Ciro Bancone

Biomechanical implications of the congenital bicuspid aortic valve: A finite element study of aortic root function from in vivo data

OBJECTIVE Congenital bicuspid aortic valves frequently cause aortic stenosis or regurgitation. Improved understanding of valve and root biomechanics is needed to achieve advancements in surgical repair techniques. By using imaging-derived data, finite element models were developed to quantify aortic valve and root biomechanical alterations associated with bicuspid geometry. METHODS A dynamic 3-dimensional finite element model of the aortic root with a bicuspid aortic valve (type 1 right/left) was developed. The models geometry was based on measurements from 2-dimensional magnetic resonance images acquired in 8 normotensive and otherwise healthy subjects with echocardiographically normal function of their bicuspid aortic valves. Numeric results were compared with those obtained from our previous model representing the normal root with a tricuspid aortic valve. The effects of raphe thickening on valve kinematics and stresses were also evaluated. RESULTS During systole, the bicuspid valve opened asymmetrically compared with the normal valve, resulting in an elliptic shape of its orifice. During diastole, the conjoint cusp occluded a larger proportion of the valve orifice and leaflet bending was altered, although competence was preserved. The bicuspid model presented higher stresses compared with the tricuspid model, particularly in the central basal region of the conjoint cusp (+800%). The presence of a raphe partially reduced stress in this region but increased stress in the other cusp. CONCLUSIONS Aortic valve function is altered in clinically normally functioning bicuspid aortic valves. Bicuspid geometry per se entails abnormal leaflet stress. The stress location suggests that leaflet stress may play a role in tissue remodeling at the raphe region and in early leaflet degeneration.

CD117‐Positive Cells in Adult Human Heart Are Localized in the Subepicardium, and Their Activation Is Associated with Laminin‐1 and α6 Integrin Expression

CD117‐positive cells contributing to cardiac cell turnover in normal and pathological conditions have recently been described in adult human heart. Since the precise spatial and temporal expression of extracellular matrix proteins and their receptors is critical for organ formation, we compared the distribution of cardiac primitive CD117‐positive cells in the human adult normal and pathological hearts with ischemic cardiomyopathy, with respect to localization and expression of laminin and integrin isoforms. In the pathological hearts, CD117‐positive cells were significantly more numerous than in the normal hearts. They were localized mainly in the atria and were up to 38‐fold more numerous in the subepicardium than in the myocardium. Compared with normal hearts, most CD117‐positive cells in the subepicardium of pathological hearts were α6 integrin‐positive. Laminin‐1, typical of developing heart, was found predominantly in the subepicardium of adult heart. Immunoblotting revealed its highest expression in the normal atrium and pathological left ventricle. Both laminin isoforms reduced apoptosis and increased proliferation and migration of CD117‐positive cells in vitro with respect to control, but the effects of laminin‐1 significantly outweighed those of laminin‐2. Signaling mediated by α6 integrin was implicated in the migration and protection from apoptosis, as documented by transfection with specific small interfering RNA. These data reveal that the increase in the number of cardiac CD117‐positive cells and the expression of laminin‐1 are observed in ischemic cardiomyopathy. Subepicardial localization of CD117‐positive cells and expression of laminin‐1 and α6 integrin subunits may all correspond to the activation of regeneration involving an epithelial‐mesenchymal transition recently described in adult heart.

Epithelial-mesenchymal transition of epicardial mesothelium is a source of cardiac CD117-positive stem cells in adult human heart

Epithelial-mesenchymal transition is implicated in the remodelling of tissues during development and in the adult life. In the heart, it gives origin to progenitors of fibroblasts, coronary endothelium, smooth muscle cells, and cardiomyocytes. Moreover, epicardially-derived cells determine myocardial wall thickness and Purkinje fibre network. Recently, the presence of numerous cardiac stem cells in the subepicardium of the adult human heart has been described and the hypothesis that epicardially-derived cells can contribute to the population of cardiac stem cells in the adult heart has been advanced. In an effort to test this hypothesis and establish a possible link between epicardium, epicardially-derived cells and cardiac stem cells in the adult human heart we have examined epicardial mesothelial cells in the normal and pathological adult human heart with ischemic cardiomyopathy in vivo and we have induced and documented their epithelial-mesenchymal transition in vitro. Noticeably, epicardial cells were missing from the surface of pathological hearts and the cells with the expression of epithelial and mesenchymal markers populated thick subepicardial space. When the fragments of epicardium from the normal hearts were cultured on the specific substrate formed by extracellular matrix derived from cardiac fibroblasts, we obtained the outgrowth of the epithelial sheet with the mRNA and protein expression characteristic of epicardium. TGFβ induced cellular and molecular changes typical of epithelial-mesenchymal transition. Moreover, the epicardially-derived cells expressed CD117 antigen. Thus, this study provides evidence that cardiac stem cells can originate from epithelial-mesenchymal transition of the epicardial cells in the adult human heart.

European Multicenter Study on Coronary Artery Bypass Grafting (E-CABG registry): Study Protocol for a Prospective Clinical Registry and Proposal of Classification of Postoperative Complications

BackgroundClinical evidence in coronary surgery is usually derived from retrospective, single institutional series. This may introduce significant biases in the analysis of critical issues in the treatment of these patients. In order to avoid such methodological limitations, we planned a European multicenter, prospective study on coronary artery bypass grafting, the E-CABG registry.DesignThe E-CABG registry is a multicenter study and its data are prospectively collected from 13 centers of cardiac surgery in university and community hospitals located in six European countries (England, Italy, Finland, France, Germany, Sweden). Data on major and minor immediate postoperative adverse events will be collected. Data on late all-cause mortality, stroke, myocardial infarction and repeat revascularization will be collected during a 10-year follow-up period. These investigators provided a score from 0 to 10 for any major postoperative adverse events and their rounded medians were used to stratify the severity of these complications in four grades. The sum of these scores for each complication/intervention occurring after coronary artery bypass grafting will be used as an additive score for further stratification of the prognostic importance of these events.DiscussionThe E-CABG registry is expected to provide valuable data for identification of risk factors and treatment strategies associated with suboptimal outcome. These information may improve the safety and durability of coronary artery bypass grafting. The proposed classification of postoperative complications may become a valuable research tool to stratify the impact of such complications on the outcome of these patients and evaluate the burden of resources needed for their treatment.Clinical Trials numberNCT02319083

Leukoreduction program for red blood cell transfusions in coronary surgery: Association with reduced acute kidney injury and in-hospital mortality

OBJECTIVE Leukocytes in allogeneic blood transfusions cause several immunomodulatory events. This before-and-after cohort study evaluated clinical outcomes after adoption of prestorage leukoreduction program for blood transfusions, with particular focus on acute kidney injury. METHODS One thousand thirty-four consecutive patients who underwent on-pump coronary artery bypass grafting between January 2004 and December 2007 were included. Propensity score analysis for transfusion was performed in the whole population; patients who were actually transfused were then divided according to leukoreduction. From these 2 groups, 147 pairs matched for propensity score were considered to evaluate with bivariate and multivariable analyses the effects of leukoreduction, with all-cause in-hospital mortality and morbidity as main outcomes. RESULTS Unadjusted in-hospital mortalities were 6.6% for the entire cohort and 44.2% for those with acute kidney injury. In the matched population, after introduction of leukoreduction, mortality rates decreased to 5.4% (vs 11.4%) and acute kidney injury (RIFLE [Risk, Injury, Failure, Loss of function, End-stage renal disease] class R or greater) dropped from 51.7% to 41.5% (relative risk -20%, P < .045). No difference emerged regarding other major complications. At multivariable analysis, intra-aortic balloon pump, RIFLE score, and propensity score for transfusion proved independent predictors of in-hospital mortality. Intra-aortic balloon pump and nonleukodepleted transfusion emerged as independent predictors of acute kidney injury. Multivariable analysis on the overall cohort of transfused patients confirmed that nonleukodepleted transfusion was an independent predictor of acute kidney injury. CONCLUSIONS Leukoreduction of allogeneic blood products is associated with decreased acute kidney injury and mortality in highly transfused patients.

Towards an individualized approach to bicuspid aortopathy: different valve types have unique determinants of aortic dilatation

OBJECTIVES Bicuspid aortic valve (BAV)-related aortopathy is increasingly recognized to be a heterogeneous disease entity, although the surgical approach, from indications to techniques, is still standard rather than individualized. We aimed to define the determinants of aortic dilatation in BAV patients stratified according to the valve morphotype. METHODS A consecutive echocardiographic series of 622 BAV patients was analysed. Among demographic (age, sex), anthropometric (height, weight, body surface area, body mass index), clinical (associated diseases) and echocardiographic variables (valve function, ventricular parameters), the determinants of aortic root and ascending tract diameter were assessed by multivariate regression models, as well as the predictors of aortic dilatation (size index >2.1 cm/m(2)) both in the overall population and separately in groups of different valve morphotypes (RL, right-left fusion; RN, right-non-coronary fusion). RESULTS Independent determinants of aortic root diameter (at sinuses) were age (P < 0.001), significant aortic regurgitation (P < 0.001), sex (female protective, P < 0.001) and valve morphotype (RN protective, P < 0.001). Independent determinants of ascending aortic diameter (tubular tract) were age (P < 0.001), RN morphotype (P < 0.001), body mass index (P = 0.005) and chronic obstructive pulmonary disease (P < 0.001). In univariate analysis, the RL morphotype was associated with dilatation (ASI > 2.1 cm/m(2)) at sinuses in 41% cases vs 22% for RN (P < 0.001), and the RN morphotype was associated with dilatation at the tubular tract in 68 vs 56% for RL (P = 0.007). The presence of root dilatation was predicted by age and absence of significant stenosis in the RL morphotype subgroup, and by severe regurgitation in the RN subgroup. In the RL-type subgroup, non-regurgitant aortic valve and chronic lung disease predicted dilatation at the ascending level; and in the RN-type subgroup, age and obesity. CONCLUSIONS The two most common BAV morphotypes are associated with aortic dilatation at two different tracts (RL at the root; RN at the tubular ascending tract) independently of valve function. Moreover, the determinants of aortic dilatation were at least in part different between the two morphotypes: this may provide stratification criteria for individualized methods of follow-up and treatment.

Microbiologically documented nosocomial infections after cardiac surgery: an 18-month prospective tertiary care centre report

OBJECTIVE The aim of this study was to prospectively evaluate frequency, characteristics, and predictors of nosocomial infections (NI) in a tertiary care centre. METHODS Study population included 925 patients (mean age 62.3+/-12.5, 32.3% females, 22.9% diabetics, 6.8% with previous cardiac procedures) operated on between June 2005 and December 2006 (CABG 48.72%, valvular procedures 30.05%, thoracic aortic 10.9%, heart transplantations 3.78% and miscellanea 6.55%, procedure status: elective 72.9%, urgent 15.9% and emergent 11.2%). The study population was divided in two groups according to development of NI. Primary endpoints were multiorgan failure (MOF) and hospital mortality in the two groups. Secondary endpoints were length of intubation, intensive care unit (ICU) stay and overall hospitalisation. Univariate and multivariate analysis of NI predictors was conducted between 115 perioperative variables. RESULTS Eighty-three patients (9%) developed a NI. Infections affected respiratory tract in 51.8%, blood stream in 20.5 and wound infection in 27.7 (13.3% deep wound). Staphylococcal species (60.6%) predominated in blood stream and surgical wound infections while Gram-negative species predominated in respiratory infections. Patients affected by NI experienced significantly higher incidence of MOF (12% vs 0.8%) and hospital mortality (24.1 vs 6.9%). Development of NI significantly lengthened all the steps of postoperative process of care (length of intubation: 49.9+/-73 h vs 19.1+/-35.2; ICU stay: 10.4+/-12.8 days vs 3.4+/-4.6 and hospitalisation 20.7+/-15.3 vs 10.6+/-7). Independent predictors of NI were immunosuppressive therapy [OR 12.9 (CI 5.07-31.2)], reintubation [OR 10.3 (CI 4.6-2.3)], stroke [OR 9.5 (CI 1.8-49)], resternotomy for bleeding [OR 6.7 (CI 1.9-23.6)], emergent/urgent status [OR 3.6 (CI 1.5-8.4)], CVVH [OR 3.2 (CI 1.4-7.5)] and length of intubation [OR 1.03 (CI 1.01-1.1)]. CONCLUSIONS NI still represents a serious complication. Presence of identified determinants of NI should prompt modification of management algorithms.

Implications of acute kidney injury after heart transplantation: what a surgeon should know

OBJECTIVE Data regarding risks and consequences of acute kidney injury (AKI) after cardiac transplantation are dismissingly few and unclear. This study defined the incidence, risk factors and prognostic implication of AKI in a single-center cohort operated on between January 1999 and December 2008. METHODS Data from 307 consecutive recipients (mean age: 47.42 ± 13.58, 20.5% female, 18.9% diabetics, 19.5% with previous cardiac operations, 26.4% hospitalized, 78.4 ± 33.7 ml min(-1) preoperative glomerular filtration rate (eGFR)) were analyzed using multivariable logistic regression modeling. AKI was defined according to RIFLE (Risk, Injury, and Failure; and Loss, and End-stage kidney disease) criteria. RESULTS RIFLE scores of I or F were detected in 14%, and continuous venovenous hemofiltration was needed in 6.1%. Risk factors for AKI were: previous cardiac operation (odds ratio (OR) 2.35; 95% confidence interval (CI), 1.11-4.9), blood transfusion (OR 1.08; 95% CI, 1.011-1.16), troponin I release >10 (OR 1.031; 95% CI, 1.001-1.064), length of ischemic time (OR 1.008; 95% CI, 1.011-1.16). Overall hospital mortality averaged 7.8% and overall 1-year mortality was 10.4%; both mortality rates increased with each RIFLE stratification (Normal 3.4%, RIFLE R = 7.1%; RIFLE I = 25.7%; and RIFLE F = 37.5% and Normal 5.6%, RIFLE R = 11.8%, RIFLE I = 25.7%, and RIFLE F = 37.5%, respectively). AKI proved independent predictors of both early and 1-year mortality. The burden of AKI significantly affected 1-year kidney function (Δ preoperative GFR-1-year GFR in AKI vs no AKI = -25.872 ± 22.54 vs -7.968 ± 34.18, p = 0.015). CONCLUSIONS AKI is a highly prevalent and prognostically important complication. Some of the risk factors for AKI identified may be modifiable.

Noninvasive positive-pressure ventilation for extubation failure after cardiac surgery: Pilot safety evaluation

OBJECTIVE Extubation failure is a serious complication after cardiac surgery. The role of noninvasive positive-pressure ventilation for acute respiratory failure in patients undergoing cardiac surgery is unknown. This study aimed to assess the safety of implementing noninvasive positive-pressure ventilation in this setting and its impact on lung function and operative outcomes. METHODS In a 6-month pilot prospective survey, the study population comprised 43 patients (32 were male with a mean age of 65.73 +/- 9 years; 3 heart transplantations, 18 coronary artery bypass grafts, 5 aortic dissections, and 17 valvular procedures; 34 active smokers, 25 with medically treated chronic obstructive pulmonary disease, 21 emergency/urgency procedures) who required noninvasive positive-pressure ventilation for acute respiratory failure after initial weaning from a respirator. The cause of acute respiratory failure (classified as post-cardiopulmonary bypass lung injury in 48.8% [21 patients], cardiogenic edema in 30.2% [13 patients], and pneumonia in 21% [9 patients]), length of noninvasive positive-pressure ventilation support, respiratory ratios (arterial oxygen tension/fraction of inspired oxygen assessed immediately before noninvasive positive-pressure ventilation, and every 6 hours after institution of pressure ventilation), and need for reintubation along with a set of predefined safety parameters were recorded. RESULTS The mean length of noninvasive positive-pressure ventilation support was 33.8 +/- 24.04 hours. Plotting respiratory ratios with length of noninvasive positive-pressure ventilation supports a significant improvement was already evident within the first 6-hour frame (133.6 +/- 39.5 vs 205 +/- 65.7; P < .001) for all causes. Noninvasive positive-pressure ventilation prevented intubation in 74.4% of the patients, with satisfactory recovery for post-cardiopulmonary bypass lung injury and cardiogenic dysfunction (90.5% and 69.2%, respectively) and poor results (55% reintubated) in those treated for pneumonia. Noninvasive positive-pressure ventilation safety approached 97.7%. CONCLUSION In appropriate candidates, noninvasive positive-pressure ventilation exerts favorable effects on lung function, preventing reintubation. The cost-effectiveness of its systematic use in this setting should be assessed.

Cardiac Fibroblast-Derived Extracellular Matrix (Biomatrix) as a Model for the Studies of Cardiac Primitive Cell Biological Properties in Normal and Pathological Adult Human Heart

Cardiac tissue regeneration is guided by stem cells and their microenvironment. It has been recently described that both cardiac stem/primitive cells and extracellular matrix (ECM) change in pathological conditions. This study describes the method for the production of ECM typical of adult human heart in the normal and pathological conditions (ischemic heart disease) and highlights the potential use of cardiac fibroblast-derived ECM for in vitro studies of the interactions between ECM components and cardiac primitive cells responsible for tissue regeneration. Fibroblasts isolated from adult human normal and pathological heart with ischemic cardiomyopathy were cultured to obtain extracellular matrix (biomatrix), composed of typical extracellular matrix proteins, such as collagen and fibronectin, and matricellular proteins, laminin, and tenascin. After decellularization, this substrate was used to assess biological properties of cardiac primitive cells: proliferation and migration were stimulated by biomatrix from normal heart, while both types of biomatrix protected cardiac primitive cells from apoptosis. Our model can be used for studies of cell-matrix interactions and help to determine the biochemical cues that regulate cardiac primitive cell biological properties and guide cardiac tissue regeneration.