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. 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. Connective tissue disorders (CTDs) are a group of genetic conditions that affect the function of the extracellular matrix, resulting in subsequent pathology of multiple systems, including the cardiovascular system. The most common of which is Marfan syndrome, an autosomal dominant condition associated with the FBN-1 genetic mutation that transcribes the fibrillin-1 extracellular matrix protein. Similar pathophysiologic patterns are observed in Ehlers-Danlos syndrome and Loeys–Dietz syndrome, inheritable conditions caused by collagen and transforming growth factor dysfunction, respectively.1Grygiel-Górniak B Oduah MT Olagunju A Klokner M. Disorders of the aorta and aortic valve in connective tissue diseases.Curr Cardiol Rep. 2020; 22: 70Crossref PubMed Scopus (12) Google Scholar Patients with CTDs often present with more severe aortopathy—including valvular regurgitation, aneurysmal dilation, and dissection—at a younger age, requiring alternative surgical consideration to patients without CTDs.2Pizano A Tenorio ER Tanaka A Oderich GS. Chapter 24. Aneurysmatic degeneration of connective tissue diseases: from diagnosis to treatment.in: Settembrini P Settembrini AM Vascular Surgery. Academic Press, Cambridge2022: 273-295Crossref Scopus (1) Google Scholar,3Zeigler SM Sloan B Jones JA. Pathophysiology and pathogenesis of Marfan syndrome.in: Halper J Progress in Heritable Soft Connective Tissue Diseases. Springer International Publishing, Cham2021: 185-206Crossref Scopus (25) Google Scholar A total of 2 previous meta-analyses have compared the clinical outcomes of valve-sparing aortic root replacement (VSARR) versus composite valve grafts in patients with CTDs. In addition to the lack of anticoagulation burden, Flynn et al4Flynn CD Tian DH Wilson-Smith A David T Matalanis G Misfeld M Mastrobuoni S El Khoury G Yan TD Systematic review and meta-analysis of surgical outcomes in Marfan patients undergoing aortic root surgery by composite-valve graft or valve sparing root replacement.Ann Cardiothorac Surg. 2017; 6: 570-581Crossref PubMed Scopus (52) Google Scholar and Soto et al5Soto ME Ochoa-Hein E Anaya-Ayala JE Ayala-Picazo M Koretzky SG. Systematic review and meta-analysis of aortic valve-sparing surgery versus replacement surgery in ascending aortic aneurysms and dissection in patients with Marfan syndrome and other genetic connective tissue disorders.J Thorac Dis. 2021; 13: 4830-4844Crossref PubMed Scopus (8) Google Scholar have demonstrated decreased rates of thromboembolic events and infective endocarditis in patients who underwent VSARR of this demographic. As a result of earlier diagnoses and improved aortic surveillance, patients with CTDs are more frequently offered prophylactic VSARR surgery, providing improved outcomes compared with nonelective surgery.6Pepper J. External aortic support and other alternative strategies in the management of aortic pathology of patients with connective tissue disorders.in: Sellke FW Coselli JS Sundt TM Bavaria JE Sodha NR Aortic Dissection and Acute Aortic Syndromes. Springer International Publishing, Cham2021: 469-482Crossref Scopus (1) Google Scholar,7Choudhary SK Goyal A. Aortic root surgery in Marfan syndrome.Indian J Thorac Cardiovasc Surg. 2019; 35: 79-86Crossref PubMed Scopus (5) Google Scholar There is limited evidence and a lack of randomized data as to whether reimplantation of the native valve8David TE Feindel CM. An aortic valve-sparing operation for patients with aortic incompetence and aneurysm of the ascending aorta.J Thorac Cardiovasc Surg. 1992; 103 (discussion 622): 617-621Abstract Full Text PDF PubMed Google Scholar or remodeling of the aortic root9Sarsam MA Yacoub M. Remodeling of the aortic valve anulus.J Thorac Cardiovasc Surg. 1993; 105: 435-438Abstract Full Text PDF PubMed Google Scholar produces superior clinical outcomes in patients with CTD. Many surgeons advocate for reimplantation techniques because of the perceived increased risk of annular dilation in remodeling VSARR despite the technique producing postoperative structures similar to native anatomy and preserving physiologic movements associated with the aortic root in systole and diastole.10Klotz S Stock S Sievers HH Diwoky M Petersen M Stierle U Richardt D. Survival and reoperation pattern after 20 years of experience with aortic valve-sparing root replacement in patients with tricuspid and bicuspid valves.J Thorac Cardiovasc Surg. 2018; 155: 1403-1411.e1Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar A 2020 meta-analysis by Zhou et al11Zhou Z Liang M Huang S Wu Z. Reimplantation versus remodeling in valve-sparing surgery for aortic root aneurysms: a meta-analysis.J Thorac Dis. 2020; 12: 4742-4753Crossref PubMed Scopus (10) Google Scholar demonstrated improved rates of reoperation and aortic regurgitation and decreased mortality in reimplantation compared with remodeling VSARR in patients without CTDs.11Zhou Z Liang M Huang S Wu Z. Reimplantation versus remodeling in valve-sparing surgery for aortic root aneurysms: a meta-analysis.J Thorac Dis. 2020; 12: 4742-4753Crossref PubMed Scopus (10) Google Scholar However, the etiology of the included study population does not represent the demographic of patients with CTDs nor does it assess the implementation of structural annuloplasty in remodeling surgery. As a result of the recent increase in published data, we aimed to produce the first feasible meta-analysis comparing the clinical outcomes of reimplantation and remodeling VSARR surgery in adult patients with CTDs, with consideration given to developing surgical techniques. PubMed, Web of Science, and Embase databases were used for preliminary study identification, using the search terms ([“connective tissue disorder” OR “Marfan's syndrome”] AND “aortic root replacement”) and reviewed in adherence with Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA).12Page MJ McKenzie JE Bossuyt PM Boutron I Hoffmann TC Mulrow CD Shamseer L Tetzlaff JM Akl EA Brennan SE Chou R Glanville J Grimshaw JM Hróbjartsson A Lalu MM Li T Loder EW Mayo-Wilson E McDonald S McGuinness LA Stewart LA Thomas J Tricco AC Welch VA Whiting P Moher D. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.BMJ. 2021; 372: n71Crossref PubMed Scopus (24752) Google Scholar The PRISMA guidelines and adherence evidence are available to view in the supplementary material. Studies that met the inclusion criteria were selected for review. The inclusion criteria required double-arm studies comparing reimplantation versus remodeling VSARR in patients with CTDs, with a mean age ≥18 years. Abstracts, conference presentations, case reports, editorials, expert opinions, and non-English language studies were excluded from screening. Search results were screened by way of assessment of the study title/abstract, and full manuscripts were reviewed by the application of the aforementioned inclusion and exclusion criteria. Uncertainty or variation of study assessment was resolved by discussion. The outcomes were independently assessed for potential patient crossover by the evaluation of study data unit location and study periods. Priority was given to bias-treated data and more recently published in the event that study location and study period presented a high risk of patient crossover. The Newcastle–Ottawa scale was used to assess the quality of all included studies, with scores ≥6 of a potential 9 considered as high quality.13Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses.Eur J Epidemiol. 2010; 25: 603-605Crossref PubMed Scopus (11234) Google Scholar Funnel plot assessment was used to determine the risk of reporting and publication bias.14Sterne JAC Sutton AJ Ioannidis JPA Terrin N Jones DR Lau J Carpenter J Rücker G Harbord RM Schmid CH Tetzlaff J Deeks JJ Peters J Macaskill P Schwarzer G Duval S Altman DG Moher D Higgins JPT. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.BMJ. 2011; 343: d4002Crossref PubMed Scopus (4508) Google Scholar Analysis data were extracted from study text, tables, and figures, with raw figures calculated from percentages where available and necessary. The obtained study data include study period and location, method, surgical techniques, demographic, and patient outcomes. The use of structural annuloplasty in remodeling surgery was extracted from surgical technique data provided in the study methods. All clinical outcomes reported by a significant number of included studies were pooled for analysis. Early and midterm outcomes include in-hospital mortality, stroke, re-exploration for bleeding, long-term mortality, reoperation rates, and postoperative occurrence of aortic regurgitation. Sensitivity analysis was performed, excluding studies and patient subgroups that received suture or ring annuloplasties. Statistical meta-analyses and forest plots were performed on Review Manager 5.3 by way of the Mantel–Haenszel test, producing odds ratios (ORs) for dichotomous data with a 95% confidence interval (CI).15Review Manager (RevMan) [computer program]. version 5.4. London: The Cochrane Collaboration; 2020.Google Scholar Fixed-effects models were used where heterogeneity (I2) was calculated to be <50%, with random effects used when I2 ≥50%. Individual forest plots were calculated where or more included studies reported postoperative clinical outcomes. and bias-treated data were where study using search preliminary search terms ([“connective tissue disorder” OR “Marfan's syndrome”] AND “aortic root replacement”) produced from PubMed, Web of Science, and Embase After the exclusion of were screened for full analysis. the studies for were excluded on the of including an patient a mean patient age of years or the of patients with CTDs. A total of 9 studies met the inclusion criteria for the assessment of the unit location and study period identified patient crossover. A subsequent of bias-treated and more recently published data in the inclusion of 7 studies subsequent a published study by David et TE J M M events after aortic root in patients with Marfan PubMed Scopus (5) Google Scholar was which provided more patient from the and study period as the included study by et M David TE David M M. outcomes of reimplantation remodeling in Marfan a Thorac Surg. Full Text Full Text PDF PubMed Scopus (10) Google Scholar After we that we data from the published study because of the use of and subsequent in selection assessment of the included studies all data to be high The Newcastle–Ottawa scale assessment is in the M David TE David M M. outcomes of reimplantation remodeling in Marfan a Thorac Surg. Full Text Full Text PDF PubMed Scopus (10) Google SM JAC of aortic valve-sparing experience with remodeling and reimplantation in Thorac Surg. (discussion Full Text Full Text PDF PubMed Scopus Google J L El Khoury G E I of valve-sparing surgery in aortic results from the J Cardiothorac Surg. PubMed Scopus (12) Google LA Aortic root for Marfan a of the and valve-sparing Thorac Surg. (discussion Full Text Full Text PDF PubMed Scopus Google J A D LA outcomes of aortic root for Marfan a of versus aortic valve-sparing Thorac Cardiovasc Surg. Full Text Full Text PDF PubMed Scopus Google B D A in aortic root surgery in Marfan bleeding, and risk of after valve-sparing or aortic root J Cardiothorac Surg. (discussion PubMed Scopus Google R Tian operation for aortic root aneurysm in patients with Marfan Cardiovasc Surg. 2010; PubMed Scopus (5) Google Scholar the of the included of of annuloplasty et et et et et et et in a included studies reported long-term mortality in patients with an mean follow-up of 10.5 years. The pooled reimplantation group demonstrated a mortality of compared with of patients who received remodeling VSARR (OR 0.66, 95% CI 0.30 to 1.48, I2 = 30%, p = mortality not the patient However, in the sensitivity the exclusion of patients who received annuloplasty in addition to remodeling surgery to an of mortality (OR 0.19, 95% CI 0.06 to 0.64, I2 = 0%, p = demonstrated postoperative in the reimplantation group to be superior to remodeling surgery without structural The rates of with an of were reported in an patients with an of in the group and in the remodeling group (OR 0.35, 95% CI 0.04 to 3.30, I2 = 81%, p = The sensitivity analysis excluding studies and subgroups of patients that received remodeling with annuloplasty VSARR years) demonstrated a reoperation of in the reimplantation group and in the remodeling group (OR 0.43, 95% CI 0.05 to 3.53, I2 = 71%, p = The meta-analysis of included studies not in the reoperation reimplantation and remodeling of the addition of structural annuloplasty in remodeling surgery. The occurrence of to severe postoperative aortic regurgitation in patients with an of years was as and in patients who received reimplantation and remodeling VSARR (OR 0.56, 95% CI 0.31 to 1.02, I2 = 47%, p = The sensitivity analysis excluding patients who received annuloplasty in addition to remodeling surgery with an of years demonstrated an occurrence of in the reimplantation and in the remodeling group (OR 0.23, 95% CI 0.10 to 0.53, I2 = 47%, p = the sensitivity analysis that patients with CTDs who received remodeling surgery in the of annuloplasty are more to aortic Patients with CTDs are earlier in as a result of improved genetic and of aortic function and In addition to management of prophylactic aortic root replacement is the E LA G R of the aortic root in and with Marfan PubMed Scopus Google E M M G R J M A G CH Marfan syndrome and connective tissue disorders in the current in in 103 and surgical management and of genetic 2020; Google Scholar the for prophylactic surgery associated CTDs, the valve-sparing surgery clinical evidence and the of in on the quality of J D D Coselli JS outcomes of valve-sparing aortic root versus composite aortic valve graft replacement for aortic root meta-analysis of J Surg. Full Text Full Text PDF PubMed Scopus Google T A L T J a support for aortic root surgery in Marfan 2018; PubMed Scopus Google Scholar The use of prophylactic surgery in with the age of patients with CTD a postoperative this the of whether preserving the native valve in VSARR the long-term in patients with CTDs. In a et B J Aortic valve reimplantation in patients with connective tissue are the Thorac Cardiovasc Surg. Full Text Full Text PDF PubMed Scopus Google Scholar and compared the long-term outcomes of VSARR in patients with CTDs against patients The follow-up reported no difference in mortality, or aortic regurgitation rates the study the structural of the of patients with CTDs. The study excluded remodeling techniques because of perceived postoperative with the study of it is that remodeling with structural annuloplasty not B J Aortic valve reimplantation in patients with connective tissue are the Thorac Cardiovasc Surg. Full Text Full Text PDF PubMed Scopus Google Scholar the of the aortic valve after surgery, postoperative aortic regurgitation is to annular dilation to CTD of the aortic required to pathology resulting from annular Lau of valve-sparing root replacement in patients with and without connective tissue J Thorac Cardiovasc Scholar the native valve is the the valve from dilation, as to remodeling surgery in which the graft is the aortic the of valve providing structural support against annular the of remodeling techniques used suture and ring structural annuloplasty to of the aortic and postoperative aortic regurgitation by way of the of the E M M G R J M A G CH Marfan syndrome and connective tissue disorders in the current in in 103 and surgical management and of genetic 2020; Google M B R P N M Reimplantation versus with ring of outcomes after valve-sparing aortic root J Cardiothorac Surg. 2018; PubMed Scopus Google Scholar The clinical of structural support in remodeling surgery is in the midterm rates of postoperative aortic regurgitation and mortality were not significant the study after sensitivity analysis and the exclusion of patients who underwent remodeling and the outcomes reimplantation surgery. this meta-analysis does not assess the of be an of postoperative aortic regurgitation the of and mortality because of the of The current body of knowledge does not allow the of remodeling with annuloplasty alone versus reimplantation clinical outcomes. studies that and experience the occurrence of postoperative aortic regurgitation and of with reporting from reoperation in patients with Marfan TE David J AM of aortic valve-sparing in Marfan PubMed Scopus Google Scholar This be by the more of the aortic the and to and aortic regurgitation to the in aortic root P I for aortic annuloplasty to aortic valve Cardiothorac Surg. 2019; PubMed Scopus Google U T I aortic root replacement in patients with Marfan Cardiothorac Surg. 2017; 6: PubMed Scopus Google Scholar techniques and clinical annular dilation, have to an increased of reimplantation VSARR in patients with CTDs, despite the consideration of postoperative A study compared the of postoperative structures after reimplantation and remodeling surgery in research The results demonstrated an increased of high and in reimplantation surgery, as to remodeling surgery, that produced models more with the native root D S Z M of on aortic root of aortic root and valve J Cardiothorac Surg. 2017; Google Scholar The results be associated with the use of grafts in reimplantation remodeling techniques the of The of grafts in reimplantation surgery has produced to more to and improved valve T M J S R M Aortic root valve-sparing root replacement with reimplantation or 2021; PubMed Scopus Google M P A M J M Richardt D Sievers HH analysis of in valve-sparing aortic root with an Thorac Cardiovasc Surg. Full Text Full Text PDF PubMed Scopus Google Scholar The assessment of reimplantation with grafts and remodeling with annuloplasty demonstrated similar results in multiple studies. The heterogeneity of and structures be considered in view of the aforementioned M T J R S M of and root remodeling and reimplantation for valve-sparing aortic root a PubMed Scopus (1) Google Scholar long-term patient data to results of reimplantation surgery using I R A S L experience of aortic valve reimplantation using the J Cardiothorac Surg. PubMed Scopus Google Scholar patients with CTDs to be a high risk of aortic dissection after root surgery and follow-up and assessment of aortic prophylactic VSARR to evidence improved long-term clinical A D J J J Soto JE B S S S D Aortic valve reimplantation in patients with connective tissue a J Cardiothorac Surg. PubMed Scopus Google Scholar the of VSARR surgery, the of and experience on patient outcomes not be N JM and risk of of valve-sparing aortic root Thorac Cardiovasc Surg. Full Text Full Text PDF PubMed Scopus Google Scholar analysis has demonstrated that remodeling without annuloplasty is not in patients with CTDs. this analysis the quality available data to patients of this demographic and research of VSARR outcomes given surgical techniques. of and studies are to the improved of research in this This meta-analysis has including the limited study included in the analysis. The occurrence of thromboembolic events and early including the of in-hospital mortality, stroke, and to for bleeding, were reported by a significant number of studies to allow However, the of events in the of patient not allow analysis. In the limited number of included studies in a assessment of funnel plots and the of of the of VSARR surgery in patients of this limited is a lack of randomized data and to for with of the included studies using The sensitivity analysis by way of data from the study by David et TE J M M events after aortic root in patients with Marfan PubMed Scopus (5) Google Scholar the study by et M David TE David M M. outcomes of reimplantation remodeling in Marfan a Thorac Surg. Full Text Full Text PDF PubMed Scopus (10) Google the of long-term aortic regurgitation. of the included studies produced data comparing reimplantation and remodeling surgery the study group of VSARR. not all demographic data are available to study et et et et et et et Tissue Disorders Aortic ≥2 Aortic Dissection in a Remodeling techniques have demonstrated midterm clinical outcomes in patients with CTDs compared with reimplantation VSARR surgery. The exclusion of patients who received structural annuloplasty produced superior rates of mortality and aortic regurgitation in the reimplantation study There be postoperative physiologic provided by remodeling surgery, and more research is required to assess the long-term effects of structural annuloplasty and remodeling surgery in patients of this demographic.