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Β-blockers treatment of cardiac surgery patients enhances isolation and improves phenotype of cardiosphere-derived cells.

ABSTRACT: Β-blockers (BB) are a primary treatment for chronic heart disease (CHD), resulting in prognostic and symptomatic benefits. Cardiac cell therapy represents a promising regenerative treatment and, for autologous cell therapy, the patients clinical history may correlate with the biology of resident progenitors and the quality of the final cell product. This study aimed at uncovering correlations between clinical records of biopsy-donor CHD patients undergoing cardiac surgery and the corresponding yield and phenotype of cardiospheres (CSs) and CS-derived cells (CDCs), which are a clinically relevant population for cell therapy, containing progenitors. We describe a statistically significant association between BB therapy and improved CSs yield and CDCs phenotype. We show that BB-CDCs have a reduced fibrotic-like CD90 + subpopulation, with reduced expression of collagen-I and increased expression of cardiac genes, compared to CDCs from non-BB donors. Moreover BB-CDCs had a distinctive microRNA expression profile, consistent with reduced fibrotic features (miR-21, miR-29a/b/c downregulation), and enhanced regenerative potential (miR-1, miR-133, miR-101 upregulation) compared to non-BB. In vitro adrenergic pharmacological treatments confirmed cytoprotective and anti-fibrotic effects of β1-blocker on CDCs. This study shows anti-fibrotic and pro-commitment effects of BB treatment on endogenous cardiac reparative cells, and suggests adjuvant roles of β-blockers in cell therapy applications.

SUBMITTER: Chimenti I

PROVIDER: S-EPMC5107949 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Β-blockers treatment of cardiac surgery patients enhances isolation and improves phenotype of cardiosphere-derived cells.

Chimenti Isotta I Pagano Francesca F Cavarretta Elena E Angelini Francesco F Peruzzi Mariangela M Barretta Antonio A Greco Ernesto E De Falco Elena E Marullo Antonino G M AG Sciarretta Sebastiano S Biondi-Zoccai Giuseppe G Frati Giacomo G

Scientific reports 20161114

Β-blockers (BB) are a primary treatment for chronic heart disease (CHD), resulting in prognostic and symptomatic benefits. Cardiac cell therapy represents a promising regenerative treatment and, for autologous cell therapy, the patients clinical history may correlate with the biology of resident progenitors and the quality of the final cell product. This study aimed at uncovering correlations between clinical records of biopsy-donor CHD patients undergoing cardiac surgery and the corresponding y ...[more]

PMID: 27841293

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Project description:AimThe aim is to assess the effects of CDCs on heart structure, function, gene expression, and systemic parameters in aged rats. Diastolic dysfunction is characteristic of aged hearts. Cardiosphere-derived cell (CDC) therapy has exhibited several favourable effects on heart structure and function in humans and in preclinical models; however, the effects of CDCs on aging have not been evaluated.Methods and resultsWe compared intra-cardiac injections of neonatal rat CDCs to vehicle (phosphate-buffered saline, PBS) in 21.8 ± 1.6 month-old rats (mean ± standard deviation; n = 23 total). Ten rats 4.1 ± 1.5 months of age comprised a young reference group. Blood, echocardiographic, haemodynamic and treadmill stress tests were performed at baseline in all animals, and 1 month after treatment in old animals. Histology and the transcriptome were assessed after terminal phenotyping. For in vitro studies, human heart progenitors from older donors, or cardiomyocytes from aged rats were exposed to human CDCs or exosomes secreted by CDCs (CDC-XO) from paediatric donors. Transcriptomic analysis revealed that CDCs, but not PBS, recapitulated a youthful pattern of gene expression in the hearts of old animals (85.5% of genes differentially expressed, P < 0.05). Telomeres in heart cells were longer in CDC-transplanted animals (P < 0.0001 vs. PBS). Cardiosphere-derived cells attenuated hypertrophy by echo (P < 0.01); histology confirmed decreases in cardiomyocyte area (P < 0.0001) and myocardial fibrosis (P < 0.05) vs. PBS. Cardiosphere-derived cell injection improved diastolic dysfunction [lower E/A (P < 0.01), E/E' (P = 0.05), end-diastolic pressure-volume relationship (P < 0.05) compared with baseline), and lowered serum brain natriuretic peptide (both P < 0.05 vs. PBS). In CDC-transplanted old rats, exercise capacity increased ∼20% (P < 0.05 vs. baseline), body weight decreased ∼30% less (P = 0.05 vs. PBS) and hair regrowth after shaving was more robust (P < 0.05 vs. PBS). Serum biomarkers of inflammation (IL-10, IL-1b, and IL-6) improved in the CDC group (P < 0.05 for each, all vs. PBS). Young CDCs secrete exosomes which increase telomerase activity, elongate telomere length, and reduce the number of senescent human heart cells in culture.ConclusionYoung CDCs rejuvenate old animals as gauged by cardiac gene expression, heart function, exercise capacity, and systemic biomarkers.

Project description:ObjectiveRoutine initiation β-blocker medications before vascular surgery is controversial due to conflicting data. The purpose of this analysis was to determine whether prophylactic use of β-blockers before major elective vascular surgery decreased postoperative cardiac events or mortality.MethodsThe Society for Vascular Surgery Vascular Quality Initiative (SVS-VQI) data set was used to perform a retrospective cohort analysis of infrainguinal lower extremity bypass (LEB), aortofemoral bypass (AFB), and open abdominal aortic aneurysm (AAA) repair patients. Chronic (>30 days preoperatively) β-blocker patients were excluded, and comparisons were made between preoperative (0-30 day) and no β-blocker groups. Patients were risk stratified using a novel prediction tool derived specifically from the SVS-VQI data set. Propensity-matched pairs and interprocedural specific risk stratification comparisons were performed. End points included in-hospital major adverse cardiac events (MACEs), including myocardial infarction (MI; defined as new ST or T wave electrocardiographic changes, troponin elevation, or documentation by echocardiogram or other imaging modality), dysrhythmia, and congestive heart failure, and 30-day mortality.ResultsThe study analyzed 13,291 patients (LEB, 68% [n = 9047]; AFB, 11% [n = 1474]; and open AAA, 21% [n = 2770]); of these, 67.7% (n = 8999) were receiving β-blockers at time of their index procedure. Specifically, 13.2% (n = 1753) were identified to have been started on a preoperative β-blocker, 54.5% (n = 7426) were on chronic β-blockers, and 32.3% (n = 4286) were on no preoperative β-blockers. Among the three procedures, patients had significant demographic and comorbidity differences and thus were not combined. A 1:1 propensity-matched pairs analysis (1459 pairs) revealed higher rates of postoperative MI with preoperative β-blockers (preoperative β-blocker relative risk, 1.65; 95% confidence interval, 1.02-2.68; P = .05 vs no β-blocker), with no difference in dysrhythmia, congestive heart failure, or 30-day mortality. When stratified into low-risk, medium-risk, and high-risk groups within each procedure, all groups of preoperative β-blocker patients had no difference or higher rates of MACEs and 30-day mortality, with the exception of high-risk open AAA patients, who had a lower rate of MI (odds ratio, 0.35; 95% confidence interval, 011-0.87; P = .04).ConclusionsExclusive of high-risk open AAA patients, preoperative β-blockers did not decrease rates of MACEs or mortality after LEB, AFB, or open AAA. Importantly, exposure to prophylactic preoperative β-blockers increased the rates of some adverse events in several subgroups. Given these data, the SVS-VQI cannot support routine initiation of preoperative β-blockers before major elective vascular surgery in most patients.

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Β-blockers treatment of cardiac surgery patients enhances isolation and improves phenotype of cardiosphere-derived cells.

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Β-blockers treatment of cardiac surgery patients enhances isolation and improves phenotype of cardiosphere-derived cells.

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