Results of the inoperable and operable with aortic valve endocarditis

Objectives To evaluate the results of the inoperable and operable with aortic valve endocarditis, focus on risk factors, significance, and management of destruction of the aortic annulus in aortic valve endocarditis. Methods The retrospective study was completed to investigate patients with aortic valve endocarditis undergoing cardiac surgery between January 2006 and November 2022 at our hospital. Results 512 patients were divided into group with destruction of the aortic annulus (n = 80) and without destruction of the aortic annulus (n = 432). There were 32 operative deaths (6.3%, 32/512). By univariate and multivariate analysis, destruction of the aortic annulus is found to be statistically significantly associated with in-hospital mortality (P < 0.001), prolonged mechanical ventilation time (mechanical ventilation time > 96 h, P = 0.018), early aortic paravalvular leak (P < 0.001), and 1-year mortality following cardiac surgery (P < 0.001), respectively. Conclusions In our study, destruction of the aortic annulus increases mortality and health care costs. Optimization of pre-, peri-, and postoperative factors can reduce mortality and morbidity in aortic valve endocarditis. Aortic root replacement could be recommended as the best practice choice for aortic valve endocarditis with periannular abscess and destruction of the aortic annulus.


Introduction
Infective endocarditis (IE) is defined by a focus of infection within the heart and is a feared disease across the field of cardiology.Even at experienced centers, operations for IE remain associated with the highest mortality of any valve disease.Approximately half of all IE patients are identified as high-risk and undergo operative treatment.Destruction of the aortic annulus, which is caused by aortic periannular abscess or aortic root abscess, is a severe complication of aortic valve endocarditis.Surgical treatment of aortic valve endocarditis with destruction of the aortic annulus is a challenging issue with high mortality and morbidity rate in the current era (1)(2)(3).
In our cohort, the main reasons for perioperative death were paravalvular leaks and septic shock with consecutive multiorgan failure and cerebral hemorrhage.One of the most frequent determinants of paravalvular leaks is destruction of the aortic annulus in aortic valve endocarditis.However, only a few reports in the available literature evaluated the incidence and predictors for destruction of the aortic annulus in aortic valve endocarditis (4).We aimed to evaluate the results of the inoperable and operable with aortic valve endocarditis, focus on risk factors, significance, and management of destruction of the aortic annulus in aortic valve endocarditis.
We hypothesized that optimization of pre-, peri-, and postoperative factors can reduce mortality and morbidity in aortic valve endocarditis.
2 Patients and methods

Design
The retrospective study was completed to investigate patients with aortic valve endocarditis undergoing cardiac surgery between January 2006 and November 2022 at our hospital.Medical records were reviewed.

Diagnosis
Patients were diagnosed according to the modified Duke criteria (5).Surgical and pathological findings were reviewed to confirm the preoperative diagnosis.

Eligibility criteria
Inclusion criteria included patients with aortic valve endocarditis undergoing cardiac surgery between January 2006 and November 2022 at our hospital.Exclusion criteria included patients without aortic valve endocarditis (Figure 1).

Surgical technique
Cardiac surgery for IE was indicated according to AATS guidelines for the management of IE.Radical debridement of all infected tissues and foreign material is followed by generous irrigation.Allografts are preferred for aortic root reconstruction in patients with annulus destruction (1).

Peri-and postoperative management
All patients were transferred to the intensive care unit after the operation.Anticoagulation management was conducted routinely.Transthoracic echocardiograph was performed postoperatively 1 to 7 days in intensive care unit.

Variables to be analyzed
Variables were evaluated (Supplementary Material).Time between symptoms and admission was defined as length from onset of symptoms to the date of admission.
Time between symptoms and surgery was defined as length from onset of symptoms to the date of operation.
In-hospital mortality was defined as death within 30 days of the operation or during the same hospital admission.
In our study, serum creatinine was used as the diagnostic standard of acute renal injury.According to Kidney Disease Improving Global Outcomes (KDIGO) classification, if serum creatinine increases by ≥0.3 mg/dl (26.5 μmol/L) within 48 h, serum creatinine is 50% higher than the baseline within first seven days, or urine output is below 0.5 ml/kg/hour for six hours, the patient is considered to have acute renal injury (5).
Multiorgan failure (MOF) is regarded as a continuous process of varying levels of organ failure rather than an all-or-none event.Lungs, cardiovascular system, kidneys, liver, coagulation system, and central nervous system are regarded as "key organs" to characterize MOF (6).
Hepatic failure is defined as a severe liver injury, potentially reversible in nature and with onset of hepatic encephalopathy within 8 weeks of the first symptoms in the absence of preexisting liver disease (7).
Respiratory failure is defined as a condition in which the respiratory system fails in one or both of its gas exchange functions, i.e., oxygenation of and/or elimination of carbon dioxide from mixed venous blood.It is defined by an arterial oxygen tension (Pa, O2) of ≤8.0 kPa (60 mmHg), an arterial carbon dioxide tension (Pa, CO2) of ≥6.0 kPa (45 mmHg) or both (8).

Follow-up
All survivors discharged from hospital were monitored to the end date of the study.At the outpatient department, all patients were investigated with echocardiogram, electrocardiogram, and xray chest film, once every 3 to 12 months.At the last follow-up, the patients were contacted by telephone or micro-message or interviewed directly at the outpatient department.

Statistical analyses
Continuous variables are reported as means ± SE.A normality test was performed for all variables in the study by Kolmogorov-Smirnov test.Survival rates were estimated using the Kaplan-Meier method.The chi-square test, the Kruskal-Walls test or the Wilcoxon rank-sum test, as appropriate, was used to evaluate relationships between the preoperative variables, and selected intraoperative and postoperative variables.The relationships with perioperative risk factors were assessed by means of contingency table methods and logistic regression analysis.Survival analysis was performed by Kaplan-Meier analysis, and differences in survival between groups were examined with the log-rank test.Multivariate Cox proportional hazard models were used.P values less than 0.05 were statistically significant.All analyses were performed using IBM SPSS version 24.0 software (IBM SPSS Inc., USA).

Ethical approval
The experiment protocol for involving humans was in accordance to Helsinki Statement and national guidelines and was approved by the Medical Ethics Committee of The People's Hospital of Guangxi Zhuang Autonomous Region, and They gave the authors approval to waive the need for patient consent for publishing data in the study about the patients.

Analysis of risk factors of multiorgan failure at admission in aortic valve endocarditis (n = 432)
Univariate analysis showed that factors are associated with multiorgan failure at admission, including body weight (P < 0.001), time between symptoms and admission (P = 0.037), vegetation length (P < 0.001), aortic insufficiency (P < 0.001), and symptomatic neurological complications (P < 0.001).When they were included in multivariate analysis models, multivariate analyses also showed that factors are associated with multiorgan failure at admission, including body weight (P < 0.001), time between symptoms and admission (P < 0.001), vegetation length (P < 0.001), aortic insufficiency (P < 0.001), and symptomatic neurological complications (P < 0.001) (Table 2).

Successful only medical therapy in aortic valve endocarditis
64 patients were successfully treated only by medical therapy in aortic valve endocarditis.Time between symptoms and admission (1.0 ± 0.1 vs. 2.7 ± 0.2 months, P < 0.001) and vegetation length (5.4 ± 0.2 vs. 10.4 ± 0.9 mm, P < 0.001) in group of successful only medical therapy were significantly less than both in group of cardiac surgery (Table 3).

Analysis of risk factors for destruction of the aortic annulus
Univariate analysis of potential risk factors for destruction of the aortic annulus in patients with aortic valve endocarditis showed that numerous factors are associated with destruction of the aortic annulus, including body weight (P < 0.001), vegetation length (P < 0.001), preoperative aortic insufficiency (P < 0.001), preoperative left ventricular end diastolic dimension (P < 0.001), and serum creatinine before surgery (P < 0.001).When they were included in multivariate analysis models, multivariate analyses also showed that numerous factors are associated with destruction of the aortic annulus, including body weight (P < 0.001), vegetation length (P < 0.001), preoperative aortic insufficiency (P < 0.001), preoperative left ventricular end diastolic dimension (P < 0.001), and serum creatinine before surgery (P < 0.001) (Table 6).

Analysis of significance of destruction of the aortic annulus in aortic valve endocarditis
Univariate and multivariate analysis of risk factors of inhospital mortality, prolonged mechanical ventilation time (mechanical ventilation time >96 h), prolonged ICU retention time, early aortic paravalvular leak following cardiac surgery, and 1-year mortality following cardiac surgery in aortic valve endocarditis showed that destruction of the aortic annulus is statistically significantly associated with in-hospital mortality (P < 0.001), prolonged mechanical ventilation time (mechanical ventilation time >96 h, P = 0.018), early aortic paravalvular leak (P < 0.001), and 1-year mortality following cardiac surgery (P < 0.001), respectively (Table 7).

Follow-up results
480 survivors were discharged and 460 patients were monitored to the end date of the study and the follow-up was  ).The presence of destruction of the aortic annulus in the setting of infective endocarditis significantly increased in-hospital mortality, and was also a significant risk factor for long-term survival.Univariate and multivariate analysis of Cox proportional hazard regression for all-time mortality indicated that numerous factors are associated with all-time mortality, including age (P < 0.001), body weight (P < 0.001), vegetation length (P < 0.001), preoperative aortic insufficiency (P < 0.001), ICU retention time (P < 0.001), serum creatinine 48 h after surgery (P < 0.001), postoperative left ventricular end diastolic dimension (P < 0.01), and packed red cells (P < 0.001) (Figure 2, Table 8).

Discussion
The present study aimed to evaluate the results of the inoperable and operable with aortic valve endocarditis, focus on risk factors, significance, and management of destruction of the aortic annulus in aortic valve endocarditis.We identified that destruction of the aortic annulus increases mortality and health care costs; optimization of pre-, peri-, and postoperative factors can reduce mortality and morbidity in aortic valve endocarditis; and aortic root replacement could be recommended as the best practice choice for aortic valve endocarditis with periannular abscess and destruction of the aortic annulus.
In our study, only 54.2% (512/944) patients with aortic valve endocarditis underwent surgery, and 28.8% (272/944) were excluded from surgery because of multiorgan failure at admission.Time between symptoms and admission is associated with multiorgan failure at admission.Vegetation length, aortic insufficiency, and symptomatic neurological complications are parameter of severity of disease.Vegetation length is associated with multiorgan failure at admission, destruction of the aortic annulus in aortic valve endocarditis and all-time mortality.Therefore, early diagnosis and treatment of aortic valve endocarditis are important, and early surgical intervention is advocated, as aortic valve endocarditis is a progressive and lifethreatening disease.Reaching a rapid and accurate diagnosis in cases of aortic valve endocarditis is still a central challenge of the disease.Delayed diagnosis and initiation of therapy lead to complications and worse clinical outcomes.Because of lack of excellent network of primary, secondary, and tertiary prevention, these patients therefore present late in the hospital and are usually diagnosed and transferred to our tertiary hospital late.A conceptual framework comprising of required baseline information and requirements for executing primary, secondary, and tertiary prevention has been advocated as a best model for aortic valve endocarditis control.
Follow-up data about morbidity and mortality indicated that almost all the deaths occurred within 12 months of surgery, which means all patients discharged from hospital must be followed up closely.Vegetation length, preoperative aortic insufficiency, serum creatinine 48 h after surgery, postoperative left ventricular end diastolic dimension, and packed red cells are associated with all-time mortality, therefor, early diagnosis and initiation of therapy to avoid larger vegetation length and preoperative aortic insufficiency, and excellent protection for the kidney, heart, and blood have significant implication for long-term outcomes.

Destruction of the aortic annulus increases mortality and health care costs
The presence of a paravalvular abscess or destruction of aortic annulus is a crucial indication for surgical management due to its known association with high in-hospital mortality.Periannular abscess or destruction of aortic annulus occurs in more than 10% of patients with aortic valve endocarditis.The previous study indicated that about 22% of patients who suffered from aortic valve endocarditis had periannular abscess and destruction of aortic annulus.Another study reported periannular extension, including abscess, pseudoaneurysm and fistula accounted for 37% of left-sided endocarditis (4, 9-10).Delayed surgery may lead to further damage to the aortic root, with a higher risk of complications and a more complex surgical process.Despite progress in treatment, the associated incidence rate and mortality rates are still high, indicating the need for more effective interventions.Generally speaking, in these cases, the main goal of surgery is to thoroughly debride the infected tissue, reconstruct the excised area, and replace the aortic valve or aortic root.The choice of aortic valve replacement or aortic root replacement for annulus reconstruction depends on the degree of annulus destruction.Aortic root replacement surgery has been the main choice in recent studies (11).In our study, 15.6% (80/512) of patients with aortic valve endocarditis suffered from periannular abscess and destruction of aortic annulus.The presence of destruction of the aortic annulus in the setting of infective endocarditis significantly increased in-hospital and long-term mortality.
Complex infection of the aortic valve with aortic root involvement and destruction of aortic annulus remains a grave challenge to the cardiac surgeon.Patients frequently present profoundly unwell and extensive surgery may be required to Kaplan-Meier curve for survival.Blue line, Group 1: Group with destruction of the aortic annulus.Green line, Group 2: Group without destruction of the aortic annulus.
correct the underlying anatomical deficits and provide source control in septic patients.Complex aortic valve endocarditis with aortic root involvement and destruction of aortic annulus continues to have a high in-hospital mortality rate of 10% to 40% (11-15).Improvement of surgical and perfusion techniques can decrease aortic cross-clamp time, cardiopulmonary bypass time, intubation time, ICU retention time, hospitalized time postoperative, paravalvular leak, chest drainage, fresh-frozen plasma, and packed red cells, therefor, contribute to better clinical outcomes.

Prevention of destruction of the aortic annulus
Preoperative LVEDD, vegetation length, preoperative aortic insufficiency, and serum creatinine before surgery are all parameter of severity of aortic valve endocarditis.Our present study showed that vegetation length and preoperative aortic insufficiency are associated with destruction of the aortic annulus in patients with aortic valve endocarditis.Therefore, early diagnosis and treatment of IE are important.Early surgical intervention is advocated, as aortic valve endocarditis is a progressive and life-threatening disease, and patients with a poor preoperative functional class are at the highest risk for in-hospital death.Early diagnosis and treatment maybe prevent the development of periannular abscess and destruction of aortic annulus.

Management of destruction of the aortic annulus
Surgical treatment of aortic valve endocarditis with aortic periannular abscess and destruction of the aortic annulus is still a challenging issue with high mortality and morbidity rate in the current era.Surgical method such as aortic valve replacement and aortic root replacement or reconstruction depend on the integrity of aortic annulus.According to the guideline of the Society of Thoracic Surgeons Clinical Practice, if the aortic annulus is healthy and strong enough for suture, it is reasonable to use a mechanical or stented tissue valve following radical debridement completed.If the aortic annulus is disrupted, aortic root replacement or reconstruction is usually the preferred choice of surgery (16, 17).
There is more and more evidence to indicate that aortic root replacement is associated with advantageous reoperation rates and rate of early paravalvular leak, a hypothesis that is also intuitive and backed by well-established surgical principles.Patients treated with an aortic root replacement were at a lower risk of reoperation and rate of early paravalvular leak at 1-year follow-up.
Destruction of the aortic annulus is associated with early aortic paravalvular leak, in-hospital mortality, and 1-year mortality.The main reasons of in-hospital mortality were early paravalvular leak and sepsis.Early paravalvular leak occurred mainly in patients with destruction of the aortic annulus treated with 6.0 Prolene sutures and patch reconstruction (early aortic paravalvular leak, 29.7%, 19/ 64).A paravalvular leak (PVL) is an incomplete apposition of a heart valve prosthesis on the native valve annulus, with a residual leakage between the artificial valve and the patient's native valve ring.This complication is the most common form of nonstructural valve dyfunction observed after a heart valve replacement.In Bentall procedure, a self-assembled composite graft allows safe proximal fixation of the conduit in patients with destroyed aortic annulus, resulting in sufficient proximal anastomosis and a very low incidence of aorta-related reoperations.Aortic paravalvular leak generally do not occur in aortic root replacement (Bentall procedure).It is reportet that modified Bentall procedure could have a role in effectively reducing paravalvular leak in aortic regurgitation related to Behcet's disease (18)(19)(20)(21).
Aortic root replacement accomplishes more comprehensive removal of infected tissue and reconstruction of cardiac morphology compared with aortic valve replacement and therefor can attain lower rates of reinfection and graft deterioration.The aortic root replacement technique is related to an advantageous postoperative profile compared with aortic valve replacement.Aortic root replacement could be recommended as the best practice choice for aortic valve endocarditis with periannular abscess and destruction of the aortic annulus (22)(23)(24)(25).

Perspectives
How to prevent multiorgan failure at admission and optimally treat destruction of the aortic annulus in aortic valve endocarditis remains grave challenge to us.Network of primary, secondary, and tertiary prevention and early diagnosis and treatment of aortic valve endocarditis will contribute to better short and long-term outcomes.

Strengths and limitations of the study
Our study for the first time clarified the risk factors, significance, and management of destruction of the aortic annulus in aortic valve endocarditis, adding value to the existing literature.Limitations of the present study include its retrospective design.There may be a selection bias because of the retrospective nature of the study and our hospital as a tertiary referral center.Well-designed research such as prospective cohort studies are needed and programs aiming at the reduction of in-hospital morbidity and mortality caused by aortic valve endocarditis are encouraged.The results and analysis of patients operated for aortic valve endocarditis is also very conflicting.Most of the risk factor CI interval is <1 suggesting they are protective.This needs to be re-evaluated.The diagnose of aortic root destruction was made during cardiac surgery, and the incidence of aortic root destruction in patients who had multiorgan failure at presentation and patients who refused surgery remained unknown.

Conclusions
In our study, destruction of the aortic annulus increases mortality and health care costs.Optimization of pre-, peri-, and post-operative factors can reduce mortality and morbidity in aortic valve endocarditis.Aortic root replacement could be recommended as the best practice choice for aortic valve endocarditis with periannular abscess and destruction of the aortic annulus.

TABLE 1
Multiorgan failure at admission in aortic valve endocarditis.

TABLE 2
Analysis of risk factors for multiorgan failure at admission in aortic valve endocarditis (n = 272).

TABLE 3
Successful only medical therapy and refusal surgery in aortic valve endocarditis.
ICU, intensive care unit.

TABLE 6
Analysis of risk factors for destruction of the aortic annulus in aortic valve endocarditis.
ICU, intensive care unit.

TABLE 8
Cox proportional hazard regression for all-time mortality.