Takotsubo Cardiomyopathy and Autoimmune Disorders: A Systematic Scoping Review of Published Cases

Introduction Takotsubo cardiomyopathy (TCM) features transient left ventricular apical dysfunction or ballooning. The underlying mechanism remains elusive; however, evidence suggests the role of different physical and psychological stressors. We systematically reviewed patients presenting with TCM and autoimmunity to explore the link between the two conditions. Methods We applied the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) to report this review. Using keywords related to autoimmune/immune-mediated diseases and TCM, we searched PubMed, Scopus, and WOS in March 2022. The final results were added to a data extraction sheet. Data were analyzed by SPSS version 26.0. Results Our search yielded 121 studies, including 155 patients. Females were considerably predominant. Most patients had a history of autoimmune disease, and almost a third had a history of cardiovascular disease. Dyspnea and chest pain were the most common chief complaints. More than 70% of patients had experienced physical stress. Myasthenia gravis, systemic lupus erythematosus, and multiple sclerosis were the most frequently reported autoimmune diseases. Conclusion There were similarities in age and sex compared to classic TCM. TCM should be considered as a differential diagnosis for ACS, especially in patients with a positive background of autoimmunity. A precise reporting system is required for further studies.


Introduction
Takotsubo cardiomyopathy (TCM) [1,2], also known as broken heart syndrome, apical ballooning syndrome, or stress cardiomyopathy, is a reversible dilating abnormality in the left ventricle's apical area resulting in systolic dysfunction [1,3].TCM was frst described in 1990 in Japan, taking its name from its similar echocardiographic appearance to the wide-based, narrow-necked pots used traditionally to trap octopuses [4].Its prevalence is 1-2.5%, mostly afecting postmenopausal women [1,3].Although the exact mechanisms remain elusive, the pathophysiology of TCM appears to involve microvascular dysfunction and catecholamine-induced cardiotoxicity [2].Physical or emotional stressors, estrogen defciency, and genetic factors can predispose individuals to this condition [1,3].
Chest pain and dyspnea are TCM's most common clinical manifestations, while other serious presentations such as cardiogenic shock and ventricular fbrillation may also occur [5].Tis condition mimics myocardial infarction, except that no coronary artery occlusion exists [1].Typical features include cardiac enzyme elevations, wall motion irregularities, and electrocardiographic abnormalities-mostly T wave inversion [2].Symptoms usually resolve spontaneously, but aggressive and invasive measures are required if hemodynamic instability develops [6].TCM cases have a desirable recovery and prognosis, and hospital mortality rates vary between 1 and 2% [2].
Te literature describes the coincidence of TCM with other conditions such as metabolic and endocrine dysfunctions [7], neurological diseases [8], psychiatric illnesses [9], and immune-mediated conditions [10,11].However, a major gap in research is the lack of a well-designed systematic review exploring the link between TCM and autoimmunity.Hence, considering the probable role of infammation and autoimmunity in TCM [11], we designed this study to systematically review the clinical and paraclinical aspects of published cases with coincident TCM and autoimmune diseases.

Methods
To report this systematic scoping review, we applied Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) [12].We searched three major databases including PubMed, Scopus, and WOS in March 2022, using keywords related to autoimmune/immune-mediated diseases and TCM (Supplementary Material (available here)).Our search yielded 3816 articles.Using relevant flters on each database (casereport flter in PubMed and article flter for Scopus and WOS), we excluded 1936 articles.In the next step, the authors independently screened the results for eligible articles in two separate rounds (Figure 1).
Our inclusion criteria consisted of English articles of any type reporting TCM patients with autoimmune disorders.We excluded those with unavailable full texts and cases with abnormal fndings in their coronary angiography in favor of coronary artery disease.We also removed duplicate cases, mainly reported in review articles.
After excluding duplications, the fnal results were added to a data extraction sheet.Data were analyzed by SPSS version 26.0.We used mean ± standard deviation (SD), median, and interquartile range (IQR) for continuous data, while frequency (percent) was used for categorical ones.

Results
Our review included a total of 155 patients with TCM associated with an autoimmune disease across 121 studies  (Supplementary Material (available here)), ranging in age from 4 to 84 years (Table 1).Te median age was 60 (IQR: 42-71) years.Among females, the median age was 60, with an IQR of 43-70.Males had a slightly lower median age [58] with a wider IQR of 30-76 years.Tere was a strong female predominance, with a female-to-male ratio of around 5.3 to 1. Interestingly, men were younger by an average of 3.2 years.Although race was not reported in most cases, African-American, Caucasian, and White patients accounted for most of the reported races (Table 1).
In terms of continental distribution, most patients were from North America, followed by Europe and Asia.Te distribution of cases by country is illustrated in Figure 1.Most (n � 55) cases were reported from the United States, after which came Japan (n � 12), Australia (n � 10), Austria (n � 10), the United Kingdom (n � 8), Italy (n � 8), and France (n � 8).Te remaining countries reported four or fewer cases (Figure 2).
Te past medical history of most (65.2%)patients was reported in the included studies (Table 2).When looking at the overall trends, most patients had a history of autoimmune disease, and almost a third of patients had a history of cardiovascular disease (any functional and/or structural heart disease, coronary artery disease, or hypertension).Te autoimmune disease was often combined with cardiovascular disease (7.1%), other diseases (13.5%), or both (15.5%).While the proportion of patients with cardiovascular disease was almost identical (28%) in both genders, women had an almost three times higher rate of autoimmune disease (57.7% vs. 20.0%).
A summary of the clinical presentations of the patients included in this review is presented in Table 3. Almost a third of studies did not report a chief complaint, and roughly, a quarter of studies reported more than one chief complaint.Te predominant chief complaint was dyspnea (46.9%) followed by chest pain (35.3%).Less common complaints (<10%) include syncope, palpitations, cyanosis, and cardiopulmonary arrest.Notably, the vital signs were not reported in roughly half the cases, with the other half having at least one abnormality.Tachycardia (23.6%) and hypotension (21%) were the most common abnormalities.An abnormal cardiovascular exam was reported in 21 cases; the remaining cases did not report any abnormalities.
In terms of the type of stress that triggered TCM, the type of trigger was unclear in 27 (17.4%)cases.Notably, 114 patients (73.5%) had a physical stress trigger, while 8 cases (5.2%) experienced psychological stress.Finally, 6 patients (3.9%) had both psychological and physical stress triggers.
An autoimmune marker was not reported in 117 cases (75.5%).Among the 38 cases where it was reported, 6 cases (15.8%) were negative and 32 were positive (    International Journal of Clinical Practice with the EF after recovery varying between 36 and 78%.Among those who had a recovery EF reported, 103 out of 110 (93.6%) achieved a normal EF.Te median time to recovery was 18.50 (IQR: 10.00-42) days (Table 5.) Te fnal outcome of 9 patients was unclear, while 133 (85.8%) survived and 13 (8.4%)succumbed to their disease.Te mean age of cases that resulted in fatalities was 64.31 ± 14.59 years, ranging from 31 to 81 years old.Eight patients (61.53%) were females and fve (38.46%) were males.MG (in fve cases) and SLE (in four cases) were the most frequently reported autoimmune disorders in this group.Te presenting ejection fraction was reported in only six of these cases, with a mean value of 30.67 ± 12.37%, ranging from 12 to 47%.

Discussion
We systematically reviewed the clinical presentations, laboratory data, ECG, and echocardiographic fndings of published cases of TCM associated with an autoimmune disease.Our results show that this association occurs predominantly in women in postmenopausal ages; this is in agreement with other studies indicating that the female sex is a strong risk factor for both disorders [134][135][136].Conversely, a study in Japan showed TCM to be more prevalent among men for unclear reasons [137], while another study reported TCM occurring in men at younger ages [134].
Many studies did not report the race of the patients; however, Whites, Caucasians, and African-Americans comprised the majority of those with known ethnicity.We could not fnd any reports on the defnite prevalence of TCM among diferent ethnicities.However, evidence suggests worse in-hospital complications among African-Americans [138].Tis parallels a study by Dias, Franco, Ross, and Hebert in terms of hospital length of stay.Interestingly, African-Americans' long-term prognosis has been better than Whites [139].
Almost a third of patients had a history of cardiovascular disease, and the proportion was the same in both genders.A systematic review of more than a thousand TCM patients reports a 54% prevalence of HTN [140].In addition to HTN, other risk factors of cardiovascular diseases including diabetes, hyperlipidemia, obesity, and chronic kidney disease can afect TCM [141].
Myasthenia gravis (MG) was the most common autoimmune disease associated with TCM, followed by systemic lupus erythematosus (SLE), multiple sclerosis, Guillain-Barre syndrome (GBS), Grave's disease, and rheumatic arthritis (RA).Limited data are available on such cooccurrences.For instance, more than 15% of MG patients may develop cardiac involvements [142,143].Cardiac complications are also common in SLE [144].In a review of the association of TCM and rheumatic disorders, 5 out of 16 were diagnosed with SLE [11].Despite few published cases of concurrent TCM and MS, the presence of medulla oblongata lesions was a common fnding, suggesting a potential role for catecholamines [145].One review study supports TCM as a probable complication of GBS, especially for those with dysautonomia [146].TCM may also present as a manifestation of thyrotoxicosis, especially Grave's disease [7,147].In one review study, RA was the second most frequent concurrent rheumatic disorder with TCM [11].
Emotional and physical stressors alone or in combination may trigger the development of TCM [148].Although most previous studies have focused on the role of emotional stressors [149], physical stressors reined emotional ones in our study.Most of our patients presented with chest pain and dyspnea, agreeing with a recent review on TCM [1].Tachycardia and hypotension were frequently observed; however, we could not fnd any study comprehensively addressing a detailed physical examination.
Most cases had elevated troponin levels, compatible with a review study on TCM [150].BNP and CK-MB were positive in about 10% and 15% of cases, respectively.Unlike acute MI, BNP elevation is a universal fnding in TCM [151,152].Studies are addressing the diagnostic value of NTproBNP/TnI, BNP/TnT, and BNP/CK-MB and ratios, especially in discriminating TCM from acute MI [153,154].
Not only the clinical presentations but also the electrocardiographic fndings may be misleading in differentiating TCM from acute coronary syndromes (ACSs) [155].Keeping in mind that normal ECGs may not be surprising [156], our results report T wave inversion as the most common ECG abnormality, followed by ST-segment elevation.However, some studies suggest a widespread pattern in ECG alterations, limiting the ability to reach a defnite localization [155,156].QT prolongation and transient Q waves were among other less frequent fndings [155].However, ECG alone cannot confrm the diagnosis, proposing the need for further evaluation [157].
Almost all patients had a reduced ejection fraction (EF) in the initial echocardiography study.We found that most patients survived and achieved a normal EF within 18 days.However, reduced LVEF is associated with an increased mortality risk [158].Another study revealed that despite the recovery of LVEF, TCM has in-hospital mortality comparable to that of acute ST-segment elevation myocardial infarction [159].
Tere were limitations to this study.Despite our eforts to establish realistic and result-orientated selection criteria, the inherent variability in the methodology and reporting system of case-report studies may contribute to heterogeneity and adversely afect the generalizability of the fndings.Tis also resulted in a considerable amount of missing or inconclusive data such as race, detailed past medical and familial history, clinical presentation, physical examination (specifcally vital signs), and pharmacological therapeutic measures, which are points to address in future endeavors.
In conclusion, this study reviewed the association of TCM and autoimmune disorders.Tere were similarities in age, sex, and other aspects to classic TCM.Te study suggests that autoimmune disease and TCM can coexist, and physicians should always consider TCM as a diferential diagnosis of ACS if no obstructive coronary artery disease is noted.Further studies are needed, requiring precise reporting of future cases to perceive the role of autoimmunity in developing TCM.6 International Journal of Clinical Practice

Table 5 )
. Almost all reported cases (112 out of 113, 99.1%) had a reduced ejection fraction (EF) in the initial echocardiography study.Te frst EF varied between 10 and 71%,

Table 1 :
Demographic data of 155 patients with Takotsubo cardiomyopathy associated with an autoimmune disease.

Table 1 :
Continued.Figure 2: Global map of reported cases of Takotsubo cardiomyopathy associated with autoimmune disease.Created with https://mapchart.net.

Table 3 :
Clinical presentation of 155 patients with Takotsubo cardiomyopathy associated with an autoimmune disease, n (%).