Humoral immune responses during heart transplantation may result in antibody-mediated rejection (AMR), which is now taken into account on endomyocardial biopsy (EMB) specimens and ranked according to ...the pathologic AMR (pAMR) grades of the International Society for Heart and Lung Transplantation classification. This classification might benefit from new immunohistological markers and validation by others biomarkers, namely donor-specific antibodies (DSA).
From the 293 protocol EMBs performed in 113 patients in our institution during a 1-year period for this prospective study, 280 EMB specimens were available with both histology and immunohistochemistry. C4d and labeling of intravascular cells by cluster of differentiation (CD) 68 were performed on paraffin sections. Available sera (n = 150) concomitant of EMB specimens were tested for the presence of DSA. All of the pAMR+ EMB specimens, along with a set of randomized pAMR0 EMB specimens, were immunolabeled for mammalian target of rapamycin (mTOR) effectors, phosphorylated 70 S6-kinase (p70S6K) and phosphorylated S6 ribosomal protein (pS6RP).
AMR was diagnosed in 37 EMB specimens (13.2%): 1 pAMR1(I+), 27 pAMR1(H+), and 9 pAMR2. The proportion of DSA-positive EMB varied according to the pAMR grade, with pAMR0, pAMR1(H+), and pAMR2 EMB presenting 17.6%, 77.3%, and 100% of DSA-positivity, respectively. Among the 30 pAMR+ specimens with available DSA testing and the 30 pAMR0 randomized specimens, mTOR pathway immunohistochemistry showed endothelial cell positivity for p70S6K in 17 pAMR+ EMB specimens (56.7%) and in 1 pAMR0 EMB specimen (3.3%). pS6RP was detected in 8 pAMR+ EMB specimens (26.7%) and in 1 pAMR0 EMB specimen (3.3%).
p70S6K and pS6RP immunohistochemistry afford new markers of AMR on EMB specimens because their expression is correlated with microcirculation inflammation and DSA. The correlation of DSA with pAMR grade suggests that this grading system is valid.
Objective To describe differences in intra- and postoperative care between general (GA) and local/regional anesthesia (LRA) in consecutive high-risk patients with aortic stenosis who underwent ...transfemoral transcatheter aortic valve implantation (TAVI). Design A retrospective review of data collected in an institutional registry. Setting An academic hospital. Participants One hundred twenty-five consecutive patients with severe aortic stenosis who underwent transfemoral TAVI. Interventions GA versus LRA followed by postoperative care. Complications were defined by pre-established criteria. Material and Methods Consecutive patients referred for transfemoral TAVI between October 2006 and October 2010 initially underwent GA (n = 91) followed by LRA after March 2010 (n= 34). Results are presented as mean ± standard deviation or median (25-75 percentiles) as appropriate. GA and LRA TAVI patients had similar preoperative characteristics. LRA was associated with a significantly shorter procedure duration (LRA: 80 67-102; GA: 120 90-140 minutes; p < 0.001), hospital stay (LRA: 8.5 7-14.5; GA: 15.5 10-24 days; p < 0.001), intraoperative requirements of catecholamines (LRA 23%; GA: 90% of patients; p < 0.001), and volume expansion (LRA: 11 8-16; GA: 22 15-36 mL/kg; p < 0.001). There were significant differences in delta creatinine (day 1, preoperative creatinine values; LRA: 0 −12 to 9; GA: −15 (−25 to 2.9) μmol, p < 0.004). The frequency of any postoperative complications was 38% (LRA) and 77% (GA) ( p = 0.11). Thirty-day mortality was 7% (GA) and 9% (LRA) ( p = 0.9). Conclusions This observational study suggests that LRA was associated with less intraoperative hemodynamic instability and significant shortening of the procedure and hospital stay. Changes in the anesthetic technique adapted to changes in TAVI interventional techniques and did not increase the rate of postoperative complications.
Lipoprotein(a) (Lpa) is the preferential lipoprotein carrier of oxidized phospholipids (OxPLs) and a well-established genetic risk factor for calcific aortic valve stenosis (CAVS). Whether Lp(a) ...predicts aortic valve microcalcification in individuals without CAVS is unknown. Our objective was to estimate the prevalence of elevated Lp(a) and OxPL levels in patients with CAVS and to determine if individuals with elevated Lp(a) but without CAVS have higher aortic valve microcalcification.
We recruited 214 patients with CAVS from Montreal and 174 patients with CAVS and 108 controls from Québec City, Canada. In a second group of individuals with high (≥75 nmol/L, n = 27) or low (<75 nmol/L, n = 28) Lp(a) levels, 18F-sodium fluoride positron emission tomography/computed tomography was performed to determine the difference in mean tissue-to-background ratio (TBR) of the aortic valve.
Patients with CAVS had 62.0% higher Lp(a) (median = 28.7, interquartile range 8.2-116.6 vs 10.9 3.6-28.8 nmol/L,
0.0001), 50% higher OxPL-apolipoprotein-B (2.2 1.3-6.0 vs 1.1 0.7-2.6 nmol/L,
0.0001), and 69.9% higher OxPL-apolipoprotein(a) (7.3 1.8-28.4 vs 2.2 0.8-8.4 nmol/L,
0.0001) levels compared with individuals without CAVS (all
0.0001). Individuals without CAVS but elevated Lp(a) had 40% higher mean TBR compared with individuals with low Lp(a) levels (mean TBR = 1.25 ± 0.23 vs 1.15 ± 0.11,
= 0.02).
Elevated Lp(a) and OxPL levels are associated with prevalent CAVS in patients studied in an echocardiography laboratory setting. In individuals with elevated Lp(a), evidence of aortic valve microcalcification by 18F-sodium fluoride positron emission tomography/computed tomography is present before the development of clinically manifested CAVS.
To analyze the cumulated incidence of glaucoma after penetrating keratoplasty (PK), anterior lamellar keratoplasty (ALK), and endothelial keratoplasty (EK).
Cohort study. Data were recorded ...prospectively and analyzed retrospectively.
A total of 1657 consecutive eyes of 1657 patients undergoing corneal transplantation between 1992 and 2013.
Penetrating keratoplasty (date range, 1992-2013), ALK (date range, 2002-2013), and Descemet's stripping automated EK (date range, 2006-2013).
Postoperative intraocular pressure (IOP), glaucoma treatments, and glaucoma-related loss of vision (loss of central visual function resulting in absence of light perception or light perception limited to the temporal visual field). Cox proportional hazard regression model was used to analyze risk factors for glaucoma after keratoplasty.
The 10-year cumulated incidence of elevated IOP and elevated IOP requiring treatment was 46.5% and 38.7%, respectively. In multivariate analysis, 4 variables were significantly associated with a higher incidence of elevated IOP requiring treatment after keratoplasty: preoperative glaucoma or IOP >20 mmHg (adjusted hazard ratio HR, 1.56; P < 0.001), penetrating keratoplasty (PK) (adjusted HR, 1.12 vs. ALK and 1.10 vs. EK; P < 0.001), postoperative lens status (adjusted HR vs. phakic eyes: 1.15 for posterior chamber intraocular lens, 1.43 for anterior chamber intraocular lens IOL, 2.83 for aphakic eyes; P < 0.001), and IOL exchange or removal during surgery (adjusted HR, 1.48; P < 0.001). Recipient age, preoperative diagnosis, filtering surgery before keratoplasty, vitrectomy associated with keratoplasty, and filtering surgery associated with keratoplasty were significantly associated with a higher incidence of elevated IOP requiring treatment after keratoplasty in univariate analysis but not in multivariate analysis. The 10-year probability of loss of vision related to glaucoma was 1.0% after EK, 2.1% after ALK, and 3.6% after PK (P = 0.036).
The incidence of elevation of IOP after keratoplasty and development of glaucoma are significantly decreased with ALK and EK compared with PK. We believe this is due to diminished surgery-induced damage to the anterior chamber angle and trabecular meshwork, and reduced postoperative use of steroids.
Background Treatment of anastomotic fistulas after bariatric surgery is difficult, and they are often associated with additional surgery, sepsis, and prolonged non-oral feeding. Objective To assess a ...new, totally endoscopic strategy to manage anastomotic fistulas. Design Prospective study. Setting Tertiary-care university hospital. Patients This study involved 27 consecutive patients from July 2007 to December 2009. Intervention This strategy involved successive procedures for endoscopic drainage of the residual cavity, diversion of the fistula with a stent, and then closure of the residual orifice with surgical clips or sealant. Main Outcome Measurements Technical success, mortality and morbidity, migration of the stent. Results Multiple or complex fistulas were present in 16 cases (59%). Endoscopic drainage (nasal-fistula drain or necrosectomy) was used in 19 cases (70%). Diversion by a covered colorectal stent was used in 22 patients (81%). To close the residual or initial opening, wound clips and glue (cyanoacrylate) were used in 15 cases (55%). Neither mortality nor severe morbidity occurred. Migration of the stent occurred in 13 cases (59%) and was treated by replacement with either a longer stent or with 2 nested stents. The mean time until resolution of fistula was 86 days from the start of endoscopic management, with a mean of 4.4 endoscopies per patient. Limitations Moderate sample size, nonrandomized study. Conclusion An entirely endoscopic approach to the management of anastomosing fistulas that develop after bariatric surgery—using sequential drainage, sutures, and diversion by stents—achieved resolution of the fistulas with minimal morbidity.
Objectives This study sought to identify the clinical and metabolic determinants of bioprosthetic valve degeneration. Background Structural valve degeneration (SVD) is the major cause of ...bioprosthetic valve failure. Recent retrospective studies have reported an association between atherosclerotic risk factors and development of SVD. Methods A total of 203 consecutive patients with aortic bioprosthetic valves were recruited. Doppler echocardiography and multidetector computed tomography (CT) examinations were performed for assessment of bioprosthesis calcification and abdominal adiposity. A cardiometabolic risk profile was also obtained. SVD was defined as an increase in mean transprosthetic gradient of ≥10 mm Hg and/or a worsening of transprosthetic regurgitation ≥1/3 class between 1-year post-operative echo and last follow-up echo (mean follow-up time was 8 ± 3 years). Results Forty-two patients (20%) were identified as developing SVD. Patients with SVD had significantly higher plasma total-cholesterol (4.6 ± 1.1 mmol/l vs. 4.1 ± 0.9 mmol/l, p = 0.05), low-density lipoprotein-cholesterol (2.5 ± 1.0 mmol/l vs. 2.2 ± 0.7 mmol/l, p = 0.02), and apolipoprotein B (ApoB) levels (0.71 ± 0.22 g/l vs. 0.64 ± 0.17 g/l, p = 0.02) and higher ApoB/ApoA-I ratios (0.48 ± 0.17 vs. 0.41 ± 0.11, p = 0.004) than those with no SVD. Multivariate analysis revealed that increased ApoB/ApoA-I ratio (odds ratio OR: 1.41, 95% confidence interval CI: 1.10 to 1.82 per 0.1 increment; p = 0.007) and the use of bisphosphonates (OR: 3.57, 95% CI: 1.14 to 10.80 p = 0.02) were the strongest independent predictors of SVD. Conclusions This is the first study to report a strong association between increased ApoB/ApoA-I ratio and the risk of developing SVD among patients with aortic bioprosthetic valves. Further studies are needed to determine if an elevated ApoB/ApoA-I ratio, which reflects the balance of proatherogenic and antiatherogenic lipoproteins, is a risk marker or a risk factor for SVD.
To assess the potential therapeutic effect of intratendinous injection of platelet-rich plasma (PRP) under ultrasound (US) guidance to treat tendon tears and tendinosis in a pilot study with ...long-term follow-up.
The study included 408 consecutive patients referred for treatment by PRP injection of tendinopathy in the upper (medial and lateral epicondylar tendons) and the lower (patellar, Achilles, hamstring and adductor longus, and peroneal tendons) limb who received a single intratendinous injection of PRP under US guidance. Clinical and US data were retrospectively collected for each anatomic compartment for upper and lower limbs before treatment (baseline) and 6 weeks after treatment. Late clinical data without US were collected until 32 months after the procedure (mean, 20.2 months). The McNemar test and regression model were used to compare clinical and US data.
QuickDASH score, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and residual US size of lesions were significantly lower after intratendinous injection of PRP under US guidance at 6 weeks and during long-term follow-up compared with baseline (P < .001 in upper and lower limb) independent of age, gender, and type of tendinopathy (P > .29). No clinical complication was reported during follow-up.
Intratendinous injection of PRP under US guidance appears to allow rapid tendon healing and is well tolerated.
Summary Background Interim results from the children with HIV early antiretroviral (CHER) trial showed that early antiretroviral therapy (ART) was life-saving for infants infected with HIV. In view ...of the few treatment options and the potential toxicity associated with lifelong ART, in the CHER trial we compared early time-limited ART with deferred ART. Methods CHER was an open-label randomised controlled trial of HIV-infected asymptomatic infants younger than 12 weeks in two South African trial sites with a percentage of CD4-positive T lymphocytes (CD4%) of 25% or higher. 377 infants were randomly allocated to one of three groups: deferred ART (ART-Def), immediate ART for 40 weeks (ART-40W), or immediate ART for 96 weeks (ART-96W), with subsequent treatment interruption. The randomisation schedule was stratified by clinical site with permuted blocks of random sizes to balance the numbers of infants allocated to each group. Criteria for ART initiation in the ART-Def group and re-initiation after interruption in the other groups were CD4% less than 25% in infancy; otherwise, the criteria were CD4% less than 20% or Centers for Disease Control and Prevention severe stage B or stage C disease. Combination therapy of lopinavir–ritonavir, zidovudine, and lamivudine was the first-line treatment regimen at ART initiation and re-initiation. The primary endpoint was time to failure of first-line ART (immunological, clinical, or virological) or death. Comparisons were done by intention-to-treat analysis, with use of time-to-event methods. This trial is registered with ClinicalTrials.gov , number NCT00102960. Findings 377 infants were enrolled, with a median age of 7·4 weeks, CD4% of 35%, and HIV RNA log 5·7 copies per mL. Median follow-up was 4·8 years; 34 infants (9%) were lost to follow-up. Median time to ART initiation in the ART-Def group was 20 weeks (IQR 16–25). Time to restarting of ART after interruption was 33 weeks (26–45) in ART-40W and 70 weeks (35–109) in ART-96W; at the end of the trial, 19% of patients in ART-40W and 32% of patients in ART-96W remained off ART. Proportions of follow-up time spent on ART were 81% in the ART-Def group, 70% in the ART-40W group, and 69% in the ART-96W group. 48 (38%) of 125 children in the ART-Def group, 32 (25%) of 126 in the ART-40W group, and 26 (21%) of 126 in the ART-96W group reached the primary endpoint. The hazard ratio, relative to ART-Def, was 0·59 (95% CI 0·38–0·93, p=0·02) for ART-40W and 0·47 (0·27–0·76, p=0·002) for ART-96W. Three children in ART-Def, three in ART-40W, and one in ART-96W switched to second-line ART. Interpretation Early time-limited ART had better clinical and immunological outcomes than deferred ART, with no evidence of excess disease progression during subsequent treatment interruption and less overall ART exposure than deferred ART. Longer time on primary ART permits longer subsequent interruption, with marginally better outcomes. Funding US National Institutes of Health.
Restrictive Annuloplasty for Ischemic Mitral Regurgitation May Induce Functional Mitral Stenosis Julien Magne, Mario Sénéchal, Patrick Mathieu, Jean G. Dumesnil, François Dagenais, Philippe Pibarot ...We performed a resting and dobutamine stress echocardiography and a 6-minute walk test (6MWT) in 24 patients with ischemic mitral regurgitation (MR) after restrictive mitral valve annuloplasty (MVA) and coronary artery bypass graft in 20 control patients. Compared with control patients, MVA patients had higher transmitral pressure gradients, which were associated with higher pulmonary arterial pressure and reduced 6MWT distance. The results show that performing a restrictive MVA in patients with ischemic MR may create a functional mitral stenosis that may in turn impair functional capacity.
Abstract Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, and dyslipidemia constitutes a major risk factor for CVD and premature atherosclerosis. ...Therapies to reduce the plasma levels of atherogenic lipoproteins are well established interventions that decrease CVD risk. However, treatment of dyslipidemia with the most widely used lipid-lowering drugs (ie, statins and ezetimibe) often fails to protect a significant proportion of patients from cardiovascular risk. The development of several novel therapies to treat lipid-related disorders and their associated risks is ongoing and includes the following: (1) reducing plasma levels of atherogenic lipoproteins using proprotein convertase subtilisin/kexin type 9 inhibitors, antisense inhibitors of Apolipoprotein (Apo)(a), microsomal triglyceride transfer protein inhibitors, antisense oligonucleotides of ApoB for inhibiting very low-density lipoprotein production, and inhibitors of angiopoietin-like protein 3 or ApoC-III for triglyceride-rich lipoprotein management upstream of low-density lipoprotein production as well as gene replacement therapy to improve low-density lipoprotein and triglyceride-rich lipoprotein clearance; and (2) emerging therapies that target high-density lipoprotein (HDL) and reverse cholesterol transport using cholesteryl ester transfer protein inhibitors, HDL peptide mimetics, and autologous infusion of pre-β HDLs. Clinical trials of several of these emerging therapies are currently being conducted. Despite the potential efficacy of these new therapies in CVD prevention, their costs might limit their use because of limited reimbursement funds. Therefore, the real challenge facing the next generation of lipid-lowering agents will most likely be accessibility, reflecting a new paradigm that applies to almost all emerging therapies for any disease in the era of precision medicine.
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