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

Effects of CD34+ Stem Cells on Left Ventricular Dysfunction Among Patients With Takotsubo Syndrome

The underlying mechanisms of microvascular dysfunction in Takotsubo cardiomyopathy remain incompletely understood. As CD34+ cells are essential to coronary microvascular homeostasis we will investigate the potential association between CD34+ cell count and changes in left ventricular function in patients with Takotsubo cardiomyopathy at baseline and 6-month follow-up.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Microvascular Dysfunction; Tako Tsubo Cardiomyopathy; CD34+ Stem Cells; Cardiac Contractility Recovery

Detailed Description

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.

• Study Type: Observational
• Enrollment (Estimated): 40

Contacts and Locations

• Study Contact: Name: Mark Jovanović, MD; Phone Number: +38640977307; Email: mark.jovanovic@kclj.si
• Study Contact Backup: Name: Principal Investigator; Email: gregor.poglajen@kclj.si

Study Locations

• Slovenia
  • Ljubljana
    • Ljubljana, Ljubljana, Slovenia, 1000
      • Recruiting
      • Advanced Heart Failure and Transplantation Program, Department of Cardiology, UMC Ljubljana, Slovenia
      • Contact: Jovanović, Prof. Poglajen; Phone Number: Jovanović: +38640977307; Email: mark.jovanovic@kclj.si ; gregor.poglajen@kclj.si

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

Adult patients, predominantly females, with cardiovascular risk factors.

Description

Inclusion Criteria:

• Minimum age 18 years
• Established TTS per InterTak registry criteria
• Signed consent form

Exclusion Criteria:

• Patients under the age of 18 years
• Ischemic heart disease with at least one complete total occlusion
• Other concurrent cardiomyopathies
• Active infectious myocarditis
• obstructive coronary artery disease
• Previous hospital stay due to acute coronary syndrome (myocardial infarction) in the last 6 months before TTS acute event
• Previous interventional coronary artery procedure in the last 6 months before TTS acute event
• Significant valvular heart disease
• Significant peripheral artery occlusive disease
• Active or remitted hematologic malignancy
• Patients receiving immunosuppressive therapy
• Significant comorbiditeis affecting patients survival (malignancy)
• Failure to obtain freely given, informed consent form.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Takotsubo patients with preserved OR mildly reduced/reduced LVEF at acute event.; Takotsubo patients divided in subgroups based on preserved or mildly reduced/reduced LVEF at acute event.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recovery of left ventricular systolic function assessed by change in left ventricular ejection fraction (LVEF)	Change in LVEF (%), measured by transthoracic echocardiography using Biplane Simpson's method.	From enrollment to the end of observational period at 6-month follow-up.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in myocardial contractility and deformation assesed by change in left ventricular global longitudinal strain (LV GLS)	Change in LV GLS (%), measured by transthoracic echocardiography using speckle-tracking method.	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)	Change in E/e' average, calculated from transthoracic echocardiography by dividing the peak early mitral inflow velocity (E-wave) by the average of the septal and lateral early diastolic mitral annular velocities (e') obtained via tissue doppler imaging.	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)	Change in E/A ratio, calculated from transthoracic echocardiography by dividing the peak early mitral inflow velocity (E-wave) by the peak atrial contraction velocity (A-wave), both measured via pulsed-wave Doppler in the apical four-chamber view.	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)	Change in TR max gradient (mmHg), measured using transthoracic echocardiography by applying continuous wave (CW) doppler to the TR jet to determine the peak velocity, then applying the modified Bernoulli equation.	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)	Change in LVEDVi (mL/m2), calculated from transthoracic echocardiography using Biplane Simpson's method and indexed to body surface area.	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)	Change in PWd (mm) and IVSd (mm), assessed by transthoracic echocardiography using parasternal long-axis view.	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)	Change in TAPSE (mm), assessed by transthoracic echocardiography and measured in the apical 4-chamber view using M-mode placed at the lateral tricuspid annulus.	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	Change in the extent of myocardial oedema, assessed by cardiac magnetic resonance imaging scan using T2-weighted imaging and T2-mapping (T2 relaxation times in miliseconds).	Baseline and 6-month follow-up.
Remnants of cardiac fibrosis assessed by the extent of late gadolinium enhancement (LGE)	Change in the extent of myocardial LGE (% of left ventricular mass), quantified by cardiac magnetic resonance (CMR).	Baseline, 6-month follow-up.
Recovery of coronary microvascular dysfunction assessed by change in angiogenesis-related biomarkers	Change in angiogenesis-related biomarker panel composite score, measured using a Luminex multiplex immunoassay.	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)	Change in serum levels of NT-proBNP (ng/L), measured in blood sample by serum biochemical analysis.	From enrollment to the end of observational period at 6-month follow-up.

Collaborators and Investigators

• Sponsor: University Medical Centre Ljubljana

Publications and helpful links

General Publications

• Templin C, Ghadri JR, Diekmann J, Napp LC, Bataiosu DR, Jaguszewski M, Cammann VL, Sarcon A, Geyer V, Neumann CA, Seifert B, Hellermann J, Schwyzer M, Eisenhardt K, Jenewein J, Franke J, Katus HA, Burgdorf C, Schunkert H, Moeller C, Thiele H, Bauersachs J, Tschope C, Schultheiss HP, Laney CA, Rajan L, Michels G, Pfister R, Ukena C, Bohm M, Erbel R, Cuneo A, Kuck KH, Jacobshagen C, Hasenfuss G, Karakas M, Koenig W, Rottbauer W, Said SM, Braun-Dullaeus RC, Cuculi F, Banning A, Fischer TA, Vasankari T, Airaksinen KE, Fijalkowski M, Rynkiewicz A, Pawlak M, Opolski G, Dworakowski R, MacCarthy P, Kaiser C, Osswald S, Galiuto L, Crea F, Dichtl W, Franz WM, Empen K, Felix SB, Delmas C, Lairez O, Erne P, Bax JJ, Ford I, Ruschitzka F, Prasad A, Luscher TF. Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy. N Engl J Med. 2015 Sep 3;373(10):929-38. doi: 10.1056/NEJMoa1406761.
• Rai B, Shukla J, Henry TD, Quesada O. Angiogenic CD34 Stem Cell Therapy in Coronary Microvascular Repair-A Systematic Review. Cells. 2021 May 8;10(5):1137. doi: 10.3390/cells10051137.
• Eerdekens R, El Farissi M, De Maria GL, Shetrit A, Sykes R, Ekenback C, Persson J, Spaak J, Couch LS, Alfonso F, Rivero F, Gonzalo N, Escaned J, Nunez Gil IJ, Cruz OV, Shamir RA, Freund O, Vanderheyden M, Belmonte M, Barbato E, Tonino PAL, Banning A, Solberg OG, Berry C, Fearon WF, Zimmermann FM. Prognostic Value of Microvascular Function in Takotsubo Syndrome: A Pooled Analysis of Individual Patient Data. JACC Cardiovasc Interv. 2025 Jul 14;18(13):1646-1656. doi: 10.1016/j.jcin.2025.05.028. Epub 2025 May 22.
• Almendro-Delia M, Lopez-Flores L, Uribarri A, Vedia O, Blanco-Ponce E, Lopez-Flores MDC, Rivas-Garcia AP, Fernandez-Cordon C, Sionis A, Martin-Garcia AC, Vazirani R, Corbi-Pascual M, Salamanca J, Perez-Castellanos A, Martinez-Selles M, Becerra VM, Aritza-Conty D, Lopez-Pais J, Guillen-Marzo M, Lluch-Requerey C, Garcia-Rubira JC, Nunez-Gil IJ; RETAKO Investigators. Recovery of Left Ventricular Function and Long-Term Outcomes in Patients With Takotsubo Syndrome. J Am Coll Cardiol. 2024 Sep 24;84(13):1163-1174. doi: 10.1016/j.jacc.2024.05.075.
• Shaikh N, Sardar M, Jacob A, Alagusundaramoorthy SS, Eng M, Checton J, Shah A. Possible predictive factors for recovery of left ventricular systolic function in Takotsubo cardiomyopathy. Intractable Rare Dis Res. 2018 May;7(2):100-105. doi: 10.5582/irdr.2018.01042.

Study record dates

Study Major Dates

• Study Start (Actual): September 6, 2021
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: May 17, 2026
• First Submitted That Met QC Criteria: May 17, 2026
• First Posted (Actual): May 22, 2026

Study Record Updates

• Last Update Posted (Actual): May 22, 2026
• Last Update Submitted That Met QC Criteria: May 17, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: heart failure; CD34+ stem cells; microvascular dysfunction; Takotsubo syndrome; cardiac contractility recovery
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Cardiomyopathies; Ventricular Dysfunction; Ventricular Dysfunction, Left; Heart Failure; Takotsubo Cardiomyopathy
• Other Study ID Numbers: 0120-118/2021/3

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No