Delivery Of Bone Marrow Mononuclear Cells Research Articles

Abstract 10915: Microvascular Obstruction Identifies a Subgroup of Patients Who Benefit From Intracoronary Stem Cell Delivery Following ST-Elevation Myocardial Infarction

Aims: Microvascular obstruction (MVO) following ST-elevation myocardial infarction (STEMI) is associated with greater infarct size, adverse left-ventricular (LV) remodeling and reduced ejection fraction. We hypothesized that patients with MVO may constitute a subgroup of patients that would benefit from intracoronary stem cell delivery with bone marrow mononuclear cells (BMCs) given previous findings that BMCs tended to improve LV function only in patients with significant LV dysfunction. Methods and Results: We analyzed the cardiac MRIs of 356 patients (303 M, 53 F) with anterior STEMIs who received autologous BMCs as part of 3 clinical trials that included the Cardiovascular Cell Therapy Research Network (CCTRN) TIME trial and its pilot (n=157), the multi-center French BONAMI trial (n=91) and the SWISS-AMI trial (n=108). All patients received 100 - 150 million intracoronary autologous BMCs or placebo / control 3 - 7 days following primary PCI and stenting. LV function, volumes, infarct size and MVO were assessed prior to infusion of BMCs and 1 year later. Patients with MVO (n=210) had reduced LVEF and much greater infarct size and LV volumes compared to patients without MVO (n=146) (all p < 0.01) (TABLE). At 12 months, patients with MVO who received BMCs had significantly greater recovery of LVEF compared to those patients with MVO who received placebo (absolute difference = 2.7 %; p < 0.05). Similarly, the changes in left-ventricular end-diastolic (LVEDV) and end-systolic volumes (LVESV) were consistent with significantly less adverse remodeling in patients with MVO who received BMCs compared to placebo ( % change; LVEDV = -9.7%; p < 0.05 and LVESVI = -14.7 %; p = 0.006). In contrast, patients without MVO experienced no benefit of BMC administration compared to placebo. Conclusion: The presence of MVO on cardiac MRI following STEMI identifies a subgroup of patients who may benefit from intracoronary stem cell delivery of BMCs.

Bone marrow mononuclear cells induce beneficial remodeling and reduce diastolic dysfunction in the left ventricle of hypertensive SS/MCWi rats

Bone marrow mononuclear cells (BMMNCs) increase capillary density and reduce fibrosis in rodents after myocardial infarction, resulting in an overall improvement in left ventricular function. Little is known about the effectiveness of BMMNC therapy in hypertensive heart disease. In the current study, we show that delivery of BMMNCs from hypertension protected SS-13(BN)/MCWi donor rats, but not BMMNC from hypertension susceptible SS/MCWi donor rats, resulted in 57.2 and 83.4% reductions in perivascular and interstitial fibrosis, respectively, as well as a 60% increase in capillary-to-myocyte count in the left ventricles (LV) of hypertensive SS/MCWi recipients. These histological changes were associated with improvements in LV compliance and relaxation (103 and 46.4% improvements, respectively). Furthermore, improved diastolic function in hypertensive SS/MCWi rats receiving SS-13(BN)/MCWi derived BMMNCs was associated with lower clinical indicators of heart failure, including reductions in end diastolic pressure (65%) and serum brain natriuretic peptide levels (49.9%) with no improvements observed in rats receiving SS/MCWi BMMNCs. SS/MCWi rats had a lower percentage of endothelial progenitor cells in their bone marrow relative to SS-13(BN)/MCWi rats. These results suggest that administration of BMMNCs can prevent or reverse pathological remodeling in hypertensive heart disease, which contributes to ameliorating diastolic dysfunction and associated symptomology. Furthermore, the health and hypertension susceptibility of the BMMNC donor are important factors influencing therapeutic efficacy, possibly via differences in the cellular composition of bone marrow.

Safety of intramyocardial injection of autologous bone marrow cells to treat myocardial ischemia in pigs

The purpose of this study is to determine the potential adverse consequences of intracardiac injections of bone marrow mononuclear cells (BMCs) to facilitate the revascularization of ischemic myocardium. Bone marrow mononuclear cells are used to treat heart failure, though there are few studies that evaluated the safety of BMC transplantation for chronic myocardial ischemia. The pigs received coronary ameroid constrictors to induce chronic myocardial ischemia and left ventricular dysfunction. At 4 weeks, autologous BMCs were injected intramyocardially by Boston Scientific Stiletto catheter with low-dose (10(7) cells) or high-dose BMC (10(8)). Control animals received saline. Blood samples were collected for hematological and chemical indices, including cardiac enzyme levels at regular time intervals postinfarction. At 7 weeks, animals underwent electrophysiological study to evaluate the arrhythmic potential of transplanted BMC, followed by necropsy and histopathology. No mortalities were associated with intramyocardial delivery of BMC or saline. At Day 0, the total creatine phosphokinase (CPK) was in the normal range in all groups. All groups had significant elevations in CPK after ameroid placement, with no significant differences between groups. At 7 weeks, CPK in all groups had returned to pretreatment levels. Electrophysiological assessment revealed that one control animal had an inducible arrhythmia. No arrhythmias were induced in low- or high-dose BMC-treated pigs. There were no histopathological changes associated with BMC injection. This study showed, in a clinically relevant large-animal model, that catheter-based intramyocardial injection of autologous BMC into ischemic myocardium is safe.

Targeted Delivery of Bone Marrow Mononuclear Cells by Ultrasound Destruction of Microbubbles Induces Both Angiogenesis and Arteriogenesis Response

Ultrasound (US)-mediated destruction of contrast microbubbles causes capillary rupturing that stimulates arteriogenesis, whereas intramuscular implantation (im) of bone marrow mononuclear cells (BM-MNCs) induces angiogenesis. We therefore studied whether US-targeted microbubble destruction combined with transplantation of BM-MNCs can enhance blood flow restoration by stimulating both angiogenesis and arteriogenesis. US-mediated destruction of phospholipid-coated microbubbles was applied onto ischemic hindlimb muscle and subsequently BM-MNCs were transfused. A significant enhancement in blood flow recovery after Bubble+US+BM-MNC infusion (34% increase, P<0.05) was observed compared with Bubble+US (25%). The ratio of capillary/muscle fiber increased by Bubble+US+BM-MNC-i.v (260%, P<0.01) than that in the Bubble+US group (172%), into which BM-MNCs were incorporated (angiogenesis). Smooth muscle alpha-actin-positive arterioles were also increased, and angiography showed augmented collateral vessel formation (arteriogenesis). Platelet-derived proinflammatory factors activated by Bubble+US induces the expression of adhesion molecules (P-selectin and ICAM-1), leading to the attachment of transplanted BM-MNCs on the endothelium. Flow assay confirmed that the platelet-derived factors cause the adhesion of BM-MNCs onto endothelium under laminar flow. This study demonstrates that the targeted delivery of BM-MNCs by US destruction of microbubbles enhances regional angiogenesis and arteriogenesis response, in which the release of platelet-derived proinflammatory factors activated by Bubble+US play a key role in the attachment of transplanted BM-MNCs onto the endothelial layer.