Age is superior to aortopathy phenotype as a predictor of aortic mechanics in patients with bicuspid valve.

OBJECTIVES: Bicuspid aortic valve (BAV) aortopathy is defined by 3 phenotypes-root, ascending, and diffuse-based on region of maximal aortic dilation. We sought to determine the association between aortic mechanical behavior and aortopathy phenotype versus other clinical variables. METHODS: From August 1, 2016, to March 1, 2023, 375 aortic specimens were collected from 105 patients undergoing elective ascending aortic aneurysm repair for BAV aortopathy. Planar biaxial data (191 specimens) informed constitutive descriptors of the arterial wall that were combined with in vivo geometry and hemodynamics to predict stiffness, stress, and energy density under physiologic loads. Uniaxial testing (184 specimens) evaluated failure stretch and failure Cauchy stress. Boosting regression was implemented to model the association between clinical variables and mechanical metrics. RESULTS: There were no significant differences in mechanical metrics between the root phenotype (N = 33, 31%) and ascending/diffuse phenotypes (N = 72, 69%). Biaxial testing demonstrated older age was associated with increased circumferential stiffness, decreased stress, and decreased energy density. On uniaxial testing, longitudinally versus circumferentially oriented specimens failed at significantly lower Cauchy stress (50th [15th, 85th percentiles]: 1.0 [0.7, 1.6] MPa vs 1.9 [1.3, 3.1] MPa; P < .001). Age was associated with decreased failure stretch and stress. Elongated ascending aortas were also associated with decreased failure stress. CONCLUSIONS: Aortic mechanical function under physiologic and failure conditions in BAV aortopathy is robustly associated with age and poorly associated with aortopathy phenotype. Data suggesting that the root phenotype of BAV aortopathy portends worse outcomes are unlikely to be related to aberrant, phenotype-specific tissue mechanics.

Can perioperative electroencephalogram and adverse hemodynamic events predict neurodevelopmental outcomes in infants with congenital heart disease?

OBJECTIVE: The study objective was to characterize preoperative and postoperative continuous electroencephalogram metrics and hemodynamic adverse events as predictors of neurodevelopment in congenital heart disease infants undergoing cardiac surgery. METHODS: From 2010 to 2021, 320 infants underwent congenital heart disease surgery at our institution, of whom 217 had perioperative continuous electroencephalogram monitoring and were included in our study. Neurodevelopment was assessed in 76 patients by the Bayley Scales of Infant and Toddler Development, 3rd edition, consisting of cognitive, communication, and motor scaled scores. Patient and procedural factors, including hemodynamic adverse events, were included by means of the likelihood of covariate selection in our predictive model. Median (25th, 75th percentile) follow-up was 1.03 (0.09, 3.44) years with 3 (1, 6) Bayley Scales of Infant and Toddler Development, 3rd Edition evaluations per patient. RESULTS: Median age at index surgery was 7 (4, 23) days, and 81 (37%) were female. Epileptiform discharges, encephalopathy, and abnormality (lethargy and coma) were more prevalent on postoperative continuous electroencephalograms, compared with preoperative continuous electroencephalograms (P < .005). In 76 patients with Bayley Scales of Infant and Toddler Development, 3rd edition evaluations, patients with diffuse abnormality (P = .009), waveform discontinuity (P = .007), and lack of continuity (P = .037) on preoperative continuous electroencephalogram had lower cognitive scores. Patients with synchrony (P < .005) on preoperative and waveform continuity (P = .009) on postoperative continuous electroencephalogram had higher fine motor scores. Patients with postoperative adverse events had lower cognitive (P < .005) and gross motor scores (P < .005). CONCLUSIONS: Phenotypic patterns of perioperative continuous electroencephalogram metrics are associated with late-term neurologic injury in infants with congenital heart disease requiring surgery. Continuous electroencephalogram metrics can be integrated with hemodynamic adverse events in a predictive algorithm for neurologic impairment.

Increasing surgeon experience and cumulative institutional experience drive decreasing hospital mortality after reoperative cardiac surgery.

OBJECTIVE: The study objective was to identify the effects of surgeon experience and age, in the context of cumulative institutional experience, on risk-adjusted hospital mortality after cardiac reoperations. METHODS: From 1951 to 2020, 36 surgeons performed 160,338 cardiac operations, including 32,871 reoperations. Hospital death was modeled using a novel tree-bagged, generalized varying-coefficient method with 6 variables reflecting cumulative surgeon and institutional experience up to each cardiac operation: (1) number of total and (2) reoperative cardiac operations performed by a surgeon, (3) cumulative institutional number of total and (4) reoperative cardiac operations, (5) year of surgery, and (6) surgeon age at each operation. These were adjusted for 46 patient characteristics and surgical components. RESULTS: There were 1470 hospital deaths after cardiac reoperations (4.5%). At the institutional level, hospital death decreased exponentially and became less variable, leveling at 1.2% after approximately 14,000 cardiac reoperations. For all surgeons as a group, hospital death decreased rapidly over the first 750 reoperations and then gradually decreased with increasing experience to less than 1% after approximately 4000 reoperations. Surgeon age up to 75 years was associated with ever-decreasing hospital death. CONCLUSIONS: Surgeon age and experience have been implicated in adverse surgical outcomes, particularly after complex cardiac operations, with young surgeons being novices and older surgeons having declining ability. However, at Cleveland Clinic, outcomes of cardiac reoperations improved with increasing primary surgeon experience, without any suggestion to mid-70s of an age cutoff. Patients were protected by the cumulative background of institutional experience that created a culture of safety and teamwork that mitigated adverse events after cardiac surgery.

Longitudinal versus circumferential biomechanical behavior of the aneurysmal ascending aorta.

OBJECTIVES: We evaluate the independent effects of patient and aortic tissue characteristics on biaxial physiologic mechanical metrics in aneurysmal and nonaneurysmal tissues, and uniaxial failure metrics in aneurysmal tissue, comparing longitudinal and circumferential behavior. METHODS: From February 2017 to October 2022, 382 aortic specimens were collected from 134 patients; 268 specimens underwent biaxial testing, and 114 specimens underwent uniaxial testing. Biaxial testing evaluated Green-Lagrange transition strain and low and high tangent moduli. Uniaxial testing evaluated failure stretch, Cauchy stress, and low and high tangent moduli. Longitudinal gradient boosting models were implemented to estimate mechanical metrics and covariates of importance. RESULTS: On biaxial testing, nonaneurysmal tissue was less deformable and exhibited a lower transition strain than aneurysmal tissue in the longitudinal (0.18 vs 0.30, P < .001) and circumferential (0.25 vs 0.30, P = .01) directions. Older age and increasing ascending aortic length contributed most to predicting transition strain. On uniaxial testing, longitudinal specimens failed at lower stretch (1.4 vs 1.5, P = .003) and Cauchy stress (1.0 vs 1.9 kPa, P < .001) than circumferential specimens. Failure stretch and Cauchy stress were most strongly associated with tissue orientation and decreased sharply with older age. Age, ascending aortic length, and tissue thickness were the most frequent covariates predicting mechanical metrics across 10 prediction models. CONCLUSIONS: Age was the strongest predictor of mechanical behavior. After adjusting for age, nonaneurysmal tissue was less deformable than aneurysmal tissue. Differences in longitudinal and circumferential mechanics contribute to tissue dysfunction and failure in ascending aneurysms. This highlights the need to better understand the effects of age, ascending aortic length, and thickness on clinical aortic behavior.

Optimizing evaluation in pediatric and young adult patients with Marfan syndrome: Novel longitudinal metrics to track growth of aortic structures.

OBJECTIVE: Surveillance metrics in pediatric and young adult Marfan syndrome (pMFS) are challenging. We evaluated the utility of aortic root cross-sectional area/height index (CSA/Ht) on echocardiogram among pMFS patients as a risk stratification and surgical triage metric. METHODS: Genotype or phenotype positive pMFS patients aged 25 years or younger seen at our center from 2001 to 2020 were identified. Time-related transition to surgery was modeled using parametric methods. Predictive utility of CSA/Ht compared with aortic root diameter (ARd) and root Z score (ARz) were modeled using nonlinear multivariable parametric and nonparametric longitudinal regression models. RESULTS: Seventy-nine patients (43% female) presented at median age of 5.8 years (15th-85th percentile, 0.75-17 years) with median follow-up of 4.4 years (range, 0-18.5 years). Baseline echocardiography data were: CSA/Ht, 3.9 ± 1.4 cm2/m; ARd, 2.4 ± 0.89 cm; and ARz, 2.4 ± 1.7. CSA/Ht tracked ARd better compared with ARz (r = 0.91 vs 0.24). Eighteen patients underwent surgery. Surgical procedures included at least 2 components in 17 (aortic, mitral, tricuspid, aortic root, and arch procedures) and isolated mitral valve procedures in 1 patient. Time-related transition to surgery showed a prominent early phase to 1 year post presentation, followed by a slowly increasing late phase. CSA/Ht had a more linear correlation versus ARz during periods of rapid somatic growth in surgical patients. Surgical repair occurred at CSA/Ht between 5 and 7 cm2/m. CONCLUSIONS: CSA/Ht tracked ARd well over time. CSA/Ht between 5 and 7 cm2/m might be a promising metric for surgical triage in pMFS patients. CSA/Ht surgical threshold values in pMFS patients occurred at lower than current accepted "surgical" threshold values for CSA/Ht in adult Marfan syndrome patients.

Worsened Tricuspid Regurgitation Following Pericardiectomy for Constrictive Pericarditis.

BACKGROUND: Worsening tricuspid regurgitation (TR) severity may occur after pericardiectomy surgery for constrictive pericarditis patients; however, its mechanisms and predictors are not well established. We evaluated the clinical characteristics, associated factors, and outcomes of worsening TR after pericardiectomy. METHODS: Consecutive patients undergoing pericardiectomy for constrictive pericarditis without tricuspid valve surgery and with pre- and postoperative echocardiography available during 2000 to 2017 were retrospectively studied. Clinical, imaging, hemodynamic, and mortality characteristics were analyzed by those with and without worsening TR by at least one grade. RESULTS: Among 381 patients (age 61 [17] years, 318 [83.5%] male), 193 (50.7%) had worsening TR post-operatively, and 75 died during the 2.5 (5.4) years follow-up. In univariable analysis, worsening TR was associated with a history of congestive heart failure (47.2% versus 31.9%, P=0.003), increased left atrial volume indexed (23 versus 20 mL/m2, P=0.020), reduced right ventricular fractional area change (47% versus 54%, P<0.001), and worsening mitral regurgitation (39.7% versus 16.6%, P<0.001). Worsened TR had a trend toward reduced survival during follow-up (log-rank P=0.080), especially those with worsened TR but no recovery of TR grade on subsequent echocardiography within the first year compared with those without worsened TR (log-rank P=0.02). In multivariable analysis, right ventricular fractional area change, left atrial volume indexed, left ventricular mass indexed, pulmonary artery systolic pressure, and right atrial pressure/pulmonary capillary wedge pressure ratio were most associated with worsened TR, while blood urea nitrogen, hematocrit, lateral and medial e' tissue Doppler and heart rate were most associated with mortality during follow-up. CONCLUSIONS: Worsening TR severity was prevalent after pericardiectomy and had a trend toward reduced survival, especially if TR severity did not recover on subsequent echocardiography. Presence of parameters associated with worsened TR and reduced survival should alert clinicians to carefully manage these patients during follow-up.

Repair, Reconstruct, or Divert: Fate of the Perforated Esophagus.

OBJECTIVES: The aim of this study was to determine differences in esophageal perforation populations undergoing different advanced interventions for perforated esophagus and identify predictors of treatment outcomes. SUMMARY BACKGROUND DATA: Contained esophageal perforation can often be managed expectantly, but uncontained perforation is uniformly fatal without invasive intervention. Treatment options for the latter range from simple endoscopic control through advanced intervention. Clinical presentation varies greatly and directs which intervention is most appropriate. METHODS: From 1996 to 2017, 335 patients were treated for esophageal perforation, and 166 for advanced interventions: 74 primary repair with tissue flap (repair), 26 esophagectomy and gastric pull-up (resection), and 66 esophagectomy and immediate diversion with planned delayed reconstruction (resection-diversion). Patient characteristics, clinical presentation, operative outcomes, and survival were abstracted. Pittsburgh Severity Scores (PSS) were retrospectively calculated. Random survival forest analysis was performed for 90-day mortality and competing risks for reconstruction after resection-diversion. RESULTS: Repair and resection patients had lower PSS than resection-diversion patients (3 vs 3 vs 6, respectively). Ninety-day mortality for repair, resection, and resection-diversion was 11% vs 7.7% vs 23%, and 5-year survival was 71% vs 63% vs 47%. Risk of death after resection-diversion was highest within 1 year, but 52% of patients had reconstruction of the upper alimentary tract within 2 years. CONCLUSIONS: Several advanced interventions exist for critically ill patients with uncontained esophageal perforation. Repair and organ preservation are always preferred; however, patients at extremes of illness might best be treated with resection-diversion, with the understanding that the competing risk of death may preclude eventual reconstruction.

Dynamic prediction of left ventricular assist device pump thrombosis based on lactate dehydrogenase trends.

AIMS: The risk of HeartMate II (HMII) left ventricular assist device (LVAD) thrombosis has been reported, and serum lactate dehydrogenase (LDH), a biomarker of haemolysis, increases secondary to LVAD thrombosis. This study evaluated longitudinal measurements of LDH post-LVAD implantation, hypothesizing that LDH trends could timely predict future LVAD thrombosis. METHODS AND RESULTS: From October 2004 to October 2014, 350 HMIIs were implanted in 323 patients at Cleveland Clinic. Of these, patients on 339 HMIIs had at least one post-implant LDH value (7996 total measurements). A two-step joint model combining longitudinal biomarker data and pump thrombosis events was generated to assess the effect of changing LDH on thrombosis risk. Device-specific LDH trends were first smoothed using multivariate boosted trees, and then used as a time-varying covariate function in a multiphase hazard model to analyse time to thrombosis. Pre-implant variables associated with time-varying LDH values post-implant using boostmtree were also investigated. Standardized variable importance for each variable was estimated as the difference between model-based prediction error of LDH when the variable was randomly permuted and prediction error without permuting the values. The larger this difference, the more important a variable is for predicting the trajectory of post-implant LDH. Thirty-five HMIIs (10%) had either confirmed (18) or suspected (17) thrombosis, with 15 (43%) occurring within 3 months of implant. LDH was associated with thrombosis occurring both early and late after implant (P < 0.0001 for both hazard phases). The model demonstrated increased probability of HMII thrombosis as LDH trended upward, with steep changes in LDH trajectory paralleling trajectories in probability of pump thrombosis. The most important baseline variables predictive of the longitudinal pattern of LDH were higher bilirubin, higher pre-implant LDH, and older age. The effect of some pre-implant variables such as sodium on the post-implant LDH longitudinal pattern differed across time. CONCLUSIONS: Longitudinal trends in surveillance LDH for patients on HMII support are useful for dynamic prediction of pump thrombosis, both early after implant and late. Incorporating upward and downward trends in LDH that dynamically update a model of LVAD thrombosis risk provides a useful tool for clinical management and decisions.

Boosted Multivariate Trees for Longitudinal Data.

Machine learning methods provide a powerful approach for analyzing longitudinal data in which repeated measurements are observed for a subject over time. We boost multivariate trees to fit a novel flexible semi-nonparametric marginal model for longitudinal data. In this model, features are assumed to be nonparametric, while feature-time interactions are modeled semi-nonparametrically utilizing P-splines with estimated smoothing parameter. In order to avoid overfitting, we describe a relatively simple in sample cross-validation method which can be used to estimate the optimal boosting iteration and which has the surprising added benefit of stabilizing certain parameter estimates. Our new multivariate tree boosting method is shown to be highly flexible, robust to covariance misspecification and unbalanced designs, and resistant to overfitting in high dimensions. Feature selection can be used to identify important features and feature-time interactions. An application to longitudinal data of forced 1-second lung expiratory volume (FEV1) for lung transplant patients identifies an important feature-time interaction and illustrates the ease with which our method can find complex relationships in longitudinal data.

Treatment of hyperglycaemia in newly diagnosed diabetic patients is associated with a reduction in oxidative stress and improvement in ß-cell function.

BACKGROUND: There exist several reports demonstrating enhancement in oxidative stress in diabetic patients; however, serial and comprehensive measurement of oxidative stress parameters in newly diagnosed diabetic patients is not yet reported. We measured the oxidative stress parameters in diabetic patients serially from the time of diagnosis and after starting treatment to study their association with glycaemia, insulin resistance and ß-cell function. METHODS: Fifty-four newly diagnosed diabetic patients were studied at diagnosis and 4 and 8 weeks after initiating anti-hyperglycaemic treatment. Oxidative stress parameters included activity of antioxidant enzymes, concentration of antioxidant molecules and damage markers. Oxidative stress score was computed as a collective measure of oxidative stress to interpret total oxidative stress state. Association of changing glucose levels with changing oxidative stress parameters over 8 weeks and association of oxidative stress score with insulin resistance and ß-cell function was analysed by homeostasis model assessment (HOMA-IR and HOMA-ß, respectively). RESULTS: Eight weeks of treatment improved HbA1C from 9.8 ± 2.1 to 7.7 ± 1.0%. There was a significant increase in oxidative stress in diabetic patients [23.8 (95% CI 20.0, 27.6)] compared with non-diabetic subjects [-1.2 (-3.4, 0.9)] (p < 0.001). Non-diabetic subjects showed a stable status over 8 weeks. Improvement in hyperglycaemia in diabetic patients was associated with an improvement in oxidative stress parameters irrespective of the anti-diabetic treatment received. Oxidative stress score fell after 8 weeks and was significantly associated with an improvement in HOMA-ß (standardized ß = -0.38, p < 0.01) but not with HOMA-IR. CONCLUSIONS: Controlling hyperglycaemia in diabetic patients alleviates oxidative stress within 8 weeks of treatment, and improvement in oxidative stress parameters was related to an improved ß-cell function.

Quick and simple evaluation of sudomotor function for screening of diabetic neuropathy.

Objective. The aim of this study was to compare SUDOSCAN, a new device to evaluate sweat function (reflecting peripheral small C-fiber status), with conventional measures of peripheral and cardiac neuropathy in patients with type 2 diabetes. Methods. 265 diabetic patients were tested for symptoms and clinical signs of neuropathy using Michigan Neuropathy Screening Instrument (MNSI), vibration perception threshold (VPT) using biothesiometer, and cardiac autonomic neuropathy (CAN) using Ewing's protocol. Sudomotor function was investigated with SUDOSCAN through measurement of electrochemical skin conductance (ESC) of hands and feet. Lower ESC is suggestive of sudomotor dysfunction. Results. Lower ESC at feet was significantly associated both with increasing symptoms (MNSI A) and increasing score on physical abnormalities (MNSI B). Lower ESC at feet was also significantly associated with increasing VPT by biothesiometry (P < 0.01), and with higher number of abnormal CAN results (P < 0.05). ESC was associated with postural fall in blood pressure (sympathetic abnormality) (P < 0.05), but not with heart rate variability (HRV) tests (parasympathetic abnormalities). Conclusions. Sudomotor dysfunction testing may be a simple test to alert physicians to peripheral nerve and cardiac sympathetic dysfunction. Ease of performance could make it useful in a busy diabetic clinic. Further studies with hard clinical outcomes are indicated.