Atorvastatin modulates matrix metalloproteinase expression, activity, and signaling in abdominal aortic aneurysms.

Statins may reduce abdominal aortic aneurysm (AAA) progression. We sought to measure how atorvastatin (AT) treatment might modulate matrix metalloproteinase (MMP) expression and/or activity in human AAA. Tissue from human AAAs at surgical repair was obtained from patients who were either not on statins (NST, n = 19) or treated with AT (n = 19). Immunoblots measured expression and zymography measured activity. Expression of most proteins was greater in the central compared with distal AAA region. Matrix metalloproteinase 1, MMP2, MMP3, MMP9, Tissue Inhibitor of Metalloproteinase (TIMP2), TIMP3, TIMP4, or total Sma Mothers Against Decapentaplegia (SMAD2) expression did not differ with treatment. There was a trend toward reduced MMP8 and TIMP1 expression and MMP2 zymographic activity in the AT-treatment group. In contrast, AT-treated samples had significantly reduced MMP13 (P = .02), latent-transforming growth factor (TGF)-beta (P = .02), and phospho-SMAD2 (P = .029) expression than NST-treated samples. We conclude that the AT-mediated decrease in MMP expression and activity reduces TGF-beta signaling in the central region of human AAAs.

Atorvastatin mediates increases in intralesional BAX and BAK expression in human end-stage abdominal aortic aneurysms.

Chronic apoptosis activation may participate in abdominal aortic aneurysm (AAA) expansion. Statin treatment slows AAA progression independent of cholesterol lowering. We hypothesized that Atorvastatin treatment alters apoptosis protein expression and activation in AAAs. Protein was isolated from the central and distal portions of end-stage human AAA tissue obtained during surgical repair from non-statin (NST) and Atorvastatin-treated (AT) patients. Expression was compared using immunoblots. Bcl-2 expression was unchanged but Bak (4-fold, p < 0.013) and Bax (3-fold, p < 0.035) expression was increased in AT (n = 12) versus NST (n = 15) patients. No cytochrome c release or caspase 3 activation was detected and Clusterin, GRP78, and BNIP1 expression was similar in NST and AT samples. Bcl-2 and Bax cDNA sequences from AAA tissue (n = 10) and the general population were identical. Thus, the increase in Bax and Bak in AT-treated AAAs did not activate the mitochondria or endoplasmic reticulum mediated apoptosis pathways. Bcl-2, Bax, and Bak have non-apoptosis related functions that include maintenance of endoplasmic reticulum (ER), homeostasis, and adaptation to stress. We speculate that Atorvastatin-mediated increases in Bax and Bak may positively affect their non-apoptosis related cell functions to account for the beneficial effect of statins to slow AAA expansion.

BAK1 gene variation and abdominal aortic aneurysms.

We sought to examine the role of genetics in the multifactorial disease, abdominal aortic aneurysm (AAA), by studying sequence variation in the BAK1 gene (BAK1) that codes for an apoptotic-promoting protein, as chronic apoptosis activation has been linked to AAA development and progression. BAK1 abdominal aorta cDNA from AAA patients and nondiseased individuals were compared with each other, as well as to the BAK1 genomic sequence obtained from matching blood samples. We found specific BAK1 single nucleotide polymorphism (SNP) containing alleles in both aneurysmic (31 cases) and healthy aortic tissue (5 cases) without seeing them in the matching blood samples. These same BAK1 SNPs have been reported, although rarely (average frequency <0.06%), in reference BAK1 DNA sequences. Based on this and other similar observations, we propose a novel hypothesis postulating that multiple variants of genes may preexist in "minority" forms within specific nondiseased tissues and be selected for, when intra- and/or extracellular conditions change. Therefore, the fact that different BAK1 variants can exist in both diseased and nondiseased AA tissues compared to matching blood samples, together with the rare occurrence of these same SNPs in reference sequences, suggests that selection may be a significant factor in AAA ontogeny.

Ten-year surgical experience with nontraumatic pericardial effusions: a comparison between the subxyphoid and transthoracic approaches to pericardial window.

HYPOTHESIS: The approach to pericardial window in patients with nontraumatic pericardial effusion impacts outcome. DESIGN: Retrospective review and comparison of all cases of pericardial window performed over 10 years. Follow-up was to patient death. SETTING: Three hospitals performing cardiothoracic surgery at a single university. PATIENTS: All patients in whom pericardial window was performed for nontraumatic pericardial effusion. MAIN OUTCOME MEASURES: Outcomes associated with the subxyphoid approach to pericardial window were compared with those associated with the transthoracic approach. The primary outcome was postsurgical recurrence of pericardial effusion. Secondary outcomes included operative time, intraoperative and postoperative complications, in-hospital mortality, hospital and intensive care unit lengths of stay, and days between surgery and death. RESULTS: Over 10 years, there were 342 patients with procedural codes for pericardial window in the medical record databases of 3 hospitals performing cardiothoracic surgery at 1 university center. One hundred fifty-one patients were excluded because the operation was performed for trauma, postoperative tamponade, or pericardial biopsy without effusion. The results are, therefore, based on the remaining 191 procedures. The subxyphoid approach was used in 78 patients, and the transthoracic approach in 113 patients. Patients were well matched for age (P = .31), sex (P = .05), preoperative tamponade (P = .08), and comorbidities (P > .05). No differences were observed between the 2 approaches in terms of recurrence of effusion, operative time, overall intraoperative or postoperative complications, and hospital or intensive care unit lengths of stay. In-hospital mortality was significantly greater in the subxyphoid group (27 of 78 vs 18 of 113 patients; P = .003). CONCLUSIONS: Over 10 years, there were 191 pericardial windows performed for nontraumatic pericardial effusions. The subxyphoid and transthoracic approaches were well tolerated by patients, required short operative times, and resulted in similar rates of overall postoperative complications and intensive care unit and hospital lengths of stay. Recurrence rates were low with both procedures.