the same day, the patient suddenly developed deviation of the mouth corner, inability to speak, accompanied by weakness in the right limb, without incontinence of urine or stool. An urgent consultation with the neurology department was requested, and immediate non-enhanced magnetic resonance arterial vascular imaging of the head were completed. An embolus is identified within the left middle cerebral artery Figure 3. An urgent cranial artery thrombectomy was performed. On the 2nd day after the operation, as well as on the 6th day of admission, the patient was conscious with temperature of 36.3°C. The repeat bedside echocardiogram demonstrated a decreased myocardial movement in the apex segments of the left ventricle, interventricular septum thickening (13 mm). LVEF was 53%. The patient was then transferred to the neurology department. On the 10th day of admission, the patient’s left ventricular inner diameter was reduced, and LVEF was 65%. Coronary computed tomography angiography (CTA) demonstrated moderate stenosis of the left anterior descending artery (involving the first diagonal branch) and the right coronary artery, along with a 50% distal stenosis in the left circumflex branch Figure 4. The electrocardiogram rechecked at the time of discharge showed a normal electrocardiogram Figure 5. After the discharge, the patient took the medications regularly and was advised to stop taking rivaroxaban after 3 months and to follow up for cardiac ultrasound examination 6 months later. Cardiac magnetic resonance examination showed left atrial enlargement and slightly thickened basal segment of the left heart wall Figure 6.Figure 1: Sinus rhythm, heart rate 98 beats per minute, QT interval > 0.44 s, low and inverted T waves in leads Ⅰ, Ⅱ, aVL, V1-V6. aVR = Augmented vector right; aVL = Augmented vector left; aVF = Augmented vector foot; SEMIP = Artificial intelligence electrocardiogram analysis systemFigure 2: (a) Fluctuations in hsTnI; (b) Fluctuations in BNP. hsTnI = High-sensitivity cardiac troponin I; BNP = B-type natriuretic peptideFigure 3: Cranial magnetic resonance imaging and non-enhanceddmagnetic resonance angiography of the head. Embolism of the left middle cerebral arteryFigure 4: Coronary CTA shows (a) moderate stenosis (approximate) of the left anterior descending artery; (b) moderate stenosis (approximate) of the first diagonal branch; (c) 50% stenosis of the distal left circumflex artery; (d) moderate stenosis of the right coronary artery. CTA = Computed tomography angiographyFigure 5: Electrocardiogram shows sinus rhythm, and the heart rate was 80 beats per minute. aVR = Augmented vector right; aVL = Augmented vector left; aVF = Augmented vector footFigure 6: Cardiac magnetic resonance imaging shows (a) an enlarged left atrium; (b) a slightly thickened interventricular septum at the basal segment of the left heart; (c and d) no hyperintense signals of delayed enhancement in the left ventricular wallThe patient’s peak high-sensitivity troponin I level was 223.1 pg/mL (normal: 0–11.6 pg/mL), which represents a mild elevation. It peaked 24–28 hours post-symptom onset and normalized within 4 days—a pattern that differs from the marked and prolonged elevation typical of acute coronary syndrome. Echocardiography on admission revealed reduced apical wall motion, an 11 cm × 9 cm apical aneurysm, left atrial enlargement (41 mm), septal thickening (13 mm), mild tricuspid regurgitation, and LVEF was 43%, with rapid recovery to 65% by hospital day 10. Wall motion abnormalities did not match the moderate left anterior descending stenosis on CTA. In this case, the coronary CTA indicated moderate stenosis of the anterior descending branch, and the myocardial area supplied by the diseased coronary vessels did not match the ventricular wall motion abnormalities. One day prior to admission, the patient experienced emotional stress from her spouse’s death, leading to myocardial injury, impaired contractility, left ventricular thrombus, and subsequent cerebral embolism, suspecting myocardial infarction with non-obstructive coronary arteries (MINOCA). The diagnosis of stress-induced cardiomyopathy (SCM) was supported by an InterTAK score of 76 points (≥ 50 indicates SCM), fulfilling key criteria including female gender, emotional trigger, atypical troponin kinetics, non-coronary wall motion abnormalities, and rapid cardiac function recovery Figure 7. Cardiac magnetic resonance imaging (MRI) was performed six months later, and the results showed persistent left atrial enlargement and mild basal septal thickening. These findings support the diagnosis of SCM complicated by coronary atherosclerosis.Figure 7: Characteristics of this case. The patient in this case is female (25 points), with an emotional trigger (24 points), neurological disorder (9 points), absence of ST-segment depression (except in lead aVR) (12 points), and QT interval prolongation (6 points), with a total score of 76 points. aVR = Augmented vector rightDISCUSSION SCM also known as Takotsubo cardiomyopathy, was first reported by Japanese scholars in 1990.1 It is a syndrome of transient left ventricular systolic dysfunction that resembles the clinical manifestations of acute coronary syndrome, induced by severe psychological and/or physical stress. At present, the specific mechanism of SCM has not been fully elucidated. Catecholamine overload, coronary microvascular dysfunction, etc., may be involved in the pathogenesis.2 It should be noted that the comorbidity of SCM and coronary heart disease is common and may jointly contribute to myocardial injury. In this case, the patient had moderate stenosis of the three coronary arteries, combined with hypertension and diabetes. Although no severe stenosis was seen in the subsequent coronary CTA, and the abnormal ventricular wall motion and impaired cardiac function recovered in a short time with drug treatment, which was different from the clinical manifestations of acute myocardial infarction, we still need to be alert to the pathogenic role of coronary atherosclerosis in the course of the disease. Intravascular coronary imaging and functional assessment may provide more information, and the secondary prevention strategy for coronary heart disease will continue in the subsequent treatment. One day before admission, the patient’s wife passed away, causing a great emotional blow. There was obvious myocardial injury, cardiac ventricular wall motion dysfunction, cardiac insufficiency combined with left ventricular thrombus formation, and finally the left ventricular thrombus led to embolism. Based on this, the cause of myocardial injury needs to be re-examined, and the possibility of myocardial infarction with MINOCA needs to be alert. Among the various causes of MINOCA, combined with our detailed collection of medical history and scales, the possibility of SCM is considered. Currently, the most widely used diagnostic criteria are the diagnostic criteria3 for SCM by the European Society of Cardiology for heart failure. This criterion4 revises the early Mayo Clinic criteria. Recently, the international SCM diagnostic criteria, namely the InterTAK5 diagnostic criteria, have been proposed. The InterTAK international registry has developed a simple scoring system. This system includes 5 clinical variables and 2 variables from the electrocardiogram (25 points for female, 24 points for emotional trigger, 13 points for physical trigger, 11 points for mental disorder, 9 points for neurological disorder, 12 points for the absence of ST-segment depression except in lead augmented vector right (aVR), and 6 points for QT interval prolongation). A score of ≥ 50 points considers SCM (0%–95%), and a score of ≤ 31 points considers acute coronary syndrome (0%–95%). The score of this patient is 76 points Figure 7. Therefore, considering the inducement of the patient’s onset, electrocardiogram changes, myocardial marker levels, coronary CTA and echocardiographic results, SCM is considered. Multiple echocardiographic re-examinations during hospitalization showed rapid recovery of cardiac function. On the 10th day of onset, the LVEF recovered to 65%. Initially, it is considered that this patient has SCM combined with coronary atherosclerotic heart disease. Intracardiac thrombus is a potential complication of various cardiac and systemic diseases, and it is one of the serious complications of acute myocardial infarction in coronary heart disease (CHD). In particular, ventricular aneurysm further increases the possibility of ventricular thrombus formation. With the popularization of percutaneous coronary intervention, the incidence of intracardiac thrombus related to CHD has significantly decreased, while intracardiac thrombus complicated by other diseases has gradually attracted attention due to its high disability and mortality rates.6 SCM is associated with severe left ventricular dysfunction and apical ballooning, which increases the risk of left ventricular thrombus and systemic embolism. Thromboembolic events in SCM may be related to decreased left ventricular systolic function and abnormal blood flow in the acute phase.7 At present, studies on SCM complicated with ventricular thrombus are limited. Studies in dilated cardiomyopathy with similar cardiac structural and functional abnormalities have shown that the incidence of thrombus/embolic events is about 11%–44%.8,9 In addition, endothelial dysfunction, hypercoagulability, activation of inflammatory pathways and release of cytokines may provide additional pathophysiological mechanisms.1,10 In this case, the patient developed obvious myocardial injury under acute psychological stress. The echocardiogram in the acute phase showed decreased motion of the apical segments of all left ventricular walls and formation of left ventricular apical aneurysm. Ventricular thrombus appeared soon even under dual antiplatelet therapy, and left middle cerebral artery embolism still occurred after adding anticoagulation. After emergency thrombectomy, the patient recovered, and no ventricular thrombus was found in the re-examined echocardiogram. This intracranial artery embolism was a cardiogenic embolus, which was considered to be caused by intracardiac thrombus formation due to severe myocardial injury caused by SCM, weakened ventricular wall and changes in endocardium in the lesion area. Hypercoagulable state1 is the basis of Virchow’s triad (such as endothelial cell injury, abnormal blood flow and platelet activation). The possible pathophysiological mechanisms related to hypercoagulability in SCM include catecholamine storm in the acute phase of the disease, followed by increased platelet activation and aggregation, with the incidence of thrombus/embolic events being 2.2%–14%.7 The degree of involvement of these factors in intracardiac thrombus formation depends on the type of primary disease, myocardial dysfunction and the duration of the disease. In the short term, in this case, the patient had decreased myocardial motion in the anterior wall, the lower 1/2 of the anterior wall, and the apical segments of all left ventricular walls, blunted left ventricular apex, and the medium echo was transformed into a smaller left ventricular diameter. This may be related to ventricular systolic dysfunction, blood stasis caused by cardiac chamber enlargement, and hypercoagulable state of intracardiac blood. Most intracardiac thrombi in patients with cardiomyopathy are more common in the left ventricle.11 In addition, some systemic diseases involving the cardiovascular system can also present as intracardiac thrombus. Once an intracardiac thrombus is formed, the embolus can embolize important organs through the blood circulation, affecting the prognosis. At present, studies on the clinical characteristics and treatment outcomes of patients with non-CHD-related intracardiac thrombus are limited, mostly in the form of case reports. Therefore, it is necessary to conduct in-depth research on this group of patients. The Chinese Expert Consensus on Anticoagulant Therapy for Cardiomyopathy11 proposes that for SCM patients with reduced ejection fraction, it is recommended to assess the risk of left ventricular thrombus through echocardiography. For high-risk patients, it is recommended to use unfractionated heparin or low-molecular-weight heparin early, and oral anticoagulants after discharge, which can be adjusted according to the individual situation of the patient.12 It is recommended to take oral anticoagulants for 2–3 months or until ventricular function recovers, which can reduce the risk of stroke in Takotsubo syndrome patients (preferable to apply). Studies have shown4,13 that SCM is associated with smoking, alcohol abuse, and hyperlipidemia. Its pathogenesis remains unclear, and possible theories include the catecholamine excess theory, the plaque rupture theory, and the genetic theory.2 Additionally, studies have indicated that estrogen levels are the reason why SCM is more common in postmenopausal women. Regarding acute neurological diseases caused by acute SCM, it may be because the central nervous system regulates arterial pressure, vascular tone, cardiac output, heart rate, rhythm, and metabolism through exciting and inhibiting autonomic nerve conduction pathways. The heart is regulated by sympathetic and parasympathetic nerves, with the regulatory centers located in the hypothalamus, brainstem, and limbic system. Damage to these areas can cause abnormalities in renin-angiotensin, water and sodium, leading to abnormal advanced autonomic nerve activity and an imbalance between sympathetic and parasympathetic nerves. The patient has a long history of hypertension, diabetes, and atherosclerosis. The acute myocardial injury has led to the imbalance of sympathetic and parasympathetic nerves that regulate the heart. In this case, the patient has left middle cerebral artery embolism. Furthermore, the massive release of epinephrine and norepinephrine also has a neurohormonal basis. Through activating the hypothalamic–pituitary–adrenal (HPA) axis and releasingadrenocorticotropic hormone, adrenal sympathetic stimulation, and influencing the increase of plasma cytokines in the HPA axis, it leads to peripheral arterial vasoconstriction, sudden increase in left ventricular afterload, and elevation of left ventricular systolic pressure.14 Currently, research on the clinical characteristics and treatment outcomes of patients with intracardiac thrombosis not related to CHD is limited, mostly consisting of case reports. Therefore, it is necessary for us to enhance our understanding of SCM, reduce its misdiagnosis rate, and improve the diagnosis and treatment process of SCM. Author contributions Peijun Rao, Guo Li and Changjiang Qin were involved in the conception and analysis of the case. All the authors summarized and interpreted the cases. Peijun Rao wrote the draft. All the authors have given final approval for the publication of the current version. Ethical statement Ethical statement is not applicable for this article as it is a case report. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Data availability statement The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.