Severe aortic stenosis: secular trends of incidence and outcomes.

BACKGROUND AND AIMS: Severe aortic stenosis (AS) is the guideline-based indication for aortic valve replacement (AVR), which has markedly increased with transcatheter approaches, suggesting possible increasing AS incidence. However, reported secular trends of AS incidence remain contradictory and lack quantitative Doppler echocardiographic ascertainment. METHODS: All adults residents in Olmsted County (MN, USA) diagnosed over 20 years (1997-2016) with incident severe AS (first diagnosis) based on quantitatively defined measures (aortic valve area ≤ 1 cm2, aortic valve area index ≤ 0.6 cm2/m2, mean gradient ≥ 40 mmHg, peak velocity ≥ 4 m/s, Doppler velocity index ≤ 0.25) were counted to define trends in incidence, presentation, treatment, and outcome. RESULTS: Incident severe AS was diagnosed in 1069 community residents. The incidence rate was 52.5 [49.4-55.8] per 100 000 patient-year, slightly higher in males vs. females and was almost unchanged after age and sex adjustment for the US population 53.8 [50.6-57.0] per 100 000 residents/year. Over 20 years, severe AS incidence remained stable (P = .2) but absolute burden of incident cases markedly increased (P = .0004) due to population growth. Incidence trend differed by sex, stable in men (incidence rate ratio 0.99, P = .7) but declining in women (incidence rate ratio 0.93, P = .02). Over the study, AS clinical characteristics remained remarkably stable and AVR performance grew and was more prompt (from 1.3 [0.1-3.3] years in 1997-2000 to 0.5 [0.2-2.1] years in 2013-16, P = .001) but undertreatment remained prominent (>40%). Early AVR was associated with survival benefit (adjusted hazard ratio 0.55 [0.42-0.71], P < .0001). Despite these improvements, overall mortality (3-month 8% and 3-year 36%), was swift, considerable and unabated (all P ≥ .4) throughout the study. CONCLUSIONS: Over 20 years, the population incidence of severe AS remained stable with increased absolute case burden related to population growth. Despite stable severe AS presentation, AVR performance grew notably, but while declining, undertreatment remained substantial and disease lethality did not yet decline. These population-based findings have important implications for improving AS management pathways.

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.

Periprosthetic Hip and Knee Infection: Is an Ipsilateral Uninfected Total Joint Arthroplasty at Risk?

BACKGROUND: Periprosthetic joint infections (PJIs) of total hip arthroplasty (THA) or total knee arthroplasty (TKA) may occur in the setting of an uninfected ipsilateral prosthetic joint. However, the risk to that uninfected ipsilateral joint is unknown. We analyzed the survivorship free from PJI in at risk THAs and TKAs following treatment of an ipsilateral knee or hip PJI, respectively. METHODS: Using our institutional total joint registry, we identified 205 patients who underwent treatment for PJI (123 THAs and 83 TKAs) with an at-risk ipsilateral in situ knee or hip, respectively, between 2000 and 2019. In total, 54% of index PJIs were chronic and 46% were acute. The mean age was 70 years, 47% were female, and the mean body mass index was 32. Kaplan-Meier survivorship analyses were performed. Mean follow-up was 6 years. RESULTS: The 5-year survivorship free of PJI in an at-risk THA after an ipsilateral TKA was treated for PJI was 97%. The 5-year survivorship free of PJI in an at-risk TKA when the ipsilateral THA was treated for PJI was 99%. Three PJIs occurred (2 THAs and 1 TKA), all over 1 year from the index ipsilateral PJI treatment. One hip PJI was an acute hematogenous infection that resulted from pneumonia. The other 2 new PJIs were caused by the same organism as the index PJI and were due to a failure of source control at the index joint. CONCLUSIONS: When diagnosed with PJI in a single joint, the risk of developing PJI in an ipsilateral prosthetic joint within 5 years was low (1 to 3% risk). In the rare event of an ipsilateral infection, all occurred greater than one year from the index PJI and 2 of 3 were with the same organism when source infection control failed. LEVEL OF EVIDENCE: Prognostic Level III.

Knee Arthroscopy Following Total Knee Arthroplasty is Not Associated With an Elevated Risk of Infection.

BACKGROUND: Recent literature has suggested that knee arthroscopy (KA) following ipsilateral primary total knee arthroplasty (TKA) may be associated with an increased risk of periprosthetic joint infection (PJI). However, prior studies on this subject have relied on insurance databases or have lacked control groups for comparison. This study aimed to evaluate the risk of PJI in patients undergoing ipsilateral KA after primary TKA at a single institution. METHODS: Our total joint registry was queried to identify 167 patients (178 knees) who underwent ipsilateral KA for any indication other than infection following primary TKA (KA + TKA group). The average time from TKA to KA was 2.1 ± 2.3 years. The average follow-up from primary TKA and from KA was 8.4 ± 5.4 years and 6.3 ± 5.4 years, respectively. The mean patient age was 63 ± 11 years, the mean body mass index was 31 ± 5, and 64% were women. The most common indications for KA were patellar clunk or patellofemoral synovial hyperplasia (66%) and arthrofibrosis (16%). Patients in the KA + TKA group were matched to 523 patients who underwent TKA without subsequent KA (TKA group) based on age, sex, date of surgery, and body mass index. The primary outcome measure was survivorship free from PJI. RESULTS: There was no statistical difference in the overall rate of PJI between the KA + TKA group (n = 2, 1.1%) compared to the TKA group (n = 3, 0.6%) (hazard ratio 2.0, 95% confidence interval 0.3 to 12.0, P = .4). At 5 and 10 years after TKA, there was no difference in survivorship free of PJI between the 2 groups (P = .8 and P = .3, respectively). CONCLUSIONS: A PJI is a rare complication of KA after TKA. The rate of PJI in patients undergoing KA following TKA is not significantly increased. LEVEL OF EVIDENCE: III.

Association of transcatheter edge-to-edge repair with improved survival in older patients with severe, symptomatic degenerative mitral regurgitation.

BACKGROUND: Randomized clinical trials demonstrated transcatheter edge-to-edge repair (TEER) efficacy in improving outcome vs. medical management for functional mitral regurgitation, but limited randomized data are available for the treatment of degenerative mitral regurgitation (DMR). We aimed to compare the outcome of older patients treated with TEER vs. unoperated DMR. METHODS AND RESULTS: Registries including consecutive patients ≥65 years with symptomatic severe DMR treated with TEER (MitraSwiss and Minneapolis Heart Institute registries) or unoperated (MIDA registry) were analysed. Survival was compared overall and after matching for age, sex, EuroSCORE II, and ejection fraction. The study included 1187 patients (872 treated with TEER and 315 unoperated). During 24 ± 17 months of follow-up, 430 patients died, 18 ± 1% at 1 year and 50 ± 2% at 4 years. Patients undergoing TEER had similar age (82 ± 6 vs. 82 ± 7 years) and sex to unoperated patients, but higher surgical risk/comorbidity (EuroSCORE II 3.98 ± 4.28% vs. 2.77 ± 2.46%), more symptoms, and atrial fibrillation (P < 0.0001). Transcatheter edge-to-edge repair was associated with lower mortality accounting for age, sex, EuroSCORE II, New York Heart Association class, atrial fibrillation, and ejection fraction [hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.37-0.58; P < 0.0001]. After propensity matching (247 pairs of patients), TEER consistently showed better survival compared with unoperated patients (49 ± 6% vs. 37 ± 3% at 4 years, P < 0.0001) even in comprehensive multivariable analysis (HR: 0.60, 95% CI: 0.40-0.91; P = 0.03). Procedural failure was infrequent but post-procedural mitral regurgitation, remaining moderate-to-severe in 66 (7.6%) patients, was associated with excess mortality vs. trivial residual regurgitation (30 ± 6% vs. 11 ± 1% at 1 year, P < 0.0001). CONCLUSION: Amongst older patients with severe symptomatic DMR at high surgical risk, mitral TEER was associated with higher survival vs. unoperated patients. Successful control of mitral regurgitation was key to survival improvement with mitral TEER, which should be actively considered in patients deemed inoperable.

Role of Lymphadenectomy during Radical Cystectomy for Nonmuscle-Invasive Bladder Cancer: Results from a Multi-Institutional Experience.

PURPOSE: While lymph node dissection (LND) at radical cystectomy (RC) for muscle-invasive bladder cancer has been studied extensively, the role of LND for nonmuscle-invasive bladder cancer (NMIBC) remains incompletely defined. Herein, we aim to assess the association between extent of LND during RC for NMIBC and local pelvic recurrence-free survival (LPRS), cancer-specific survival (CSS) and overall survival (OS). MATERIALS AND METHODS: A multi-institutional retrospective review was performed of patients with NMIBC undergoing RC at 3 large tertiary referral centers. To identify a threshold for lymph node yield (LNY) to optimize LPRS, CSS and OS, separate Cox regression models were developed for each possible LNY threshold. Model performance including Q-statistics and hazard ratios (HRs) were used to identify optimal LNY thresholds. RESULTS: A total of 1,647 patients underwent RC for NMIBC, with a median LNY of 15 (quartiles 9,23). Model performance curves suggested LNY of 10 and 20 to optimize LPRS and CSS/OS, respectively. On multivariable regression, LNY >10 was associated with lower risk of LPR compared to LNY ≤10 (HR 0.63, 95% CI 0.42-0.93, p=0.02). Similarly, LNY >20 was associated with improved CSS (HR 0.67, 95% CI 0.52-0.87, p=0.002) and OS (HR 0.75, 95% CI 0.64-0.88, p <0.001) compared to LNY ≤20. Similar results were observed in the cT1 and cTis subgroups. CONCLUSIONS: Greater extent of LND during RC for NMIBC is associated with improved LPRS, CSS and OS, supporting the inclusion of LND during RC for NMIBC, particularly among patients with cTis or cT1 disease. Future prospective studies are warranted to assess the ideal anatomical template of LND in NMIBC.

Systemic manifestations and symptom burden of facioscapulohumeral muscular dystrophy in a referral cohort.

INTRODUCTION/AIMS: The full spectrum of the clinical phenotype of facioscapulohumeral muscular dystrophy (FSHD), beyond skeletal muscle weakness, remains poorly characterized. In this study, we describe systemic manifestations and symptom burden in a large series of FSHD patients. METHODS: We performed a retrospective chart review of FSHD patients seen at our institution between 2000 and 2017. We reviewed patients' responses to a comprehensive review of symptoms and the results of diagnostic testing for sensorineural hearing loss, cardiac disease, dysphagia, ocular abnormalities, and respiratory insufficiency. We assessed the association between disease manifestations and age of onset, genetic profile, and disease duration. RESULTS: We identified 87 patients with FSHD. The most common reported symptoms included pain (71%), difficulty sleeping (41%), headaches (27%), and altered mood (24%). When tested, 7 of 16 (44%) patients had sensorineural hearing loss, 20 of 60 (33%) had cardiac arrhythmias or conduction defects, 17 of 45 (38%) had echocardiogram abnormalities, 12 of 25 (48%) had reduced forced vital capacity, and 4 of 10 (40%) had oropharyngeal dysphagia. However, patients with these abnormalities represented 8%, 23%, 20%, 14%, and 5% of total number of patients, respectively, as uniform screening was lacking. Ocular pathology attributable to FSHD was not detected. DISCUSSION: FSHD demonstrates a broad clinical phenotype. Increased vigilance among neurologists to screen for systemic manifestations of the disease is warranted. More uniform screening and future population-based studies are needed to compare findings in FSHD patients with the general population.

Risk factors for lumbosacral radiculoplexus neuropathy.

INTRODUCTION/AIMS: Recently, our group found an association between diabetes mellitus (DM) and lumbosacral radiculoplexus neuropathy (LRPN) in Olmsted County, Minnesota; we found a higher risk (odds ratio [OR], 7.91) for developing LRPN in diabetic compared with nondiabetic patients. However, the influence of other comorbidities and anthropomorphic variables was not studied. METHODS: Demographic and clinical data from 59 LRPN patients and 177 age/sex-matched controls were extracted using the Rochester LRPN epidemiological study. Differences between groups were compared by chi-square/Fisher exact test or Wilcoxon rank-sum test. Uni- and multivariate logistic regression analysis were performed. RESULTS: Factors predictive of LRPN on univariate analysis were DM (OR, 7.91; 95% confidence interval [CI], 4.11-15.21), dementia (OR, 6.36; 95% CI, 1.13-35.67), stroke (OR, 3.81; 95% CI, 1.32-11.01), dyslipidemia (OR, 2.844; 95% CI, 1.53-5.27), comorbid autoimmune disorders (OR, 2.72; 95% CI, 1.07-6.93), hypertension (OR, 2.25; 95% CI, 1.2-4.13), obesity (OR, 2.05; 95% CI, 1.11-3.8), body mass index (BMI) (OR, 1.1; 95% CI, 1.04-1.15), and weight (OR, 1.02; 95% CI, 1.009-1.037). On multivariate logistic regression analysis only DM (OR, 8.03; 95% CI, 3.86-16.7), comorbid autoimmune disorders (OR, 4.58; 95% CI, 1.45-14.7), stroke (OR, 4.13; 95% CI, 1.2-14.25), and BMI (OR, 1.07; 95% CI, 1.01-1.13) were risk factors for LRPN. DISCUSSION: DM is the strongest risk factor for the development of LRPN, followed by comorbid autoimmune disorders, stroke, and higher BMI. Altered metabolism and immune dysfunction seem to be the most influential factors in the development of LRPN.

Evaluation of PD-L1 and B7-H3 expression as a predictor of response to adjuvant chemotherapy in bladder cancer.

INTRODUCTION AND OBJECTIVES: PD-L1 and B7-H3 have been found to be overexpressed in urothelial carcinoma (UC) of the urinary bladder. Recent studies have also demonstrated that B7-H3 and PD-L1 can promote resistance to platinum-based drugs but the predictive value of B7-H3 expression in patients treated with platinum-based chemotherapy is unknown. This study aims to investigate the association of PD-L1 and B7-H3 tumor expression with oncological outcomes in patients who underwent radical cystectomy (RC) and received subsequent adjuvant chemotherapy. MATERIALS AND METHODS: Immunohistochemistry was performed on paraffin-embedded sections from bladder and lymph node specimens of 81 patients who had RC for bladder cancer. PD-L1 and B7-H3 expression on tumor cells was assessed by immunohistochemistry in both primary tumors and lymph node specimens. Association with clinicopathologic outcomes was determined using Fisher's exact test and postoperative survival using Kaplan-Meier survival curves and Cox regression model. RESULTS: B7-H3 expression in cystectomy specimens was more common than PD-L1 expression (72.8% vs. 35.8%). For both markers, no association was found with pathologic tumor stage, lymph node (LN) status, and histological subtype. Similar findings were observed for double-positive tumors (PD-L1+B7-H3+). Concordance between the primary tumor and patient-matched lymph nodes was found in 76.2% and 54.1% of patients for PD-L1 and B7-H3, respectively. PD-L1 tumor expression was not associated with oncologic outcomes. However, B7-H3 expression was associated with recurrence-free survival (HR: 2.38, 95% CI 1.06-5.31, p = 0.035) and cancer-specific survival (HR: 2.67, 95% CI 1.18-6.04, p = 0.019). CONCLUSIONS: In our single institutional study, B7-H3 is highly expressed in patients with UC treated with adjuvant chemotherapy and it was associated with decreased recurrence-free survival and cancer-specific survival. Pending further validation in larger cohorts, B7-H3 expression may function as a predictor of response to adjuvant chemotherapy and thus be useful in patient and regimen selection.

A Contemporary Analysis of Urethral Recurrence following Radical Cystectomy.

PURPOSE: Oncologic outcomes following urethral recurrence (UR) remain incompletely described, with reports limited by small cohort sizes. We evaluated risk factors for UR as well as cancer-specific survival (CSS) and overall survival (OS) among patients with UR. MATERIALS AND METHODS: We reviewed our institutional radical cystectomy (RC) registry to identify patients with UR. Cox proportional hazards regression was used to assess risk factors for UR. Kaplan-Meier and Cox models were used to assess the relationship between UR and CSS/OS as well as to compare outcomes following symptomatic vs asymptomatic presentation of UR. RESULTS: Overall, 2,930 patients underwent RC from 1980 to 2018, with a median postoperative followup of 7.1 years (IQR 2.8-13.1), of whom 144 (4.9%) were subsequently diagnosed with UR. Carcinoma in situ (HR 1.98, 95% CI 1.30-3.04), multifocal disease (HR 1.59, 95% CI 1.07-2.36) and prostatic urethral involvement at RC (HR 3.01, 95% CI 1.98-4.57) were associated with increased risk of UR. UR was associated with decreased CSS (HR 7.30, 95% CI 5.46-9.76) and OS (HR 1.86, 95% CI 1.54-2.24). A total of 63/144 patients were diagnosed with UR based on symptoms, while 104/144 patients with UR underwent urethrectomy. Patients with symptomatic UR had higher tumor stage at urethrectomy (≥pT2 in 13.1% vs 3.1%, p=0.007), while patients with asymptomatic UR experienced longer median CSS (12.1 vs 6.1 years) and OS (8.30 vs 4.82 years; p=0.05 for both). CONCLUSIONS: We identified pathological risk factors for UR after RC and report adverse subsequent survival outcomes for these patients. Presentation with symptomatic UR was associated with higher tumor stage and poorer prognosis, supporting a value to continued urethral surveillance after RC.

Functional tricuspid regurgitation of degenerative mitral valve disease: a crucial determinant of survival.

AIMS: To assess functional tricuspid regurgitation (FTR) determinants, consequences, and independent impact on outcome in degenerative mitral regurgitation (DMR). METHODS AND RESULTS: All patients diagnosed with isolated DMR 2003-2011, with structurally normal tricuspid leaflets, prospective FTR grading and systolic pulmonary artery pressure (sPAP) estimation by Doppler echocardiography at diagnosis were identified and long-term outcome analysed. The 5083 DMR eligible patients [63 ± 16 years, 47% female, ejection fraction (EF) 63 ± 7%, and sPAP 35 ± 13 mmHg] presented with FTR graded trivial in 45%, mild in 37%, moderate in 15%, and severe in 3%. While pulmonary hypertension (PHTN-sPAP ≥ 50 mmHg) was the most powerful FTR severity determinant, other strong FTR determinants were older age, female sex, lower left ventricle EF, DMR, and particularly atrial fibrillation (AFib) (all P ≤ 0.002). Functional tricuspid regurgitation moderate/severe was independently linked to more severe clinical presentation, more oedema, lower stroke volume, and impaired renal function (P ≤ 0.01). Survival (95% confidence interval) throughout follow-up [70% (69-72%) at 10 years] was strongly associated with FTR severity [82% (80-84%) for trivial, 69% (66-71%) for mild, 51% (47-57%) for moderate, and 26% (19-35%) for severe, P < 0.0001]. Excess mortality persisted after comprehensive adjustment [adjusted hazard ratio 1.40 (1.18-1.67) for moderate FTR and 2.10 (1.63-2.70) for severe FTR, P ≤ 0.01]. Excess mortality persisted adjusting for sPAP/right ventricular function (P < 0.0001), by matching [adjusted hazard ratios 2.08 (1.50-2.89), P < 0.0001] and vs. expected survival [risk ratio 1.79 (1.48-2.16), P < 0.0001]. Within 5-year of diagnosis valve surgery was performed in 73% (70-75%) and 15% (13-17%) of severe and moderate DMR and in only 26% (19-34%) and 6% (4-8%) of severe and moderate FTR. Valvular surgery improved outcome without alleviating completely higher mortality associated with FTR (P < 0.0001). CONCLUSION: In this large DMR cohort, FTR was frequent and causally, not only linked to PHTN but also to other factors, particularly AFib. Higher FTR severity is associated at diagnosis with more severe clinical presentation. Long term, FTR is independently of all confounders, associated with considerably worse mortality. Functional tricuspid regurgitation moderate and even severe is profoundly undertreated. Thus careful assessment, consideration for tricuspid surgery, and testing of new transcatheter therapy is warranted.

Excess Mortality Associated With Functional Tricuspid Regurgitation Complicating Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Functional tricuspid regurgitation (FTR) is common in heart failure with reduced ejection fraction and mostly consequent to pulmonary hypertension. However, the intrinsic clinical implications of FTR are not fully understood. METHODS: The cohort of all Mayo Clinic patients from 2003 to 2011 diagnosed with heart failure stage B-C and ejection fraction<50%, with FTR grading and systolic pulmonary artery pressure estimation by Doppler echocardiography was identified and outcomes were analyzed. Patients with pacemakers/defibrillators, organic valve disease, or previous valve surgery were excluded. The primary outcome measure was overall mortality (censored at implantation of a defibrillator, ventricular assist device, or cardiac transplantation), adjusting for clinical and echocardiographic associates with mortality and major comorbidities. RESULTS: Among 13 026 patients meeting inclusion criteria, FTR was detected in 88% (N=11 507: 33% trivial, 32% mild, 17% moderate, and 6% severe), aged 68±14 years, 35% women, ejection fraction 36±10%, systolic pulmonary artery pressure 41±14 mm Hg with 20% atrial fibrillation. Covariates independently associated with FTR included elevated systolic pulmonary artery pressure, older age, female sex, lower ejection fraction, mitral regurgitation, and atrial fibrillation (all P<0.0001). FTR was independently associated with more dyspnea, impaired kidney function, and lower cardiac output ( P<0.003 for all). For long-term outcome, higher FTR degree compared with trivial tricuspid regurgitation was independently associated with higher mortality (adjusted hazard ratios 1.09 [1.01-1.17] for mild FTR, 1.21 [1.11-1.33] for moderate FTR and 1.57 [1.39-1.78] for severe FTR); hence, 5-year survival was substantially lower with increasing severity of functional FTR, 68±1% for trivial FTR, 58±2% for mild FTR, 45±2% for moderate FTR, and 34±4% for severe FTR. CONCLUSIONS: In this large cohort of patients with heart failure with reduced ejection fraction, FTR was common and independently associated with pulmonary hypertension, atrial fibrillation, and more severe heart failure presentation. Long-term, higher FTR severity is associated with considerably worse survival, independently of baseline characteristics. Given these untoward outcomes associated with FTR in patients with heart failure with reduced ejection fraction, clinical trials should be directed at testing FTR treatment.

Causes and mechanisms of isolated mitral regurgitation in the community: clinical context and outcome.

AIMS: To define the hitherto unknown aetiology/mechanism distributions of mitral regurgitation (MR) in the community and the linked clinical characteristics/outcomes. METHODS AND RESULTS: We identified all isolated, moderate/severe MR diagnosed in our community (Olmsted County, MN, USA) between 2000 and 2010 and classified MR aetiology/mechanisms. Eligible patients (n = 727) were 73 ± 18 years, 51% females, with ejection fraction (EF) 49 ± 17%. MR was functional (FMR) in 65%, organic (OMR) in 32% and 2% mixed. Functional MR was linked to left ventricular remodelling (FMR-v) 38% and isolated atrial dilatation (FMR-a) 27%. At diagnosis FMR-v vs. FMR-a, vs. OMR displayed profound differences (all P < 0.0001) in age (73 ± 14, 80 ± 10, 68 ± 21years), male-sex (59, 33, 51%), atrial-fibrillation (28, 54, 13%), EF (33 ± 14, 57 ± 11, 61 ± 10%), and regurgitant-volume (38 ± 13, 37 ± 11, 51 ± 24 mL/beat). Dominant MR mechanism was Type I (normal valve-movement) 38%, Type II (excessive valve-movement) 25%, Type IIIa (diastolic movement-restriction) 3%, and Type IIIb (systolic movement-restriction) 34%. Outcomes were mediocre with excess-mortality vs. general-population in FMR-v [risk ratio 3.45 (2.98-3.99), P < 0.0001] but also FMR-a [risk ratio 1.88 (1.52-2.25), P < 0.0001] and OMR [risk ratio 1.83 (1.50-2.22), P < 0.0001]. Heart failure was frequent, particularly in FMR-v (5-year 83 ± 3% vs. 59 ± 4% FMR-a, 40 ± 3% OMR, P < 0.0001). Mitral surgery during patients' lifetime was performed in 4% of FMR-v, 3% of FMR-a, and 37% of OMR. CONCLUSION: Moderate/severe isolated MR in the community displays considerable aetiology/mechanism heterogeneity. Functional MR dominates, mostly FMR-v but FMR-a is frequent and degenerative MR dominates OMR. Outcomes are mediocre with excess-mortality particularly with FMR-v but FMR-a, despite normal EF incurs notable excess-mortality and frequent heart failure. Pervasive undertreatment warrants clinical trials of therapies tailored to specific MR cause/mechanisms.

Clinical Outcome of Degenerative Mitral Regurgitation: Critical Importance of Echocardiographic Quantitative Assessment in Routine Practice.

BACKGROUND: Echocardiographic quantitation of degenerative mitral regurgitation (DMR) is recommended whenever possible in clinical guidelines but is criticized and its scalability to routine clinical practice doubted. We hypothesized that echocardiographic DMR quantitation, performed in routine clinical practice by multiple practitioners, predicts independently long-term survival and thus is essential to DMR management. METHODS: We included patients diagnosed with isolated mitral valve prolapse from 2003 to 2011 and any degree of mitral regurgitation quantified by any physician/sonographer in routine clinical practice. Clinical/echocardiographic data acquired at diagnosis were retrieved electronically. The end point was mortality under medical treatment analyzed by Kaplan-Meier method and proportional hazard models. RESULTS: The cohort included 3914 patients (55% male) mean age (±standard deviation) 62±17 years with left ventricular ejection fraction 63±8% and median after routinely-measured effective regurgitant orifice area (EROA) [interquartile range], 19 [0-40] mm2. During follow-up (6.7±3.1 years), 696 patients died under medical management, and 1263 underwent mitral surgery. In multivariate analysis, routinely-measured EROA was associated with mortality (adjusted hazard ratio, 1.19; 95% confidence interval, 1.13-1.24; P<0.0001 per 10 mm2) independently of left ventricular ejection fraction and end-systolic diameter, symptoms, and age/comorbidities. The association between routinely-measured EROA and mortality persisted with competitive risk modeling (adjusted hazard ratio, 1.15; 95% confidence interval, 1.10-1.20; P<0.0001 per 10 mm2), or in patients without guideline-based class I/II surgical triggers (adjusted hazard ratio, 1.19; 95% confidence interval, 1.10-1.28; P<0.0001 per 10 mm2) and in all subgroups examined (all P<0.01). Spline curve analysis showed that, compared with general population mortality, excess mortality appears for moderate DMR (EROA ≥20 mm2), becomes notable at EROA ≥30 mm2, and steadily increases with higher EROA levels (eg, higher EROA levels beyond the 40 mm2 threshold). CONCLUSIONS: Echocardiographic DMR quantitation is scalable to routine practice and is independently associated with clinical outcome. Routinely-measured EROA is strongly associated with long-term survival under medical treatment. Excess mortality versus the general population appears in the moderate DMR range and steadily increases with higher EROA. Hence, individual EROA values should be integrated into therapeutic considerations, in addition to categorical DMR grading.

Outcome and undertreatment of mitral regurgitation: a community cohort study.

BACKGROUND: Mitral regurgitation is the most common valve disease worldwide but whether the community-wide prevalence, poor patient outcomes, and low rates of surgical treatment justify costly development of new therapeutic interventions remains uncertain. Therefore, we did an observational cohort study to assess the clinical characteristics, outcomes, and degree of undertreatment of mitral regurgitation in a community setting. METHODS: We used data from Mayo Clinic electronic health records and the Rochester Epidemiology Project to identify all cases of moderate or severe isolated single-valvular mitral regurgitation (with no other severe left-sided valvular disease or previous mitral surgery) diagnosed during a 10-year period in the community setting in Olmsted County (MN, USA). We assessed clinical characteristics, mortality, heart failure incidence, and results of cardiac surgery post-diagnosis. FINDINGS: Between Jan 1, 2000, and Dec 31, 2010, 1294 community residents (median age at diagnosis 77 years [IQR 66-84]) were diagnosed with moderate or severe mitral regurgitation by Doppler echocardiography (prevalence 0·46% [95% CI 0·42-0·49] overall; 0·59% [0·54-0·64] in adults). Left-ventricular ejection fraction below 50% was frequent (recorded in 538 [42%] patients), and these patients had a slightly lower regurgitant volume than those with an ejection fraction of 50% or higher (mean 39 mL [SD 16] vs 45 mL [21], p<0·0001). Post-diagnosis mortality was mainly cardiovascular in nature (in 420 [51%] of 824 patients for whom the cause of death was available) and higher than expected for residents of the county for age or sex (risk ratio [RR] 2·23 [95% CI 2·06-2·41], p<0·0001). This excess mortality affected all subsets of patients, whether they had a left-ventricular ejection fraction lower than 50% (RR 3·17 [95% CI 2·84-3·53], p<0·0001) or of 50% or higher (1·71 [1·53 -1·91], p<0·0001) and with primary mitral regurgitation (RR 1·73 [95% CI 1·53-1·96], p<0·0001) or secondary mitral regurgitation (2·72 [2·48-3·01], p<0·0001). Even patients with a low comorbidity burden combined with favourable characteristics such as left-ventricular ejection fraction of 50% or higher (RR 1·28 [95% CI 1·10-1·50], p<0·0017) or primary mitral regurgitation (1·29 [1·09-1·52], p=0·0030) incurred excess mortality. Heart failure was frequent (mean 64% [SE 1] at 5 years postdiagnosis), even in patients with left-ventricular ejection fraction of 50% or higher (49% [2] at 5 years postdiagnosis) or in those with primary mitral regurgitation (48% [2]). Mitral surgery was ultimately done in only 198 (15%) of 1294 patients, of which the predominant type of surgery was valve repair (in 149 [75%] patients). Mitral surgery was done in 28 (5%) of 538 patients with left-ventricular ejection fraction below 50% and in 170 (22%) of 756 patients with ejection fraction of 50% or higher, and in 34 (5%) of 723 with secondary mitral regurgitation versus 164 (29%) of 571 with primary regurgitation. All other types of cardiac surgery combined were performed in only 3% more patients (237 [18%] patients) than the number who underwent mitral surgery. INTERPRETATION: In the community, isolated mitral regurgitation is common and is associated with excess mortality and frequent heart failure postdiagnosis in all patient subsets, even in those with normal left-ventricular ejection fraction and low comorbidity. Despite these poor outcomes, only a minority of affected patients undergo mitral (or any type of cardiac) surgery even in a community with all means of diagnosis and treatment readily available and accessible. This suggests that in a wider population there might be a substantial unmet need for treatment for this disorder. FUNDING: Mayo Clinic Foundation.

Clinical characteristics and depression score response after parathyroidectomy in primary hyperparathyroidism.

OBJECTIVE: Several studies indicate that patients with primary hyperparathyroidism (PHPT) undergoing parathyroid surgery have improvement in mood and neuropsychological functioning. The current analysis aims to examine the relationship between biochemical and clinical variables and the improvement in depression scores and in specific symptoms, after parathyroidectomy. DESIGN: A prospective observational case-control study at a referral centre. PATIENTS: Patients with PHPT undergoing parathyroidectomy (n = 88) or thyroid surgery (n = 85). MEASUREMENTS: The Patient Health Questionnaire-9 (PHQ-9) was utilized to obtain depression scores at enrolment and 12 months after surgery. The changes in PHQ-9 were analysed and correlated with baseline clinical and biochemical parameters. RESULTS: At enrolment, there was no difference between the groups in the number with a depression diagnosis (PHPT 34.1%, thyroid surgery, 35.5%, P = 0.86). However, baseline PHQ-9 scores were significantly higher in PHPT (median 7.5, range 0-27) than thyroid surgery patients (median 3.0, range 0-18, P < 0.0001). Following surgery, all PHQ-9 scores, total and symptom group (cognitive, somatic) improved and were no longer different between PHPT (total PHQ-9 median 2, range 0-16) and thyroid (median 1, range 0-14, P = 0.31) groups. Baseline parathyroid hormone level, but not calcium, had a weak relationship with change in PHQ-9 score after parathyroid surgery (P = 0.003). Baseline PHQ-9 score was correlated with change in PHQ-9 score at 12 months after parathyroid surgery (P < 0.001). CONCLUSIONS: Depression scores improve in both somatic and cognitive domains after parathyroidectomy for PHPT and baseline severity of depression predicts the response.

A risk-stratified approach to neoadjuvant chemotherapy in muscle-invasive bladder cancer: implications for patients classified with low-risk disease.

PURPOSE: To validate published risk criteria for informing use of neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC), and to examine outcomes of low-risk (LR) patients treated with immediate radical cystectomy (RC). METHODS: We identified 1931 patients who underwent RC for MIBC from 1980 to 2016. Patients were considered high risk (HR) with hydronephrosis, lymphovascular invasion, variant histology and/or cT3/4 disease. Kaplan-Meier survival estimates were compared to patients classified as LR, and logistic regression was used to examine factors associated with pathologic downstaging. RESULTS: A total of 1025 LR and 906 HR patients were identified. Median follow-up was 6.3 years (IQR 2.6-12), during which time 1321 (68%) patients died, 753 (39%) from bladder cancer. HR patients had significantly lower 5-year CSS than LR patients (50% vs. 68%, p = 0.001). Of 561 cisplatin-eligible LR patients treated with RC without NAC, 293 (52%) had pathologic non-organ confined disease; of these, 81 (14%) received adjuvant chemotherapy; 78 (14%) did not due to a perioperative event, while 134 (24%) did not due to patient/provider choice. NAC in LR patients was associated with greater odds of pT0 (OR 3.05; p < 0.001) and < pT2 (OR 2.53; p < 0.001) disease, but was not significantly associated with CSS (p = 0.31). CONCLUSIONS: Our results validate the proposed risk groups. Among LR patients treated without NAC, 52% experienced pathologic upstaging, and 14% were unable to receive adjuvant chemotherapy due to a perioperative event. These data support offering NAC to both HR and LR MIBC patients, and may be useful for patient counseling.

Continuous glucose monitoring to assess glycemic control in the first 6 weeks after pancreas transplantation.

BACKGROUND: Current therapy for Type 1 diabetes (T1D) is characterized by significant glucose variability (GV). Pancreas transplantation (PT) is performed in certain T1D patients with and without end-stage renal disease. To date, GV has been examined to a limited extent after PT. METHODS: We investigated GV using continuous glucose monitoring (CGM) 3-6 weeks after PT. RESULTS: Eleven patients had simultaneous kidney pancreas transplantation (SPK), nine pancreas after kidney (PAK), and six pancreas transplantation alone (PTA). Mean CGM showed no difference between SPK, 126.5 ± 13.9, PAK 119.9 ± 12.8, and PTA 131.1 ± 29 mg/dL (P value .6). Percentage of time in range (TIR, 70-180 mg/dL) was 92% for SPK, 93.4% in PAK, and 88.5% in PTA with only 0.3%, 1.5%, and 0.3% of time <70 mg/dL. Percentage >180 mg/dL was 7.9% for SPK, 4.9% PAK, and 11% in PTA. Other measures of GV were similar in the three cohorts. In six patients, CGM was performed before and after PT and improved significantly. GV was also better compared with a matched cohort of T1D patients. CONCLUSIONS: All 3 types of PT resulted in excellent glucose control 3-6 weeks post-procedure. CGM outcomes represent an important objective outcome after PT.

Pediatric ileocolic intussusception: new observations and unexpected implications.

BACKGROUND: Ileocolic intussusception occurs when the terminal ileum "telescopes" into the colon. We observed that ileocolic intussusception lengths are similar regardless of location in the colon. OBJECTIVE: To examine the uniformity of ileocolic intussusception length and its relationship to colon location, symptom duration and reducibility. MATERIALS AND METHODS: We retrospectively reviewed ultrasound-diagnosed pediatric ileocolic intussusceptions initially treated with pneumatic reduction at the Mayo Clinic or Texas Children's Hospital. We recorded demographic, imaging and surgical findings including age, gender, symptom duration, location of the ileocolic intussusception, reducibility with air enema and, if fluoroscopically irreducible, surgical findings. RESULTS: We identified 119 ileocolic intussusceptions (64% boys), with 81% in the right colon. There was no significant relationship between ileocolic intussusception length and colon location (P=0.15), nor ileocolic intussusception length and symptom duration (P=0.36). Ileocolic intussusceptions were more distal with increasing symptom duration (P=0.016). Successful reductions were unrelated to symptom duration (P=0.84) but were more likely with proximal versus distal locations (P=0.02). CONCLUSION: Ileocolic intussusception lengths are relatively uniform regardless of location along the course of the colon where they present. Our findings suggest that most of the apparent distal propagation of ileocolic intussusceptions is not caused by increasing telescoping of small bowel across the ileocecal valve but rather by foreshortening of the right colon. This implies poor cecal fixation and confirms fluoroscopic and surgical observations of cecal displacement from the right lower quadrant with ileocolic intussusceptions. The movement of the leading edge of the ileocolic intussusception during reduction is first due to "relocating" the cecum into the right lower quadrant after which the reduction of small bowel back across the ileocecal valve then occurs.