Calcification of surgical aortic bioprostheses and its impact on clinical outcome.

AIMS: Aortic valve calcification (AVC) of surgical valve bioprostheses (BP) has been poorly explored. We aimed to evaluate in-vivo and ex-vivo BP AVC and its prognosis value. METHODS AND RESULTS: Between 2011 and 2019, AVC was assessed using in-vivo computed tomography (CT) in 361 patients who had undergone surgical valve replacement 6.4±4.3 years earlier. Ex-vivo CT scans were performed for 37 explanted BP. The in-vivo CT scans were interpretable for 342 patients (19 patients [5.2%], were excluded). These patients were 77.2±9.1 years old and 64.3% were male. Mean in-vivo AVC was 307±500 Agatston unit (AU). The AVC was 562±570 AU for the 183 (53.5%) patients with structural valve degeneration (SVD) and 13±43 AU for those without SVD (p<0.0001). In-vivo and ex-vivo AVC were strongly correlated (r=0.88, p<0.0001). An in-vivo AVC>100 AU (n=147, 43%) had a specificity of 96% for diagnosing Stage 2-3 SVD (area under the curve=0.92). Patients with AVC>100 AU had a worse outcome compared with those with AVC≤100 AU (n=195). In multivariable analysis, AVC was a predictor of overall mortality (hazard ratio [HR] and 95% confidence interval=1.16[1.04-1.29]; p=0.006), cardiovascular mortality (HR=1.22[1.04-1.43]; p=0.013), cardiovascular events (HR=1.28 [1.16-1.41]; p<0.0001), and re-intervention (HR=1.15 [1.06-1.25]; p<0.0001). After adjustment for Stage 2-3 SVD diagnosis, AVC remained a predictor of overall mortality (HR=1.20 [1.04-1.39]; p=0.015) and cardiovascular events (HR=1.25 [1.09-1.43]; p=0.001). CONCLUSION: CT scan is a reliable tool to assess BP leaflet calcification. An AVC>100 AU is tightly associated with SVD and it is a strong predictor of overall mortality and cardiovascular events.

Differential Immune Response to Bioprosthetic Heart Valve Tissues in the α1,3Galactosyltransferase-Knockout Mouse Model.

Structural valve deterioration (SVD) of bioprosthetic heart valves (BHVs) has great clinical and economic consequences. Notably, immunity against BHVs plays a major role in SVD, especially when implanted in young and middle-aged patients. However, the complex pathogenesis of SVD remains to be fully characterized, and analyses of commercial BHVs in standardized-preclinical settings are needed for further advancement. Here, we studied the immune response to commercial BHV tissue of bovine, porcine, and equine origin after subcutaneous implantation into adult α1,3-galactosyltransferase-knockout (Gal KO) mice. The levels of serum anti-galactose α1,3-galactose (Gal) and -non-Gal IgM and IgG antibodies were determined up to 2 months post-implantation. Based on histological analyses, all BHV tissues studied triggered distinct infiltrating cellular immune responses that related to tissue degeneration. Increased anti-Gal antibody levels were found in serum after ATS 3f and Freedom/Solo implantation but not for Crown or Hancock II grafts. Overall, there were no correlations between cellular-immunity scores and post-implantation antibodies, suggesting these are independent factors differentially affecting the outcome of distinct commercial BHVs. These findings provide further insights into the understanding of SVD immunopathogenesis and highlight the need to evaluate immune responses as a confounding factor.

Oxidative Stress in Structural Valve Deterioration: A Longitudinal Clinical Study.

The cause of structural valve deterioration (SVD) is unclear. Therefore, we investigated oxidative stress markers in sera from patients with bioprosthetic heart valves (BHVs) and their association with SVD. Blood samples were taken from SVD (Phase A) and BHV patients during the first 24 (Phase B1) and >48 months (Phase B2) after BHV implantation to assess total antioxidant capacity (TAC), malondialdehyde (MDA), and nitrotyrosine (NT). The results show that MDA levels increased significantly 1 month after surgery in all groups but were higher at 6 months only in incipient SVD patients. NT levels increased gradually for the first 24 months after implantation in the BHV group. Patients with transcatheter aortic valve implantation (TAVI) showed even higher levels of stress markers. After >48 months, MDA and NT continued to increase in BHV patients with a further elevation after 60-72 months; however, these levels were significantly lower in the incipient and established SVD groups. In conclusion, oxidative stress may play a significant role in SVD, increasing early after BHV implantation, especially in TAVI cases, and also after 48 months' follow-up, but decreasing when SVD develops. Oxidative stress potentially represents a target of therapeutic intervention and a biomarker of BHV dysfunction.

The role of antibody responses against glycans in bioprosthetic heart valve calcification and deterioration.

Bioprosthetic heart valves (BHVs) are commonly used to replace severely diseased heart valves but their susceptibility to structural valve degeneration (SVD) limits their use in young patients. We hypothesized that antibodies against immunogenic glycans present on BHVs, particularly antibodies against the xenoantigens galactose-α1,3-galactose (αGal) and N-glycolylneuraminic acid (Neu5Gc), could mediate their deterioration through calcification. We established a large longitudinal prospective international cohort of patients (n = 1668, 34 ± 43 months of follow-up (0.1-182); 4,998 blood samples) to investigate the hemodynamics and immune responses associated with BHVs up to 15 years after aortic valve replacement. Early signs of SVD appeared in <5% of BHV recipients within 2 years. The levels of both anti-αGal and anti-Neu5Gc IgGs significantly increased one month after BHV implantation. The levels of these IgGs declined thereafter but anti-αGal IgG levels declined significantly faster in control patients compared to BHV recipients. Neu5Gc, anti-Neu5Gc IgG and complement deposition were found in calcified BHVs at much higher levels than in calcified native aortic valves. Moreover, in mice, anti-Neu5Gc antibodies were unable to promote calcium deposition on subcutaneously implanted BHV tissue engineered to lack αGal and Neu5Gc antigens. These results indicate that BHVs manufactured using donor tissues deficient in αGal and Neu5Gc could be less prone to immune-mediated deterioration and have improved durability.

The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: the BAMI trial.

AIMS: Bone marrow-derived mononuclear cell (BM-MNC) therapy may improve myocardial recovery in patients following acute myocardial infarction (AMI), though existing trial results are inconsistent. METHODS AND RESULTS: Originally an open-label, multicentre Phase III trial, BAMI was designed to demonstrate the safety and efficacy of intracoronary infusion of BM-MNCs in reducing the time to all-cause mortality in patients with reduced left ventricular ejection fraction (LVEF, ≤45%) after primary angioplasty (PPCI) for ST-elevation AMI. Unexpectedly low recruitment means the trial no longer qualifies as a hypothesis-testing trial, but is instead an observational study with no definitive conclusions possible from statistical analysis. In total, 375 patients were recruited: 185 patients were randomized to the treatment arm (intracoronary infusion of BM-MNCs 2-8 days after PPCI) and 190 patients to the control arm (optimal medical therapy). All-cause mortality at 2 years was 3.26% [6 deaths; 95% confidence interval (CI): 1.48-7.12%] in the BM-MNC group and 3.82% (7 deaths; 95% CI: 1.84-7.84%) in the control group. Five patients (2.7%, 95% CI: 1.0-5.9%) in the BM-MNC group and 15 patients (8.1%, CI : 4.7-12.5%) in the control group were hospitalized for heart failure during 2 years of follow-up. Neither adverse events nor serious adverse events differed between the two groups. There were no patients hospitalized for stroke in the control group and 4 (2.2%) patients hospitalized for stroke in the BM-MNC group. CONCLUSIONS: Although BAMI is the largest trial of autologous cell-based therapy in the treatment of AMI, unexpectedly low recruitment and event rates preclude any meaningful group comparisons and interpretation of the observed results.

Determination of Redox Status in Serum.

Free radicals of oxidative and nitrosative stress can trigger both pro-inflammatory and anti-inflammatory responses. In the transplant setting, reactive oxygen species (ROS) and reactive nitrogen species (RNS) are produced at the rejection site by different cell types including endothelial cells and macrophages. In particular, production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) seems to play an important role in promoting inflammation after exposure to inflammatory stimuli. In xenotransplantation, NO produced by iNOS upregulate multiple vasoactive substances, cytokines, chemokines, and growth factors, whereas production of NO by endothelial nitric oxide synthase (eNOS) could confer a protective effect to the graft. Accordingly, further research is needed to better understand the associated mechanisms in order to enhance protection and prevent tissue damage. Here, we describe simple methods to determine the redox state in serum that could be applied to animal models such as for xenotransplantation studies, as well as to clinical samples. Notably, caution should be taken when interpreting results of ROS and RNS measurements due to this dual role of free radicals in protecting and injuring the graft.

A single nucleotide deletion resulting in a frameshift in exon 4 of TAB2 is associated with a polyvalular syndrome.

OBJECTIVE: Polyvalvularmyxomatous degeneration is a rare clinical condition. A 51-year-old male patient presented at our centre with all four heart valves with myxomatous degeneration and severe mitral and aortic regurgitation due to leaflet prolapse. The patient referred five further family members with valvular heart disease at different stages of presentation. The aim of this study was to investigate the genetic basis of this familial polyvalvularmyxomatous degeneration which was associated with mild dysmorphic facial anomalies and short stature. DESIGN: A detailed family history was recorded. Nine members of the family, affected or not by valvular heart disease, were studied clinically, echocardiographically and by detailed genetic analyses. RESULTS: Six of the nine family members had echocardiographic features of different degrees of degenerative heart valve disease. In addition, the affected subjects shared similar mild dysmorphic facial anomalies and short stature. Exome sequencing identified a rare heterozygous single nucleotide deletion in the TAB2 gene in all affected family members, which was absent in the unaffected members. CONCLUSIONS: A variant in the TAB2 gene is proposed as the cause of syndromic congenital heart disease, displaying congenital myxomatous degenerative heart valve disease, mild dysmorphic fascial anomalies and short stature in this family.

Elicited and pre-existing anti-Neu5Gc antibodies differentially affect human endothelial cells transcriptome.

Humans cannot synthesize N-glycolylneuraminic acid (Neu5Gc) but dietary Neu5Gc can be absorbed and deposited on endothelial cells (ECs) and diet-induced anti-Neu5Gc antibodies (Abs) develop early in human life. While the interaction of Neu5Gc and diet-induced anti-Neu5Gc Abs occurs in all normal individuals, endothelium activation by elicited anti-Neu5Gc Abs following a challenge with animal-derived materials, such as following xenotransplantation, had been postulated. Ten primary human EC preparations were cultured with affinity-purified anti-Neu5Gc Abs from human sera obtained before or after exposure to Neu5Gc-glycosylated rabbit IgGs (elicited Abs). RNAs of each EC preparation stimulated in various conditions by purified Abs were exhaustively sequenced. EC transcriptomic patterns induced by elicited anti-Neu5Gc Abs, compared with pre-existing ones, were analyzed. qPCR, cytokines/chemokines release, and apoptosis were tested on some EC preparations. The data showed that anti-Neu5Gc Abs induced 967 differentially expressed (DE) genes. Most DE genes are shared following EC activation by pre-existing or anti-human T-cell globulin (ATG)-elicited anti-Neu5Gc Abs. Compared with pre-existing anti-Neu5Gc Abs, which are normal component of ECs environment, elicited anti-Neu5Gc Abs down-regulated 66 genes, including master genes of EC function. Furthermore, elicited anti-Neu5Gc Abs combined with complement-containing serum down-regulated most transcripts mobilized by serum alone. Both types of anti-Neu5Gc Abs-induced a dose- and complement-dependent release of selected cytokines and chemokines. Altogether, these data show that, compared with pre-existing anti-Neu5Gc Abs, ATG-elicited anti-Neu5Gc Abs specifically modulate genes related to cytokine responses, MAPkinase cascades, chemotaxis, and integrins and do not skew the EC transcriptome toward a pro-inflammatory profile in vitro.

Generation of cattle knockout for galactose-α1,3-galactose and N-glycolylneuraminic acid antigens.

Two well-characterized carbohydrate epitopes are absent in humans but present in other mammals. These are galactose-α1,3-galactose (αGal) and N-glycolylneuraminic acid (Neu5Gc) which are introduced by the activities of two enzymes including α(1,3) galactosyltransferase (encoded by the GGTA1 gene) and CMP-Neu5Gc hydroxylase (encoded by the CMAH gene) that are inactive in humans but present in cattle. Hence, bovine-derived products are antigenic in humans who receive bioprosthetic heart valves (BHVs) or those that suffer from red meat syndrome. Using programmable nucleases, we disrupted (knockout, KO) GGTA1 and CMAH genes encoding for the enzymes that catalyse the synthesis of αGal and Neu5Gc, respectively, in both male and female bovine fibroblasts. The KO in clonally selected fibroblasts was detected by polymerase chain reaction (PCR) and confirmed by Sanger sequencing. Selected fibroblasts colonies were used for somatic cell nuclear transfer (SCNT) to produce cloned embryos that were implanted in surrogate recipient heifers. Fifty-three embryos were implanted in 33 recipients heifers; 3 pregnancies were carried to term and delivered 3 live calves. Primary cell cultures were established from the 3 calves and following molecular analyses confirmed the genetic deletions. FACS analysis showed the double-KO phenotype for both antigens confirming the mutated genotypes. Availability of such cattle double-KO model lacking both αGal and Neu5Gc offers a unique opportunity to study the functionality of BHV manufactured with tissues of potentially lower immunogenicity, as well as a possible new clinical approaches to help patients with red meat allergy syndrome due to the presence of these xenoantigens in the diet.

Presentation Mode of Glycans Affect Recognition of Human Serum anti-Neu5Gc IgG Antibodies.

Recognition of carbohydrates by antibodies can be affected by antigen composition and density. This had been investigated in a variety of controllable multivalent systems using synthetic carbohydrate antigens, yet such effects on anticarbohydrate antibodies in circulating human serum have not been fully addressed thus far. All humans develop a polyclonal and diverse response against carbohydrates containing a nonhuman sialic acid form, N-glycolylneuraminic acid (Neu5Gc). This red meat-derived monosaccharide is incorporated into a diverse collection of human glycans resulting in circulating anti-Neu5Gc antibodies in human sera. Such antibodies can cause exacerbation of diseases mediated by chronic inflammation such as cancer and atherosclerosis. We aimed to evaluate how different presentation modes of Neu5Gc-glycans can affect the detection of anti-Neu5Gc IgGs in human serum. Here, we compare serum IgG recognition of Neu5Gc-containing glycoproteins, glycopeptides, and synthetic glycans. First, Neu5Gc-positive or Neu5Gc-deficient mouse strains were used to generate glycopeptides from serum glycoproteins. Then we developed a reproducible ELISA to screen human sera against Neu5Gc-positive glycopeptides for detection of human serum anti-Neu5Gc IgGs. Finally, we evaluated ELISA screens against glycopeptides in comparison with glycoproteins, as well as against elaborated arrays displaying synthetic Neu5Gc-glycans. Our results demonstrate that the presentation mode and diversity of Neu5Gc-glycans are critical for detection of the full collection of human serum anti-Neu5Gc IgGs.

The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: rationale and design of the BAMI trial.

Over the past 13 years bone marrow-derived mononuclear cells (BM-MNCs) have been widely investigated for clinical efficacy in patients following acute myocardial infarction (AMI). These early phase II trials have used various surrogate markers to judge efficacy and, although promising, the results have been inconsistent. The phase III BAMI trial has therefore been designed to demonstrate that intracoronary infusion of BM-MNCs is safe and will significantly reduce the time to first occurrence of all-cause death in patients with reduced left ventricular ejection fraction after successful reperfusion for ST-elevation AMI (powered with the aim of detecting a 25% reduction in all-cause mortality). This is a multinational, multicentre, randomized, open-label, controlled, parallel-group phase III study aiming to enrol approximately 3000 patients in 11 European countries with at least 17 sites. Eligible patients who have impaired left ventricular ejection (≤45%) following successful reperfusion for AMI will be randomized to treatment or control group in a 1:1 ratio. The treatment group will receive intracoronary infusion of BM-MNCs 2-8 days after successful reperfusion for AMI added on top of optimal standard of care. The control group will receive optimal standard of care. The primary endpoint is time from randomization to all-cause death. The BAMI trial is pivotal and the largest trial to date of BM-MNCs in patients with impaired left ventricular function following AMI. The aim of the trial is to provide a definitive answer as to whether BM-MNCs reduce all-cause mortality in this group of patients.

Response of the human myocardium to ischemic injury and preconditioning: The role of cardiac and comorbid conditions, medical treatment, and basal redox status.

BACKGROUND: The diseased human myocardium is highly susceptible to ischemia/reoxygenation (I/R)-induced injury but its response to protective interventions such as ischemic preconditioning (IPreC) is unclear. Cardiac and other pre-existing clinical conditions as well as previous or ongoing medical treatment may influence the myocardial response to I/R injury and protection. This study investigated the effect of both on myocardial susceptibility to I/R-induced injury and the protective effects of IPreC. METHODS AND RESULTS: Atrial myocardium from cardiac surgery patients (n = 300) was assigned to one of three groups: aerobic control, I/R alone, and IPreC. Lactate dehydrogenase leakage, as a marker of cell injury, and cell viability were measured. The basal redox status was determined in samples from 90 patients. The response to I/R varied widely. Myocardium from patients with aortic valve disease was the most susceptible to injury whereas myocardium from dyslipidemia patients was the least susceptible. Tissue from females was better protected than tissue from males. Myocardium from patients with mitral valve disease was the least responsive to IPreC. The basal redox status was altered in the myocardium from patients with mitral and aortic valve disease. CONCLUSIONS: The response of the myocardium to I/R and IPreC is highly variable and influenced by the underlying cardiac pathology, dyslipidemia, sex, and the basal redox status. These results should be taken into account in the design of future clinical studies on the prevention of I/R injury and protection.

Effect of bioprostheses anti-calcification treatment: comparative follow-up between Mitroflow LX and Magna pericardial xenografts using a propensity score-weighted analysis.

Objectives: The efficacy of anti-calcification treatment of bioprosthetic heart valves remains unclear. The aim of this study was to compare the clinical outcomes between Mitroflow LX valve, without anti-calcification treatment, and the Carpentier-Edwards Perimount Magna (P-Magna), with anti-calcification treatment. Methods: Between 2005 and 2012, 625 consecutive patients underwent aortic valve replacement either with a Mitroflow LX ( n = 329) or a P-Magna ( n = 296). Variables regarding patient-related risk factors and operative data were accounted for an inverse probability of treatment weighting analysis. Then, adjusted survival outcomes and the rate of structural valve disease (SVD) were assessed for each group. Results: Mean follow-up times were 4.1 ± 2.29 years and 3.9 ± 2.63 years, respectively ( P = 0.34). Adjusted overall survival rate was higher in the P-Magna group than in the Mitroflow LX group at 8 years (69.1% vs 51.9%, respectively) [HR = 1.44, 95% CI: 1.01 to 2.06; P = 0.0467]. Similarly, the 8-year cardiac-related survival rate was also higher in the P-Magna group [HR = 1.99, 95% CI: 1.19 to 3.32; P = 0.0083]. One patient (0.8%) with P-Magna and 23 patients (18.5%) with Mitroflow LX group developed SVD (0.24% per patient-year vs 4.5% per patient-year, respectively; P < 0.001). At 5 and 8 years, valve-related survival rates did not differ significantly between both groups [HR = 1.67, 95% CI: 0.95 to 2.95; P = 0.075]. Conclusions: The P-Magna prosthesis showed significantly better overall and cardiac-related survival than the Mitroflow LX. The higher early SVD and reoperation rates seen with the Mitroflow LX prosthesis did not impact negatively on valve-related survival.

Characterization of immunogenic Neu5Gc in bioprosthetic heart valves.

BACKGROUND: The two common sialic acids (Sias) in mammals are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated form N-glycolylneuraminic acid (Neu5Gc). Unlike most mammals, humans cannot synthesize Neu5Gc that is considered foreign and recognized by circulating antibodies. Thus, Neu5Gc is a potential xenogenic carbohydrate antigen in bioprosthetic heart valves (BHV) that tend to deteriorate in time within human patients. METHODS: We investigated Neu5Gc expression in non-engineered animal-derived cardiac tissues and in clinically used commercial BHV, and evaluated Neu5Gc immunogenicity on BHV through recognition by human anti-Neu5Gc IgG. RESULTS: Neu5Gc was detected by immunohistochemistry in porcine aortic valves and in porcine and bovine pericardium. Qualitative analysis of Sia linkages revealed Siaα2-3>Siaα2-6 on porcine/bovine pericardium while the opposite in porcine aortic/pulmonary valve cusps. Similarly, six commercial BHV containing either porcine aortic valve or porcine/bovine/equine pericardium revealed Siaα2-3>Siaα2-6 expression. Quantitative analysis of Sia by HPLC showed porcine/bovine pericardium express 4-fold higher Neu5Gc levels compared to the porcine aortic/pulmonary valves, with Neu5Ac at 6-fold over Neu5Gc. Likewise, Neu5Gc was expressed on commercial BHV (186.3±16.9 pmol Sia/µg protein), with Neu5Ac at 8-fold over Neu5Gc. Affinity-purified human anti-Neu5Gc IgG showing high specificity toward Neu5Gc-glycans (with no binding to Neu5Ac-glycans) on a glycan microarray, strongly bound to all tested commercial BHV, demonstrating Neu5Gc immune recognition in cardiac xenografts. CONCLUSIONS: We conclusively demonstrated Neu5Gc expression in native cardiac tissues, as well as in six commercial BHV. These Neu5Gc xeno-antigens were recognized by human anti-Neu5Gc IgG, supporting their immunogenicity. Altogether, these findings suggest BHV-Neu5Gc/anti-Neu5Gc may play a role in valve deterioration warranting further investigation.

Improving the Diagnosis of Infective Endocarditis in Prosthetic Valves and Intracardiac Devices With 18F-Fluordeoxyglucose Positron Emission Tomography/Computed Tomography Angiography: Initial Results at an Infective Endocarditis Referral Center.

BACKGROUND: The diagnosis of infective endocarditis (IE) in prosthetic valves and intracardiac devices is challenging because both the modified Duke criteria (DC) and echocardiography have limitations in this population. The added value of (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT) and (18)F-FDG PET/CT angiography (PET/CTA) was evaluated in this complex scenario at a referral center with a multidisciplinary IE unit. METHODS AND RESULTS: Ninety-two patients admitted to our hospital with suspected prosthetic valve or cardiac device IE between November 2012 and November 2014 were prospectively included. All patients underwent echocardiography and PET/CT, and 76 had cardiac CTA. PET/CT and echocardiography findings were evaluated and compared, with concordant results in 54% of cases (κ=0.23). Initial diagnoses with DC at admission, PET/CT, and DC+PET/CT were compared with the final diagnostic consensus reached by the IE Unit. DC+PET/CT enabled reclassification of 90% of cases initially classified as possible IE with DC and provided a conclusive diagnosis (definite/rejected) in 95% of cases. Sensitivity, specificity, and positive and negative predictive values were 52%, 94.7%, 92.9%, and 59.7% for DC; 87%, 92.1%, 93.6%, and 84.3% for PET/CT; and 90.7%, 89.5%, 92%, and 87.9% for DC+PET/CT. Use of PET/CTA yielded even better diagnostic performance values than PET/nonenhanced CT (91%, 90.6%, 92.8%, and 88.3% versus 86.4%, 87.5%, 90.2%, and 82.9%) and substantially reduced the rate of doubtful cases from 20% to 8% (P<0.001). DC+PET/CTA reclassified an additional 20% of cases classified as possible IE with DC+PET/nonenhanced CT. In addition, PET/CTA enabled detection of a significantly larger number of anatomic lesions associated with active endocarditis than PET/nonenhanced CT (P=0.006) or echocardiography (P<0.001). CONCLUSIONS: (18)F-FDG PET/CT improves the diagnostic accuracy of the modified DC in patients with suspected IE and prosthetic valves or cardiac devices. PET/CTA yielded the highest diagnostic performance and provided additional diagnostic benefits.

Aortic Arch Mycotic Aneurysm Due to Scedosporium Apiospermum Reconstructed With Homografts.

A 39-year-old female, active parenteral drug user was diagnosed of spondylodiscitis. A computed tomography (CT) scan showed an extensive aortic arch aneurysm. A positron emission tomography (PET)-CT scan, showing significant aortic wall uptake of the tracer through the whole aortic arch and the D8-D9 intervertebral disc, allowed us to suspect an aortitis despite negative blood cultures. The aneurysm was resected and reconstructed with 2 aortic homografts. Cultures of specimens from the aortic wall were positive to the fungi Scedosporium apiospermum. A new PET-CT scan 4 months after surgery showed absence of tracer uptake both at the homografts site and intervertebral disc.

Ischemic postconditioning of the isolated human myocardium: Role of the applied protocol.

BACKGROUND: Ischemic postconditioning (IPostC), has been proposed as a useful approach to reduce infarct size in all species, but its clinical utility remains unclear. OBJECTIVE: To investigate the role played by the protocol used on the efficacy of IPostC in protecting the diseased human myocardium. METHODS: Myocardial atrial samples from patients were subjected to a 90 min ischemia/120 min reoxygenation followed by different IPostC protocols to investigate the role of the time of ischemia (30, 60, 90 and 120 s) and the number of cycles (1, 2, 3 and 4) with 60 and 120 s of total ischemic time. Muscles were also subjected to ischemic preconditioning (IPreC). The release of lactate dehydrogenase (LDH) and the measurement of tetrazolium bromide (MTT) were determined. RESULTS: IPostC increased the LDH and decreased the MTT values from those of control, independently of the duration of the conditioning ischemia. LDH and MTT values also worsened by augmenting the number of IPostC cycles whereas they were significantly improved by IPreC. However, analysis of individual results indicated that in approximately 1/3 of the cases IPostC exhibited some degree of protection especially in the presence of increased ischemic injury. CONCLUSIONS: The present findings show that IPostC of the human myocardium may be influenced by the protocol used and also by the degree of the preceding ischemic injury. IPostC was beneficial in approximately 1/3 of the cases; however in the remaining cases it increased ischemic damage and, therefore, these results raise a word of caution on its broad clinical use.

Can simulation help to answer the demand for echocardiography education?

There has been a recent explosion of education and training in echocardiography in the specialties of anesthesiology and critical care. These devices, by their impact on clinical management, are changing the way surgery is performed and critical care is delivered. A number of international bodies have made recommendations for training and developed examinations and accreditations.The challenge to medical educators in this area is to deliver the training needed to achieve competence into already over-stretched curricula.The authors found an apparent increase in the use of simulators, with proven efficacy in improving technical skills and knowledge. There is still an absence of evidence on how it should be included in training programs and in the accreditation of certain levels.There is a conviction that this form of simulation can enhance and accelerate the understanding and practice of echocardiography by the anesthesiologist and intensivists, particularly at the beginning of the learning curve.

Differences in performance of five types of aortic valve prostheses: haemodynamic assessment by dobutamine stress echocardiography.

BACKGROUND: In patients being considered for aortic valve replacement, there remains controversy over which design or tissue offers the best performance. We aimed to evaluate in a single study the haemodynamic performances of five different widely used aortic valve prostheses: stentless porcine xenograft (Elan), stentless bovine pericardium (Pericarbon Freedom), stented porcine xenograft (Aspire), stented bovine pericardium (More) and mechanical (Ultracor). We also compared them with normal aortic valves and stenosed valves of variable severity. METHODS AND RESULTS: Preoperative echocardiography and dobutamine stress echocardiography at 1 year postoperatively were undertaken in 106 patients (n=18-24 from each group). Stentless bioprostheses, whether porcine or bovine, displayed superior haemodynamics across nearly all echocardiographic parameters: lower gradients, larger effective orifice area, higher dimensionless severity index (DSI) and lower resistance, when compared with stented or mechanical prostheses. Comparing both stented designs, bovine tissue performed the worst at rest, but with stress, there was no difference. The stress performances of the stentless bioprostheses were similar to the mildly stenosed native aortic valve, whereas the performances of the stented and mechanical prostheses resembled that of native valves with mild-to-moderate stenoses. Haemodynamic differences, however, did not translate into differences in left ventricular mass reduction at 1 year. CONCLUSIONS: Stentless bioprostheses displayed haemodynamics superior to stented or mechanical prostheses and had the closest performance to a normal, native aortic valve. Stress DSI data, least reliant on variable annulus/valve sizes and flow rates, provided the best haemodynamic discrimination.

Mitral valve restoration using the No-React(R) MitroFix™: a novel concept.

BACKGROUND: Mitral Valve Repair (MVRP) has been shown to be significantly superior to Mitral Valve Replacement (MVR). Since the majority of repairs involve the Posterior Mitral Leaflet (PML) and not the Anterior Mitral Leaflet (AML), the monocuspidalisation of the Mitral Valve (MV) can be achieved with a bio-posterior leaflet that imitates a closed PML. This approach may have the benefit of restoring the competence of the MV without reducing its effective orifice area. METHODS: We have used a new concept and device, the MitroFixTM, to correct MV regurgitation due to pathology of the PML. The device comes with functional sizers both of which have identical shape and size. This allows the surgeon to pre-test the success of the restoration. From December 2006 to October 2011, 51 MitroFixTM devices were implanted at three institutions. RESULTS: The mean age of the patients (32 males and 19 females) was 67.7 years. 37 of them were in NYHA class III or IV and all patients suffered from severe mitral valve regurgitation (MR). 31 patients underwent combined surgery. Successful implantation of the MitroFix™ device was performed in 51/53 patients.Mean cross-clamp time was 63.6 min (range: 29-118 min). Six patients had additional reconstructive procedures of the AML (chordae transfer, neo-chordae, triangular resection). At discharge, 33 patients showed no MR in the TTE and 17 patients exhibited trivial (I) or moderate (II) MR. The mean gradient was 4.0 mmHg and mean EOA was 2.52cm^2 (range: 1.5-4.0cm2). All patients were classified as being in NYHA class I or II. CONCLUSION: The MitroFixTM Mitral Valve Restoration Device is a new concept that offers an effective treatment of MR. The restoration of the mitral valve with the MitroFix™ device offers the advantage of preserving the AML and providing good coaptation with a prosthetic PML. Importantly, this preliminary evaluation indicates a mean effective orifice area ( EOA ) of 2.5cm2 in MV receiving a MitroFix™ device, witch is higher than EOA resulting from MVR or MVRP. The present study has also shown that severe regurgitation due to ischemic/rheumatic MR, endocarditis and complex prolapse of the PML are clear candidates for correction with the MitroFix™. Larger studies and a longer follow up period are needed to validate these promising results.