Long-term Clinical and Echocardiographic Outcomes in Young and Middle-aged Adults Undergoing the Ross Procedure.

Importance: There is no ideal valve substitute for young adults requiring aortic valve replacement. Multicenter data supporting use of the Ross procedure with respect to long-term postoperative valve-related mortality and reintervention, as well as function of the autograft and pulmonary homograft, are needed. Objective: To determine the long-term clinical and echocardiographic outcomes in young and middle-aged patients undergoing the Ross procedure. Design, Setting, and Participants: A retrospective multicenter international cohort study with a median follow-up period of 9.2 years was conducted in 5 experienced centers regularly performing the Ross procedure. Consecutive patients aged 18 to 65 years were included by each center between 1991 and 2018. Main Outcomes and Measures: Survival and autograft-related and homograft-related reintervention. Serial echocardiographic measurements of valve function were analyzed using mixed-effects modeling. Results: During the study period, 1431 patients (74.3% men; n = 1063) were operated on at a median age of 48.5 years (mean [SD], 47.7 [9.5]; range, 18.1-65; interquartile range, 42.7-54.0). Implantation techniques were root inclusion in 355 (24.9%), root replacement in 485 (34.0%), and subcoronary implantation in 587 (41.1%). Right ventricular outflow tract reconstruction was performed with homografts in 98.6% (n = 1189) and bioprostheses in 1.4% (n = 17). Ten patients (0.7%) died before discharge. Median follow-up was 9.2 years (13 015 total patient-years). Survival after 10 and 15 years was 95.1% (95% CI, 93.8%-96.5%) and 88.5% (95% CI, 85.9%-91.1%), respectively. Freedom from autograft and homograft reintervention after 15 years was 92.0% and 97.2%, respectively. Late events were autograft endocarditis in 14 patients (0.11% per patient-year), homograft endocarditis in 11 patients (0.08% per patient-year), and stroke in 37 patients (0.3% per patient-year). Conclusions and Relevance: Given its excellent short-term and long-term outcome in young and middle-aged adults in this study, the Ross procedure should be considered in young and middle-aged adults who require aortic valve replacement. Patients should be referred to an experienced center with a program dedicated to the Ross procedure.

Collagen analysis of the ascending aortic dilatation associated with bicuspid aortic valve disease compared with tricuspid aortic valve.

Dilatation of the ascending aorta is a common occurrence in patients with bicuspid aortic valve (BAV). The aim of the current study was to characterize collagen content in advanced glycation end products (AGEs) of dilated aortic tissue from two distinct areas, concave and convex aortic sites in patients with BAV and TAV. Collagen contents extracted from 100 mg tissue was isolated by enzymatic digestion using pepsin and the nondigested material was further digested using cyanogen bromide, insoluble collagen fraction (ICF) was extracted by hydrochloric acid hydrolysis. BAV tissue showed diminished fluorescence of the pepsin extracted fraction (PEF) compared with TAV tissue (12.4 ± 1.0% vs 32.9 ± 7.6%, p = 0.05). Patients with BAV had PEF of collagens significantly diminished in the dilated ascending aorta, especially in its convex portion, in course of aging and increment of dilated diameters. It is suggestible that BAV patients present more highly AGE-modified collagens in their ascending aorta.

Is the outcome in acute aortic dissection type A influenced by of femoral versus central cannulation?

BACKGROUND: The purpose of this study was to evaluate the single-center experience in initial femoral versus central cannulation of the extracorporeal circulation for acute aortic dissection type A (AADA). METHODS: Between January 2003 and December 2015, 235 patients underwent repair of AADA. All patients were evaluated for the type of arterial cannulation (femoral vs. central) for initial bypass. Demographic data and outcome parameters were accessed. RESULTS: One hundred and twenty seven (54.0%) were initially cannulated in the central aortic vessels (ascending aorta or subclavian/axillary artery) and 108 (46.0%) in the femoral artery. Patients were comparable between age (62.4±14.4 vs. 62.9±14.4 years, P=0.805), gender (male, 62.2 vs. 69.4%, P=0.152) and previous sternotomy (15.7 vs. 16.7%, P=0.861) between both cannulation groups; while EuroSCORE I (11.5±4.0 vs. 12.7±4.2, P=0.031) and ASA Score (3.5±0.81 vs. 3.8±0.57, P=0.011) were significantly higher in the femoral artery cannulation group. Bypass (249±102 vs. 240±81 min, P=0.474), X-clamp (166±85 vs. 157±67 min, P=0.418) and circulatory arrest time (51.6±28.7 vs. 48.3±21.7 min, P=0.365) were similar between the groups as were lowest temperature (18.1±2.0 vs. 18.1±2.2, P=0.775). Postoperative neurologic deficit and 30-day mortality were comparable between both cannulation groups (11.7 vs. 7.2%, P=0.449 and 20.2 vs. 16.9%, P=0.699, central vs. peripheral cannulation). Multivariate analysis revealed only EuroScore I above 13 as single preoperative predictor for mortality. CONCLUSIONS: AADA can be operated with both femoral and central cannulation with similar results. Risk for early mortality was driven by the preoperative clinical and hemodynamic status before operation rather than the cannulation technique.

The Extracellular Matrix Signature in Vein Graft Disease.

BACKGROUND: Vein graft disease is a major and yet unsolved problem in cardiac revascularization surgery. Although accumulation of extracellular matrix is characteristic for vein graft disease, detailed analysis of the fibrotic material is lacking. Because alterations of collagen cross-links are typical for organ fibrosis, we performed a comprehensive analysis of collagen and elastin in vein graft disease. METHODS: Collagen, elastin, and their respective cross-links were analyzed using histology and amino acid analysis. The expression of collagen-modifying enzymes was analyzed using SYBR Green quantitative real-time polymerase chain reaction. Fibrillin expression was analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction. RESULTS: Diseased vein grafts showed a marked increase of collagen and of intermediate collagen cross-links, which are markers for newly synthesized collagen. Furthermore, we identified in vein graft disease increased levels of mature hydroxylysine aldehyde-derived cross-links typical for skeletal tissues. This was accompanied by upregulation of lysyl hydroxylase 2 and lysyl oxidase expression. Furthermore, vein graft disease showed a reduction of the elastin/collagen ratio, using elastin cross-links as a marker of elastin content, which was accompanied by an increase of fibrillin-1. CONCLUSIONS: Vein graft disease was accompanied by marked alterations in the composition of the extracellular matrix. The altered collagen cross-link pattern and the reduced elastin/collagen ratio might synergistically increase the stiffness in diseased vein grafts. Furthermore, hydroxylysine aldehyde-derived cross-links can cause a decreased degradability of collagens by matrix-metalloproteinases. Our data suggest collagen cross-links as a therapeutic target in vein graft disease.

Patient age at the Ross operation in children influences aortic root dimensions and aortic regurgitation.

BACKGROUND: The Ross operation provides the advantage of growth potential of the pulmonary autograft in the aortic position. However, development of autograft dilatation and regurgitation may occur. We sought to assess the progression of autograft diameters and aortic regurgitation (AR) with regard to patient age at the time of the Ross operation. METHODS: Autograft echo dimensions from 48 children <16 years of age at the time of the Ross operation, who had follow-up echocardiograms at <20 years of age, were analyzed using hierarchical multilevel modeling. The z values of autograft dimensions were calculated according to the normal aortic dimensions. Mean follow-up was 5.1 ± 3.3 years. The mean age at the time of the Ross operation was 10.0 ± 4.3 years. RESULTS: The mean z values of all patients showed a significant increase with follow-up time at the sinus (0.5 ± 0.1/year, P < .001) and the sinotubular junction (0.7 ± 0.2/year, P < .001) but not at the annulus (0.1 ± 0.1/year, P = .59). There was no significant difference in the z values of sinus and the sinotubular junction between younger and older children at implantation and with time. The initial annulus z value was significantly larger in younger children (P < .0001), whereas the annual increase was significantly higher in older children (P = .021). Age at operation has no impact on the initial AR grade (P = .60). The AR tends to increase more quickly in older patients (P = .040). Sinus and sinotubular junction dilate with time, regardless of patient age. CONCLUSIONS: Young children show larger initial annulus sizes than older children. However, annulus diameters tend to normalize in young children, whereas they increase in older children. Autograft regurgitation develops slowly, but significantly, and predominantly in older children. Stabilizing measures to prevent autograft root dilatation are warranted in adolescents, but they are not required in young children.

Haemodynamic performance of a new pericardial aortic bioprosthesis during exercise and recovery: comparison with pulmonary autograft, stentless aortic bioprosthesis and healthy control groups.

OBJECTIVES: Since blood flow impairment by aortic valve prosthesis is characteristically dynamic, this dynamic component is best and thoroughly appreciated by exercise Doppler echocardiography. We sought to determine the haemodynamics of a new pericardial aortic bioprosthesis [Trifecta™-aortic valve bioprosthesis (T-AVB), St Jude Medical, MN, USA] at rest and during exercise and a 10-min recovery period in comparison with alternative aortic valve prostheses, e.g. Ross operation (RO), stentless aortic valve [Medtronic freestyle-aortic valve bioprosthesis (MF-AVB)] and a healthy control group (CO). METHODS: Haemodynamics at rest and during supine exercise stress testing and a 10-min recovery period were evaluated in 32 patients (mean age: 70.8 ± 6.7 years) with T-AVB (mean follow-up: 5 ± 2 months), 49 with RO (mean age: 43.5 ± 13.7 years), 39 with an MF-AVB (mean age: 64.6 ± 9.4 years) and 26 healthy patients (mean age: 39 ± 9 years). Measurements included mean outflow tract gradient (δp mean, mmHg), effective orifice area index (EOAI, cm(2)/m(2)) and valvular resistance (vR, dyn s cm(-5)). RESULTS: Mean body surface area for T-AVB was 1.93 ± 0.24 m(2) (median 1.97 m(2)). Mean δp mean at rest was 7.2 ± 3.4 mmHg, mean EOAI 0.86 ± 0.23 cm(2)/m(2) and mean vR 50.7 ± 23.2 dyn s cm(-5). Supine stress testing did increase the mean EOAI to 0.98 ± 0.27 cm(2)/m(2), the mean vR to 62.6 ± 25.3 dyn s cm(-5) and the mean δp mean to 10.21 ± 4.7 mmHg, respectively (P < 0.05 for all comparisons). During the post-exercise recovery period, δp mean, EOAI and vR showed a prompt normalization within 5 min of cessation of exercise. At all the three measurement points, T-AVB and MF-AVB revealed low gradients, satisfactory EOAI and low vR. Compared with the RO and a healthy control group, both groups showed significantly inferior performance throughout the exercise and post-exercise study protocol (P < 0.05). In comparison with T-AVB, patients with an MF-AVB only showed significant inferior performance throughout series with respect to a higher vR, indicating a smaller increase in the EOAI during exercise. During the 10-min post-exercise period, T-AVB recovered significantly earlier than MF-AVB. CONCLUSIONS: When comparing two different types of aortic valve bioprostheses with a gold standard group (RO) and a healthy population, both aortic valve bioprostheses perform inferior but reveal promising haemodynamics during exercise. During post-exercise haemodynamic recovery, only the T-AVB revealed a nearly physiological recovery pattern compared with the RO and a healthy control group.

Mid-term results of different aortic valve-sparing procedures in Marfan syndrome.

BACKGROUND AND AIM OF THE STUDY: Marfan patients with aortic root aneurysm are typically treated with the Bentall procedure, though aortic valve-sparing procedures (AVSPs) are also possible. The study aim was to compare the authors' experience with two such techniques performed at their institution, namely a reimplantation according to David (David I) and remodeling according to Yacoub. METHODS: Between 1996 and 2009, a total of 37 Marfan patients underwent an AVSP at the authors' institution. Of these patients, 25 (mean age 32 +/- 14.9 years) underwent surgery according to David (group D), and 12 (mean age 35 +/- 10.9 years) according to Yacoub (group Y). The patients underwent both clinical and echocardiographic follow up examinations at a mean of 42.0 +/- 36.4 months after surgery. RESULTS: One patient from each group had moved abroad and was lost to follow up. The remaining 35 patients were alive at follow up, and none presented with any major neurological or bleeding complications. In addition, no significant differences were noted between the groups in terms of NYHA classification, left ventricular function, or left ventricular diameter. At follow up, aortic valve function was also comparable between groups, with a peak/mean gradient of 9.4 +/- 6.4/5.3 +/- 3.5 mmHg and 5.1 +/- 3.3/2.8 +/- 1.5 mmHg for groups D and Y, respectively (p = 0.081/0.058). The measured mean grades of aortic valve regurgitation were comparable in groups D and Y (0.6 +/- 0.7 and 1.1 +/- 0.6, respectively; p = 0.055). However, aortic root dimensions obtained via M-mode were smaller in group D patients (29.6 +/- 2.3 mm) than in group Y patients (36.1 +/- 6.6 mm) (p = 0.027). Only three patients from group Y required reoperation on the aortic valve due to valvular regurgitation (p = 0.028); two of these had presented with aortic dissection at the first operation. CONCLUSION: Both types of AVSP can be performed with comparably good interim clinical results, and also low mortality and morbidity, in patients with Marfan syndrome.

Locally different endothelial nitric oxide synthase protein levels in ascending aortic aneurysms of bicuspid and tricuspid aortic valve.

Aims. Dysregulated expression of the endothelial nitric oxide synthase (eNOS) is observed in aortic aneurysms associated with bicuspid aortic valve (BAV). We determined eNOS protein levels in various areas in ascending aortic aneurysms. Methods and Results. Aneurysmal specimens were collected from 19 patients, 14 with BAV and 5 with tricuspid aortic valve (TAV). ENOS protein levels were measured in the outer curve (convexity), the opposite side (concavity), the distal and above the sinotubular junction (proximal) aneurysm. Cultured aortic cells were treated with NO synthesis inhibitor L-NAME and the amounts of 35 apoptosis-related proteins were determined. In patients with BAV, eNOS levels were significantly lower in the proximal aorta than in the concavity and distal aorta. ENOS protein levels were also lower in the convexity than in the concavity. While the convexity and distal aorta showed similar eNOS protein levels in BAV and TAV patients, levels were higher in TAV proximal aorta. Inhibition of NO synthesis in aneurysmal aortic cells by L-NAME led to a cytosolic increase in the levels of mitochondrial serine protease HTRA2/Omi. Conclusion. ENOS protein levels were varied at different areas of the aneurysmal aorta. The dysregulation of nitric oxide can lead to an increase in proapoptotic HTRA2/Omi.

Elevation of matrix metalloproteinases in different areas of ascending aortic aneurysms in patients with bicuspid and tricuspid aortic valves.

Our aim is to investigate the elevation of matrix proteins in tissues obtained from distal, above the sinotubular junction (proximal), concave, and convex sites of aneurysms in the ascending aorta using a simultaneous multiplex protein detection system. Tissues were collected from 41 patients with ascending aortic aneurysms. A total of 31 patients had a bicuspid aortic valve (BAV), whereas 10 had a tricuspid aortic valve (TAV). Concave and convex aortic site samples were collected from all patients, whereas proximal and distal convexity samples were obtained from 19 patients with BAV and 7 patients with TAV. Simultaneous detection of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) was performed at each of the four aortic sites. MMP-2 levels were higher in the concave aortic sites than in the convex aortic sites. In contrast, MMP-8 levels were higher in the convex sites than in the concave sites, as were MMP-9 levels. In both BAV and TAV patients, TIMP-3 levels were higher in the concave sites than in the convex sites. However, TIMP-2 and TIMP-4 levels were significantly elevated in the sinotubular proximal aorta of BAV patients. Simultaneous detection of MMPs and TIMPs revealed different levels at different aortic sites in the same patient.

Upregulation of the high mobility group AT-hook 2 gene in acute aortic dissection is potentially associated with endothelial-mesenchymal transition.

The high mobility group AT-hook 2 (HMGA2) gene is proposed to regulate the genes involved in the epithelial-mesenchymal transition (EMT). One form of EMT is endothelial-mesenchymal transition (EndMT). We analyzed the expression profile of the HMGA2 gene in different human aortic diseases. Aortic specimens were collected from 51 patients, including 19 with acute aortic dissection, 26 with aortic aneurysm, two with Marfan syndrome and four aortic valves. Quantitative real-time polymerase chain reaction was carried out for HMGA2 and immunohistochemical analyses were performed for HMGA2, SNAI1, Vimentin, CD34, MKI-67 and TGFB1. The expression of let-7d microRNA, which is assumed to play a role in the regulation of HMGA2, was also quantified. The level of HMGA2 gene expression was significantly higher in acute aortic dissection compared with all the other samples (193.1 vs. 8.1 fold normalized to calibrator, P<0.001). The immunohistochemical investigation showed that HMGA2, SNAI1, and Vimentin proteins were mainly detected in the endothelial cells of the vasa vasorum. The HMGA2 gene is upregulated in acute aortic dissection. This is the first report describing a link between HMGA2 and acute aortic dissection. The HMGA2, SNAI1 and Vimentin proteins were mainly detected in the endothelium of the vasa vasorum. It seems that HMGA2 overexpression in acute aortic dissection occurs in a let-7d-independent manner and is associated with EndMT of the vasa vasorum.

Major adverse cardiac and cerebrovascular events after the Ross procedure: a report from the German-Dutch Ross Registry.

BACKGROUND: The purpose of the study is to report major cardiac and cerebrovascular events after the Ross procedure in the large adult and pediatric population of the German-Dutch Ross registry. These data could provide an additional basis for discussions among physicians and a source of information for patients. METHODS AND RESULTS: One thousand six hundred twenty patients (1420 adults; 1211 male; mean age, 39.2±16.2 years) underwent a Ross procedure between 1988 and 2008. Follow-up was performed on an annual basis (median, 6.2 years; 10 747 patient-years). Early and late mortality were 1.2% (n=19) and 3.6% (n=58; 0.54%/patient-year), respectively. Ninety-three patients underwent 99 reinterventions on the autograft (0.92%/patient-year); 78 reinterventions in 63 patients on the pulmonary conduit were performed (0.73%/patient-year). Freedom from autograft or pulmonary conduit reoperation was 98.2%, 95.1%, and 89% at 1, 5, and 10 years, respectively. Preoperative aortic regurgitation and the root replacement technique without surgical autograft reinforcement were associated with a greater hazard for autograft reoperation. Major internal or external bleeding occurred in 17 (0.15%/patient-year), and a total of 38 patients had composite end point of thrombosis, embolism, or bleeding (0.35%/patient-year). Late endocarditis with medical (n=16) or surgical treatment (n=29) was observed in 38 patients (0.38%/patient-year). Freedom from any valve-related event was 94.9% at 1 year, 90.7% at 5 years, and 82.5% at 10 years. CONCLUSIONS: Although longer follow-up of patients who undergo Ross operation is needed, the present series confirms that the autograft procedure is a valid option to treat aortic valve disease in selected patients. The nonreinforced full root technique and preoperative aortic regurgitation are predictors for autograft failure and warrant further consideration. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00708409.

Altered microRNAs in bicuspid aortic valve: a comparison between stenotic and insufficient valves.

BACKGROUND AND AIM OF THE STUDY: Bicuspid aortic valve (BAV), the most common form of congenital heart disease, is a leading cause of aortic stenosis (AS) and aortic insufficiency (AI). AS is typically caused by calcific valve disease. Recently, microRNAs (miRNAs) have been shown to modulate gene expression. The study aim was to examine the miRNAs that were altered in the aortic valve leaflets of patients with AS compared to those in patients with AI. In-vitro experiments were also carried out to determine if these miRNAs could modulate calcification-related genes. METHODS: Aortic valve samples (fused and unfused leaflets) were collected from nine male patients (mean age 44.9 +/- 13.8 years) undergoing aortic valve replacement (AVR). PIQOR miRXplore Microarrays containing 1,421 miRNAs were used and hybridized to fused leaflet samples labeled with Cy5; unfused samples were used as controls and labeled with Cy3. A quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to validate the miRNA array results. Cultured human aortic valve interstitial cells (AVICs) were treated with miRNA mimics, and qRT-PCR was carried out to determine any changes in mRNAs. RESULTS: By microarray analysis, seven miRNAs were shown to be statistically different between the AS and AI patients. In the stenotic samples, the MiR-26a and miR-195 levels were shown (by qRT-PCR) to be reduced by 65% and 59%, respectively (p < 0.05), and MiR-30b to be reduced by 62% (p < 0.06). Human AVICs treated with miR-26a or miR-30b mimics showed decreased mRNA levels of calcification-related genes. MiR-26a repressed BMP2 by 36%, alkaline phosphatase (ALPL) by 38%, and SMAD1 by 26%, while MiR-30b reduced the expression of SMAD1 by 18% and of SMAD3 by 12%. In contrast, miR-195-treated AVICs had increased mRNA levels of calcification-related genes, such as BMP2 by 68% and RUNX2 by 11%. CONCLUSION: MiR-26a, miR-30b, and miR-195 were each decreased in the aortic valves of patients requiring AVR due to AS, compared to those requiring replacement due to AI. These miRNAs appear to modulate calcification-related genes in vitro.

The Ross operation - a feasible and safe option in the setting of a bicuspid aortic valve?

OBJECTIVES: The Ross operation in the setting of a bicuspid aortic valve (BAV) remains controversial. Using data from the German Ross Registry, we sought to investigate the effect of the presence of a BAV on autograft function and diameters over time after the Ross operation compared with the presence of a tricuspid aortic valve (TAV). METHODS: A total of 1277 patients (mean age 42.2 + or - 15.3 years) with intra-operatively documented aortic valve morphology during the Ross operation were analysed in the present study (sub-coronary technique, n=648, root replacement technique, n=629 patients). A BAV was present in 70.9% of patients. Clinical and echocardiographic follow-up was performed preoperatively and at pre-specified intervals (mean follow-up 5.7 + or - 3.8 years, 6806 patient-years). Hierarchical multilevel modelling techniques were used for the statistical analysis of serial measurements and comparisons among groups. RESULTS: Initial neo-aortic regurgitation was lower in the BAV group (0.52 vs 0.62 aortic insufficiency (AI) grades, p=0.008), whereas the annual increase of it did not differ among groups. In both surgical techniques, no significant development of neo-aortic regurgitation (<0.02 AI grades per year) could be detected. Initial aortic annulus and sinus dimensions did not differ in the presence of a BAV. However, BAV patients developed a higher degree of annulus and sinus dilatation over time (0.20mm per year vs 0.06 mm per year, p=0.003; 0.24 vs 0.11 mm per year, p=0.013). This effect persisted when allowing for the two different surgical techniques. Baseline sinotubular junction (STJ) diameters did not differ among groups and annual increase thereof was similar (29.15 mm vs 28.9 mm, p=0.69; 0.44 mm vs 0.35 mm, p=0.15). CONCLUSIONS: For the observed time period, postoperative neo-aortic regurgitation after the Ross procedure did not differ between patients with a BAV or a TAV. Root dimensions, although clinically not relevant, increased in both valve entities supporting surgical reinforcement strategies. We cannot consider a BAV as a contraindication for the Ross operation.