Thirty-Year Survival after Cardiac Surgery for Patients with Turner Syndrome.

OBJECTIVE: To evaluate long-term survival in patients with Turner syndrome after congenital heart surgery with a focus on left heart obstructive lesions (LHOLs). STUDY DESIGN: We queried the Pediatric Cardiac Care Consortium, a US-based registry of congenital heart surgery, for patients with Turner syndrome undergoing congenital heart surgery at <21 years of age between 1982 and 2011. Outcomes were obtained from the Pediatric Cardiac Care Consortium and from national death and transplant registries through 2019. Survival of patients with Turner syndrome and nonsyndromic patients with similar LHOL was compared by Kaplan-Meier survival curves and Cox regression adjusted for age, congenital heart disease, and era. RESULTS: We identified 179 patients with Turner syndrome operated for LHOL: 161 with 2-ventricle lesions (coarctation n = 149, aortic stenosis n = 12) and 18 with hypoplastic left heart (HLH) variants. There were 157 with 2-ventricle LHOL and 6 with HLH survived to discharge. Among survivors to hospital discharge, the 30-year transplant-free survival was 90.4% for Turner syndrome with 2-ventricle lesions and 90.9% for nonsyndromic comparators (adjusted hazard ratio [aHR] 1.15, 95% CI 0.64-2.04). The postdischarge survival for HLH was 33% for Turner syndrome and 51% for nonsyndromic patients, with these numbers being too small for meaningful comparisons. There was a higher risk for cardiovascular disease events in patients with Turner syndrome vs male (aHR 3.72, 95% CI 1.64-8.39) and female comparators (aHR 4.55, 95% CI 1.87-11.06) excluding heart failure deaths. CONCLUSIONS: The 30-year transplant-free survival is similar for patients with Turner syndrome and nonsyndromic comparators with operated 2-ventricle LHOL without excess congenital heart disease risk. However, patients with Turner Syndrome still face increased cardiovascular disease morbidity, stressing the importance of lifelong comorbidity surveillance in this population.

Adrenergic deficiency leads to impaired electrical conduction and increased arrhythmic potential in the embryonic mouse heart.

To determine if adrenergic hormones play a critical role in the functional development of the cardiac pacemaking and conduction system, we employed a mouse model where adrenergic hormone production was blocked due to targeted disruption of the dopamine ß-hydroxylase (Dbh) gene. Immunofluorescent histochemical evaluation of the major gap junction protein, connexin 43, revealed that its expression was substantially decreased in adrenergic-deficient (Dbh-/-) relative to adrenergic-competent (Dbh+/+ and Dbh+/-) mouse hearts at embryonic day 10.5 (E10.5), whereas pacemaker and structural protein staining appeared similar. To evaluate cardiac electrical conduction in these hearts, we cultured them on microelectrode arrays (8×8, 200 µm apart). Our results show a significant slowing of atrioventricular conduction in adrenergic-deficient hearts compared to controls (31.4±6.4 vs. 15.4±1.7 ms, respectively, p<0.05). To determine if the absence of adrenergic hormones affected heart rate and rhythm, mouse hearts from adrenergic-competent and deficient embryos were cultured ex vivo at E10.5, and heart rates were measured before and after challenge with the ß-adrenergic receptor agonist, isoproterenol (0.5 µM). On average, all hearts showed increased heart rate responses following isoproterenol challenge, but a significant (p<0.05) 225% increase in the arrhythmic index (AI) was observed only in adrenergic-deficient hearts. These results show that adrenergic hormones may influence heart development by stimulating connexin 43 expression, facilitating atrioventricular conduction, and helping to maintain cardiac rhythm during a critical phase of embryonic development.

Impact of Cardiac Neurodevelopmental Evaluation for Children with Congenital Heart Disease.

Children with congenital heart disease (CHD) are at increased risk for neurodevelopmental delays. This study of school-aged children with single ventricle CHD compared access to services for those who did and did not complete an evaluation. Children completing an evaluation had more academic services, including an Individualized Education Plan (66% vs 34%,P = .017), small group academic instruction (54% vs 20%,P = .01), any instructional supports (77% vs 44%,P = .008). A barrier to not completing the evaluation was lack of knowledge about the Cardiac Neurodevelopmental Program (82%). The neurodevelopmental evaluation is an impactful tool that can increase access to school services in vulnerable CHD patients.

Cyproheptadine-Induced Acute Liver Failure.

We present the case of a 55-year-old white female with no history of liver or gastrointestinal disease, admitted with acute liver failure following a trial of cyproheptadine for appetite stimulation. The patient was managed with supportive care, symptomatic treatment, and discontinuation of cyproheptadine. To our knowledge, this is the first described case of cyproheptadine-induced acute liver failure in over 20 years.

Azathioprine-induced hepatitis and cholestasis occurring 1†year after treatment.

Azathioprine is an immunosuppressive medication used in the management of many autoimmune conditions. Commonly reported adverse effects from azathioprine therapy are nausea and bone marrow suppression, while less common side effects include hepatotoxicity. We present the case of a 47-year-old man with a history of myasthenia gravis on azathioprine for 1 year, who presented to our institution with painless jaundice. On initial laboratory evaluation, the level of aspartate aminotransferase, alanine aminotransferase and total bilirubin were markedly elevated. Owing to the potential diagnosis of acute liver failure secondary to azathioprine toxicity, this medication was discontinued. A liver biopsy demonstrating drug-induced liver injury, along with high serum levels of 6-methylmercaptopurine nucleotide confirmed the diagnosis of azathioprine-induced hepatotoxicity. Upon discontinuation of the medication, the patient's transaminases and bilirubin levels improved steadily over the four-day hospital course. This case emphasises azathioprine's potential for hepatotoxicity, even 1 year after the initiation of its use.

Distinctive left-sided distribution of adrenergic-derived cells in the adult mouse heart.

Adrenaline and noradrenaline are produced within the heart from neuronal and non-neuronal sources. These adrenergic hormones have profound effects on cardiovascular development and function, yet relatively little information is available about the specific tissue distribution of adrenergic cells within the adult heart. The purpose of the present study was to define the anatomical localization of cells derived from an adrenergic lineage within the adult heart. To accomplish this, we performed genetic fate-mapping experiments where mice with the cre-recombinase (Cre) gene inserted into the phenylethanolamine-n-methyltransferase (Pnmt) locus were cross-mated with homozygous Rosa26 reporter (R26R) mice. Because Pnmt serves as a marker gene for adrenergic cells, offspring from these matings express the ß-galactosidase (ßGAL) reporter gene in cells of an adrenergic lineage. ßGAL expression was found throughout the adult mouse heart, but was predominantly (89%) located in the left atrium (LA) and ventricle (LV) (p<0.001 compared to RA and RV), where many of these cells appeared to have cardiomyocyte-like morphological and structural characteristics. The staining pattern in the LA was diffuse, but the LV free wall displayed intermittent non-random staining that extended from the apex to the base of the heart, including heavy staining of the anterior papillary muscle along its perimeter. Three-dimensional computer-aided reconstruction of XGAL+ staining revealed distribution throughout the LA and LV, with specific finger-like projections apparent near the mid and apical regions of the LV free wall. These data indicate that adrenergic-derived cells display distinctive left-sided distribution patterns in the adult mouse heart.