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How do you create a vibrant entrepreneurial life science ecosystem? How research communities in the Rhine-Main-Neckar region around Heidelberg have grown and flourished.

Mortality and morbidity after combined heart and liver transplantation in the failing Fontan: An updated dual center retrospective study.

INTRODUCTION: As the adult Fontan population with Fontan associated liver disease continues to increase, more patients are being referred for transplantation, including combined heart and liver transplantation. METHODS: We report updated mortality and morbidity outcomes after combined heart and liver transplant in a retrospective cohort series of 40 patients (age 14 to 49 years) with Fontan circulation across two centers from 2006-2022. RESULTS: The 30-day, 1-year, 5-year and 10-year survival rate was 90%, 80%, 73% and 73% respectively. Sixty percent of patients met a composite comorbidity of needing either post-transplant mechanical circulatory support, renal replacement therapy or tracheostomy. Cardiopulmonary bypass time > 283 min (4.7 h) and meeting the composite comorbidity were associated with mortality by Kaplan Meier analysis. CONCLUSION: Further study to mitigate early mortality and the above comorbidities as well as the high risk of bleeding and vasoplegia in this patient population is warranted.

Cardiac magnetic resonance predictors for successful primary biventricular repair of unbalanced complete common atrioventricular canal.

BACKGROUND: Patients with unbalanced common atrioventricular canal can be difficult to manage. Surgical planning often depends on pre-operative echocardiographic measurements. We aimed to determine the added utility of cardiac MRI in predicting successful biventricular repair in common atrioventricular canal. METHODS: We conducted a retrospective cohort study of children with common atrioventricular canal who underwent MRI prior to repair. Associations between MRI and echocardiographic measures and surgical outcome were tested using logistic regression, and models were compared using area under the receiver operator characteristic curve. RESULTS: We included 28 patients (median age at MRI: 5.2 months). The optimal MRI model included the novel end-diastolic volume index (using the ratio of left ventricular end-diastolic volume to total end-diastolic volume) and the left ventricle-right ventricle angle in diastole (area under the curve 0.83, p = 0.041). End-diastolic volume index ≤ 0.18 and left ventricle-right ventricle angle in diastole ≤ 72° yield a sensitivity of 83% and specificity of 81% for successful biventricular repair. The optimal multimodality model included the end-diastolic volume index and the echocardiographic atrioventricular valve index with an area under the curve of 0.87 (p = 0.026). CONCLUSIONS: Cardiac MRI can successfully predict successful biventricular repair in patients with unbalanced common atrioventricular canal utilising the end-diastolic volume index alone or in combination with the MRI left ventricle-right ventricle angle in diastole or the echocardiographic atrioventricular valve index. A prospective cardiac MRI study is warranted to better define the multimodality characteristic predictive of successful biventricular surgery.

Neurocognitive function and health-related quality of life in adolescents and young adults with CHD with pulmonary valve dysfunction.

BACKGROUND: Neurocognitive impairment and quality of life are two important long-term challenges for patients with complex CHD. The impact of re-interventions during adolescence and young adulthood on neurocognition and quality of life is not well understood. METHODS: In this prospective longitudinal multi-institutional study, patients 13-30 years old with severe CHD referred for surgical or transcatheter pulmonary valve replacement were enrolled. Clinical characteristics were collected, and executive function and quality of life were assessed prior to the planned pulmonary re-intervention. These results were compared to normative data and were compared between treatment strategies. RESULTS: Among 68 patients enrolled from 2016 to 2020, a nearly equal proportion were referred for surgical and transcatheter pulmonary valve replacement (53% versus 47%). Tetralogy of Fallot was the most common diagnosis (59%) and pulmonary re-intervention indications included stenosis (25%), insufficiency (40%), and mixed disease (35%). There were no substantial differences between patients referred for surgical and transcatheter therapy. Executive functioning deficits were evident in 19-31% of patients and quality of life was universally lower compared to normative sample data. However, measures of executive function and quality of life did not differ between the surgical and transcatheter patients. CONCLUSION: In this patient group, impairments in neurocognitive function and quality of life are common and can be significant. Given similar baseline characteristics, comparing changes in neurocognitive outcomes and quality of life after surgical versus transcatheter pulmonary valve replacement will offer unique insights into how treatment approaches impact these important long-term patient outcomes.

Conjugated hyperbilirubinemia is associated with increased morbidity and mortality after neonatal heart surgery.

BACKGROUND: Cholestasis characterised by conjugated hyperbilirubinemia is a marker of hepatobiliary dysfunction following neonatal cardiac surgery. We aimed to characterise the incidence of conjugated hyperbilirubinemia following neonatal heart surgery and examine the effect of conjugated hyperbilirubinemia on post-operative morbidity and mortality. METHODS: This was a retrospective study of all neonates who underwent surgery for congenital heart disease (CHD) at our institution between 1/1/2010 and 12/31/2020. Patient- and surgery-specific data were abstracted from local registry data and review of the medical record. Conjugated hyperbilirubinemia was defined as perioperative maximum conjugated bilirubin level > 1 mg/dL. The primary outcome was in-hospital mortality. Survival analysis was conducted using the Kaplan-Meier survival function. RESULTS: Conjugated hyperbilirubinemia occurred in 8.5% of patients during the study period. Neonates with conjugated hyperbilirubinemia were more likely to be of younger gestational age, lower birth weight, and non-Caucasian race (all p < 0.001). Patients with conjugated hyperbilirubinemia were more likely to have chromosomal and non-cardiac anomalies and require ECMO pre-operatively. In-hospital mortality among patients with conjugated hyperbilirubinemia was increased compared to those without (odds ratio 5.4). Post-operative complications including mechanical circulatory support, reoperation, prolonged ventilator dependence, and multi-system organ failure were more common with conjugated hyperbilirubinemia (all p < 0.04). Patients with higher levels of conjugated bilirubin had worst intermediate-term survival, with patients in the highest conjugated bilirubin group (>10 mg/dL) having a 1-year survival of only 6%. CONCLUSIONS: Conjugated hyperbilirubinemia is associated with post-operative complications and worse survival following neonatal heart surgery. Cholestasis is more common in patients with chromosomal abnormalities and non-cardiac anomalies, but the underlying mechanisms have not been delineated.

Comparing Long-Term Sequelae of the Systemic Right Ventricle: An Overview of Single Versus Biventricular Arrangements.

Patients with systemic right ventricles (RV) are at risk for heart failure and sudden cardiac death. Contributing factors to RV dysfunction include increased afterload from the systemic circulation, coronary insufficiency, progressive tricuspid valve regurgitation, the presence of residual lesions after palliation and arrhythmias. While all patients with a systemic right ventricle (SRV) are vulnerable to heart failure, there are distinct differences between patients with congenital dextro-transpostion of the great arteries (d-TGA) repaired by atrial switch, unrepaired congenitally corrected transposition of the great arteries (cc-TGA) and single systemic right ventricles palliated with a Fontan operation. Herein, we explore both the similarities and differences in progression of heart failure by phenotype as well as both the advancements and limitations in treatment options by each type of SRV.

Plasma metabolites associated with biomarker evidence of neurodegeneration in cognitively normal older adults.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that currently has no cure. Identifying biochemical changes associated with neurodegeneration prior to symptom onset, will provide insight into the biological mechanisms associated with neurodegenerative processes, that may also aid in identifying potential drug targets. The current study therefore investigated associations between plasma neurofilament light chain (NF-L), a marker of neurodegeneration, with plasma metabolites that are products of various cellular processes. Plasma NF-L, measured by ultrasensitive Single molecule array (Simoa) technology (Quanterix) and plasma metabolites, measured by mass-spectrometry (AbsoluteIDQ® p400HR kit, BIOCRATES), were assessed in the Kerr Anglican Retirement Village Initiative in Ageing Health (KARVIAH) cohort comprising 100 cognitively normal older adults. Metabolites belonging to biogenic amine (creatinine, symmetric dimethylarginine, asymmetric dimethylarginine; ADMA, kynurenine, trans-4-hydroxyproline), amino acid (citrulline, proline, arginine, asparagine, phenylalanine, threonine) and acylcarnitine classes were observed to have positive correlations with plasma NF-L, suggesting a link between neurodegeneration and biological pathways associated with neurotransmitter regulation, nitric oxide homoeostasis, inflammation and mitochondrial function. Additionally, after stratifying participants based on low/high brain amyloid-ß load (Aß ±) assessed by positron emission tomography, while creatinine, SDMA and citrulline correlated with NF-L in both Aß- and Aß+ groups, ADMA, proline, arginine, asparagine, phenylalanine and acylcarnitine species correlated with NF-L only in the Aß+ group after adjusting for confounding variables, suggesting that the association of these metabolites with neurodegeneration may be relevant to AD-related neuropathology. Metabolites identified to be associated with plasma NF-L may have the potential to serve as prognostic markers for neurodegenerative diseases, however, further studies are required to validate the current findings in an independent cohort, both cross-sectionally and longitudinally.

Single-Center Comparison of Outcomes Following Cardiac Surgery in Low Birth Weight and Standard Birth Weight Neonates.

OBJECTIVE: To compare outcomes between low birth weight (LBW; <2.5 kg) and standard birth weight neonates undergoing cardiac surgery. STUDY DESIGN: A single-center retrospective study of neonates undergoing cardiac surgery with cardiopulmonary bypass from 2012 to 2018. LBW neonates were 1:2 propensity score-matched to standard birth weight neonates (n = 93 to n = 186) using clinical characteristics. The primary and secondary outcomes were survival to hospital discharge and postoperative complications, respectively. After matching, regression analyses were conducted to compare outcomes. RESULTS: The LBW group had a higher proportion of premature neonates than the standard birth weight group (60% vs 8%; P < .01) and were less likely to survive to hospital discharge (88% vs 95%; OR, 0.39; 95% CI, 0.15-0.97). There was no difference in unplanned cardiac reoperations or catheter-based interventions, cardiac arrest, extracorporeal membrane oxygenation, infection, and end-organ complications between the groups. Among LBW infants, survival was improved at weight >2 kg. CONCLUSIONS: LBW is a risk factor for decreased survival. LBW neonates weighing >2 kg have survival comparable to those weighing >2.5 kg.

Pulmonary arterial hypertension in adults with systemic right ventricles referred for cardiac transplantation.

BACKGROUND: Systemic right ventricular (RV) failure may progress necessitating referral for orthotropic heart transplantation (OHT). Pulmonary hypertension (PH) frequently coexists in adult congenital heart disease and can complicate the assessment for OHT. METHODS: Single-center case series of six patients (median age 34.9 years [IQR, 31.9-42.4]) with systemic RV physiology with PH referred for OHT evaluation from 2008 to 2017. RESULTS: One-third (n = 6) of 18 patients with systemic RV physiology referred for OHT evaluation had pulmonary arterial hypertension (PAH) defined as mean pulmonary artery pressure (mPAP) > 25 mm Hg and pulmonary vascular resistance (PVR) > 3 Wood Units. Two of the six patients were considered OHT-ineligible due to PH and comorbidities. Of the remaining four, two had pre-capillary PH and underwent heart-lung transplant (HLTx). The other two demonstrated reversibility of PVR with vasodilator testing and underwent OHT alone, one of whom died post-transplant from PH crisis. CONCLUSIONS: Pulmonary arterial hypertension is common in systemic RV patients referred for OHT. Systemic RV dysfunction places these patients at risk for post-capillary PH but pre-capillary PH can exist. Despite management with selective pulmonary vasodilators and afterload reduction, criteria for listing patients for HLTx vs OHT are not known and need further elucidation.

Risk factors for mortality in paediatric cardiac ICU patients managed with extracorporeal membrane oxygenation.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation is frequently used in patients with cardiac disease. We evaluated short-term outcomes and identified factors associated with hospital mortality in cardiac patients supported with veno-arterial extracorporeal membrane oxygenation. METHODS: A retrospective review of patients supported with veno-arterial extracorporeal membrane oxygenation at a university-affiliated children's hospital was performed. RESULTS: A total of 253 patients with cardiac disease managed with extracorporeal membrane oxygenation were identified; survival to discharge was 48%, which significantly improved from 39% in an earlier era (1995-2001) (p=0.01). Patients were categorised into surgical versus non-surgical groups on the basis of whether they had undergone cardiac surgery before or not, respectively. The most common indication for extracorporeal membrane oxygenation was extracorporeal cardiopulmonary resuscitation: 96 (51%) in the surgical group and 45 (68%) in the non-surgical group. In a multiple covariate analysis, single-ventricle physiology (p=0.01), duration of extracorporeal membrane oxygenation (p<0.01), and length of hospital stay (p=0.03) were associated with hospital mortality. Weekend or night shift cannulation was associated with mortality in non-surgical patients (p=0.05). CONCLUSION: We report improvement in survival compared with an earlier era in cardiac patients supported with extracorporeal membrane oxygenation. Single-ventricle physiology continues to negatively impact survival, along with evidence of organ dysfunction during extracorporeal membrane oxygenation, duration of extracorporeal membrane oxygenation, and length of stay.

Psychological distress in adults with congenital heart disease: focus beyond depression.

BACKGROUND: Adults with congenital heart disease face psychological challenges although an understanding of depression vs. anxiety symptoms is unclear. We analyzed the prevalence of elevated symptoms of anxiety and depression and explored associations with demographic and medical factors as well as quality of life. METHODS: Adults with congenital heart disease enrolled from an outpatient clinic completed the Hospital Anxiety and Depression Scale and two measures of quality of life: the Linear Analogue Scale and the Satisfaction with Life Scale. Medical data were obtained by chart review. RESULTS: Of 130 patients (median age = 32 years; 55% female), 55 (42%) had elevated anxiety symptoms and 16 (12%) had elevated depression symptoms on subscales of the Hospital Anxiety and Depression Scale. Most patients with elevated depression symptoms also had elevated anxiety symptoms (15/16; 94%). Of 56 patients with at least one elevated subscale, 37 (66%) were not receiving mental health treatment. Compared to patients with 0 or 1 elevated subscales, patients with elevations in both (n=15) were less likely to be studying or working (47% vs. 81%; p=0.016) and reported lower scores on the Linear Analogue Scale (60 vs. 81, p<0.001) and the Satisfaction with Life Scale (14 vs. 28, p<0.001). CONCLUSIONS: Among adults with congenital heart disease, elevated anxiety symptoms are common and typically accompany elevated depressive symptoms. The combination is associated with unemployment and lower quality of life. Improved strategies to provide psychosocial care and support appropriate engagement in employment are required.

Neurological Injury and Cerebral Blood Flow in Single Ventricles Throughout Staged Surgical Reconstruction.

BACKGROUND: Patients with a single ventricle experience a high rate of brain injury and adverse neurodevelopmental outcome; however, the incidence of brain abnormalities throughout surgical reconstruction and their relationship with cerebral blood flow, oxygen delivery, and carbon dioxide reactivity remain unknown. METHODS: Patients with a single ventricle were studied with magnetic resonance imaging scans immediately prior to bidirectional Glenn (pre-BDG), before Fontan (BDG), and then 3 to 9 months after Fontan reconstruction. RESULTS: One hundred sixty-eight consecutive subjects recruited into the project underwent 235 scans: 63 pre-BDG (mean age, 4.8±1.7 months), 118 BDG (2.9±1.4 years), and 54 after Fontan (2.4±1.0 years). Nonacute ischemic white matter changes on T2-weighted imaging, focal tissue loss, and ventriculomegaly were all more commonly detected in BDG and Fontan compared with pre-BDG patients (P<0.05). BDG patients had significantly higher cerebral blood flow than did Fontan patients. The odds of discovering brain injury with adjustment for surgical stage as well as ≥2 coexisting lesions within a patient decreased (63%-75% and 44%, respectively) with increasing amount of cerebral blood flow (P<0.05). In general, there was no association of oxygen delivery (except for ventriculomegaly in the BDG group) or carbon dioxide reactivity with neurological injury. CONCLUSIONS: Significant brain abnormalities are commonly present in patients with a single ventricle, and detection of these lesions increases as children progress through staged surgical reconstruction, with multiple coexisting lesions more common earlier than later. In addition, this study demonstrated that BDG patients had greater cerebral blood flow than did Fontan patients and that an inverse association exists of various indexes of cerebral blood flow with these brain lesions. However, CO2 reactivity and oxygen delivery (with 1 exception) were not associated with brain lesion development. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02135081.

Comparison of 3D Echocardiogram-Derived 3D Printed Valve Models to Molded Models for Simulated Repair of Pediatric Atrioventricular Valves.

Mastering the technical skills required to perform pediatric cardiac valve surgery is challenging in part due to limited opportunity for practice. Transformation of 3D echocardiographic (echo) images of congenitally abnormal heart valves to realistic physical models could allow patient-specific simulation of surgical valve repair. We compared materials, processes, and costs for 3D printing and molding of patient-specific models for visualization and surgical simulation of congenitally abnormal heart valves. Pediatric atrioventricular valves (mitral, tricuspid, and common atrioventricular valve) were modeled from transthoracic 3D echo images using semi-automated methods implemented as custom modules in 3D Slicer. Valve models were then both 3D printed in soft materials and molded in silicone using 3D printed "negative" molds. Using pre-defined assessment criteria, valve models were evaluated by congenital cardiac surgeons to determine suitability for simulation. Surgeon assessment indicated that the molded valves had superior material properties for the purposes of simulation compared to directly printed valves (p < 0.01). Patient-specific, 3D echo-derived molded valves are a step toward realistic simulation of complex valve repairs but require more time and labor to create than directly printed models. Patient-specific simulation of valve repair in children using such models may be useful for surgical training and simulation of complex congenital cases.

Single-center outcomes of combined heart and liver transplantation in the failing Fontan.

Long-term outcomes of the Fontan operation include Fontan failure and liver disease. Combined heart-liver transplantation (CHLT) is an option for select patients although limited data exist on this strategy. A retrospective review of Fontan patients 18 years or older referred for cardiac transplant evaluation between 2000 and 2013 at the Hospital of the University of Pennsylvania was performed. All patients were considered for potential CHLT. Clinical variables such as demographics, perioperative factors, and short-term outcomes were reviewed. Of 17 referrals for cardiac transplantation, seven Fontan patients underwent CHLT. All patients who underwent CHLT had either advanced fibrosis or cirrhosis on liver biopsy. There were no perioperative deaths. The most common postoperative morbidity was acute kidney injury. Short-term complications include one episode of acute liver rejection but no cardiac rejection greater than 1R. CHLT is an acceptable therapeutic option for patients with failing Fontan physiology who exhibit concomitant advanced liver fibrosis. However, optimal patient selection is currently undefined, and long-term outcomes are not known.

Long-Term Outcomes of Pediatric Cardiac Patients Supported by Extracorporeal Membrane Oxygenation.

OBJECTIVE: Extracorporeal membrane oxygenation is an important form of short-term mechanical support in children with cardiac disease, but information on long-term outcomes and quality of life is limited. The primary objective of this study was to determine the long-term outcomes of children previously supported by extracorporeal membrane oxygenation for cardiac etiologies. DESIGN: A retrospective analysis was performed on patients with cardiac disease managed with extracorporeal membrane oxygenation between January 1, 1995, and December 31, 2012, at the Children's Hospital of Philadelphia. Survivors completed patient- and parent-reported verbal and written surveys, and univariate analyses assessed risk factors for long-term outcomes. SETTING: Tertiary-care children's hospital. PATIENTS: Patients with cardiac disease managed with extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Over 18 years, 396 patients were managed with extracorporeal membrane oxygenation with 43% survival to discharge. The median age at cannulation was 78 days. The majority had congenital heart disease (86%), surgery prior to extracorporeal membrane oxygenation (71%), and cardiopulmonary arrest as the primary extracorporeal membrane oxygenation indication (53%). With 6-year median follow-up, 66% are known to be deceased, including 38 deaths after hospital discharge. Among survivors at discharge, 65 (38%) completed the phone survey, and 33 (19%) completed the written survey. Negative clinical outcomes, defined as having at least significant physical limitations or "fair" or "poor" health, were present in 18% of patients. No patient- or extracorporeal membrane oxygenation-related variables were associated with negative outcomes in univariate analyses. There were significantly lower self-reported and parent-reported written Pediatric Quality of Life Inventory quality of life scores in children compared with healthy individual normative data but no differences in adolescents. CONCLUSIONS: In this series of pediatric cardiac patients supported by extracorporeal membrane oxygenation, mortality was 66% with 6-year median follow-up. The majority reported positive outcomes with respect to health and physical limitations, but children reported lower quality of life compared with healthy individuals.

Acquired and Congenital Coronary Artery Diseases.

OBJECTIVES: The objectives of this review are to discuss the spectrum of coronary artery anomalies and the evidence behind current treatment strategies. DATA SOURCE: MEDLINE and PubMed. CONCLUSION: Coronary artery anomalies exist in up to 1% of the population and most of these do not cause symptoms or ischemia and do not require any surgical intervention whereas others are potentially fatal. The type of surgical intervention is often dictated by the type of lesion, and upon the unique anatomic and physiologic variables associated with each lesion. Postoperative care can be challenging particularly after surgical repair of anomalous left coronary artery from the pulmonary artery.

The role of type 2 diabetes in neurodegeneration.

A growing body of evidence links type-2 diabetes (T2D) with dementia and neurodegenerative diseases such as Alzheimer's disease (AD). AD is the most common form of dementia and is characterised neuropathologically by the accumulation of extracellular beta amyloid (Aß) peptide aggregates and intracellular hyper-phosphorylated tau protein, which are thought to drive and/or accelerate inflammatory and oxidative stress processes leading to neurodegeneration. Although the precise mechanism remains unclear, T2D can exacerbate these neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism and CNS insulin resistance are features of both AD and T2D. Cell culture and animal studies have indicated that the early accumulation of Aß may play a role in CNS insulin resistance and impaired insulin signalling. From the viewpoint of insulin resistance and impaired insulin signalling in the brain, these are also believed to initiate other aspects of brain injury, including inflammatory and oxidative stress processes. Here we review the clinical and experimental pieces of evidence that link these two chronic diseases of ageing, and discuss underlying mechanisms. The evaluation of treatments for the management of diabetes in preclinical, and clinical studies and trials for AD will also be discussed.