Apoptotic Cell Death in Bicuspid-Aortic-Valve-Associated Aortopathy.

The bicuspid aortic valve (BAV) is the most common cardiovascular congenital abnormality and is frequently associated with proximal aortopathy. We analyzed the tissues of patients with bicuspid and tricuspid aortic valve (TAV) regarding the protein expression of the receptor for advanced glycation products (RAGE) and its ligands, the advanced glycation end products (AGE), as well as the S100 calcium-binding protein A6 (S100A6). Since S100A6 overexpression attenuates cardiomyocyte apoptosis, we investigated the diverse pathways of apoptosis and autophagic cell death in the human ascending aortic specimen of 57 and 49 patients with BAV and TAV morphology, respectively, to identify differences and explanations for the higher risk of patients with BAV for severe cardiovascular diseases. We found significantly increased levels of RAGE, AGE and S100A6 in the aortic tissue of bicuspid patients which may promote apoptosis via the upregulation of caspase-3 activity. Although increased caspase-3 activity was not detected in BAV patients, increased protein expression of the 48 kDa fragment of vimentin was detected. mTOR as a downstream protein of Akt was significantly higher in patients with BAV, whereas Bcl-2 was increased in patients with TAV, assuming a better protection against apoptosis. The autophagy-related proteins p62 and ERK1/2 were increased in patients with BAV, assuming that cells in bicuspid tissue are more likely to undergo apoptotic cell death leading to changes in the wall and finally to aortopathies. We provide first-hand evidence of increased apoptotic cell death in the aortic tissue of BAV patients which may thus provide an explanation for the increased risk of structural aortic wall deficiency possibly underlying aortic aneurysm formation or acute dissection.

Durability and clinical experience using a bovine pericardial prosthetic aortic valve.

OBJECTIVES: To report the implant experience and long-term outcomes from a large tertiary care referral center on surgical aortic valve replacement (SAVR) with a contemporary stented pericardial bioprosthesis with anticalcification treatment. METHODS: Patients underwent SAVR using the Trifecta valve at a single institution. Endpoints included procedural outcomes, adverse events, prosthesis-patient mismatch (PPM), long-term survival, and valve durability. Follow-up included 30-day, 6-month, and annual assessments. Treatment for structural valve deterioration (SVD) included surgical explant and valve-in-valve (V-in-V) transcatheter aortic valve implantation (TAVI). RESULTS: SAVR was performed in 1241 patients (median age, 73.5 ± 6.4 years; 54% male; median logistic EuroSCORE, 7.8) with concomitant procedures in 713 cases (57.5%). Intraprocedural mortality was 1.4%, and 30-day mortality was 6.0%. At hospital discharge, 68 patients (5.5%) had moderate PPM, and no patients had severe PPM. Adverse events included cardiac arrhythmias (44.7%, mostly atrial fibrillation), respiratory failure (22.9%), acute renal failure requiring temporary renal replacement therapy (12.9%), and low cardiac output syndrome (3.3%). Follow-up data were available over a total of 5469 patient-years (median duration of follow-up, 4.7 years). Freedom at 8 years from all-cause mortality, valve-related mortality, reoperation for SVD (redo SAVR or V-in-V TAVI), and endocarditis were 78.4%, 98.0%, 93.3%, and 96.5%, respectively. Of the 30 patients with SVD, 17 were treated by V-in-V TAVI and 13 underwent surgical explant. CONCLUSIONS: Outcomes from this large single-center cohort at increased surgical risk demonstrate excellent long-term durability of the Trifecta valve for SAVR and feasibility of treating SVD by V-in-V TAVI.

Target Enzyme Activity and Phosphorylation of Pathway Molecules As Specific Biomarkers in Transplantation.

Therapeutic drug monitoring of immunosuppressants in the clinic is based on the measurement of blood concentration (pharmacokinetics). However, pharmacokinetic monitoring of immunosuppressants does not allow prediction of individual differences in pharmacological effects on immune cells. Pharmacodynamic (PD) monitoring via direct determination of target enzyme activity and phosphorylation of pathway molecules may enhance therapeutic drug monitoring and allow prediction of individual responses to immunosuppressants. This review discusses the clinical relevance of monitoring the activity of inosine-5'-monophosphate dehydrogenase (IMPDH), the target enzyme of mycophenolic acid, and of the phosphorylation of mechanistic target of rapamycin (mTOR) molecules. Significant progress regarding a robust and practicable assay for the determination of IMPDH activity as a specific PD parameter of mycophenolic acid activity has been achieved. The development of a rapid and reliable IMPDH assay system suitable for use in clinical practice was an important step that allowed thorough pharmacokinetics-PD investigations in large numbers of mycophenolic acid-treated patients. A reproducible and validated IMPDH assay was used in a few clinical trials by different research groups and is based on the chromatographic determination of newly generated xanthine monophosphate in mononuclear cell lysates. This assay requires only small volumes of blood and can be reliably used in multicenter trials; however, more clinical data from larger cohorts are needed to determine its clinical utility. Regarding monitoring of mTOR inhibitors (mTORis), the results of the first study that provided data on measurement of mTOR pathway molecules [p70 ribosomal protein S6 kinase (p70S6 kinase) and phosphorylated ribosomal protein S6] suggest that they are suitable targets for individualized PD monitoring of sirolimus and everolimus after organ transplantation. At present, only the phospho-flow phosphorylated ribosomal protein S6 assay has been validated in vitro and evaluated for confounding factors in vivo. The reported specific biomarkers for IMPDH activity and phosphorylation of mTOR molecules must be validated in clinical settings and multicenter studies to prove their clinical validity.