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Abstract Background The objective was to evaluate the long-term outcomes of the St Jude Medical (Saint Paul, Minn) mechanical valve prosthesis implantation. Methods Since 1979, every patient receiving this prosthesis has been followed annually. Results From January 1979 to December 2014, 1023 patients were accrued. Patients' ages ranged from 18 to 85 years. Aortic valve replacement was performed in 584 patients, and mitral valve replacement was performed in 439 patients. Follow-up was 95% complete. Operative mortality was 3% (17/584, aortic valve replacement) and 4% (18/439, mitral valve replacement). In patients undergoing aortic valve replacement, late actuarial survival was 62% ± 2%, 32% ± 2%, and 14% ± 3% at 10, 20, and 30 years, respectively. Thirty-year freedom from reoperation, thromboembolism, valve thrombosis, bleeding, and endocarditis was 92% ± 2%, 79% ± 3%, 96% ± 1%, 56% ± 5%, and 92% ± 2%, respectively. In patients undergoing mitral valve replacement, late actuarial survival was 64% ± 3%, 28% ± 3%, and 14% ± 3% at 10, 20, and 30 years, respectively. Thirty-year freedom from reoperation, thromboembolism, valve thrombosis, bleeding, and endocarditis was 85% ± 5%, 55% ± 6%, 99% ± 1%, 57% ± 6%, and 95% ± 2%, respectively. The incidence of bleeding was 2.5% and 2.0% per patient-year for aortic valve replacement and mitral valve replacement, respectively. The incidence of thromboembolism was 1.6% and 2.9% per patient-year for aortic valve replacement and mitral valve replacement, respectively. Conclusions Annual follow-up of all of our patients receiving a St Jude Medical mechanical valves prosthesis has allowed better identification valve-related issues and events. After 3 decades of observation with close follow-up, the St Jude Medical mechanical valve continues to be a reliable prosthesis. [ABSTRACT FROM AUTHOR]

Objective Membrane type-1 matrix metalloproteinase (MT1-MMP) is elevated during thoracic aortic aneurysm (TAA) development in mouse models, and plays an important role in the activation of matrix metalloproteinase (MMP)-2 and the release of matrix- bound transforming growth factor-β. In this study, we tested the hypothesis that MT1-MMP is subject to protein kinase C (PKC)–mediated regulation, which alters intracellular trafficking and activity with TAAs. Methods Levels of MMP-2, native and phosphorylated MT1-MMP, and PKC-δ were measured in aortic tissue from patients with small TAAs (<5 cm; n = 8) and large TAAs (>6.5 cm; n = 8), and compared with values measured in normal controls (n = 8). Cellular localization of green fluorescent protein (GFP)-tagged MT1-MMP was assessed in aortic fibroblasts isolated from control and 4-week TAA mice. The effects of PKC-mediated phosphorylation on MT1-MMP cellular localization and function (active MMP-2 vs phospo-Smad2 abundance) were assessed after treatment with a PKC activator (phorbol-12-myristate-13-acetate [PMA], 100 nM) with and without a PKC-δ–specific inhibitor (röttlerin, 3 μM). Results Compared with controls, MT1-MMP abundance was increased in aortas from both TAA groups. Active MMP-2 was increased only in the large TAA group. The abundances of phosphorylated MT1-MMP and activated PKC-δ were enhanced in the small TAA group compared with the large TAA group. MT1-MMP was localized on the plasma membrane in aortic fibroblasts from control mice and in endosomes from TAA mice. Treatment with PMA induced MT1-MMP-GFP internalization, enhanced phospho-Smad2, and reduced MMP-2 activation, whereas röttlerin pretreatment inhibited these effects. Conclusions Phosphorylation of MT1-MMP mediates its activity through directing cellular localization, shifting its role from MMP-2 activation to intracellular signaling. Thus, targeted inhibition of MT1-MMP may have therapeutic relevance as an approach to attenuating TAA development. [ABSTRACT FROM AUTHOR]

Objective: Valve sparing root replacement (VSRR) is an attractive option for the management of aortic root aneurysms with a normal native aortic valve. Therefore, we reviewed our experience with a modification of the David V VSRR and compared it with stented pericardial bioprosthetic valve conduit (BVC) root replacement in an age-matched cohort of older patients. Methods: A total of 48 VSRRs were performed at our institution, excluding those on bicuspid aortic valves. We compared these cases with 15 aortic root replacements performed using a BVC during the same period. Subgroup analysis was performed comparing 16 VSRR cases and 15 age-matched BVC cases. Results: The greatest disparity between the VSRR and BVC groups was age (53 vs 69 years, respectively; P < .0005). The matched patients were similar in terms of baseline demographics and differed only in concomitant coronary artery bypass grafting (2 VSRR vs 7 BVC patients; P = .036). None of the VSRR and 3 of the BVC procedures were performed for associated dissection (P = .101). Postoperative aortic insufficiency grade was significantly different between the 2 groups (P = .004). The cardiopulmonary bypass, crossclamp, and circulatory arrest times were not different between the VSRR and BVC groups (174 vs 187 minutes, P = .205; 128 vs 133 minutes, P = .376; and 10 vs 13 minutes, respectively; P = .175). No differences were found between the 2 groups with respect to postoperative complications. One postoperative death occurred in the BVC group and none in the VSRR group. The postoperative length of stay and aortic valve gradients were less in the VSRR group (6 vs 8 days, P = .038; 6 vs 11.4 mm Hg, P = .001). The intensive care unit length of stay was significantly less in the VSRR group (54 vs 110 hours, P = .001). Conclusions: VSRR is an effective alternative to the BVC for aortic root aneurysm. [ABSTRACT FROM AUTHOR]

Objective The recently implemented integrated 6-year (I-6) format represents a significant change in cardiothoracic surgical residency training. We report the results of the first nationwide survey assessing I-6 program directors' impressions of this new format. Methods A 28-question web-based survey was distributed to program directors of all 24 Accreditation Council for Graduate Medical Education-accredited I-6 training programs in November 2013. The response rate was a robust 67%. Results Compared with graduates of traditional residencies, most I-6 program directors with enrolled residents believed that their graduates will be better trained (67%), be better prepared for new technological advances (67%), and have superior comprehension of cardiothoracic disease processes (83%). Just as with traditional program graduates, most respondents believed their I-6 graduates would be able to independently perform routine adult cardiac and general thoracic operations (75%) and were equivocal on whether additional specialty training (eg, minimally invasive, heart failure, aortic) was necessary. Most respondents did not believe that less general surgical training disadvantaged I-6 residents in terms of their career (83%); 67% of respondents would have chosen the I-6 format for themselves if given the choice. The greater challenges in training less mature and experienced trainees and vulnerability to attrition were noted as disadvantages of the I-6 format. Most respondents believed that I-6 programs represent a natural evolution toward improved residency training rather than a response to declining interest among medical school graduates. Conclusions High satisfaction rates with the I-6 format were prevalent among I-6 program directors. However, concerns with respect to training relatively less experienced, mature trainees were evident. [ABSTRACT FROM AUTHOR]

Objective: Bleeding is a potentially serious complication of aortic surgery. We report our experience with the use of a periaortic bovine pericardial baffle to control intractable intraoperative bleeding. Methods: All patients who underwent aortic root, ascending, or arch replacements between January 2002 and April 2013 were reviewed. A bovine pericardial periaortic baffle was created to shunt shed blood into the right atrium. The transverse sinus was sutured closed in patients undergoing primary sternotomy. Baffle recipients were compared with the remaining patients undergoing aortic surgery. The Fisher exact test was used to determine statistical significance for categoric variables. Continuous variables were compared using the nonparametric Wilcoxon rank-sum test. All factors with a P value less than .2 were considered for multivariate logistic regression to determine independent associations with baffle use. Results: A total of 413 patients were identified, of whom 23 received a baffle. Operative mortality for patients receiving a baffle was 4% (1/23) compared with 6% (25/390) (P = 1) for the remaining patients. Prolonged ventilation was more common in the baffle recipients (P < .0005); otherwise, there were no differences in postoperative morbidity. Multivariate analysis of all patients undergoing aortic surgery revealed infectious endocarditis (P < .0005; odds ratio, 15.1; 95% confidence interval, 4.8-47.2), redo sternotomy (P < .0005; odds ratio, 11.9; 95% confidence interval, 4.1-34.1), and male gender (P = .04; odds ratio, 4.6; 95% confidence interval, 1.1-19.3) to be predictive of baffle placement. Conclusions: Patients requiring salvage periaortic pericardial baffle for intractable intraoperative hemorrhage experienced an operative mortality similar to that in the remaining patients undergoing aortic surgery. Infectious endocarditis requiring root replacement or reoperative aortic surgery should alert the surgeon to the potential need for baffle placement, including prophylactic transverse sinus closure. [Copyright &y& Elsevier]

Objective(s): Previous studies have shown that individual risk factors are poor predictors of mortality after heart transplantation in patients with congenital heart disease. We developed composite risk factor groups to better predict mortality after cardiac transplantation. Methods: We conducted a cross-sectional retrospective analysis of all heart transplants performed for congenital heart disease at a single congenital heart transplant center between 1996 and 2011. Patient, procedural, and hospital course data were obtained through a review of medical records. Univariate analyses were performed using the Fisher exact test for categorical data and the Mann-Whitney U test for continuous variables. Overall mortality was examined using Kaplan-Meier estimates for univariate analysis and Cox regression analysis for multivariate analysis. A comparison of patients with functional single ventricles (SVs) versus biventricular (BV) hearts was performed. Mean follow-up duration for the whole group was 51 ± 43 months (median, 43 months). Results: Forty-six patients underwent heart transplantation during the study period. Mean age at transplant was 9.0 ± 9.1 years; 45% (n = 21) were in the SV group and 55% (n = 25) were in the BV group. The SV group had significantly more previous sternotomies (P = .006) and longer bypass times (266 ± 78 vs 207 ± 64 minutes; P = .001). High panel-reactive antibody levels (>10%) were also more common in the SV group (38% vs 13%; P = .08). Overall hospital mortality was 4.3% (n = 2, both SVs). There was no significant difference in operative mortality (10% SV vs 0% BV; P = .20) or major morbidity (33% SV vs 44% BV; P = .51) between the 2 groups. High-risk groups identified by univariate analysis were patients with an SV diagnosis + dialysis (P < .0005), SV + mechanical assist device (VAD)/extracorporeal membrane oxygenation (ECMO) (P = .026), or VAD/ECMO + renal insufficiency (P = .006)/VAD/ECMO + dialysis (P < .0005), and SV + reoperation (P = .016). By multivariate analysis, preoperative renal insufficiency (P = .038) and the composite SV + dialysis (P = .005) were predictors of overall mortality. Although survival at 2 years was lower in the SV cohort (73% vs 96%; P = .16), this benefit was not apparent (63% vs 69%) at late follow-up. Conclusions: Preoperative renal insufficiency and SV + dialysis are strong predictors of overall mortality and identify high-risk congenital heart transplant recipients. Although individual risk factors may not predict survival, a composite of factors may be more useful in identifying the high-risk recipient. [Copyright &y& Elsevier]

Background: Thoracic aortic aneurysms (TAAs) develop through an asymptomatic process resulting in gross dilation that progresses to rupture if left undetected and untreated. If detected, patients with TAA are followed over time until the risk of rupture outweighs the risk of surgical repair. Current methodologies for tracking TAA size are limited to expensive computed tomography or magnetic resonance imaging because no acceptable population screening tools are currently available. Previous studies from this laboratory and others have identified differential protein profiles for the matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs), in ascending TAA tissue from patients with bicuspid aortic valves (BAVs), versus patients with idiopathic degenerative disease and a tricuspid aortic valve (TAV). In addition, altered microRNA (miR) expression levels have also been reported in TAAs compared with normal aortic tissue. The objective of our study was to identify circulating factors within plasma that could serve as potential biomarkers for distinguishing etiologic subtypes of aneurysm disease. Methods: Ascending TAA tissue and plasma specimens were obtained from patients with BAV (n = 21) and TAV (n = 21) at the time of surgical resection. The protein abundance of key MMPs (1, 2, 3, 8, and 9), TIMPs (1, 2, 3, and 4), and miRs (1, 21, 29a, 133a, 143, and 145) was examined using a multianalyte protein profiling system or by quantitative polymerase chain reaction, respectively. Results were compared with normal aortic tissue and plasma obtained from patients without aortic disease (n = 10). Results: Significant (P < .05) differences in standardized miR-1 and miR-21 abundance between BAV and TAV aortic tissue samples and different tissue and plasma profiles of analyte differences from normal aorta where observed between the BAV and TAV groups. Linear regression analysis revealed significant linear relationships in plasma and tissue measurements only for MMP-8 and TIMP-1, TIMP-3, and TIMP-4 (P < .05). Receiver operator curve analysis revealed specific cassettes of analytes predictive of TAA disease. Relative to normal aorta, BAV proteolytic balance was significantly increased for MMP-1, MMP-2, and MMP-7, and for decreased MMP-8 and MMP-9. In contrast, TAV proteolytic balance relative to normal aorta was significantly increased only for MMP-1 and decreased for MMP-8 and MMP-9. Conclusions: Taken together, these unique data demonstrate differential plasma profiles of MMPs, TIMPs, and miRs in ascending TAA specimens from patients with BAV and TAV. These results suggest that circulating biomarkers may form the foundation for a broader platform of biomarkers capable of detecting the presence of TAA using a simple blood test and may also be useful in personalized strategies to distinguish between etiologic subtypes of TAAs in patients with aneurysm disease. [Copyright &y& Elsevier]

Aortic valve stenosis is a common cause of left ventricular pressure overload, a pathologic process that elicits myocyte hypertrophy and alterations in extracellular matrix composition, both of which contribute to increases in left ventricular stiffness. However, clinical and animal studies suggest that increased myocardial extracellular matrix fibrillar collagen content occurs later in the time course of left ventricular pressure overload at a time coincident with severe abnormalities in diastolic function followed by the development of symptomatic heart failure. Aortic valve replacement remains the most effective treatment for elimination of chronic pressure overload secondary to aortic stenosis but has traditionally been recommended only after the onset of clinical symptoms. Long-term follow-up of patients with symptomatic aortic stenosis after aortic valve replacement suggests that valve replacement may not result in complete reversal of the maladaptive changes that occur within the myocardial extracellular matrix secondary to the pressure overload state. To the contrary, residual left ventricular extracellular matrix abnormalities such as these are likely responsible for persistent abnormalities in diastolic function and increased morbidity and mortality after aortic valve replacement. Defining the mechanisms and pathways responsible for regulating the myocardial extracellular matrix during the natural history of aortic stenosis may provide a means by which to detect crucial structural milestones and thereby permit more precise identification of the development of maladaptive left ventricular remodeling. [Copyright &y& Elsevier]

Objective: Patients with severe left ventricular pressure overload secondary to aortic stenosis can present with signs and symptoms of heart failure despite normal left ventricular ejection fraction. This process occurs, at least in part, as a result of left ventricular pressure overload–induced extracellular matrix remodeling that promulgates increased left ventricular stiffness and impaired diastolic function. However, the determinants that drive extracellular matrix remodeling in this form of left ventricular pressure overload remain to be fully defined. Methods: Left ventricular pressure overload was induced in mature pigs (n = 15) by progressive ascending aortic cuff inflation (once per week for 4 weeks), whereby left ventricular mass, left ventricular ejection fraction, and regional myocardial stiffness (rKm) were compared with referent controls (n = 12). Determinants of extracellular matrix remodeling were assessed by measuring levels of mRNA expression for fibrillar collagens, matrix metalloproteinases, and tissue inhibitors of matrix metalloproteinase 1 and 4. Results: With left ventricular pressure overload, left ventricular mass and rKm increased by 2- and 3-fold, respectively, compared with control, with no change in left ventricular ejection fraction. Left ventricular myocardial collagen increased approximately 2-fold, which was accompanied by reduced solubility (ie, increased cross-linking) with left ventricular pressure overload, but mRNA expression for fibrillar collagen and matrix metalloproteinases remained relatively unchanged. In contrast, a robust increase in mRNA expression for tissue inhibitors of matrix metalloproteinase-1 and 4 occurred with left ventricular pressure overload. Conclusions: In a progressive model of left ventricular pressure overload, which recapitulates the phenotype of aortic stenosis, increased extracellular matrix accumulation and subsequently increased myocardial stiffness were not due to increased fibrillar collagen expression but rather to determinants of post-translational control that included increased collagen stability (thereby resistant to matrix metalloproteinase degradation) and increased endogenous matrix metalloproteinase inhibition. Targeting these extracellular matrix post-translational events with left ventricular pressure overload may hold both diagnostic and therapeutic relevance. [Copyright &y& Elsevier]

Background: The present study examined a cardiac passive restraint device which applies epicardial pressure (HeartNet Implant; Paracor Medical, Inc, Sunnyvale, Calif) in a clinically relevant model of dilated cardiomyopathy to determine effects on hemodynamic and myocardial blood flow patterns. Methods: Dilated cardiomyopatht was established in 10 pigs (3 weeks of atrial pacing, 240 beats/min). Hemodynamic parameters and regional left ventricular blood flow were measured under baseline conditions and after acute placement of the HeartNet Implant. Measurements were repeated after adenosine infusion, allowing maximal coronary vasodilation and coronary flow reserve to be determined. Results: Left ventricular dilation and systolic dysfunction occurred relative to baseline as measured by echocardiography. Left ventricular end-diastolic dimension increased and left ventricular fractional shortening decreased (3.8 ± 0.1 vs 6.1 ± 0.2 cm and 31.6% ± 0.5% vs 16.2% ± 2.1%, both P < .05, respectively), consistent with the dilated cardiomyopathy phenotype. The HeartNet Implant was successfully deployed without arrhythmias and a computed median mid–left ventricular epicardial pressure of 1.4 mm Hg was applied by the HeartNet Implant throughout the cardiac cycle. Acute HeartNet placement did not adversely affect steady state hemodynamics. With the HeartNet Implant in place, coronary reserve was significantly blunted. Conclusions: In a large animal model of dilated cardiomyopathy, the cardiac passive restraint device did not appear to adversely affect basal resting myocardial blood flow. However, after acute HeartNet Implant placement, left ventricular maximal coronary reserve was blunted. These unique results suggest that cardiac passive restraint devices that apply epicardial transmural pressure can alter myocardial blood flow patterns in a model of dilated cardiomyopathy. Whether this blunting of coronary reserve holds clinical relevance with chronic passive restraint device placement remains unestablished. [Copyright &y& Elsevier]

Objective: Thoracic aortic aneurysms result from dysregulated remodeling of the vascular extracellular matrix, which may occur as a result of altered resident cellular function. The present study tested the hypothesis that aortic fibroblasts undergo a stable change in cellular phenotype during thoracic aortic aneurysm formation. Methods: Primary murine aortic fibroblasts were isolated from normal and thoracic aortic aneurysm-induced aortas (4 weeks post induction with 0.5mol/L CaCl2 15minutes) by the outgrowth method. Normal and thoracic aortic aneurysm cultures were examined using a focused polymerase chain reaction array to determine fibroblast-specific changes in gene expression in the absence and presence of biological stimulation (endothelin-1, phorbol-12-myristate-13-acetate, angiotensin-II). The relative expression of 38 genes, normalized to 4 housekeeping genes, was determined, and genes displaying a minimum 2-fold increase/decrease or genes with significantly different normalized cycle threshold values were considered to have altered expression. Results: At steady state, thoracic aortic aneurysm fibroblasts revealed elevated expression of several matrix metalloproteinases (Mmp2, Mmp11, Mmp14), collagen genes/elastin (Col1a1, Col1a2, Col3a1, Eln), and other matrix proteins, as well as decreased expression of Mmp3, Timp3, and Ltbp1. Moreover, gene expression profiles in thoracic aortic aneurysm fibroblasts were different than normal fibroblasts after equivalent biological stimuli. Conclusions: This study demonstrated for the first time that isolated primary aortic fibroblasts from thoracic aortic aneurysm-induced mice possess a unique and stable gene expression profile, and when challenged with biological stimuli, induce a transcriptional response that is different from normal aortic fibroblasts. Together, these data suggest that aortic fibroblasts undergo a stable phenotypic change during thoracic aortic aneurysm development, which may drive the enhancement of extracellular matrix proteolysis in thoracic aortic aneurysm progression. [Copyright &y& Elsevier]

Objective: The matrix metalloproteinases (MMPs) have been implicated in the aggressive course of non–small cell lung cancer (NSCLC). However, there are a large number of MMP subtypes with diverse proteolytic substrates and different induction pathways. This study tested the hypothesis that a differential MMP profile would exist between NSCLC and normal lung and that MMP patterns would differ between NSCLC histologic types. Methods: NSCLC samples and remote normal samples were obtained from patients with stage I or II NSCLC with either squamous cell (n = 22) or adenocarcinoma (n = 19) histologic characteristics. Absolute concentrations for each of the MMP subclasses were determined by a calibrated and validated multiplex suspension array: collagenases (MMP-1, -8, and -13), gelatinases (MMP-2 and -9), lysins (MMP-2 and -7), and elastase (MMP-12). Results: Overall, MMP levels were significantly increased in NSCLC compared with normal. For example, MMP-1 and MMP-7 increased by approximately 10-fold in NSCLC (P < .05). Moreover, a different MMP portfolio was observed between NSCLC histologic types. For example MMP-1, -8, -9, and -12 increased by more than 4-fold in squamous cell versus adenocarcinoma (P < .05). In those patients who had recurrence within 3 years of resection, 3-fold higher levels of MMP-8 and -9 were observed (P < .05). Conclusion: Increased levels of a number of MMP types occur with NSCLC, but the MMP profile was distinctly different between histologic types and in those patients with recurrence. These different MMP profiles may be important in the mechanistic basis for the natural history of different NSCLC types, as well as identifying potential prognostic and therapeutic targets. [Copyright &y& Elsevier]

Objective: A robust release of endothelin-1 with subsequent endothelin-A subtype receptor activation occurs in patients after cardiac surgery requiring cardiopulmonary bypass. Increased endothelin-A subtype receptor activation has been identified in patients with poor left ventricular function (reduced ejection fraction). Accordingly, this study tested the hypothesis that a selective endothelin-A subtype receptor antagonist administered perioperatively would favorably affect post-cardiopulmonary bypass hemodynamic profiles in patients with a preexisting poor left ventricular ejection fraction. Methods: Patients (n = 29; 66 ± 2 years) with a reduced left ventricular ejection fraction (37% ± 2%) were prospectively randomized in a blinded fashion, at the time of elective coronary revascularization or valve replacement requiring cardiopulmonary bypass, to infusion of the highly selective and potent endothelin-A subtype receptor antagonist sitaxsentan at 1 or 2 mg/kg (intravenous bolus; n = 9, 10 respectively) or vehicle (saline; n = 10). Infusion of the endothelin-A subtype receptor antagonist/vehicle was performed immediately before separation from cardiopulmonary bypass and again at 12 hours after cardiopulmonary bypass. Endothelin and hemodynamic measurements were performed at baseline, at separation from cardiopulmonary bypass (time 0), and at 0.5, 6, 12, and 24 hours after cardiopulmonary bypass. Results: Baseline plasma endothelin (4.0 ± 0.3 fmol/mL) was identical across all 3 groups, but when compared with preoperative values, baseline values obtained from age-matched subjects with a normal left ventricular ejection fraction (n = 37; left ventricular ejection fraction > 50%) were significantly increased (2.9 ± 0.2 fmol/mL, P < .05). Baseline systemic (1358 ± 83 dynes/sec/cm−5) and pulmonary (180 ± 23 dynes/sec/cm−5) vascular resistance were equivalent in all 3 groups. As a function of time 0, systemic vascular resistance changed in an equivalent fashion in the post-cardiopulmonary bypass period, but a significant endothelin-A subtype receptor antagonist effect was observed for pulmonary vascular resistance (analysis of variance; P < .05). For example, at 24 hours post-cardiopulmonary bypass, pulmonary vascular resistance increased by 40 dynes/sec/cm−5 in the vehicle group but directionally decreased by more than 40 dynes/sec/cm−5 in the 2 mg/kg endothelin-A subtype receptor antagonist group (P < .05). Total adverse events were equivalently distributed across the endothelin-A subtype receptor antagonist/placebo groups. Conclusion: These unique findings demonstrated that infusion of an endothelin-A subtype receptor antagonist in high-risk patients undergoing cardiac surgery was not associated with significant hemodynamic compromise. Moreover, the endothelin-A subtype receptor antagonist favorably affected pulmonary vascular resistance in the early postoperative period. Thus, the endothelin-A subtype receptor serves as a potential pharmacologic target for improving outcomes after cardiac surgery in patients with compromised left ventricular function. [Copyright &y& Elsevier]

Vascular remodeling within the aorta results in a loss of structural integrity with consequent aneurysm formation. This degradation is more common in the abdominal aorta but also occurs above the diaphragm in the thoracic aorta. Conventionally, the aorta has been considered a large vascular conduit with uniform cellular and extracellular structure and function. Evidence is accumulating, however, to suggest that variations exist between the thoracic and abdominal aorta, thereby demonstrating regional heterogeneity. Further pathophysiologic studies of aortic dilation in each of these regions have identified disparities in atherosclerotic plaque deposition, vessel mechanics, protease profiles, and cell-signaling pathways. Improved understanding of this spatial heterogeneity might promote evolution in the management of aneurysm disease through computational models of aortic wall stress, imaging of proteolytic activity, targeted pharmacologic treatment, and application of region-specific gene therapy. [Copyright &y& Elsevier]

Objective: The mechanisms contributing to ascending thoracic aortic aneurysms associated with bicuspid aortic valves may differ from ascending thoracic aortic aneurysms with tricuspid aortic valves. Matrix metalloproteinases and their endogenous inhibitors have been causally linked to ascending thoracic aortic aneurysm formation. This study tested the hypothesis that specific and different matrix metalloproteinase and tissue inhibitors of metalloproteinase profiles would be observed in ascending thoracic aortic aneurysm samples from patients with bicuspid aortic valves versus tricuspid aortic valves. Methods: Ascending thoracic aortic aneurysm samples taken from patients with bicuspid aortic valve (n = 53) and patients with tricuspid aortic valve (n = 46) were assessed for representative subtypes of all matrix metalloproteinase classes and all 4 known tissue inhibitors of metalloproteinases. Levels were compared [optical density units, median (interquartile range)] both to reference control ascending aortic samples (n = 26) and within each valve group by aneurysm diameter (≤3.9 cm, 4.0-5.9 cm and ≥6.0 cm). Results: Different and specific matrix metalloproteinase and tissue inhibitors of metalloproteinase profiles were observed in the ascending thoracic aortic aneurysm groups. In bicuspid aortic valves, matrix metalloproteinase-2 increased by 34% when compared with either tricuspid aortic valves or control (P < .05), and matrix metalloproteinase-14 decreased by 59% compared with tricuspid aortic valves (P < .05). In tricuspid aortic valve samples, tissue inhibitors of metalloproteinase-2 decreased by 35% when compared with either tricuspid aortic valves or control (P < .05), and matrix metalloproteinase-13 increased by 140% in the 4.0- to 5.9-cm diameter range (P < .05). Conclusions: A unique matrix metalloproteinase and tissue inhibitor of metalloproteinase portfolio was observed in ascending thoracic aortic aneurysms from patients with bicuspid aortic valve compared with patients with tricuspid aortic valve. These differences, suggesting disparate mechanisms of extracellular matrix remodeling, may provide unique biochemical targets for ascending thoracic aortic aneurysm prognostication and treatment in these 2 groups of patients. [Copyright &y& Elsevier]

Background: An important component of matrix remodeling during thoracic aortic aneurysm progression is the balance between matrix metalloproteinases and their endogenous inhibitors (tissue inhibitors of metalloproteinases). However, whether and to what degree matrix metalloproteinase/tissue inhibitor of metalloproteinases profiles change over time with an evolving thoracic aortic aneurysm remains unclear. Methods: Descending thoracic aortic aneurysms were induced in mice (FVB strain, 15 minutes of 0.5 mol/L CaCl2 exposure) and followed for 24 hours, 72 hours, 1week, 2 weeks, 4 weeks, or 8 weeks (each group, n = 13). Thoracic aortic aneurysm size was determined by means of video micrometry, and immunoblotting was used to measure aortic matrix metalloproteinase 2, 8, 9, and 12 and tissue inhibitor of metalloproteinases 1 and 4 levels (expressed as a percentage of control values, n = 13). Results: Increased aortic diameter was detected by 72 hours and reached a maximal size at 4 weeks (135% ± 4% increase from baseline, P < .05), which is consistent with thoracic aortic aneurysm progression. Active matrix metalloproteinase 8 (collagenase) levels increased at 72 hours (178% ± 49%, P < .05 from control), and active matrix metalloproteinase 12 (elastase) levels increased by 24 hours (138% ± 11%, P < .05), whereas active matrix metalloproteinase 2 levels increased at 72 hours and 1 week after thoracic aortic aneurysm induction (72 hours: 158% ± 12%, 1 week: 162% ± 19%; P < .05). At 1 week after thoracic aortic aneurysm induction, active matrix metalloproteinase 9 and 12 levels decrease (matrix metalloproteinase 9: 55% ± 5%; matrix metalloproteinase 12: 63% ± 5%; P < .05); however, matrix metalloproteinase 9 and 12 levels were increased from these values at 4 and 8 weeks (P < .05). Tissue inhibitor of metalloproteinases 1 levels were decreased at 1 week (52% ± 15%, P < .05) and later returned to control values, whereas tissue inhibitor of metalloproteinases 4 levels increased at the late thoracic aortic aneurysm time points (4 weeks: 278% ± 46%; 8 weeks: 213% ± 40%; P < .05). Conclusions: These findings show 2 phases of matrix metalloproteinase abundance during murine thoracic aortic aneurysm formation. The late tissue inhibitor of metalloproteinases 4 increase might explain prevention of further aortic dilation past 4 weeks. Unique matrix metalloproteinase/tissue inhibitor of metalloproteinases temporal relationships occurred during the natural history of thoracic aortic aneurysm progression that might hold both diagnostic and therapeutic relevance. [Copyright &y& Elsevier]

Background: Cardiac surgical procedures can be associated with significant morbidity and mortality. Recently, it has been recognized that statins might induce multiple biologic effects independent of lipid lowering that could potentially ameliorate adverse surgical outcomes. Accordingly, this study tested the central hypothesis that pretreatment with statins before cardiac surgery would reduce adverse postoperative surgical outcomes. Methods: Demographic and outcomes data were collected retrospectively for 3829 patients admitted for planned cardiac surgery between February 1994 and December 2002. Statin pretreatment occurred in 1044 patients who were comparable with non–statin-pretreated (n = 2785) patients with regard to sex, race, and age. Primary outcomes examined included postoperative mortality (30-day) and a composite morbidity variable. Results: The odds of experiencing 30-day mortality and morbidity were significantly less in the statin-pretreated group, with unadjusted odds ratios of 0.43 (95% confidence interval [CI], 0.28-0.66) and 0.72 (95% CI, 0.61-0.86), respectively. Risk-adjusted odds ratios for mortality and morbidity were 0.55 (95% CI, 0.32-0.93) and 0.76 (95% CI, 0.62-0.94), respectively, by using a logistic regression model and 0.51 (95% CI, 0.27-0.94) and 0.71 (95% CI, 0.55-0.92), respectively, in the propensity-matched model, demonstrating significant reductions in 30-day morbidity and mortality. In a subsample of patients undergoing valve-only surgery (n = 716), fewer valve-only patients treated with statins experienced mortality, although these results were not statistically significant (1.96% vs 7.5%). Conclusions: These findings indicate that statin pretreatment before cardiac surgery confers a protective effect with respect to postoperative outcomes. [Copyright &y& Elsevier]