Multivalvular Endocarditis: A Rare Condition with Poor Prognosis

Background. Infective endocarditis (IE) is a severe condition. Our aim was to describe the profile and prognosis of patients with multivalvular infective endocarditis (MIE) and compare them to single-valve IE (SIE). Methods. We used a retrospective analysis of the Spanish IE Registry (2008–2020). Results. From 4064 definite cases of valvular IE, 577 (14.2%) had MIE. In patients with MIE, the most common locations were mitral (552, 95.7%) and aortic (550, 95.3%), with mitral-aortic involvement present in 507 patients (87.9%). The most common etiologies were S. viridans (192, 33.3%) and S. aureus (113, 19.6%). MIE involved only native valves in 450 patients (78.0%). Compared with patients with SIE, patients with MIE had a similar age (69 vs. 67 years, respectively, p = 0.27) and similar baseline characteristics, but were more frequently men (67.1% vs. 72.9%, p = 0.005) and had a higher incidence of intracardiac complications (36.2% vs. 50.4%, p < 0.001), heart failure (42.7% vs. 52.9%, p < 0.001), surgical indication (67.7 vs. 85.1%, p < 0.001), surgery (46.3% vs. 56.3%), and in-hospital mortality (26.9% vs. 34.3%, p < 0.001). MIE was an independent predictor of in-hospital mortality (odds ratio (OR) 1.3, 95% confidence interval (CI) 1.1–1.7, p = 0.004) but did not have an independent association with 1-year mortality (OR 1.1, 95% CI 0.9–1.4, p = 0.43). Conclusions. About one-seventh of the valvular IE patients had MIE, mainly due to mitral-aortic involvement. MIE is associated with a poor in-hospital prognosis. An early diagnosis and treatment of IE might avoid its spread to a second valve.


Materials and Methods
The Spanish Collaboration on Endocarditis, Grupo de Apoyo al Manejo de la endocarditis infecciosa en ESpaña (GAMES), is a national observational prospective registry that has been previously described [16][17][18][19]. Multidisciplinary teams, including infectious disease physicians, cardiologists, cardiac surgeons, microbiologists, echocardiographers, and other imaging specialists, have completed standardized case report forms with information regarding IE episodes and follow-up data. A complete list of GAMES members is shown in Appendix A. IE patients at 38 Spanish hospitals between January 2008 and 2020 were included. Inclusion criteria were the diagnosis of definite valvular IE by modified Duke criteria [20]. IE management, including the decision to perform surgery and the type of surgery, was performed by the local medical team following the 2009 and 2015 European Society of Cardiology recommendations [1]. MIE was considered present when two or more valves were involved. Valve involvement was defined by echocardiography as valves with vegetations or new regurgitation or by direct intraoperative visualization of vegetations.
This study complied with the principles outlined in the Declaration of Helsinki and was approved by the ethics committee of participating centers.

Statistical Methods
Continuous variables are summarized as means ± standard deviations (SDs) or medians and interquartile ranges when normal distribution was not observed, as per the Kolmogorov-Smirnov goodness-of-fit test; categorical variables are expressed as numbers and percentages. Student's t-test, Mann-Whitney U test, or paired t-test was used to compare the continuous variables. The categorical variables were compared using the χ 2 test or Fisher's exact test. Kaplan-Meier curves were used to assess the cumulative survival of patients with valvular IE according to the presence of SIE or MIE. The curves were compared with the log-rank test. Multivariable logistic regression analyses (backward selection) were performed to determine the mortality predictors and to assess the independent association of MIE with mortality. All variables with a p-value < 0.10 in univariate analyses were included in the multivariable analyses. The statistical analysis was performed using SPSS, version 22.0 (IBM, Armonk, NY, USA).

Discussion
In our large national cohort of valvular IE, one-seventh of patients had MIE, which was associated with a poor prognosis.
MIE can involve native and prosthetic valves. The primary event is bacterial adherence to damaged valves during bacteriemia, with later persistence and growth within the cardiac lesions causing local extensions and tissue damage [21]. MIE can be the result of a simultaneous infection in two previously damaged valves in a patient with persistent bacteriemia or, more often, sequential seeding of a previously damaged valve [11]. In other cases, the infection of the first valve creates a new valvular lesion. A jet of aortic regurgitation may damage and infect the anterior mitral leaflet, which can also cause mechanical complications in the leaflets and mitral valve apparatus [11,21,22] [11,22,21]. Other proposed mechanisms are the formation of an anterior abscess spreading and the destruction of the mitral annulus, or the prolapsing aortic IE "kissing vegetation phenomenon" [23]. Bilateral IE is uncommon (12% in our series) and might be

Discussion
In our large national cohort of valvular IE, one-seventh of patients had MIE, which was associated with a poor prognosis.
MIE can involve native and prosthetic valves. The primary event is bacterial adherence to damaged valves during bacteriemia, with later persistence and growth within the cardiac lesions causing local extensions and tissue damage [21]. MIE can be the result of a simultaneous infection in two previously damaged valves in a patient with persistent bacteriemia or, more often, sequential seeding of a previously damaged valve [11]. In other cases, the infection of the first valve creates a new valvular lesion. A jet of aortic regurgitation may damage and infect the anterior mitral leaflet, which can also cause mechanical complications in the leaflets and mitral valve apparatus [11,21,22]. Other proposed mechanisms are the formation of an anterior abscess spreading and the destruction of the mitral annulus, or the prolapsing aortic IE "kissing vegetation phenomenon" [23]. Bilateral IE is uncommon (12% in our series) and might be related to shunts produced by congenital heart diseases [3], intracardiac devices, or repeated injections by drug users.
Surgical treatment is frequently needed in IE and even more so in MIE. About 85% of our MIE patients had a surgical indication, a higher proportion than in SIE, although only in 56% of MIE patients was surgery finally performed. MIE patients develop heart failure more often than SIE patients, and heart failure is a common surgical indication [1]. In addition, patients with MIE frequently present extensive tissue destruction [24]. These two factors are probably related to the higher rate of surgical treatment in MIE than in SIE [3,4,6,9].
The prognostic influence of MIE is unclear. An association with poor outcomes has been described in some studies [3][4][5][12][13][14][15]26] but not in others [2,[6][7][8][9]11,24]. Prosthetic IE is an important compounding factor when we compare MIE with SIE, as prosthetic IE is associated with a poor prognosis [4]. Table 3 summarizes the main information previously published regarding MIE. The mean age was higher in our cohort than in the published studies, probably because most previous data came from surgical series, and patients eligible for surgery are usually younger. Comparisons of SIE and information regarding medically treated patients are scarce. Moreover, a surgical series of selected patients shows excellent results that do not reflect everyday clinical practice. Our series of MIE is the largest reported to date and includes both patients treated with and without surgery.
The limitations of this study should be noted. Local medical teams were responsible for IE management, including deciding on surgery, and any judgments may have been influenced by factors not registered in this study. In any case, our data come from a large national database and show a clear association of MIE with IE prognosis.

Conclusions
About one-seventh of the valvular IE patients had MIE, mainly due to mitral-aortic involvement. MIE is associated with a poor in-hospital prognosis. An early diagnosis and treatment of IE might avoid its spread to a second valve.