Patients with multivalvular infective endocarditis demonstrate adverse cardiac remodeling before surgery with increased postoperative mortality risk

Introduction

Infectious endocarditis (IE) is a clinically rare heart valve disease compared to rheumatic valvular disease and valvular degeneration, with a relatively low overall incidence ranging from 2.4/100,000 to 11.6/100,000 person-years (1). Despite diagnostic and therapeutic advances, over 30% of IE patients still require surgical intervention, with mortality rates remaining high (2). The treatment for IE mainly includes active drug therapy and early surgery (3-5). The results of meta-analysis suggest that early surgery can significantly reduce the risk of death in IE patients (6,7). The European Society of Cardiology has updated the latest guidelines for IE, recommending emergency or elective surgery for patients with heart failure, unmanageable infection and high risk of embolism caused by IE (8). On the whole, the surgical indications considered from the three aspects of heart failure, infection and embolism in the previous guidelines are still followed (9). However, the scope of valve injury is not considered in all current guidelines for IE. IE can cause damage to any valve of the heart. The most commonly involved left heart valves, namely mitral and aortic valves, less involved right heart valves, namely tricuspid and pulmonary valves, and the damage of two valves in one side of the heart cavity is more common. It is not uncommon that three or even four valves of the left and right heart are involved. The Mayo Clinic study showed that multivalvular endocarditis (MVE) is associated with a worse prognosis after surgery (10), which we generally attribute to the complexity and greater surgical trauma of multivalvular surgery. However, it remains unknown whether patients with MVE already have more severe cardiac remodeling or a more pronounced tendency toward cardiac remodeling before surgery than patients with single valvular endocarditis (SVE). Numerous studies have shown that valve dysfunction can lead to heart remodeling, and that surgery can prevent or even partially reverse this remodeling, but such studies have mainly focused on rheumatic valvular disease and valve degeneration (11-13). IE is an acute course, while cardiac remodeling is considered as a chronic process (14), so that the role of cardiac remodeling in IE is usually ignored. Regardless of whether there are differences in cardiac remodeling between MVE and SVE, and whether such differences are associated with prognostic differences, the extent of valvular damage should be considered as one of the surgical indications based on the current findings (10), and the degree of cardiac remodeling is a potentially effective indicator for preoperative monitoring of IE. This study followed IE patients who underwent surgery for up to 12 years to explore differences in adverse cardiac remodeling and postoperative outcomes between MVE and SVE patients. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1016/rc).

Methods

Study design and patient enrollment

The study was a retrospective cohort study of 343 IE patients aged 18–65 years who underwent heart valve surgery at Valve Surgery Center of Beijing Anzhen Hospital from January 2010 to December 2022. The number of cases in Beijing Anzhen Hospital during the study period determined the sample size. No additional exclusion criteria were applied. The diagnosis of IE was made in accordance with Duke diagnostic criteria (9). Preoperative echocardiography was performed within 7 days prior to surgery for all patients to assess valvular damage, extent of involvement and vegetation characteristics. All echocardiographic measurement in this study were performed strictly in accordance with the recommendations of the American Society of Echocardigraphy and the European Association of Cardiovascular Imaging (15). The scope of involvement referred to the number of valves exhibiting at least one of the following echocardiographic criteria: (I) rupture, perforation, retraction, prolapse, abscess, fistula formation; (II) definite vegetation (oscillating intracardiac mass on valve or supporting structures); or (III) new significant valvular regurgitation (moderate or greater severity). Patients were then classified into the MVE group (n=143) and the SVE group (n=200) based on the preoperative echocardiographic findings demonstrating involvement of two or more valves versus only one valve, respectively, according to the above criteria. This echocardiographic classification was subsequently confirmed by the intraoperative findings and the actual valves repaired or replaced. All patients were operated under general anesthesia with cryogenic cardiopulmonary bypass, following the general principles of IE surgery, including complete removal of infected tissue as far as possible, appropriate debridement and subsequent reconstruction or replacement. The admission data and the results of preoperative echocardiography were collected retrospectively. Due to the three-tier referral system in China, most patients had already received empirical antibiotic therapy at primary hospitals before being referred to Beijing Anzhen Hospital, a tertiary care center.Consequently, most blood cultures obtained upon admission to Beijing Anzhen Hospital were negative, precluding reliable pathogen identification. The primary end point event was all-cause death, and the secondary end point event was a composite end point event, including death, stroke, recurrent infection, and resurgery. Follow-up was conducted by telephone and outpatient visits. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University (approval No. KS2022064). Informed consent was waived in this retrospective study.

Statistical analysis

Statistical analyses were performed in R 4.3.1 and SPSS 25.0. Inverse probability of treatment weighting (IPTW) was used to equalize the baseline data of the two groups of patients, and a baseline table before and after IPTW was established to visualize the standardized mean difference before and after IPTW. Kaplan-Meier survival analysis was used to compare the incidence of primary and secondary endpoint events before and after IPTW between the two groups at baseline, and hazard ratio (HR) values were obtained by Cox risk regression. Normal distribution test and two-independent sample T-test were conducted for preoperative ultrasound indexes and cardiac remodeling indexes of the two groups. Continuous data were expressed as mean ± standard deviation (SD) (x¯±s), while non-conforming distribution was expressed as median (P25, P75) and analyzed by non-parametric tests. Categorical variables were expressed in frequency and percentage, using Chi-squared test. P value <0.05 was considered statistically significant.

Results

Patient characteristics

The SVE and MVE groups included 200 and 143 IE patients respectively. Baseline characteristics of the two groups and differences between them are summarized in Table 1. Patients in the SVE group were older (46.6 vs. 42.5 years, P=0.01), had a higher smoking rate [58 (40.6%) vs. 49 (24.5%), P=0.002] and showed a lower proportion of patients with fever at admission [85 (59.4%) vs. 154 (77%), P=0.001]. There were no significant differences in other baseline characteristics (Table 1). All baseline variables were well balanced [standard mean difference (SMD) <10%] after IPTW for baseline data of the two groups (Table 1, Figure 1). The covariates adjusted for in the IPTW model included: age, body mass, left ventricular ejection fraction (LVEF), smoking, drinking, fever, diabetes, hypertension, embolic events, previous heart surgery, and prosthetic valve portability. These covariates were selected based on clinical relevance and baseline differences.

Figure 1 Standardized mean difference before and after IPTW of baseline variables. SMD >10% is usually considered as variable imbalance. BMI, body mass index; IPTW, inverse probability of treatment weighting; LVEF, left ventricular ejection fraction; SMD, standard mean difference.

Prognostic analysis

The mean follow-up time of MVE and SVE groups was 47.93 and 69.98 months respectively. Kaplan-Meier survival analysis and Cox risk regression analysis showed that compared with the single valve infective endocarditis group, the postoperative survival rate of patients with multivalvular infective endocarditis group was higher (unadjusted: HR =2.67, P=0.005; IPTW adjusted: HR =3.05, P=0.001) and survival rate without complex endpoint events (unadjusted: HR =2.67, P<0.001; IPTW adjusted, HR =2.69, P<0.001) were both worse (Figure 2).

Figure 2 Results of Kaplan-Meier survival analysis and Cox risk regression analysis. (A) Kaplan-Meier survival analysis and Cox risk regression analysis before IPTW. (B) Kaplan-Meier survival analysis and Cox risk regression analysis after IPTW. (C) Event survival analysis without composite endpoints and Cox risk regression analysis before IPTW. (D) Event survival analysis without composite endpoints and Cox risk regression analysis after IPTW. HR, hazard ratio; IPTW, inverse probability of treatment weighting; MVE, multivalvular endocarditis; SVE, single valvular endocarditis.

Preoperative ventricular remodeling

Compared with the patients in SVE group, left ventricular end-diastolic diameter (6.1 vs. 5.4 cm, P<0.001) and left ventricular end-systolic diameter (4.1 vs. 3.6 cm, P<0.001) of the patients in MVE group were significantly larger. Left ventricular mass (LVM) (254.3 vs. 201.0, P<0.001) and left ventricular mass index (LVMi) (147.1 vs. 119.8, P<0.001) were also greater. However, LVEF (60.6% vs. 61.4%, P=0.33) was not different between the two groups. In addition, preoperative echocardiography showed no difference in interventricular septal thickness (1.00 vs. 0.97, P=0.23) and posterior left ventricular wall thickness (0.89 vs. 0.86, P=0.43) between the two groups (Table 2).

Discussion

IE is a microbial infection of the valvular or non-valvular endothelial or intracardiac artificial material, and the typical lesions of IE are intracardiac neoplasms consisting of fibrin and platelets in which bacterial and/or fungal pathogens proliferate. In addition, it is often accompanied by severe damage to the valve (16). Therefore, the surgical treatment of IE is mainly around surgical intervention of the valve. So far, there are still several challenges in the diagnosis and management of IE, such as the timing of IE surgery, which has always been a great problem for clinicians. Compared with rheumatic valvular disease and degenerative valvular disease, the overall prognosis of IE is relatively poor. The 1- and 5-year survival rates are 85–90% and 70–80%, respectively (17,18).

Unlike other valve diseases, IE may cause extensive valve destruction in a short time with the spread of infection. The mitral and aortic valves in the left heart are most commonly involved, and the tricuspid and pulmonary valves in the right heart valves are less involved. The damage of two valves in one side of the heart cavity is more common and it is not uncommon to involve three or even four valves in the left and right heart. Notably, the ESC guidelines prioritize early surgery for heart failure, uncontrolled infection, or embolism but omit the extent of valvular damage. The omission stems from the lack of robust evidence correlating valvular damage extent with clinical outcomes, particularly its role in driving cardiac remodeling and long-term mortality. While heart failure, uncontrolled infection and embolism are directly linked to acute mortality, multivalvular damage may contribute to subclinical cardiac dysfunction that manifests later. Our study brides this gap by demonstrating that multivalvular involvement associates with adverse remodeling and increased postoperative death, providing the missing evidence to refine surgical indications.

In our study, patients with IE were divided into SVE and MVE groups based on the range of valves involved in IE. Due to the limited sample size, we chose to balance the baseline by IPTW rather instead of subgroup analysis to exclude confounding factors. Subsequent survival analysis showed significant differences in postoperative outcomes between the two groups. At the baseline level before IPTW, patients in the MVE group were older and more likely to smoke, suggesting that the MVE group had worse preoperative basic physical status. However, survival analyses adjusted by IPTW at baseline did not show a reduction in the previous difference in prognosis, but rather a more significant difference. Due to the characteristics of IE disease itself, patients are prone to recurrent infection, stroke and reoperation events after surgery. In order to evaluate the postoperative prognosis of the two groups of patients in a more comprehensive and systematic way, we also conducted survival analysis for the composite endpoint events including death, infection recurrence, stroke and reoperation. The results showed that the postoperative survival rate without complex endpoint events in the MVE group was also significantly lower than that in the SVE group, as shown in Table 3.

Preoperative ultrasound data of the two groups were obtained from the results of the most recent echocardiography before surgery. Left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD) of patients in the MVE group were significantly larger than those in the SVE group, indicating that patients in the MVE group showed more obvious functional compensation at least in the left ventricle after extensive valve injury than those in the SVE group. In order to further explore the cardiac remodeling status, the LVM and LVMi of patients in the two groups were calculated using the Devereux correction formula, and the results showed that the LVM and LVMi of patients in the MVE group were also significantly larger than those in the SVE group, which further verified that the MVE group had a more pronounced progression of cardiac remodeling before surgery compared with the SVE group. The pathophysiological mechanism of the relationship between the extent of valve injury and the degree of cardiac remodeling needs to be further studied at the anatomical and hemodynamic levels, and may also involve the influence of left-right cardiac interaction on cardiac remodeling. There was no significant difference in preoperative LVEF between the two groups, and the average LVEF was over 60%, indicating that IE cardiac remodeling was mostly in the early stage of compensation, and the difference in cardiac damage between the two groups could not be reflected in the systolic and diastolic function of the heart. LVEF is the most commonly used clinical indicator of heart failure, and it is obviously unreasonable to use LVEF <50% or less as an indication of surgery. Studies related to aortic stenosis have shown that using LVEF <50% as a cut-off value to assess whether surgery is performed results in increased mortality (19).

Wedin et al. found that preoperative cardiac remodeling was more pronounced in patients with severe aortic stenosis than in patients without aortic valve malformation (LVMi 134 vs. 104 g/m², P<0.001), and it was also demonstrated that preoperative cardiac remodeling was associated with a higher readmission rate for heart failure in patients with bilobal malformation (20). Therefore, according to our research results, it is speculated that preoperative poor cardiac remodeling in MVE patients is one of the factors leading to their worse postoperative prognosis. However, to verify this hypothesis, it is necessary to exclude more confounding factors in a larger sample size cohort, and further classify the causes of postoperative death of patients to clarify the proportion of death caused by heart failure.

There were several limitations worth considering in this study. First, its single-center, retrospective design may introduce selection bias and limit the generalizability of findings. Although we included consecutive patients from a high-volume center, results may not fully reflect outcomes in diverse healthcare settings. Second, despite rigorous adjustment for baseline confounders using IPTW, residual confounding from unmeasured variables (e.g., subtle differences in surgical expertise or unrecorded comorbidities) could persist. Third, cardiac remodeling is a dynamic process. Our study relied solely on preoperative echocardiography, lacking longitudinal data to track remodeling progression preoperatively or regression postoperatively. Finally, the observational nature of this study precludes definitive conclusions about causality between multivalvular involvement, accelerated remodeling, and poorer outcomes.

Conclusions

Our findings demonstrate that MVE patients exhibit subclinical cardiac remodeling preoperatively and experience significantly poorer than SVE patients, suggesting that surgical indications in current IE guidelines may not be well applied to patients with extensive valvular damage, who may benefit from closer cardiac ultrasound monitoring and early surgical intervention before cardiac remodeling progresses.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1016/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1016/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1016/prf

Funding: This work was supported by National Natural Science Foundation of China (No. 82241205), Beijing Municipal Science & Technology Commission (No. Z221100007422015) and Beijing Hospitals Authority Clinical Medicine Development Special Funding (No. ZLRL202317).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1016/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Beijing Anzhen Hospital, Capital Medical University (approval No. KS2022064). Informed consent was waived in this retrospective study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial 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/.

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