The Role of CD34+ Stem Cells in the Pathogenesis of Takotsubo Syndrome

Takotsubo syndrome presents with a transient non-ischemic acute heart failure and relatively fast recovery of myocardial contractility. This medical condition is often precipitated by a previous trigger, such as physical or emotional stress. However, in approximately one-third of Takotsubo patients, the trigger remains unidentified. In terms of acute clinical presentation, Takotsubo patients with and without acute coronary syndrome-related symptoms have been recognized. Early recognition of the latter group is challenging due to the lack of clear indication for transthoracic echocardiography and coronary angiography with left ventriculography in this patient cohort, representing the gold standard in diagnostics of Takotsubo patients. Therefore, the prevalence of Takotsubo patients without acute coronary syndrome-related symptoms appears to be underestimated. In addition, novel data reveal that both short- and long-term prognoses in Takotsubo patients are comparable to the prognosis in acute coronary syndrome patients. Furthermore, chronic heart failure has been recognized in a subgroup of Takotsubo patients. To sum up, Takotsubo syndrome represents a heterogeneous medical condition, with a potential for adverse outcomes. This calls for new approaches to the diagnostics and treatment of this patient population.

Coronary microvascular dysfunction has been proposed as a crucial pathophysiological mechanism underlying Takotsubo pathogenesis, including the left ventricular dysfunction at acute episode and the degree/rate of left ventricular contractility improvement. As CD34+ cells are essential to coronary microvascular homeostasis we speculated on potential association between CD34+ cell count and changes in left ventricular function in patients with Takotsubo cardiomyopathy at baseline and 6-month follow-up.

In this single-center prospective pilot cohort study we included 34 consecutive patients with Takotsubo cardiomyopathy treated at our center between September 2021 and January 2026. Patients with a history of malignancy and concurrent acute coronary syndrome-mimicking conditions (myocardial infarction, myocarditis, etc) were not considered for this analysis. Takotsubo cardiomyopathy diagnosis was established per InterTac Registry criteria. Patients were enrolled within 24h of admission and underwent comprehensive clinical examination, blood biochemical and hematological analysis, and echocardiography at baseline and 6-month follow-up. Additionally, we expect at least half of the enrolled patients to complete cardiac MRI scan at baseline and 6-month follow-up. CD34+ cell count was measured using Beckman-Coulter Navios EX flow cytometry with standard antibodies according to ISAGE protocol.

The study results might enhance undertsanding of the pathophgysiological mechanism underlying structural and functional myocardial recovery among Takotsubo patients. Also, the study outcomes might provide crucial context for justifying further research work on investigating potential therapeutic effects of CD34+ cells on myocardial contractility recovery among Takotsubo patients.

• Improvement in myocardial contractility and deformation assesed by change in left ventricular global longitudinal strain (LV GLS) [Time frame: From enrollment to the end of observational period at 6-month follow-up.]
• Reduction in left ventricular filling pressure assessed by change in early mitral inflow velocity (E-wave) and the average of the septal and lateral early diastolic mitral annular velocities ratio (E/e' average) [Time frame: From enrollment to the end of observational period at 6-month follow-up.]
• Recovery of impaired myocardial relaxation assessed by change in peak early mitral inflow velocity and peak atrial contraction wave velocity ratio (E/A ratio) [Time frame: From enrollment to the end of observational period at 6-month follow-up.]
• Reduction in pulmonary artery systolic pressure assessed by change in tricuspid regurgitation maximum gradient (TR max gradient) [Time frame: From enrollment to the end of observational period at 6-month follow-up.]
• Reduction in left ventricular size assessed by left ventricular end-diastolic volume index (LVEDVi) [Time frame: From enrollment to the end of observational period at 6-month follow-up.]
• Reduction in left ventricular wall thickness assessed by posterior (inferolateral) wall diameter (PWd) and interventricular septal diameter (IVSd) [Time frame: From enrollment to the end of observational period at 6-month follow-up.]
• Improvement in right ventricular systolic function assessed by tricuspid annular plane systolic excursion (TAPSE) [Time frame: From enrollment to the end of observational period at 6-month follow-up.]
• Reduction in the extent of myocardial oedema assessed by cardiac magnetic resonance imaging [Time frame: Baseline and 6-month follow-up.]
• Remnants of cardiac fibrosis assessed by the extent of late gadolinium enhancement (LGE) [Time frame: Baseline, 6-month follow-up.]
• Recovery of coronary microvascular dysfunction assessed by change in angiogenesis-related biomarkers [Time frame: From enrollment to the end of observational period at 6-month follow-up.]
• Reduction in cardiac congestion assessed by change in serum levels of natriuretic peptides (NT-proBNP) [Time frame: From enrollment to the end of observational period at 6-month follow-up.]