Unraveling the Mechanisms of Valvular Heart Disease to Identify Medical Therapy Targets: A Scientific Statement From the American Heart Association.

Valvular heart disease is a common cause of morbidity and mortality worldwide and has no effective medical therapy. Severe disease is managed with valve replacement procedures, which entail high health care-related costs and postprocedural morbidity and mortality. Robust ongoing research programs have elucidated many important molecular pathways contributing to primary valvular heart disease. However, there remain several key challenges inherent in translating research on valvular heart disease to viable molecular targets that can progress through the clinical trials pathway and effectively prevent or modify the course of these common conditions. In this scientific statement, we review the basic cellular structures of the human heart valves and discuss how these structures change in primary valvular heart disease. We focus on the most common primary valvular heart diseases, including calcific aortic stenosis, bicuspid aortic valves, mitral valve prolapse, and rheumatic heart disease, and outline the fundamental molecular discoveries contributing to each. We further outline potential therapeutic molecular targets for primary valvular heart disease and discuss key knowledge gaps that might serve as future research priorities.

PROX1 Inhibits PDGF-B Expression to Prevent Myxomatous Degeneration of Heart Valves.

BACKGROUND: Cardiac valve disease is observed in 2.5% of the general population and 10% of the elderly people. Effective pharmacological treatments are currently not available, and patients with severe cardiac valve disease require surgery. PROX1 (prospero-related homeobox transcription factor 1) and FOXC2 (Forkhead box C2 transcription factor) are transcription factors that are required for the development of lymphatic and venous valves. We found that PROX1 and FOXC2 are expressed in a subset of valvular endothelial cells (VECs) that are located on the downstream (fibrosa) side of cardiac valves. Whether PROX1 and FOXC2 regulate cardiac valve development and disease is not known. METHODS: We used histology, electron microscopy, and echocardiography to investigate the structure and functioning of heart valves from Prox1ΔVEC mice in which Prox1 was conditionally deleted from VECs. Isolated valve endothelial cells and valve interstitial cells were used to identify the molecular mechanisms in vitro, which were tested in vivo by RNAScope, additional mouse models, and pharmacological approaches. The significance of our findings was tested by evaluation of human samples of mitral valve prolapse and aortic valve insufficiency. RESULTS: Histological analysis revealed that the aortic and mitral valves of Prox1ΔVEC mice become progressively thick and myxomatous. Echocardiography revealed that the aortic valves of Prox1ΔVEC mice are stenotic. FOXC2 was downregulated and PDGF-B (platelet-derived growth factor-B) was upregulated in the VECs of Prox1ΔVEC mice. Conditional knockdown of FOXC2 and conditional overexpression of PDGF-B in VECs recapitulated the phenotype of Prox1ΔVEC mice. PDGF-B was also increased in mice lacking FOXC2 and in human mitral valve prolapse and insufficient aortic valve samples. Pharmacological inhibition of PDGF-B signaling with imatinib partially ameliorated the valve defects of Prox1ΔVEC mice. CONCLUSIONS: PROX1 antagonizes PDGF-B signaling partially via FOXC2 to maintain the extracellular matrix composition and prevent myxomatous degeneration of cardiac valves.

Increased extracellular matrix stiffness regulates myofibroblast transformation through induction of autophagy-mediated Kindlin-2 cytoplasmic translocation.

The extracellular matrix (ECM) mechanical properties regulate biological processes, such as fibroblast-myofibroblast transformation (FMT), which is a crucial component in pelvic organ prolapse (POP) development. The 'Kindlin-2' protein, expressed by fibroblasts, plays an important role in the development of the mesoderm, which is responsible for connective tissue formation; however, the role of Kindlin-2 in FMT remains to be explored. In this study, we aimed to explore the role of Kindlin-2 in FMT as it relates to POP. We found that ECM stiffness induces autophagy to translocate Kindlin-2 to the cytoplasm of L929 cells, where it interacts with and degrades MOB1, thereby facilitating Yes-associated protein (YAP) entry into the nucleus and influencing FMT progression. Stiffness-induced autophagy was inhibited when using an autophagy inhibitor, which blocked the translocation of Kindlin-2 to the cytoplasm and partially reversed high-stiffness-induced FMT. In patients with POP, we observed an increase in cytoplasmic Kindlin-2 and nuclear YAP levels. Similar changes in vaginal wall-associated proteins were observed in a mouse model of acute vaginal injury. In conclusion, Kindlin-2 is a key gene affecting ECM stiffness, which regulates FMT by inducing autophagy and may influence the development of POP.

Silencing of cysteine and serine rich nuclear protein 1 inhibits apoptosis, senescence and collagen degradation in human-derived vaginal fibroblasts in response to oxidative stress or DNA damage.

Pelvic organ prolapse (POP) is a group of diseases caused by extracellular matrix (ECM) degradation in pelvic supportive tissues. Cysteine and serine rich nuclear protein 1 (CSRNP1) is involved in cell proliferation and survival regulation, and reportedly facilitates collagen breakdown in human chondrocytes. The present study aimed to probe the effect of CSRNP1 on collagen metabolism in human-derived vaginal fibroblasts. High expression of CSRNP1 was found in POP patient-derived vaginal fibroblasts in comparison to normal-derived vaginal fibroblasts. Following functional experiments revealed that CSRNP1 overexpression led to proliferation inhibition, apoptosis and collagen degradation in normal vaginal fibroblasts. In line with this, silencing of CSRNP1 inhibited hydrogen peroxide (H2O2)-triggered apoptosis, ROS generation and collagen loss in normal vaginal fibroblasts. Silencing of CSRNP1 also reduced the expression of cell senescence markers p21 and γ-H2Ax (the histone H2Ax phosphorylated at Ser139), as well as curbed collagen breakdown in normal vaginal fibroblasts caused by a DNA damage agent etoposide. Transcriptomic analysis of vaginal fibroblasts showed that differentially expressed genes affected by CSRNP1 overexpression were mainly enriched in the Wnt signaling pathway. Treatment with a Wnt pathway inhibitor DKK1 blocked CSRNP1 knockdown-caused collagen deposition. Mechanistically, CSRNP1 was identified to be a target of Snail family transcriptional repressor 2 (SNAI2). Forced expression of CSRNP1 reversed the anti-apoptotic, anti-senescent and anti-collagen loss effects of SNAI2 in normal vaginal fibroblasts exposed to H2O2 or etoposide. Our study indicates that the SNAI2/CSRNP1 axis may be a key driver in POP progression, which provides a potential therapeutic strategy for POP.

Mitral valve prolapse: arrhythmic risk during pregnancy and postpartum.

BACKGROUND AND AIMS: Arrhythmic mitral valve prolapse (AMVP) is linked to life-threatening ventricular arrhythmias (VAs), and young women are considered at high risk. Cases of AMVP in women with malignant VA during pregnancy have emerged, but the arrhythmic risk during pregnancy is unknown. The authors aimed to describe features of women with high-risk AMVP who developed malignant VA during the perinatal period and to assess if pregnancy and the postpartum period were associated with a higher risk of malignant VA. METHODS: This retrospective international multi-centre case series included high-risk women with AMVP who experienced malignant VA and at least one pregnancy. Malignant VA included ventricular fibrillation, sustained ventricular tachycardia, or appropriate shock from an implantable cardioverter defibrillator. The authors compared the incidence of malignant VA in non-pregnant periods and perinatal period; the latter defined as occurring during pregnancy and within 6 months after delivery. RESULTS: The authors included 18 women with AMVP from 11 centres. During 7.5 (interquartile range 5.8-16.6) years of follow-up, 37 malignant VAs occurred, of which 18 were pregnancy related occurring in 13 (72%) unique patients. Pregnancy and 6 months after delivery showed increased incidence rate of malignant VA compared to the non-pregnancy period (univariate incidence rate ratio 2.66, 95% confidence interval 1.23-5.76). CONCLUSIONS: The perinatal period could impose increased risk of malignant VA in women with high-risk AMVP. The data may provide general guidance for pre-conception counselling and for nuanced shared decision-making between patients and clinicians.

Degenerative mitral regurgitation due to flail leaflet: sex-related differences in presentation, management, and outcomes.

BACKGROUND AND AIMS: Presentation, outcome, and management of females with degenerative mitral regurgitation (DMR) are undefined. We analysed sex-specific baseline clinical and echocardiographic characteristics at referral for DMR due to flail leaflets and subsequent management and outcomes. METHODS: In the Mitral Regurgitation International Database (MIDA) international registry, females were compared with males regarding presentation at referral, management, and outcome (survival/heart failure), under medical treatment, post-operatively, and encompassing all follow-up. RESULTS: At referral, females (n = 650) vs. males (n = 1660) were older with more severe symptoms and higher MIDA score. Smaller cavity diameters belied higher cardiac dimension indexed to body surface area. Under conservative management, excess mortality vs. expected was observed in males [standardized mortality ratio (SMR) 1.45 (1.27-1.65), P < .001] but was higher in females [SMR 2.00 (1.67-2.38), P < .001]. Female sex was independently associated with mortality [adjusted hazard ratio (HR) 1.29 (1.04-1.61), P = .02], cardiovascular mortality [adjusted HR 1.58 (1.14-2.18), P = .007], and heart failure [adjusted HR 1.36 (1.02-1.81), P = .04] under medical management. Females vs. males were less offered surgical correction (72% vs. 80%, P < .001); however, surgical outcome, adjusted for more severe presentation in females, was similar (P ≥ .09). Ultimately, overall outcome throughout follow-up was worse in females who displayed persistent excess mortality vs. expected [SMR 1.31 (1.16-1.47), P < .001], whereas males enjoyed normal life expectancy restoration [SMR 0.92 (0.85-0.99), P = .036]. CONCLUSIONS: Females with severe DMR were referred to tertiary centers at a more advanced stage, incurred higher mortality and morbidity under conservative management, and were offered surgery less and later after referral. Ultimately, these sex-related differences yielded persistent excess mortality despite surgery in females with DMR, while males enjoyed restoration of life expectancy, warranting imperative re-evaluation of sex-specific DMR management.

PER2/P65-driven glycogen synthase 1 transcription in macrophages modulates gut inflammation and pathogenesis of rectal prolapse.

Rectal prolapse in serious inflammatory bowel disease is caused by abnormal reactions of the intestinal mucosal immune system. The circadian clock has been implicated in immune defense and inflammatory responses, but the mechanisms by which it regulates gut inflammation remain unclear. In this study, we investigate the role of the rhythmic gene Period2 (Per2) in triggering inflammation in the rectum and its contribution to the pathogenesis of rectal prolapse. We report that Per2 deficiency in mice increased susceptibility to intestinal inflammation and resulted in spontaneous rectal prolapse. We further demonstrated that PER2 was essential for the transcription of glycogen synthase 1 by interacting with the NF-κB p65. We show that the inhibition of Per2 reduced the levels of glycogen synthase 1 and glycogen synthesis in macrophages, impairing the capacity of pathogen clearance and disrupting the composition of gut microbes. Taken together, our findings identify a novel role for Per2 in regulating the capacity of pathogen clearance in macrophages and gut inflammation and suggest a potential animal model that more closely resembles human rectal prolapse.

The MIDA-Q Mortality Risk Score: A Quantitative Prognostic Tool for the Mitral Valve Prolapse Spectrum.

BACKGROUND: Mitral valve prolapse (MVP) is responsible for a considerable disease burden but is widely heterogeneous. The lack of a comprehensive prognostic instrument covering the entire MVP spectrum, encompassing the quantified consequent degenerative mitral regurgitation (DMR), hinders clinical management and therapeutic trials. METHODS: The new Mitral Regurgitation International Database Quantitative (MIDA-Q) registry enrolled 8187 consecutive patients (ages 63±16 years, 47% women, follow-up 5.5±3.3 years) first diagnosed with isolated MVP, without or with DMR quantified prospectively (measuring effective regurgitant orifice [ERO] and regurgitant volume) in routine practice of 5 tertiary care centers from North America, Europe, and the Middle East. The MIDA-Q score ranges from 0 to 15 by accumulating guideline-based risk factors and DMR severity. Long-term survival under medical management was the primary outcome end point. RESULTS: MVP was associated with DMR absent/mild (ERO <20 mm2) in 50%, moderate (ERO 20-40 mm2) in 25%, and severe or higher (ERO ≥40 mm2) in 25%, with mean ERO 24±24 mm2, regurgitant volume 37±35 mL. Median MIDA-Q score was 4 with a wide distribution (10%-90% range, 0-9). MIDA-Q score was higher in patients with EuroScore II ≥1% versus <1% (median, 7 versus 3; P < 0.0001) but with wide overlap (10%-90% range, 4-11 versus 0-7) and mediocre correlation (R2 0.18). Five-year survival under medical management was strongly associated with MIDA-Q score, 97±1% with score 0, 95±1% with score 1 to 2, 82±1% with score 3 to 4, 67±1% with score 5 to 6, 60±1% with score 7 to 8, 44±1% with score 9 to 10, 35±1% with score 11 to 12, and 5±4% with MIDA-Q score ≥13, with hazard ratio 1.31 [1.29-1.33] per 1-point increment. Excess mortality with higher MIDA-Q scores persisted after adjustment for age, sex, and EuroScore II (adjusted hazard ratio, 1.13 [1.11-1.15] per 1-point increment). Subgroup analysis showed persistent association of MIDA-Q score with mortality in all possible subsets, in particular, with EuroScore II<1% (hazard ratio, 1.08 [1.02-1.14]) or ≥1% (hazard ratio, 1.11 [1.08-1.13]) and with no/mild DMR (hazard ratio, 1.14 [1.10-1.19]) or moderate/severe DMR (hazard ratio, 1.13 [1.10-1.16], all per 1-point increment with P<0.0001). Nested-model and bootstrapping analyses demonstrated incremental prognostic power of MIDA-Q score (all P<0.0001). CONCLUSIONS: This large, international cohort of isolated MVP, with prospective DMR quantification in routine practice, demonstrates the wide range of risk factor accumulation and considerable heterogeneity of outcomes after MVP diagnosis. The MIDA-Q score is strongly, independently, and incrementally associated with long-term survival after MVP diagnosis, irrespective of presentation, and is therefore a crucial prognostic instrument for risk stratification, clinical trials, and management of patients diagnosed with all forms of MVP.

Early growth response 2, a novel target of pelvic organ prolapse, is highly expressed in anterior vaginal wall tissues with pelvic organ prolapse.

Pelvic organ prolapse (POP) is a common disorder among women that negatively affects women's quality of life. Early growth response 2 (EGR2) is a transcription factor that regulates cell growth. The present study aimed to explore the role of EGR2 in POP progression and provided a new target for the treatment and prevention of POP. Firstly, we extracted primary vaginal anterior wall fibroblasts from POP tissues and non-POP tissues and then constructed an EGR2-silencing lentivirus for further study. Immunoblotting, qPCR, TUNEL assay, CCK-8 assay, dual luciferase assay, and ELISA assay were carried out. EGR2 expression was much higher in POP tissues than in control tissues, and EGR2 expression positively correlated with cytokine signaling 3 (SOCS3) expression. Knockdown of EGR2 increased cell proliferation, upregulated PCNA expression, and reduced apoptosis in POP fibroblasts. Moreover, we found that the knockdown of EGR2 increased COL1A1, COL3A1, and Elastin expression and decreased MMP2 and MMP9 activities, and knockdown of EGR2 increased TGF-ß/Smad pathway activity in POP fibroblasts. Interestingly, the results of dual luciferase assay demonstrated that EGR2 was able to increase SOCS3 transcriptional activity. EGR2 knockdown alleviated the apoptosis of POP fibroblasts by reducing SOCS3 expression and improving the proliferation and collagen synthesis of POP fibroblasts. Overall, our study illustrated that EGR2 was highly expressed in POP tissues, and knockdown of EGR2 alleviated apoptosis and reduced matrix degradation in POP fibroblasts. This study might provide a new insight into the pathogenesis of POP.

Arrhythmic risk profile in mitral valve prolapse: A systematic review and metanalysis of 1715 patients.

INTRODUCTION: Mitral valve prolapse (MVP) is a common clinical condition in the general population. A subgroup of patients with MVP may experience ventricular arrhythmias and sudden cardiac death ("arrhythmic mitral valve prolapse" [AMVP]) but how to stratify arrhythmic risk is still unclear. Our meta-analysis aims to identify predictive factors for arrhythmic risk in patients with MVP. METHODS: We systematically searched Medline, Cochrane, Journals@Ovid, Scopus electronic databases for studies published up to December 28, 2022 and comparing AMVP and nonarrhythmic mitral valve prolapse (NAMVP) for what concerns history, electrocardiographic, echocardiographic and cardiac magnetic resonance features. The effect size was estimated using a random-effect model as odds ratio (OR) and mean difference (MD). RESULTS: A total of 10 studies enrolling 1715 patients were included. Late gadolinium enhancement (LGE) (OR: 16.67; p = .005), T-wave inversion (TWI) (OR: 2.63; p < .0001), bileaflet MVP (OR: 1.92; p < .0001) and mitral anulus disjunction (MAD) (OR: 2.60; p < .0001) were more represented among patients with AMVP than in NAMVP. Patients with AMVP were shown to have longer anterior mitral leaflet (AML) (MD: 2.63 mm; p < .0001), posterior mitral leaflet (MD: 2.96 mm; p < .0001), thicker AML (MD: 0.49 mm; p < .0001), longer MAD length (MD: 1.24 mm; p < .0001) and higher amount of LGE (MD: 1.41%; p < .0001) than NAMVP. AMVP showed increased mechanical dispersion (MD: 8.04 ms; 95% confidence interval: 5.13-10.96; p < .0001) compared with NAMVP. CONCLUSIONS: Our meta-analysis proved that LGE, TWI, bileaflet MVP, and MAD are predictive factors for arrhythmic risk in MVP patients.

Insights into malignant mitral valve degenerative disease from a sudden cardiac death cohort highlighting significant measurement differences from normal.

AIMS: Mitral valve prolapse (MVP) is an accepted cause of sudden cardiac death (SCD) in most autopsy series. Diagnosis at autopsy relies upon subjective assessment with no established objective pathological criteria. This study set out to establish objective measurements to help pathologists dealing with SCD. METHODS: We diagnosed 120 (1.5%) cases of MVP in 8108 cases of SCD. We measured the mitral annulus, anterior and posterior leaflets, rough zone and mitral annular disjunction (MAD) in 27 MVP cases and compared them to 54 age- and sex-matched normal mitral valves. RESULTS: Age of death was 39 ± 16 years, with 59 females and 61 males. History of mild MV disease was present in 19 (16%). Eleven (9%) died associated with exertion. Left ventricular hypertrophy was present in nine (15%) females and 10 (16%) males. Both MV leaflets showed thickening and ballooning in all individuals. MVP showed highly significantly increased annular circumference, elongation and thickening of both leaflets as well as increased MAD (all P < 0.001). Left ventricular fibrosis was present in 108 (90%), with interstitial fibrosis in the posterolateral wall and papillary muscle in 88 (81%) and coexisting replacement fibrosis in 40 (37%). CONCLUSION: This is the largest MVP associated with SCD series highlighting a young cohort with equal representation of males and females. There is involvement of both leaflets with significant annular dilatation, elongation and thickening of both leaflets with MAD. Left ventricular fibrosis explains arrhythmia. Our quantitative measurements should serve as a reference for pathologists assessing post-mortem hearts for MVP.

Mitral Annulus Disjunction: A Comprehensive Cardiovascular Magnetic Resonance Phenotype and Clinical Outcomes Study.

BACKGROUND: Clinical importance of mitral annulus disjunction (MAD) is not well established. PURPOSE: Characterize a population of MAD all-comers diagnosed by cardiac magnetic resonance imaging (MRI). STUDY TYPE: Retrospective. POPULATION: MAD confirmed in 222 patients, age of 49.2 ± 19.3 years, 126 (56.8%) males. FIELD STRENGTH/SEQUENCE: 1.5 T and 3 T/steady-state free precession and inversion recovery. ASSESSMENT: Clinical history, outcomes, imaging, and arrhythmia data. MAD defined as a separation ≥2 mm between left ventricular myocardium and mitral annulus. Presence and pattern of late gadolinium enhancement (LGE) were analyzed. LGE in the papillary muscles and adjacent to MAD were identified as MAD related. Ventricular arrhythmias (VA) were grouped into non-sustained ventricular arrhythmias (NSVA) or sustained. Cardiovascular death assessed. STATISTICAL TESTS: Differences between baseline characteristics were compared. Univariate regression was used to investigate possible associations between ventricular arrhythmia and cardiovascular death with characteristics associated with the severity of MAD. A multivariable logistic regression included significant variables from the univariate analysis and was performed for MAD-related and global LGE. RESULTS: MAD extent 5.0 ± 2.6 mm. MV annulus expanded during systole for MAD ≥6 mm. Systolic expansion associated with prolapse, billowing, and curling. LGE present in 82 patients (36.9%). Twenty-three patients (10.4%) showed MAD-related LGE by three different observers. No association of LGE with MAD extent (P = 0.545) noted. Follow-up 4.1 ± 2.4 years. No sustained VA observed. In univariable analysis, NSVA was more prevalent in patients with MAD ≥6 mm (33.3% vs. 9.9%), but this was attenuated on multivariate analysis (P = 0.054). The presence of NSVA was associated with global LGE but not MAD-related LGE in isolation (P = 0.750). Three patients died of cardiovascular causes (1.4%) and none had MAD-related LGE. None died of sudden cardiac arrest. CONCLUSION: In patients referred for cardiac MRI, mitral valve dysfunction was associated with MAD severity. Scar was not related to the extent of MAD, but associated with NSVA. The risk of sustained arrhythmias and cardiovascular death was low in this population. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Palatal prolapse during nasal expiration in patients with myasthenia gravis.

INTRODUCTION/AIMS: We have encountered patients with myasthenia gravis (MG) who exhibited palatal prolapse (PP) during nasal expiration in the supine position while awake. This may be an overlooked cause of dyspnea in MG patients. This study aimed to examine and describe the characteristics of MG patients with PP. METHODS: We reviewed the medical records of 183 consecutive patients who were diagnosed with MG in our hospital from 2012 to 2021. Thirty-two patients underwent laryngoscopy because of bulbar symptoms. Eight of these patients (25%) exhibited PP on laryngoscopy. Clinical features of these eight patients were retrospectively characterized. RESULTS: Median age of the eight patients with PP was 70 years. Six were men. Median body mass index was 21.6 kg/m2 . All patients exhibited PP in the supine position but not the sitting position. Although no patient had abnormal findings on spirometry nor chest computed tomography, six reported dyspnea or difficulty with nasal expiration only in the supine position. PP improved in all four patients who underwent edrophonium testing. All eight patients eventually improved after immunotherapy. DISCUSSION: PP during nasal expiration may be a cause of dyspnea in MG patients, along with respiratory muscle impairment, lung disease, and vocal cord paralysis. Laryngoscopy in the supine position is required to confirm.

Restrictive opioid prescribing after surgery for prolapse and incontinence: a randomized, noninferiority trial.

BACKGROUND: Opioids are routinely prescribed for postoperative pain control after gynecologic surgery with growing evidence showing that most prescribed opioids go unused. Restrictive opioid prescribing has been implemented in other surgical specialties to combat the risk for opioid misuse and diversion. The impact of this practice in the urogynecologic patient population is unknown. OBJECTIVE: This study aimed to determine if a restrictive opioid prescription protocol is noninferior to routine opioid prescribing in terms of patient satisfaction with pain control after minor and major surgeries for prolapse and incontinence. STUDY DESIGN: This was a single-center, randomized, noninferiority trial of opioid-naïve patients who underwent minor (eg, colporrhaphy or mid-urethral sling) or major (eg, vaginal or minimally invasive abdominal prolapse repair) urogynecologic surgery. Patients were excluded if they had contraindications to all multimodal analgesia and if they scored ≥30 on the Pain Catastrophizing Scale. Subjects were randomized on the day of surgery to the standard opioid prescription protocol (wherein patients routinely received an opioid prescription upon discharge [ie, 3-10 tablets of 5 mg oxycodone]) or to the restrictive protocol (no opioid prescription unless the patient requested one). All patients received multimodal pain medications. Participants and caregivers were not blinded. Subjects were asked to record their pain medication use and pain levels for 7 days. The primary outcome was satisfaction with pain control reported at the 6-week postoperative visit. We hypothesized that patient satisfaction with the restrictive protocol would be noninferior to those randomized to the standard protocol. The noninferiority margin was 15 percentage points. Pain level scores, opioid usage, opioid prescription refills, and healthcare use were secondary outcomes assessed for superiority. RESULTS: A total of 133 patients were randomized, and 127 (64 in the standard arm and 63 in the restrictive arm) completed the primary outcome evaluation and were included in the analysis. There were no statistically significant differences between the study groups, and this remained after adjusting for the surgery type. Major urogynecologic surgery was performed in 73.6% of the study population, and minor surgery was performed in 26.4% of the population. Same-day discharge occurred for 87.6% of all subjects. Patient satisfaction was 92.2% in the standard protocol arm and 92.1% in the restrictive protocol arm (difference, -0.1%; P=.004), which met the criterion for noninferiority. No opioid usage in the first 7 days after hospital discharge was reported by 48.4% of the patients in the standard protocol arm and by 70.8% in the restrictive protocol arm (P=.009). Opioid prescription refills occurred in 8.5% of patients with no difference between the study groups (9.4% in the standard arm vs 6.7% in the restrictive arm; P=.661). No difference was seen in the rate of telephone calls and urgent visits for pain control between the study arms. CONCLUSION: Among women who underwent minor and major surgery for prolapse and incontinence, patient satisfaction rates were noninferior after restrictive opioid prescribing when compared with routine opioid prescribing.

Effectiveness and safety of a novel, collapsible pessary for management of pelvic organ prolapse.

BACKGROUND: Pessaries are an effective treatment for pelvic organ prolapse, yet currently available pessaries can cause discomfort during removal and insertion. An early feasibility trial of an investigational, collapsible pessary previously demonstrated mechanical feasibility during a brief 15-minute office trial. Longer-term, patient-centered safety and efficacy data are needed. OBJECTIVE: This study aimed to assess the effectiveness and safety of the investigational vaginal pessary for pelvic organ prolapse at 3 months. STUDY DESIGN: This was a prospective, 7-center, open-label equivalence study with participants serving as their own controls. Subjects were current users of a Gellhorn or ring pessary with ≥stage 2 prolapse. Subjective and objective data were collected at baseline for 1 month while subjects used their current pessary. Data were then collected throughout a 3-month treatment phase with the study pessary. The primary outcome was change in Pelvic Floor Distress Inventory-20 score. Secondary outcome measures included objective assessment of prolapse support, changes in the Pelvic Floor Impact Questionnaire-7, and pain with insertion and removal, measured using a visual analog scale. Data from subjects fitted with the study pessary were analyzed using an intention-to-treat approach, and those who dropped out were assigned scores at the upper limit of the predefined equivalence limits. Secondary per protocol analyses included subjects who completed treatment. The study was powered to 80% with a minimal important change equivalence limit of 18.3 points on the Pelvic Floor Distress Inventory-20 scale. Square root transformations were used for nonparametric data, and P values were adjusted for multiple comparisons. RESULTS: A total of 78 subjects were enrolled, however, 16 withdrew before study pessary placement. The study pessary was fitted in 62 subjects (50 ring and 12 Gellhorn pessary users), and 48 (62%) completed the 3-month intervention. The change in Pelvic Floor Distress Inventory-20 scores at 3 months demonstrated equivalence when compared with the subjects' baseline scores (mean difference, -3.96 [improvement]; 90% confidence interval, -11.99 to 4.08; P=.002). Among those completing study, the Pelvic Floor Distress Inventory-20 scores, equivalence was not demonstrated and scores favored the study pessary (mean difference, -10.45; 90% confidence interval, -20.35 to 0.54; P=.095). Secondary outcomes included objective measures of support, which were similar (mean difference: Ba, 0.54 cm; Bp, 0.04 cm, favoring study pessary; improvement in mean Pelvic Floor Impact Questionnaire-7 scores for those who completed the trial: before, 32.23; after, 16.86; P=.019), and pain with insertion and removal, which was lower with the study pessary than with the subject's own pessary (mean difference visual analog scale score insertion, 9.91 mm; P=.019; removal, 11.23 mm; P=.019). No serious adverse events related to the pessary were reported. CONCLUSION: Equivalence was demonstrated in the primary outcome of the study pessary when compared with current, noncollapsible pessaries in terms of change in severity and bother of pelvic floor symptoms. Among participants who completed the trial, the Pelvic Floor Impact Questionnaire-7 improved with study pessary use and change in Pelvic Floor Distress Inventory-20 scores were nonequivalent, favoring the study pessary. Subjects reported significantly lower pain scores with both pessary insertion and removal with the novel collapsible pessary when compared with their standard pessary.

Preoperative prolapse phenotype is predictive of surgical outcome with minimally invasive sacrocolpopexy.

BACKGROUND: The gold-standard treatment for advanced pelvic organ prolapse is sacrocolpopexy. However, the preoperative features of prolapse that predict optimal outcomes are unknown. OBJECTIVE: This study aimed to develop a clinical prediction model that uses preoperative scores on the Pelvic Organ Prolapse Quantification examination to predict outcomes after minimally invasive sacrocolpopexy for stages 2, 3, and 4 uterovaginal prolapse and vaginal vault prolapse. STUDY DESIGN: A 2-institution database of pre- and postoperative variables from 881 cases of minimally invasive sacrocolpopexy was analyzed. Data from patients were analyzed in the following 4 groups: stage 2 uterovaginal prolapse, stage 3 to 4 uterovaginal prolapse, stage 2 vaginal vault prolapse, and stage 3 to 4 vaginal vault prolapse. Unsupervised machine learning was used to identify clusters and investigate associations between clusters and outcome. The k-means clustering analysis was performed with preoperative Pelvic Organ Prolapse Quantification points and stratified by previous hysterectomy status. The "optimal" surgical outcome was defined as postoperative Pelvic Organ Prolapse Quantification stage <2. Demographic variables were compared by cluster with Student t and chi-square tests. Odds ratios were calculated to determine whether clusters could predict the outcome. Age at surgery, body mass index, and previous prolapse surgery were used for adjusted odds ratios. RESULTS: Five statistically distinct prolapse clusters (phenotypes C, A, A>P, P, and P>A) were found. These phenotypes reflected the predominant region of prolapse (apical, anterior, or posterior) and whether support was preserved in the nonpredominant region. Phenotype A (anterior compartment prolapse predominant, posterior support preserved) was found in all 4 groups of patients and was considered the reference in the analysis. In 111 patients with stage 2 uterovaginal prolapse, phenotypes A and A>P (greater anterior prolapse than posterior prolapse) were found, and patients with phenotype A were more likely than those with phenotype A>P to have an optimal surgical outcome. In 401 patients with stage 3 to 4 uterovaginal prolapse, phenotypes C (apical compartment predominant, prolapse in all compartments), A, and A>P were found, and patients with phenotype A>P were more likely than those with phenotype A to have ideal surgical outcome. In 72 patients with stage 2 vaginal vault prolapse, phenotypes A, A>P, and P (posterior compartment predominant, anterior support preserved) were found, and those with phenotype A>P were less likely to have an ideal outcome than patients with phenotype A. In 297 patients with stage 3 to 4 vaginal vault prolapse, phenotypes C, A, and P>A (prolapse greater in posterior than in anterior compartment) were found, but there were no significant differences in rate of ideal outcome between phenotypes. CONCLUSION: Five anatomic phenotypes based on preoperative Pelvic Organ Prolapse Quantification scores were present in patients with stages 2 and 3 to 4 uterovaginal prolapse and vaginal vault prolapse. These phenotypes are predictive of surgical outcome after minimally invasive sacrocolpopexy. Further work needs to confirm the presence and predictive nature of these phenotypes. In addition, whether the phenotypes represent a progression of prolapse or discrete prolapse presentations resulting from different anatomic and life course risk profiles is unknown. These phenotypes may be useful in surgical counseling and planning.

Three-year outcomes of a randomized clinical trial of perioperative vaginal estrogen as adjunct to native tissue vaginal apical prolapse repair.

BACKGROUND: As the muscular and connective tissue components of the vagina are estrogen responsive, clinicians may recommend vaginal estrogen to optimize tissues preoperatively and as a possible means to reduce prolapse recurrence, but long-term effects of perioperative intravaginal estrogen on surgical prolapse management are uncertain. OBJECTIVE: This study aimed to compare the efficacy of perioperative vaginal estrogen vs placebo cream in reducing composite surgical treatment failure 36 months after native tissue transvaginal prolapse repair. STUDY DESIGN: This was an extended follow-up of a randomized superiority trial conducted at 3 tertiary US sites. Postmenopausal patients with bothersome anterior or apical vaginal prolapse were randomized 1:1 to 1-g conjugated estrogen cream (0.625 mg/g) or placebo, inserted vaginally twice weekly for ≥5 weeks preoperatively and continued twice weekly for 12 months postoperatively. All participants underwent vaginal hysterectomy (if the uterus was present) and standardized uterosacral or sacrospinous ligament suspension at the surgeon's discretion. The primary report's outcome was time to failure by 12 months postoperatively, defined by a composite outcome of objective prolapse of the anterior or posterior walls beyond the hymen or the vaginal apex descending below one-third the total vaginal length, subjective bulge symptoms, and/or retreatment. After 12 months, participants could choose to use-or not use-vaginal estrogen for atrophy symptom bother. The secondary outcomes included Pelvic Organ Prolapse Quantification points, subjective prolapse symptom severity using the Patient Global Impression of Severity and the Patient Global Impression of Improvement, and prolapse-specific subscales of the 20-Item Pelvic Floor Distress Inventory and the Pelvic Floor Impact Questionnaire-Short Form 7. Data were analyzed as intent to treat and "per protocol" (ie, ≥50% of expected cream use per medication diary). RESULTS: Of 206 postmenopausal patients, 199 were randomized, and 186 underwent surgery. Moreover, 164 postmenopausal patients (88.2%) provided 36-month data. The mean age was 65.0 years (standard deviation, 6.7). The characteristics were similar at baseline between the groups. Composite surgical failure rates were not significantly different between the estrogen group and the placebo group through 36 months, with model-estimated failure rates of 32.6% (95% confidence interval, 21.6%-42.0%) and 26.8% (95% confidence interval, 15.8%-36.3%), respectively (adjusted hazard ratio, 1.55; 95% confidence interval, 0.90-2.66; P=.11). The results were similar for the per-protocol analysis. Objective failures were more common than subjective failures, combined objective and subjective failures, or retreatment. Using the Patient Global Impression of Improvement, 75 of 80 estrogen participants (94%) and 72 of 76 placebo participants (95%) providing 36-month data reported that they were much or very much better 36 months after surgery (P>.99). These data included reports from 51 of 55 "surgical failures." Pelvic Organ Prolapse Quantification measurements, Patient Global Impression of Severity scores, and prolapse subscale scores of the 20-Item Pelvic Floor Distress Inventory and Pelvic Floor Impact Questionnaire-Short Form 7 all significantly improved for both the estrogen and placebo groups from baseline to 36 months postoperatively without differences between the groups. Of the 160 participants providing data on vaginal estrogen usage at 36 months postoperatively, 40 of 82 participants (49%) originally assigned to the estrogen group were using prescribed vaginal estrogen, and 47 of 78 participants (60%) assigned to the placebo group were using vaginal estrogen (P=.15). CONCLUSION: Adjunctive perioperative vaginal estrogen applied ≥5 weeks preoperatively and 12 months postoperatively did not improve surgical success rates 36 months after uterosacral or sacrospinous ligament suspension prolapse repair. Patient perception of improvement remained very high at 36 months.

Patient perspectives in adverse event reporting after vaginal apical prolapse surgery.

BACKGROUND: Many clinical trials use systematic methodology to monitor adverse events and determine grade (severity), expectedness, and relatedness to treatments as determined by clinicians. However, patient perspectives are often not included in this process. OBJECTIVE: This study aimed to compare clinician vs patient grading of adverse event severity in a urogynecologic surgical trial. Secondary objectives were to estimate the association of patient grading of adverse events with decision-making and quality of life outcomes and to determine if patient perspective changes over time. STUDY DESIGN: This was a planned supplementary study (Patient Perspectives in Adverse Event Reporting [PPAR]) to a randomized trial comparing 3 surgical approaches to vaginal apical prolapse. In the parent trial, adverse events experienced by patients were collected per a standardized protocol every 6 months during which clinicians graded adverse event severity (mild, moderate, severe/life-threatening). In this substudy, we obtained additional longitudinal patient perspectives for 19 predetermined "PPAR adverse events." Patients provided their own severity grading (mild, moderate, severe/very severe/life-threatening) at initial assessment and at 12 and 36 months postoperatively. Clinicians and patients were masked to each other's reporting. The primary outcome was the interrater agreement (kappa statistic) for adverse event severity between the initial clinician and patient assessment, combining patient grades of mild and moderate. The association between adverse event severity and the Decision Regret Scale, Satisfaction with Decision Scale, the 12-Item Short-Form Health Survey, and Patient Global Impression of Improvement scores was assessed using the Spearman correlation coefficient (ρ) for continuous scales, the Mantel-Haenszel chi-square test for Patient Global Impression of Improvement, and t tests or chi-square tests comparing the assessments of patients who rated their adverse events or symptoms as severe with those who gave other ratings. To describe patient perspective changes over time, the intraobserver agreement was estimated for adverse event severity grade over time using weighted kappa coefficients. RESULTS: Of the 360 randomly assigned patients, 219 (61%) experienced a total of 527 PPAR adverse events (91% moderate and 9% severe/life-threatening by clinician grading). Mean patient age was 67 years; 87% were White and 12% Hispanic. Among the patients reporting any PPAR event, the most common were urinary tract infection (61%), de novo urgency urinary incontinence (35%), stress urinary incontinence (22%), and fecal incontinence (13%). Overall agreement between clinician and participant grading of severity was poor (kappa=0.24 [95% confidence interval, 0.14-0.34]). Of the 414 adverse events that clinicians graded as moderate, patients graded 120 (29%) as mild and 80 (19%) as severe. Of the 39 adverse events graded as severe by clinicians, patients graded 15 (38%) as mild or moderate. Initial patient grading of the most severe reported adverse event was mildly correlated with worse Decision Regret Scale (ρ=0.2; P=.01), 12-Item Short-Form Health Survey (ρ=-0.24; P<.01), and Patient Global Impression of Improvement (P<.01) scores. There was no association between adverse event severity and Satisfaction with Decision Scale score. Patients with an initial grading of "severe" had more regret, lower quality of life, and poorer global impressions of health than those whose worst severity grade was mild (P<.05). Agreement between the patients' initial severity ratings and their ratings at 12 months (kappa=0.48 [95% confidence interval, 0.39-0.58]) and 36 months (kappa=0.45 [95% confidence interval, 0.37-0.53]) was fair. CONCLUSION: Clinician and patient perceptions of adverse event severity are discordant. Worse severity from the patient perspective was associated with patient-centered outcomes. Including the patient perspective provides additional information for evaluating surgical procedures.

Pelvic floor injury during vaginal birth is life-altering and preventable: what can we do about it?

Pelvic floor disorders after childbirth have distressing lifelong consequences for women, requiring more than 300,000 women to have surgery annually. This represents approximately 10% of the 3 million women who give birth vaginally each year. Vaginal birth is the largest modifiable risk factor for prolapse, the pelvic floor disorder most strongly associated with birth, and is an important contributor to stress incontinence. These disorders require 10 times as many operations as anal sphincter injuries. Imaging shows that injuries of the levator ani muscle, perineal body, and membrane occur in up to 19% of primiparous women. During birth, the levator muscle and birth canal tissues must stretch to more than 3 times their original length; it is this overstretching that is responsible for the muscle tear visible on imaging rather than compression or neuropathy. The injury is present in 55% of women with prolapse later in life, with an odds ratio of 7.3, compared with women with normal support. In addition, levator damage can affect other aspects of hiatal closure, such as the perineal body and membrane. These injuries are associated with an enlarged urogenital hiatus, now known as antedate prolapse, and with prolapse surgery failure. Risk factors for levator injury are multifactorial and include forceps delivery, occiput posterior birth, older maternal age, long second stage of labor, and birthweight of >4000 g. Delivery with a vacuum device is associated with reduced levator damage. Other steps that might logically reduce injuries include manual rotation from occiput posterior to occiput anterior, slow gradual delivery, perineal massage or compresses, and early induction of labor, but these require study to document protection. In addition, teaching women to avoid pushing against a contracted levator muscle would likely decrease injury risk by decreasing tension on the vulnerable muscle origin. Providing care for women who have experienced difficult deliveries can be enhanced with early recognition, physical therapy, and attention to recovery. It is only right that women be made aware of these risks during pregnancy. Educating women on the long-term pelvic floor sequelae of childbirth should be performed antenatally so that they can be empowered to make informed decisions about management decisions during labor.

Associated factors of vaginal laxity and female sexual function: a cross-sectional study.

BACKGROUND: Female sexual dysfunction (FSD), including vaginal laxity (VL), can lead to a decrease in quality of life and affect partner relationships. AIM: We aimed to investigate the associated factors of VL and FSD and their relationship with other pelvic floor disorders in a female population. METHODS: This cross-sectional study was conducted at Chelsea and Westminster Hospital from July to December 2022. All women referred to clinical care at the urogynecology clinic were included. Participants were assessed according to sociodemographic and clinical aspects, the Pelvic Organ Prolapse Quantification system, sexual function, VL, sexual attitudes, sexual distress, sexual quality of life, vaginal symptoms, and pelvic floor disorders. Unadjusted and adjusted associated factors of VL and FSD were analyzed. OUTCOMES: The primary outcome was the identification of the associated factors of VL and FSD in a female population, and secondary outcomes included the association between VL and pelvic organ prolapse (POP) with the questionnaire scores. RESULTS: Among participants (N = 300), vaginal delivery, multiparity, perineal laceration, menopause, and gel hormone were significantly more frequent in those reporting VL (all P < .05). When compared with nulliparity, primiparity and multiparity increased the odds of VL by approximately 4 and 12 times, respectively (unadjusted odds ratio [OR], 4.26 [95% CI, 2.05-8.85]; OR, 12.77 [95% CI, 6.53-24.96]). Menopause and perineal laceration increased the odds of VL by 4 and 6 times (unadjusted OR, 4.65 [95% CI, 2.73-7.93]; OR, 6.13 [95% CI, 3.58-10.49]). In multivariate analysis, menopause, primiparity, multiparity, and POP remained associated with VL. CLINICAL IMPLICATIONS: Parity, as an obstetric factor, and menopause and staging of POP, as clinical factors, were associated with VL. STRENGTHS AND LIMITATIONS: The investigation of associated factors for VL will contribute to the understanding of its pathophysiology. The study design makes it impossible to carry out causal inference. CONCLUSION: Menopause, primiparity, multiparity, and POP were highly associated with VL complaints in multivariate analysis.