Autologous Atrial Appendage Derived Cells in the Treatment of Heart Failure

Epicardial Delivery of Autologous Atrial Appendage Micrografts During Coronary Artery Bypass Surgery - Safety and Feasibility Study

This study aims to evaluate the safety and clinical feasibility of epicardially delivered autologous atrial appendage micrografts in the treatment of heart failure. The micrografts consisting atrial-derived cells and their extracellular matrix, are placed on an infarction scar during CABG surgery.

Study Overview

• Status: Completed
• Conditions: Heart Failure
• Intervention / Treatment: Procedure: CABG surgery; Procedure: AADC therapy

Detailed Description

The atrial appendages are a tissue reservoir for cardiomyocyte stem and precursor cells. During coronary artery bypass graft (CABG) surgery part of the right atrial appendage can be excised upon insertion of the right atrial cannula of the heart-lung machine. This study aims to address the surgical feasibility and patient safety of epicardially delivered atrial appendage micrografts during CABG surgery.

Autologous cardiac cells are harvested from right atrial appendage during CABG of six patients. Micrografts consisting atrial appendage-derived cells (AADCs) and their extracellular matrix (ECM) of the atrial appendage are mechanically processed. The cells are placed on a tissue-engineered sheet with fibrin gel and tissue clue and further delivered epicardially on top of a infarction scar. Parameters including echocardiography reflecting cardiac insufficiency are studied pre- and post-operatively as well as at three and six months of the follow-up. Cardiac functional magnetic resonance imaging is performed preoperatively and at six-months follow-up. 20 patients will be recruited to serve as a control group. They are scheduled for elective CABG and are treated according to the normal hospital protocol, without the ECM sheet.

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Finland
  • Helsinki, Finland, 00029
    • Annu Nummi

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Informed consent obtained
• Left ventricular ejection fraction (LVEF) between ≤50% and ≥15%
• New York Heart Association (NYHA) Class II-IV heart failure symptoms

Exclusion Criteria:

• Heart failure due to left ventricular outflow tract obstruction
• History of life-threatening and possibly repeating ventricular arrhythmias or resuscitation, or an implantable cardioverter-defibrillator
• Stroke or other disabling condition within 3 months before screening
• Severe valve disease or scheduled valve surgery
• Renal dysfunction (GFR <84 ml/min/1.73m)
• Other disease limiting life expectancy
• Contraindications for coronary angiogram or MRI
• Participation in some other clinical trial

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AACD-Therapy group; 6 patients are recruited to the AADC-therapy group. Autologous atrial appendage derived cells (AADCs) are harvested from the appendage tissue removed during the venal cannulation of bypass. The cells and their extracellular matrix are placed with tissue clue to Cormatrix-sheet and further on top of the myocardium in the area of infarction scar. The procedure is done simultaneously with CABG surgery. The patients will be carefully monitored after the operations and cardiac MRI and echocardiogram will be performed previously to surgery as well as during the follow ups.	Procedure: CABG surgery; Elective CABG surgery; Procedure: AADC therapy; Atrial appendage derived cells are placed on the site of a infarct scar with matrix sheet
Active Comparator: Control group; 20 patients are recruited to form the control group. They are patients scheduled for elective CABG surgery and they meet the same inclusion and exclusion criteria as the therapy group. There patients are followed as the hospital protocol with out any additional imagination or blood tests.	Procedure: CABG surgery; Elective CABG surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety; need for vasoactive medication	For assessing haemodynamics during the operation and at the intensive care unit	6 months
Safety; cardiac index in l/min/m	For assessing haemodynamics during the operation and at the intensive care unit	6 months
Safety; hemoglobin in g/l	For assessing haemodynamics during the operation and at the intensive care unit	6 months
Safety; oxygen saturation in the pulmonary arterial blood (SvO2) in %	For assessing haemodynamics during the operation and at the intensive care unit	6 months
Safety; serum potassium level in mmol/l	For assessing haemodynamics during the operation and at the intensive care unit	6 months
Safety; blood glucose level in mmol/l	For assessing haemodynamics during the operation and at the intensive care unit	6 months
Safety; Left ventricular ejection fraction (EF) in %	For assessing cardiac function during and after the operation by echocardiogram	6 months
Safety; pericardial effusion in mm	For assessing cardiac function after the operation by echocardiogram	6 months
Safety: telemetric monitoring of rhythm	For assessing cardiac function after the operation	6 months
Feasibility: Success in completing the delivery of the cell sheet to the myocardium	Measured in 0= success, 1= no success	6 months
Feasibility: Waiting time in minutes for the cell sheet	Waiting time in minutes for the finished cell sheet to be placed on the myocardium after doing all the required anastomoses	6 months
Feasibility: Waiting time in minutes for the heart	Waiting time in minutes for the the heart after doing all the anastomoses and before the cell sheet is finished	6 months
Feasibility: Closing the right atrial appendage	Closing the right atrial appendage after removing the standardized tissue piece for preparing the cell sheet. According to the hospital protocol, appendage is closed with purse string suture. 0 = no additional suturing needed, 1 = additional suturing needed.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Left ventricular wall thickness	Measured by MRI	6 months
Change in the amount of myocardial scar tissue	Measured by MRI	6 months
Change in left ventricular ejection fraction	Measured by MRI	6 months
Plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels		6 months
New York Heart Association class		6 months
Days in hospital		1 month
Changes in the quality of life.	measured by questionnaire	6 months
Change in movement and diastolic function of left ventricular wall	Measured by MRI	6 months
Local changes in systolic and diastolic function	Measured by echocardiogram	3 months

Collaborators and Investigators

• Sponsor: Helsinki University Central Hospital
• Investigators: Study Director: Ari Harjula, Prof, Heart and Lung Center, Helsinki University Hospital

Publications and helpful links

General Publications

• Lehtinen M, Patila T, Vento A, Kankuri E, Suojaranta-Ylinen R, Poyhia R, Harjula A; Helsinki BMMC Collaboration. Prospective, randomized, double-blinded trial of bone marrow cell transplantation combined with coronary surgery - perioperative safety study. Interact Cardiovasc Thorac Surg. 2014 Dec;19(6):990-6. doi: 10.1093/icvts/ivu265. Epub 2014 Aug 20.
• Lehtinen M, Schildt J, Ahonen A, Nikkinen P, Lauerma K, Sinisalo J, Kankuri E, Vento A, Patila T, Harjula A; Helsinki BMMC Collaboration. Combining FDG-PET and 99mTc-SPECT to predict functional outcome after coronary artery bypass surgery. Eur Heart J Cardiovasc Imaging. 2015 Sep;16(9):1023-30. doi: 10.1093/ehjci/jev032. Epub 2015 Mar 9.
• Lehtinen M, Patila T, Kankuri E, Lauerma K, Sinisalo J, Laine M, Kupari M, Vento A, Harjula A; Helsinki BMMC Collaboration. Intramyocardial bone marrow mononuclear cell transplantation in ischemic heart failure: Long-term follow-up. J Heart Lung Transplant. 2015 Jul;34(7):899-905. doi: 10.1016/j.healun.2015.01.989. Epub 2015 Feb 7.
• Lampinen M, Vento A, Laurikka J, Nystedt J, Mervaala E, Harjula A, Kankuri E. Rational Autologous Cell Sources For Therapy of Heart Failure - Vehicles and Targets For Gene and RNA Therapies. Curr Gene Ther. 2016;16(1):21-33. doi: 10.2174/1566523216666160104141809.
• Nummi A, Mulari S, Stewart JA, Kivisto S, Teittinen K, Nieminen T, Lampinen M, Patila T, Sintonen H, Juvonen T, Kupari M, Suojaranta R, Kankuri E, Harjula A, Vento A; AADC consortium. Epicardial Transplantation of Autologous Cardiac Micrografts During Coronary Artery Bypass Surgery. Front Cardiovasc Med. 2021 Sep 14;8:726889. doi: 10.3389/fcvm.2021.726889. eCollection 2021.
• Nummi A, Nieminen T, Patila T, Lampinen M, Lehtinen ML, Kivisto S, Holmstrom M, Wilkman E, Teittinen K, Laine M, Sinisalo J, Kupari M, Kankuri E, Juvonen T, Vento A, Suojaranta R, Harjula A; AADC consortium. Epicardial delivery of autologous atrial appendage micrografts during coronary artery bypass surgery-safety and feasibility study. Pilot Feasibility Stud. 2017 Dec 20;3:74. doi: 10.1186/s40814-017-0217-9. eCollection 2017.

Study record dates

Study Major Dates

• Study Start: February 1, 2016
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): December 1, 2019

Study Registration Dates

• First Submitted: December 28, 2015
• First Submitted That Met QC Criteria: January 31, 2016
• First Posted (Estimate): February 3, 2016

Study Record Updates

• Last Update Posted (Actual): March 5, 2020
• Last Update Submitted That Met QC Criteria: March 3, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: heart failure; cell therapy; coronary artery bypass surgery; autologous micrografts; atrial appendage; epicardial cell delivery
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure
• Other Study ID Numbers: 180/13/03/02/2013

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No