thymosin-beta(4) and Heart-Failure

Despite recent improvements in interventional medicine, cardiovascular disease still represents the major cause of morbidity worldwide, with myocardial infarction being the most common cardiac injury. This has sustained the development of several regenerative strategies based on the use of stem cells and tissue engineering approaches in order to achieve cardiac repair and regeneration by enhancing coronary neovascularization, modulating acute inflammation and supporting myocardial regeneration to provide new functional muscle.. The actin monomer binding peptide, Thymosin β4 (Tβ4), has recently been described as a powerful regenerative agent with angiogenic, anti-inflammatory and cardioprotective effects on the heart and which specifically acts on its resident cardiac progenitor cells. In this review we will discuss the state of the art regarding the many roles of Tβ4 in preserving and regenerating the mammalian heart, with specific attention to its ability to activate the quiescent adult epicardium and specific subsets of epicardial progenitor cells for repair.. The therapeutic potential of Tβ4 for the treatment of cardiac failure is herein evaluated alongside existing, emerging and prospective novel treatments.

Topics: Animals; Cardiotonic Agents; Heart Failure; Humans; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Neovascularization, Physiologic; Pericardium; Regeneration; Thymosin; Tissue Engineering

Tβ4 is an integral factor in repair of myocardium in animal models. To investigate whether Tβ4 is important in human cardiac disease and has a role in mediating the beneficial cardiac effects of bone-marrow-derived stem cell (BMSC) therapy, we measured serial plasma Tβ4 levels in patients enrolled on the REGENERATE-IHD cell therapy trial.. Plasma Tβ4 concentrations were measured in 13 patients who received BMSCs and 14 controls.. There was a significant increase in plasma Tβ4 in the BMSC group 24 h after intracardiac injection. Increases in Tβ4 levels were associated with improvement in New York Heart Association symptom class.. This exploratory study highlights the need for further study of Tβ4 in human cardiovascular disease.

Topics: Aged; Bone Marrow Cells; Cell Count; Chronic Disease; Female; Heart Failure; Heart Function Tests; Humans; Male; Middle Aged; Myocardial Ischemia; Myocardium; Natriuretic Peptide, Brain; Peptide Fragments; Stem Cell Transplantation; Thymosin; Treatment Outcome

Restoring blood flow after myocardial infarction (MI) is essential for survival of existing and newly regenerated tissue. Endogenous vascular repair processes are deployed following injury but are poorly understood. We sought to determine whether developmental mechanisms of coronary vessel formation are intrinsically reactivated in the adult mouse after MI. Using pulse-chase genetic lineage tracing, we establish that de novo vessel formation constitutes a substantial component of the neovascular response, with apparent cellular contributions from the endocardium and coronary sinus. The adult heart reverts to its former hypertrabeculated state and repeats the process of compaction, which may facilitate endocardium-derived neovascularization. The capacity for angiogenic sprouting of the coronary sinus vein, the adult derivative of the sinus venosus, may also reflect its embryonic origin. The quiescent epicardium is reactivated and, while direct cellular contribution to new vessels is minimal, it supports the directional expansion of the neovessel network toward the infarcted myocardium. Thymosin β4, a peptide with roles in vascular development, was required for endocardial compaction, epicardial vessel expansion, and smooth muscle cell recruitment. Insight into pathways that regulate endogenous vascular repair, drawing on comparisons with development, may reveal novel targets for therapeutically enhancing neovascularization.

Topics: Adult Stem Cells; Animals; Coronary Sinus; Coronary Vessels; Endothelial Cells; Heart Failure; Male; Mice; Myocardial Infarction; Myocytes, Smooth Muscle; Neovascularization, Pathologic; Pericardium; Regeneration; Thymosin

Diabetes mellitus causes microcirculatory rarefaction and may impair the responsiveness of ischemic myocardium to proangiogenic factors.. This study sought to determine whether microvascular destabilization affects organ function and therapeutic neovascularization in diabetes mellitus.. Diabetic human myocardial explants revealed capillary rarefaction and pericyte loss compared to nondiabetic explants. Hyperglycemia in db pigs, even without ischemia, induced capillary rarefaction in the myocardium (163 ± 14 c/hpf in db vs. 234 ± 8 c/hpf in wt hearts; p < 0.005), concomitant with a distinct loss of EF (44.9% vs. 53.4% in nondiabetic controls; p < 0.05). Capillary density further decreased in chronic ischemic hearts, as did EF (both p < 0.05). Treatment with rAAV.Tβ4 enhanced capillary density and maturation in db hearts less efficiently than in wt hearts, similar to collateral growth. rAAV.VEGF-A, though stimulating angiogenesis, induced neither pericyte recruitment nor collateral growth. As a result, rAAV.Tβ4 but not rAAV.VEGF-A improved EF in db hearts (34.5 ± 1.4%), but less so than in wt hearts (44.8 ± 1.5%).. Diabetes mellitus destabilized microvascular vessels of the heart, affecting the amplitude of therapeutic neovascularization via rAAV.Tβ4 in a translational large animal model of hibernating myocardium.

Topics: Animals; Coronary Disease; Coronary Vessels; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Genetic Therapy; Heart Failure; Heart Transplantation; Humans; Microvessels; Myocardial Stunning; Myocardium; Neovascularization, Physiologic; Stroke Volume; Swine; Thymosin; Translational Research, Biomedical; Vascular Endothelial Growth Factor A

While cardiovascular diseases remain the major worldwide cause of mortality and morbidity, there is an urgent need to tackle the clinical and economic burden of heart failure. Since the mammalian heart is unable to adequately regenerate beyond early postnatal stages, individuals surviving acute myocardial infarction are at risk of heart failure. Understanding the embryonic mechanisms of vasculogenesis and cardiogenesis, as well as the mechanisms retained for regeneration in species such as the zebrafish, will inform on strategies for human myocardial repair. Due to their fundamental role in heart development, epicardium-derived cells (EPDCs) have emerged as a population with potential to restore myocardium and coronary vasculature. The ability to revive ordinarily dormant EPDCs lies in the identification of key molecular cues used in the embryo to orchestrate cardiovascular development. One such stimulatory factor, Thymosin β4 (Tβ4), restores the quiescent adult epicardium to its pluripotent embryonic state. Tβ4 treatment of infarcted hearts induces dramatic EPDC proliferation and formation of a network of perfused, functional vessels to enhance blood flow to the ischaemic myocardium. Moreover, Tβ4 facilitates an epicardial contribution of mature de novo cardiomyocytes, structurally and functionally coupled with resident myocardium, which may contribute towards the functional improvement of Tβ4-treated hearts post-MI.

Topics: Adult; Animals; Cell Proliferation; Heart Failure; Humans; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Neovascularization, Physiologic; Pericardium; Regeneration; Stem Cells; Thymosin

Thymosin β4 (Tβ4) is a peptide known for its abilities to protect and facilitate regeneration in a number of tissues following injury. Its cardioprotective effects have been evaluated in different animal models and, currently, a clinical trial is being planned in patients suffering from acute myocardial infarction. This paper focuses on the effects of Tβ4 on cardiac function in animal studies utilizing different imaging modalities for outcome measurements.

Topics: Animals; Disease Models, Animal; Heart Failure; Humans; Myocardial Infarction; Thymosin