Denis R. Merk

Inhibition of microRNA-29b reduces murine abdominal aortic aneurysm development

MicroRNAs (miRs) regulate gene expression at the posttranscriptional level and play crucial roles in vascular integrity. As such, they may have a role in modifying abdominal aortic aneurysm (AAA) expansion, the pathophysiological mechanisms of which remain incompletely explored. Here, we investigate the role of miRs in 2 murine models of experimental AAA: the porcine pancreatic elastase (PPE) infusion model in C57BL/6 mice and the AngII infusion model in Apoe-/- mice. AAA development was accompanied by decreased aortic expression of miR-29b, along with increased expression of known miR-29b targets, Col1a1, Col3a1, Col5a1, and Eln, in both models. In vivo administration of locked nucleic acid anti-miR-29b greatly increased collagen expression, leading to an early fibrotic response in the abdominal aortic wall and resulting in a significant reduction in AAA progression over time in both models. In contrast, overexpression of miR-29b using a lentiviral vector led to augmented AAA expansion and significant increase of aortic rupture rate. Cell culture studies identified aortic fibroblasts as the likely vascular cell type mediating the profibrotic effects of miR-29b modulation. A similar pattern of reduced miR-29b expression and increased target gene expression was observed in human AAA tissue samples compared with that in organ donor controls. These data suggest that therapeutic manipulation of miR-29b and its target genes holds promise for limiting AAA disease progression and protecting from rupture.

MicroRNA-21 Blocks Abdominal Aortic Aneurysm Development and Nicotine-Augmented Expansion

miR-21 modulates abdominal aortic aneurysm development by regulating cell proliferation and apoptosis within the aortic wall. miR-21, a Red Alert for AAA Abdominal aortic aneurysms (AAAs) constitute a major public health burden, with few treatment options. In this common condition associated with increased age, male gender, high blood pressure, and especially smoking, the major conduit vessel within the abdomen slowly enlarges and may rupture, often fatally. MicroRNAs are short molecules that can simultaneously regulate translation of multiple genes. One example, microRNA-21 (miR-21), has been shown to control gene expression patterns that influence a variety of cellular processes including maturation, migration, proliferation, and survival. In a new study, Maegdefessel et al. investigated the role of miR-21 in two well-established mouse models of AAA: one in which the aorta is exposed to enzymatic degradation of supporting tissue and another in which mice predisposed to vascular disease spontaneously form AAA in response to the peptide hormone angiotensin II. In both models, miR-21 expression increased within the aortic wall as the AAA developed. miR-21 was also elevated in samples of aorta from patients with AAA compared with healthy controls. Nicotine, the major constituent of tobacco, accelerated AAA growth in both mouse models and caused an even larger increase in miR-21 expression. This appeared to be a protective response because preventing an increase in miR-21 with an inhibitor increased AAA growth and rupture rates in both models. In contrast, exogenous supplementation of miR-21 slowed aneurysm growth and prevented rupture, even in the presence of nicotine. This was partly mediated through miR-21’s suppressive effects on the protein PTEN (phosphatase and tensin homolog). Cell culture studies demonstrated that inflammatory stimuli, known to influence AAA development, increased miR-21 expression. These results suggest that enhanced miR-21 expression is an endogenous response to pathological aortic dilation and may offer a new therapeutic pathway that could be targeted to treat AAA in patients. Identification and treatment of abdominal aortic aneurysm (AAA) remains among the most prominent challenges in vascular medicine. MicroRNAs are crucial regulators of cardiovascular pathology and represent possible targets for the inhibition of AAA expansion. We identified microRNA-21 (miR-21) as a key modulator of proliferation and apoptosis of vascular wall smooth muscle cells during development of AAA in two established murine models. In both models (AAA induced by porcine pancreatic elastase or infusion of angiotensin II), miR-21 expression increased as AAA developed. Lentiviral overexpression of miR-21 induced cell proliferation and decreased apoptosis in the aortic wall, with protective effects on aneurysm expansion. miR-21 overexpression substantially decreased expression of the phosphatase and tensin homolog (PTEN) protein, leading to increased phosphorylation and activation of AKT, a component of a pro-proliferative and antiapoptotic pathway. Systemic injection of a locked nucleic acid–modified antagomir targeting miR-21 diminished the pro-proliferative impact of down-regulated PTEN, leading to a marked increase in the size of AAA. Similar results were seen in mice with AAA augmented by nicotine and in human aortic tissue samples from patients undergoing surgical repair of AAA (with more pronounced effects observed in smokers). Modulation of miR-21 expression shows potential as a new therapeutic option to limit AAA expansion and vascular disease progression.

miR-29b Participates in Early Aneurysm Development in Marfan Syndrome

Rationale: Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-&bgr; (TGF-&bgr;) signaling. Although TGF-&bgr; blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-&bgr; causes aneurysms remain ill-defined. Objective: We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS. Methods and Results: Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, is increased in the ascending aorta of Marfan (Fbn1C1039G/+) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1C1039G/+ aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1C1039G/+ ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor &kgr;B, a repressor of miR-29b, and a factor suppressed by TGF-&bgr;, was also observed in Fbn1C1039G/+ aorta. Furthermore, administration of a nuclear factor &kgr;B inhibitor increased miR-29b levels, whereas TGF-&bgr; blockade or losartan effectively decreased miR-29b levels in Fbn1C1039G/+ mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies. Conclusions: We identify increased miR-29b expression as key to the pathogenesis of early aneurysm development in MFS by regulating aortic wall apoptosis and extracellular matrix abnormalities.

Minimally Invasive Hybrid Coronary Artery Revascularization

BACKGROUND Here we report the short- and long-term results of a minimally invasive hybrid approach in 117 patients. METHODS From 1996 to 2007, revascularization of the left anterior descending artery was performed in 1,696 patients by minimally invasive direct coronary artery bypass grafting (MIDCAB), in 89 patients by beating-heart totally endoscopic coronary artery bypass grafting (TECAB) and in 30 patients by arrested-heart TECAB. Of these patients, 117 were scheduled for a hybrid procedure. Revascularization of the left anterior descending artery was performed by either MIDCAB (107 patients), beating-heart TECAB (8 patients) or arrested-heart TECAB (2 patients). Percutaneous coronary intervention of vessels other than the left anterior descending artery was performed 4 to 6 weeks preoperatively (53 cases), intraoperatively (5 cases), or 2 to 45 days postoperatively (59 cases). Demographic data, perioperative outcome, and annual follow-up were obtained from all patients. RESULTS Minimally invasive bypass and stenting could be completed in all patients. Two high-risk patients (1.9%) died postoperatively. Follow-up of all patients adds up to 208 patient-years. Eight patients died during follow-up. Kaplan-Meier survival was 92.5% (95% confidence interval [CI]: 86.5% to 98.4%) at 1 year and 84.8% (95% CI: 73.5% to 94.9%) at 5 years. Follow-up angiogram of symptomatic patients showed 1 bypass occlusion and 5 in-stent restenosis with need for reintervention. Freedom from major adverse cardiac and cerebral events (including reintervention) and angina was 85.5% (95% CI: 76.9% to 94.1%) at 1 year and 75.5% (95% CI: 62.7% to 87.3%) at 5 years. CONCLUSIONS Minimally invasive hybrid coronary revascularization is a safe approach with good long-term results. It should be performed in selected patients at centers with considerable experience in minimally invasive bypass surgery and requires close cooperation between cardiologists and surgeons.

Does Reasonable Incomplete Surgical Revascularization Affect Early or Long-Term Survival in Patients With Multivessel Coronary Artery Disease Receiving Left Internal Mammary Artery Bypass to Left Anterior Descending Artery?

Background— The objective was to evaluate the impact of complete revascularization (CR) versus reasonable incomplete surgical revascularization (IR) in others than left anterior descending artery territory on early and late survival in patients with multivessel coronary artery disease (CAD). Methods and Results— During a 7-year period, 8.806 consecutive patients with multivessel CAD affecting the proximal left anterior descending artery or left main stem underwent sternotomy for isolated coronary artery bypass grafting including left internal mammary artery–left anterior descending artery bypass. A total of 936 patients (10.6%) had IR of the circumflex or right coronary artery territory. IR was based on the traditional classification. Follow-up was 3.5±2.2 years. Patient groups were comparable regarding age (CR 67.1 versus IR 67.6 years), ejection fraction (57.2% versus 57.5%), and logEuroscore (4.5% versus 4.5%). Patients receiving IR presented with more complex CAD. Mean number of distal anastomoses was 3.0±0.8 CR versus 2.4±0.6 IR. Operation time (176 versus 187 minutes) and cross-clamp time (52 versus 56 minutes) were longer in the IR group (P<0.001). Hospital mortality was 3.3% CR versus 3.2% IR (P=0.520). Independent risk factors for hospital mortality were age, pulmonary hypertension, chronic obstructive pulmonary disease, peripheral vascular disease, and emergency indication, but not IR (P=0.922). Arterial revascularization was protective. Cumulative survival at 1-year was 93.1% CR versus 93.6% IR and at 5 years 82.2 CR versus 80.9% IR (P=0.457). Conclusions— In presence of left internal mammary artery-to-left anterior descending artery bypass, reasonable IR of the circumflex or right coronary artery territory did not adversely affect early or long-term survival in patients with multivessel CAD. In patients presenting with 1 poor target vessel; however, IR is a good therapeutic option and the benefit of CR should be balanced against the risks.

A Randomized Multicenter Trial of Minimally Invasive Rapid Deployment Versus Conventional Full Sternotomy Aortic Valve Replacement

BACKGROUND Minimally invasive surgical procedures (MIS) may offer several advantages over conventional full sternotomy (FS) aortic valve replacement (AVR). A novel class of aortic valve prostheses has been developed for rapid-deployment AVR (RDAVR). We report a randomized, multicenter trial comparing the outcomes for MIS-RDAVR with those of conventional FS-AVR. METHODS A total of 100 patients with aortic stenosis were enrolled in a prospective, multicenter, randomized comparison trial (CADENCE-MIS). Exclusion criteria included ejection fraction below 25%, AVR requiring concomitant procedures, and recent myocardial infarction or stroke. Patients were randomized to undergo MIS-RDAVR through an upper hemisternotomy (n = 51) or AVR by FS with a conventional stented bioprosthesis (n = 49). Three patients were excluded before the procedure, and 3 more patients who were randomized to undergo RDAVR were excluded because of their anatomy. Procedural, early clinical outcomes, and functional outcomes were assessed for the remaining 94 patients. Hemodynamic performance was assessed by an echocardiography core laboratory. RESULTS Implanted valve sizes were similar between groups (22.9 ± 2.1 vs 23.0 ± 2.1 mm, p = 0.9). MIS-RDAVR was associated with significantly reduced aortic cross-clamp times compared with FS-AVR (41.3 ± 20.3 vs 54.0 ± 20.3 minutes, p < 0.001), although cardiopulmonary bypass times were similar (68.8 ± 29.0 vs 74.4 ± 28.4 minutes, p = 0.21). Early clinical outcomes were similar between the two groups, including quality of life measures. The RDAVR patients had a significantly lower mean transvalvular gradient (8.5 vs 10.3 mm Hg, p = 0.044) and a lower prevalence of patient-prosthesis mismatch (0% vs 15.0%, p = 0.013) 3 months postoperatively compared with the FS-AVR patients. CONCLUSIONS RDAVR by the MIS approach is associated with significantly reduced myocardial ischemic time and better valvular hemodynamic function than FS-AVR with a conventional stented bioprosthesis. Rapid deployment valves may facilitate the performance of MIS-AVR.

Minimal invasive aortic valve replacement surgery is associated with improved survival: a propensity-matched comparison

OBJECTIVES To compare early and long-term outcomes of minimally invasive surgery (MIS) versus full sternotomy (FS) isolated aortic valve replacement (AVR). METHODS We retrospectively analysed all patients who underwent isolated bioprosthetic AVR between 2003 and March 2012 at our institution. Matching was performed based on a propensity score, which was obtained using the output of a logistic regression on relevant preoperative risk factors. Mean follow-up was 3.1±2.7 years (range 0-9.0 years) and was 99.8% complete. RESULTS A total of 2051 patients (FS, 1572; MIS, 479) underwent isolated bioprosthetic AVR during the study period. MIS patients were significantly younger (67.8±11.2 vs 70.4±9.4 years) and had a lower logistic EuroSCORE (6.6±6.4 vs 11.2±13.4%, both P<0.001). Propensity matching resulted in 477 matched patients from each group, with no significant differences in any of the preoperative variables. Aortic cross-clamp times were significantly longer in MIS patients (59.4±16.0 vs 56.9±14.6 min, P=0.008). Nonetheless, MIS AVR was associated with a significantly lower incidence of intra-aortic balloon pump usage (0.4 vs 2.1%, P=0.042) and in-hospital mortality (0.4 vs 2.3%, P=0.013), while FS patients had a lower rate of re-exploration for bleeding (1.5 vs 4.2%, P=0.019). Five- and 8-year survival post-AVR was significantly higher in MIS patients (89.3±2.4% and 77.7±4.7% vs 81.8±2.2% and 72.8±3.1%, respectively, P=0.034). Cox regression analysis revealed MIS (hazard ratio: 0.47, 95% confidence interval: 0.26-0.87) as an independent predictor of long-term survival. CONCLUSION MIS AVR is associated with very good early and long-term survival, despite longer myocardial ischaemic times. MIS AVR can be performed safely with results that are at least equivalent to those achieved through an FS.

Predictors of permanent pacemaker implantation after Medtronic CoreValve bioprosthesis implantation.

AIMS High-grade conduction disturbances requiring permanent pacemaker (PPM) implantation occur in up to 40% of patients following transcatheter aortic valve implantation (TAVI). The aim of this study was to identify pre-operative risk factors for PPM implantation after TAVI with the Medtronic CoreValve prosthesis (CVP). METHODS AND RESULTS We retrospectively analysed 109 patients following transfemoral CVP implantation performed between 2008 and 2009 at the Leipzig Heart Center. Patients who had indwelling PPM at the time of TAVI (n = 21) were excluded, leaving 88 patients for analysis. Mean age was 80.3 ± 6.6 years and logistic EuroScore predicted risk of mortality was 23.3 ± 12.1%. A total of 32 patients (36%) underwent PPM implantation post-TAVI during the same hospital admission. A total of 27/88 (31%) had evidence of pre-operative abnormal conduction, including first degree AV block and left bundle brunch block. Statistically significant risk factors for the need for post-operative PPM were patient age >75 years [P = 0.02, odds ratio (OR) 4.6], pre-operative heart rate <65 beats per minute (b.p.m.; P = 0.04, OR 2.9), CVP oversizing >4 mm (P = 0.03, OR 2.8), CVP prosthesis >26 mm (OR 2.2), atrial fibrillation (P = 0.001, OR 5.2), and ventricular rate <65 b.p.m. at the first post-operative day (P = 0.137, OR 6.0). CONCLUSION PPM implantation occurs frequently after transfemoral TAVI with the CVP. Older age, chronic atrial fibrillation, pre-operative bradycardia, and larger or significantly oversized prostheses were independent risk factors for PPM implantation following TAVI with the CVP.

Iatrogenic type A aortic dissection during cardiac procedures: early and late outcome in 48 patients

OBJECTIVE Iatrogenic aortic dissection (IAD) is a rare complication of cardiac procedures. We herein describe our management and results of this complication. METHODS A total of 55 279 patients underwent open heart surgery at our centre from 1995 to 2010, and 135 262 patients underwent cardiac catheterization over the same time period. We identified 48 patients from this cohort who underwent emergency surgery for IAD that occurred either during or shortly after cardiac surgery, or following cardiac catheterization. RESULTS The incidence of IAD was 0.06% (n = 36) for cardiac surgical procedures and 0.01% (n = 12) for cardiac catheterization procedures. The mean patient age was 66 ± 14 years and 50% were female. Intraoperative IAD occurred during aortic cannulation in 12 patients, insertion of the cardioplegia cannula in 7 patients, manipulation of the aortic crossclamp in 4 patients or during other events in 8 patients. IAD occurred early postcardiac surgery in 5 patients, and during cardiac catheterization in the remaining 12 patients. IAD was treated by emergent replacement of the ascending aorta and the aortic arch (when involved), as well as aortic root replacement or repair as indicated. Early mortality was 41.7: 35.5% for intraoperative IAD, 60.0% for postoperative IAD and 50.0% for cardiac catheterization-associated IAD (P = 0.5). Histological investigation revealed atherosclerosis in 61.2% of patients, cystic medial necrosis in 22.2%, aortitis in 2.8% and other pathologies in 13.8%. Follow-up was 100% complete with a 5-year survival of 40 ± 0.4%. CONCLUSION IAD is a rare but dangerous complication of cardiac surgery and cardiac catheterization, and is frequently associated with pre-existing aortic pathology.

A planning system for transapical aortic valve implantation

Stenosis of the aortic valve is a common cardiac disease. It is usually corrected surgically by replacing the valve with a mechanical or biological prosthesis. Transapical aortic valve implantation is an experimental minimally invasive surgical technique that is applied to patients with high operative risk to avoid pulmonary arrest. A stented biological prosthesis is mounted on a catheter. Through small incisions in the fifth intercostal space and the apex of the heart, the catheter is positioned under flouroscopy in the aortic root. The stent is expanded and unfolds the valve which is thereby implanted into the aortic root. Exact targeting is crucial, since major complications can arise from a misplaced valve. Planning software for the perioperative use is presented that allows for selection of the best fitting implant and calculation of the safe target area for that implant. The software uses contrast enhanced perioperative DynaCT images acquired under rapid pacing. In a semiautomatic process, a surface segmentation of the aortic root is created. User selected anatomical landmarks are used to calculate the geometric constraints for the size and position of the implant. The software is integrated into a PACS network based on DICOM communication to query and receive the images and implants templates from a PACS server. The planning results can be exported to the same server and from there can be rertieved by an intraoperative catheter guidance device.