Luka Lezaic

Effects of Intracoronary CD34+ Stem Cell Transplantation in Nonischemic Dilated Cardiomyopathy Patients 5-Year Follow-Up

Rationale: CD34+ transplantation in dilated cardiomyopathy was associated with short-term improvement in left ventricular ejection fraction and exercise tolerance. Objective: We investigated long-term effects of intracoronary CD34+ cell transplantation in dilated cardiomyopathy and the relationship between intramyocardial cell homing and clinical response. Methods and Results: Of 110 dilated cardiomyopathy patients, 55 were randomized to receive CD34+ stem cell transplantation (SC group) and 55 received no cell therapy (controls). In the SC group, CD34+ cells were mobilized by granulocyte colony-stimulating factor and collected via apheresis. Patients underwent myocardial scintigraphy and cells were injected in the artery supplying segments with the greatest perfusion defect. At baseline, 2 groups did not differ in age, sex, left ventricular ejection fraction, or N-terminal B-type natriuretic peptide levels. At 5 years, stem cell therapy was associated with increased left ventricular ejection fraction (from 24.3 ± 6.5% to 30.0 ± 5.1%; P=0.02), increased 6-minute walk distance (from 344 ± 90 m to 477 ± 130 m; P<0.001), and decreased N-terminal B-type natriuretic peptide (from 2322 ± 1234 pg/mL to 1011 ± 893 pg/mL; P<0.01). Left ventricular ejection fraction improvement was more significant in patients with higher myocardial homing of injected cells. During follow-up, 27 (25%) patients died and 9 (8%) underwent heart transplantation. Of the 27 deaths, 13 were attributed to pump failure and 14 were attributed to sudden cardiac death. Total mortality was lower in the SC group (14%) than in controls (35%; P=0.01). The same was true of pump failure (5% vs 18%; P=0.03), but not of sudden cardiac death (9% vs 16%; P=0.39). Conclusions: Intracoronary stem cell transplantation may be associated with improved ventricular function, exercise tolerance, and long-term survival in patients with dilated cardiomyopathy. Higher intramyocardial homing is associated with better stem cell therapy response.

Comparison of Transendocardial and Intracoronary CD34+ Cell Transplantation in Patients With Nonischemic Dilated Cardiomyopathy

Background— In an open-label blinded study, we compared intracoronary and transendocardial CD34+ cell transplantation in patients with nonischemic dilated cardiomyopathy. Methods and Results— Of the 40 patients with dilated cardiomyopathy, 20 were randomized to receive intracoronary injection and 20 received transendocardial CD34+ cell delivery. In both groups, CD34+ cells were mobilized by filgrastim, collected via apheresis, and labeled with technetium-99m radioisotope for single-photon emission computed tomographic imaging. In the intracoronary group, cells were injected intracoronarily in the artery supplying segments of greater perfusion defect on myocardial perfusion scintigraphy. In the transendocardial group, electroanatomic mapping was used to identify viable but dysfunctional myocardium, and transendocardial cell injections were performed. Nuclear single-photon emission computed tomographic imaging for quantification of myocardial retention was performed 18 hours thereafter. At baseline, groups did not differ in age, sex, left ventricular ejection fraction, or N-terminal pro-brain natriuretic peptide levels. The number of CD34+ cells was also comparable (105±31×106 in the transendocardial group versus 103±27×106 in the intracoronary group, P=0.62). At 18 hours after procedure, myocardial retention was higher in the transendocardial group (19.2±4.8%) than in the intracoronary group (4.4±1.2%, P<0.01). At 6 months, left ventricular ejection fraction improved more in the transendocardial group (+8.1±4.3%) than in the intracoronary group (+4.2±2.3%, P=0.03). The same pattern was observed for the 6-minute walk test distance (+125±33 m in the transendocardial group versus +86±13 m in the intracoronary group, P=0.03) and N-terminal pro-brain natriuretic peptide (−628±211 versus −315±133 pg/mL, P=0.04). Conclusions— In patients with dilated cardiomyopathy, transendocardial CD34+ cell transplantation is associated with higher myocardial retention rates and greater improvement in ventricular function, N-terminal pro-brain natriuretic peptide, and exercise capacity compared with intracoronary route. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01350310.

Effects of Intracoronary Stem Cell Transplantation in Patients With Dilated Cardiomyopathy

BACKGROUND We investigated clinical effects of intracoronary transplantation of CD34+ cells in patients with dilated cardiomyopathy (DCM). METHODS Of 55 patients with DCM, 28 were randomized to CD34+ transplantation (SC group), and 27 patients did not receive stem cell therapy (controls). In the SC group, peripheral blood CD34+ cells were mobilized by granulocyte-colony stimulating factor and collected via apheresis. Patients underwent myocardial scintigraphy and CD34+ cells were injected in the coronary artery supplying the segments with reduced viability. RESULTS At baseline, the 2 groups did not differ in age, gender, left ventricular ejection fraction (LVEF), or NT-proBNP levels. At 1 year, stem cell therapy was associated with an increase in LVEF (from 25.5 ± 7.5% to 30.1 ± 6.7%; P = .03), an increase in 6-minute walk distance (from 359 ± 104 m to 485 ± 127 m; P = .001), and a decrease in NT-proBNP (from 2069 ± 1996 pg/mL to 1037 ± 950 pg/mL; P = .01). The secondary endpoint of 1-year mortality or heart transplantation was lower in patients receiving SC therapy (2/28, 7%) than in controls (8/27, 30%) (P = .03), and SC therapy was the only independent predictor of outcome on multivariable analysis (P = .04). CONCLUSIONS Intracoronary stem cell transplantation could lead to improved ventricular remodeling, better exercise tolerance and potentially improved survival in patients with DCM.

CD34 + Stem Cell Therapy in Nonischemic Dilated Cardiomyopathy Patients

Recent trends indicate that patients with nonischemic dilated cardiomyopathy represent the largest subpopulation of heart failure patients with a significant need for alternative treatment modalities. Similar to patients with ischemic cardiomyopathy, patients with nonischemic dilated cardiomyopathy have been found to have myocardial regions with flow abnormalities, which may represent targets for neoangiogenic therapies. CD34+ stem cells might contribute to the formation of new blood vessels from existing vascular structures in ischemic tissues by the direct incorporation of injected cells into the newly developing vasculature or by the production and secretion of angiogenic cytokines. This review summarizes the long‐term clinical effects and potential underlying mechanisms of CD34+ cell therapy in patients with nonischemic dilated cardiomyopathy.

Optimal scan time for evaluation of parathyroid adenoma with [18F]-fluorocholine PET/CT

Abstract Background. Parathyroid adenomas, the most common cause of primary hyperparathyroidism, are benign tumours which autonomously produce and secrete parathyroid hormone. [18F]-fluorocholine (FCH), PET marker of cellular proliferation, was recently demonstrated to accumulate in lesions representing enlarged parathyroid tissue; however, the optimal time to perform FCH PET/CT after FCH administration is not known. The aim of this study was to determine the optimal scan time of FCH PET/CT in patients with primary hyperparathyroidism. Patients and methods. 43 patients with primary hyperparathyroidism were enrolled in this study. A triple-phase PET/CT imaging was performed five minutes, one and two hours after the administration of FCH. Regions of interest (ROI) were placed in lesions representing enlarged parathyroid tissue and thyroid tissue. Standardized uptake value (SUVmean), retention index and lesion contrast for parathyroid and thyroid tissue were calculated. Results. Accumulation of FCH was higher in lesions representing enlarged parathyroid tissue in comparison to the thyroid tissue with significantly higher SUVmean in the second and in the third phase (p < 0.0001). Average retention index decreased significantly between the first and the second phase and increased significantly between the second and the third phase in lesions representing enlarged parathyroid tissue and decreased significantly over all three phases in thyroid tissue (p< 0.0001). The lesion contrast of lesions representing enlarged parathyroid tissue and thyroid tissue was significantly better in the second and the third phase compared to the first phase (p < 0.05). Conclusions. According to the results the optimal scan time of FCH PET/CT for localization of lesions representing enlarged parathyroid tissue is one hour after administration of the FCH.

Effects of Intracoronary CD34+ Stem Cell Transplantation in Nonischemic Dilated Cardiomyopathy Patients

Rationale: CD34+ transplantation in dilated cardiomyopathy was associated with short-term improvement in left ventricular ejection fraction and exercise tolerance. Objective: We investigated long-term effects of intracoronary CD34+ cell transplantation in dilated cardiomyopathy and the relationship between intramyocardial cell homing and clinical response. Methods and Results: Of 110 dilated cardiomyopathy patients, 55 were randomized to receive CD34+ stem cell transplantation (SC group) and 55 received no cell therapy (controls). In the SC group, CD34+ cells were mobilized by granulocyte colony-stimulating factor and collected via apheresis. Patients underwent myocardial scintigraphy and cells were injected in the artery supplying segments with the greatest perfusion defect. At baseline, 2 groups did not differ in age, sex, left ventricular ejection fraction, or N-terminal B-type natriuretic peptide levels. At 5 years, stem cell therapy was associated with increased left ventricular ejection fraction (from 24.3 ± 6.5% to 30.0 ± 5.1%; P=0.02), increased 6-minute walk distance (from 344 ± 90 m to 477 ± 130 m; P<0.001), and decreased N-terminal B-type natriuretic peptide (from 2322 ± 1234 pg/mL to 1011 ± 893 pg/mL; P<0.01). Left ventricular ejection fraction improvement was more significant in patients with higher myocardial homing of injected cells. During follow-up, 27 (25%) patients died and 9 (8%) underwent heart transplantation. Of the 27 deaths, 13 were attributed to pump failure and 14 were attributed to sudden cardiac death. Total mortality was lower in the SC group (14%) than in controls (35%; P=0.01). The same was true of pump failure (5% vs 18%; P=0.03), but not of sudden cardiac death (9% vs 16%; P=0.39). Conclusions: Intracoronary stem cell transplantation may be associated with improved ventricular function, exercise tolerance, and long-term survival in patients with dilated cardiomyopathy. Higher intramyocardial homing is associated with better stem cell therapy response.

18F-choline PET/CT for parathyroid scintigraphy: significantly lower radiation exposure of patients in comparison to conventional nuclear medicine imaging approaches

BACKGROUND Parathyroid subtraction scintigraphy (PSS) is the most commonly used imaging method for localisation of hyperfunctioning parathyroid glands (HPGs) in primary hyperparathyroidism (PHP), a common endocrine disorder. Hybrid (SPECT/CT) imaging with 99mTc-sestaMIBI (MIBI) at an early and delayed phase (dual-phase imaging) may be the most accurate conventional imaging approach, but includes additional radiation exposure due to added CT imaging. Recently, 18F-choline (FCH) PET/CT was introduced for HPG imaging, which can also be performed using the dual-phase approach. To date, no studies have compared organ doses and the effective dose (ED) from conventional subtraction scintigraphy, dual-phase MIBI SPECT/CT, and FCH PET/CT in the localisation of HPGs. AIM In addition to the comparison of the diagnostic performance of FCH PET/CT and conventional scintigraphic imaging methods, the aim of the study was to measure the organ doses and the ED for conventional subtraction parathyroid imaging protocols, using dual-phase MIBI SPECT/CT as a potential conventional imaging method of choice and FCH dual-phase PET/CT as a potential future imaging method of choice for the localisation of HPGs. Materials, methods. Thirty-six patients referred for parathyroid imaging with a clinical indication of PHP underwent preoperative PSS and dual-phase SPECT/CT imaging with the addition of FCH PET/CT. The diagnostic performance of the imaging modalities was assessed by using histology results as a gold standard. Radiation exposure was calculated for the administered activities of radiopharmaceuticals using ICRP80 weighting factors and for CT exposure at hybrid imaging using dose-length products and the ImPACT CT Patient Dosimetry Calculator. RESULTS The diagnostic performance of FCH PET/CT was significantly better than that of conventional imaging modalities (sensitivity of 97% vs 64% and 46% for MIBI SPECT/CT and PSS, respectively, with comparable specificity of over 95% for all modalities). The highest radiation exposure was caused by conventional PSS (7.4 mSv), followed by dual-phase MIBI SPECT/CT (6.8 mSv). The radiation exposure was the lowest for dual-phase FCH PET/CT imaging (2.8 mSv). The added CT imaging for both hybrid approaches did not cause significant additional radiation exposure (1.4 mSv for MIBI SPECT/CT, additional 26.4% to overall exposure; 0.8 mSv for FCH PET/CT, additional 42.4% to overall exposure). CONCLUSION In comparison to conventional scintigraphic imaging of HPGs, emerging hybrid (SPECT/CT, PET/CT) imaging techniques combine superior diagnostic performance with lower radiation exposure to patients.

Long-term effects of stem cell transplantation in heart failure

Background: We investigated long-term effects of intracoronary transplantation of CD34+ cells in patients with dilated cardiomyopathy (DCM). Methods: Of 110 DCM patients, 55 were randomized to CD34+ cell transplantation (SC) group, and 55 patients received no cell therapy (controls). In the SC group, peripheral CD34+cells were mobilized by G-CSF and collected via apheresis. Patients underwent myocardial scintigraphy and CD34+ cells were injected in the artery supplying the segments with reduced viability. Patients were followed for 5 years. Results: At baseline, the 2 groups did not differ in age, gender, left ventricular ejection fraction (LVEF), or NT-proBNP levels. At 5 years, stem cell therapy was associated with an increase in LVEF (from 24.3 ± 6.5 % to 30.0 ± 5.1 %; P = 0.02), an increase in 6-minute walk distance (from 344 ± 90 m to 477 ± 130 m; P < 0.001), and a decrease in NT-proBNP (from 2322 ± 1234 pg/mL to 1011 ± 893 pg/mL; P < 0.01). During followup, 27 (25 %) patients died and 9 (8 %) underwent heart transplantation. Of the 27 deaths, 13 were attributed to pump failure, and 14 to sudden cardiac death. Total mortality was lower in SC group (8/55 [14 %]) than in controls (19/55 [35 %]) (P = 0.01). The same was true of pump failure (3/55 [5 %] vs. 10/55 [18 %], P = 0.03), but not of sudden cardiac death (5/55 [9 %] vs. 9/55 [16 %], P = 0.39). SC therapy was an independent predictor of outcome on multivariable analysis (P = 0.04). Conclusions: Intracoronary stem cell transplantation may be associated with improved ventricular remodeling, exercise tolerance, and longterm survival in patients with DCM.

Imaging and 1-day kinetics of intracoronary stem cell transplantation in patients with idiopathic dilated cardiomyopathy

BACKGROUND Stem cell transplantation is an emerging method of treatment for patients with cardiovascular disease. There are few studies completed or ongoing on stem cell therapy in patients with idiopathic dilated cardiomyopathy (IDCM). Information on stem cell homing and distribution in the myocardium after transplantation might provide important insight into effectiveness of transplantation procedure. AIM To assess early engraftment, retention and migration of intracoronarily transplanted stem cells in the myocardium of patients with advanced dilated cardiomyopathy of non-ischaemic origin using stem cell labeling with (99m)Tc-exametazime (HMPAO). MATERIALS, METHODS Thirty-five patients with IDCM and advanced heart failure were included in the study. Autologous hematopoietic (CD34+) stem cells were harvested by peripheral blood apheresis after bone marrow stimulation, labeled with (99m)Tc-HMPAO, tested for viability and injected into coronary vessel supplying areas of myocardium selected by myocardial perfusion scintigraphy as dysfunctional yet viable. Imaging was performed 1h and 18h after transplantation. RESULTS Myocardial stem cell retention ranged from 0 to 1.44% on early and 0-0.97% on delayed imaging. Significant efflux of stem cells occurred from site of delivery in this time period (p<0.001). Stem cell viability was not affected by labeling. CONCLUSION Stem cell labeling with (99m)Tc-HMPAO is a feasible method for stem cell tracking after transplantation in patients with IDCM.

Effects of Intracoronary CD34+ Stem Cell Transplantation in Nonischemic Dilated Cardiomyopathy PatientsNovelty and Significance

Rationale: CD34+ transplantation in dilated cardiomyopathy was associated with short-term improvement in left ventricular ejection fraction and exercise tolerance. Objective: We investigated long-term effects of intracoronary CD34+ cell transplantation in dilated cardiomyopathy and the relationship between intramyocardial cell homing and clinical response. Methods and Results: Of 110 dilated cardiomyopathy patients, 55 were randomized to receive CD34+ stem cell transplantation (SC group) and 55 received no cell therapy (controls). In the SC group, CD34+ cells were mobilized by granulocyte colony-stimulating factor and collected via apheresis. Patients underwent myocardial scintigraphy and cells were injected in the artery supplying segments with the greatest perfusion defect. At baseline, 2 groups did not differ in age, sex, left ventricular ejection fraction, or N-terminal B-type natriuretic peptide levels. At 5 years, stem cell therapy was associated with increased left ventricular ejection fraction (from 24.3 ± 6.5% to 30.0 ± 5.1%; P=0.02), increased 6-minute walk distance (from 344 ± 90 m to 477 ± 130 m; P<0.001), and decreased N-terminal B-type natriuretic peptide (from 2322 ± 1234 pg/mL to 1011 ± 893 pg/mL; P<0.01). Left ventricular ejection fraction improvement was more significant in patients with higher myocardial homing of injected cells. During follow-up, 27 (25%) patients died and 9 (8%) underwent heart transplantation. Of the 27 deaths, 13 were attributed to pump failure and 14 were attributed to sudden cardiac death. Total mortality was lower in the SC group (14%) than in controls (35%; P=0.01). The same was true of pump failure (5% vs 18%; P=0.03), but not of sudden cardiac death (9% vs 16%; P=0.39). Conclusions: Intracoronary stem cell transplantation may be associated with improved ventricular function, exercise tolerance, and long-term survival in patients with dilated cardiomyopathy. Higher intramyocardial homing is associated with better stem cell therapy response.