Diana Aicher

Valve Configuration Determines Long-Term Results After Repair of the Bicuspid Aortic Valve

Background— Reconstruction of the regurgitant bicuspid aortic valve has been performed for >10 years, but there is limited information on long-term results. We analyzed our results to determine the predictors of suboptimal outcome. Methods and Results— Between November 1995 and December 2008, 316 patients (age, 49±14 years; male, 268) underwent reconstruction of a regurgitant bicuspid aortic valve. Intraoperative assessment included extent of fusion, root dimensions, circumferential orientation of the 2 normal commissures (>160°, ≤160°), and effective height after repair. Cusp pathology was treated by central plication (n=277), triangular resection (n=138), or pericardial patch (n=94). Root dilatation was treated by subcommissural plication (n=100), root remodeling (n=122), or valve reimplantation (n=2). All patients were followed up echocardiographically (cumulative follow-up, 1253 years; mean, 4±3.1 years). Clinical and morphological parameters were analyzed for correlation with 10-year freedom from reoperation with the Cox proportional hazards model. Hospital mortality was 0.63%; survival was 92% at 10 years. Freedom from reoperation at 5 and 10 years was 88% and 81%; freedom from valve replacement, 95% and 84%. By univariable analysis, statistically significant predictors of reoperation were age (hazard ratio [HR]=0.97), aortoventricular diameter (HR=1.24), effective height (HR=0.76), commissural orientation (HR=0.95), use of a pericardial patch (HR=7.63), no root replacement (HR=3.80), subcommissural plication (HR=2.07), and preoperative aortic regurgitation grade 3 or greater. By multivariable analysis, statistically significant predictors for reoperation were age (HR=0.96), aortoventricular diameter (HR=1.30), effective height (HR=0.74), commissural orientation (HR=0.96), and use of a pericardial patch (HR=5.16). Conclusions— Reconstruction of bicuspid aortic valve can be performed reproducibly with good early results. Recurrence and progression of regurgitation, however, may occur, depending primarily on anatomic features of the valve.

Aortic valve repair leads to a low incidence of valve-related complications

OBJECTIVE Aortic valve replacement for aortic regurgitation (AR) has been established as a standard treatment but implies prosthesis-related complications. Aortic valve repair is an alternative approach, but its mid- to long-term results still need to be defined. METHODS Over a 12-year period, 640 patients underwent aortic valve repair for regurgitation of a unicuspid (n=21), bicuspid (n=205), tricuspid (n=411) or quadricuspid (n=3) aortic valve. The mechanism of regurgitation involved prolapse (n=469) or retraction (n=20) of the cusps, and dilatation of the root (n=323) or combined pathologies. Treatment consisted of cusp repair (n=529), root repair (n=323) or a combination of both (n=208). The patients were followed clinically and echocardiographically; follow-up was complete in 98.5% (cumulative follow-up: 3035 patient years). RESULTS Hospital mortality was 3.4% in the total patient cohort and 0.8% for isolated aortic valve repair. The incidences of thrombo-embolism (0.2% per patient per year) and endocarditis (0.16%per patient per year) were low. Freedom from re-operation at 5 and 10 years was 88% and 81% in bicuspid and 97% and 93% in tricuspid aortic valves (p=0.0013). At re-operation, 13 out of 36 valves could be re-repaired. Freedom from valve replacement was 95% and 90% in bicuspid and 97% and 94% in tricuspid aortic valves (p=0.36). Freedom from all valve-related complications at 10 years was 88%. CONCLUSIONS Reconstructive surgery of the aortic valve is feasible with low mortality in many individuals with aortic regurgitation. Freedom from valve-related complications after valve repair seems superior compared to available data on standard aortic valve replacement.

Histone deacetylase activity is essential for the expression of HoxA9 and for endothelial commitment of progenitor cells

The regulation of acetylation is central for the epigenetic control of lineage-specific gene expression and determines cell fate decisions. We provide evidence that the inhibition of histone deacetylases (HDACs) blocks the endothelial differentiation of adult progenitor cells. To define the mechanisms by which HDAC inhibition prevents endothelial differentiation, we determined the expression of homeobox transcription factors and demonstrated that HoxA9 expression is down-regulated by HDAC inhibitors. The causal involvement of HoxA9 in the endothelial differentiation of adult progenitor cells is supported by the finding that HoxA9 overexpression partially rescued the endothelial differentiation blockade induced by HDAC inhibitors. Knockdown and overexpression studies revealed that HoxA9 acts as a master switch to regulate the expression of prototypical endothelial-committed genes such as endothelial nitric oxide synthase, VEGF-R2, and VE-cadherin, and mediates the shear stress–induced maturation of endothelial cells. Consistently, HoxA9-deficient mice exhibited lower numbers of endothelial progenitor cells and showed an impaired postnatal neovascularization capacity after the induction of ischemia. Thus, HoxA9 is regulated by HDACs and is critical for postnatal neovascularization.

Homeobox A9 transcriptionally regulates the EphB4 receptor to modulate endothelial cell migration and tube formation

Abstract— Homeobox genes (Hox) encode for transcription factors, which regulate cell proliferation and migration and play an important role in the development of the cardiovascular system during embryogenesis. In this study, we investigated the role of HoxA9 for endothelial cell migration and angiogenesis in vitro and identified a novel target gene, the EphB4 receptor. Inhibition of HoxA9 expression decreased endothelial cell tube formation and inhibited endothelial cell migration, suggesting that HoxA9 regulates angiogenesis. Because Eph receptor tyrosine kinases importantly contribute to angiogenesis, we examined whether HoxA9 may transcriptionally regulate the expression of EphB4. Downregulation of HoxA9 reduced the expression of EphB4. Chromatin-immunoprecipitation revealed that HoxA9 interacted with the EphB4 promoter, whereas a deletion construct of HoxA9 without DNA-binding motif (&Dgr;aa 206-272) did not bind. Consistently, HoxA9 wild-type overexpression activated the EphB4 promoter as determined by reporter gene expression. HoxA9 binds to the EphB4 promoter and stimulates its expression resulting in an increase of endothelial cell migration and tube forming activity. Thus, modulation of EphB4 expression may contribute to the proangiogenic effect of HoxA9 in endothelial cells.

Aortic Valve Repair Using a Differentiated Surgical Strategy

Background—Reconstruction of the aortic valve for aortic regurgitation (AR) remains challenging, in part because of not only cusp or root pathology but also a combination of both can be responsible for this valve dysfunction. We have systematically tailored the repair to the individual pathology of cusps and root. Methods—Between October 1995 and August 2003, aortic valve repair was performed in 282 of 493 patients undergoing surgery for AR and concomitant disease. Root dilatation was corrected by subcommissural plication (n=59), supracommissural aortic replacement (n=27), root remodeling (n=175), or valve reimplantation within a graft (n=24). Cusp prolapse was corrected by plication of the free margin (n=157) or triangular resection (n =36), cusp defects were closed with a pericardial patch (n=16). Additional procedures were arch replacement (n=114), coronary artery bypass graft (n=60) or mitral repair (n=24). All patients were followed-up (follow-up 99.6% complete), and cumulative follow-up was 8425 patient-months (mean, 33±27 months). Results—Eleven patients died in hospital (3.9%). Nine patients underwent reoperation for recurrent AR (3.3%). Actuarial freedom from AR grade ≥II at 5 years was 81% for isolated valve repair, 84% for isolated root replacement, and 94% for combination of both; actuarial freedom from reoperation at 5 years was 93%, 95%, and 98%, respectively. No thromboembolic events occurred, and there was 1 episode of endocarditis 4.5 years postoperatively. Conclusions—Aortic valve repair is feasible even for complex mechanisms of AR with a systematic and individually tailored approach. Operative mortality is low and mid-term durability is encouraging. The incidence of valve-related morbidity is low compared with valve replacement.

Preoperative aortic root geometry and postoperative cusp configuration primarily determine long-term outcome after valve-preserving aortic root repair

OBJECTIVE Technical controversies exist in valve-preserving aortic root replacement. We sought to determine predictors of long-term stability of the aortic valve. METHODS A total of 430 patients (aged 57 ± 15 years, 323 male) underwent valve-preserving aortic root surgery (remodeling in 401, reimplantation in 29) between 1995 and 2009 and were followed echocardiographically. Factors influencing late recurrence of aortic valve regurgitation grade II or greater (n = 45) or need for reoperation on the aortic valve (n = 25) were analyzed. RESULTS Early mortality was 2.8% (1.9% for elective cases), and actuarial survival at 10 years was 83.5% ± 2.4%. Ten-year freedom from aortic valve regurgitation grade II or greater was 85.0% ± 2.5%. Preoperative aortoventricular junction diameter greater than 28 mm and postoperative effective height of the aortic cusp less than 9 mm were identified as significant predictors for late aortic valve regurgitation grade II or greater in multivariate analysis (both P < .001). Ten-year freedom from reoperation on the aortic valve was 89.3% ± 2.5%. Preoperative aortoventricular junction diameter greater than 28 mm (P < .001), use of pericardial patch (P = .022), and effective height of the aortic cusp less than 9 mm (P = .049) were identified as significant predictors for reoperation in multivariate analysis. Operative technique (remodeling, reimplantation), Marfan syndrome, bicuspid valve anatomy, concomitant central cusp plication, size of prosthesis used, and acute dissection were not associated with an increased risk of late aortic valve regurgitation grade II or greater or reoperation. In patients with preoperative aortoventricular junction diameter greater than 28 mm (n = 94), the addition of central cusp plication significantly improved freedom from aortic valve regurgitation grade II or greater (P = .006) regardless of root procedures (remodeling, P = .011; reimplantation, P = .053). CONCLUSIONS Long-term stability of valve-preserving aortic root replacement was influenced not by the technique of root repair but by the preoperative aortic root geometry and postoperative cusp configuration.

RING+STRING Successful Repair Technique for Ischemic Mitral Regurgitation With Severe Leaflet Tethering

Background— Residual/recurrent mitral valve regurgitation is observed in 30% after undersized ring annuloplasty (RING) for ischemic mitral regurgitation (IMR). RING addresses primarily annular dilatation but does not correct severe leaflet tethering attributable to papillary muscle (PM) displacement. We proposed adjunctive PM repositioning under transesophageal echocardiography (TEE) guidance in the loaded beating heart using a transventricular suture (STRING). Methods and Results— Patients with tenting height ≥10 mm were identified as high-risk patients for repair failure. In these patients (n=30, age 68±11 years, ejection fraction 37±14%), RING (partial, median 29 mm) was combined with the adjunctive STRING-technique. A Teflon-pledgeted 3-0-polytetrafluoroethylene-suture was anchored in the posterior PM via horizontal aortotomy, exteriorized through the aorto-mitral continuity, and tied in the loaded beating heart under TEE guidance. Tenting height (14±2 mm versus 6±1 mm, P<0.001) and tenting area (3.9±0.9 cm2 versus 1.0±0.2 cm2, P<0.001) decreased. The distance between pPM and aorto-mitral continuity decreased (44±4 mm versus 37±3 mm, P<0.001). Survival at 2 years was similar compared with a historical matched control-group (89% versus 73%, P=0.13), whereas freedom from MR>II was higher in the RING+STRING-group (94% versus 71%, P=0.01). End-diastolic (61.7±7.2 mm versus 54.8±9.2 mm, P<0.001) and end-systolic (48.5±8.5 mm versus 42.7±7.8 mm, P=0.002) ventricular diameters decreased in the RING+STRING-group but persisted in the control-group (60.4±7.8 mm versus 58.9±7.5 mm, P=0.38; 47.8±9.6 mm versus 48.3±9.5 mm, P=0.52). During follow-up (median 26 months) only 1 patient of the study-group required reoperation for degenerative MR, while 2 control-group patients underwent reoperation for recurrent functional MR. Conclusions— Our novel approach for IMR attenuates high risk of repair failure in patients with severe leaflet tethering and results in reverse remodeling.

Correction of leaflet prolapse in valve-preserving aortic replacement: pushing the limits?

BACKGROUND For aortic dilatation with morphologically intact leaflets, valve-preserving aortic replacement has become an accepted treatment modality. Leaflet prolapse, however, may be present, making composite replacement the most frequent choice. Alternatively, valve preservation may be combined with correction of leaflet prolapse. The results of this approach should be comparable with those of valve-preserving aortic surgery in the presence of normal leaflets. METHODS Between 1995 and 2002, 156 patients were treated by valve-preserving surgery. The aortic valve was bicuspid in 46, and tricuspid in 110 instances. In 88 aortic valves, apparently normal leaflet coaptation (normal, 12 bicuspid and 76 tricuspid), and in 68 instances, prolapse of one or more leaflets, was observed. Root remodeling (n = 133) or aortic replacement with valve reimplantation (n = 23) were performed. Leaflet prolapse was corrected by triangular resection (n = 16) or plicating sutures (n = 59), mostly placed in the central portion of the leaflet. RESULTS Neither operative mortality nor 5-year survival were influenced by the additional correction of prolapse. Freedom from reoperation at 1 year (normal, 98.8%; prolapse, 96.5%) and 5 years (normal, 97.3%; prolapse, 96.5%) were comparable in both cohorts, as was freedom from aortic regurgitation > or = II at 1 year (normal, 98.8%; prolapse, 94.2%) and 5 years (94.4%). CONCLUSIONS Surgical correction of leaflet prolapse in combination with proximal aortic replacement is feasible with good results. Midterm results are identical with those known for morphologically normal leaflets. Repair of prolapse allows for preservation of the native valve in most patients with aortic regurgitation and aortic pathology, and thus appears a beneficial addition to valve-preserving surgery.

Valve-preserving operation in acute aortic dissection type A

BACKGROUND The standard treatment in patients with acute aortic dissection type A (AADA) and aortic regurgitation is either supracommissural aortic or composite replacement of ascending aorta and valve. Valve-preserving surgical procedures provide a promising alternative. We retrospectively analyzed midterm results after these different approaches. METHODS From October 1995 to December 1999, 52 patients (35 men, 17 women) underwent repair of AADA. Patient ages ranged from 30 to 83 years. Composite replacement was chosen for degenerated aortic valves or prior valve replacement (group A; n = 8). With normal root diameter, supracommissural replacement of the ascending aorta was performed (group B; n = 22). For preexisting root dilatation the aortic root was either remodeled (root diameter 30 to 50 mm, group C; n = 17) or the valve reimplanted within a vascular graft (root diameter more than 50 mm, group D; n = 5). RESULTS All patients underwent either proximal (n = 46) or total (n = 6) arch replacement under circulatory arrest. Eight patients (15.4%) died (group A: n = 3; group B: n = 3; group C: n = 2). Freedom from aortic regurgitation of grade 2 or more at 2 years was 100% in groups A and D, 90.9% in group C, and 75% following supracommissural replacement. At 2 years freedom from proximal reoperation was 100% in groups A, C, and D and 84.5% in group B. CONCLUSIONS In AADA valve-preserving root replacement leads to improved stability of aortic valve function without an increased operative risk. Midterm results are promising and may show further superiority over supracommissural aortic replacement in the future.

Aortic root and cusp configuration determine aortic valve function

OBJECTIVE Normalisation of aortic root and cusp configuration is a prerequisite for successful aortic valve repair (AVR). Using transthoracic echocardiography, we studied aortic root dimensions relative to body size in normal subjects and AVR patients. METHODS Aortic roots of healthy volunteers (n=130, age 27.9 ± 16.9 years) were examined for aortoventricular (AV), sinus (S), sinutubular-junction diameters (ST) and effective height (height difference between the AV plane and central coaptation point, eH) by transthoracic echocardiography. In 651 patients, after AVR residual aortic valve insufficiency (AI) and eH were determined. The relationships between eH versus root dimensions and eH versus residual AI were analysed by analysis of variance with Bonferroni post hoc testing. RESULTS Root dimensions correlated with each other and body size (r=0.74-0.91). In addition, a correlation between AV (r=0.73), sinus diameter (r=0.76), body height (r=0.77), body surface area (r=0.81) and eH was found. After AVR, eH was 9.8 ± 0.9 mm in 235 patients without postoperative AI, 9.4 ± 1.1mm in 370 with mild AI, 7.9 ± 1.4mm in 43 patients with moderate AI and 6 ± 1mm in three patients with severe AI. The difference in means of effective height between the groups was significant (p<0.005). Of 497 AVR patients with an eH ≥ 9 mm, 309 had no or trivial AI, 186 had mild AI and only two had moderate AI. CONCLUSIONS Parameters of aortic root dimensions follow a seemingly constant pattern in humans of different sizes. Effective height has a constant relationship to root dimensions and body size. In AVR, normalisation of eH leads to a high probability of normal or near-normal aortic valve function.