DCM Support: cell therapy and circulatory support for dilated cardiomyopathy patients with severe ventricular impairment

Abstract

Aims

The DCM Support trial (NCT03572660) uses a percutaneous circulatory support device (Impella CP, Abiomed, Danvers, MA, USA) to improve the safety of an intracoronary cell infusion procedure in patients with dilated cardiomyopathy (DCM) and a severely reduced left ventricular ejection fraction (LVEF).

Methods and results

DCM Support is a single‐site, single‐arm Phase II trial enrolling 20 symptomatic DCM patients with an LVEF ≤ 35% despite optimal medical and device therapy. After 5 days of granulocyte colony‐stimulating factor therapy and a subsequent bone marrow aspiration, patients undergo an intracoronary infusion of autologous bone‐marrow‐derived mononuclear cells. The Impella CP device is used to provide haemodynamic support during the infusion procedure. The trial's primary endpoint is change in LVEF from baseline at 3 months. Secondary efficacy endpoints are change in LVEF from baseline at 12 months, and change in exercise capacity, New York Heart Association class, quality of life, and N‐terminal pro‐B‐type natriuretic peptide levels from baseline at 3 and 12 months. Safety endpoints include procedural safety and major adverse cardiac events at 3 and 12 months.

Conclusions

This is the first trial to assess the safety and efficacy of cytokine and autologous intracoronary cell therapy with a procedural circulatory support device for patients with severe left ventricular impairment. This novel combination may allow us to target a patient population most at need of this therapy.

Introduction

Non‐ischaemic dilated cardiomyopathy (DCM) is a leading cause of heart failure and the most common indication for heart transplantation worldwide. ¹ Although progress in the treatment of DCM has resulted in prolonged survival rates, the prognosis and quality of life for symptomatic patients remain poor. ²

Current conventional drug and device therapies for DCM do not correct underlying defects in cardiac muscle. Heart transplantation is the only treatment to address cardiomyocyte loss and fibrosis; however, donor shortages and strict selection criteria mean this is not a realistic option for most patients. Cell therapy for DCM has generated enthusiasm as it addresses cardiomyocyte loss and the progression of myocardial dysfunction.

Clinical trials of cell therapy for DCM, especially when paired with an adjunctive cytokine therapy such as granulocyte colony‐stimulating factor (G‐CSF), have demonstrated positive results in the improvement of cardiac function and symptoms. ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³ Overall, patients with more significant left ventricular (LV) impairment appear to derive the most benefit from cell therapy. ¹⁴ , ¹⁵ However, as these patients are at a higher risk of complications during interventional procedures, very few studies have exclusively targeted this patient group.

DCM Support (NCT03572660), therefore, uses a percutaneous circulatory support device (Impella CP, Abiomed, Danvers, MA, USA) to improve the safety of the cell infusion procedure in patients with severely impaired LV function [defined as a left ventricular ejection fraction (LVEF) ≤ 35%]. DCM Support uses the same methodology for G‐CSF administration, cell processing, and intracoronary infusion as our previous Phase II clinical trial REGENERATE‐DCM (NCT01302171), which demonstrated significant improvements in LVEF, New York Heart Association (NYHA) class, N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) levels, exercise capacity, and quality of life scores. ³

DCM Support is the first trial to use this novel combination therapy to investigate whether patients with severely impaired LV function can be safely treated with autologous cell therapy.

Study design

PICO can be found in Supporting Information, Figure S1 .

Study objectives

DCM Support aims to evaluate the safety and efficacy of cytokine therapy and an intracoronary autologous bone‐marrow‐derived cell infusion with a procedural percutaneous circulatory support device in patients with DCM and a severely reduced ejection fraction.

The trial's primary endpoint is change in LVEF from baseline at 3 months as measured by cardiac computed tomography (CT). CT is our chosen imaging method as these patients may have a device (which would preclude them from a research cardiac magnetic resonance scan as per our local protocol), and a sole imaging modality is preferable for uniformity given the small sample size. CT has comparable reliability and reproducibility compared with magnetic resonance imaging (and is superior to Echo). ¹⁶ Secondary efficacy endpoints are change in LVEF at from basline at 12 months and change in exercise capacity, NYHA, quality of life, and NT‐proBNP from baseline at 3 and 12 months. Safety endpoints include procedural safety and major adverse cardiac events at 3 and 12 months. A full list of endpoints can be found in Table 1 .

Table 1.

Endpoints for DCM Support

Primary endpoint	Change in LVEF from baseline measured by cardiac CT at 3 months
Secondary efficacy endpoints	Change in LVEF from baseline measured by cardiac CT at 12 months Change in exercise capacity from baseline at 3 and 12 months as assessed by 6 minute walk test Change in NYHA class from baseline at 3 and 12 months Change in quality of life (as measured by MLHFQ and EQ‐5D‐5L) from baseline at 3 and 12 months Change in NT‐proBNP from baseline at 3 and 12 months
Secondary safety endpoints	Procedural safety as assessed by in‐hospital procedural‐related morbidity/mortality Assessment of cumulative MACE [all‐cause death, myocardial infarction, hospitalization for heart failure, and major arrhythmias (defined as VT and VF)] at 3 and 12 months Assessment of individual components of MACE at 3 and 12 months Assessment of heart failure admissions as measured by the number of admissions for heart failure in the 12 months prior to procedure compared with the 12 months post‐procedure (measured at 3 and 12 months) Assessment of stroke at 3 and 12 months Change in troponin measured at Days 0 and 6 Change in renal function from baseline at 3 and 12 months as measured by creatinine levels Change in C‐reactive protein from baseline at 3 and 12 months

CT, computed tomography; LVEF, left ventricular ejection fraction; MACE, major adverse cardiac events; MLHFQ, Minnesota Living with Heart Failure Questionnaire; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association; VF, ventricular fibrillation; VT, ventricular tachycardia.

Study population

Only symptomatic patients (NYHA ≥ 2) with a confirmed diagnosis of DCM, a severely impaired ejection fraction (≤35%), and on optimal medical and device therapy are considered for this study. Prior to recruitment, a full clinical history and examination is undertaken to confirm that the patient meets the inclusion and exclusion criteria (listed in Table 2 ).

Table 2.

Eligibility criteria for DCM Support

Inclusion criteria

Patients with a confirmed diagnosis of dilated cardiomyopathy under the supervision of a physician or a heart failure nurse specialist. NYHA class ≥ 2 symptoms despite having received optimal medical therapy and appropriate device therapy, as per clinical guidelines for an interval of at least 3 months. No other treatment options available as part of the current best standard of care. LVEF ≤ 35% on any imaging modality performed as part of the screening phase. Patient between 18 and 85 years old.

Exclusion criteria

Congenital heart disease. Clinically significant valvular heart disease. Patients who are not suitable for a percutaneous mechanical support device (e.g. unsuitable femoral artery anatomy, unable to lie flat for prolonged time to accommodate the stem cell infusion, and presence of LV thrombus). Weight of patient that exceeds the maximum limit of the cardiac catheterization laboratory table/CT scanner. Cardiomyopathy 2° to a reversible cause that has not been treated, for example, thyroid disease, alcohol abuse, hypophosphataemia, hypocalcaemia, cocaine abuse, selenium toxicity, and chronic uncontrolled tachycardia. Cardiomyopathy in association with a neuromuscular disorder, for example, Duchenne's progressive muscular dystrophy. Previous cardiac surgery. Contra‐indication for bone marrow aspiration (thrombocytopaenia, platelet count < 80 × 109/L or extensive surgical scarring/anatomical deformity at site of bone marrow puncture). Known active infection on admission as defined by a temperature >37.5°C or on a short course of antibiotics. An active infection of hepatitis B, hepatitis C, syphilis, or HTLV. Known HIV infection. Chronic inflammatory disease requiring ongoing medication. Concomitant disease with a life expectancy of <1 year. Follow‐up impossible (no fixed abode, etc.). Neoplastic disease without documented remission within the past 5 years. Patients on renal replacement therapy. Subjects of childbearing potential unless βHCG negative and are on adequate contraception during the trial. Patients falling into the vulnerable category or lacking capacity. Patients who are unable to understand or read written English will be excluded from the trial. Killip Class III or above.

CT, computed tomography; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

Overview of study flow

DCM Support is a single‐site, single‐arm, open‐label Phase II trial being conducted at the Barts Heart Centre (Barts Health NHS Trust, London, UK). It is recruiting 20 patients from hospitals and heart failure clinics throughout the United Kingdom. The study is being conducted in full accordance with the Declaration of Helsinki and has been approved by an NHS Research Ethics Committee. A joint Trial Steering Committee and Data Safety and Monitoring Board will review overall safety throughout the trial. The sponsor may terminate the study early for reasonable cause. Study data are collected and managed using REDCap (Research Electronic Data Capture), an electronic, web‐based data capture tool hosted at Barts Cancer Centre, Queen Mary University of London.

The overall study flow is depicted in Figure 1 . Informed consent is obtained before any study‐related investigation is performed. After admission (Day 0), patients undergo daily subcutaneous G‐CSF (10 mcg/kg) therapy for 5 days. On Day 5, 54 mL of bone marrow is aspirated from the posterior iliac crest and processed at a specialized GMP‐compliant, MHRA‐regulated laboratory using the open Ficoll technique. The bone marrow mononuclear cells (BMMNCs) are then re‐suspended in 10 mL of normal saline before being returned to the hospital for infusion later that day.

Figure 1.

Overview of study flow. 6MWT, 6 min walk test; CT, computed tomography; G‐CSF, granulocyte colony‐stimulating factor; LVEF, left ventricular ejection fraction; MACE, major adverse cardiac events; MLHFQ, Minnesota Living with Heart Failure Questionnaire; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; NYHA, New York Heart Association.

Before cell infusion, the Impella CP device is inserted after access has been obtained under ultrasound guidance via the right femoral artery using a 14 F sheath as per the manufacturer's instructions. We use our existing large bore access Standard Operating Procedure from our Transaortic Valve Insertion (TAVI) programme (a CT scan assessment of peripheral arteries and an ultrasound‐guided puncture of the femoral artery). Following the manufacturer's recommendation, body weight heparin is administered, and activated clotting time checked to ensure >250 s. The Impella CP catheter is inserted under fluoroscopy across the aortic valve utilizing the Impella wire and a 6 F pigtail in the aortic root as per the manufacturer's instructions. The Impella CP device is then connected to the controller and turned on to provide haemodynamic support (up to 4 L/min of blood flow across the aortic valve) for the intracoronary BMMNC infusion.

Once the Impella device has been sited and continuous flow has been established, the BMMNCs are infused into the coronary arteries using recognized angioplasty techniques. The decision on radial or femoral access for BMMNC infusion is the operator's choice. A diagnostic angiogram is performed, and standard views and guide catheters are used to intubate the target coronary artery. The aim is to infuse the BMMNCs into more than 90% of the left ventricle. Vessel selection is at the operator's discretion based on left‐sided or right‐sided dominance.

Prior to cell infusion using a microcatheter, coronary flow stasis is achieved using a rapid exchange balloon catheter (0.5 mm smaller than the vessel). Once the balloon has been inflated, 3.3 mL of cells is infused over a 3 min period. This process is repeated three times until all 10 mL of cells has been infused.

Following the final infusion of cells, the flow rate on the Impella is gradually decreased before deactivation and removal in the cath lab. The Impella femoral artery puncture is closed using the Manta® vascular closure device, and the radial/femoral angioplasty access is closed as per local protocol. The patient is returned to a monitored bed for standard post percutaneous coronary intervention (PCI) procedure observations. Patients are discharged the following day dependent on their clinical condition and after a vascular access site assessment.

After hospital discharge, all study patients are contacted via telephone 1 month post‐procedure. In‐hospital follow‐up assessments are performed at 3 and 12 months as per Figure 1 .

Study duration

The aim is to recruit over 2 years with a study duration for each patient being 1 year. A study patient's participation may be terminated early for reasonable cause, such as the investigator's medical decision. At any time, the patient has the right to withdraw consent without a negative impact on their medical treatment. However, we will ask for the patient's permission for telephone contact if they do not wish to attend the in‐hospital follow‐up visit.

Sample size and statistical analysis

This is a single‐site, single‐arm Phase II study evaluating an intracoronary infusion of stem cells with a procedural percutaneous circulatory support device in patients with severe heart failure secondary to DCM. The results from our completed REGENERATE‐DCM trial ³ (in which patients' clinical condition improved significantly) were used to calculate the target sample size. The REGENERATE‐DCM trial showed an absolute improvement in LVEF of 5.37 ± 7.39% at 3 months in the stem cell arm. If the current trial of 20 patients was to match these figures, it would remain powered to detect this improvement in LVEF with a power of 90% and a significance level of 5%. The two main differences with REGENERATE‐DCM are DCM Support's use of a procedural Impella CP device and a patient population with a lower ejection fraction (the G‐CSF administration, cell production and cell infusion remain the same). Given that cell therapy appears to lead to a bigger change in LVEF for those with a lower baseline, alongside the proposed benefits of a procedural Impella (as outlined in the Discussion), and that we have increased the sample size to 20 patients, it is likely that we will have sufficient power to detect a similar difference from baseline. The statistical analysis plan will be created prior to analysis.

Discussion

Clinical trials of cell therapy for DCM, especially when paired with an adjunctive cytokine therapy such as G‐CSF, have demonstrated positive results in the improvement of cardiac function and symptoms. ³ , ⁴ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ , ¹¹ , ¹² , ¹³

DCM Support is the first trial to use a novel combination of cell and cytokine therapy alongside a procedural percutaneous circulatory support device. By enrolling patients with a severely impaired ejection fraction (LVEF ≤ 35%), DCM Support is targeting a patient group that appears to derive the most benefit from cell therapy. ¹⁴ , ¹⁵ However, this patient group is also at higher risk for complications during the intracoronary BMMNC infusion. It is well established that balloon inflation during PCI can lead to cardiac ischaemia, which, in turn, compromises cardiac function, and there is evidence regarding an increased risk of adverse outcomes in patients with chronic heart failure undergoing PCI. ¹⁷ DCM Support uses the Impella CP device to de‐risk the cell infusion procedure. The Impella device is currently used in clinical practice to facilitate high‐risk coronary interventional procedures (especially in patients with severely impaired LV function or cardiogenic shock). ¹⁸ , ¹⁹ , ²⁰ , ²¹ The device is known to reduce end‐diastolic wall stress and pulmonary capillary wedge pressure, ¹⁸ , ²² , ²³ therefore preventing acute decompensation.

It has been suggested that these important haemodynamic changes associated with Impella use may also benefit cell‐based therapies. Patients with advanced heart failure exhibit increased LV‐loading pressures, which, in turn, create a hostile microenvironment that adversely affects the retention, survival, and proliferation of delivered cells. ²⁴ , ²⁵ , ²⁶ The use of circulatory support may improve such a malignant environment by reducing LV‐loading pressures. By decreasing end‐diastolic wall stress and the mechanical compressive forces placed on the coronaries and microvasculature, ²⁷ a percutaneous circulatory assist device may enhance cellular retention and engraftment by improving coronary blood flow. ²¹ A porcine model successfully confirmed that the Impella is able to reduce end‐diastolic wall stress and increase coronary perfusion to the infarct zone in a model of myocardial ischaemia. ²⁷ DCM Support is the first clinical trial to use the Impella device to offload the left ventricle during cell infusion.

Some trials have used cell therapy in conjunction with left ventricular assist device (LVAD) implantation to test whether this is an effective bridge to transplantation or whether it can lead to successful temporary weaning of the LVAD with variable results. ²⁸ Three studies have explored the combination of LVAD and cell therapy for advanced heart failure. Ascheim et al. investigated the safety and efficacy of a transepicardial delivery of 25 × 10⁶ allogeneic mesenchymal precursor cells (MPCs) in 30 non‐ischaemic heart failure patients at the time of LVAD implantation. The procedure was safe and increased the likelihood of successful LVAD weaning. ²⁹ Another study evaluated the transepicardial delivery of various autologous bone marrow cells (0.5 × 10⁶ CD34⁺ cells, 1.0 × 10⁶ CD34⁻ cells, and 1.0 × 10⁶ BMMNCs) versus control (1 mL of PlasmaLyte; Baxter International Inc., Deerfield, IL, USA) in six patients with ischaemic heart failure at the time of LVAD implantation. ³⁰ After transplantation, the hearts were examined, and no histological or inflammatory differences were found between the cell‐injected and saline‐injected segments of myocardium. The most recent, and by far the largest, study was undertaken by Yau et al. One hundred and fifty‐nine patients undergoing LVAD implantation were randomized to either a transepicardial delivery of 150 × 10⁶ allogeneic mesenchymal progenitor cells or sham (2:1 ratio). ³¹ The procedure was demonstrated to be safe, but the probability that MPCs increased the likelihood of successful weaning was 69% (below the predefined threshold for success) and the mean proportion of successful temporary weaning from LVAD support over 6 months did not significantly differ between the groups.

To date, no trials have used a procedural percutaneous circulatory support removed in the cath lab after the cell infusion. The above trials implanted devices for months, thereby exposing the patient to the related complications (such as gastrointestinal bleeding, which has a reported incidence of up to 39% ³² ). The high co‐morbidity rates associated with the long‐term implantable LVAD devices may also mask the benefits of cell therapy. Due to their less invasive nature and shorter duration of use, percutaneous circulatory support devices are associated with lower device‐related morbidity compared with implantable LVADs. The improved procedural safety for these patients, alongside the theoretical benefits regarding cell engraftment, may lead to clearer safety and efficacy signals both procedurally and at follow‐up as the left ventricle responds to cell therapy.

DCM Support has been designed as a single‐arm trial due to the logistical, ethical, and safety issues related to having a placebo/sham control arm in this patient group. Although there is no direct control group, procedural safety analyses will be compared with the invasive arms of the REGENERATE‐DCM trial. In order to understand the proposed higher benefit to patients with a lower ejection fraction, exploratory within‐group efficacy analyses will be undertaken and evaluated compared with the cell‐treated arm in REGENERATE‐DCM (where the inclusion criterion was LVEF ≤ 45%).

To conclude, this is the first study to assess the safety and efficacy of cytokine and autologous cell therapy with a procedural circulatory support device in patients with severe LV impairment. This novel combination may allow us to target a patient population most at need of this therapy. It could also provide a method by which to safely deliver other biological therapies to patients with severely impaired LV function.

Conflict of interest

The authors have nothing to declare.

Funding

This work was supported by a grant awarded by the Barts Charity Cardiovascular Programme (MGU0284).

Supporting information

Figure S1. PICO.

Reid, A. , Hussain, M. , Veerapen, J. , Ramaseshan, R. , Hall, R. , Bowles, R. , Jones, D. A. , and Mathur, A. (2023) DCM Support: cell therapy and circulatory support for dilated cardiomyopathy patients with severe ventricular impairment. ESC Heart Failure, 10: 2664–2671. 10.1002/ehf2.14393.