Cardiovascular disease, and in particular ischemic heart disease (IHD), is a major cause of morbi... more Cardiovascular disease, and in particular ischemic heart disease (IHD), is a major cause of morbidity and mortality in the very elderly (> 80 years) worldwide. These patients represent a rapidly growing cohort presenting for percutaneous coronary intervention (PCI), now constituting more than one in five patients treated with PCI in real-world practice. Furthermore, they often have greater ischemic burden than their younger counterparts, suggesting that they have greater scope of benefit from coronary revascularization therapy. Despite this, the very elderly are frequently under-represented in clinical revascularization trials and historically there has been a degree of physician reluctance in referring them for PCI procedures, with perceptions of disappointing outcomes, low success and high complication rates. Several issues have contributed to this, including the tendency for older patients with IHD to present late, with atypical symptoms or non-diagnostic ECGs, and reservation...
The vasculature plays an indispensible role in organ development and maintenance of tissue homeos... more The vasculature plays an indispensible role in organ development and maintenance of tissue homeostasis, such that disturbances to it impact greatly on developmental and postnatal health. Although cell turnover in healthy blood vessels is low, it increases considerably under pathological conditions. The principle sources for this phenomenon have long been considered to be the recruitment of cells from the peripheral circulation and the re-entry of mature cells in the vessel wall back into cell cycle. However, recent discoveries have also uncovered the presence of a range of multipotent and lineage-restricted progenitor cells in the mural layers of postnatal blood vessels, possessing high proliferative capacity and potential to generate endothelial, smooth muscle, hematopoietic or mesenchymal cell progeny. In particular, the tunica adventitia has emerged as a progenitor-rich compartment with niche-like characteristics that support and regulate vascular wall progenitor cells. Prelimina...
Macrophages regulate blood vessel structure and function in health and disease. The origins of ti... more Macrophages regulate blood vessel structure and function in health and disease. The origins of tissue macrophages are diverse, with evidence for local production and circulatory renewal. We identified a vascular adventitial population containing macrophage progenitor cells and investigated their origins and fate. Single-cell disaggregates from adult C57BL/6 mice were prepared from different tissues and tested for their capacity to form hematopoietic colony-forming units. Aorta showed a unique predilection for generating macrophage colony-forming units. Aortic macrophage colony-forming unit progenitors coexpressed stem cell antigen-1 and CD45 and were adventitially located, where they were the predominant source of proliferating cells in the aortic wall. Aortic Sca-1(+)CD45(+) cells were transcriptionally and phenotypically distinct from neighboring cells lacking stem cell antigen-1 or CD45 and contained a proliferative (Ki67(+)) Lin(-)c-Kit(+)CD135(-)CD115(+)CX3CR1(+)Ly6C(+)CD11b(-)...
Journal of cardiovascular translational research, 2009
Combined analysis of the electrical and mechanical function of the heart holds promise as a means... more Combined analysis of the electrical and mechanical function of the heart holds promise as a means of acquiring a better understanding of a variety of cardiac diseases that ultimately may lead to heart failure. The NOGA XP Cardiac Navigation System is a unique, nonfluoroscopic, catheter-based technology that achieves real-time acquisition of three-dimensional, endoventricular electromechanical maps. Through the provision of point-by-point measurements of endocardial electrical activation and voltage and mechanical shortening, electromechanical mapping has been evaluated for its ability to identify regional myocardial ischemia and characterize tissue viability. A decade of preclinical and clinical research has verified its safety and feasibility and raised the possibility of its application as a diagnostic adjunct to conventional angiography in the catheterization laboratory. However, this role has not yet been realized outside of the research setting. Instead, a more prominent niche ...
Journal of cardiovascular translational research, 2010
Method for delivery remains a central component of stem cell-based cardiovascular research. Compa... more Method for delivery remains a central component of stem cell-based cardiovascular research. Comparative studies have demonstrated the advantages of administering cell therapy directly into the myocardium, as distinct from infusing cells into the systemic or coronary vasculature. Intramyocardial delivery can be achieved either transepicardially or transendocardially. The latter involves percutaneous, femoral arterial access and the retrograde passage of specially designed injection catheters into the left ventricle, making it less invasive and more relevant to wider clinical practice. Imaging-based navigation plays an important role in guiding catheter manipulation and directing endomyocardial injections. The most established strategy for three-dimensional, intracardiac navigation is currently endoventricular, electromechanical mapping, which offers superior spatial orientation compared to simple x-ray fluoroscopy. Its provision of point-by-point, electrophysiologic and motion data a...
Cellular therapy for cardiovascular disease heralds an exciting frontier of research. Mesenchymal... more Cellular therapy for cardiovascular disease heralds an exciting frontier of research. Mesenchymal stromal cells (MSCs) are present in adult tissues, including bone marrow and adipose, from which they can be easily isolated and cultured ex vivo. Although traditional isolation of these cells by plastic adherence results in a heterogeneous composite of mature and immature cell types, MSCs do possess plasticity of differentiation and under appropriate in vitro culture conditions can be modified to adopt cardiomyocyte and vascular cell phenotypic characteristics. In vivo preclinical studies have demonstrated their capacity to facilitate both myocardial repair and neovascularization in models of cardiac injury. The mechanisms underlying these effects appear to be mediated predominantly through indirect paracrine actions, rather than direct regeneration of endogenous cells by transdifferentiation, especially because current transplantation strategies achieve only modest engraftment of cell...
To determine the relationship between optical coherence tomography (OCT) images of the retina and... more To determine the relationship between optical coherence tomography (OCT) images of the retina and retinal substructure in vitro and in vivo. In vitro, OCT images of human and bovine retina were acquired after sequential excimer laser ablation of the inner retinal layers. Measurements of bands in the OCT images were compared with measurements of retinal layers on histology of the ablated specimens. In vivo, OCT images were acquired of retinal lesions in which there was a displacement of pigmented retinal pigment epithelial (RPE) cells: retinitis pigmentosa and laser photocoagulation (eight eyes each). The mean thickness of human inner OCT bands (131 microm; 95% confidence interval [CI], 122-140 microm) was 7.3 times that of the retinal nerve fiber layer (RNFL). This band persisted despite ablation greater than 140 microm. The inner aspect of the outer OCT band corresponded to the apical RPE, but the mean thickness of this band in human tissue (55 microm; 95% CI, 48-62 microm) was 2.6 times the thickness of the RPE-choriocapillaris complex. OCT measurement of total retinal thickness was accurate (coefficient of variance, 0.05) and precise (coefficient of correlation with light microscopy, 0.98). Hyperpigmented lesions gave rise to high signal, attenuating deeper signal; hypopigmented lesions had the opposite effect on deeper signal. The inner band is not RNFL specific, partly consisting of a surface-related signal. The location, not thickness, of the outer band corresponds to RPE melanin. Given the additional effect of polarization settings, precise OCT measurement of specific retinal layers is currently precluded.
Despite current treatment options, cardiac failure is associated with significant morbidity and m... more Despite current treatment options, cardiac failure is associated with significant morbidity and mortality highlighting a compelling clinical need for novel therapeutic approaches. Based on promising pre-clinical data, stem cell therapy has been suggested as a possible therapeutic strategy. Of the candidate cell types evaluated, mesenchymal stromal/stem cells (MSCs) have been widely evaluated due to their ease of isolation and ex vivo expansion, potential allogeneic utility and capacity to promote neo-angiogenesis and endogenous cardiac repair. However, the clinical application of MSCs for mainstream cardiovascular use is currently hindered by several important limitations, including suboptimal retention and engraftment and restricted capacity for bona fide cardiomyocyte regeneration. Consequently, this has prompted intense efforts to advance the therapeutic properties of MSCs for cardiovascular disease. In this review, we consider the scope of benefit from traditional plastic adherence-isolated MSCs and the lessons learned from their conventional use in preclinical and clinical studies. Focus is then given to the evolving strategies aimed at optimizing MSC therapy, including discussion of cell-targeted techniques that encompass the preparation, pre-conditioning and manipulation of these cells ex vivo, methods to improve their delivery to the heart and innovative substrate-directed strategies to support their interaction with the host myocardium.
Cardiovascular disease, and in particular ischemic heart disease (IHD), is a major cause of morbi... more Cardiovascular disease, and in particular ischemic heart disease (IHD), is a major cause of morbidity and mortality in the very elderly (> 80 years) worldwide. These patients represent a rapidly growing cohort presenting for percutaneous coronary intervention (PCI), now constituting more than one in five patients treated with PCI in real-world practice. Furthermore, they often have greater ischemic burden than their younger counterparts, suggesting that they have greater scope of benefit from coronary revascularization therapy. Despite this, the very elderly are frequently under-represented in clinical revascularization trials and historically there has been a degree of physician reluctance in referring them for PCI procedures, with perceptions of disappointing outcomes, low success and high complication rates. Several issues have contributed to this, including the tendency for older patients with IHD to present late, with atypical symptoms or non-diagnostic ECGs, and reservation...
The vasculature plays an indispensible role in organ development and maintenance of tissue homeos... more The vasculature plays an indispensible role in organ development and maintenance of tissue homeostasis, such that disturbances to it impact greatly on developmental and postnatal health. Although cell turnover in healthy blood vessels is low, it increases considerably under pathological conditions. The principle sources for this phenomenon have long been considered to be the recruitment of cells from the peripheral circulation and the re-entry of mature cells in the vessel wall back into cell cycle. However, recent discoveries have also uncovered the presence of a range of multipotent and lineage-restricted progenitor cells in the mural layers of postnatal blood vessels, possessing high proliferative capacity and potential to generate endothelial, smooth muscle, hematopoietic or mesenchymal cell progeny. In particular, the tunica adventitia has emerged as a progenitor-rich compartment with niche-like characteristics that support and regulate vascular wall progenitor cells. Prelimina...
Macrophages regulate blood vessel structure and function in health and disease. The origins of ti... more Macrophages regulate blood vessel structure and function in health and disease. The origins of tissue macrophages are diverse, with evidence for local production and circulatory renewal. We identified a vascular adventitial population containing macrophage progenitor cells and investigated their origins and fate. Single-cell disaggregates from adult C57BL/6 mice were prepared from different tissues and tested for their capacity to form hematopoietic colony-forming units. Aorta showed a unique predilection for generating macrophage colony-forming units. Aortic macrophage colony-forming unit progenitors coexpressed stem cell antigen-1 and CD45 and were adventitially located, where they were the predominant source of proliferating cells in the aortic wall. Aortic Sca-1(+)CD45(+) cells were transcriptionally and phenotypically distinct from neighboring cells lacking stem cell antigen-1 or CD45 and contained a proliferative (Ki67(+)) Lin(-)c-Kit(+)CD135(-)CD115(+)CX3CR1(+)Ly6C(+)CD11b(-)...
Journal of cardiovascular translational research, 2009
Combined analysis of the electrical and mechanical function of the heart holds promise as a means... more Combined analysis of the electrical and mechanical function of the heart holds promise as a means of acquiring a better understanding of a variety of cardiac diseases that ultimately may lead to heart failure. The NOGA XP Cardiac Navigation System is a unique, nonfluoroscopic, catheter-based technology that achieves real-time acquisition of three-dimensional, endoventricular electromechanical maps. Through the provision of point-by-point measurements of endocardial electrical activation and voltage and mechanical shortening, electromechanical mapping has been evaluated for its ability to identify regional myocardial ischemia and characterize tissue viability. A decade of preclinical and clinical research has verified its safety and feasibility and raised the possibility of its application as a diagnostic adjunct to conventional angiography in the catheterization laboratory. However, this role has not yet been realized outside of the research setting. Instead, a more prominent niche ...
Journal of cardiovascular translational research, 2010
Method for delivery remains a central component of stem cell-based cardiovascular research. Compa... more Method for delivery remains a central component of stem cell-based cardiovascular research. Comparative studies have demonstrated the advantages of administering cell therapy directly into the myocardium, as distinct from infusing cells into the systemic or coronary vasculature. Intramyocardial delivery can be achieved either transepicardially or transendocardially. The latter involves percutaneous, femoral arterial access and the retrograde passage of specially designed injection catheters into the left ventricle, making it less invasive and more relevant to wider clinical practice. Imaging-based navigation plays an important role in guiding catheter manipulation and directing endomyocardial injections. The most established strategy for three-dimensional, intracardiac navigation is currently endoventricular, electromechanical mapping, which offers superior spatial orientation compared to simple x-ray fluoroscopy. Its provision of point-by-point, electrophysiologic and motion data a...
Cellular therapy for cardiovascular disease heralds an exciting frontier of research. Mesenchymal... more Cellular therapy for cardiovascular disease heralds an exciting frontier of research. Mesenchymal stromal cells (MSCs) are present in adult tissues, including bone marrow and adipose, from which they can be easily isolated and cultured ex vivo. Although traditional isolation of these cells by plastic adherence results in a heterogeneous composite of mature and immature cell types, MSCs do possess plasticity of differentiation and under appropriate in vitro culture conditions can be modified to adopt cardiomyocyte and vascular cell phenotypic characteristics. In vivo preclinical studies have demonstrated their capacity to facilitate both myocardial repair and neovascularization in models of cardiac injury. The mechanisms underlying these effects appear to be mediated predominantly through indirect paracrine actions, rather than direct regeneration of endogenous cells by transdifferentiation, especially because current transplantation strategies achieve only modest engraftment of cell...
To determine the relationship between optical coherence tomography (OCT) images of the retina and... more To determine the relationship between optical coherence tomography (OCT) images of the retina and retinal substructure in vitro and in vivo. In vitro, OCT images of human and bovine retina were acquired after sequential excimer laser ablation of the inner retinal layers. Measurements of bands in the OCT images were compared with measurements of retinal layers on histology of the ablated specimens. In vivo, OCT images were acquired of retinal lesions in which there was a displacement of pigmented retinal pigment epithelial (RPE) cells: retinitis pigmentosa and laser photocoagulation (eight eyes each). The mean thickness of human inner OCT bands (131 microm; 95% confidence interval [CI], 122-140 microm) was 7.3 times that of the retinal nerve fiber layer (RNFL). This band persisted despite ablation greater than 140 microm. The inner aspect of the outer OCT band corresponded to the apical RPE, but the mean thickness of this band in human tissue (55 microm; 95% CI, 48-62 microm) was 2.6 times the thickness of the RPE-choriocapillaris complex. OCT measurement of total retinal thickness was accurate (coefficient of variance, 0.05) and precise (coefficient of correlation with light microscopy, 0.98). Hyperpigmented lesions gave rise to high signal, attenuating deeper signal; hypopigmented lesions had the opposite effect on deeper signal. The inner band is not RNFL specific, partly consisting of a surface-related signal. The location, not thickness, of the outer band corresponds to RPE melanin. Given the additional effect of polarization settings, precise OCT measurement of specific retinal layers is currently precluded.
Despite current treatment options, cardiac failure is associated with significant morbidity and m... more Despite current treatment options, cardiac failure is associated with significant morbidity and mortality highlighting a compelling clinical need for novel therapeutic approaches. Based on promising pre-clinical data, stem cell therapy has been suggested as a possible therapeutic strategy. Of the candidate cell types evaluated, mesenchymal stromal/stem cells (MSCs) have been widely evaluated due to their ease of isolation and ex vivo expansion, potential allogeneic utility and capacity to promote neo-angiogenesis and endogenous cardiac repair. However, the clinical application of MSCs for mainstream cardiovascular use is currently hindered by several important limitations, including suboptimal retention and engraftment and restricted capacity for bona fide cardiomyocyte regeneration. Consequently, this has prompted intense efforts to advance the therapeutic properties of MSCs for cardiovascular disease. In this review, we consider the scope of benefit from traditional plastic adherence-isolated MSCs and the lessons learned from their conventional use in preclinical and clinical studies. Focus is then given to the evolving strategies aimed at optimizing MSC therapy, including discussion of cell-targeted techniques that encompass the preparation, pre-conditioning and manipulation of these cells ex vivo, methods to improve their delivery to the heart and innovative substrate-directed strategies to support their interaction with the host myocardium.
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Papers by Peter Psaltis