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Papers by Dan Spiegelstein
Circulation, 2009
Background-The identification and isolation of human cardiac progenitor cells (hCPCs) offer new a... more Background-The identification and isolation of human cardiac progenitor cells (hCPCs) offer new approaches for myocardial regeneration and repair. Still, the optimal source of human cardiac progenitor cells and the influence of patient characteristics on their number remain unclear. Using a novel method to isolate human cardiac progenitor cells, we aimed to define the optimal source and association between their number and patient characteristics. Methods and Results-We developed a novel isolation method that produced viable cells (7ϫ10 6 Ϯ6.53ϫ10 5 /g) from various tissue samples obtained during heart surgery or endomyocardial biopsies (113 samples from 94 patients 23 to 80 years of age). The isolated cardiac cells were grown in culture with a stem cell expansion medium. According to fluorescence-activated cell sorting analysis, cultured cells derived from the right atrium generated higher amounts of c-kit ϩ (24Ϯ2.5%) and Islet-1 ϩ cells (7%) in culture (mean of passages 1, 2, and 3) than did cultured cells from the left atrium (7.3Ϯ3.5%), right ventricle (4.1Ϯ1.6%), and left ventricle (9.7Ϯ3%; Pϭ0.001). According to multivariable analysis, the right atrium as the cell source and female sex were associated with a higher number of c-kit ϩ cells. There was no overlap between c-kit ϩ and Islet-1 expression. In vitro assays of differentiation into osteoblasts, adipocytes, and myogenic lineage showed that the isolated human cardiac progenitor cells were multipotent. Finally, the cells were transplanted into infarcted myocardium of rats and generated myocardial grafts. Conclusion-Our results show that the right atrium is the best source for c-kit ϩ and Islet-1 progenitors, with higher percentages of c-kit ϩ cells being produced by women. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.109.849588/DC1.
Annals of Thoracic Surgery, 2010
Background. Closed and open annuloplasty rings are both used for mitral valve repair. This study ... more Background. Closed and open annuloplasty rings are both used for mitral valve repair. This study compared the clinical and echocardiographic results in patients with degenerative mitral disease undergoing MV repair with closed semirigid rings vs open bands. Methods. Between 2004 and 2008, 377 patients (mean age, 59 ؎ 12 years) underwent mitral valve repair. Valve pathology was degenerative in 273 (72%). Closed rings were used in 163 (60%) and open rings in 110 (40%). Patients had similar characteristics and comorbidities. In addition to annuloplasty, repair techniques included leaflet resection (48% and 77%, p < 0.01), artificial chordal (55% and 36%, p < 0.01), and edge-to-edge repair (4% and 4%, p ؍ 0.79), in closed and open groups, respectively. Results. One patient in each group died (0.7%). Mean follow-up was 19 ؎ 14 (closed group) and 34 ؎ 15 months (open group; p < 0.01). Freedom from reoperation was 97.5% (closed group) vs 96.5% (open group). At followup, New York Heart Association functional class was similar between groups, and 91% in the closed group and 84% in the open group were free from moderate or severe mitral regurgitation (p ؍ 0.05). Closed group patients had a longer line of leaflet coaptation (9.1 ؎ 2.7 mm) vs the open group (7.1 ؎ 1.9 mm; p < 0.01). Conclusions. Patients with closed semirigid annuloplasty rings demonstrated significantly longer lines of leaflet coaptation and tendency toward better echocardiographic midterm results than patients with open bands and may, therefore, benefit from improved repair durability. (Ann Thorac Surg 2010;90:489 -96)
Journal of Thoracic and Cardiovascular Surgery, 2010
Objectives: We sought to compare early and late clinical and echocardiographic outcomes of patien... more Objectives: We sought to compare early and late clinical and echocardiographic outcomes of patients undergoing minimally invasive mitral valve repair by means of the port-access and median sternotomy approaches.
American Journal of Physiology-heart and Circulatory Physiology, 2007
We hypothesized that pretreatment of an infarcted heart by mechanical transmyocardial revasculari... more We hypothesized that pretreatment of an infarcted heart by mechanical transmyocardial revascularization (TMR) before transplantation of bone marrow cells (BMCs) or BMC-expressing angiogenic growth factors would increase transplanted BMC survival and enhance myocardial repair. Female Lewis rats underwent coronary ligation 3 wk before creation of 10 needle TMR channels (3 groups) or no TMR (3 groups), followed by transplantation of 3 x 10(6) male donor BMCs, BMC transfected with vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and insulin-like growth factor-1 (IGF-1) (BMC + VBI), or medium alone. At 1, 3, and 7 days, we evaluated transplanted cell survival, vascular densities, and left ventricular (LV) function (N = 4 per group x 6 groups x 3 time points). At 3 days, vascular densities in the scar were increased by TMR + BMC + VBI and by BMC + VBI (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), and at 7 days, vascular densities were greatest in rats receiving TMR + BMC + VBI (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Transplanted cell survival at 3 and 7 days was increased by TMR and by BMC + VBI. Combined therapy with TMR + BMC + VBI resulted in the greatest cell survival at 3 days (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) versus BMC. After 7 days, LV ejection fraction (LVEF) was lowest in rats receiving neither BMC nor TMR and greatest in rats receiving TMR + BMC + VBI (P = 0.004). We concluded that mechanical pretreatment of infarcted myocardium by TMR enhances the effect of subsequent cell-based gene therapy on transplanted cell survival, angiogenesis, and LV function. Scar pretreatment with TMR combined with cell-based multigene therapy may maximize myocardial repair.
Annals of Thoracic Surgery, 2007
Methods. Female Lewis rats underwent coronary ligation 3 weeks before transplantation with male d... more 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 realtime polymerase chain reaction, angiogenesis by quantitative histology, and LV function by echocardiography. At 4 weeks, regional perfusion was quantitated with microspheres.
Methods. Female Lewis rats underwent coronary ligation 3 weeks before transplantation with male d... more 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 realtime polymerase chain reaction, angiogenesis by quantitative histology, and LV function by echocardiography. At 4 weeks, regional perfusion was quantitated with microspheres.
Circulation, 2009
Background-The identification and isolation of human cardiac progenitor cells (hCPCs) offer new a... more Background-The identification and isolation of human cardiac progenitor cells (hCPCs) offer new approaches for myocardial regeneration and repair. Still, the optimal source of human cardiac progenitor cells and the influence of patient characteristics on their number remain unclear. Using a novel method to isolate human cardiac progenitor cells, we aimed to define the optimal source and association between their number and patient characteristics. Methods and Results-We developed a novel isolation method that produced viable cells (7ϫ10 6 Ϯ6.53ϫ10 5 /g) from various tissue samples obtained during heart surgery or endomyocardial biopsies (113 samples from 94 patients 23 to 80 years of age). The isolated cardiac cells were grown in culture with a stem cell expansion medium. According to fluorescence-activated cell sorting analysis, cultured cells derived from the right atrium generated higher amounts of c-kit ϩ (24Ϯ2.5%) and Islet-1 ϩ cells (7%) in culture (mean of passages 1, 2, and 3) than did cultured cells from the left atrium (7.3Ϯ3.5%), right ventricle (4.1Ϯ1.6%), and left ventricle (9.7Ϯ3%; Pϭ0.001). According to multivariable analysis, the right atrium as the cell source and female sex were associated with a higher number of c-kit ϩ cells. There was no overlap between c-kit ϩ and Islet-1 expression. In vitro assays of differentiation into osteoblasts, adipocytes, and myogenic lineage showed that the isolated human cardiac progenitor cells were multipotent. Finally, the cells were transplanted into infarcted myocardium of rats and generated myocardial grafts. Conclusion-Our results show that the right atrium is the best source for c-kit ϩ and Islet-1 progenitors, with higher percentages of c-kit ϩ cells being produced by women. The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.109.849588/DC1.
Annals of Thoracic Surgery, 2010
Background. Closed and open annuloplasty rings are both used for mitral valve repair. This study ... more Background. Closed and open annuloplasty rings are both used for mitral valve repair. This study compared the clinical and echocardiographic results in patients with degenerative mitral disease undergoing MV repair with closed semirigid rings vs open bands. Methods. Between 2004 and 2008, 377 patients (mean age, 59 ؎ 12 years) underwent mitral valve repair. Valve pathology was degenerative in 273 (72%). Closed rings were used in 163 (60%) and open rings in 110 (40%). Patients had similar characteristics and comorbidities. In addition to annuloplasty, repair techniques included leaflet resection (48% and 77%, p < 0.01), artificial chordal (55% and 36%, p < 0.01), and edge-to-edge repair (4% and 4%, p ؍ 0.79), in closed and open groups, respectively. Results. One patient in each group died (0.7%). Mean follow-up was 19 ؎ 14 (closed group) and 34 ؎ 15 months (open group; p < 0.01). Freedom from reoperation was 97.5% (closed group) vs 96.5% (open group). At followup, New York Heart Association functional class was similar between groups, and 91% in the closed group and 84% in the open group were free from moderate or severe mitral regurgitation (p ؍ 0.05). Closed group patients had a longer line of leaflet coaptation (9.1 ؎ 2.7 mm) vs the open group (7.1 ؎ 1.9 mm; p < 0.01). Conclusions. Patients with closed semirigid annuloplasty rings demonstrated significantly longer lines of leaflet coaptation and tendency toward better echocardiographic midterm results than patients with open bands and may, therefore, benefit from improved repair durability. (Ann Thorac Surg 2010;90:489 -96)
Journal of Thoracic and Cardiovascular Surgery, 2010
Objectives: We sought to compare early and late clinical and echocardiographic outcomes of patien... more Objectives: We sought to compare early and late clinical and echocardiographic outcomes of patients undergoing minimally invasive mitral valve repair by means of the port-access and median sternotomy approaches.
American Journal of Physiology-heart and Circulatory Physiology, 2007
We hypothesized that pretreatment of an infarcted heart by mechanical transmyocardial revasculari... more We hypothesized that pretreatment of an infarcted heart by mechanical transmyocardial revascularization (TMR) before transplantation of bone marrow cells (BMCs) or BMC-expressing angiogenic growth factors would increase transplanted BMC survival and enhance myocardial repair. Female Lewis rats underwent coronary ligation 3 wk before creation of 10 needle TMR channels (3 groups) or no TMR (3 groups), followed by transplantation of 3 x 10(6) male donor BMCs, BMC transfected with vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and insulin-like growth factor-1 (IGF-1) (BMC + VBI), or medium alone. At 1, 3, and 7 days, we evaluated transplanted cell survival, vascular densities, and left ventricular (LV) function (N = 4 per group x 6 groups x 3 time points). At 3 days, vascular densities in the scar were increased by TMR + BMC + VBI and by BMC + VBI (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05), and at 7 days, vascular densities were greatest in rats receiving TMR + BMC + VBI (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05). Transplanted cell survival at 3 and 7 days was increased by TMR and by BMC + VBI. Combined therapy with TMR + BMC + VBI resulted in the greatest cell survival at 3 days (P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; 0.05) versus BMC. After 7 days, LV ejection fraction (LVEF) was lowest in rats receiving neither BMC nor TMR and greatest in rats receiving TMR + BMC + VBI (P = 0.004). We concluded that mechanical pretreatment of infarcted myocardium by TMR enhances the effect of subsequent cell-based gene therapy on transplanted cell survival, angiogenesis, and LV function. Scar pretreatment with TMR combined with cell-based multigene therapy may maximize myocardial repair.
Annals of Thoracic Surgery, 2007
Methods. Female Lewis rats underwent coronary ligation 3 weeks before transplantation with male d... more 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 realtime polymerase chain reaction, angiogenesis by quantitative histology, and LV function by echocardiography. At 4 weeks, regional perfusion was quantitated with microspheres.
Methods. Female Lewis rats underwent coronary ligation 3 weeks before transplantation with male d... more 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 realtime polymerase chain reaction, angiogenesis by quantitative histology, and LV function by echocardiography. At 4 weeks, regional perfusion was quantitated with microspheres.