Intramyocardial Bone Marrow Cell Injection Research Articles

Intramyocardial bone marrow cell injection does not lead to functional improvement in patients with chronic ischaemic heart failure without considerable ischaemia.

BackgroundIt has been suggested that bone marrow cell injection may have beneficial effects in patients with chronic ischaemic heart disease. However, previous trials have led to discrepant results of cell-based therapy in patients with chronic heart failure. The aim of this study was to evaluate the efficacy of intramyocardial injection of mononuclear bone marrow cells in patients with chronic ischaemic heart failure with limited stress-inducible myocardial ischaemia.Methods and resultsThis multicentre, randomised, placebo-controlled trial included 39 patients with no-option chronic ischaemic heart failure with a follow-up of 12 months. A total of 19 patients were randomised to autologous intramyocardial bone marrow cell injection (cell group) and 20 patients received a placebo injection (placebo group). The primary endpoint was the group difference in change of left ventricular ejection fraction, as determined by single-photon emission tomography. On follow-up at 3 and 12 months, change of left ventricular ejection fraction in the cell group was comparable with change in the placebo group (P = 0.47 and P = 0.08, respectively). Also secondary endpoints, including left ventricle volumes, myocardial perfusion, functional and clinical parameters did not significantly change in the cell group as compared to placebo. Neither improvement was demonstrated in a subgroup of patients with stress-inducible ischaemia (P = 0.54 at 3‑month and P = 0.15 at 12-month follow-up).ConclusionIntramyocardial bone marrow cell injection does not improve cardiac function, nor functional and clinical parameters in patients with severe chronic ischaemic heart failure with limited stress-inducible ischaemia.Clinical Trial Registration: NTR2516Electronic supplementary materialThe online version of this article (10.1007/s12471-018-1213-2) contains supplementary material, which is available to authorized users.

Safety and efficacy of percutaneous intramyocardial bone marrow cell injection for chronic myocardial ischemia: Long-term results.

Intramyocardial injection of bone marrow cells (BMC) in refractory angina patients with chronic myocardial ischemia has shown to be safe and improve clinical status during short-term follow-up. However, scarce data are available on long-term (>12 months) safety and efficacy. Therefore, the occurrence of clinical events and the long-term clinical effects of intramyocardial BMC injection were evaluated in patients with chronic myocardial ischemia up to 10 years after treatment. Patients (n = 100, age 64 ± 9 years, male 88%) with chronic myocardial ischemia who underwent intramyocardial BMC injection between 2004 and 2010 were evaluated. During yearly outpatient clinic visits, the occurrence of clinical events was documented. In addition, clinical status was assessed according to the Canadian Cardiovascular Society (CCS) score and quality of life was measured using the Seattle Angina Questionnaire. These parameters were evaluated at baseline and during the first year, followed by cross-sectional long-term follow-up which was performed in 2011 and 2014. No adverse events considered related to the procedure occurred during 10 years of follow-up. Observed annual mortality rate and annual myocardial infarction rate were 3.8% and 1.9% per year, respectively. When compared to baseline, CCS class and quality of life remained significantly better during 5-year follow-up after BMC treatment (both P < 0.05). The present long-term follow-up study shows that intramyocardial BMC injection in patients with chronic myocardial ischemia is safe and improves both angina complaints and quality of life up to 5 years after BMC treatment.

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

BackgroundWe 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 resultsIn 120 patients (64±9years, 88% men) with refractory angina, 97±13×106 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 3months 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. ConclusionThe 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.

Effect of intramyocardial bone marrow-derived mononuclear cell injection on cardiac sympathetic innervation in patients with chronic myocardial ischemia

Intramyocardial bone marrow cell injection has been associated with improvements in myocardial perfusion and left ventricular function. The current substudy of a randomized, placebo-controlled, double-blinded study, investigated the effect of intramyocardial bone marrow cell injection on myocardial sympathetic innervation in patients with chronic myocardial ischemia. In a total of 16 patients (64 ± 8 years, 13 men), early and late iodine-123 metaiodobenzylguanidine (MIBG) imaging was performed before and 3 months after intramyocardial bone marrow cell injection. No improvements were observed in global early H/M ratio (P = 0.40), late H/M ratio (P = 0.43) and cardiac washout rate (P = 0.98). However, late 123-I MIBG SPECT defect score showed a trend to improvement in the bone marrow cell group (from 31.0 ± 7.1 to 28.1 ± 14.9) as compared to the placebo group (from 33.6 ± 8.5 to 34.5 ± 9.8, P = 0.055 between groups). This trend was mainly driven by a substantial improvement in three bone marrow cell-treated patients, which all had diabetes and severe MIBG defects. In these patients, the extent and severity of MIBG defects improved substantially independent of myocardial perfusion and cell injection sites. The present study does not demonstrate improvements in global cardiac sympathetic nerve innervation after intramyocardial bone marrow cell injection in patients with chronic myocardial ischemia. However, regional analysis of sympathetic nerve innervation reveals improvements in three diabetic patients independent of myocardial perfusion, suggestive of a therapeutic effect on diabetic cardiac sympathetic dysinnervation.

Long term effects of intramyocardial bone marrow cell injection on anginal symptoms and quality of life in patients with chronic myocardial ischemia

Long term effects of intramyocardial bone marrow cell injection on anginal symptoms and quality of life in patients with chronic myocardial ischemia

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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

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. 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. 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. 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.

Intramyocardial Bone Marrow–Derived Mononuclear Cell Injection for Chronic Myocardial Ischemia

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.

Bone Marrow Cell Injection for Chronic Myocardial Ischemia: The Past and the Future

Intramyocardial bone marrow cell injection is currently being investigated as a new therapeutic option for the treatment of chronic myocardial ischemia. Experimental studies and early phase clinical trials established a favorable safety profile of this approach and suggested that bone marrow cell injection was associated with clinical and functional improvements. Recently, a randomized, double-blind, placebo-controlled trial demonstrated that intramyocardial bone marrow cell injection was associated with beneficial effects on myocardial perfusion and anginal symptoms. However, the mechanisms by which bone marrow cells may improve myocardial perfusion are only partially understood, and several issues remain to be addressed. This review aims to provide a summary of the current experience with bone marrow cell therapy as a novel treatment option for patients with chronic myocardial ischemia. Therefore, the most frequently used cell types will be reviewed along with the mechanisms through which bone marrow cells may improve myocardial perfusion and function. In addition, possible routes of delivery are compared, and the results of currently available experimental and clinical studies are discussed.

Efficiency of Intramyocardial Injections of Autologous Bone Marrow Mononuclear Stem Cells in Patients with Ischemic Heart Failure: Long-Term Results

Introduction: Intramyocardial injection of autologous bone marrow mononuclear cells (BMMC) is believed to be a promising method for the treatment of patients with chronic ischemic heart disease. Hypothesis: To evaluate long-term results of intramyocardial bone marrow cell injection in patients with severe ischemic heart failure. Methods: Ninety nine ischemic heart failure patients (age 58 ± 5) with left ventricle ejection fraction (LVEF) ≤35% and III-IV NYHA and CCS functional classes without possibility for conventional revascularization were randomized into two groups: 1 group (n=49) - received intramyocardial BMMC injection and patients of the second group (n=50) were treated with standard medical therapy for HF. The NOGA system was used to administer 4.9 x107 BMMC into the infarction border zone. We analyzed all clinical data at 6 and 12 month of the follow-up period. Results: None of the patients developed periprocedural complications following BMMC injections. In the first group, the injections led to improvement of CCS class (3.5 ± 0.5 vs 2.1 ± 0.6 after 6 months and 1.9 ± 0.6 after 12 months (p<0.05 vs. baseline) and NYHA functional class (3.4 ± 0.1 vs 2.3 ± 0.2 after 6 months and 2.0 ± 0.2 after 12 months; p<0.05). The same characteristics in patients of the 2 group therapy remained unaltered (p = NS). LVEF increased in group 1 (34 ± 2% vs 42 ± 3%; p<0.05) while it tended to decrease in the control group (34 ± 2% vs 31 ± 3%; p = NS). Summed rest score improved in the first group after 6 months (14.7 ± 5.4 vs 10.7 ± 4.9; p<0.05). The improvement of stress score was more noticeable (18.2 ± 5.4 vs 9.4 ± 4.2; p<0.05). Neither stress nor rest score changed in patients of the second group. At the moment after 12 month follow up period 5 patients (10.2%) from group 1 died compared with 14 patients (28%) from group 2 (log rank test, p=0.008). Conclusions: Intramyocardial injection of autologous bone marrow mononuclear cells in ischemic heart failure patients is a safe procedure that improves clinical symptoms and has beneficial effecton LV function.

Intramyocardial Bone Marrow Cell Injection for Chronic Myocardial Ischemia

Previous studies have suggested that bone marrow cell injection may improve myocardial perfusion and left ventricular (LV) function in patients with chronic myocardial ischemia. To investigate the effect of intramyocardial bone marrow cell injection on myocardial perfusion and LV function in patients with chronic myocardial ischemia. 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). severe angina pectoris despite optimal medical therapy and myocardial ischemia. All patients were ineligible for conventional revascularization. Intramyocardial injection of 100 x 10(6) autologous bone marrow-derived mononuclear cells or placebo solution. 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). 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). 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. trialregister.nl Identifier: NTR400 and isrctn.org Identifier: ISRCTN58194927.

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. In 24 patients (19 male; 65 +/- 9 years) with refractory angina (Canadian Cardiovascular Society [CCS] class III-IV) 84.6 +/- 28.7 x 10(6) bone marrow-derived mononuclear cells were injected intramyocardially (using the NOGA system) in regions with ischemia on Tc-99m tetrofosmin single photon emission computed tomography (SPECT). Diastolic function was evaluated at baseline and at three months using magnetic resonance imaging (MRI) and tissue Doppler imaging (TDI). MRI revealed an increased early (E) peak filling rate (374 +/- 121 mL/second vs. 412 +/- 102 mL/second; P = 0.04), whereas the atrial (A) peak filling rate remained unchanged (340 +/- 81 mL/second vs. 334 +/- 93 mL/second; P = not significant [NS]). The E/A peak flow ratio increased from 1.09 +/- 0.33 to 1.23 +/- 0.47 at three months (P = 0.02). TDI demonstrated a significant improvement in early diastolic velocity (E') from 4.4 +/- 1.7 cm/second to 4.8 +/- 1.6 cm/second at three months (P = 0.03), whereas the late diastolic velocity (A') remained unchanged (6.0 +/- 1.6 cm/second vs. 6.0 +/- 1.7 cm/second; P = NS). Consequently, the E'/A' ratio increased from 0.74 +/- 0.19 to 0.84 +/- 0.28 at three months (P = 0.02). Intramyocardial bone marrow cell injection in patients with chronic myocardial ischemia improved MRI and TDI-derived parameters of diastolic function.

Abstract 1861: Myocardial Assistance by Grafting a New Bioartificial Upgraded Myocardium (MAGNUM Clinical Trial): One Year Outcome

Objectives Cell transplantation for myocardial regeneration is limited by poor graft viability and low cell retention. In addition, in ischemic cardiomyopathy the extracellular matrix is deeply altered. Therefore it could be important to associate a procedure aiming at regenerating myocardial cells and restoring the extracellular matrix function. We evaluated intrainfarct stem cell therapy associated with a cell-seeded collagen scaffold grafted onto infarcted ventricles. Methods In 15 patients (aged 54.2±3.8 years) presenting LV postischemic myocardial scars (age of the infarcts 8.2±3.5 months) and with indication for a single OP-CABG, bone marrow was collected by aspiration from the iliac crest. The cell suspension was loaded on Ficoll-Paque density gradient and 300 ± 28 million mononuclear bone marrow cells (BMC) were implanted during surgery in the scar. A type I collagen matrix seeded with the same number of BMC (300 ± 28 million cells) was added on top of the scarred area and fixed onto the epicardium by 6 single PDS sutures and covered by a second non-cellularized matrix. Results There was no mortality and any related adverse events (follow-up 15±4.2 months), no malignant cardiac arrhythmias were reported, no patient was lost to follow-up. NYHA FC improved from 2.3±0.5 to 1.4±0.3 (p=0.005). LV end-diastolic volume evolved from 142±24 to 117±21mL (p=0.03), LV filling deceleration time improved from 162±7ms to 196±8ms (p=0.01). Scar area thickness progress from 6±1.4 to 9±1.5mm (p=0.005). EF improved from 25±7 to 33±5% (p=0.04). Conclusions Simultaneous intramyocardial injection of BMC and fixation of a cell seeded matrix onto the epicardium is feasible and safe. The cell seeded collagen matrix seems to increase the thickness of the infarct scar with viable tissues and help to normalize cardiac wall stress in injured regions, thus limiting ventricular remodelling and improving diastolic function. Functional improvements can not be conclusively related to the cells and matrix due to the association of CABG. Cardiac tissue engineering seems to be a promising way for the creation of “bioartificial myocardium”. Efficacy and safety of this approach should be evaluated in a large randomized controlled trial.

Transmyocardial laser revascularization plus cell therapy for refractory angina

We report that the use of transmyocardial laser revascularization combined with intramyocardial injection is a therapeutic option for patients with severe ischemic heart disease (IHD) not amenable to conventional myocardial revascularization. Recently, cell therapy with autologous bone marrow cells (BMC) has been tested in clinical trials for severe IHD. We tested the hypothesis that TMLR combined with intramyocardial injection of BMC is safe, and may help increase the functional capacity and myocardial perfusion in patients with refractory angina. We enrolled 8 patients (7 men), 64 ± 4 years old, with refractory angina, non-candidates for another procedure. TMLR (8 ± 2 laser drills) was performed via a limited thoracotomy. BMC were obtained prior to surgery, and the lymphomonocytic fraction was separated by density gradient centrifugation. During surgery, 5 mL containing approximately 1.6 ± 0.2 × 10 8 BMC (CD34+ = 1.7 ± 0.4%) was delivered by multiple injections in the ischemic myocardium. We observed a reduction in the ischemic score as assessed by MRI from 1.56 ± 0.09 (B) to 0.93 ± 0.10 (6M) ( P = 0.01), as well as a reduction in functional class of angina from 3.6 ± 0.2 (B) to 1.4 ± 0.2 (6M) ( P < 0.0001). We concluded that, in this early experience, the combined strategy of TMLR plus cell therapy appeared to be safe, and may have synergistically acted to reduce myocardial ischemia, with clinically relevant improvement in functional capacity.

Direct Intramyocardial But Not Intracoronary Injection of Bone Marrow Cells Induces Ventricular Arrhythmias in a Rat Chronic Ischemic Heart Failure Model

Therapeutic efficacy of bone marrow (BM) cell injection for treating ischemic chronic heart failure has not been established. In addition, experimental data are lacking on arrhythmia occurrence after BM cell injection. We hypothesized that therapeutic efficacy and arrhythmia occurrence induced by BM cell injection may be affected by the cell delivery route. Three weeks after left coronary artery ligation, wild-type female rats were injected with 1x10(7) mononuclear BM cells derived from green fluorescent protein-transgenic male rats through either a direct intramyocardial or a retrograde intracoronary route. Both intramyocardial and intracoronary injection of BM cells demonstrated similar improvement in left ventricular ejection fraction measured by echocardiography and a similar graft size analyzed by real-time polymerase chain reaction for the Y chromosome-specific Sry gene. Noticeably, intramyocardial injection of BM cells induced frequent ventricular premature contractions (108+/-73 per hour at 7 days after BM cell injection), including multiform, consecutive ventricular premature contractions and ventricular tachycardia for the initial 14 days; intracoronary injection of BM cells and intramyocardial injection of phosphate-buffered saline rarely induced arrhythmias. Immunohistochemistry demonstrated that intramyocardial BM cell injection formed distinct cell clusters containing donor-derived cells and accumulated host-derived inflammatory cells in the infarct border zone, whereas intracoronary BM cell injection provided more homogeneous donor cell dissemination with less inflammation and without disrupting the native myocardial structure. BM cell injection is able to improve cardiac function in ischemic chronic heart failure but has a risk of arrhythmia occurrence when the intramyocardial route is used. Such arrhythmias may be prevented by using the intracoronary route.

Electrophysiological and arrhythmogenic effects of intramyocardial bone marrow cell injection in patients with chronic ischemic heart disease

Bone marrow cell injection has been introduced to treat patients with ischemic heart disease. However, focal application of bone marrow cells may generate an arrhythmogenic substrate. To assess the electrophysiological and arrhythmogenic effects of intramyocardial bone marrow cell injection in patients with chronic myocardial ischemia. Bone marrow was aspirated in 20 patients (65+/-11 years, 19 male) with drug-refractory angina and myocardial ischemia. Electroanatomical mapping (NOGA, Biosense-Webster, Waterloo, Belgium) was performed during mononuclear cell isolation. Areas for cell injection were selected based on the localization of ischemia on SPECT. These areas were mapped in detail to evaluate local bipolar electrogram duration, amplitude and fragmentation. Mononuclear cells were injected in the ischemic area with the NOGA system. SPECT and electroanatomical mapping were repeated at 3 months. Holter monitoring was repeated at 3 and 6 months. SPECT revealed a decrease in the number of segments with ischemia (3.5+/-2.5 vs. 1.1+/-1.0 at 3 months; P<0.01) and an increased left ventricular ejection fraction (44+/-13% vs. 49+/-17% at 3 months; P=0.02). The number of ventricular premature beats remained unchanged (10+/-24x10(2)/24h vs. 8+/-23x10(2)/24h at 3 months (P=NS) and 12+/-30x10(2)/24h at 6 months (P=NS)). At 3 months follow-up, bone marrow cell injection did not prolong electrogram duration (15.9+/-4.6 ms vs. 15.6+/-4.0 ms; P=NS), decrease electrogram amplitude (3.8+/-1.5 mV vs. 3.8+/-1.5 mV; P=NS), or increase fragmentation (2.0+/-0.5 vs. 1.9+/-0.4; P=NS). Intramyocardial bone marrow cell injection does not increase the incidence of ventricular arrhythmias and does not alter the electrophysiological properties of the injected myocardium.