Takotsubo cardiomyopathy (TTC) is a transient myocardial dysfunction syndrome, so named because the appearance of the left ventricle look like the traditional Japanese octopus jar with a narrow neck and round bottom, due to its pathognomonic echocardiographic features of apical ballooning (1). TTC are defined by strict criteria which include a trigger (physical or emotional stress), specific echocardiographic findings, ECG features and the exclusion of differential diagnoses (2). Among hypothesized mechanics, the role of endogenous catecholamines, microvascular disorders, hormonal and genetic factors have been suggested. Risk factors include female sex, age, and neurological or psychological conditions (2). The estimated incidence is 2% of all troponin-positive patients presenting with suspected acute coronary syndrome, with a plausible underestimation of the phenomenon (3). Although ventricular dysfunction due to TTC is usually reversible within a few days to weeks, in-hospital mortality is 4.5%, related to cardiogenic shock and extracardiac consequences (4).

Postoperative TTC after cardiac surgery have seldomly been reported. In the present work, we aim to investigate the incidence of TTC after cardiac surgery, its risk factors, and subsequent outcomes.

In a single-centre cohort study, we retrospectively screened patients who underwent cardiac surgery with cardiopulmonary bypass from January 2007 to March 2019 using a prospectively collected database, including 35 perioperative data. The cohort study was approved by our local institutional review board committee. Data are part of the REGISTRY for the improvement of Postoperative OutcomeS in Cardiac and Thoracic Surgery (RIPOSTE) database (NCT03209674). Since this study was observational, the need for written consent was waived according to French Law (Law 88-1138 relative to Biomedical Research of December 20, 1988, modified on August 9, 2004). Lack of patients’ opposition to the use of data was systematically sought for.

Patients who had previously had TTC were not involved in setting the research question or the outcome measures.

Takotsubo cardiomyopathy diagnosis was defined as the association of an acute left ventricular dysfunction with focal wall abnormalities extended beyond a single coronary artery that recovers spontaneously within days or weeks, repolarization abnormalities on ECG (ST-segment elevation or depression, T-wave inversion and/or prolongation in the QTc interval), modest increases in CPK and troponin and the exclusion of differential diagnoses such as a culprit coronary obstruction, a myocarditis, or a pheochromocytoma (2).

In patients in whom TTC diagnosis was retained, ECG, echocardiography, and preoperative coronary angiography were systematically reviewed and described.

In this study which combined cases extracted from a large registry and a systematic literature search, we found eighty-one cases of TTC following cardiac surgery. Although the incidence seems to be low, 83% of patients developed cardiogenic shock requiring vasopressors and/or ionotropic agents; and mortality was 5/81, 6%. Of note, most procedures involved mitral or tricuspid valve repair or replacement.

Because TTC is usually associated with transient LVEF decrease, with quick recovery, the prognosis has long been supposed to be benign. However, more recent studies demonstrated that subsequent in-hospital mortality reaches 4.5%, which is equivalent to the STEMI one (4). In this context, we found a subsequent mortality was 6% in TTC after cardiac surgery. Postoperative TTC had a low incidence (0.1% in our institutional cohort) and affected women in 79% of cases in whole cohort, which is consistent with the at-risk population described so far. TTC occurs early after surgery; but we found two case of late-onset TTC (11, 16).

The association between TTC and atrioventricular valvular procedures (80% mitral, 11% tricuspid) suggests a possible involvement of the type of cardiac procedure which was performed. First, a plausible mechanism may be the abrupt change in ventricular loading conditions when chronic atrioventricular regurgitation is suddenly corrected, may lead to a parallel sharp increase in endogenous catecholamines, independent of the surgical conditions. As described, TTC is initiated by an increase in plasmatic catecholamine levels, with evidence of cardiac sympathetic hyperactivity on iodine-123–meta-iodobenzylguanidine (I-MIBG) scintigraphy (26). Therefore, TTC may also be related to an adrenergic response to a sudden ventricular load mismatch. Consequently, reasoned use of catecholamines in TTC has therefore been suggested. Myocardial fibers are not uniformly receptive to hormones (27), and catecholamines, due to a regional distribution of sympathetic adrenoreceptors (28). This asymmetry is thought to explain the region wall motion abnormalities encountered in TTC, the most prominent being apical ballooning. Second, chronic atrioventricular regurgitations, be they mitral or tricuspid, cause progressive ventricular and atrial enlargement through altered protein expression, sarcomere remodeling and myocyte elongation leading to self-sustaining dilatation and regurgitation worsening (29–31). When indicated, valve surgery aims to restore valve competency, and abruptly terminating retrograde flow due to regurgitation. In the specific case of chronic severe atrioventricular repairs, the sudden decrease in ventricular preload and increase in afterload, leads to a mismatch in myocardial mechanics, peak in ventricular myocardial stress and transient increase in myocardial O₂ consumption. These elements may be very specific to mitral and tricuspid procedures, as all other cardiac surgery procedures usually put ventricles in a more favorable physiological environment as compared to the preoperative state, as demonstrated by in silico modelization. Briefly, sudden correction of mitral regurgitation increased left and right ventricular fiber stress by 40 and 15%, respectively, whereas tricuspid regurgitation correction increased left and right ventricular fiber stress by 26 and 19%, respectively (32). Concordant data were found in cardiac magnetic resonance imaging experimentation showing significant decreases in end-diastolic, end-systolic, and stroke volumes after mitral valve surgery, which were associated with a significant postoperative decrease of mean kinetic energy and systolic and early diastolic kinetic energy peaks (33).

However, we showed that post cardiac surgery TTC did not occurred only after mitral or tricuspid procedure; therefore, the physiopathology is not unequivocal.

Finally, the involvement of inflammation, which may be related to cardiopulmonary bypass and usual cardiac postoperative state, may be an additional risk, albeit, impossible to analyze independently. Indeed, inflammation has previously been related to TTC, with the participation of systemic inflammatory cells (with a higher proportion of classical CD14⁺⁺CD16^– and lower proportion of non-classical CD14⁺⁺CD16⁺ expressing monocytes in patients with TTC) and cytokines (higher levels of interleukin-6 and CXCL1 chemokines in patients with TTC) (34). While we did not assay our patients, thus, cannot confirm these same assumptions; CPB-related inflammation has also been associated with monocyte activation (35) and interleukin-6 elevation (36). To that extent, CPB-related inflammation may be considered akin to a minor form of cytokine release syndrome, which has extensively been associated with TTC in other settings than cardiac surgery (37–39).

We reported here a high rate of cardiogenic shock complicating TTC after cardiac surgery. As of now, acute heart failure is the most common complication of TTC in non-surgery patients (29%) (40) but cardiogenic shock account for only 5–6.1% (40, 41), and mortality from 2.6 to 14.5% (40–42). Meanwhile, after in surgery patients, 0.2–10% of those undergoing coronary or valvular cardiac procedures develop post cardiotomy cardiogenic shock (43, 44). This discrepancy between cardiogenic shock rate in TTC following cardiac surgery and in those in medical settings, could be explained by factors who potentialized cardiac dysfunction such cardiotomy and cardiopulmonary bypass induced inflammation. Furthermore, the incidence of cardiogenic shock could be overestimated by the retrospective character of the studies included with a possible selection bias with only the most serious cases reported in the literature; and the unavailability of the incidence of cardiogenic shock in the case series of 52 patients.

A strength of our study lies on the stringent criteria used to define TTC. TTC after cardiac surgery must be distinguished from other postoperative complications. Indeed, in the context of cardiac surgery, confounding factors may be incriminated toward misdiagnosis TTC. Lack of myocardial protection, coronary embolism, coronary vasospasm (45) and exogenous catecholamine-mediated toxicity are indeed plausible (46) (of note, in this cohort, no patient received catecholamines before surgery). Abnormalities on ECG or/and on echocardiography A in a coronary territory must direct toward a coronary origin or a gas embolism of the left ventricular dysfunction, whereas a diffuse left ventricular dysfunction could direct rather toward a lack of myocardial protection during cardiopulmonary bypass.

The troponin elevation is unspecific in cardiac surgery, since the procedure itself induces an elevation, even in the absence of postoperative cardiac complications.

Specifically, regarding mitral valve surgery, the loss of ventricular-annular continuity observed when both leaflets and papillary muscles are excised is another possible cause of left ventricular dysfunction. However, the preservation of the posterior mitral leaflet and its subvalvular apparatus is recommended when possible (47). In our institutional patients, 3 out of 10 had partial resection of the posterior mitral leaflet, which may have contributed to the left ventricular dysfunction.

We acknowledge several limitations. Our cohort was a single-center retrospective case-series. Given the conflicting factors in this context, the diagnosis of TTC could be difficult and although the data collection was prospective, the TTC incidence could be underestimate. Regarding the systematic review of the literature, we found only case reports and one case-control study with limited data on some valuable data; increasing the risks of confounding and bias. In the lack of large study and based only on case reports, this study could reflect imperfectly the real prevalence and course of post cardiac surgery TTC patients.

In this study which combined cases extracted from a large registry and a systematic literature search, we confirmed the existence of TTC following cardiac surgery and observed that TTC occurred preferentially after mitral and tricuspid procedures.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by the Clinique Ambroise Paré Ethics Committee. The patients/participants of our cohort provided their written informed consent for the use of their de-identified data.

DL, OT, and LN have substantially contributed to the conception and the design of the study and were major contributors in writing the original manuscript. LN, PE, and PS have also substantially contributed to the conception and the design of the study and were contributors in revision of the manuscript. DL, MB, OT, MH, AB, and J-CD have substantially contributed to the acquisition and analysis of the data. All authors read and approved the final manuscript.