Super Recurrence of Takotsubo Syndrome: Clinical Characteristics and Late Cardiac Outcomes

Recurrent takotsubo syndrome (TS) events are uncommon, with reported frequency of 1% to 6%.^{1, 2, 3} There is evidence for late subclinical cardiac dysfunction after a single TS event.⁴ Patients with multiple TS events might be vulnerable to late cardiac dysfunction, although this scenario has not been examined. To further inform this uncertainty, we evaluated the clinical characteristics and late cardiac outcomes of patients with ≥2 TS recurrences (super recurrence), compared with patients without recurrence.

The data that support the findings of this study are available from the corresponding author on reasonable request. From 2001 to 2022, we prospectively followed up 506 consecutive patients with TS from a single US center (average age, 68±13 years; 460 [91%] women; and 9 [1.8%] patients with ≥2 TS recurrences). Because TS recurrence is time dependent, we limited the comparator group (those without recurrence) to 49 (9.7%) patients with ≥10 years of follow‐up after index TS event. Median follow‐up for patients with super recurrence was 8.0 (interquartile range, 6.2–13.7) years; and for those without recurrence, it was 12.5 (interquartile range, 11.0–14.2) years. TS diagnosis used internationally accepted criteria.² This study was approved by the Allina Health Institutional Review Board, and subjects gave informed consent. Continuous variables were summarized with medians and interquartile ranges and compared between groups using Wilcoxon rank sum tests. Categorical variables were summarized with counts (percentages) and compared using χ² or Fisher exact tests. The analysis was performed using R version 4.2.2 (R Core Team, 2022) in RStudio 2022.12.0 (Posit Public Benefit Corporation).

The clinical characteristics of the patients are compared in the Table. Patients with super recurrence were younger, with significantly higher peak troponin, lower ejection fraction, and more frequent emotional trigger, depression/anxiety diagnoses, and cancer diagnoses than those without recurrence. Considering initial and recurrent TS events, the left ventricular ballooning pattern was concordant (all apical ballooning) in 5 (56%) patients and discordant (different ballooning patterns) in 4 (44%) patients. Furthermore, 6 (67%) patients experienced a trigger (physical or emotional) that differed from the trigger associated with the index event. Before recurrent events, most patients with super recurrence were receiving β‐blockers, angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers, and psychoactive medications.

At long‐term follow‐up, all 9 patients were alive, with ejection fraction ≥50% (measured at 1–60 months after the most recent TS recurrence). Evidence of myocardial disease was present in 2 (22%) patients during follow‐up: (1) left ventricular dysfunction (ejection fraction, 27%) and left bundle‐branch block (LBBB) at 1.6 years after fifth TS recurrence: cardiovascular magnetic resonance demonstrated mild left ventricular enlargement without late gadolinium enhancement or increased extracellular volume; ejection fraction improved to 55% after cardiac resynchronization therapy; (2) abnormal cardiovascular magnetic resonance at 2.8 years after fifth TS recurrence: focal late gadolinium enhancement in the basal inferolateral segment (midwall), elevated extracellular volume, ejection fraction of 65%, and normal wall motion.

At long‐term follow‐up, 46 of 49 (94%) patients had normal left ventricular ejection fraction, measured at median 11.8 years (range, 1 month–17.8 years) after the TS event. Evidence of cardiac disease was present in 7 (14%) patients as follows: (1) left ventricular dysfunction (ejection fraction of 20% and LBBB) at 4 years post‐TS event, treated with resynchronization therapy; (2) atrial fibrillation at 2 years post‐TS event, subsequently with asymptomatic LBBB at 8 years post‐TS event (ejection fraction, 60%); (3) cardiac amyloidosis (unspecified type) at 8 years post‐TS event; (4) left ventricular dysfunction (ejection fraction, 25%) at 10 years post‐TS event; (5) left ventricular dysfunction (ejection fraction, 35%) during terminal illness and severe sepsis; (6) left ventricular dysfunction (ejection fraction of 15% and LBBB) during atrial fibrillation with uncontrolled rate at 12 years post‐TS event; and (7) asymptomatic LBBB (ejection fraction, 65%) at 8 years after TS event.

To our knowledge, this is the first report to document the clinical characteristics and outcomes of TS super recurrence (≥2 TS recurrences), an uncommon scenario afflicting ≈2% of patients in our single‐center cohort. Notable findings include the following: first, patients with super recurrence represent a vulnerable phenotype of relatively younger women, with predominant emotional triggers, frequent presence of psychiatric comorbidities, and frequent use of prescription psychotropic drugs. In large series, emotional triggers are present in about 30% of TS events,² substantially less than the 65% in our super recurrence cohort. Others have documented an increased TS recurrence risk in patients with preexisting psychiatric illness.⁵ Second, whether TS super recurrence causes cumulative cardiac injury is uncertain. Although 2 patients with super recurrence (both with 5 recurrent TS events) had late cardiac abnormalities, the findings were variable and might represent coincidental conditions. Furthermore, patients without recurrence also experienced a variety of late cardiac conditions unrelated to TS. Third, recurrent events are an important clinical problem for some patients with TS; recurrent events are not necessarily prevented by β‐blockers or angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers. Finally, the combination of lower ejection fraction and greater peak troponin suggest patients with super recurrence experience more severe cardiac injury during TS events. The small number of patients with super recurrence precludes analysis using a multivariable model and is a limitation of this study.

No therapy has proven to be effective for prevention of TS recurrence. It is our practice to continue β‐blockers and to inform patients that prevention therapy is imperfect. Nearly 90% of patients with super recurrence had a depression/anxiety diagnosis. It is important to ensure these patients have appropriate treatment of associated mental health conditions.