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Competing Interests: Conflict of Interest Statement Dr Gillinov serves as a consultant to Edwards Lifesciences, Medtronic, Abbott, ClearFlow, Artivion, AtriCure, and Johnson and Johnson. Dr Burns serves as a consultant to Edwards Lifesciences and Medtronic. Dr Roselli serves as a consultant to Artivion, Cook, Medtronic, Terumo Aortic, and W.L. Gore. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

Objective: To investigate outcomes after aortic root allograft reoperation, identify risk factors for morbidity and mortality, and describe practice evolution since publication of our 2006 allograft reoperation study., Methods: From January 1987 to July 2020, 602 patients underwent 632 allograft-related reoperations at Cleveland Clinic: 144 before 2006 (early era, which suggested radical explant was superior to aortic-valve-replacement-within-allograft [AVR-only]), and 488 from 2006 to present (recent era). Indications for reoperation were structural valve deterioration in 502 (79%), infective endocarditis in 90 (14%), and nonstructural valve deterioration/noninfective endocarditis in 40 (6.3%). Reoperative techniques included radical allograft explant in 372 (59%), AVR-only in 248 (39%), and allograft preservation in 12 (1.9%). Perioperative events and survival were assessed among indications, techniques, and eras., Results: Operative mortality by indication was 2.2% (n = 11) for structural valve deterioration, 7.8% (n = 7) in those with infective endocarditis, and 7.5% (n = 3) for nonstructural valve deterioration/noninfective endocarditis, and by surgical approach 2.4% (n = 9) after radical explant, 4.0% (n = 10) for AVR-only, and 17% (n = 2) for allograft preservation. Operative adverse events occurred in 4.9% (n = 18) of radical explants and 2.8% (n = 7) of AVR-only procedures (P = .2). Patients undergoing radical explants received larger valves than those undergoing AVR-only (median, 25 vs 23 mm)., Conclusions: Aortic root allograft reoperations present a technical challenge but can be performed with low mortality and morbidity. Radical explant offers outcomes similar to AVR-only while allowing for implant of larger prostheses. Increasing experience with allograft reoperations has permitted excellent outcomes; thus, risk of reoperation should not dissuade surgeons from using allografts for invasive aortic valve infective endocarditis and other indications., (Copyright © 2023. Published by Elsevier Inc.)

Objective: The objectives of this study were to investigate patient characteristics, valve pathology, bacteriology, and surgical techniques related to outcome of patients who underwent surgery for isolated native (NVE) or prosthetic (PVE) mitral valve endocarditis., Methods: From January 2002 to January 2020, 447 isolated mitral endocarditis operations were performed, 326 for NVE and 121 for PVE. Multivariable analysis of time-related outcomes used random forest machine learning., Results: Staphylococcus aureus was the most common causative organism. Of 326 patients with NVE, 88 (27%) underwent standard mitral valve repair, 43 (13%) extended repair, and 195 (60%) valve replacement. Compared with NVE with standard repair, patients who underwent all other operations were older, had more comorbidities, worse cardiac function, and more invasive disease. Hospital mortality was 3.8% (n = 17); 0 (0%) after standard valve repair, 3 (7.0%) after extended repair, 8 (4.1%) after NVE replacement, and 6 (5.0%) after PVE re-replacement. Survival at 1, 5, and 10 years was 91%, 75%, and 62% after any repair and 86%, 62%, and 44% after replacement, respectively. The most important risk factor for mortality was renal failure. Risk-adjusted outcomes, including survival, were similar in all groups. Unadjusted extended repair outcomes, particularly early, were similar or worse than replacement in terms of reinfection, reintervention, regurgitation, gradient, and survival., Conclusions: A patient- and pathology-tailored approach to surgery for isolated mitral valve endocarditis has low mortality and excellent results. Apparent superiority of standard valve repair is related to patient characteristics and pathology. Renal failure is the most powerful risk factor. In case of extensive destruction, extended repair shows no benefit over replacement., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Dr Elgharably has a financial relationship with Edwards Lifesciences and Dr Witten has a financial relationship with LifeNet Health. All other authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

Objective: Intrinsic risk of infection of cryopreserved allograft aortic root replacements remains poorly understood despite their long history of use. The objective of this study was to determine this intrinsic risk of allograft infection and its risk factors when allografts are implanted for both nonendocarditis indications and infective endocarditis., Methods: From January 1987 to January 2017, 2042 patients received 2110 allograft aortic valves at a quaternary medical center, 1124 (53%) for nonendocarditis indications and 986 (47%) for endocarditis indications (670 [68%] prosthetic valve endocarditis). Staphylococcus aureus caused 193 of 949 cases of endocarditis (20%), 71 (7.3%) in persons who injected drugs. Periodic surveillance and cross-sectional follow-up achieved 85% of possible follow-up time. The primary end point was allograft infection in patients with nonendocarditis and endocarditis indications. Risk factors were identified by hazard function decomposition and machine learning., Results: During follow-up, 30 allografts (26 explanted) became infected in patients in the nonendocarditis group and 49 (41 explanted) in patients with endocarditis. At 20 years, the probability of allograft infection was 5.6% in patients in the nonendocarditis group and 14% in patients with endocarditis. Risk factors for allograft infection in patients in the nonendocarditis group were younger patient age and older donor age. Risk factors for allograft infection in patients with endocarditis were earlier implant year, injection drug use, and younger age. In patients with endocarditis, 18% of allograft infections were caused by the original organism., Conclusions: The low infection rates, both in patients without and with endocarditis, support continued use of allografts in the modern era, in particular for the treatment of invasive endocarditis of the aortic root., (Copyright © 2021 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Bacterial pathogens have evolved virulence factors to colonize, replicate, and disseminate within the vertebrate host. Although there is an expanding body of literature describing how bacterial pathogens regulate their virulence repertoire in response to environmental signals, it is challenging to directly visualize virulence response within the host tissue microenvironment. Multimodal imaging approaches enable visualization of host-pathogen molecular interactions. Here we demonstrate multimodal integration of high spatial resolution imaging mass spectrometry and microscopy to visualize Staphylococcus aureus envelope modifications within infected murine and human tissues. Data-driven image fusion of fluorescent bacterial reporters and matrix-assisted laser desorption/ionization Fourier transform ion cyclotron resonance imaging mass spectrometry uncovered S. aureus lysyl-phosphatidylglycerol lipids, localizing to select bacterial communities within infected tissue. Absence of lysyl-phosphatidylglycerols is associated with decreased pathogenicity during vertebrate colonization as these lipids provide protection against the innate immune system. The presence of distinct staphylococcal lysyl-phosphatidylglycerol distributions within murine and human infections suggests a heterogeneous, spatially oriented microbial response to host defenses., Competing Interests: Declaration of interests The authors declare no interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Advanced aortic valve infective endocarditis (IE) with progression and destruction beyond the valve cusps-invasive IE-is incompletely characterized. This study aimed to characterize further the invasive disease extent, location, and stage and correlate macroscopic operative findings with microscopic disease patterns and progression., Methods: A total of 43 patients with invasive aortic valve IE were prospectively enrolled from August 2017 to July 2018. Of these patients, 23 (53%) had prosthetic valve IE, 2 (5%) had allograft IE, and 18 (42%) had native aortic valve IE. Surgical findings and intraoperative photography were analyzed for invasion location, extent, and stage. Surgical samples were formalin fixed and analyzed histologically. The time course of disease and management were evaluated., Results: Pathogens included Staphylococcus aureus in 17 patients (40%). Invasion predominantly affected the non-left coronary commissure (76%) and was circumferential in 15 patients (35%) (14 had prosthetic valves). Extraaortic cellulitis was present in 29 patients (67%), abscess in 13 (30%), abscess cavity in 29 (67%), and pseudoaneurysm in 8 (19%); 7 (16%) had fistulas. Histopathologic examination revealed acute inflammation, abscess formation, and lysis of connective tissue but not of myocardium or elastic tissue. Median time from onset of symptoms to antibiotics was 5 days, invasion confirmation 15 days, and surgery 37 days. Patients with S aureus had a 21-day shorter time course than patients non-S aureus. New or worsening heart block developed in 8 patients., Conclusions: Advanced invasive aortic valve IE demonstrates consistent gross patterns and stages correlating with histopathologic findings. Invasion results from a confluence of factors, including pathogen, time, and host immune response, and primarily affects the fibrous skeleton of the heart and expands to low-pressure regions., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: A substantial proportion of infective endocarditis (IE) cases are complicated by local invasion. The purpose of this study was to identify patient and disease characteristics associated with local invasion in surgically treated IE patients., Methods: This was a nested case-control study. All episodes of IE for patients admitted to Cleveland Clinic from 1 January 2013 to 30 June 2016 were identified from the Cleveland Clinic IE Registry. Patients ≥18 years of age who underwent surgery for IE were included. Among these, cases were those with local invasion, controls were those without. Local invasion, defined as periannular extension, paravalvular abscess, intracardiac fistula or pseudoaneurysm, was ascertained from the surgical operative note. Associations of selected factors with local invasion were examined in a multivariable logistic regression model., Results: Among 511 patients who met inclusion criteria, 215 had local invasion. Mean age was 56 years; 369 were male. Overall 345 (68%) had aortic valve, 228 (45%) mitral valve, and 66 (13%) tricuspid or pulmonic valve involvement. Aortic valve involvement (OR 6.23, 95% CI 3.55-11.44), bioprosthetic valve (OR 3.88, 95% CI 2.36-6.44), significant paravalvular leak (OR 3.80, 95% CI 1.60-9.89), new atrioventricular nodal block (OR 3.77, 95% CI 1.87-7.90), infection with streptococci other than viridans group streptococci (OR 7.54, 95% CI 2.42-24.87) and presence of central nervous system emboli (OR 1.85, 95% CI 1.13-3.04) were associated with local invasion., Discussion: Intracardiac and microorganism factors, but not comorbid conditions, are associated with local invasion in IE., (Copyright © 2020 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The value of allografts for aortic root replacement is controversial, with recent concern about limited durability. Currently, we prefer allografts for invasive infective endocarditis. Purposes of this study were to assess allograft performance and durability in our cumulative experience with aortic allografts., Methods: From January 1987 to January 2017, 2042 adults received 2110 aortic allograft root replacements at our institution: 986 (47%) for infective endocarditis (669 [68%] for prosthetic valve endocarditis) and 1124 (53%) for other indications. Mean recipient age was 54 ± 15 years, and mean allograft donor age was 35 ± 13 years. Follow-up was 85% complete and comprised 17,253 patient-years of data. Longitudinal allograft performance was extracted from 6339 available echocardiographic studies. Durability was assessed by explant for allograft structural failure., Results: Allograft mean gradient at hospital discharge was 6 mm Hg and 9, 13, and 15 mm Hg at 5, 10, and 15 years post-implant, respectively. Severe aortic regurgitation was 0% at hospital discharge, but 14%, 25%, and 35% at 5, 10, and 15 years, respectively. A total of 405 allografts were explanted for structural failure, actuarially 2%, 14%, 34%, and 51% at 5, 10, 15, and 20 years, respectively. Risk factors for structural failure were younger recipient age, larger body surface area, hypertension, and thoracic aorta disease; donor factors were older age and larger allograft size. Implant for infective endocarditis was not associated with accelerated structural failure., Conclusions: This study affirms allografts' long-term acceptable hemodynamic performance and durability. Concern about structural failure should not limit allograft use. Recipient hypertension, allograft size, and donor age are modifiable risk factors., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Limited data exist regarding the clinical characteristics and contemporary outcomes of patients with pulmonary valve (PoV) infective endocarditis (IE)., Methods: This is a retrospective cohort study of patients with a confirmed diagnosis of IE affecting the PoV at our centre between January 2002 and October 2018. Electronic medical records were reviewed to gather the clinical and echocardiographic variables. The population was subdivided according to risk factor profiles: group 1: miscellaneous risk factors; group 2: patients with congenital heart disease (CHD); and group 3: patients who inject drugs (PWID). The primary outcome was all-cause mortality., Results: Out of 2,124 cases of IE during the study period, 24 (1.1%) patients had PoV IE. The majority of cases of PoV IE occurred in patients with prosthetic valves (54.2%). Coagulase-negative Staphylococci species were the most common micro-organisms. Seventy-five per cent (75%) of the patients required surgical management. The median follow-up was 2.8 years (interquartile range: 0.2-5.3 years). Patients with miscellaneous risk factors were older (p<0.01), and had higher rates of hypertension (p=0.01) and hyperlipidaemia (p=0.04). There was a statistically significant difference in survival between the groups (p=0.03), mainly driven by better outcomes of patients with CHD, compared to those with miscellaneous risk factors., Conclusions: In a contemporary 16-year series, a high proportion of patients with PoV IE required surgical management. Patients with PoV IE and CHD had better survival, compared to patients with miscellaneous risk factors at a median follow-up of 2.8 years., (Copyright © 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Infective endocarditis is a life-threatening infection of heart valves and adjacent structures characterized by vegetations on valves and other endocardial surfaces, with tissue destruction and risk of embolization. We used high-resolution mass spectrometry to define the proteome of staphylococcal and non-staphylococcal vegetations and Terminal Amine Isotopic Labeling of Substrates (TAILS) to define their proteolytic landscapes. These approaches identified over 2000 human proteins in staphylococcal and non-staphylococcal vegetations. Individual vegetation proteomes demonstrated comparable profiles of quantitatively major constituents that overlapped with serum, platelet, and neutrophil proteomes. Staphylococcal vegetation proteomes resembled one another more than the proteomes of non-staphylococcal vegetations. TAILS demonstrated extensive proteolysis within vegetations, with numerous previously undescribed cleavages. Several proteases and pathogen-specific proteins, including virulence factors, were identified in most vegetations. Proteolytic peptides in fibronectin and complement C3 were identified as potential infective endocarditis biomarkers. Overlap of staphylococcal and non-staphylococcal vegetation proteomes suggests a convergent thrombotic and immune response to endocardial infection by diverse pathogens. However, the differences between staphylococcal and non-staphylococcal vegetations and internal variance within the non-staphylococcal group indicate that additional pathogen- or patient-specific effects exist. Pervasive proteolysis of vegetation components may arise from vegetation-intrinsic proteases and destabilize vegetations, contributing to embolism.

Background: Reconstruction of the intervalvular fibrosa (IVF) for invasive double-valve infective endocarditis (IE) is a technically challenging operation. This study presents the long-term outcomes of two surgical techniques for IVF reconstruction., Methods: From 1988 to 2017, 138 patients with invasive double-valve IE underwent surgical reconstruction of the IVF, along with double-valve replacement (Commando procedure, n = 86) or aortic valve replacement with mitral valve repair (hemi-Commando procedure, n = 52). Mean follow-up was 41 ± 5.9 months., Results: Reoperation was required in 82% of patients, and 34% underwent emergency surgery. Pathologic features included positive blood cultures (90%), prosthetic valve IE (75%), aortic root abscess (78%), mitral annular abscess (24%), and intracardiac fistula (12%). There were 28 hospital deaths: 21 (24%) in the Commando group and 7 (14%) in the hemi-Commando group (P = .12). Overall survival at 1, 5, and 10 years was 67%, 48%, and 37%, respectively. Coronary artery disease, native valve IE, and causative organism (Staphylococcus aureus, coagulase-negative Staphylococcus, and viridans streptococci) were risk factors for late mortality. Freedom from reoperation at 1, 5, and 8 years was 87%, 74%, and 55%, respectively. Freedom from recurrent IE at 1, 5, and 8 years was 90%, 78%, and 67%, respectively., Conclusions: Although it is technically demanding, surgery for invasive IE involving IVF, which provides the only chance for cure, can be performed with reasonable clinical outcomes. In cases of IE invading the IVF and limited to the anterior mitral valve leaflet, a hemi-Commando procedure that includes mitral valve repair has improved early outcomes., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Right-sided infective endocarditis is increasing because of increasing prevalence of predisposing conditions, and the role and outcomes of surgery are unclear. We therefore investigated the surgical outcomes for right-sided infective endocarditis., Methods: From January 2002 to January 2015, 134 adults underwent surgery for right-sided infective endocarditis. Patients were grouped according to predisposing condition. Hospital outcomes, time-related death, and reoperation for infective endocarditis were analyzed., Results: A total of 127 patients (95%) had tricuspid valve and 7 patients (5%) pulmonary valve infective endocarditis; 66 patients (49%) had isolated right-sided infective endocarditis, and 68 patients (51%) had right- and left-sided infective endocarditis. Predisposing conditions included injection drug use (30%), cardiac implantable devices (26%), chronic vascular access (19%), and other/none (25%). One native tricuspid valve was excised, 76% were repaired or reconstructed, and 23% were replaced. Intensive care unit and postoperative hospital stays were similar among groups. Injection drug users had the best early survival (no hospital mortality), and patients with chronic vascular access had the worst late survival (18% at 5 years). Survival was worst for concomitant mitral valve versus isolated right-sided infective endocarditis or concomitant aortic valve infective endocarditis. Survival after tricuspid valve replacement was worse than after repair/reconstruction. Estimated glomerular filtration rate was the strongest risk factor for death, not predisposing condition. Eleven patients underwent 12 reoperations for infective endocarditis; more reoperations occurred in injection drug users (P = .03)., Conclusions: Overall outcomes after surgery are variable and affected by patient condition, not predisposing condition. Injection drug use carries a higher risk of reoperation for infective endocarditis. Earlier surgery may permit more valve repairs and improve outcomes. Whenever possible, tricuspid valve replacement should be avoided., (Copyright © 2018. Published by Elsevier Inc.)