Sodium/glucose cotransporter 2 (SGLT2) inhibitors improve cardiac function by reducing JunD expression in human diabetic hearts.

BACKGROUND: The pathogenesis of experimental diabetic cardiomyopathy may involve the activator protein 1 (AP-1) member, JunD. Using non-diabetic heart transplant (HTX) in recipients with diabetes, we examined the effects of the diabetic milieu (hyperglycemia and insulin resistance) on cardiac JunD expression over 12 months. Because sodium/glucose cotransporter-2 inhibitors (SGLT2i) significantly reverse high glucose-induced AP-1 binding in the proximal tubular cell, we investigated JunD expression in a subgroup of type 2 diabetic recipients receiving SGLT2i treatment. METHODS: We evaluated 77 first HTX recipients (40 and 37 patients with and without diabetes, respectively). Among the recipients with diabetes, 17 (45.9%) were receiving SGLT2i treatment. HTX recipients underwent standard clinical evaluation (metabolic status, echocardiography, coronary computed tomography angiography, and endomyocardial biopsy). In the biopsy samples, we evaluated JunD, insulin receptor substrates 1 and 2 (IRS1 and IRS2), peroxisome proliferator-activated receptor-γ (PPAR-γ), and ceramide levels using real-time polymerase chain reaction and immunofluorescence. The biopsy evaluations in this study were performed at 1-4 weeks (basal), 5-12 weeks (intermediate), and up to 48 weeks (final, end of 12-month follow-up) after HTX. RESULTS: There was a significant early and progressive increase in the cardiac expression of JunD/PPAR-γ and ceramide levels, along with a significant decrease in IRS1 and IRS2 in recipients with diabetes but not in those without diabetes. These molecular changes were blunted in patients with diabetes receiving SGLT2i treatment. CONCLUSION: Early pathogenesis in human diabetic cardiomyopathy is associated with JunD/PPAR-γ overexpression and lipid accumulation following HTX in recipients with diabetes. Remarkably, this phenomenon was reduced by concomitant therapy with SGLT2i, which acted directly on diabetic hearts.

Mini-organs forum: how to advance organoid technology to organ transplant community.

The generation of human mini-organs, the so-called organoids, is one of the biggest scientific advances in regenerative medicine. This technology exploits traditional three-dimensional culture techniques that support cell-autonomous self-organization responses of stem cells to derive micrometer to millimeter size versions of human organs. The convergence of the organoid technology with organ transplantation is still in its infancy but this alliance is expected to open new venues to change the way we conduct both transplant and organoid research. In this Forum we provide a summary on early achievements facilitating organoid derivation and culture. We further discuss on early advances of organoid transplantation also offering a comprehensive overview of current limitations and challenges to instruct organoid maturation. We expect that this Forum sets the ground for initial discussions between stem cell biologists, bioengineers, and the transplant community to better direct organoid basic research to advance the organ transplantation field.

T- and B-cell therapy in solid organ transplantation: current evidence and future expectations.

Cell therapy has emerged as an attractive therapeutic option in organ transplantation. During the last decade, the therapeutic potency of Treg immunotherapy has been shown in various preclinical animal models and safety was demonstrated in first clinical trials. However, there are still critical open questions regarding specificity, survival, and migration to the target tissue so the best Treg population for infusion into patients is still under debate. Recent advances in CAR technology hold the promise for Treg-functional superiority. Another exciting strategy is the generation of B-cell antibody receptor (BAR) Treg/cytotoxic T cells to specifically regulate or deplete alloreactive memory B cells. Finally, B cells are also capable of immune regulation, making them promising candidates for immunomodulatory therapeutic strategies. This article summarizes available literature on cell-based innovative therapeutic approaches aiming at modulating alloimmune response for transplantation. Crucial areas of investigation that need a joined effort of the transplant community for moving the field toward successful achievement of tolerance are highlighted.

Risk Factors and Outcome of Multidrug-Resistant Infections after Heart Transplant: A Contemporary Single Center Experience.

(1) Background: The aim of this study was to assess risk factors for multidrug-resistant/extensively drug-resistant (MDR/XDR) bacterial infections in heart transplant (HT) patients within three months after surgery and its impact on patient outcome. (2) Methods: Retrospective analysis of clinical, hemato-chemical, imaging, treatment and outcome data from 47 heart transplant recipients from January 2016 to December 2018. MDR/XDR infections were compared to non-MDR/XDR and noninfected patients. (3) Results: Most participants were males, median age 51 years: 35 (74.5%) developed an infection after HT; 14 (29.8%) were MDR/XDR infections. Prolonged hospital stay before HT correlated to MDR/XDR infection (p < 0.001). Sequential organ failure assessment (SOFA) score at sampling day was higher in MDR/XDR (p = 0.027). MDR/XDR were mostly blood-stream (BSI) (p = 0.043) and skin-soft tissue (SSTI) (p = 0.047) infections. Gram-negative infections were the most frequent, specifically carbapenem-resistant Klebsiella pneumoniae. Antibiotic therapy duration for MDR/XDR infections was longer (p = 0.057), eradication rate lower (p = 0.083) and hospital stay longer (p = 0.005) but not associated with a worse outcome. (4) Conclusions: MDR/XDR infections affect compromised HT recipients with a history of prolonged hospitalization, causing a lower rate of eradication and increased hospital stay. These frequently present as BSI and SSTI. We emphasize the need to prevent contamination of central venous catheters and the surgical site.

A new hemodynamic index to predict late right failure in patients implanted with last generation centrifugal pump.

BACKGROUND: Right ventricular failure (RVF) is a severe event that increases perioperative mortality after left ventricle assist device (LVAD) implantation. Right ventricular (RV) function is particularly affected by the LVAD speed by altering RV preload and afterload as well as the position of the interventricular septum. However, there are no studies focusing on the relationship between pump speed optimization and risk factors for the development of late RVF. METHODS: Between 2015 and 2019, 50 patients received LVAD implantation at San Camillo Hospital in Rome. Of these, 38 who underwent pump speed optimization were included. Post-optimization hemodynamic data were collected. We assessed a new Hemodynamic Index (HI), calculated as follows:  HI = MAP × PCWP CVP × RPM set RPM max , to determine the risk of late RVF, which was defined as the requirement for rehospitalization and inotropic support. RESULTS: Ten patients had late RVF after LVAD implantation. Five patients required diuretic therapy and speed optimization. Three patients required inotropic support with adrenaline 0.05 µg/kg/min. Two patients needed prolonged continuous venovenous hemofiltration and high dose inotropic support. Multivariate analysis revealed that a low HI (odds ratio 11.5, 95% confidence interval, 1.85-65.5, p [.003]) was an independent risk factor for late RVF after LVAD implantation. CONCLUSION: We demonstrated a low HI being a significant risk factor for the development of RVF after LVAD implantation. We suggest implementing HI as a decision support tool for goal-direct optimization of the device aiming to reduce the burden of late-onset RVF during the follow-up.

[Cardiology units and organizational models of heart transplantation centers in Italy: a survey by the Italian Association of Hospital Cardiologists-Italian Society of Organ Transplantation (ANMCO-SITO)]. / Cardiologie e modelli organizzativi dei centri trapianto di cuore: indagine ANMCO-SITO.

BACKGROUND: The extent and quality of the involvement of cardiology units in health programs delivered by Italian centers for heart transplantation (HTx) have not been investigated previously. METHODS: The Italian Association of Hospital Cardiologists (ANMCO) and the Italian Society for Organ Transplantation (SITO) developed and delivered a nationwide survey to the Directors of the Italian centers for HTx to investigate the extent to which cardiology units contribute to HTx programs. The survey investigated: (i) the organization of the centers and institutional frame under which cardiology units contributed to HTx programs; (ii) the volumes of procedures and clinical services delivered by cardiology units to HTx centers for listing patients, following those waiting for HTx, managing acute heart failure, selecting and allocating organs to recipients, following and managing organ rejection after HTx. RESULTS: Of the 14 Italian centers involved, 13 provided full responses to the survey. Between 2017-2019, on average, 46% of the respondents performed up to 15 HTx/year, and additional 46% performed between 16 and 30 HTx/year. Of the respondents, 62% were included in a department of cardiac Surgery which did not include a cardiology unit; furthermore, 54% declared not to be included in a formal network for heart failure management. Cardiology units were the source for referrals of candidates to HTx in 85% cases. Of the respondents, 15% declared to be able to provide cardiological services thorough intra-center multidisciplinary team including cardiologists, whereas cardiological services were outsourced in 61% of the respondents. The clinical follow-up of patients waiting for HTx was performed directly by surgeons in 38% of the respondents. Worsening heart failure was managed directly by the HTx center in 33% of the cases using dedicated beds. Post-HTx follow-up, including endomyocardial biopsy, involved external cardiology units in less than 25% of the centers. CONCLUSIONS: The ANMCO-SITO survey shows that in Italy a very wide variability exists in terms of organization of HTx centers and their relationships with cardiology units for delivering specific cardiological services and procedures. In large majority, patient referral to HTx centers is mediated by cardiology units, whereas HTx was rarely included in a structured cardiological network for heart failure management.

Post-heart transplantation lymphoproliferative diseases (PTLDs) and the diagnostic role of [18f] FDG-PET/CT.

BACKGROUND: The incidence of cancer is higher in transplant patients than in the normal population, mostly due to the assumption of immunosuppressants able to reduce the possibility of rejection. In addition, immunocompromised patients have a greater susceptibility to EBV, HPV and HIV, infectious agents that by themselves may favor the onset of malignancies. Post-transplant lymphoproliferative diseases (PLDs) are among the most frequent neoplasms in transplant patients which like other aggressive neoplasms may be identified by the [18f] fluoro-D-deoxyglucose positron emission tomography/computed tomography (FDG-PET/CT). METHODS: We evaluated the clinical use of FDG-PET/CT in detecting PTLDs and other neoplasms performed at the lowest clinical or laboratory suspicion of malignancy in 127 consecutive subjects who underwent heart transplantation. RESULTS: A SUV>4 more confirmed the suspect of malignancy and induced us to further investigations. Of the 127 transplant subjects who underwent FDG-PET/CT, 64 showed a SUV value >4. Of these 64, 8 had PTLDs, 49 other neoplasms (urinary tract tumors, thyroid cancer, HPV cancer related, Kaposi' sarcoma and EBV related head and neck neoplasms) and 7 patients with chronic non-neoplastic inflammatory diseases. CONCLUSIONS: In the present study, FDG-PET/CT examination was of great use for an early identification and for an early treatment of PTLDs and other neoplasms.

Liver histopathological findings in advanced heart failure: a reappraisal of cardiac cirrhosis concept.

Cardiogenic liver disease is a common yet poorly characterized complication of advanced heart failure (HF), and may impact clinical management in the setting of heart transplant evaluation. In this retrospective study, we describe clinical and histopathological features of liver injury in advanced HF, with a focus on the role of liver biopsy. Included were 45 HF patients, assessed for possible heart transplant, who underwent liver biopsy for suspected liver disease. Median duration of HF symptoms was 5 years. Most patients had stiff hepatomegaly and elevated bilirubin. Viral hepatitis (19 patients, 42.2%) was the most common cause of prior known liver disease. Sinusoidal dilatation was detected in the majority of patients (64.4%). Median necroinflammatory index was 3 and median fibrosis was 1, consistent with a small burden of histologically proven liver disease. Viral hepatitis was the only variable associated with a higher grade of necroinflammation and fibrosis. Nine of the 14 (64.3%) advanced fibrosis/cirrhosis patients had a viral hepatitis infection. Fibrosis was significantly associated with splenomegaly. The MELD score was not correlated with cardiac index. A coarse liver echo-pattern had a 29% positive and 63% negative predictive value for advanced fibrosis/cirrhosis. Severe liver disease is uncommon in patients with advanced HF in the absence of splenomegaly or primary causes of liver disease. Ultrasound data need to be carefully evaluated, as it may overstate the severity of liver disease. Liver biopsy may be needed to accurately stage liver disease before excluding patients from advanced treatment strategies.

Biomaterials and heart recovery: cardiac repair, regeneration and healing in the MCS era: a state of the "heart".

Regenerative medicine is an emerging interdisciplinary field of scientific research that, supported by tissue engineering is, nowadays, a valuable and reliable solution dealing with the actual organs shortage and the unresolved limits of biological or prosthetic materials used in repair and replacement of diseased or damaged human tissues and organs. Due to the improvements in design and materials, and to the changing of clinical features of patients treated for valvular heart disease the distance between the ideal valve and the available prostheses has been shortened. We will then deal with the developing of new tools aiming at replacing or repair cardiac tissues that still represent an unmet clinical need for the surgeons and indeed for their patients. In the effort of improving treatment for the cardiovascular disease (CVD), scientists struggle with the lack of self-regenerative capacities of finally differentiated cardiovascular tissues. In this context, using several converging technological approaches, regenerative medicine moves beyond traditional transplantation and replacement therapies and can restore tissue impaired function. It may also play an essential role in surgery daily routine, leading to produce devices such as injectable hydrogels, cardiac patches, bioresorbable stents and vascular grafts made by increasingly sophisticated biomaterial scaffolds; tailored devices promptly fabricated according to surgeon necessity and patient anatomy and pathology will hopefully represent a daily activity in the next future. The employment of these devices, still far from the in vitro reproduction of functional organs, has the main aim to achieve a self-renewal process in damaged tissues simulating endogenous resident cell populations. In this field, the collaboration and cooperation between cardiothoracic surgeons and bioengineers appear necessary to modify these innovative devices employed in preclinical studies according to the surgeon's needs.

Nonsurgical Strategies to Reduce Mortality in Patients Undergoing Cardiac Surgery: An Updated Consensus Process.

OBJECTIVE: A careful choice of perioperative care strategies is pivotal to improve survival in cardiac surgery. However, there is no general agreement or particular attention to which nonsurgical interventions can reduce mortality in this setting. The authors sought to address this issue with a consensus-based approach. DESIGN: A systematic review of the literature followed by a consensus-based voting process. SETTING: A web-based international consensus conference. PARTICIPANTS: More than 400 physicians from 52 countries participated in this web-based consensus conference. INTERVENTIONS: The authors identified all studies published in peer-reviewed journals that reported on interventions with a statistically significant effect on mortality in the setting of cardiac surgery through a systematic Medline/PubMed search and contacts with experts. These studies were discussed during a consensus meeting and those considered eligible for inclusion in this study were voted on by clinicians worldwide. MEASUREMENTS AND MAIN RESULTS: Eleven interventions finally were selected: 10 were shown to reduce mortality (aspirin, glycemic control, high-volume surgeons, prophylactic intra-aortic balloon pump, levosimendan, leuko-depleted red blood cells transfusion, noninvasive ventilation, tranexamic acid, vacuum-assisted closure, and volatile agents), whereas 1 (aprotinin) increased mortality. A significant difference in the percentages of agreement among different countries and a variable gap between agreement and clinical practice were found for most of the interventions. CONCLUSIONS: This updated consensus process identified 11 nonsurgical interventions with possible survival implications for patients undergoing cardiac surgery. This list of interventions may help cardiac anesthesiologists and intensivists worldwide in their daily clinical practice and can contribute to direct future research in the field.

Optimizing the Safety Profile of Everolimus by Delayed Initiation in De Novo Heart Transplant Recipients: Results of the Prospective Randomized Study EVERHEART.

BACKGROUND: Although everolimus potentially improves long-term heart transplantation (HTx) outcomes, its early postoperative safety profile had raised concerns and needs optimization. METHODS: This 6-month, open-label, multicenter randomized trial was designed to compare the cumulative incidence of a primary composite safety endpoint comprising wound healing delays, pericardial effusion, pleural effusion needing drainage, and renal insufficiency events (estimated glomerular filtration rate ≤30/mL/min per 1.73 m) in de novo HTx recipients receiving immediate everolimus (EVR-I) (≤144 hours post-HTx) or delayed everolimus (EVR-D) (4-6 weeks post-HTx with mycophenolate mofetil as a bridge) with reduced-dose cyclosporine A. Cumulative incidence of biopsy-proven rejection ≥ 2R, rejection with hemodynamic compromise, graft loss, or death was the secondary composite efficacy endpoint. RESULTS: Overall, 181 patients were randomized to the EVR-I (n = 89) or EVR-D (n = 92) arms. Incidence of primary safety endpoint was higher for EVR-I than EVR-D arm (44.9% vs 32.6%; P = 0.191), mainly driven by a higher rate of pericardial effusion (33.7% vs 19.6%; P = 0.04); wound healing delays, acute renal insufficiency events, and pleural effusion occurred at similar frequencies in the study arms. Efficacy failure was not significantly different in EVR-I arm versus EVR-D arm (37.1% vs 28.3%; P = 0.191). Three patients in the EVR-I arm and 1 in the EVR-D arm died. Incidence of clinically significant adverse events leading to discontinuation was higher in EVR-I arm versus EVR-D arm (P = 0.02). CONCLUSIONS: Compared with immediate initiation, delayed everolimus initiation appeared to provide a clinically relevant early safety benefit in de novo HTx recipients, without compromising efficacy.

Cerebral perfusion issues in acute type A aortic dissection without preoperative malperfusion: how do surgical factors affect outcomes?

OBJECTIVES: Both preoperative (disease-related) and operative (management-related) variables make the assessment of the outcomes of acute type A aortic dissection (ATAAD) surgery a difficult task. Our aim was to evaluate the impact of operative factors, including arterial cannulation site, route of cerebral perfusion and surgeon's specific experience with ATAAD ('aortic surgeon'), on the early results of surgical management, with particular attention to neurological injury. METHODS: Penn classification was used to identify clinically homogeneous risk groups of ATAAD patients undergoing surgery. Between January 2007 and June 2014, 111 of 183 ATAAD patients treated with open surgery in a single centre were in Penn Class Aa (no ischaemic complications at presentation). They were divided in two groups depending on the arterial cannulation site: femoral artery (FemA; 56 patients) or right axillary artery (RAxA; 55 patients). Study outcomes included: 30-day mortality, major adverse cardiac and cerebrovascular events at 30 days, neurological complications and in particular, patterns of stroke as defined by Bamford classification. RESULTS: No significant differences in preoperative variables were observed between cannulation-site groups, except for myocardial ischaemic time (60.9 ± 30.4 min in the RAxA group vs 81.7 ± 52.3 in the FemA group, P = 0.014) and cerebral perfusion time (42.1 ± 25.5 min in the RAxA group vs 52.9 ± 32.6 in the FemA group, P = 0.048). Outcomes in terms of mortality and neurological injury did not differ except for a higher incidence of lacunar cerebral infarction (LACI) in the RAxA group (14.5 vs 3.6%, P = 0.043), mainly but not exclusively explained by a higher incidence of LACI in unilateral (17.2%) than in bilateral cerebral perfusion (6.9%) within the RAxA group. The 'non-aortic surgeon' was associated instead with 30-day mortality and composite outcome in multivariable analysis (respectively, OR 6.40, P = 0.002 and OR 4.68, P = 0.001). CONCLUSIONS: The RAxA cannulation and FemA cannulation are associated with comparable 30-day mortality following surgery for aortic dissection. However, the possible higher risk of LACI-type strokes in the RAxA group, especially when associated with unilateral brain perfusion, should be considered when RAxA cannulation is performed in ATAAD. The hypothesis that more experienced surgeons may produce better earlier outcomes warrants further investigation.

Pattern of resolution of pulmonary hypertension, long-term allograft right ventricular function, and exercise capacity in high-risk heart transplant recipients listed under oral sildenafil.

Unresponsive pulmonary hypertension (PH) implies poor posttransplant outcomes. Data on late adaptation of the right ventricle (RV) are still few. This study evaluated three-yr RV function and remodeling, exercise capacity, and hemodynamic data in a selected group of patients initially disqualified because of PH. Between May 2005 and December 2009, 31 consecutive patients were qualified for oral sildenafil because of unresponsive PH at baseline right heart catheterization (RHC). After a 12-wk trial, RHC disclosed PH reversibility (mean PVR: 5.41 ± 3 Wood units, mean TPG 14.5 ± 5.6 mmHg, and mean systolic PAP 68.9 ± 15.1 mmHg), allowing listing even though as high-risk procedures. All patients underwent heart transplantation. RV failure developed in three patients (9.6%), and hospital mortality was 3.2%. Protocol RHC disclosed pulmonary hemodynamic profile normalization within the third postoperative month, allowing weaning from sildenafil in the 30 hospital survivors. One- and three-yr RHCs confirmed stable PH reversal (n = 26, all three-yr survivors). Parameters of late RV function and remodeling proved satisfactory. Parameters of functional capacity (Vo2 peak 19.7 ± 3.6 mL/kg/min and slope VE/Vco2 34.8 ± 2.7) proved homogeneous to those measured in transplant recipients with normal preoperative pulmonary artery pressure. Oral sildenafil is effective in allowing candidacy, safe transplantation, and long-term survival in PH recipients initially disqualified.

Human leukocyte antigen-DR mismatch is associated with increased in-hospital mortality after a heart transplant.

OBJECTIVES: Although previous studies have investigated the effect of human leukocyte antigen matching on long-term outcomes after heart transplants, its role in the prognosis after a heart transplant remains unclear, particularly with respect to short-term survival. MATERIALS AND METHODS: We evaluated the human leukocyte antigen mismatch on in-hospital mortality of 158 consecutive patients who had undergone a heart transplant between 2000 and 2008. Human leukocyte antigens-A, -B, and -DR were determined by means of serologic and molecular techniques. Univariate analysis and a multiple logistic regression models evaluated the effect of human leukocyte antigen variants on mortality, independent of clinical variables. RESULTS: In-hospital mortality was 11.4%. Higher prevalence of acute kidney injury (50.0% vs 12.9%), higher levels of troponins 48 hours after transplant (15.6 ± 12.0 ng/mL vs 9.7 ± 9.4 ng/mL), prolonged ischemia (188.2 ± 32.5 min vs 162.6 ± 40.7 min), higher frequency of reoperation (61.1% vs 17.9%), and higher human leukocyte antigen-DR mismatch (1.61 ± 0.5 vs 1.30 ± 0.6) were found in patients who died. By logistic regression analysis, humanleukocyte antigen-DR mismatch is associated with in-hospital mortality (OR=5.159, 95% CI=1.348-19.754), independent of the effect of covariates such as recipient age, mismatch sex, mismatch human leukocyte antigen-A, human leukocyte antigen-B, acute kidney injury, reoperation, ischemia duration, and levels of troponins. CONCLUSIONS: Human leukocyte antigen-DR mismatch is associated with in-hospital mortality in heart transplant.

Adefovir treatment for chronic hepatitis B in heart transplant recipients.

Chronic hepatitis B is prevalent in the transplant setting and may cause significant complications. Effective control of viral replication is needed. Besides lamivudine, very little data are available on safety and efficacy of other drugs. We describe our experience with adefovir dipivoxil (ADV) in eight heart transplant recipients. Studies included a baseline liver biopsy, thrice-monthly clinical, biochemical, and virological evaluations, including genotyping and viral load, polymerase gene sequencing for resistance mutations, liver and kidney function tests, and liver ultrasound. Of eight patients, six had fibrosis score ≤2 and negative HBeAg and seven had hepatitis B virus (HBV) genotype D. Upon ADV start, median HBV-DNA was 5.8 logs IU/mL and alanine aminotransferase (ALT) levels were mostly normal. All patients had prior mild-to-moderate renal functional impairment. Seven of eight patients started ADV after a previous course of lamivudine. Five of these seven patients became HBV-DNA undetectable within eight months. One patient with low baseline viremia started ADV de novo and suppressed HBV-DNA. Median treatment duration was 66 months. ADV daily dose was halved in one patient due to renal function worsening. No ALT flares, hypophosphatemia, liver decompensation, liver cancer, or emergence of resistance was observed. Our data suggest that ADV may be a safe and effective rescue treatment for heart transplant recipients with lamivudine-resistant chronic hepatitis B.

Cardiac primitive cells become committed to a cardiac fate in adult human heart with chronic ischemic disease but fail to acquire mature phenotype: genetic and phenotypic study.

Adult human heart hosts a population of cardiac primitive CD117-positive cells (CPCs), which are responsible for physiological tissue homeostasis and regeneration. While the bona fide stem cells express telomerase, their progenies are no longer able to preserve telomeric DNA; hence the balance between their proliferation and differentiation has to be tightly controlled in order to prevent cellular senescence and apoptosis of CPCs before their maturation can be accomplished. We have examined at cellular and molecular level the proliferation, apoptosis and commitment of CPCs isolated from normal (CPC-N) and age-matched pathological adult human hearts (CPC-P) with ischemic heart disease. In the CPC-P, genes related to early stages of developmental processes, nervous system development and neurogenesis, skeletal development, bone and cartilage development were downregulated, while those involved in mesenchymal cell differentiation and heart development were upregulated, together with the transcriptional activation of TGFß/BMP signaling pathway. In the pathological heart, asymmetric division was the prevalent type of cardiac stem cell division. The population of CPC-P consisted mainly of progenitors of cardiac cell lineages and less precursors; these cells proliferated more, but were also more susceptible to apoptosis with respect to CPC-N. These results indicate that CPCs fail to reach terminal differentiation and functional competence in pathological conditions. Adverse effects of underlying pathology, which disrupts cardiac tissue structure and composition, and cellular senescence, resulting from cardiac stem cell activation in telomere dysfunctional environment, can be responsible for such outcome.

Blood transfusion after on-pump coronary artery bypass grafting: focus on modifiable risk factors.

OBJECTIVES: Perioperative transfusions are known to increase morbidity and mortality after coronary artery bypass grafting (CABG). The aims of the study were (1) to identify the clinical profile of the patient subset at highest risk from transfusion and (2) to disclose causative relationship and dose-dependency of transfusion on hospital mortality. METHODS: A prospective observational design was employed on a cohort of 1047 consecutive patients (median age 63.2 ± 9.3, 18.8% female, 30.6% diabetics, 31.9% urgent/emergent, 15.3% with low preoperative left ventricular ejection fraction (LVEF)) who underwent on-pump isolated CABG between January 2004 and December 2007. Univariate and multivariate regression analysis and post-hoc risk stratification, by means of propensity scoring and binary segmentation, were adopted. RESULTS: The following independent risk factors were identified: age, body surface area (BSA), preoperative glomerular filtration rate, preoperative haemoglobin, surgical priority, length of cardiopulmonary bypass, intraoperative haemodilution and early postoperative blood loss. The patient population was stratified in quintiles of transfusional risk, by means of propensity scoring. As to modifiable risk factors, patients in the highest quintiles of risk were those with BSA ( < 1.73, preoperative haemoglobin < 12 g/dl, intraoperative haemoglobin < 8.0 g/dl and those undergoing cardiopulmonary bypass > 90'). Binary segmentation was performed to avoid any association between red cell transfusion and worse outcomes being causative and dose-dependent. A dose-dependent pattern was disclosed, with patients receiving > 5 units being at highest risk. CONCLUSIONS: High exposure to blood transfusions may be prevented by preoperative patient stratification and by the close tailoring of management strategies on planning and implementing surgical timing, as well as by cardiopulmonary bypass technique.