{'fraction_non_alphanumeric': 0.03955810699985528, 'fraction_numerical': 0.02402431376332674, 'mean_word_length': 5.2951715760704525, 'pattern_counts': {'":': 0, '<': 3, '<?xml version=': 0, '>': 4, 'https://': 1, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 4, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Revisiting the guidelines and choice the ideal substitute for aortic valve endocarditis

Aortic valve replacement is the most commonly performed cardiac surgical operation worldwide for infective endocarditis (IE). Long-term durability and avoidance of infection relapse are the treatment goals. However, no detailed guidelines on prosthesis selection and surgical strategy are available. Management should be guided by a comprehensive evaluation of infection extension and its microbiological characteristics, the clinical profile of the patient and the risk of infection recurrence. We conducted a literature search of the PubMed database, EMBASE and Cochrane Library (through November 2019) for studies reporting to the use of biological substitutes in aortic valve endocarditis (AVE). Studies comparing long-term outcomes in the use of allogenic and autologous with conventional prostheses were investigated. Conventional mechanical or stented xenografts are the preferred choice for localized aortic infection. In cases of complex IE with the involvement of the root or the aorto-mitral continuity, the use of homografts are recommended, according to surgeon’s and center experience. Homograft use needs to be balanced against the risk of structural degeneration. Prosthetic bioroot or prosthetic valved conduit with a mechanical or bioprosthetic valve are acceptable alternatives. The choice of aortic valves substitute and surgical strategy in IE is multifaceted. Principles guiding the selection of prosthesis and surgical approach rely on the long-term durability and the avoidance of infection relapse. A decisional algorithm considering the extension of the infection and its microbiological characteristics, the clinical profile of the patient and the risk of infection recurrence is provided. A multidisciplinary effort is required to achieve consistent outcomes.

We reviewed the literature comparing different surgical strategies for treatment of AVE including our own experience and discuss current evidence-based practice whilst proposing an algorithm to guide valve choice.

Methods
We included all randomized controlled trials, significant retrospective studies and sub-studies evaluating outcomes of patients undergoing aortic valve replacement for endocarditis. The literature search through PubMed from its inception up to 5 th November 2019 included the following keywords with the related MeSH terms: "endocarditis", "aortic valve", "heart valve prosthesis", "allograft", "autograft", "cardiac surgery", "aortic valve replacement". Guidelines, professional society recommendations, registries, editorials, case series, prior systematic reviews were considered as additional references. Four thousand one hundred eleven patients for xenograft prosthetic (XP), 2,454 for cryopreserved aortic homograft (CAH), 665 for the mechanical prosthetic (MP), and <200 for Ross operation and aortic valve repair extracted and evaluated (Tables S1,S2).

Homograft replacement for AVE
The survival benefits associated with the use of the aortic homograft for aortic valve replacement were established in a landmark paper from the Brisbane group and Harefield group almost 40 years ago (5,6,9). Allogenic tissue is more likely to be used in patients with active endocarditis and the most severely infected field (5)(6)(7)(8)(9)(10)12,13). The Harvard group reported a significant increase in the proportion of patients treated with allogenic tissue when abscess formation occurred (67% vs. 41% for mechanical valve and 30% for xenograft valves, P<0.001) or when there is infection with methicillin-resistant Staphylococcus (26% vs. 13% for mechanical prosthesis and 12% for xenograft) (8).
Several studies have reported substantially inferior infection relapse rates with aortic homograft substitutes. Fukushima et al. (9) showed low rate (0.2%) of re-infection at 30 days and 5.5% rate of late infection with a median time of 5 years (4 months to 16 years) post-homograft implantation. Arabkhani et al. (10) revealed excellent results at up to 27 years postoperatively using aortic homografts, with a low incidence of reoperation for re-infection (2.2%). Allogenic tissues have favorable responses to antibiotic treatment [effective in 21-25% of cases (7,8)]. Musci et al. (22) reported 221 homograft aortic root replacements in 1,163 patients with active endocarditis and peri-annular abscess highlighting a lower rate of recurrence of infection (5.4%) in native valve endocarditis (NVE) and prosthetic valve endocarditis with a 10-year freedom from reoperation rate of 92.9%±3.2% and 92.1%±2.5%, respectively. Early mortality was 16% (NVE) and 25% for (PVE) with improved 10-year survival in NVE (47% vs. 35%). More than 25% of deaths were intraoperative, highlighting the operative complexity among critically ill patients. Yankah et al. (23) showed excellent clinical performance and durability with low reinfection and a late mortality rate of 7.9%. Patient survival was 97% and 91% at 1-and 10-year, respectively. Perrotta et al. (24) demonstrated a 5-year cumulative survival of 88% in homografts versus 66% in prostheses in PVE. Kim et al. (8) showed lower risk of reinfection within 1-year in homograft recipients.
We used the homograft for aortic and mitral valve disease in 56.2% and 21% of patients with abscess formation (5,(25)(26)(27)(28) (Figure 1). Sometimes, a double homograft is used in aggressive IE with extension to the aorto-mitral junction and mitral valve (25)(26)(27)(28). We performed monobloc implants in two-thirds of recipients, and a separate bloc with partial mitral homograft insertion in the remaining (5,27,28). The technique of implant provided good results even with fragile tissues (28) .
The limited use of allogeneic tissue may be due to the enthusiasm that antibiotic therapy alone is building for some cases of PVE (29), previously considered as a clear indication for surgery (1). The inclination to use allogeneic tissues in extensive infection of heart structure, either in native or prosthesis valve disease, is supported by Steffen et al. (30). The authors have shown that CAH has antibacterial activity despite long-term conservation for 5 years. Antimicrobial combinations (gentamicin, piperacillin, vancomycin, metronidazole, amphotericin B, flucloxacillin, meropenem, tobramycin and colistin) applied during allogenic tissue processing have a significant influence on their infection resistance. Homograft tissue of ascending aortic revealed a significantly enhanced bacterial resistance against staphylococcal bacteria (S epidermidis and S aureus) with less bacterial contamination compared to homograft aortic valves. More effective resistance was found against P aeruginosa using flucloxacillin and E coli with meropenem and colistin (31). Application of antibiotic after thawing CAH led to a significant decrease in the recurrence of infections (32); a phenomenon not demonstrated in conventional prosthesis or Dacron graft, although the risk of vascular graft infection is reduced by pretreating the prosthesis with antibiotics (33). Indeed, the antibiotic/fibrin compound showed a favorable effect of delayed release of antibiotics in the early prevention of the relapse of infection (33). Furthermore, new suggestions are regarding more effective concentrations of β-lactam antibiotics which may enhance this action, providing additional immunity to infection recurrence (33). The favorable response of allogeneic tissue to antibiotic treatment is already documented in the pivotal series where CAH was successfully treated medically (from 21% to 25%) (5,9,10).

Ross procedure for AVE
The Ross procedure is of limited use in endocarditis (11,34). The increased surgical complexity alongside the potential for long-term failure of 2 valves (aortic and pulmonary) has been discouraging, with a 3-fold increase in operative mortality compared to conventional aortic valve replacement (35). However, a volume-outcome relationship has been reported with lower mortality in highvolume centers (0.3-1.1%) (6,8). This rekindled the role of the pulmonary autograft in management of AVE, when avoiding prosthetic material is necessary, increased risk of relapsing infection or in women of childbearing age (36). The Ross operation has shown optimal long-term results with low rates of valve-related complications for recurrent endocarditis ( Figure 2). Patients with life expectancy >15 years, active lifestyle and no severe comorbidities should be referred to centers with high surgical experience (36,39).

Stented/non-stented xenograft
The major concern for xenografts is the increased risk of SVD. A recent meta-analysis including all types of available aortic xenograft (porcine and pericardial) revealed that SVD commonly starts 8 years post-surgery, exponentially increasing after 10 years, which is comparable to a homograft (42,43). Carpentier-Edwards Perimount stented aortic (CEP) (Edwards Lifesciences Inc., Irvine, California, USA) pericardial valve is widely used in North America and Europe. In one study involving 2,559 patients, 13.9% of recipients were <60 years and 111 (4%) had IE. The authors reported actuarial freedom from SVD at 20 years of 48.5%, and an expected valve durability (median survival time without SVD) of 19 years. Freedom from recurrent endocarditis was 88.8% at 20 years (44). The Cleveland Clinic group included 12,569 patients (mean follow-up duration >5.8 years) with CEP implanted in the aortic position. Three hundred fifty-four prostheses were  Long-term durability of CEP was better than expected in younger patients. Bioprosthetic valves are recommended i n y o u n g p a t i e n t s w i t h AV E w h o w i s h t o a v o i d anticoagulation (1). It is important to implant large bioprostheses (>21 mm) for future potential transcatheter valve-in-valve procedures in case of SVD. Transcatheter interventions on small-sized valves should be avoided due to the potential risk of early attenuated leaflet motion, transcatheter heart valve thrombosis and SVD (46). No significant difference in freedom from reoperation at 8 years was found when Perimount and Hancock II valves were compared (98% and 97% respectively) with low endocarditis reoperation rates in both (47).

Mechanical prosthesis
There are no randomized studies comparing mechanical vs. bioprosthetic valves in endocarditis (2,4,8,14,53). The inferior survival benefit associated with bioprosthetic valves were established by a French multicenter AVE study (53) where patients underwent homograft (16%), bioprosthetic (19%), or mechanical (65%) replacement with 5-year follow-up. The advantage reported in the mechanical group was likely related to the younger age and reduced comorbidities of the patients in this group. The Stanford group (3) (8,54). The data coincided with David et al. (2), who reported excellent results when mechanical valves were used with synthetic patches or prosthetic valve conduits in complicated AVE.

Future perspectives
The increasing use of cardiac implantable electronic devices and the recent TAVR expansion have significant implications for potential IE on these percutaneously implanted devices and the infection risk profile of the patients undergoing these procedures.
The use of TAVR is not indicated in endocarditis. The use of sutureless valves may be an alternative, especially in cases of endocarditis in high-risk patients in which reduced operative times are desirable. However, the current experience and results on the benefit of sutureless valves in AVE are scarce (55-57).

Discussion
The incidence of IE is 3-10 per 100,000 ranging from 35% (2) to 39.1% (58) for native aortic valve involvement and from 56% (59), to 64.4% (58) in patients with previous aortic valve surgery. In AVE, the surgeon has 2 dilemmas: (I) the timing of the operation (II) and choice of the valve substitute depending on the extent and position of the infectious lesion. Timing for surgery of AVE is conditioned by uncontrolled infection, risk of embolism and heart failure (Figures 4-6).

Choice of substitute and extension of IE
Patients with one or more aortic valve leaflet(s) involvement at risk of bacterial embolism (large vegetation >10 mm), and/or with left ventricular dysfunction, should be offered surgery. Successful outcomes encompass the following general principles: (I) restoration of aortic valve competence; (II) restoration/preservation of annular structural integrity; (III) absence of residual infection postsurgery. The general principle of a radical debridement of the entire infected area applies and intraoperative TEE is mandatory for AVE.
Aortic valve replacement is the most common surgical operation performed for IE. Aortic valve repair may be performed in localized infections with uncomplicated NVE of the aortic valve (60) (Class I Level B) caused by highly sensitive streptococci treated for 2-week with antibiotic therapy and involving the mitral valve as primary localization (26,27). It has a high re-operation rate despite being limited to experienced surgeons (60,61). For localized infections of the native aortic valve (Class I Level B), aortic valve replacement remains the most effective surgical method for several categories of patients. Long-term durability and avoidance of re-infection is the treatment goal. Yet, no precise guidelines on prosthesis selection exist, and the choice of surgical strategy for aortic IE remains a "dark art" (2,3,8,16). Many surgeons prefer conventional mechanical or stented xenografts alone or combined with polyester or pericardial patch when reconstruction of the annulus is required (15-18) (Class IIa Level B) (16). The choice of conventional valvesmechanical or tissue prostheses-is guided by the following criteria: age, life expectancy, comorbidities, and expected compliance with anticoagulation. It is reasonable to avoid the use of conventional mechanical valves in patients with any intracranial bleeding or those who have suffered a major stroke (Class IIa Level C) (16).
For extended infections, aortic root replacement and reconstruction of regional contiguity is the recommended

Indications for surgery in patients with AVE based on classification of recommendation (COR) and level of evidence (LOE) surgeon should be performed operation on within days
Class I Level B Class IIa Level C approach. Complicated aortic IE may present with severe aortic annular destruction, annular abscess and colonization of infected foci in contiguous structures (e.g., aortic root).
Our analysis revealed that the superiority of homograft for AVE did not translate into a significant survival benefit at 15 years compared to conventional prosthesis (7,(26)(27)(28). The dogma of early SVD, higher reoperation risk and survival is both intuitive and biologically plausible. It is indirectly supported by studies that show higher morbidity and worse survival among patients undergoing reoperations for homograft AVR (18,20,21). Although there is a clear risk of redo operation for severe aortic valve calcification and aortic root of homograft compared to that conventional prosthesis, in-hospital mortality remains 2-5.5% in the elective setting (7,9,10) that is comparable to other prosthesis (2,3,8,18,41). However, homograft failure is likely to result in fatal cardiac events, in emergency surgery either for SVD or relapse of infection.
Based on current evidence, we propose four algorithms for the choice of valve for surgery of AVE (Figures 2,4-6). We considered the most important anatomic and technical determinants for the choice of valve substitute, alongside the clinical characteristics of the patient. Factors to consider include risk of embolization, durability, risk of infection recurrence, and severity of infective extension (in relation to its primary location). Immunological, histopathological and microbiological characterization of the target infective lesion is crucial when considering a homograft and autograft due to the living nature of this prosthesis (5)(6)(7)(8)(9)(10)(11)37,38,(63)(64)(65)(66)(67)(68).

Area of uncertainty
In the future, the use of allogenic tissue preserved at 4 ℃ which improves immunological and inflammatory  response, instead of cryo-preservation, will allow better physiological integration of valvular substitutes and cardiovascular structure, thereby improving long-term durability and clinical outcomes (65)(66)(67)(68)(69). We are unaware of any randomized trials that have compared the use of aortic homograft with decellularized allograft (DAVA) for AVE, and it is unlikely that such a trial will be conducted. Therefore, the current recommendation for the use of DAVA in the treatment of AVE is based on observational data (70,71). The use of DAVA (n=42) was compared with standard cryopreserved homograft (CAH) (n=29) and the rate of patients who had AVE was equivalent (DAVA 26% vs. CAH 21%, respectively). Freedom from reoperation at 10 years was 51% in recipients of DAVA compared with 80% for those who received a CAH (95% CI, 34-76% vs. 95% CI, 60-100%; P=0.06). At 10-year survival rates were 76% in patients who had a DAVA compared to 57% whereas the valve substitute was a CAH (95% CI, 61-93% vs. 95% CI, 38-79%; P=0.09) (71). Although evidence suggested that sterilization of decellularized valves could have a detrimental effect on the durability of cryopreserved allogenic tissue (72), similar fibrosis and calcification are observed in failed DAVA and CAH (70). Furthermore, a difference between the various modalities of the decellularization process in the preparation of the DAVA with different results at the follow-up is described. As a matter of fact, da Costa (72) reported a 98% freedom from reoperation at an average of 19 months of follow-up while Helder had a rate of 92% at 5 years outcomes (71).

Guidelines
The Society of Thoracic Surgeons (15) assigned Class I and IIa classifications with a Level of Evidence B to the use of a conventional mechanical or stented XP if radical debridement is carried out and the valve can be anchored to healthy and strong tissue. Class IIa, Level of evidence B is also assigned to the use of homograft. The choice of allogenic tissue is considered reasonable for native and prosthetic AVE particularly with periannular abscess and extensive annular or aortic wall destruction requiring aortic root replacement or reconstruction, as well as in cases of extensive aorto-ventricular discontinuity. The AATS 2016 guidelines (16,73) echo these recommendations for the use of allogenic tissue in destructive native or prosthetic aortic valve IE, with indicated surgery of aortic root; however, the choice of prosthetic bioroot or prosthetic valved conduit with a mechanical or bioprosthetic valve are considered acceptable alternatives although it should be guided by the grade of surgeon's training and experience (Class IIa, Level B).

Conclusions
The guidelines and position papers of professional societies advise that both recommendations for the use of conventional valves or homografts are categorized as Class I and II. The reason is because there is opposing evidence and/or a divergence of viewpoints related to the benefit and efficacy of a procedure or treatment. The benefits and efficacy of aortic homograft are less well established by evidence and opinions. It is categorized as Class IIb because the data was derived from a single randomized trial or non-randomized studies (Level of evidence B). One of the reasons for the infrequent use of allogenic tissue is that the excellent clinical outcomes associated with their use in the field of AVE that has been reported in observational studies have not been replicated in the randomized, controlled trials. There is a concern that observational studies can be biased in favor of homografts by unmatched confounders related to the unmeasurable and incomparable findings of the operating surgeons.
The scarcity of robust clinical evidence still hampers our understanding of IE management. Ethical Statement: The authors are accountable for all aspects of this manuscript in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. As a review article, explicit ethical approval was not required. Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the noncommercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.