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1.
Cell Transplant ; 28(7): 856-863, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31046425

RESUMO

Ventricular arrhythmias (VA) are of major concern in the field of cell therapy, potentially limiting its safety and efficacy. We sought to investigate the effects of CD34+ cell therapy on VA burden in patients with chronic heart failure (CHF). We performed registry data analysis of patients with CHF and implanted ICD/CRT devices treated with transendocardial CD 34+ cell therapy. Demographic, echocardiographic, and biochemical parameters were analyzed. Device records were reviewed and the number and type of VA 1 year prior to and 1 year after cell therapy were analyzed. All patients underwent electroanatomical mapping, and myocardial scar was defined as unipolar voltage (UV) <8.3 mV and linear local shortening (LLS) <6%. Of 209 patients screened, 48 met inclusion criteria. The mean age of the patients was 52 years and 88% were male. Nonischemic and ischemic cardiomyopathy were present in 55% and 45% of patients. The average serum creatinine was 91±26 µmol/L, serum bilirubin 18±9 µmol/L, NT-proBNP 1767 (468, 2446) pg/mL, LVEF 27±9% and 6' walk test 442±123 m. The average scar burden in patients with nonischemic and ischemic DCM was 58±15% and 51±25% (P=0.48). No significant difference in VA burden was observed before and after cell therapy (48% vs. 44%; P=0.68). ICD activation occurred in 19% and 27% of patients before and after cell therapy (P=0.33). According to our results, transendocardial CD34+ cell therapy does not appear to increase the risk of VA in chronic heart failure patients.

2.
Circ Res ; 124(5): 690-692, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30817255
3.
Circ Heart Fail ; 12(2): e005454, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30759999

RESUMO

Ventricular assist device (VAD) technology has evolved significantly over the past decades and currently represents one of the most important treatment strategies for patients with advanced chronic heart failure. There is increasing evidence that in selected patients undergoing long-term VAD support, improvement of myocardial structure and function may occur. However, there seems to be a significant discrepancy between structural and functional recovery of the failing myocardium, as only a small fraction of VAD-supported patients demonstrate reverse structural remodeling and eventually reach clinically significant and stable, functional improvement. More recently, cell therapy has gained a growing interest in the heart failure community because of its potential to augment reverse remodeling of the failing myocardium. Although theoretically the combination of long-term VAD support and cell therapy may offer significant advantages over using these therapeutic modalities separately, it remains largely unexplored. This review aims to summarize the current state of the art of the effects of VAD support and cell therapy on the reverse remodeling of the failing myocardium and to discuss the rationale for using a combined treatment strategy to further promote myocardial recovery in patients with advanced chronic heart failure.

4.
Eur J Heart Fail ; 21(8): 1032-1041, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30790396

RESUMO

AIMS: Ischaemic heart failure (IHF) patients have a poor prognosis even with current guideline-derived therapy. Intramyocardial injections of autologous or allogeneic mesenchymal stromal cells might improve cardiac function leading to better clinical outcome. METHODS: The SCIENCE (Stem Cell therapy in IschEmic Non-treatable Cardiac diseasE) consortium has initiated a Horizon 2020 funded multicentre phase II study in six European countries. It is a double-blind, placebo-controlled trial testing the safety and efficacy of allogeneic Cardiology Stem Cell Centre Adipose-derived Stromal Cells (CSCC_ASC) from healthy donors or placebo in 138 symptomatic IHF patients. Main inclusion criteria are New York Heart Association class II-III, left ventricular ejection fraction < 45% and N-terminal pro-B-type natriuretic peptide levels > 300 pg/mL. Patients are randomized in a 2:1 pattern to receive intramyocardial injections of either CSCC_ASC or placebo. CSCC_ASC and placebo treatments are prepared centralized at Rigshospitalet in 5 mL vials as an off-the-shelf product. Vials are distributed to all clinical partners and stored in nitrogen vapour tanks ready to be used directly after thawing. A total of 100 × 106 CSCC_ASC or placebo are injected directly into viable myocardium in the infarct border zone using the NOGA XP system (BDS, Cordis, Johnson & Johnson, USA). Primary endpoint is a centralized core-laboratory assessed change in left ventricular end-systolic volume at 6-month follow-up measured by echocardiography. The trial started in January 2017, 58 patients were included and treated until July 2018. CONCLUSION: The SCIENCE trial will provide clinical data on efficacy and safety of intramyocardial cell therapy of allogeneic adipose-derived stromal cells from healthy donors in patients with IHF.

5.
ESC Heart Fail ; 2018 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-30378288

RESUMO

Hospitalization for acute heart failure (HF) is associated with a substantial morbidity burden and with associated healthcare costs and an increased mortality risk. However, few if any major medical innovations have been witnessed in this area in recent times. Levosimendan is a first-in-class calcium sensitizer and potassium channel opener indicated for the management of acute HF. Experience in several clinical studies has indicated that administration of intravenous levosimendan in intermittent cycles may reduce hospitalization and mortality rates in patients with advanced HF; however, none of those trials were designed or powered to give conclusive insights into that possibility. This paper describes the rationale and protocol of LeoDOR (levosimendan infusions for patients with advanced chronic heart failure), a randomized, double-blind, placebo-controlled, international, multicentre trial that will explore the efficacy and safety of intermittent levosimendan therapy, in addition to optimized standard therapy, in patients following hospitalization for acute HF. Salient features of LeoDOR include the use of two treatment regimens, in order to evaluate the effects of different schedules and doses of levosimendan during a 12 week treatment phase, and the use of a global rank primary endpoint, in which all patients are ranked across three hierarchical groups ranging from time to death or urgent heart transplantation or implantation of a ventricular assist device to time to rehospitalization and, lastly, time-averaged proportional change in N-terminal pro-brain natriuretic peptide. Secondary endpoints include changes in HF symptoms and functional status at 14 weeks.

6.
Circ Heart Fail ; 11(7): e004962, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29980595

RESUMO

BACKGROUND: To describe the baseline characteristics of patients with heart failure and preserved left ventricular ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF) comparing sacubitril/valsartan to valsartan in reducing morbidity and mortality. METHODS AND RESULTS: We report key demographic, clinical, and laboratory findings, and baseline therapies, of 4822 patients randomized in PARAGON-HF, grouped by factors that influence criteria for study inclusion. We further compared baseline characteristics of patients enrolled in PARAGON-HF with those patients enrolled in other recent trials of heart failure with preserved ejection fraction (HFpEF). Among patients enrolled from various regions (16% Asia-Pacific, 37% Central Europe, 7% Latin America, 12% North America, 28% Western Europe), the mean age of patients enrolled in PARAGON-HF was 72.7±8.4 years, 52% of patients were female, and mean left ventricular ejection fraction was 57.5%, similar to other trials of HFpEF. Most patients were in New York Heart Association class II, and 38% had ≥1 hospitalizations for heart failure within the previous 9 months. Diabetes mellitus (43%) and chronic kidney disease (47%) were more prevalent than in previous trials of HFpEF. Many patients were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (85%), ß-blockers (80%), calcium channel blockers (36%), and mineralocorticoid receptor antagonists (24%). As specified in the protocol, virtually all patients were on diuretics, had elevated plasma concentrations of N-terminal pro-B-type natriuretic peptide (median, 911 pg/mL; interquartile range, 464-1610), and structural heart disease. CONCLUSIONS: PARAGON-HF represents a contemporary group of patients with HFpEF with similar age and sex distribution compared with prior HFpEF trials but higher prevalence of comorbidities. These findings provide insights into the impact of inclusion criteria on, and regional variation in, HFpEF patient characteristics. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

7.
Cell Transplant ; 27(7): 1027-1030, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29974792

RESUMO

Noncompaction cardiomyopathy is a rare congenital heart disorder characterized by an arrest of the myocardial compaction process. This results in the altered formation of coronary microvessels with a resulting decrease in myocardial perfusion. Transendocardial CD34+ cell transplantation has been shown to increase myocardial perfusion and function in patients with non-ischemic heart failure. In our first-in-man case study, we investigated the feasibility, safety and clinical effect of transendocardial CD34+ cell therapy in a patient with noncompaction cardiomyopathy.

8.
Circ Res ; 123(3): 389-396, 2018 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-29880546

RESUMO

RATIONALE: Preclinical data in heart failure models suggest that repetitive stem cell therapy may be superior to single-dose cell administration. OBJECTIVE: We investigated whether repetitive administration of CD34+ cells is superior to single-dose administration in patients with nonischemic dilated cardiomyopathy. METHODS AND RESULTS: Of 66 patients with dilated cardiomyopathy, New York Heart Association functional class III, and left ventricular ejection fraction (LVEF) <40% enrolled in the study, 60 were randomly allocated to repetitive cell therapy (group A, n=30) or single-cell therapy (group B, n=30). Patients received G-CSF (granulocyte colony-stimulating factor) for 5 days, and 80 million CD34+ cells were collected by apheresis and injected transendocardially. In group A, cell therapy was repeated at 6 months. All patients were followed for 1 year, and the primary end point was the difference in change in LVEF between the groups. At baseline, the groups did not differ in age, sex, LVEF, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or 6-minute walk test distance. When directly comparing groups A and B at 1 year, there was no significant difference in change in LVEF (from 32.2±9.3% to 41.2±6.5% in group A and from 30.0±7.0% to 37.9±5.3% in group B, P=0.40). From baseline to 6 months, both groups improved in LVEF (+6.9±3.3% in group A, P=0.001 and +7.1±3.5% in group B, P=0.001), NT-proBNP (-578±211 pg/mL, P=0.02 and -633±305 pg/mL, P=0.01), and 6-minute walk test (+87±21 m, P=0.03 and +92±25 m, P=0.02). In contrast, we observed no significant changes between 6 months and 1 year (LVEF: +2.1±2.3% in group A, P=0.19 and +0.8±3.1% in group B, P=0.56; NT-proBNP: -215±125 pg/mL, P=0.26 and -33±205 pg/mL, P=0.77; 6-minute walk test: +27±11 m, P=0.2 and +12±18 m, P=0.42). CONCLUSIONS: In patients with dilated cardiomyopathy, repetitive CD34+ cell administration does not seem to be associated with superior improvements in LVEF, NT-proBNP, or 6-minute walk test when compared with single-dose cell therapy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02248532.

9.
Pulm Circ ; 8(2): 2045893218755979, 2018 Apr-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29480154

RESUMO

Pulmonary arterial hypertension (PAH) is an incurable disease characterized by an increase in pulmonary arterial pressure due to pathological changes to the pulmonary vascular bed. As a result, the right ventricle (RV) is subject to an increased afterload and undergoes multiple changes, including a decrease in capillary density. All of these dysfunctions lead to RV failure. A number of studies have shown that RV function is one of the main prognostic factors for PAH patients. Many stem cell therapies targeting the left ventricle are currently undergoing development. The promising results observed in animal models have led to clinical trials that have shown an improvement of cardiac function. In contrast to left heart disease, stem cell therapy applied to the RV has remained poorly studied, even though it too may provide a therapeutic benefit. In this review, we discuss stem cell therapy as a treatment for RV failure in PAH. We provide an overview of the results of preclinical and clinical studies for RV cell therapies. Although a large number of studies have targeted the pulmonary circulation rather than the RV directly, there are nonetheless encouraging results in the literature that indicate that cell therapies may have a direct beneficial effect on RV function. This cell therapy strategy may therefore hold great promise and warrants further studies in PAH patients.

10.
Circ Res ; 122(1): 28-30, 2018 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-29301843
11.
Stem Cells Transl Med ; 7(2): 168-172, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29380563

RESUMO

We investigated the effects of CD34+ cell therapy on right ventricular (RV) function in patients with nonischemic dilated cardiomyopathy (DCM). We enrolled 60 patients with DCM who were randomized to CD34+ cell therapy (Stem Cells (SC) Group n = 30), or no cell therapy (Controls, n = 30). The SC Group received granulocyte-colony stimulating factor, and CD34+ cells were collected by apheresis and injected transendocardially. Patients were followed for 6 months. At baseline, the groups did not differ in age, gender, left ventricular ejection fraction, N-terminal probrain natriuretic peptide, or parameters of RV function. At 6 months, we found a significant improvement in RV function in the SC Group (tricuspid annular plane systolic excursion [TAPSE]: +0.44 ± 0.64 cm, p = .001; peak systolic tissue Doppler velocity of tricuspid annulus [St]: +1.5 ± 2.1 cm/s; p = .001; percent of fractional area change [FAC]: +8.6% ± 5%, p = .01), but not in Controls (TAPSE: -0.07 ± 0.32 cm, p = .40; St: -0.1 ± 1.2 cm/s; p = .44; FAC: -1.2% ± 3.2%, p = .50). On repeat electroanatomical mapping, we found an improvement in interventricular septum viability in 19 of 30 patients from the SC Group; this correlated with the improvements in RV function (13/19 in the improved septum group versus 3/11 in the remaining cohort, p = .029). These results suggest that patients with DCM, changes in RV function correlate with changes of viability of interventricular septum. CD34+ cell therapy appears to be associated with improved right ventricular function in this patient cohort. (Clinical Trial Registration Information: www.clinicaltrials.gov; NCT02248532). Stem Cells Translational Medicine 2018;7:168-172.

12.
Eur Heart J Cardiovasc Imaging ; 19(8): 916-925, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28977353

RESUMO

Aims: Risk stratification in heart failure (HF) relies on several established clinical risk scores, however, myocardial deformation, right heart metrics, and exercise performance have not usually been considered. This study sought to assess the incremental value of advanced echocardiographic and cardiopulmonary exercise testing (CPX) parameters to validated risk scores in HF. Methods and results: The Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) and Metabolic Exercise Test Data Combined with Cardiac and Kidney Indexes (MECKI) scores were applied to 208 ambulatory patients with dilated cardiomyopathy (DCM) who completed echocardiography in conjunction with CPX as part of the Stanford Exercise Testing registry. Patients were followed for the composite end point of death, heart transplant, left ventricular device implantation, and hospitalization for acute HF. Mean age, left ventricular ejection fraction (LVEF), and left ventricular global longitudinal strain (LVGLS) were 47 ± 13 years, 33 ± 13%, and -10.6 ± 4.4%, respectively, while right ventricular free-wall longitudinal strain was -18.8 ± 5.5%. Partial correlation mapping identified strong correlations between LVEF, LVGLS, and LV systolic strain rate, with a moderate correlation between these metrics and peak VO2. Over a median follow up of 5.3 years, the composite end point occurred in 60 patients. Cox proportional hazards identified MAGGIC score [hazard ratio (HR) (2.04 [1.39-3.01], P < 0.01], peak VO2 HR (0.52 [0.28-0.97], P = 0.04), and right atrial volume indexed (RAVI) HR (1.31 [1.07-1.61], P < 0.01) as independent correlates of outcome. RAVI remained an independent correlate when combined with the MECKI score (2.21 [1.59-3.07]), P < 0.01, RAVI, 1.33 [1.06-1.67], P = 0.01). Conclusion: Our study demonstrates that RAVI is complementary to well-validated HF risk scores and highlights the importance of exercise performance in DCM.

13.
Genet Test Mol Biomarkers ; 21(12): 736-741, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29087733

RESUMO

BACKGROUND/OBJECTIVES: Heart failure (HF) is associated with disturbances in mitochondrial energy production. This mitochondrial dysfunction is reflected by depletion of mitochondrial DNA (mtDNA) in different tissues. Our aims were to determine if there was a correlation between mtDNA content measured in myocardial tissue and the easily accessible peripheral blood cells of patients with non-ischemic HF; and to determine if there was a correlation between myocardial mtDNA and left ventricular (LV) ejection fraction. METHODS: We prospectively collected paired myocardial tissue and peripheral blood samples from 13 consecutive end-stage non-ischemic HF patients undergoing cardiac transplantation. mtDNA content was assessed with real-time quantitative PCR by calculating the relative ratio of two specific mitochondrial sequences and one nuclear control gene sequence. RESULTS: HF patients with lower myocardial mtDNA content had a significantly lower LV ejection fraction (r = 0.65, p = 0.016). Peripheral blood mtDNA content correlated positively with right ventricular myocardial mtDNA content (r = 0.63, p = 0.021). We also observed that averaged myocardial DNA content tended to correlate with peripheral blood mtDNA content (r = 0.53, p = 0.061). CONCLUSIONS: In non-ischemic HF patients, myocardial mtDNA content is positively correlated with peripheral blood mtDNA content and LV function as assessed by echocardiography.


Assuntos
DNA Mitocondrial/sangue , Insuficiência Cardíaca/genética , Mitocôndrias/genética , Adulto , Idoso , DNA Mitocondrial/genética , DNA Mitocondrial/metabolismo , Feminino , Insuficiência Cardíaca/metabolismo , Transplante de Coração , Ventrículos do Coração , Humanos , Masculino , Pessoa de Meia-Idade , Miocárdio/metabolismo , Eslovênia , Função Ventricular Esquerda/genética , Função Ventricular Esquerda/fisiologia
14.
Transfus Apher Sci ; 56(4): 566-570, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28800845

RESUMO

Durable engraftment of transplanted CD34+ cells largely depends on the quality of the cell product. Limited data are currently available about extended storage of immunoselected CD34+ cells. The aim of our study was to assess the stability of CD34+ cell product with the cells stored in high concentration (80×106 in 6mL) in small bags intended for cell implantation. Cell products were prepared by leukapheresis and immunoselection (Clinimacsplus procedure) from 13 patients with chronic dilated cardiomyopathy. CD34+ cell products were stored at 2-8°C and analyzed at time 0 (fresh products), 24, 48h, 4 and 6 days. Product viability, absolute number of viable CD34+ cells and apoptosis were determined by flow cytometry. Microbiological contamination of the cell products was tested by BACTEC system. The mean viability of CD34+ cells decreased by 2.7% within 24h, by 13.4% within 48h and by 37.5% within 6 days. The mean recovery of viable CD34+ cells was 91.1%, 74.8%, 66.3% and 56.2% at 24, 48h, 4 and 6 days, respectively. The mean fraction of early apoptotic cells in fresh and stored products was 4.9±3.5% at 0h, 5.9±3.8% at 24h, 4.2±3.1% at 48h, 6.3±2.6% at 4 days and 9.3±4.6% at 6 days. All products were negative for microbial contamination.


Assuntos
Antígenos CD34 , Apoptose , Preservação de Sangue , Separação Celular/métodos , Transplante de Células-Tronco de Sangue Periférico , Células-Tronco de Sangue Periférico , Adulto , Idoso , Autoenxertos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco de Sangue Periférico/citologia , Células-Tronco de Sangue Periférico/metabolismo , Fatores de Tempo
15.
Echocardiography ; 34(8): 1179-1186, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28681553

RESUMO

BACKGROUND: Left ventricular (LV) contractile reserve assessed using imaging and cardiopulmonary exercise testing (CPX) has been shown to predict outcome in patients with dilated cardiomyopathy (DCM). Few clinical studies have, however, analyzed the relationship between them. METHODS: A cohort of 75 ambulatory patients with DCM underwent stress treadmill echocardiography with CPX. LV contractile reserve was calculated as absolute change (ΔLVEF=LVEFpeak -LVEFrest ) and percent change (%LVEF=[(LVEFpeak -LVEFrest )/LVEFpeak) ]×100) in LVEF, circumferential and longitudinal strain (LS). Exercise capacity was measured as peak oxygen uptake (peak VO2 ) and ventilatory efficiency as the slope of minute ventilation to CO2 production (VE/VCO2 slope). Values of contractile reserve were compared to matched controls. We also explored which metric of ventricular response (absolute or percent change) was less dependent on baseline LV function. RESULTS: Patients with DCM had a mean age, rest and peak LVEF of 44±10 years, 42±10% and 50±12%, respectively. Among parameters of contractile reserve, peak cardiac output was the strongest parameter associated with peak VO2 (r=.63, P<.001). Along with age, sex, and BMI, it explained more than 70% of the variance in peak VO2 . In contrast, LVEF and LS were only weakly related to peak VO2 . With regard to ventilatory efficiency, the strongest parameter that emerged was right atrial volume index (r=.36, P<.001). Percent change in LVEF was more independent of baseline function than absolute change. CONCLUSION: Echocardiographic contractile reserve and CPX provide complementary information. Percent change in contractile reserve was most independent of baseline function, therefore may be preferred when analyzing the ventricular response to exercise.


Assuntos
Cardiomiopatia Dilatada/diagnóstico , Teste de Esforço/métodos , Tolerância ao Exercício/fisiologia , Ventrículos do Coração/fisiopatologia , Contração Miocárdica/fisiologia , Adulto , Cardiomiopatia Dilatada/fisiopatologia , Ecocardiografia sob Estresse , Feminino , Seguimentos , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Reprodutibilidade dos Testes , Estudos Retrospectivos , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia
16.
Mech Ageing Dev ; 166: 42-47, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28636901

RESUMO

Age-related telomere attrition in stem/progenitor cells may diminish their functional capacity and thereby impair the outcome of cell-based therapies. The aim of the present study was to investigate the effect of CD34+ cell telomere length and hTERT expression on the clinical outcome of autologous CD34+ cell transplantation. We studied 43 patients with cardiomyopathy. Their peripheral blood CD34+ cells were mobilized with granulocyte colony-stimulating factor, enriched by immunoselection and delivered transendocardially. Relative telomere length and expression levels of hTERT were measured using a real-time PCR assay. Immunoselected CD34+ cells had longer telomere length compared to leukocytes in leukapheresis products (p=0.001). In multivariate analysis, CD34+ cell telomere length was not associated with the clinical outcome (b=3.306, p=0.540). While hTERT expression was undetectable in all leukapheresis products, 94.4% of the CD34+ enriched cell products expressed hTERT. Higher CD34+hTERT expression was associated with a better clinical outcome on univariate analysis (b=87.911, p=0.047). Our findings demonstrate that CD34+ cell telomere length may not influence the clinical outcome in cardiomyopathy patients treated with autologous CD34+ cell transplantation. Larger studies are needed to validate the impact of the CD34+hTERT expression on the clinical outcome of autologous CD34+ cell transplantation.


Assuntos
Antígenos CD34 , Regulação Enzimológica da Expressão Gênica , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/terapia , Transplante de Células-Tronco , Células-Tronco/enzimologia , Telomerase/biossíntese , Homeostase do Telômero , Adolescente , Adulto , Idoso , Autoenxertos , Doença Crônica , Feminino , Insuficiência Cardíaca/patologia , Humanos , Masculino , Pessoa de Meia-Idade
17.
DNA Cell Biol ; 36(9): 737-746, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28613929

RESUMO

Epigenetic dysregulation has been shown to limit functional capacity of aging hematopoietic stem cells, which may contribute to impaired outcome of hematopoietic stem cell-based therapies. The aim of our study was to gain better insight into the epigenetic profile of CD34+-enriched cell products intended for autologous CD34+ cell transplantation in patients with cardiomyopathy. We found global DNA methylation content significantly higher in immunoselected CD34+ cells compared to leukocytes in leukapheresis products (2.33 ± 1.03% vs. 1.84 ± 0.86%, p = 0.04). Global DNA hydroxymethylation content did not differ between CD34+ cells and leukocytes (p = 0.30). By measuring methylation levels of 94 stem cell transcription factors on a ready-to-use array, we identified 15 factors in which average promoter methylation was significantly different between leukocytes and CD34+ cells. The difference was highest for HOXC12 (58.18 ± 6.47% vs. 13.34 ± 24.18%, p = 0.0009) and NR2F2 (51.65 ± 25.89% vs. 7.66 ± 21.43%, p = 0.0045) genes. Our findings suggest that global DNA methylation and hydroxymethylation patterns as well as target methylation profile of selected genes in CD34+-enriched cell products do not differ significantly compared to leukapheresis products and, thus, can tell us little about the functional capacity and regenerative properties of CD34+ cells. Future studies should examine other CD34+ cell graft characteristics, which may serve as prognostic tools for autologous CD34+ cell transplantation.


Assuntos
Antígenos CD34/metabolismo , Metilação de DNA , Epigênese Genética , Transplante de Células-Tronco Hematopoéticas , Adulto , Autoenxertos , Fator II de Transcrição COUP/genética , Cardiomiopatias/terapia , DNA/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
18.
Int J Cardiol ; 243: 389-395, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28571618

RESUMO

Patients in the latest stages of heart failure are severely compromised, with poor quality of life and frequent hospitalizations. Heart transplantation and left ventricular assist device implantation are viable options only for a minority, and intermittent or continuous infusions of positive inotropes may be needed as a bridge therapy or as a symptomatic approach. In these settings, levosimendan has potential advantages over conventional inotropes (catecholamines and phosphodiesterase inhibitors), such as sustained effects after initial infusion, synergy with beta-blockers, and no increase in oxygen consumption. Levosimendan has been suggested as a treatment that reduces re-hospitalization and improves quality of life. However, previous clinical studies of intermittent infusions of levosimendan were not powered to show statistical significance on key outcome parameters. A panel of 45 expert clinicians from 12 European countries met in Rome on November 24-25, 2016 to review the literature and envision an appropriately designed clinical trial addressing these needs. In the earlier FIGHT trial (daily subcutaneous injection of liraglutide in heart failure patients with reduced ejection fraction) a composite Global Rank Score was used as primary end-point where death, re-hospitalization, and change in N-terminal-prohormone-brain natriuretic peptide level were considered in a hierarchical order. In the present study, we tested the same end-point post hoc in the PERSIST and LEVOREP trials on oral and repeated i.v. levosimendan, respectively, and demonstrated superiority of levosimendan treatment vs placebo. The use of the same composite end-point in a properly powered study on repetitive levosimendan in advanced heart failure is strongly advocated.


Assuntos
Cardiotônicos/administração & dosagem , Conferências de Consenso como Assunto , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/epidemiologia , Hidrazonas/administração & dosagem , Piridazinas/administração & dosagem , Administração Oral , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Esquema de Medicação , Europa (Continente)/epidemiologia , Medicina Baseada em Evidências/normas , Medicina Baseada em Evidências/tendências , Insuficiência Cardíaca/diagnóstico , Humanos , Infusões Intravenosas , Roma/epidemiologia , Simendana
19.
Clin Transplant ; 31(6)2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28314079

RESUMO

BACKGROUND: We sought to investigate a correlation between serum testosterone levels and graft function early after heart transplantation. METHODS: In a cross-sectional study, we measured serum testosterone levels 4 weeks after heart transplantation in 49 consecutive male recipients. Echocardiography was carried out to evaluate graft function. Low serum testosterone was defined as <11 nmol/L. RESULTS: Low serum testosterone was present in 21 (43%) recipients (Group A), and 28 (57%) had normal testosterone levels (Group B). The two groups did not differ in age and presence of renal dysfunction, arterial hypertension, diabetes, or hyperlipidemia. Donor age and allograft ischemic time were not different between the two groups. Both groups had comparable tacrolimus through levels, dose of mycophenolate mophetil, and methylprednisolone. Patients in Group A had significantly lower LVEF (58±5% vs 65±6% vs Group B, P=.001) and TAPSE (1.3±0.3 cm vs 1.6±0.3 cm in Group B, P=.01). In comparison with Group B, more patients in Group A were found to have low grade (1R) rejection (25% vs 3%; P=.02). CONCLUSION: Low serum testosterone levels appear to be associated with impaired graft function and an increased incidence of low-grade rejection episodes early after heart transplantation.


Assuntos
Biomarcadores/sangue , Rejeição de Enxerto/sangue , Transplante de Coração/efeitos adversos , Complicações Pós-Operatórias , Testosterona/sangue , Estudos Transversais , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/patologia , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco
20.
Stem Cells Transl Med ; 6(6): 1515-1521, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28296283

RESUMO

We sought to evaluate the physiological background and the effects of CD34+ cell transplantation on diastolic parameters in nonischemic dilated cardiomyopathy patients (DCM). We enrolled 38 DCM patients with NYHA class III and LVEF < 40% who underwent transendocardial CD34+ cell transplantation. Peripheral blood CD34+ cells were mobilized by G-CSF, collected via apheresis, and injected transendocardially in the areas of myocardial hibernation. Patients were followed for 1 year. At baseline, estimated filling pressures were significantly elevated (E/e' ≥ 15) in 18 patients (Group A), and moderately elevated (E/e '< 15) in 20 patients (Group B). The groups did not differ in age (54 ± 9 years vs. 52 ± 10 years; p = .62), gender (male: 85% vs. 78%; p = .57), or LVEF (31 ± 7% vs. 34 ± 6%; p = .37). When compared to Group B patients in Group A had more segments with myocardial scar (4.9 ± 2.7 vs. 2.7 ± 2.9; p = .03), myocardial hibernation (2.2 ± 1.6 vs. 0.9 ± 1.1; p = .02), and longer average local relaxation time on electroanatomical mapping (378 ± 41 ms vs. 333 ± 34 ms, p = .01). During follow-up there was an improvement in diastolic parameters in Group A (E/e': from 24.3 ± 12.1 to 16.3 ± 8.0; p = .005), but not in Group B (E/e': from 10.2 ± 3.7 to 13.2 ± 9.1; p = .19). Accordingly, in Group A, we found an increase in 6-minute walk distance (from 463 ± 83 m to 546 ± 91 m; p = .03), and a decrease in NT-proBNP (from 2140 ± 1743 pg/ml to 863 ± 836 pg/ml; p = .02). In nonischemic DCM, diastolic dysfunction appears to correlate with areas of myocardial scar and hibernation. Transendocardial CD34+ cell transplantation may improve diastolic parameters in this patient cohort. Stem Cells Translational Medicine 2017;6:1515-1521.

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