Restrictive annuloplasty or replacement on reverse remodeling for nonischemic dilated cardiomyopathy.

BACKGROUND: For patients with nonischemic dilated cardiomyopathy (NIDCM), the indications for and results of mitral surgery remain controversial. We reviewed a strategy of mitral repair and replacement for clinically relevant secondary mitral regurgitation (MR) in patients with NIDCM. METHODS: We retrospectively reviewed 65 patients with advanced NIDCM (LVEF < 40%) who underwent mitral surgery. Of them, 47 (72%) underwent mitral annuloplasty and 18 (28%) replacement for secondary MR. The primary endpoint was postoperative reduction in indexed LV end-systolic volume (LVESVI). RESULTS: At baseline, there was no intergroup difference in LVESVI (123 ± 47 vs. 147 ± 37 ml/m2, P = 0.055), LVEF (27 ± 8% vs. 25 ± 6%, P = 0.41), incidence of severe MR (57% (27/47) vs. 72% (13/18), P = 0.40), or EuroSCORE II score (6.2% vs. 7.6%, P = 0.90). At 6 months, the annuloplasty group reduced LVESVI to a greater degree than the replacement group (P < 0.001), yielding significantly smaller postoperative LVESVI (96 ± 59 vs. 154 ± 61 ml/m2, P < 0.001) and better LVEF (P < 0.001). The rates of moderate/severe recurrent MR were 17% (8/47) and 0%, respectively. Multivariable analysis demonstrated that mitral annuloplasty (OR 6.10, 95% CI 1.14-32.8, P = 0.035) was significantly associated with postoperative LV reverse remodeling. Cumulative survival was not different between the groups (P = 0.26). CONCLUSIONS: In patients with NIDCM, mitral annuloplasty reduced LV volume to a greater degree than did mitral replacement. These findings may assist with surgical options for secondary MR associated with NIDCM.

Transcatheter Mitral Annuloplasty: Carillon Device.

Functional mitral regurgitation (FMR) is a common valvular heart disease in the geriatric population across the United States. This patient cohort is multimorbid and often has a prohibitive risk for conventional open-heart surgery. The diverse anatomic pathology of FMR is a complex problem and unfortunately does not have a universal solution. Carillon Mitral Contour System (Cardiac Dimensions, Kirkland, WA, USA) is a new device that provides transcatheter annular remodeling. In this review article, the authors summarize the evidence for the Carillon Mitral Contour System for FMR.

Predicting postoperative systolic dysfunction in mitral regurgitation: CT vs. echocardiography.

Introduction: Volume overload from mitral regurgitation can result in left ventricular systolic dysfunction. To prevent this, it is essential to operate before irreversible dysfunction occurs, but the optimal timing of intervention remains unclear. Current echocardiographic guidelines are based on 2D linear measurement thresholds only. We compared volumetric CT-based and 2D echocardiographic indices of LV size and function as predictors of post-operative systolic dysfunction following mitral repair. Methods: We retrospectively identified patients with primary mitral valve regurgitation who underwent repair between 2005 and 2021. Several indices of LV size and function measured on preoperative cardiac CT were compared with 2D echocardiography in predicting post-operative LV systolic dysfunction (LVEFecho <50%). Area under the curve (AUC) was the primary metric of predictive performance. Results: A total of 243 patients were included (mean age 57 ± 12 years; 65 females). The most effective CT-based predictors of post-operative LV systolic dysfunction were ejection fraction [LVEFCT; AUC 0.84 (95% CI: 0.77-0.92)] and LV end systolic volume indexed to body surface area [LVESViCT; AUC 0.88 (0.82-0.95)]. The best echocardiographic predictors were LVEFecho [AUC 0.70 (0.58-0.82)] and LVESDecho [AUC 0.79 (0.70-0.89)]. LVEFCT was a significantly better predictor of post-operative LV systolic dysfunction than LVEFecho (p = 0.02) and LVESViCT was a significantly better predictor than LVESDecho (p = 0.03). Ejection fraction measured by CT demonstrated significantly greater reproducibility than echocardiography. Discussion: CT-based volumetric measurements may be superior to established 2D echocardiographic parameters for predicting LV systolic dysfunction following mitral valve repair. Validation with prospective study is warranted.

Interpapillary muscle distance independently predicts recurrent mitral regurgitation.

OBJECTIVE: Ischaemic secondary mitral regurgitation (ISMR) after surgery is due to the displacement of papillary muscles resulting from progressive enlargement of the left ventricle end-diastolic diameter (LVEDD). Our aim was to prove that if the interpapillary muscle distance (IPMD) is surgically stabilized, an increase in LVEDD will not lead to a recurrence of ischaemic mitral regurgitation (MR). METHODS: Ninety-six patients with ISMR, who underwent surgical revascularisation and annuloplasty, were randomly assigned in a 1:1 ratio to undergo papillary muscle approximation (PMA). At the 5-year follow-up, we assessed the correlation between PMA and echocardiographic improvements, the effect size of PMA on echocardiographic improvements, and a prediction model for recurrent MR using inferential tree analysis. RESULTS: There was a significant correlation between PMA and enhancements in both the α and ß angles (Spearman's rho > 0.7, p < 0.01). The α angle represents the angle between the annular plane and either the A2 annular-coaptation line or the P2 annular-coaptation line. The ß angle indicates the angle between the annular plane and either the A2 annular-leaflet tip line or the P2 annular-leaflet tip line. PMA led to substantial improvements in LVEDD, tenting area, α and ß angles, with a large effect size (Hedge's g ≥ 8, 95% CI ORs ≠ 1). The most reliable predictor of recurrent MR grade was the interpapillary distance, as only patients with an interpapillary distance greater than 40 mm developed ≥ 3 + grade MR. For patients with an IPMD of 40 mm or less, the best predictor of recurrent MR grade was LVEDD. Among the patients, only those with LVEDD greater than 62 mm showed moderate (2+) MR, while only those with LVEDD less than or equal to 62 mm had absent to mild (1+) MR. CONCLUSION: Prediction of recurrent ischaemic MR is not independent of progressive LVEDD increase. PMA-based surgical procedure stabilises IPMD.

The study of loading mode with in-vitro fatigue testing for mitral annuloplasty ring.

To maintain the physiological dynamics of the mitral annulus, mitral annuloplasty rings (MAR) must be flexible. Enhanced flexibility implies decreased resistance to fatigue and potential for fatigue fracture. This study established new methods to test the flexible fatigue life of MAR in-vitro using numerical analysis; the purpose is that the fatigue test could reflect the real stress distribution in-vivo. Based on the conventional test methods (C1, D1), this paper presents a novel test method (C2, D2). Four testing methods for open-end annuloplasty rings (C1, C2) and closed-end annuloplasty rings (D1, D2) were modelled and their stress distribution calculated by finite element analysis. The mean absolute error (Χ) and the Pearson correlation coefficient (Φ) were used to quantify the difference in stress distribution between the loading modes in-vivo and in-vitro. For closed-end annuloplasty rings, the novel test method (D2) is not obvious better than conventional test methods(D1) in duplicating the stress distribution (ΦD1 = 0.88 vs ΦD2 = 0.92). However, the maximum values of stress in the novel test method are closer to the maximum value of stress under in-vivo loading (ΧD1 = 5.2Mpa vs ΧD2 = 4.4Mpa). For open-end annuloplasty rings, the novel test method(C2) is obviously superior to the conventional test method(C1) in duplicating both the stress distribution and the stress peak values of the in-vivo loading (ΦC1 = 0.22 vs ΦC2 = 0.98; ΧC1 = 59.1Mpa vs ΧC2 = 11.0Mpa). The in-vitro loading methods described in this article more closely approximated in-vivo conditions compared to traditional methods. They are simpler to operate, more efficient and can help manufacturers expedite new product development, assist regulatory agencies with product quality oversight.

Giant left atrial myxoma causing mitral regurgitation through annulus dilatation.

Key Clinical Message: Giant left atrial myxoma causing mitral regurgitation through mitral annulus dilatation without affecting leaflet function is rarely reported. Abstract: This is a case of a 37-year-old man suffering from worsening exertional dyspnea detected left atrial myxoma 92 × 43 mm. Radical mass resection and mitral annuloplasty were performed simultaneously. Giant left atrial myxoma causing mitral regurgitation through mitral annulus dilatation without affecting leaflet function is rarely reported.

Annuloplasty effect of transcatheter edge-to-edge repair with MitraClip system on multiple degenerative mitral regurgitations.

Background: Previous reports have shown a mitral annuloplasty-like effect after MitraClip, i.e. a shortening of the anterior-posterior diameter of mitral valve annulus. However, the clinical benefit of this phenomenon is unclear. Case summary: An 87-year-old woman with multiple degenerative mitral regurgitation (MR) jets, including a central-medial jet and a lateral jet, underwent MitraClip procedure. After a single clip implantation, anterior-posterior diameter of mitral annulus was shortened and both MR jets were significantly reduced. Discussion: Even in the case of multiple MR jets, a single clip deployment with the MitraClip system may provide an acceptable MR reduction if the clip shows the mitral annuloplasty effect.

Anaesthetic management of a patient with Gerbode defect.

Gerbode defect is a rare left ventricle to right atrium shunt that can be acquired or congenital. The incidence of acquired defects has been growing and is caused by previous cardiac surgery, endocarditis, trauma and myocardial infarct. It can be challenging and the anesthesiologist should maintain a suspicion when there is circulatory failure after a cardiac surgery. It can be diagnosed by trans-esophageal echocardiography. In this case we presented the anesthetic management and the successful surgical correction of an acquired ventricular-atrial defect secondary to a previous mitral valve replacement.

Computational Modeling of the Subject-Specific Effects of Annuloplasty Ring Sizing on the Mitral Valve to Repair Functional Mitral Regurgitation.

Surgical repair of functional mitral regurgitation (FMR) that occurs in nearly 60% of heart failure (HF) patients is currently performed with undersizing mitral annuloplasty (UMA), which lacks short- and long-term durability. Heterogeneity in valve geometry makes tailoring this repair to each patient challenging, and predictive models that can help with planning this surgery are lacking. In this study, we present a 3D echo-derived computational model, to enable subject-specific, pre-surgical planning of the repair. Three computational models of the mitral valve were created from 3D echo data obtained in three pigs with HF and FMR. An annuloplasty ring model in seven sizes was created, each ring was deployed, and post-repair valve closure was simulated. The results indicate that large annuloplasty rings (> 32 mm) were not effective in eliminating regurgitant gaps nor in restoring leaflet coaptation or reducing leaflet stresses and chordal tension. Smaller rings (≤ 32 mm) restored better systolic valve closure in all investigated cases,but excessive valve tethering and restricted motion of the leaflets were still present. This computational study demonstrates that for effective correction of FMR, the extent of annular reduction differs between subjects, and overly reducing the annulus has deleterious effects on the valve.

First case report of the use of two stents following coronary artery obstruction during indirect mitral annuloplasty.

The case of a 71-year-old male with end stage heart failure and severe mitral regurgitation is presented, where percutaneous indirect mitral annuloplasty was performed. During device implantation in the coronary sinus the circumflex artery was compromised at two anatomic locations, while the mitral regurgitation was efficiently reduced. After weighing risks and alternative therapeutic options, stent implantation was chosen as bailout strategy to leave the device in place and retain the efficient MR reduction. The anatomical proximity of Cx and coronary sinus in the mitral valve plane bears the risk of circumflex artery damage during surgical and interventional mitral repair. Usually, a device exchange solves the problem of arterial flow limitation in most cases. While stent implantation remains off label use in this setting and should not be performed without critical evaluation, it has been performed successfully in similar clinical settings as well (e.g. artery stenosis by surgical suture).

Mitral valve repair with the use of the "Memo 3D ReChord" ring.

BACKGROUND: From a variety of ring types, semirigid ring is more preferred for mitral annuloplasty during mitral valve repair particularly in patients whose native mitral saddle shape annulus is well maintained. During mitral annuloplasty artificial chord implantation with the appropriate neochord length is surgically challenging. We present our experience of using the Memo 3D ReChord, a semirigid ring with additional chordal guiding system for mitral valve repair. PATIENTS AND METHODS: From September 2018 to February 2020, we successfully treated ten patients with severe (4+/4+) degenerative mitral valve regurgitation due to posterior leaflet prolapse with chordal rupture with the implantation Memo 3D ReChord and neo-chords. RESULTS: We implanted from one to three neo-chords and always a ring in our patients. None of the patients had any residual mitral valve regurgitation at the end of the repair and on their discharge evaluated through transesophageal and transthoracic echocardiography respectively. There was no mortality at 30-days or on midterm follow-up. During the 3-month follow-up no regurgitation was noticed either. We included in our study only the patients successfully treated. We also used it in two patients, who underwent valve replacement during the same operation due to mild to moderate mitral valve regurgitation. CONCLUSIONS: This, in our knowledge, is the first Greek series of the implantation of the Memo 3D Rechord. The initial excellent results give us the enthusiasm to continue while long-term results and the durability of this technique are necessary to establish this semirigid annuloplastic ring in our every-day practice.

Reverse cardiac remodeling in patients undergoing combination therapy of transcatheter mitral valve repair.

Aims: For patients with severe mitral valve regurgitation (MR), different kinds of transcatheter mitral valve repair (TMVr) exist, targeting the leaflets, annulus, and chordae. The concomitant combination (COMBO) therapy of TMVrs is rarely used as treatment, and there are very few publications about this therapeutic strategy. We evaluated the effect of COMBO-TMVr on the cardiac left chambers and clinical data, including survival. Methods: We included 35 patients at high risk who underwent concomitant sequential transcatheter mitral valve edge-to-edge repair (M-TEER) and another TMVr for severe MR in our hospital between March 2015 and April 2018. Of these, 13 had adequate follow-up transthoracic echocardiography (TTE) up to around 1 year after the procedure. Results: Survival for all patients was 83% at 1 year, 71% at 2 years, and 63% at 3 years, respectively. In the 13 patients with adequate TTE follow-up, M-TEER plus either Cardioband (n = 4), Carillon Mitral Contour System (n = 7), or Neochord (n = 2) were used, respectively. Ten patients had secondary, and three patients primary MR. After 1 year, changes [median (Q1, Q3)] of left ventricular (LV) end-systolic diameter of -9.9 cm (-11.1, 0.4), LV end-diastolic diameter of -3.3 cm (-8.5, 0.0), LV end-systolic volume (LVESV) of -17.4 mL (-32.6, -0.4), LV end-diastolic volume (LVEDV) of -13.5 mL (-15.9, -3.2), LV mass of -19.5 g (-24.2, -7.6), and left atrial volume (LAV) index (LAVi) of -16.4 mL (-23.3, -11.3) were observed. A significant reduction was also seen in the change ratios of LVESV, LVEDV, LV mass, and LAVi, respectively. Conclusion: We found that COMBO therapy of TMVr seems feasible and may support reverse remodeling of left cardiac chambers during 1 year after the procedure in a cohort of patients at high risk.

Cardiac computed tomography based analysis of mitral annulus, coronary sinus and left circumflex artery in patients with mitral regurgitation: Implications for transcatheter mitral annuloplasty techniques.

INTRODUCTION: CT imaging analysis of mitral annulus (MA), coronary sinus (CS) and left circumflex artery (LCX) is critical to transcatheter mitral annuloplasty (TMA), which, however, is scantly reported. We aimed to comprehensively assess MA, CS and LCX anatomy and geometry in mitral regurgitation (MR) based on 3-D reconstruction of cardiac CT images. METHODS: Patients with primary or secondary MR and patients without MR were recruited and underwent cardiac CT examination. MR severity was evaluated by echocardiography. 3-D reconstruction of cardiac CT images was done by the Mimics Research 21.0 software. A MA-centered two dimensional coordinate system, a CS plane, a MA plane and a series of auxiliary planes along the posterior MA were created for the measurement of parameters defining MA, CS and LCX anatomy and geometry during the cardiac cycle. RESULTS: The secondary MR group had a significantly higher MA perimeter index than the other two groups during the cardiac cycle. The CS diameters at most sites, and the posterior MA radian were substantially greater in the two MR groups. Distances between the CS and MA at some locations were significant different among the three groups. The secondary MR group had a significantly smaller CS-MA plane angle than the other two groups during systole, and than control group during diastole. The site where the CS crossed LCX was pinpointed. CONCLUSION: The comprehensive information from this study may help improve the results of TMA and enhance the design of devices for a better annuloplasty effect.

Comparative study of coronary artery bypass grafting combined with off-pump mitral valvuloplasty versus coronary artery bypass grafting alone in patients with moderate ischemic mitral regurgitation.

INTRODUCTION: Whether mitral surgery should be performed simultaneously with coronary artery bypass grafting (CABG) in patients with moderate ischemic mitral regurgitation (MIMR) is controversial. This study was performed to introduce a method of off-pump mitral valvuloplasty after off-pump CABG (OPCABG) and compare it with OPCABG alone. METHODS: Eighty-three patients with MIMR underwent OPCABG. Among them, 21 patients (Group A) underwent posterior mitral annuloplasty without cardiopulmonary bypass, and 62 patients (Group B) underwent OPCABG alone. The primary endpoint of follow-up was the mitral regurgitation area. RESULTS: The mean mitral regurgitant area in Group A and B was 6.42 ± 1.02 and 5.49 ± 1.24 cm2 preoperatively (p = .479), 2.93 ± 1.35 and 3.28 ± 1.93 cm2 at 1 week postoperatively (p = .516), 3.06 ± 2.16 and 3.09 ± 1.85 cm2 at 3 months postoperatively (p = .839), and 3.02 ± 1.60 and 3.7 cm2 (median) at 1 year postoperatively (p = .043). There was less regurgitation in Group A at the mid-term. Intragroup comparison showed significant differences between the preoperative and postoperative values in both groups, with no difference in the regurgitant area at each postoperative time point in Group A but a significant difference between 3 months and 1 year postoperatively in Group B (p = .042). Multiple linear regression showed that the mid-term mitral regurgitant area changes were negatively correlated with graft flow and positively correlated with age. CONCLUSION: In patients with MIMR who underwent OPCABG plus off-pump mitral valve annuloplasty, the mitral regurgitant area was smaller and mitral regurgitation recurrence was less frequent at the mid-term follow-up.

Effect of Left Ventricular Hyperenhancement in Magnetic Resonance Imaging on Reverse Remodeling After Mitral Valve Repair for Moderate Ischemic Mitral Regurgitation.

We aimed to investigate cardiac magnetic resonance imaging (MRI)-derived predictors of a lack of left ventricular (LV) reverse remodeling after undersized mitral annuloplasty (uMAP) for moderate ischemic mitral regurgitation (IMR). We retrospectively reviewed 31 patients who underwent uMAP for moderate IMR and cardiac MRI evaluation between 2004 and 2017. Cardiac MRI evaluation included cine MRI LV and right ventricular volumetric measurements and gadolinium-enhanced MRI assessment of myocardial scarring. LV dimensions were assessed preoperatively, postoperatively, and at follow-up using serial transthoracic echocardiography, and the mid-term (median, 49 months) predictors of a lack of LV reverse remodeling were analyzed. At the mid-term follow-up (mean follow-up period: 85 ± 40 months), 15 patients exhibited reverse LV remodeling. The relative reduction in LV dimension at follow-up was negatively correlated with the preoperative number of LV segments with myocardial infarction (MI) (defined as an LV segment with >25% enhancement). The optimal cut-off for predicting a lack of reverse LV remodeling at follow-up was >5 LV segments with MI, with a sensitivity and specificity of 92% and 92%, respectively. This cut-off value also predicted all-cause mortality at follow-up, with a sensitivity and specificity of 88% and 67%, respectively. The presence of >5 LV segments with MI on gadolinium-enhanced MRI might be a useful predictor of lack of reverse LV remodeling and all-cause mortality outcomes after undersized mitral annuloplasty for moderate IMR.

Subannular repair for functional mitral regurgitation with reduced systolic ventricle function: rationale and design of REFORM-MR registry.

BACKGROUND: Functional mitral regurgitation (FMR) is one of the most common heart valve diseases that is a sequel of left ventricular remodelling. Although mitral valve annuloplasty is a standard treatment of FMR, the recurrence of FMR is a major drawback and occurs in 10-50% of patients. The REFORM-MR registry aims to investigate the effectiveness of standardized papillary muscle relocation and ring annuloplasty and to identify the risk factors associated with recurrent FMR. METHODS: REFORM-MR is a prospective, multicenter registry that enrols consecutive FMR patients across five sites in Germany. All patients with FMR and restricted movement of leaflets during systole (i.e., type IIIb mitral regurgitation) undergoing standardized subannular repair in combination with mitral valve annuloplasty are included in the study. The primary objective is to examine the effect of combined papillary muscle relocation and ring annuloplasty on the recurrence of FMR at 2 years postoperatively. The secondary objectives are MACCE rate, reinterventions on the mitral valve and cardiac-related mortality in the study cohort. Echocardiography core-lab and MRI core-lab will provide anonymized analysis of the imaging data in the REFORM-MR registry. Student's t-test or Mann-Whitney U test for continuous variables and the Chi-Square or Fisher exact test for categorical variables are used for group comparisons. Kaplan-Meier analyses is performed for survival and safety outcomes. RESULTS: As of May 2021, a total of 97 patients were enrolled across five sites in Germany. CONCLUSIONS: The results of this study will help define the outcomes of combined papillary muscle relocation and ring annuloplasty in the FMR treatment in a multicentre setting and to improve the understanding of the limitations of subannular repair procedures while treating patients with type III FMR. Trial registration clinicaltrials.gov Identifier: NCT03470155.

Coronary sinus for cardiac resynchronization therapy: leave it alone and go for the branch! a case report.

Background: Coronary sinus is the target of an increasing number of percutaneous interventional procedures. Thus, in some patients, conventional cardiac resynchronization therapy (CRT) may not be feasible or preferable, and 'alternative' CRT approaches should be applied. Case summary: We present the case of a successful CRT via direct left bundle branch permanent pacing (LBBP) in a patient with relative contraindication to conventional CRT because of previous percutaneous indirect mitral annuloplasty. Discussion: LBBP is emerging as a promising technique for physiological cardiac pacing and CRT. It may represent the technique of choice when coronary sinus is not viable for the implant of a conventional left ventricular catheter.

Numerical modeling for efficiency and endurance assessment of an indirect mitral annuloplasty device.

In recent years, several transcatheter systems have been introduced for treatment of common mitral regurgitation (MR). Such a system that is based on indirect mitral annuloplasty (IMA) is currently indicated for functional MR. Very few clinical studies have been performed to assess the efficiency and durability of such devices, despite their high risk of fracture resulting from ongoing exposure to large cyclic deformations. In this study, numerical models of moderate primary MR were created to test the implantation procedure of a customized IMA device and its sealing efficiency. The ability of the implanted device to reduce systolic leakage was evaluated and affirmed with a model of a more generic device. The long-term durability of the device was tested using a range of Nickel Titanium material properties. Our results demonstrated a considerable reduction in leakage for both the simplified generic device and the more detailed customized device models. The device met different fatigue criteria, confirming its resiliency and safety even after 10 years, even under the harsher conditions of primary MR. This is the first study to assess the performance and fatigue risk of IMA devices for the treatment of more complicated MR conditions. These findings may pave the way for further research to ultimately consider the device in selective cases of PMR.

Restrictive annuloplasty on remodeling and survival in patients with end-stage ischemic cardiomyopathy.

OBJECTIVES: To elucidate the influence of concomitant restrictive mitral annuloplasty (RMA) on postoperative left ventricular (LV) reverse remodeling and survival in patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting (CABG). METHODS: This study comprised 157 patients with ischemic cardiomyopathy (LV ejection fraction ≤40%) who underwent CABG and completed echocardiographic examination at 1 year after surgery, with 84 (54%) undergoing concomitant RMA for clinically relevant ischemic mitral regurgitation. The primary end point was postoperative reduction in LV end-systolic volume index (LVESVI). The secondary end point was overall survival. Median follow-up was 5.1 years. RESULTS: At baseline, patients who underwent CABG with RMA had a larger LVESVI (83 ± 23 vs 75 ± 24 mm; P = .046). One-year postoperatively, CABG with RMA reduced the LVESVI more than did CABG alone (37% vs 21% from baseline; P < .001), yielding nearly identical postoperative LVESVI (53 ± 27 vs 61 ± 26 mm; P = .065). In multivariable logistic regression analysis, concomitant RMA was associated with significant LV reverse remodeling (odds ratio, 2.79; 95% CI, 1.34-5.78; P = .006). The prevalence in moderate or severe mitral regurgitation was not different between the groups (7% vs 10%; P = .58). Survival rates were similar between the groups (5 years, 78% vs 83%; P = .35). CONCLUSIONS: In patients with ischemic cardiomyopathy undergoing CABG, concomitant RMA was associated with significant reduction in LVESVI. The influence of LV reverse remodeling on survival remains undetermined.