Saskia L.M.A. Beeres

Intramyocardial Bone Marrow Cell Injection for Chronic Myocardial Ischemia: A Randomized Controlled Trial

CONTEXT Previous studies have suggested that bone marrow cell injection may improve myocardial perfusion and left ventricular (LV) function in patients with chronic myocardial ischemia. OBJECTIVE To investigate the effect of intramyocardial bone marrow cell injection on myocardial perfusion and LV function in patients with chronic myocardial ischemia. DESIGN, SETTING, AND PATIENTS Randomized, double-blind, placebo-controlled trial at a Netherlands university hospital, May 1, 2005-March 3, 2008 (6-month follow-up ended September 2008) of 50 patients with chronic myocardial ischemia (mean age [SD], 64 [8] years; 43 men). INCLUSION CRITERIA severe angina pectoris despite optimal medical therapy and myocardial ischemia. All patients were ineligible for conventional revascularization. INTERVENTIONS Intramyocardial injection of 100 x 10(6) autologous bone marrow-derived mononuclear cells or placebo solution. MAIN OUTCOME MEASURES Primarily, the summed stress score, a 17-segment score for stress myocardial perfusion assessed by Tc-99m tetrofosmin single-photon emission computed tomography (SPECT). Secondary included LV ejection fraction (LVEF), Canadian Cardiovascular Society (CCS) class, and Seattle Angina Questionnaire quality-of-life score (mean difference >5% considered clinically significant). RESULTS After 3-month follow-up, the summed stress score (mean [SD]) improved from 23.5 (4.7) to 20.1 (4.6) (P < .001) in the bone marrow cell group, compared with a decrease from 24.8 (5.5) to 23.7 (5.4) (P = .004) in the placebo group. In the bone marrow cell-treated patients who underwent magnetic resonance imaging (MRI), a 3% absolute increase in LVEF was observed at 3 months (95% CI, 0.5% to 4.7%; n = 18), but the placebo group showed no improvement. CCS angina score improved significantly in the bone marrow cell group (6-month absolute difference, -0.79; 95% CI, -1.10 to -0.48; P < .001) compared with no significant improvement in the placebo group. Quality-of-life score increased from 56% (9%) to 64% (12%) at 3 months and 69% (12%) at 6 months in bone marrow cell-treated patients, compared with a smaller increase in the placebo group from 57% (11%) to 61% (14%) to 64% (17%). The improvements in CCS class and quality of life score were significantly greater in bone marrow cell-treated patients than in placebo-treated patients (P = .03 and P = .04, respectively). CONCLUSIONS In this short-term study of patients with chronic myocardial ischemia refractory to medical treatment, intramyocardial bone marrow cell injection resulted in a statistically significant but modest improvement in myocardial perfusion compared with placebo. Further studies are required to assess long-term results and efficacy for mortality and morbidity. TRIAL REGISTRATIONS trialregister.nl Identifier: NTR400 and isrctn.org Identifier: ISRCTN58194927.

Cell therapy for ischaemic heart disease

Over the past decades, substantial advances in risk factor modification, pharmacological treatment, and revascularisation therapy have significantly reduced the mortality of ischaemic heart disease (IHD). Nevertheless, IHD remains a leading cause of morbidity and mortality. Cell therapy is currently being investigated as a potential treatment modality for patients with IHD. Preclinical studies suggested that cell therapy may have a favourable effect on tissue perfusion and contractile performance by promoting vascularisation and myocyte formation. Following these encouraging preclinical results, cell therapy has rapidly been introduced into the clinical setting. This paper aims to provide an overview of the basic principles of cardiac cell therapy. First, the potential mechanisms through which cell therapy may improve cardiac performance and the different cell populations that have been tested in preclinical studies are discussed. Thereafter, the different routes of cell delivery are reviewed, along with the results of the currently available clinical studies investigating the safety, feasibility and efficacy of cardiac cell therapy for patients with IHD. Originally, cell therapy was thought to improve cardiac performance through transdifferentiation of the injected cells into cardiomyocytes. Although several early studies supported the ability of cell therapy to regenerate cardiomyocytes,1 w1 subsequent studies failed to support these initial observations.w2–4 Since then, it has become apparent that the mechanistic underpinnings of cardiac cell therapy appear to be far more complex (fig 1). Several groups offered fusion of donor cells with host cardiomyocytes as an explanation for previous claims of transdifferentiation.w4 w5 Others reported that cell therapy may promote vascularisation by physical incorporation of the injected cells into new capillaries or in perivascular cells.2 w6 Still, the discrepancy between the massive cell death occurring within 24 h after cell transfer and the sustained functional improvement shown by many groups suggest that other mechanisms may be involved. …

Effect of intramyocardial bone marrow cell injection on diastolic function in patients with chronic myocardial ischemia.

To evaluate the effect of intramyocardial bone marrow cell injection on diastolic function in patients with chronic myocardial ischemia.

Intramyocardial bone marrow-derived mononuclear cell injection for chronic myocardial ischemia: the effect on diastolic function.

Background—The present substudy of a recently published randomized trial aimed to investigate the effect of intramyocardial bone marrow cell injection on diastolic function in patients with chronic myocardial ischemia. Methods and Results—In a total of 50 patients, diastolic function was evaluated before and 3 months after bone marrow cell injection using standard echocardiography and strain analysis. In addition, MRI-derived transmitral flow measurements were obtained in a subset of 36 patients. Left ventricular ejection fraction increased from 50±5% to 54±7% in the bone marrow cell group, which was a significant improvement as compared with the placebo group (52±5% versus 51±7%, P=0.001). Filling pressure estimate E/E′ ratio improved from 14±5 at baseline to 12±4 at 3 months in the bone marrow cell group, whereas no improvement was observed in the placebo group (13±4 versus 13±5). The improvement in E/E′ ratio was significantly larger in the bone marrow cell group (P=0.008). Furthermore, the E/A peak flow ratio as assessed by MRI showed a significant increase in the bone marrow cell group as compared with the placebo group (+0.16±0.25 versus −0.04±0.21, P=0.01), which was mainly related to an increase in the early (E) peak flow rate in the bone marrow cell group (from 407±96 mL/s to 468±110 mL/s, P=0.009 as compared with the placebo group). Conclusions—The current study demonstrates that intramyocardial bone marrow cell injection is associated with a beneficial effect on myocardial relaxation and filling pressures in patients with chronic myocardial ischemia. Clinical Trial Registration—URL: http://www.trialregister.nl. Unique identifier: NTR400/ISRCTN58194927.

Intramyocardial injection of bone marrow mononuclear cells in chronic myocardial ischemia patients after previous placebo injection improves myocardial perfusion and anginal symptoms: An intra-patient comparison

BACKGROUND We recently demonstrated in a randomized, double-blind, placebo-controlled trial that intramyocardial bone marrow cell (BMC) injection is associated with improvements in myocardial perfusion and anginal symptoms in chronic myocardial ischemia patients. In the present study the results of the crossover phase of this trial, in which patients previously treated with placebo received autologous BMC injections are reported. This allows a unique intra-patient comparison on the effect of BMC versus placebo injection with elimination of patient-related confounding factors. METHODS In 16 patients (14 male, 64 ± 10 years), who previously received intramyocardial placebo injections in the setting of a randomized trial, 100 × 10(6) BMC were injected using the NOGA-system. Canadian Cardiovascular Society angina score and quality of life were evaluated at baseline, 3 and 6 months. Tc-99m single photon emission computed tomography and magnetic resonance imaging were performed at baseline and 3 months to assess myocardial perfusion and left ventricular (LV) function. RESULTS Canadian Cardiovascular Society score and quality of life improved significantly after BMC injection as compared to placebo (P = 0.01 and P = 0.02, respectively). Single photon emission computed tomography revealed a significant greater improvement (P = 0.03) in summed stress score after BMC injection as compared to placebo. LV end-systolic volume significantly decreased after BMC injection but not after placebo injection. LV end-diastolic volume and LV ejection fraction did not change. CONCLUSION Intramyocardial BMC injection in patients with chronic myocardial ischemia who previously received intramyocardial placebo treatment resulted in significant improvement in angina symptoms and myocardial perfusion. These results confirm the outcome of our previously reported randomized trial.

Repeated Intramyocardial Bone Marrow Cell Injection in Previously Responding Patients With Refractory Angina Again Improves Myocardial Perfusion, Anginal Complaints, and Quality of Life

Background—Intramyocardial bone marrow cell injection is associated with improvements in myocardial perfusion and anginal symptoms in patients with refractory angina pectoris. This study evaluates the effect of repeated intramyocardial bone marrow cell injection in patients with residual or recurrent myocardial ischemia. Methods and Results—Twenty-three patients (17 men; 69±9 years) who had improved myocardial perfusion after the first injection but had residual or recurrent angina and ischemia on single-photon emission computed tomographic myocardial perfusion imaging were included. Patients again received intramyocardial injection of 100×106 autologous bone marrow mononuclear cells, 4.6±2.5 years after their first injection. No periprocedural complications occurred. Myocardial perfusion assessed using single-photon emission computed tomographic myocardial perfusion imaging improved from a summed stress score of 27.3±5.8 at baseline to 24.5±4.4 at 3 months (P=0.002) and 25.4±4.9 at 12 months of follow-up (P=0.002). Perfusion improvement after 3 months was comparable with the effect of the first injection (P=0.379). Anginal complaints improved ⩽12 months after cell injection in Canadian Cardiovascular Society score (mean change at 3, 6, and 12 months: 0.6±0.9%, 0.5±0.9%, and 0.6±0.9%, respectively; Pslope=0.007, first versus repeated; P=0.188) and in quality of life score as measured by Seattle Angina Questionnaire (mean change at 3, 6, and 12 months: 7±14%, 8±14%, and 7±15%, respectively; Pslope=0.020, first versus repeated; P=0.126). Conclusions—Repeated bone marrow cell injection in previously responding patients with refractory angina is associated with improvements in myocardial perfusion, anginal complaints, and quality of life score ⩽12 months of follow-up. Clinical Trial Registration—URL: http://www.trialregister.nl. Unique identifier: NTR2664.

Predictors of response to intramyocardial bone marrow cell treatment in patients with refractory angina and chronic myocardial ischemia

BACKGROUND We previously showed that intramyocardial bone marrow cell (BMC) injection in patients with refractory angina and chronic myocardial ischemia improves myocardial perfusion, cardiac function and disease-related complaints. Treatment effect varied between patients, but the predictors of response remain to be identified. Therefore, the aim of the present study was to assess whether patient characteristics, procedural data and baseline measurements influence the response to intramyocardial BMC treatment in a large cohort of refractory angina patients. METHODS AND RESULTS In 120 patients (64 ± 9 years, 88% men) with refractory angina, 97 ± 13 × 10(6) BMCs were injected intramyocardially in regions with stress-inducible ischemia as assessed by single photon emission computed tomography (SPECT). Canadian Cardiovascular Society angina (CCS) class, quality-of-life score, exercise testing, SPECT and magnetic resonance imaging were performed at baseline and at 3 months follow-up demonstrating significant improvements in CCS class, quality-of-life, exercise capacity, myocardial perfusion and left ventricular function (all variables P<0.001). Multivariate analysis was performed to evaluate the influence of patient characteristics, procedural data and baseline measurements on BMC treatment response. Based on the improvement of myocardial perfusion at stress, diabetes and a large number of ischemic segments at baseline were shown to be independently associated with a large response to BMC therapy. CONCLUSION The present study demonstrates that diabetes and a large number of ischemic segments are predictors of a large response to intramyocardial BMC injection in refractory angina and chronic ischemia. Furthermore, the safety and efficacy results of previous trials are now confirmed in a larger study population.

Intramyocardial bone marrow cell transplantation and the progression of coronary atherosclerosis in patients with chronic myocardial ischemia.

Background: Cell therapy has been proposed as a novel treatment strategy for patients with ischemic heart disease. However, two recent studies suggested that cardiac cell transplantation might aggravate coronary atherosclerosis. The aim of the current study was to assess whether intramyocardial bone marrow cell transplantation in patients with chronic myocardial ischemia is associated with progression of coronary atherosclerosis. Methods: In 30 patients with chronic ischemia, bone marrow was aspirated from the iliac crest. During mononuclear cell isolation, coronary angiography was performed. Thereafter, 94±18x106 cells were injected intramyocardially (NOGA system) in regions with ischemia on technetium‐99m tetrofosmin SPECT. Results: During the 12‐month follow‐up period, there was no clinical evidence of progression of atherosclerosis. CCS class improved from 3.4±0.5 to 2.4±0.8 at 3 months, 2.4±0.9 at 6 months and 2.5±0.9 at 12 months (P<0.01). MRI‐determined left ventricular ejection fraction increased from 51±12% to 54±12% at 3 months (P<0.01) and the number of ischemic segments per patient on SPECT decreased from 5.2±2.6 to 2.1±2.2 at 3 months (P<0.01). Repeat coronary angiography at 4 months revealed that bone marrow cell transplantation did not decrease minimal luminal diameter (1.81±0.80 mm versus 1.79±0.82 mm, P = NS) or mean luminal diameter (2.48±0.85 mm versus 2.46±0.86 mm, P = NS). Similarly, the percentage diameter stenosis (32±19% versus 32±20%, P = NS) and the atheromatosis severity score (4.78±2.40 versus 4.80±2.40, P = NS) remained unchanged. Conclusion: Intramyocardial bone marrow cell transplantation in patients with chronic myocardial ischemia was not associated with significant progression of atherosclerosis.

Early administration of abciximab in patients with acute myocardial infarction improves angiographic and clinical outcome after primary angioplasty

Adjunctive use of abciximab during percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) improves clinical outcome. This study addresses the outcome of patients with AMI treated with abciximab, initiated either before transport to a PCI center (early group) or immediately upon arrival at the catheterization laboratory (late group) for primary PCI. Of 446 consecutive patients with AMI, angiographic data and clinical complications were evaluated up to 6 months after primary PCI. Patients received abciximab before transport (early group; n = 138) or just before the intervention (late group; n = 308). Baseline data, including transport time (45 ± 15 min; range, 15–60 min), were comparable in both groups. Early reperfusion was more prevalent in the early group (35% vs. late 19%; P < 0.001). Furthermore, a better final TIMI 3 flow was noted in the early group (91% vs. late 83%; P = 0.05). Although mortality reduction attributable to early abciximab treatment could not be demonstrated, major adverse cardiac events (MACE) occurred in 27% in the early group and 36% in the late group (P = 0.05). Revascularization rates were similar, but repeat acute coronary syndromes were less frequent in the early group (11% vs. late group 20%; P = 0.04). In multivariate analysis, cardiogenic shock, out‐of‐hospital cardiac arrest, and previously known coronary artery disease were independent predictors of higher MACE rate, whereas early reperfusion and final TIMI 3 flow reduced 6‐month MACE rate. Abciximab pretreatment of patients with AMI for primary PCI results in better initial and final TIMI flow and tends to improve 6‐month clinical outcome.

Feasibility of trans-endocardial cell transplantation in chronic ischaemia

..... ell transplantation is currently being explored as a novel therapeutic option for patients with chronic myocardial ischaemia. The main goal of bone marrow cell transplantation is to augment blood flow in ischaemic myocardium through induction of angiogenesis. Improved collateral perfusion and enhanced left ventricular function have already been documented in animal models with chronic myocardial ischemia. 1 Until now, most clinical studies were carried out in patients with acute myocardial infarction. Only two studies containing (10 patients assessed the safety and feasibility of autologous bone marrow cell transplantation in patients with angina and ischaemia. 23 Further studies are needed to confirm the safety, feasibility and effectiveness reported in these pilot trials. The present phase I/II study tested the feasibility, safety and clinical effects of trans-endocardial transplantation of autologous bone marrow-derived mononuclear cells in patients with drug-refractory angina and myocardial ischaemia. Moreover, we aimed to determine whether cell transplantation is associated with improved myocardial function and perfusion by means of technetium-99m tetrofosmin gated single photon emission computed tomography (SPECT). METHODS