Single-Nucleus Multiomic Analyses Identifies Gene Regulatory Dynamics of Phenotypic Modulation in Human Aneurysmal Aortic Root.

Aortic root aneurysm is a potentially life-threatening condition that may lead to aortic rupture and is often associated with genetic syndromes, such as Marfan syndrome (MFS). Although studies with MFS animal models have provided valuable insights into the pathogenesis of aortic root aneurysms, this understanding of the transcriptomic and epigenomic landscape in human aortic root tissue remains incomplete. This knowledge gap has impeded the development of effective targeted therapies. Here, this study performs the first integrative analysis of single-nucleus multiomic (gene expression and chromatin accessibility) and spatial transcriptomic sequencing data of human aortic root tissue under healthy and MFS conditions. Cell-type-specific transcriptomic and cis-regulatory profiles in the human aortic root are identified. Regulatory and spatial dynamics during phenotypic modulation of vascular smooth muscle cells (VSMCs), the cardinal cell type, are delineated. Moreover, candidate key regulators driving the phenotypic modulation of VSMC, such as FOXN3, TEAD1, BACH2, and BACH1, are identified. In vitro experiments demonstrate that FOXN3 functions as a novel key regulator for maintaining the contractile phenotype of human aortic VSMCs through targeting ACTA2. These findings provide novel insights into the regulatory and spatial dynamics during phenotypic modulation in the aneurysmal aortic root of humans.

Long-term outcomes following valve-sparing root replacement with concomitant mitral repair.

OBJECTIVES: To examine the late outcomes of valve-sparing root replacement and concomitant mitral valve repair in patients who have been followed prospectively for more than 2 decades. METHODS: From 1992 to 2020, 54 consecutive patients (mean age, 47 ± 16 years; 80% men) underwent valve-sparing root replacement (45 reimplantation and 9 remodeling) with concomitant repair of the mitral valve. Patients were followed prospectively for a median of 9 years (IQR, 3-14 years). RESULTS: No patient experienced perioperative death or stroke. There were 3 late deaths and the 15-year overall survival was 96.0% (95% CI, 74.8%-99.4%), similar to the age- and sex-matched population. Over the follow-up period, 6 patients had reoperation of the aortic valve and 3 on the mitral valve. Of those, 2 had reoperation on both aortic and mitral valves for a total of 7 reoperations in this cohort. The cumulative proportion of reoperation at 10 years of either or both valves were as follows: aortic valve 11.4% (95% CI, 3.9%-33.3%), mitral valve 4.2% (95% CI, 0.6%-28.4%), and both valves 11.4% (95% CI, 3.9%-33.3%). The estimated probability of developing moderate/severe aortic insufficiency at 15 years was 18.5% (95% CI, 9.0%-34.2%). On final echocardiographic follow-up, none of the patients had developed moderate/severe mitral regurgitation. CONCLUSIONS: In this single-center series of concomitant valve-sparing root replacement and mitral valve repair, we observed excellent clinical outcomes with a low risk of death or valve-related complications. Continued surveillance of late valve function is necessary.

Perioperative Assessment of the Hemodynamic Ventriculoarterial Junction of the Aortic Root by Three-Dimensional Echocardiography.

Improved strategies in aortic valve-preserving operations appreciate the dynamic, three-dimensional complexity of the aortic root and its valve. This depends not only on detailed four-dimensional imaging of the planar dimensions of the aortic root but also on quantitative assessment of the valvar leaflets and their competency. The zones of apposition and resulting hemodynamic ventriculoarterial junction formed in diastole determine valvar competency. Current understanding and assessment of this junction is limited, often relying on intraoperative direct surgical inspection. However, this direct inspection itself is limited by evaluation in a nonhemodynamic state with limited field of view. In this review, we discuss the anatomy of the aortic root, including its hemodynamic junction. We review current echocardiographic approaches toward interrogating the incompetent aortic valve for presurgical planning. Furthermore, we introduce and standardize a complementary approach to assessing this hemodynamic ventriculoarterial junction by three-dimensional echocardiography to further personalize presurgical planning for aortic valve surgery.

Midterm Clinical Outcomes of Reimplantation Versus Remodeling Valve-Sparing Aortic Root Replacement in Patients With Connective Tissue Disorders: A Meta-Analysis.

This meta-analysis aimed to compare the midterm clinical outcomes of reimplantation versus remodeling techniques for valve-sparing aortic root replacement (VSARR) in patients with connective tissue disorders (CTDs). Studies were screened and identified after the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines from the PubMed, Web of Science, and Embase databases. Forest plots were produced using Review Manager 5.3 (Cochrane, UK). Studies comparing early and midterm clinical outcomes of reimplantation versus remodeling VSARR in patients with CTD with a mean age ≥18 years were included. The sensitivity analysis excluded studies and subgroups of patients that received ring or suture annuloplasty in addition to remodeling surgery. The study selection identified 9 eligible studies. After analysis of the study period and location for patient crossover, 7 retrospective studies consisting of 597 patients (301 reimplantation and 296 remodeling) were pooled. The pooling revealed no significant difference in postoperative mortality (estimated mean follow-up of 10.5 years) (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.30 to 1.48, I2 = 30%, p = 0.32), reoperation (OR 0.35, CI 0.04 to 3.30, I2 = 81%, p = 0.36), or occurrence of postoperative aortic regurgitation of ≥2 (OR 0.56, CI 0.31 to 1.02, I2 = 47%, p = 0.06). The sensitivity analysis excluding annuloplasty demonstrated improved mortality (OR 0.19, CI 0.06 to 0.64, I2 = 0%, p = 0.007) and decreased aortic regurgitation of ≥2 (OR 0.23, CI 0.10 to 0.53, I2 = 47%, p = 0.0005) in reimplantation VSARR. The rates of reoperation remained insignificant in the sensitivity analysis (OR 0.43, CI 0.05 to 3.53, I2 = 71%, p = 0.43). In conclusion, this meta-analysis has demonstrated no significant difference in the midterm clinical outcomes of reimplantation versus remodeling techniques of VSARR. The sensitivity analysis excluding studies and patient subgroups that received remodeling and annuloplasty suggests remodeling alone to be inferior to reimplantation in patients with CTDs. Further research is required to assess remodeling and annuloplasty against reimplantation in patients of this demographic because the current body of knowledge does not allow sufficient analysis.

Outcomes of aortic root replacement with tricuspid aortic valve reimplantation in patients with residual aortic regurgitation.

OBJECTIVE: To characterize residual aortic regurgitation (AR), identify its risk factors, and evaluate outcomes following aortic root replacement with aortic valve reimplantation. METHODS: From 2002 to 2020, 756 patients with a tricuspid aortic valve underwent elective reimplantation for aortic root aneurysm. AR on transthoracic echocardiograms before hospital discharge was graded as mild or greater. Machine learning was used to identify risk factors for residual AR and subsequent aortic valve reoperation. RESULTS: Sixty-five patients (8.6%) had mild (58 [7.7%]) or moderate (7 [0.93%]) residual postoperative AR. They had more severe preoperative AR (38% vs 12%; P < .0001), thickened cusps (7.7% vs 2.2%; P = .008), aortic valve repair (38% vs 23%; P = .004), and multiple returns to cardiopulmonary bypass for additional repair (11% vs 3.3%; P = .003) than those without AR. Predictors of residual AR were severe preoperative AR, smaller aortic root graft, and concomitant cusp repair. At 10 years, patients with versus without residual AR had more moderate or severe AR (48% vs 7.0%; P < .0001) and freedom from reoperation was worse (89% vs 98%; P < .0001). Residual AR was a risk factor for early reoperation. Concomitant coronary bypass, lower body mass index, and lower ejection fraction were risk factors for late reoperation. Ten-year survival was similar among patients with and without residual AR (97% vs 93%; P = .43). CONCLUSIONS: Residual AR after elective reimplantation of a tricuspid aortic valve for aortic root aneurysm is uncommon. Patients with severe preoperative AR and those who undergo valve repair have higher risk for residual AR, which can progress and increase risk of aortic valve reoperation.

Cardiovascular Events After Aortic Root Repair in Patients With Marfan Syndrome.

BACKGROUND: The usefulness of aortic valve sparing operations to treat aortic root aneurysm in patients with Marfan syndrome (MS) remains controversial. OBJECTIVES: The purpose of this study was to evaluate the occurrence of cardiovascular events in patients with MS who have undergone valve-preserving aortic root replacement. METHODS: Patients with MS who had aortic valve sparing operations (reimplantation of the aortic valve or remodeling of the aortic root) from 1988 through 2019 were followed prospectively for a median of 14 years. Pertinent data from clinical, echocardiographic, computed tomography, and magnetic resonance images of the aorta were collected and analyzed. RESULTS: There were 189 patients whose mean age was 36 years, and 67% were men. Ten patients presented with acute type A dissection and 29 had mitral regurgitation. There were 52 patients at risk at 20 years. Mortality rate at 20 years was 21.5% (95% CI: 14.7%-30.8%); advancing age and preoperative aortic dissections were associated with increased risk of death by multivariable analysis. At 20 years, the cumulative incidence of moderate or severe aortic insufficiency was 14.5% (95% CI: 9.5%-22.0%), reoperation on the aortic valve was 7.5% (95% CI: 3.9%-14.7%), and new distal aortic dissections was 19.9% (95% CI: 13.9%-28.5%). Remodeling of aortic root was associated with greater risk of developing aortic insufficiency and aortic valve reoperation than reimplantation of the aortic valve. CONCLUSIONS: Aortic valve sparing operations provide stable aortic valve function and low rates of valve-related complications during the first 2 decades of follow-up but aortic dissections remain problematic in patients with MS.

Valve-sparing root reimplantation with a Valsalva graft for a trileaflet aortic valve.

Valve-sparing root reimplantation has become an attractive alternative to conventional aortic root replacement in young patients as a means to avoid the anticoagulation required for mechanical roots while improving the durability compared to bioprosthetic valved conduits. In this video tutorial, we present our step-by-step process for performing a valve-sparing root reimplantation with a Valsalva graft for a patient with an aortic root aneurysm and a trileaflet aortic valve.

Multi-modality imaging evaluation and pre-surgical planning for aortic valve-sparing operations in patients with aortic root aneurysm.

Cardiac computed tomography (CT) and magnetic resonance (CMR) supplement echocardiography in the evaluation of those with aortic root and ascending aortic dilation, determining timing for intervention, guiding pre-surgical planning and post-operative surveillance. The dynamic, three-dimensional complexity of the aortic root and how it relates to the base of the left ventricle must be understood in any surgical approach addressing the aneurysmal aortic root. With improved imaging technology and the importance for proper patient counseling, it is no longer acceptable to enter the operating theater without a detailed blue print of what the problem is, and how best to address it. In addition, reliance on surgical expertise alone for intraoperative evaluation and decision making could be suboptimal due to the unloaded condition of the aortic root and the variance of experience of the surgeons to successfully repair the aortic valve. This is exemplified by the selective surgeons and centers who have the ability to tackle these aortic valve and root pathologies, compared to mitral valve repair techniques that have been codified and are generalizable. This review discusses a multimodality imaging approach in the patient with aortic root aneurysm, focusing on the precision added with pre-surgical CT assessment to guide aortic-valve sparing operations. This precision is afforded with a detailed understanding of the anatomy of the aortic root and underlying support, and its accurate evaluation by standard two- and three-dimensional imaging. Furthermore, we describe the evolving ability to predict the location of ventricular components of the atrioventricular conduction axis with further clinical imaging to personalize surgical strategies.

Remodeling of the aortic root-a 28-year journey.

Background: Root remodeling is one form of valve-preserving root replacement for aortic regurgitation and root aneurysm. The objective of this review was to summarize our experience with root remodeling encompassing 28 years. Methods: We performed root remodeling in 1,189 patients (76% male, mean age 53±14 years) between October 1995 and September 2022. The original valve morphology was unicuspid in 33 (2%), bicuspid in 472 (40%) and tricuspid in 684 (58%) patients. Fifty-four patients (5%) had Marfan's syndrome. Objective measurement of valve configuration was performed in 804 (77%) and an external suture annuloplasty was added in 524 patients (44%). Cusp repair was performed in 1,047 (88%) patients, most commonly for prolapse (n=972; 82%). Mean follow-up was 6.7±5.5 years [1 month to 28 years]. Follow-up was 95% complete (7,700 patient-years). Results: Survival was 71% at 20 years; freedom from cardiac death was 80%. Freedom from aortic regurgitation ≥2 was 77% at 15 years. Freedom from reoperation was 89% and was higher in tricuspid aortic valves (94%) compared to bicuspid (84%) and unicuspid valves (P<0.001). Since the introduction of effective height measurement, freedom from reoperation has remained stable at 15 years (91%). With the addition of a suture annuloplasty, freedom from reoperation was 94% at 12 years. The difference with or without annuloplasty (91%) was not significant (P=0.949). Conclusions: Root remodeling is a viable option in valve-preserving root replacement. Concomitant cusp prolapse is frequent and can be corrected reproducibly by intraoperative measurement of effective height. The long-term benefit of an annuloplasty still needs to be defined.

Pathology and pathophysiology of the aortic root.

Pathologies of the aortic root amenable to repair with valve preservation include aneurysm formation, development of aortic insufficiency (AI) and aortic dissection. In the normal aortic root, the walls are constructed of 50-70 layers of concentric lamellar units. These units consist of sheets of elastin sandwiching smooth muscle cells interspersed with collagen and glycosaminoglycans. Medial degeneration results in disruption of the extracellular matrix (ECM), loss of smooth muscle cells and pooling of proteoglycans/glycosaminoglycans. These structural changes are associated with aneurysm formation. Aortic root aneurysms are commonly linked to hereditary thoracic aortic diseases including Marfan syndrome and Loeys-Dietz syndrome. One important pathway for hereditary thoracic aortic diseases is the transforming growth factor-ß (TGF-ß) cell-signalling pathway. Pathogenic gene mutations affecting various levels of this pathway have been implicated in aortic root aneurysm formation. Secondary effects of aneurysm formation include AI. Severe chronic AI leads to a pressure and volume load on the heart. Once symptoms develop or significant left ventricular remodelling and dysfunction occurs, the patient's prognosis is poor without surgery. Another consequence of aneurysm formation and medial degeneration is the risk of aortic dissection. Aortic root surgery is performed in 34-41% of surgeries for type A aortic dissection. Predicting those who will experience aortic dissections remains a challenge. Finite element analysis, study of fluid-structure interactions and aortic wall biomechanics are important areas of ongoing research.

Aortic valve-sparing root replacement or Bentall?

Surgery of the aortic root is a challenging operation for which different techniques have been developed and refined over the last five decades. We present a review of surgical strategies and their most relevant modifications along with a summary of the most recent evidence on early and long-term outcomes. Additionally, we provide brief descriptions of the use of the valve-sparing technique in various clinical settings, including high-risk patients such as those with connective tissue disorders or concomitant dissection.

Flanged Bentall and Cabrol Procedures for Complex Aortic Root Diseases.

For complex aortic root lesions, the flanged Bentall procedure has more advantages than the traditional one. Here, we report two patients with complex root lesions treated with the flanged Bentall and Cabrol procedure: one was a 25-year-old male with interventricular septal dissection with Behçet's disease, and the other was a 4-year-old female with a very large ascending aortic aneurysm with a small annulus and Loeys-Dietz syndrome. Both patients recovered uneventfully and obtained good short-term results.

Twenty-five years of root remodelling for root aneurysm and tricuspid aortic valve.

OBJECTIVES: The aim of this retrospective study was to assess the long-term results of root remodelling with tricuspid aortic valves and the effects of concomitant cusp repair and annuloplasty. METHODS: Between October 1995 and December 2021, 684 patients with root aneurysm and regurgitant tricuspid valves were treated by root remodelling. The mean age was 56.5 [standard deviation (SD): 14] years, and 538 (77.6%) were male. Relevant aortic regurgitation was present in 68.3%. Concomitant procedures were performed in 374 patients. The long-term results were analysed. The mean follow-up of 7.2 (SD: 5.3) years (median 6.6 years); it was 95% complete (4934.4 patient-years). RESULTS: Cusp prolapse was repaired in 83%, and an annuloplasty was added in 353 instances (51.6%). Hospital mortality was 2.3%, and survival was 81.7% (SD: 1.2) and 55.7% (SD: 5.8) at 10 and 20 years; age and measurement of effective height were independent predictors for death. Freedom from Aortic insufficiency (AI) II was 90.5 (SD: 1.9) at 10 years and 76.7 (SD: 4.5) at 20 years. Cusp repair of all cusps showed a lower freedom from recurrent AI ≥II at 10 years (P < 0.001). Suture annuloplasty showed a lower freedom from recurrent AI II at 10 years (P = 0.07). Freedom from reoperation was 95.5 (SD: 1.1) and 92.8 (SD: 2.8) at 10 and 20 years. The addition of an annuloplasty showed no difference (P = 0.236). Cusp repair had no effect on valve durability (P = 0.390). CONCLUSIONS: Root remodelling leads to good long-term stability. The addition of cusp repair improves the valve stability over time. The addition of suture annuloplasty improves early valve competency; it showed no effect on freedom from reoperation up to 10 years.

Aortic valve reimplantation in patients with connective tissue disorders: Are the leaflets durable?

OBJECTIVE: The durability of reimplanted myxomatous aortic valves in root replacements for patients with connective tissue disorders (CTD) is unclear; therefore, we sought to evaluate the long-term resilience of these repairs. METHODS: From January 1980 to January 2020, 214 patients with CTD and 645 without CTD underwent primary, elective aortic valve reimplantation operations at Cleveland Clinic. The CTD cohort included 164 (77%) with Marfan, 23 (11%) with Loeys-Dietz, and 7 (3.3%) with Ehlers-Danlos CTD. We accounted for differing patient characteristics between the groups by propensity score matching to compare outcomes, yielding 96 matched pairs. Longitudinal echocardiographic measures were compared using nonlinear mixed effects models. RESULTS: In the CTD cohort, there were no operative mortalities (30-day or in-hospital), 1 (0.47%) stroke, and 1 (0.47%) early in-hospital reoperation for valve dysfunction. Ten-year prevalence of no aortic regurgitation was 86%, mild 11%, and moderate 3%. Ten-year freedom from reoperation was 97%. In propensity matched cohorts, there were no significant differences in in-hospital outcomes, longitudinal aortic regurgitation and mean gradient, risk of reoperation on the aortic valve, or risk of late death. CONCLUSIONS: Aortic valve reimplantation is a durable operation in patients with CTD and root aneurysms. These patients do not experience early degeneration of their reimplanted aortic valves.

Aortic root replacement in the setting of a mildly dilated nonsyndromic ascending aorta.

OBJECTIVE: There is controversy on how to address mild aortic root dilation during concomitant aortic valve replacement: composite aortic valve conduit replacement or separate ascending aorta and aortic valve replacement. We reviewed our experience to address the issue. METHODS: We retrospectively reviewed 778 adult nonsyndromic patients with aortic root diameter 55 mm or less who received replacement of the ascending aorta and aortic valve from January 1994 to June 2017. Patients were divided into 2 groups based on the type of aortic root intervention: composite aortic valve conduit replacement in 406 patients (52%) and separate ascending aorta and aortic valve replacement in 372 patients (48%). Propensity matching was used to mitigate differences in baseline patient characteristics and produced 188 matched pairs. RESULTS: Sinus of Valsalva diameter was 43 mm (39-47). Operative mortality occurred in 3 patients (2%) in the composite aortic valve conduit replacement group and in 5 patients (3%) in the separate ascending aorta and aortic valve replacement group (P = .470). Median follow-up was 9.6 years (8.4-10.1). Long-term mortality was similar in the 2 groups (P = .083). Repeat operation was performed in 13 patients (7%) in the composite aortic valve conduit replacement group and in 19 patients (10%) in the separate ascending aorta and aortic valve replacement group (P = .365). Sinus of Valsalva diameter decreased 2 mm (-4-0; median follow-up 41 months) in the propensity-matched separate ascending aorta and aortic valve replacement group. CONCLUSIONS: In patients with mild aortic root dilation, separate ascending aorta and aortic valve replacement results in a similar risk of repeat operation and mortality in comparison with composite aortic valve replacement. Separate ascending aorta and aortic valve replacement is not associated with subsequent aortic root dilation on medium-term echocardiography follow-up.