Characteristics and Outcomes In Patients With Left-Sided Infective Endocarditis Undergoing Left-Sided Valve Surgery With or Without Concomitant Tricuspid Annuloplasty

Background: In patients with left-sided infective endocarditis (LSIE) undergoing left-sided valve surgery (LVS), the effects of concomitant tricuspid annuloplasty (TA) on clinical features and prognosis remain unknown. Methods: This is a single-center retrospective study conducted in a tertiary hospital in China. A total of 207 consecutive patients ≥ 18 years with a denite LSIE diagnosis who underwent LVS between 2008 and 2017 were included. Patients were divided into two groups: LVS alone (n=157) and LVS+TA group (n=50), to identify differences between the clinical features, echocardiogdraphic parameters and outcomes. Results: The mean age was 44.6±15.6 years and 150 (72.5%) were male. Of the 207 patients, 71 (34.3%) patients had aortic valve involved alone, 115 (55.6%) had mitral valve involved alone and 21 (10.1%) had both valved involved. The average hospital stays were 38±16 days and the median follow-up duration was 34.4 (IQR 19.8-56.3) months. Demographic and baseline characteristics were comparable between the two groups, except that the renal function in LVS alone group was better than LVS +TA group (eGFR 97.2±28.8 vs. 87.6±30.7, P=0.046). Signicant reductions in left and right atrial diameter, left ventricular diameter, mitral and tricuspid regurgitation (TR) degree, and pulmonary arterial systolic pressure were reported in both groups, of which the differences were more prominent in LVS+ TA group than LVS alone group (P<0.05). The rate of postoperative complications was higher in LVS+ TA group than that in LVS group (44.0% vs. 23.6%, P=0.005). However, the in-hospital mortality and long-term mortality was similar in both groups. After multi-factor adjustment, concomitant TA was not signicantly associated with in-hospital and long-term mortality. Conclusions: Concomitant TA at the time of LVS signicantly improved cardiac diameter but increased postoperative complications. It might not be associated with improved survival in LSIE patients.


Introduction
Despite the improvements in medical and surgical interventions, infective endocarditis remains a potentially lethal disease with the mortality ranging from 20-30% [1][2][3][4]. Early surgery signi cantly decreases the allcause mortality and the incidence of embolic events in patients with left-sided infective endocarditis (LSIE) compared with conservative management, and it is recommended for patients meeting speci c indications such as severe valve dysfunction [5][6][7]. As a prevalent condition, tricuspid regurgitation (TR) has attracted more and more discussions. Over 80% of tricuspid regurgitation is attributed to secondary (functional) causes including tricuspid annuli and right ventricle dilation, while primary causes account for less than 20% of TR.
Functional TR is often secondary to left-sided heart disease, predominantly mitral valve disease [8][9][10]. For patients undergoing mitral-valve surgery, the rate of functional TR is up to 50% [11]. Recent study has revealed that increasing TR severity is correlated with worse prognosis regardless of left ventricular function or pulmonary hypertension, and severe TR may not predictably improve after left-sided valve surgery [6]. Nevertheless, concomitant tricuspid valve repair during left-sided valve surgery is bene cial from reducing cardiac-related mortality [12]. Consequently, the American valvular heart disease guideline recommends concomitant tricuspid annuloplasty (TA) for patients with severe TR undergoing left-sided valve surgery (LVS) [13]. However, there is a paucity of evidence available to de ne the bene t of concomitant TV surgery in paitents with LSIE who need LVS. Most studies for the surgical management of functional TR are based on rheumatic or degenerative valvular disease, while IE accounts for only 16% of the etiology of left-sided heart disease [14]. Unlike the chronic onset and presence of the latent phase in rheumatic or degenerative valvular disease, IE commonly presents with more acute onset and more aggressive progression due to different underlying pathophysiology. Thus, the previous evidence from rheumatic or degenerative valvular disease can hardly extended to LSIE patients. In addition, most recommendations are categorized as Level of Evidence C, indicating the lack of high-quality trial or observational data. Therefore, our study aims to evaluate the effect of concomitant TA on clinical features and prognosis at the time of LVS among LSIE patients.

Study Population
This is a single-center retrospective observational study conducted in a tertiary referral hospital, the First A liated Hospital of Sun Yat-sen University. From January 1 st of 2008 to September 30 th of 2017, a total of 480 consecutive patients with clinical suspicion of IE were screened. We excluded patients who were younger than 18 years old (n=32), without de nite IE (n=34) according to the modi ed Duke Criteria were included in the study [15], and without comprehensive echocardiographic evidence of endocarditis (n=32). Patients with evidence of right-sided endocarditis (n=37), cardiac implantable electronic devices (pacemakers and implantable cardioverter-de brillators) (n=4), both-sided IE (n=11), and congenital heart disease-related IE (n=21) were also excluded, given these subtypes have completely distinct clinical, microbiological, and prognostic characteristics from LSIE. We also excluded 102 patients who didn't undergo IE surgery. Finally, a total of 207 patients ≥18 years old with a de nite LSIE diagnosis undergoing LVS were included in the study ( Figure 1). Patients were further divided into two groups depending on the type of de nitive interventions they received: LVS group (n=157), and LVS+TA group (n=50). The LVS group conducted left-sided valve surgery alone, while the LVS+ TA group underwent concomitant TA with LVS.

De nition of terms
The estimated glomerular ltration ratio (eGFR) was calculated using the 2009 CKD-EPI (Chronic Kidney included heart failure, arrhythmia, massive pericardial effusion, and low cardiac output syndrome. The study outcome for this analysis was in-hospital and long-term all-cause mortality. Since the high in-hospital mortality rate, the long-term all-cause mortality was calculated from both index admission and from discharge respectively.

Data collection and measurement of echocardiographic parameters
Baseline data were collected from the electronic medical record system, including the patients' demographic characteristics, previous history of underlying diseases, clinical presentations, laboratory test results on admission, transthoracic/transesophageal echocardiographic data, complications and microscopic studies of associated pathogens. The clinical severities were assessed by the Pitt bacteremia scores (PBS) ranging from 0 to 14 points with the higher score indicating the severer status [23].
Transthoracic echocardiograms (TTE) were performed at baseline preoperatively and postoperatively. The median duration of postoperative TTE performed were 8 (inter-quartile range, IQR: 7-13) days post operation. Left ventricular ejection fraction (LVEF) was measured by Simpson's method. In accordance of the recommendations from American Society of Echocardiography, the severity of tricuspid regurgitation was assessed using color Doppler ow images in TTE and graded qualitatively as mild (1+), moderate (2+), or severe (3+ or 4+) following the jet area-central jets of < 5, 5-10, or > 10 cm 2 respectively [24]. The pulmonary artery systolic pressure was calculated as the addition of estimated right atrial pressure (ranging from 5 to 10 mmHg given the varied size of inferior vena cava) and the systolic right atrial-ventricular pressure gradient (PG/ΔP), which was calculated by the modified Bernoulli equation: ΔP = 4 × v 2 (v: the maximal velocity of the TR jet area) [25].

Surgery procedures
All operations were performed under conventional cardiopulmonary bypass, mild or moderate hypothermia through median sternotomy. Mitral or aortic valve surgeries were performed before examining the tricuspid valve. For patients who underwent concomitant TA, either De Vega annuloplasty or ring annuloplasty were used according to the surgeon's comprehensive evaluations following the latest guidelines' recommendations at that time [26-28].

Statistical Analysis
Continuous normally distributed variables were described as mean value with standard deviation (SD) or median (IQR) when appropriate. For quantitative variables, the groups were compared by a two-tailed Student's t-test or Mann-Whitney U-test when necessary. Categorical variables were expressed as number of event and a percentage, and they were examined by the χ2 test or Fisher's exact test when appropriate. Categorical echocardiographic variables change between pre-and post-operation were analyzed using McNemar's statistical test.
Multivariable logistic regression models were applied to determine whether concomitant TA were associated with in-hospital mortality postoperation after adjusting for confounding factors. Multivariable cox regression models were used to explore the association of concomitant TA with long-term survival adjusted for Page 6/20 prede ned covariates. The survival time was calculated from death or the last time of follow up to hospital discharge. Since the high rate of in-hospital mortality, the survival time between death or last time of follow up to hospital admission were also discussed.
All hypothesis tests were two-sided, and a P value < 0.05 was considered as statistically signi cant. Statistical analysis was performed with SPSS software V22.0 (SPSS Inc., Chicago, IL, USA).

Baseline Characteristics of Patients
The baseline characteristics of the overall study population were demonstrated in Table    Demographic and baseline characteristics were comparable between the two groups, except that patients undergoing LVS with concomitant TA had signi cantly higher rate of atrial brillation (16.0% vs. 6.4%, P = 0.035) and worse renal function than those without TA (eGFR 87.6 ± 30.7 vs 97.2 ± 28.8, P = 0.046). The Pitt bacteremia scores were comparable between the two groups (P = 0.134).

Echocardiographic characteristics
A comparison of echocardiographic characteristics among patients undergoing left-sided surgery with or without concomitant TA was presented in Table 2. At baseline, the LVS + TA group had greater left atrial diameter (LA), right atrial diameter (RA), right ventricular diameter (RV), more severe mitral regurgitation (MR) and TR, higher PASP as well as larger vegetations compared with LVS group (P < 0.05).

Complications and outcomes
Strati ed by surgical interventions with or without concomitant TA, the complications, surgical treatment and outcomes were summarized in  In-hospital mortality, n (%) 9 (4.  Table 1 -2). No signi cant differences were indicated in in-hospital mortality nor long-term mortality between the LVS group and the LVS + TA group. After being adjusted for Pitt bacteremia score and eGFR, concomitant TA was not signi cantly associated with inhospital mortality nor long-term mortality. However, Pitt bacteremia score was signi cantly associated with poor short-term and long-term prognosis (P < 0.001) ( Table 4-5).

Discussion
As a common manifestation in LSIE, functional TR is thought to be associated with progressive right-sided heart failure and poor prognosis. The principle of concomitant TA at the time of LVS with certain indications was developed by virtue of other valvular diseases, including rheumatic heart disease and degenerative valvular heart disease [13]. However, there is a paucity of available evidence to elaborate on whether concomitant TA improves the prognosis of LSIE. Our study revealed that concomitant TA had signi cantly advanced effects on TR severity alleviation, right atrial dimension diminution, afterload reduction, as well as right heart function enhancement. However, concomitant TA at the time of LVS was associated with prolonged operation time, increased perioperative complications without improved short-term nor long-term prognosis.
In left-sided heart diseases, the right ventricular afterload usually increases (with or without pulmonary hypertension), followed by right ventricular remodeling and tricuspid annular dilation. Tricuspid annular dilation further results in poor lea et apposition and lea et coaptation mode, which eventually leads to functional TR [8]. The prevalence of functional TR with or without tricuspid annular dilatation in patients undergoing surgery for mitral regurgitation has ranged from 8-65% [29][30][31]. Patients with higher functional TR was independently associated with worse prognosis [32]. According to previous study, concomitant TA at the time of LVS in patients with functional moderate to severe TR was associated with decreased TR degree and late TR progression, improved right ventricular function and remodeling, as well as better long-term prognosis without increasing surgical risks [33][34][35][36][37][38][39]. Left uncorrected at the time of LVS, mild or moderate degrees of functional TR may progress over time in approximately 25% of patients, and reoperation was associated with high mortality, resulting in reduced long-term survival [13,40]. Therefore, concomitant TA procedure for moderate to severe TR in left-sided surgery is a class I recommendation according to the American College of Cardiology/ American Heart Association and the European Society of Cardiology [13,41].
However, according to Society of Thoracic Surgeons Adult Cardiac Surgery Database (STSACSD, version 2.73, 2011 to 2013), only 79% of patients with severe TR and 39% of patients with moderate TR undergo concomitant TA at the time of mitral surgery, possible due to the concern of safety and increased mortality or postoperative complications [42]. In our study, moderate to severe TR was presented in up to 24.8% of LSIE patients (Supplementary Table 3 The TR severity was signi cantly improved after LVS independent of TA and the attenuation of TR in the LVS + TA group was signi cantly greater than that without TA, which was consistent with previous study [36]. The RA diameter and PASP were also signi cantly reduced after concomitant TA.
However, in our current study, concomitant TA at the time of LVS was associated with increased procedure time and postoperative complications without improved prognosis. According to previous study, operative mortality was almost double for multiple-valve procedures as compared with single-valve procedures. Moreover, patients with emergency status and endocarditis were signi cant associated with increased mortality in multiple-valve procedure [42]. Nearly one-quarter of IE patients with surgical indications do not undergo surgery, and operation for active IE was associated with high risk, with an overall in-hospital mortality of 20% [43,44]. The possible reason was that patients with LSIE are usually urgent and progressive rapidly, which are quite different from rheumatic heart disease and degenerative heart disease with relatively latent progression and long duration. Therefore, whether functional tricuspid regurgitation should be treated at the time of LVS in patients with LSIE needs further robust clinical trials and evidence.
Another interesting nding in our study was that the risk of systemic embolisms was reduced in moderate to severe TR group (Supplementary Table 4), which was also elucidated among mitral stenosis patients in a previous study [45]. We speculate that the underlying rationale behind is the reduction of pulmonary arterial and venous ow with subsequent resolution of congestion and stasis in the left atrium [45].

Strengths And Limitations
To our knowledge, this is the rst study evaluating the prognosis of concomitant TA in LSIE patients who underwent LVS. Nevertheless, this present study has several limitations. First, our study was a single-center retrospective study with quite small sample size, with inevitable selection bias to some extent. For instance, the proportion of patients with valve replacement in our study was remarkable higher than what the guideline recommends, possibly attributable to higher referral rate of surgery-suitable patients from regional hospitals and surgeon selection bias. Second, the diameter of tricuspid annulus was not routinely measured in our center over the study period, consequently we were not able to present and investigate the relationship between tricuspid annulus dilation and prognosis. Third, the rate of loss to follow-up was quite high in our study, however, the baseline characteristics were overall comparable. Although it's not easy to carry out a randomized control trial due to the relatively low incidence rate, further robust prospective multicenter randomized control trials with long-term follow-up are still necessary to explicate the prognostic value of concomitant TA with LVS in LSIE patients.