Lack of microsomal prostaglandin E(2) synthase-1 in bone marrow-derived myeloid cells impairs left ventricular function and increases mortality after acute myocardial infarction.

Background: Microsomal prostaglandin E(2) synthase-1 (mPGES-1), encoded by the Ptges gene, catalyzes prostaglandin E(2) biosynthesis and is expressed by leukocytes, cardiac myocytes, and cardiac fibroblasts. Ptges(-/-) mice develop more left ventricle (LV) dilation, worse LV contractile function, and higher LV end-diastolic pressure than Ptges(+/+) mice after myocardial infarction. In this study, we define the role of mPGES-1 in bone marrow-derived leukocytes in the recovery of LV function after coronary ligation.

An adult uterine hemangioblast: evidence for extramedullary self-renewal and clonal bilineage potential.

Stem cells exhibit long-term self-renewal by asymmetric division and multipotent differentiation. During embryonic development, cell fate is determined with predictable orientation, differentiation, and partitioning to form the organism. This includes the formation of a hemangioblast from which 2 derivative cell clusters commit to either a hematopoietic or an endothelial lineage.

The influence of operative techniques on the outcomes of bicuspid aortic valve disease and aortic dilatation.

Background: Bicuspid aortic valve is associated with aortic aneurysm formation that may extend beyond the ascending aorta.

Methods: Between 1979 and 1997, 143 bicuspid aortic valve patients had aortic valve operations with replacement of an aneurysmal ascending aorta: 93 (65%) underwent full root replacement and 50 (35%) underwent separate valve and graft replacement. Distal aortic anastomosis was open in 42 patients (29%) and closed in 101 (71%).

Aging impairs the angiogenic response to ischemic injury and the activity of implanted cells: combined consequences for cell therapy in older recipients.

Objective: Cell therapy has received much attention for its potential to regenerate ischemic organs, but initial clinical trials in aged patients did not replicate the dramatic benefits recorded in preclinical studies with young animals. This study was designed to improve our understanding of age-related changes in the response to ischemic injury and the regenerative capacity of implanted cells in the context of cell therapy for older recipients.

Methods And Results: Restoration of regional perfusion after hind limb femoral artery ligation was impaired (P < .

Ultrasound-targeted gene delivery induces angiogenesis after a myocardial infarction in mice.

Objectives: This study evaluated the capacity of ultrasound-targeted microbubble destruction (UTMD) to deliver angiogenic genes, improve perfusion, and recruit progenitor cells after a myocardial infarction (MI) in mice.

Background: Angiogenic gene therapy after an MI may become a clinically relevant approach to improve the engraftment of implanted cells if targeted delivery can be accomplished noninvasively. The UTMD technique uses myocardial contrast echocardiography to target plasmid gene delivery to the myocardium and features low toxicity, limited immunogenicity, and the potential for repeated application.

c-Kit function is necessary for in vitro myogenic differentiation of bone marrow hematopoietic cells.

In recent years, the differentiation of bone marrow cells (BMCs) into myocytes has been extensively investigated, but the findings remain inconclusive. The purpose of this study was to determine the conditions necessary to induce myogenic differentiation in short-term cultures of adult BMCs, and to identify the BMC subpopulation responsible for this phenomenon. We report that high-density cultures of murine hematopoietic BMCs gave rise to spontaneous beating cell clusters in the presence of vascular endothelial and fibroblast growth factors.

Tracking cardiac engraftment and distribution of implanted bone marrow cells: Comparing intra-aortic, intravenous, and intramyocardial delivery.

Objectives: Cell therapy improved cardiac function after a myocardial infarction in several preclinical studies; however, the functional benefits were limited in the initial clinical trials, perhaps because of inadequate cell engraftment. We used noninvasive molecular imaging to compare the distribution and myocardial retention of cells implanted by using clinical delivery routes.

Methods: Bone marrow stromal cells isolated from male rats and transfected with a firefly luciferase reporter gene were injected by using 3 increasingly invasive techniques (ie, intravenous, intra-aortic, and intramyocardial) into female rats 3 or 28 days after coronary ligation.

Cell-based gene therapy modifies matrix remodeling after a myocardial infarction in tissue inhibitor of matrix metalloproteinase-3-deficient mice.

Objective: Cell-based gene therapy can enhance the effects of cell transplantation by temporally and spatially regulating the release of the gene product. The purpose of this study was to evaluate transient matrix metalloproteinase inhibition by implanting cells genetically modified to overexpress a natural tissue inhibitor of matrix metalloproteinases (tissue inhibitor of matrix metalloproteinase-3) into the hearts of mutant (tissue inhibitor of matrix metalloproteinase-3-deficient) mice that exhibit an exaggerated response to myocardial infarction. Following a myocardial infarction, tissue inhibitor of matrix metalloproteinase-3-deficient mice undergo accelerated cardiac dilatation and matrix disruption due to uninhibited matrix metalloproteinase activity.

Improvement in cardiac function after bone marrow cell thearpy is associated with an increase in myocardial inflammation.

The mechanisms for the beneficial impact of bone marrow cell (BMC) therapy after myocardial infarction (MI) are ill defined. We hypothesized that the implanted cells improve function by attenuating post-MI inflammation and repair. In mice, 3 x 10(5) fresh BMCs were implanted immediately after coronary ligation.

Skeletal myoblasts preserve remote matrix architecture and global function when implanted early or late after coronary ligation into infarcted or remote myocardium.

Background: The inability of skeletal myoblasts to transdifferentiate into cardiomyocytes suggests that their beneficial effects on cardiac function after a myocardial infarction are mediated by paracrine effects. We evaluated the roles of these factors in the preservation of matrix architecture (in the infarct and remote regions) by varying the timing (postmyocardial infarction) and delivery site of the implanted cells.

Methods And Results: Skeletal myoblasts (5x10(6)) or control media were injected into the infarct or noninfarcted myocardium at 5 or 30 days after coronary artery ligation in rats.

The aortopathy of bicuspid aortic valve disease has distinctive patterns and usually involves the transverse aortic arch.

Objectives: Bicuspid aortic valves are associated with a poorly characterized connective tissue disorder that predisposes to aortic catastrophes. Because no criterion exists dictating the appropriate extent of aortic resection in aneurysmal disease of the bicuspid aortic valve, we studied the patterns of aortic dilation in this population.

Methods: Sixty-four patients with bicuspid aortic valves who underwent computed tomographic or magnetic resonance angiography and echocardiography were retrospectively identified between January 2002 and March 2006.

Microsomal prostaglandin E2 synthase-1 deletion leads to adverse left ventricular remodeling after myocardial infarction.

Background: Pharmacological inhibition of cyclooxygenase-2 increases the risk of myocardial infarction (MI) and stroke. Microsomal prostaglandin (PG) E(2) synthase-1 (mPGES-1), encoded by the Ptges gene, functions downstream from cyclooxygenase-2 in the inducible PGE(2) biosynthetic pathway. We caused acute MI in Ptges(+/+) and Ptges(-/-) mice to define the role of mPGES-1 in cardiac ischemic injury.

Preservation of heart function in diabetic rats by the combined effects of muscle cell implantation and insulin therapy.

Background: Diabetic cardiomyopathy is a common cause of heart failure in diabetic patients, but current treatments do not directly improve ventricular function. Cell transplantation can prevent cardiac dilatation after injury, and may also prevent congestive heart failure in diabetic cardiomyopathy.

Aim: This study evaluated the functional effects of smooth muscle cells (SMCs) implanted into the myocardium of insulin- and non insulin-treated diabetic rats.

The MRL mouse heart does not recover ventricular function after a myocardial infarction.

Introduction: Murphy Roth Large (MRL) mice have a remarkable regenerative capacity. A recent report demonstrated rapid cardiac healing in these mice following cryogenically induced right ventricular injury, suggesting the potential for new regenerative therapies to restore cardiac function in mammals. We therefore evaluated the cardiac regenerative wound-healing response and functional recovery of MRL mice in response to a clinically relevant left ventricular coronary ligation.

Activation of c-kit is necessary for mobilization of reparative bone marrow progenitor cells in response to cardiac injury.

Cardiovascular disease is the number-one cause of mortality in the developed world. The aim of this study is to define the mechanisms by which bone marrow progenitor cells are mobilized in response to cardiac ischemic injury. We used a closed-chest model of murine cardiac infarction/reperfusion, which segregated the surgical thoracotomy from the induction of cardiac infarction, so that we could study isolated fluctuations in cytokines without the confounding impact of surgery.

TIMP-3 deficiency accelerates cardiac remodeling after myocardial infarction.

The activity of TIMP-3, a natural tissue inhibitor of matrix metalloproteinases (MMPs), is decreased in the failing heart. This study evaluated the response to coronary ligation of cardiac structure, function, and matrix remodeling in wild-type (WT) mice, and those deficient in TIMP-3 (timp-3(-/-)). The coronary artery was ligated in timp-3(-/-) and age-matched WT mice.

Aortic valve-sparing operations for aortic root and ascending aortic aneurysms.

Purpose Of Review: Techniques of aortic root replacement have been developed that preserve the native aortic valve. These techniques avoid anticoagulation in patients who would otherwise receive a composite valve graft with a mechanical valve.

Recent Findings: Longer-term data on the longevity of the main two techniques of aortic valve-sparing operations, the root remodeling and the valve reimplantation technique, are now becoming available.

c-kit dysfunction impairs myocardial healing after infarction.

Background: We hypothesized that c-kit receptor function in the bone marrow is important for facilitating healing, leading to efficient cardiac repair after myocardial infarction (MI).

Methods And Results: We used Kit(W)/Kit(W-v) c-kit mutant mice and their wild-type littermates to assess the importance of c-kit function in cardiac remodeling after coronary ligation. We found that mutant mice developed 1.

Initial results of the chordal-cutting operation for ischemic mitral regurgitation.

Objective: Division of secondary chords (chordal cutting) has been proposed as a method for decreasing mitral valve leaflet tethering and mitral regurgitation in patients with ischemic mitral regurgitation. However, very little clinical data exist to date for this procedure.

Methods: We compared echocardiographic and clinical data in patients who underwent chordal-cutting mitral valve repair (n = 43) and those undergoing conventional mitral valve repair (control, n = 49) for ischemic mitral regurgitation.

Enhanced angiogenesis with multimodal cell-based gene therapy.

Background: We evaluated the synergism of transient vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) overexpression on angiogenesis and left ventricular (LV) function after bone marrow cell (BMC) transplantation, to determine the potential of multimodal cell-based gene therapy for myocardial repair.

Methods: Female Lewis rats underwent coronary ligation 3 weeks before transplantation with male donor BMC, BMC transfected with VEGF (BMC+VEGF), bFGF (BMC+bFGF), VEGF and bFGF (BMC+VEGF+bFGF), or medium (control) (n = 3 each group at 3 days, 1 week and 2 weeks; n = 6 each group at 4 weeks; n = 75 total). Three days, 1 week, 2 weeks, and 4 weeks after transplantation, transgene expression was quantitated by real-time polymerase chain reaction, angiogenesis by quantitative histology, and LV function by echocardiography.

Stem cell factor deficiency is vasculoprotective: unraveling a new therapeutic potential of imatinib mesylate.

Evidence suggests that bone marrow (BM) cells may give rise to a significant proportion of smooth muscle cells (SMCs) that contribute to intimal hyperplasia after vascular injury; however, the molecular pathways involved and the timeline of these events remain poorly characterized. We hypothesized that the stem cell factor (SCF)/c-Kit tyrosine kinase signaling pathway is critical to neointimal formation by BM-derived progenitors. Wire-induced femoral artery injury in mice reconstituted with wild-type BM cells expressing yellow fluorescent protein was performed, which revealed that 66+/-12% of the SMCs (alpha-smooth muscle actin-positive [alphaSMA(+)] cells) in the neointima were from BM.

Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines.

Clinical trials of bone marrow stem/progenitor cell therapy after myocardial infarction (MI) have shown promising results, but the mechanism of benefit is unclear. We examined the nature of endogenous myocardial repair that is dependent on the function of the c-kit receptor, which is expressed on bone marrow stem/progenitor cells and on recently identified cardiac stem cells. MI increased the number of c-kit+ cells in the heart.