Renal Function Parameters and Serum Sodium Enhance Prediction of Wait-List Outcomes in Pediatric Liver Transplantation.

BACKGROUND AND AIMS: Reliance on exception points to prioritize children for liver transplantation (LT) stems from concerns that the Pediatric End-Stage Liver Disease (PELD) score underestimates mortality. Renal dysfunction and serum sodium disturbances are negative prognosticators in adult LT candidates and various pediatric populations, but are not accounted for in PELD. We retrospectively evaluated the effect of these parameters in predicting 90-day wait-list death/deterioration among pediatric patients (<12 years) listed for isolated LT in the United States between February 2002 and June 2018. APPROACH AND RESULTS: Among 4,765 patients, 2,303 (49.3%) were transplanted, and 231 (4.8%) died or deteriorated beyond transplantability within 90 days of listing. Estimated glomerular filtration rate (eGFR) (hazard ratio [HR] 1.09 per 5-unit decrease, 95% confidence interval [CI] 1.06-1.10) and dialysis (HR 7.24, 95% CI 3.57-14.66) were univariate predictors of 90-day death/deterioration (P < 0.001). The long-term benefit of LT persisted in patients with renal dysfunction, with LT as a time-dependent covariate conferring a 2.4-fold and 17-fold improvement in late survival among those with mild and moderate-to-severe dysfunction, respectively. Adjusting for PELD, sodium was a significant nonlinear predictor of outcome, with 90-day death/deterioration risk increased at both extremes of sodium (HR 1.20 per 1-unit decrease below 137 mmol/L, 95% CI 1.16-1.23; HR per 1-unit increase above 137 mmol/L 1.13, 95% CI 1.10-1.17, P < 0.001). A multivariable model incorporating PELD, eGFR, dialysis, and sodium demonstrated improved performance and superior calibration in predicting wait-list outcomes relative to the PELD score. CONCLUSIONS: Listing eGFR, dialysis, and serum sodium are potent, independent predictors of 90-day death/deterioration in pediatric LT candidates, capturing risk not accounted for by PELD. Incorporation of these variables into organ allocation systems may highlight patient subsets with previously underappreciated risk, augment ability of PELD to prioritize patients for transplantation, and ultimately mitigate reliance on nonstandard exceptions.

Majority Rules? Assessing Access to Kidney Transplantation in a Predominantly Hispanic Population.

BACKGROUND: Despite being the national's largest ethnic minority, Hispanic Americans have inferior kidney transplant opportunities. San Antonio, Texas is the largest US city with a majority Hispanic population. We assessed the impact of this unique ethnic milieu on waitlisting and transplant practices among Hispanic patients. METHODS: We studied patients >18 years old listed at our center for a kidney-only transplant between 2003-2022. Timing of waitlisting, transplant rates and waitlist outcomes were compared between Hispanic and non-Hispanic White patients. RESULTS: We evaluated 11,895 patients, of whom 67% (n = 8,008) were Hispanic, and 20% (n = 2,341) were White. Preemptive listing was less frequent in Hispanic patients (18% vs 37%). One-third of listed Hispanic patients (37%) and half of White patients (50%) were transplanted, with living-donor kidney transplant performed in 59% (n = 1,755) and 77% (n = 898), respectively. Adjusting for age, sex, blood type, preemptive listing, immunologic sensitization, education, employment, and listing era, Hispanic patients remained less likely to receive a deceased-donor transplant (HR 0.82, 95% CI 0.71 - 0.95). On covariate adjustment, White patients were more likely to experience waitlist death or deterioration (HR 1.23, 95% CI 1.12 - 1.36). CONCLUSIONS: Although waitlist attrition was more favorable among Hispanic patients, waitlist registration was delayed and kidney transplants less frequent compared to White patients. These data demonstrate that majority status alone does not mitigate ethnic disparities in kidney transplantation, while underlining the critical need for ongoing efforts to address physician and patient attitudes relating to suitability of Hispanic patients for transplantation.

Minimally invasive heart valve surgery: how and why in 2012.

Cardiac surgical procedures via traditional sternotomy are safe and effective operations performed by cardiothoracic surgeons worldwide. However, postoperative limitations in upper extremity activity during bone healing are seen as undesirable by some. Percutaneous catheter-based attempts to emulate the outcomes of traditional cardiac surgical procedures have largely fallen short of established standards of efficacy and durability. The field of minimally invasive heart valve surgery thus developed out of a need to offer smaller, better-tolerated incisions to patients while maintaining high-quality clinical outcomes. These operations are safe and effective when performed by proficient surgical teams, allowing patients to resume normal activities more rapidly. We explore current evidence supporting the practice of minimally invasive heart valve surgery in 2012 and analyze the clinical impact of these nascent surgical platforms.

Risk of conventional cardiac surgery among patients with severe left ventricular dysfunction in the era of mechanical circulatory support.

BACKGROUND: Despite suggestions that severe left ventricle dysfunction may warrant selection of durable mechanical circulatory support over conventional surgery, comparative studies are lacking due to incomplete characterization of patients at highest risk after conventional surgery. We sought to define subsets of patients with severe left ventricle dysfunction who are at greatest mortality risk following conventional cardiac surgery. METHODS: We studied 892 patients aged ≥ 18 years who underwent conventional coronary or valve surgery from 1993 to 2014, with preoperative ejection fraction ≤ 25%. Exclusions were transcatheter interventions, major concomitant procedures, active endocarditis, and prior/concurrent durable mechanical circulatory support use. Logistic and Cox regression identified determinants of early and late mortality. RESULTS: Median age was 70 years (interquartile range, 62-76 years), 46% (n = 411) had New York Heart Association (NYHA) functional class IV symptoms, and 16% (n = 142) had undergone prior surgery. Operative mortality was 7.5%. NYHA functional class IV (odds ratio [OR], 1.88; P = .033), prior cardiac surgery (OR, 2.13; P = .017), peripheral vascular disease (OR, 2.55; P = .001), emergency status (OR, 2.68; P = .024), and intra-aortic balloon pump use (OR, 4.95; P < .001) independently predicted operative death. Risk imparted by presence of both NYHA functional class IV symptoms and prior surgery was additive, with a 4-fold increase in early mortality risk (OR, 3.95; P = .003). Prior surgery increased the hazard of late death by 60% (P < .001). In patients without prior surgery, late mortality was greatest in those aged ≥ 70 years (hazard ratio, 1.86; P < .001), especially if NYHA functional class IV symptoms were concurrently present (hazard ratio, 2.25; P < .001). Surgery type (coronary artery bypass graft surgery, aortic valve surgery, or mitral valve surgery) did not predict long-term outcome. CONCLUSIONS: In patients referred for conventional surgery with an ejection fraction ≤ 25%, prior cardiac surgery, and/or NYHA functional class IV symptoms-particularly in those aged ≥ 70 years-confer significant and sustained survival disadvantages. Such high-risk subsets may benefit from durable mechanical circulatory support consideration.

Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice.

While reports suggest a single dose of senolytics may improve vasomotor function, the structural and functional impact of long-term senolytic treatment is unknown. To determine whether long-term senolytic treatment improves vasomotor function, vascular stiffness, and intimal plaque size and composition in aged or hypercholesterolemic mice with established disease. Senolytic treatment (intermittent treatment with Dasatinib + Quercetin via oral gavage) resulted in significant reductions in senescent cell markers (TAF(+) cells) in the medial layer of aorta from aged and hypercholesterolemic mice, but not in intimal atherosclerotic plaques. While senolytic treatment significantly improved vasomotor function (isolated organ chamber baths) in both groups of mice, this was due to increases in nitric oxide bioavailability in aged mice and increases in sensitivity to NO donors in hypercholesterolemic mice. Genetic clearance of senescent cells in aged normocholesterolemic INK-ATTAC mice phenocopied changes elicited by D+Q. Senolytics tended to reduce aortic calcification (alizarin red) and osteogenic signaling (qRT-PCR, immunohistochemistry) in aged mice, but both were significantly reduced by senolytic treatment in hypercholesterolemic mice. Intimal plaque fibrosis (picrosirius red) was not changed appreciably by chronic senolytic treatment. This is the first study to demonstrate that chronic clearance of senescent cells improves established vascular phenotypes associated with aging and chronic hypercholesterolemia, and may be a viable therapeutic intervention to reduce morbidity and mortality from cardiovascular diseases.

Nonbiased Molecular Screening Identifies Novel Molecular Regulators of Fibrogenic and Proliferative Signaling in Myxomatous Mitral Valve Disease.

BACKGROUND: Pathological processes underlying myxomatous mitral valve degeneration (MMVD) remain poorly understood. We sought to identify novel mechanisms contributing to the development of this condition. METHODS AND RESULTS: Microarrays were used to measure gene expression in 11 myxomatous and 11 nonmyxomatous human mitral valves. Differential gene expression (thresholds P<0.05; fold-change >1.5) and pathway activation (Ingenuity) were confirmed using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Contributions of bone morphogenetic protein 4 and transforming growth factor (TGF)-ß2 to differential gene expression were evaluated in vitro. Contributions of angiotensin II to differential pathway activation were examined in mice in vivo. A total of 2602 genes were differentially expressed between myxomatous and nonmyxomatous valves. Canonical TGF-ß signaling was increased in MMVD because of increased ligand expression and derepression of SMA mothers against decapentaplegic 2/3 signaling and was confirmed with quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Myxomatous valves demonstrated activation of canonical bone morphogenetic protein and Wnt/ß-catenin signaling and upregulation of their common target runt-related transcription factor 2. Our data set provided transcriptional and immunohistochemical evidence for activated immune cell infiltration. In vitro treatment of mitral valve interstitial cells with TGF-ß2 increased ß-catenin signaling at mRNA and protein levels, suggesting interactions between TGF-ß2 and Wnt signaling. In vivo infusion of mice with angiotensin II recaptured several changes in signaling pathways characteristic of human MMVD. CONCLUSIONS: These data support a new disease framework whereby activation of TGF-ß2, bone morphogenetic protein 4, Wnt/ß-catenin, or immune signaling plays major roles in the pathogenesis of MMVD. We propose these pathways act in a context-dependent manner to drive phenotypic changes that fundamentally differ from those observed in aortic valve disease and open novel avenues guiding future research into the pathogenesis of MMVD.

Untreated aortic valve stenosis identified at the time of coronary artery bypass grafting: thresholds associated with adverse prognosis.

OBJECTIVES: Aortic valve replacement (AVR) for severe aortic valve stenosis (AS) is a Class I indication at the time of coronary artery bypass grafting (CABG). Management of less-than-severe AS in patients undergoing CABG is uncertain however, because the thresholds at which untreated AS impacts long-term outcome are unclear. METHODS: We identified 312 patients who underwent isolated CABG between 1993 and 2006 with mild or moderate AS [aortic valve area (AVA) 1-2 cm(2)], and matched them to patients undergoing CABG alone during the same period with similar characteristics but without AS (AVA >2 cm(2)). Long-term survival after CABG and its determinants were analysed using Cox proportional hazards models with AVR as a time-dependent covariate. RESULTS: Late survival was lower in patients with untreated moderate AS (12 years 23 ± 5.1%) versus mild (42 ± 3.8%) or no AS (38 ± 3.3%) (P = 0.01). Adjusting for age, ejection fraction, heart failure, creatinine, diabetes, peripheral vascular disease (PVD) and interval AVR, moderate AS independently predicted higher mortality [hazard rate (HR) 2.01, 95% confidence interval (CI) 1.49-2.73; P < 0.001]; whereas incremental risk was insignificant for patients with mild AS (HR 1.09, 95% CI 0.85-1.66; P = 0.33). Further stratification showed that highest late postoperative mortality occurred with an AVA of 1-1.25 cm(2) (adjusted HR 2.45, 95% CI 1.57-3.82; P < 0.001), while risk was intermediate with an AVA of 1.25-1.5 cm(2) (HR 1.83, 95% CI 1.28-2.61; P = 0.001). CONCLUSIONS: Untreated moderate AS is an independent determinant of excess late mortality following isolated CABG, and mortality risk increases with decreasing AVA. Those with moderate-to-severe AS (AVA 1-1.25 cm(2)) have more than 2-fold greater long-term mortality compared with those without AS. These data define AS severity thresholds for clinical trials aimed at defining whether valve intervention might mitigate this risk.

The prognostic impact of concomitant coronary artery bypass grafting during aortic valve surgery: implications for revascularization in the transcatheter era.

OBJECTIVE: Clinicians may give greater consideration to medical management versus coronary artery bypass grafting (CABG) for coronary artery disease (CAD) at the time of aortic valve intervention. We evaluated the prognostic impact of revascularization strategy during aortic valve replacement (AVR). METHODS: We studied 1308 consecutive patients with significant CAD (≥50% stenosis) undergoing AVR with or with out CABG between 2001 and 2010. Late mortality and its determinants were analyzed using multivariable Cox models. RESULTS: Patients undergoing CABG (n = 1043; 18%) had more frequent angina (50% vs 26%; P < .001), left ventricular dysfunction (22% vs 14%; P = .003), advanced (>70% stenosis) CAD (85% vs 48%; P < .001), and incidence of triple-vessel/left-main CAD (44% vs 8%; P < .001). Whereas operative mortality was comparable between patients undergoing AVR plus CABG versus isolated AVR (2.9% vs 3.0%; P = .90), 5-year (72% vs 64%) and 8-year (50% vs 39%) survival was higher following CABG (P = .007). Adjusting for older age (hazard ratio [HR], 1.28 per 5 years), female sex (HR, 1.23), peripheral vascular disease (HR, 1.71), New York Heart Association functional class III to IV (HR, 1.48), and diabetes (HR, 1.50) concomitant CABG at AVR reduced late mortality risk by more than one-third (HR, 0.62, 95% confidence interval, 0.49-0.79; P < .001). CABG continued to confer a survival advantage in patients with moderate (50%-70%) (HR, 0.62; P = .02) and severe (>70%) CAD (HR, 0.62; P = .002). CONCLUSIONS: In patients undergoing AVR with coexistent CAD, concomitant CABG reduces risk of late death by more than one-third, without augmenting operative mortality. This survival advantage persists in moderate (50% to 70%) and severe (>70%) CAD. These findings underline the prognostic importance of revascularization in this population and should influence decisions regarding revascularization strategy in patients undergoing transcatheter valve therapy.

Do differences in early hemodynamic performance of current generation biologic aortic valves predict outcomes 1 year following surgery?

OBJECTIVE: Small early postoperative hemodynamic differences were noted in a randomized comparison of 3 current-generation bioprosthetic aortic valves. Whether these differences persist and influence clinical outcomes 1 year following implantation is unknown. METHODS: Three hundred adults with severe aortic stenosis undergoing valve replacement were randomized to receive the Epic (St Jude, St Paul, Minn) (n = 99), Magna (Edwards LifeSciences Inc, Irvine, Calif) (n = 100), or Mitroflow (Sorin Biomedica Spa, Saluggio, Italy) (n = 101) bioprostheses. Hemodynamic valve performance was examined by echocardiography at 1 year, and clinical outcomes were assessed in 241 patients (79 Epic, 77 Magna, and 85 Mitroflow; P = .437). RESULTS: Mean age was 75 ± 8 years and 164 were men (68%). Between dismissal and 1 year there were 9 deaths (3.7%) (Epic: 3.7%, Magna: 5.0%, and Mitroflow: 2.3%; P = .654), 6 episodes of heart failure (2.5%) (Epic: 1.3%, Magna: 1.3%, and Mitroflow: 5.8%; P = .265), 27 instances of atrial fibrillation/flutter (11.2%) (Epic: 8.1%, Magna: 11.0%, and Mitroflow: 7.9%; P = .577) and no strokes/transient ischemic attacks. One-year echocardiography demonstrated small hemodynamic differences between Epic, Magna, and Mitroflow bioprostheses in mean gradient (15.2 ± 5.5, 12.3 ± 4.3, and 16.2 ± 5.7 mm Hg, respectively; P < .001) and indexed aortic valve area (0.93 ± 0.28, 1.04 ± 0.28, and 0.96 ± -0.26 cm(2)/m(2), respectively; P = .015). Several early trends persisted when stratifying data by echocardiographic annulus diameter, universal annulus size, and implant size, particularly with annular size ≥23 mm. Overall left ventricular mass index regression between dismissal and 1 year was -16.5 ± 28.1 g/m(2), and was similar among groups (P = .262). There were no aortic valve reoperations. CONCLUSIONS: Despite midterm persistence of small hemodynamic differences amongst current-generation porcine and pericardial aortic valves, our prospective randomized comparison reveals that clinical outcomes and mass regression are equivalent between devices at 1 year. These encouraging trends must continue to be assessed during longitudinal follow-up.

Rituximab for non-Hodgkin's lymphoma: a story of rapid success in translation.

Translational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non-Hodgkin's lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation.

Risk assessment methods for cardiac surgery and intervention.

Surgical risk models estimate operative outcomes while controlling for heterogeneity in 'case mix' within and between institutions. In cardiac surgery, risk models are used for patient counselling, surgical decision-making, clinical research, quality assurance and improvement, and financial reimbursement. Importantly, risk models are only as good as the databases from which they are derived; physicians and investigators should, therefore, be aware of shortcomings of clinical and administrative databases used for modelling risk estimates. The most frequently modelled outcome in cardiac surgery is 30-day mortality. However, results of randomized trials to compare conventional surgery versus transcatheter aortic valve implantation (TAVI) indicate attrition of surgical patients at 2-4 months postoperatively, suggesting that 3-month survival or mortality might be an appropriate procedural end point worth modelling. Risk models are increasingly used to identify patients who might be better-suited for TAVI. However, the appropriateness of available statistical models in this application is controversial, particularly given the tendency of risk models to misestimate operative mortality in high-risk patient subsets. Incorporation of new risk factors (such as previous mediastinal radiation, liver failure, and frailty) in future surgical or interventional risk-prediction tools might enhance model performance, and thereby optimize patient selection for TAVI.

Left ventricular dysfunction after mitral valve repair--the fallacy of "normal" preoperative myocardial function.

OBJECTIVE: A proportion of patients experience a decrease in left ventricular (LV) ejection fraction (EF) after mitral valve repair; however, predictors and long-term consequences remain unclear. METHODS: A study of 1705 patients with severe, degenerative mitral valve regurgitation and normal preoperative EF (>60%) undergoing mitral valve repair from 1993 to 2012 was performed. Multivariate logistic regression and Cox proportional hazards models were used to determine the predictors of early postoperative LV dysfunction (EF < 50%) and long-term survival, respectively. RESULTS: Postoperative outcomes were comparable between patients; however, those with an EF of <50% (n = 314, 18.4%) had significantly greater enlargement in systolic dimension (left ventricular end-systolic diameter, -0.6 vs 4.3 mm; P < .001) and decrease in right ventricular systolic pressure (-2.7 vs -7.8 mm Hg; P < .001) immediately after repair. On longitudinal follow-up, early LV impairment persisted, with EF recovering to preoperative levels (>60%) in only one third of patients with postrepair EF <50% versus two thirds of those with an EF of ≥ 50% (P < .001). The overall survival at 5, 10, and 15 years of follow-up was 95%, 85%, and 70.8%, respectively. Although early postoperative EF < 50% was not a significant determinant of late survival, when adjusting for older age (hazard ratio [HR], 1.09), hypertension (HR, 1.38), New York Heart Association class III or IV (HR, 1.71), and preoperative atrial fibrillation (HR, 2.33), postoperative EF < 40% conferred a 70% increase in the hazard of late death (HR, 1.74; 95% confidence interval, 1.03-2.92; P = .037). A preoperative right ventricular systolic pressure >49 mm Hg and left ventricular end-systolic diameter >36 mm were independently associated with a 4.4- and 6.5-fold increased risk of developing a postoperative EF < 40% (P < .001, for both). CONCLUSIONS: De novo postoperative LV dysfunction is not uncommon in patients with "normal" preoperative EF undergoing mitral valve repair. LV dysfunction can persist, impairing recovery of LV size, function, and survival. The consideration of mitral repair before the onset of excessive LV dilation or pulmonary hypertension, even in those with preserved EF, seems warranted.

Assessment of coronary artery disease risk in 5463 patients undergoing cardiac surgery: when is preoperative coronary angiography necessary?

OBJECTIVES: We sought to critically analyze the routine use of conventional coronary angiography (CCA) before noncoronary cardiac surgery and to assess clinical prediction models that might allow more selective use of CCA in this setting. METHODS: We studied 5463 patients undergoing aortic valve surgery, mitral valve surgery, or septal myectomy with or without coronary artery bypass grafting from 2001 to 2010. Preoperative CCAs were evaluated for the presence of significant coronary artery disease (CAD). Random forests and logistic regression methods were used to determine the predictors of significant (≥50%) coronary stenosis. RESULTS: Preoperative CCA was performed in 4711 patients (86%). Two thirds of those with angina, previous myocardial infarction, or percutaneous coronary intervention had significant CAD found on CCA, versus one third of patients free of these risk factors (P < .001). Among 3019 patients without angina, previous myocardial infarction or percutaneous coronary intervention, older age, male gender, diabetes, and peripheral vascular disease independently predicted significant CAD (P < .001 for all; C-index = 0.74). Specifically, a multivariate model with these variables identified 10% (301 of 3019) of patients as having a low (≤10%) probability of coronary stenosis, of whom fewer than 5% had significant CAD and fewer than 1% had left main or triple-vessel coronary disease. CONCLUSIONS: In the absence of angina, previous myocardial infarction, or percutaneous coronary intervention, preoperative CCA identified significant CAD in only one third of patients. Our clinical prediction models could enhance the identification of patients at low risk of significant CAD for whom CCA might potentially be avoided before cardiac surgery. This strategy may improve the efficiency of cardiac surgical care delivery by diminishing procedure-related morbidity and offering significant cost savings.

Evidence, lack of evidence, controversy, and debate in the provision and performance of the surgery of acute type A aortic dissection.

Acute type A aortic dissection is a lethal condition requiring emergency surgery. It has diverse presentations, and the diagnosis can be missed or delayed. Once diagnosed, decisions with regard to initial management, transfer, appropriateness of surgery, timing of operation, and intervention for malperfusion complications are necessary. The goals of surgery are to save life by prevention of pericardial tamponade or intra-pericardial aortic rupture, to resect the primary entry tear, to correct or prevent any malperfusion and aortic valve regurgitation, and if possible to prevent late dissection-related complications in the proximal and downstream aorta. No randomized trials of treatment or techniques have ever been performed, and novel therapies-particularly with regard to extent of surgery-are being devised and implemented, but their role needs to be defined. Overall, except in highly specialized centers, surgical outcomes might be static, and there is abundant room for improvement. By highlighting difficulties and controversies in diagnosis, patient selection, and surgical therapy, our over-arching goal should be to enfranchise more patients for treatment and improve surgical outcomes.