Apoptotic vascular smooth muscle cell depletion via BCL2 family of proteins in human ascending aortic aneurysm and dissection.

AIMS: This study investigates the expression patterns of BCL2 (B-cell CLL/lymphoma2) family of proteins and the extent of vascular smooth muscle cell (VSMC) apoptosis in thoracic aortic aneurysms (TAA), type-A aortic dissections (TAD), and nondilated ascending aortic samples. METHODS: Aortic wall specimens were obtained from patients undergoing surgical repair for TAA (n = 24), TAD (n = 20), and normal aortic tissues from organ donors (n = 6). The expression pattern of BCL2, BCL2L1 (BCL2-like1), BAK1 (BCL2-antagonist/killer1), and BAX (BCL2-associated X protein) proteins was investigated by immunohistochemistry. Furthermore, colocalization of alpha smooth muscle actin (ACTA2) and caspase3 (CASP3) in aortic VSMCs was analyzed by double-immunofluorescence staining. Onset of DNA fragmentation was measured by TUNEL assay. RESULTS: Apoptotic index was significantly increased in both TAD group (31.3 ± 17.2, P < 0.001) and TAA group (21.1 ± 12.7, P = 0.001) relative to control aortas (2.0 ± 1.2). Anti-CASP3 and ACTA2 double-immunostaining confirmed apoptosis in VSMCs in TAA and TAD groups but not in controls. Proapoptotic BAX expression was significantly elevated in VSMCs of TAA patients, compared with that of controls (OR = 20; P = 0.02; 95% CI, 16-250). In contrast, antiapoptotic BCL2L1 expression was higher in controls compared with that of TAA group (OR = 11.2; P = 0.049; 95% CI, 1.0-123.9). Furthermore, BAX/BCL2 ratio was significantly increased in both TAA (1.2 ± 0.7, P < 0.001) and TAD (0.6 ± 0.4, P = 0.05) groups relative to controls (0.2 ± 0.1, P < 0.001). CONCLUSIONS: Apoptotic VSMC depletion in human TAA/TAD is associated with disturbance of the balance between proapoptotic and antiapoptotic members of the BCL2 family proteins, which may have a role in the pathogenesis of vascular remodelling in aortic disease. In light of the future studies, targeting apoptotic pathways in TAA and TAD pathogenesis may provide therapeutic benefits to patients by slowing down the progression and even possibly preventing the TAD.

Stem cell mediated cardiovascular repair.

Recent increase in the interest in stem and progenitor cells may be attributed to their behavioural characteristics. A consensus has been reached that embryonic or adult stem cells have therapeutic potential. As cardiovascular health issues are still the major culprits in many developed countries, stem and progenitor cell driven approaches may give the clinicians a new arsenal to tackle many significant health issues. However, stem and progenitor cell mediated cardiovascular regeneration can be achieved via complex and dynamic molecular mechanisms involving a variety of cells, growth factors, cytokines, and genes. Functional contributions of transplanted cells on target organs and their survival are still critical problems waiting to be resolved. Moreover, the regeneration of contracting myocardial tissue has controversial results in human trials. Thus, moderately favourable clinical results should be interpreted carefully. Determining the behavioural programs, genetic and transcriptional control of stem cells, mechanisms that determine cell fate, and functional characteristics are the primary targets. In addition, ensuring the long-term follow-up of cells with efficient imaging techniques in human clinical studies may provide a resurgence of the initial enthusiasm, which has faded over time. Here, we provide a brief historical perspective on stem cell driven cardiac regeneration and discuss cardiac and vascular repair in the context of translational science.

Effects of preoperative short term use of atorvastatin on endothelial progenitor cells after coronary surgery: a randomized, controlled trial.

OBJECTIVES: We investigated the effects of short-term use of atorvastatin on CD34+/VEGF-R2+/CD133+/CD45- endothelial progenitor cell (EPC) count after on-pump coronary artery bypass surgery (CABG). METHODS: Between Feb-2010 and May-2010, we randomly assigned, in a placebo-controlled, double-blind study, 60 consecutive patients who underwent isolated, first-time CABG to receive either 14-day atorvastatin (40 mg/day) or placebo preoperatively. Urgent CABG and recent myocardial infarction were excluded. EPCs were quantified (cells/µl) by flow cytometric phenotyping obtained from venous blood samples collected preoperatively (T(1)), 6-hours (T(2)), and on the 5th day postoperatively (T(3)). Levels of markers of inflammation and serum cardiac troponin I were also measured preoperatively and daily until day-5 after surgery. RESULTS: There were no differences in baseline risk factors including cholesterol profiles, and EuroSCORES between the groups. The composite primary end-point, favored statin group with higher amount of circulating, early EPC count (cells/µl) at all time points compared with placebo (T(1), 2.30±0.02 versus 1.58±0.03, p<0.001; T(2), 5.00±0.06 versus 2.19±0.06, p<0.001; T(3), 3.03±0.08 versus 1.78±0.02, p<0.001). Postoperative hsCRP rise were inversely correlated with EPC count, and were significantly lower in the statin group (T(1), 0.8 ± 0.1 versus 2.2±1.5, p<0.001; T(2), 72.9±3.2 versus 96.0±3.6, p<0.001; T(3), 4.3±1.2 versus 11.4±4.1, p<0.001). Furthermore, the incidence of postoperative atrial fibrillation was significantly lower in the statin group compared to placebo (3.3% versus 23%, p=0.02). CONCLUSIONS: Short-term atorvastatin use increases circulating early EPCs both pre- and post-operatively and is associated with better preservation of sinus rhythm and reduced hsCRP levels. (ClinicalTrials.gov number, NCT01096875).

Thrombotic gene polymorphisms and postoperative outcome after coronary artery bypass graft surgery.

BACKGROUND: Emerging perioperative genomics may influence the direction of risk assessment and surgical strategies in cardiac surgery. The aim of this study was to investigate whether single nucleotide polymorphisms (SNP) affect the clinical presentation and predispose to increased risk for postoperative adverse events in patients undergoing coronary artery bypass grafting surgery (CABG). METHODS: A total of 220 patients undergoing first-time CABG between January 2005 and May 2008 were screened for factor V gene G1691A (FVL), prothrombin/factor II G20210A (PT G20210A), angiotensin I-converting enzyme insertion/deletion (ACE-ins/del) polymorphisms by PCR and Real Time PCR. End points were defined as death, myocardial infarction, stroke, postoperative bleeding, respiratory and renal insufficiency and event-free survival. Patients were compared to assess for any independent association between genotypes for thrombosis and postoperative phenotypes. RESULTS: Among 220 patients, the prevalence of the heterozygous FVL mutation was 10.9% (n = 24), and 3.6% (n = 8) were heterozygous carriers of the PT G20210A mutation. Genotype distribution of ACE-ins/del was 16.6%, 51.9%, and 31.5% in genotypes I/I, I/D, and D/D, respectively. FVL and PT G20210A mutations were associated with higher prevalence of totally occluded coronary arteries (p < 0.001). Furthermore the risk of left ventricular aneurysm formation was significantly higher in FVL heterozygote group compared to FVL G1691G (p = 0.002). ACE D/D genotype was associated with hypertension (p = 0.004), peripheral vascular disease (p = 0.006), and previous myocardial infarction (p = 0.007). CONCLUSIONS: FVL and PT G20210A genotypes had a higher prevalence of totally occluded vessels potentially as a result of atherothrombotic events. However, none of the genotypes investigated were independently associated with mortality.

[Clinical outcome and factors affecting surgical decision for repair versus replacement in patients with mitral regurgitation]. / Mitral kapak yetmezliginin cerrahi tedavisinde onarim veya replasman seçimini etkileyen faktörler ve klinik sonuçlar.

OBJECTIVE: We aimed to identify characteristics differentiating patients undergoing mitral valve replacement versus valve repair for mitral regurgitation (MR) and to investigate retrospectively mid-term clinical and functional outcomes. METHODS: From January, 2004 to January, 2009 146 patients underwent mitral valve surgery (62 male / 84 female; age: 55.9+/-13.6 [18-80] years) by one surgical team. Mitral valve replacement was performed in 101 patients (69.2 %) and valve repair was performed in 45 patients (30.8%). Mean follow-up time was 586+/-413 days. Life tables were constructed for the analysis of 5-year complication free survival and comparisons were performed between the groups using Log-rank test within 95%CI. RESULTS: The choice of surgical technique depended on the etiology of MR. Degenerative (p=0.001) and ischemic (p=0.014) MR were more common in patients undergoing repair whereas patients with complex rheumatic mitral valve disease (p=0.001) with subvalvular involvement commonly underwent replacement. Overall 30-day mortality was 3.2% (replacement, 3.96%vs repair, 2.22%, p=0.59). Although there was no significant difference between the groups regarding baseline left ventricular ejection fraction (EF) (ischemic p=0.61; non-ischemic p=0.34), improvement was more pronounced in the repair group for both etiologies (ischemic MR, p=0.001; non- ischemic MR p=0.002). Survival at 5-years was 91.7+/-4.7% after repair and 83.5+/-9.2% after replacement, respectively (p=0.83). Freedom from grade 2 or more mitral regurgitation, reoperation, endocarditis, and thromboembolism were 95+/-5% vs 97+/-3% (p=0.71); 95+/-4% vs 98+/-2% (p=0.98); 94+/-4% vs 100% (p=0.16); and 85+/-8% vs 100% (p=0.095) in replacement and repair groups, respectively. CONCLUSION: This study demonstrates that mitral valve repair is associated with an acceptable operative mortality, satisfactory mid-term survival and better preservation of left ventricular function. Significant differences in favor of repair are expected in long-term follow-up particularly regarding freedom from thromboembolism and endocarditis.