Kai Jaquet

Combined delivery approach of bone marrow mononuclear stem cells early and late after myocardial infarction: the MYSTAR prospective, randomized study

Background Combined intracoronary and intramyocardial administration might improve outcomes for bone-marrow-derived stem cell therapy for acute myocardial infarction (AMI). We compared the safety and feasibility of early and late delivery of stem cells with combined therapy approaches.Methods Patients with left ventricular ejection fraction less than 45% after AMI were randomly assigned stem cell delivery via intramyocardial injection and intracoronary infusion 3–6 weeks or 3–4 months after AMI. Primary end points were changes in infarct size and left ventricular ejection fraction 3 months after therapy.Results A total of 60 patients were treated. The mean changes in infarct size at 3 months were −3.5 ± 5.1% (95% CI −5.5% to −1.5%, P = 0.001) in the early group and −3.9 ± 5.6% (95% CI −6.1% to −1.6%, P = 0.002) in the late group, and changes in ejection fraction were 3.5 ± 5.6% (95% CI 1.3–5.6%, P = 0.003) and 3.4 ± 7.0% (95% CI 0.7–6.1%, P = 0.017), respectively. At 9–12 months after AMI, ejection fraction remained significantly higher than at baseline in both groups. In the early and late groups, a mean of 200.3 ± 68.7 × 106 and 194.8 ± 60.4 × 106 stem cells, respectively, were delivered to the myocardium, and 1.30 ± 0.68 × 109 and 1.29 ± 0.41 × 109 cells, respectively, were delivered into the artery. A high number of cells was required for significant improvements in the primary end points.Conclusions Combined cardiac stem cell delivery induces a moderate but significant improvement in myocardial infarct size and left ventricular function.

Percutaneous intramyocardial stem cell injection in patients with acute myocardial infarction: first-in-man study

Background: Clinical studies on intracoronary stem cell infusion in patients with acute myocardial infarction (AMI) have shown promising results for left ventricular ejection fraction (LVEF). However, preclinical studies have shown that intramyocardial cell injection is better than the intracoronary approach. Objective: To test safety and feasibility of intramyocardial cell injection and left ventricular electromechanical mapping (EMM) early after AMI. Design: On day 10.5 (5) (mean (SD)) after AMI and percutaneous coronary intervention with stent implantation (culprit lesion: 15 LAD, 3 circumflex and 2 right coronary arteries) 20 patients (mean (SD) 60.4 (11.4) years) received bone marrow derived mononuclear cells in the low-voltage area using EMM-guided percutaneous intramyocardial injection. EMM and coronary angiography were performed in 15 patients at 6-months’ follow-up. Echocardiography, recording of laboratory data and clinical assessment (6-month and 12-month follow-up) were carried out in all 20 patients. Results: None of the patients showed periprocedural complications. Three patients received an implantable cardioverter-defibrillator for primary prevention of sudden cardiac death and 6 (30%) patients showed in-stent restenosis. One patient underwent bypass surgery owing to chronic stent occlusion after 6 months. 2.0 (0.6)×108 cells, including 1.0 (0.3)×106 CD45dim/CD34hi stem cells, were injected in each patient. EMM showed a mean (SD) improvement from a baseline unipolar voltage of 45.5 (14.3)% to 59.3 (19.8)% of normal voltage (p = 0.002) and reduction of the low-voltage area from 28.7 (12.1)% to 20.3 (13.5)%; (p = 0.016). During the 12-month follow-up, the left ventricular ejection fraction (LVEF) improved from 40.8 (6.9)% to 47.1 (10.6)%; (p = 0.037). Conclusion: Left ventricular EMM and percutaneous intramyocardial cell injection in patients with AMI was shown to be a safe procedure. It is associated with improved LVEF and electromechanical parameters after 12-months’ follow-up. Trial registration number: Eudra-CT-No 2005-003629-19.

Percutaneous endocardial injection of erythropoietin: Assessment of cardioprotection by electromechanical mapping

Apart from its well‐known stimulation of erythropoiesis, erythropoietin (EPO) exhibits angiogenic and anti‐apoptotic effects. These cellular protective effects have also been described in experimental acute myocardial infarction models. We investigated the effects of EPO in a porcine model of chronic progressive myocardial ischaemia.

Transplantation of Bone Marrow-Derived Stem Cells Improves Myocardial Diastolic Function: Strain Rate Imaging in a Model of Hibernating Myocardium

BACKGROUND The aim of this study was to evaluate the cardioprotective effects of bone marrow-derived stem cells on myocardial compliance in a chronic ischemia model regarding strain rate (SR) parameters during dobutamine stress echocardiography (DSE). METHODS Ameroid constrictors were placed around the circumflex arteries of 23 domestic pigs to induce chronic vessel occlusions. Fifteen pigs received transendocardially bone marrow derived stem cells, and 8 received placebo injections (a 0.9% solution of NaCl) into the ischemic region. At week 6, the animals were evaluated regarding myocardial fibrosis, neovascularization, apoptosis, and diastolic function during DSE. RESULTS Stem cell-injected hearts showed significantly less fibrosis, higher ejection fractions, significant neovascularization, and less ventricular dilatation than controls (P < .05). Strain rate imaging revealed improved diastolic function, with higher early diastolic SR values and lower E/Ea ratios compared with controls (P < .05). Early diastolic SR during DSE identifies viable myocardium (extent of fibrosis, r = 0.86, P = .0001). CONCLUSION The endocardial injection of stem cells improves diastolic function in chronic ischemic myocardium and helps attenuate postinfarction remodeling.

Limited Immune-Modulating Activity of Porcine Mesenchymal Stromal Cells Abolishes Their Protective Efficacy in Acute Kidney Injury

We demonstrated previously that administration of mesenchymal stromal cells (MSCs) after renal ischemia/reperfusion injury (IRI) in rats protected renal function and hastened repair through complex paracrine mechanisms. Here we investigated kidney-protective actions of MSCs in a porcine IRI model that may have relevance to human acute kidney injury (AKI). Groups of female pigs with bilateral IRI were infused with autologous or male allogeneic MSCs. No acute or late complications were observed, but unexpectedly, MSC therapy also had no beneficial effects on kidney function and histology. In vitro, we demonstrated substantial functional and phenotypic overlaps between rodent, human, and porcine MSCs, all of which exhibited trilineage differentiation, characteristic antigen profiles, and secretion of renoprotective vascular endothelial growth factor (VEGF)-A and insulin-like growth factor-1 (IGF-1). However, in striking contrast to human MSCs, porcine MSCs failed to inhibit the mixed lymphocyte reaction (MLR) and induced robust production of proinflammatory interleukin-6 (IL-6). In summary, in contrast to rodent models, treatment of porcine IRI with MSCs was not kidney-protective. This, we conclude, is due to the fact that porcine MSCs exert inadequate immune-modulating effects, further demonstrating that successful therapy of IRI with MSCs critically depends on their anti-inflammatory actions. As a consequence, treatment of AKI with MSCs is not informative regarding the investigation of the underlying mechanisms in this large animal model. We expect, however, that the treatment of human IRI of the kidney with immune-modulating MSCs will be as effective as in rodent models.

Intramyocardial Transplantation of Bone Marrow-Derived Stem Cells: Ultrasonic Strain Rate Imaging in a Model of Hibernating Myocardium

BACKGROUND The aim of this study was to evaluate potential cardioprotective effects of bone marrow-derived stem cells in chronic ischemic myocardium regarding strain rate parameters during dobutamine stress echocardiography. METHODS An ameroid constrictor was placed around the circumflex artery in 23 pigs to induce hibernating myocardium. Pigs received autologous mesenchymal stem cells (auto MSCs), allogeneic MSC (allo MSC), autologous mononuclear cells (auto MNCs), or placebo injections into the ischemic region. During dobutamine stress echocardiography, peak systolic strain rates (SR(sys)) and systolic and postsystolic strain values (epsilon(sys), epsilon(ps)) were determined. The animals were evaluated regarding myocardial fibrosis, neovascularization, apoptosis, and myocardial beta-adrenergic receptor density. RESULTS The median ejection fraction was reduced in the control group compared with the auto MSC-, allo MSC-, and auto MNC-treated pigs (36.5% vs 46.0% vs 46.0% vs 41.5%; P = .001, respectively). Histopathology revealed a decreased myocardial fibrosis in auto MSC- (16.3%), allo MSC- (11.3%), and auto MNC- (16.7%) treated pigs compared with controls (31.0%; P = .004). The fibrosis and echocardiographic deformation data correlated in the posterior walls: rest peak SR(sys)r = -0.92; epsilon(sys)r = -0.86; 10 microg dobutamine stimulation peak SR(sys)r = -0.88, epsilon(sys), r = -0.87 (P = .0001). CONCLUSION Endocardial injection of stem cells may induce cardioprotective effects in chronic ischemic myocardium and helps to keep the ischemic myocardium viable.

Endocardial Electrogram Analysis after Intramyocardial Injection of Mesenchymal Stem Cells in the Chronic Ischemic Myocardium

Background: Cell injection therapies have been introduced for the treatment of patients with coronary heart disease. However, intramyocardial injection of bone marrow (BM)‐derived cells may generate proarrhythmogenicity.

Percutaneous, transendocardial injection of bone marrow-derived mononuclear cells in heart failure patients following acute ST-elevation myocardial infarction: ALSTER-Stem Cell trial.

AIMS Patients with symptomatic heart failure following acute ST-elevation myocardial infarction (STEMI) received transendocardial application of bone marrow-derived mononuclear cells (BMC) to improve left ventricular (LV) function and clinical outcome. METHODS AND RESULTS Patients (n=12) with LV ejection fraction (EF) <45% and NYHA Class ≥II received NOGA-guided transendocardial injection of BMC into the infarction border zone 17.5±0.8 days following successful interventional revascularisation after STEMI. A matched control group (n=11) was generated from the source data of the previously published LIPSIAbciximab-STEMI trial. Primary and secondary endpoints were derived from comparisons of baseline vs. six-month follow-up cardiac magnetic resonance imaging (CMR) measurements and clinical assessments. Following cell therapy we observed a significant increase of EF (+7.9±1.5%, p=0.001) while the control group showed no change. This effect was driven by a reduction of LV end-systolic volume (ESV) by -27.5±6.5 ml (p=0.001); LV end-diastolic volume (EDV) and scar volu-me remained unchanged. A significant decrease of NYHA Class was found only in the cell therapy group (-0.75 vs. -0.18, p=0.04). Findings were also translated into enhancement of clinical assessments (rehospitalisation for decompensated heart failure, six-minute walk test, NT-proBNP levels). CONCLUSION The data suggest transendocardial injection of BMC can be used safely in patients with sympto-matic heart failure following acute STEMI. These prospective, preliminary data of a well-characterised, small cohort suggest efficiency compared to routine treatment.

Stem cell therapy in cardiovascular disorders.

Heart insufficiency remains the leading cause of death despite pharmacological and interventional therapy as well as primary and secondary prevention. Laboratory research on cardiac repair implementing stem cells and progenitor cells has raised great expectations as well as controversies. The potential of diverse progenitor cells to repair damaged heart tissue includes replacement (tissue transplant), restoration (activation of resident cardiac progenitor cells, paracrine effects), and regeneration (stem cell engraftment forming new myocytes). Based on promising experimental results clinical trials including several hundreds of patients with ischemic heart disease have been initiated using mostly bone marrow-derived cells. Probably, due to a lack of standardization of cell isolation and delivery methods these trials showed controverse results regarding effectiveness. However, significant therapeutic regeneration of human myocardium could not be proven until now. Several issues are at debate concerning the translation of the experimental data into the clinic discussing the adequate cell type, dosing, timing, and delivery mode of myocardial stem cell therapy. This review focuses on the potential and clinical translation of cell based therapies in cardiovascular disease.

Regional Diastolic and Systolic Function by Strain Rate Imaging for the Detection of Intramural Viability during Dobutamine Stress Echocardiography in a Porcine Model of Myocardial Infarction

The aim of this study was to evaluate diastolic and systolic strain rate measurements for differentiation of transmural/nontransmural infarction during dobutamine stress echocardiography (DSE). An ameroid constrictor was placed around the circumflex artery in 23 pigs inducing chronic vessel occlusion. Five pigs without constrictor served as controls. During high‐dose DSE systolic strain rates (SRsys), systolic and postsystolic strain values (ɛsys, ɛps) and early and late diastolic strain rates (SRE and SRA) were determined. At week 6, animals were evaluated regarding myocardial fibrosis. Histology revealed nontransmural in 14 and transmural infarction in 9 animals. In controls, dobutamine induced a linear increase of SRsys to 12.3 ± 0.4 s−1 at 40 μg/kg per minute (P = 0.001) and a linear decrease of SRE to −6.6 ± 0.3 s−1 (P = 0.001). In the nontransmural group, SRsys, ɛsys, ɛps at rest, and during DSE were higher and SRE was lower than in the transmural infarction group (P = 0.01). Best predictors for viability were SRsys (ROC 0.96, P = 0.0003), SRE at 10 μg/kg per minute dobutamine stimulation (ROC 0.94, P = 0.001) and positive SR values during isovolumetric relaxation at 40 μg/kg per minute dobutamine (ROC 0.86, P = 0.004). The extension of fibrosis correlated with SRsys at rest, ɛsys at rest, and SRE at rest (P < 0.001). For the detection of viability similar diagnostic accuracies of SRE and SRsys were seen (sensitivity 93%/93%, specificity 96%/94%, respectively). Diastolic SR analysis seems to be equipotent for the identification of viable myocardium in comparison to systolic SR parameters and allows the differentiation of nontransmural from transmural myocardial infarction with high diagnostic accuracy. (Echocardiography 2010;27:552‐562)