Increased central venous pressure is inherent in Fontan circulation but not strongly related to Fontan complication. Abnormalities of the lymphatic circulation may play a crucial role in early Fontan ...complications.
This was a retrospective, single-center study of patients undergoing Fontan operation from 2008 to 2015. The primary outcome was significant early Fontan complication defined as secondary in-hospital treatment due to peripheral edema, ascites, pleural effusions, protein-losing enteropathy, or plastic bronchitis. All patients received T2-weighted magnetic resonance images to assess abdominal and thoracic lymphatic perfusion pattern 6 months after Fontan completion with respect to localization, distribution, and extension of lymphatic perfusion pattern (type 1-4) and with application of an area score (0-12 points).
Nine out of 42 patients developed early Fontan complication. Patients with complication had longer chest tube drainage (mean 28 interquartile range IQR: 13-60 vs. 13 IQR: 2-22 days,
= 0.01) and more often obstructions in the Fontan circuit 6 months after surgery (56 vs. 15%,
= 0.02). Twelve patients showed little or no abnormalities of lymphatic perfusion (lymphatic perfusion pattern type 1). Most frequently magnetic resonance imaging showed lymphatic congestion in the supraclavicular region (24/42 patients). Paramesenteric lymphatic congestion was observed in eight patients. Patients with early Fontan complications presented with higher lymphatic area score (6 min-max: 2-10 vs. 2 min-max: 0-8),
= 0.001) and greater distribution and extension of thoracic lymphatic congestion (type 3-4:
= 5/9 vs.
= 1/33,
= 0.001).
Early Fontan complication is related to hemodynamic factors such as circuit obstruction and to the occurrence and extent of lymphatic congestion.
Congenital hyperinsulinism (CHI) is a significant cause of hypoglycaemia in neonates and infants with the potential for permanent neurologic injury. Accurate calculations of the incidence of rare ...diseases such as CHI are important as they inform health care planning and can aid interpretation of genetic testing results when assessing the frequency of variants in large-scale, unselected sequencing databases. Whilst minimal incidence rates have been calculated for four European countries, the incidence of CHI in the UK is not known. In this study we have used referral rates to a central laboratory for genetic testing and annual birth rates from census data to calculate the minimal incidence of CHI within the UK from 2007 to 2016. CHI was diagnosed in 278 individuals based on inappropriately detectable insulin and/or C-peptide measurements at the time of hypoglycaemia which persisted beyond 6 months of age. From these data, we have calculated a minimum incidence of 1 in 28,389 live births for CHI in the UK. This is comparable to estimates from other outbred populations and provides an accurate estimate that will aid both health care provision and interpretation of genetic results, which will help advance our understanding of CHI.
Holt-Oram syndrome (HOS) is a rare autosomal dominant heart-hand syndrome due to mutations in the TBX5 transcription factor. Affected individuals can have structural cardiac defects and/or conduction ...abnormalities, and exclusively upper limb defects (typically bilateral, asymmetrical radial ray defects). TBX5 mutations reported include nonsense, missense, splicing mutations and exon deletions. Most result in a null allele and haploinsufficiency, but some impair nuclear localisation of TBX5 protein or disrupt its interaction with co-factors and downstream targets. We present a five generation family of nine affected individuals with an atypical HOS phenotype, consisting of ulnar ray defects (ulnar hypoplasia, short fifth fingers with clinodactyly) and very mild radial ray defects (short thumbs, bowing of the radius and dislocation of the radial head). The cardiac defects seen are those more rarely reported in HOS (atrioventricular septal defect, hypoplastic left heart syndrome, mitral valve disease and pulmonary stenosis). Conduction abnormalities include atrial fibrillation, atrial flutter and sick sinus syndrome. TBX5 mutation screening (exons 3-10) identified no mutations. Array comparative genomic hybridisation (CGH) revealed a 48 kb duplication at 12q24.21, encompassing exons 2-9 of the TBX5 gene, with breakpoints within introns 1-2 and 9-10. The duplication segregates with the phenotype in the family, and is likely to be pathogenic. This is the first known report of an intragenic duplication of TBX5 and its clinical effects; an atypical HOS phenotype. Further functional studies are needed to establish the effects of the duplication and pathogenic mechanism. All typical/atypical HOS cases should be screened for TBX5 exon duplications.
The population of adults with CHD continues to expand,and thus the number of women with CHD who contemplate pregnancy or become pregnant is also growing. Mothers with low-risk defects can be managed ...by general cardiologist,whereas those with more complex defects should be managed by or with the assistance of ACHD cardiologists. It is important to acknowledge that all patients with CHD may have unique anatomy or physiology, despite their classification as having a simple, moderate, or complex defect. As such, clinicians evaluating these patients should have adequate knowledge and expertise when assessing patient's risk for pregnancy,when performing imaging or hemodynamic studies, and when managing these patients during pregnancy. The American Board of Medical Specialties has recently recognized ACHD as a subspecialty of cardiovascular disease to treat the specialized needs of these patients in adulthood. ACHD experts can provide expertise in the management of specific defects or lesions, imaging techniques, prepregnancy risk assessment,and can manage these patients or comanage them with other medical providers during their pregnancy. Because many of these ACHD patients are lost to follow-up in adulthood, pregnancy represents a time when these patients seek medical care(and for some, represents a time of vulnerability and increased risk). This represents an opportunity to establish or reestablish care with ACHD specialists and to reestablish continuing long-term care for their CHD. Pregnancy also provides an opportunity to create partnerships between primary care physicians,adult cardiologists, and ACHD specialists to provide optimal care for these women throughout their lives.
Abstract Background Heart failure represents a common end-stage syndrome for many adults with congenital heart disease (ACHD). These patients, however, have been excluded from most heart ...transplantation research. It is not known how current criteria, derived from non-ACHD populations, used to determine priority at the time of transplant listing, impact the outcomes for ACHD patients listed for heart transplantation. Objectives The goal of this study was to investigate outcomes of ACHD in comparison to non-ACHD patients while listed for heart transplantation. Methods We conducted a retrospective study using the Scientific Registry of Transplant Recipients on patients ≥18 years of age listed in the United States between 1999 and 2014. The probability of mortality or delisting due to clinical worsening was estimated using cumulative incidence functions, where transplantation was a competing event. Results Among 1,290 ACHD and 38,557 non-ACHD patients listed, 237 ACHD and 6,377 non-ACHD patients died or were delisted due to clinical worsening. Death or delisting for clinical worsening was more likely for ACHD patients initially listed as status 1A (24% ACHD vs. 17% non-ACHD after 180 days; p < 0.001). There were no significant differences between ACHD and non-ACHD patients listed as status 1B or 2. In multivariable analysis, factors associated with death or delisting due to clinical worsening within 1 year in ACHD included: estimated glomerular filtration rate <60 ml/min/1.73 m2 (hazard ratio HR: 1.4; 95% confidence interval CI: 1.0 to 1.9; p = 0.043); albumin <3.2 g/dl (HR: 2.0; 95% CI: 1.3 to 2.9; p <0.001); and hospitalization at the time of listing, whether in the intensive care unit (HR: 2.3; 95% CI: 1.6 to 3.5; p < 0.001) or not (HR: 1.9; 95% CI: 1.2 to 3.0; p = 0.006) relative to outpatients. Conclusions Wait-list mortality or delisting due to worsening clinical status is disproportionately common for ACHD patients listed as status 1A. An allocation system that takes into account the distinctive aspects of ACHD patients may help better care for this growing population.
Holt-Oram syndrome (HOS) is an uncommon autosomal dominant disorder defined by congenital cardiac defects, some anatomical deformities in the upper limb and conduction abnormalities. Sequence ...alteration of TBX5 gene located on chromosome 12 has associated with HOS.
We present the case of a 26-year-old female with known upper limb alteration and ventricular septal defect who later in life developed Crohn's disease.
To the best of our knowledge association of Holt-Oram syndrome with Crohn's disease has not been reported in literature before. Therefore, a possible genetic connection between Holt-Oram syndrome and Crohn's disease remains to be determined.
Aims/hypothesis
Congenital hyperinsulinism caused by mutations in the K
ATP
-channel-encoding genes (K
ATP
HI) is a potentially life-threatening disorder of the pancreatic beta cells. No optimal ...medical treatment is available for patients with diazoxide-unresponsive diffuse K
ATP
HI. Therefore, we aimed to create a model of K
ATP
HI using patient induced pluripotent stem cell (iPSC)-derived islets.
Methods
We derived iPSCs from a patient carrying a homozygous
ABCC8
V187D
mutation, which inactivates the sulfonylurea receptor 1 (SUR1) subunit of the K
ATP
-channel. CRISPR-Cas9 mutation-corrected iPSCs were used as controls. Both were differentiated to stem cell-derived islet-like clusters (SC-islets) and implanted into NOD-SCID gamma mice.
Results
SUR1-mutant and -corrected iPSC lines both differentiated towards the endocrine lineage, but SUR1-mutant stem cells generated 32% more beta-like cells (SC-beta cells) (64.6% vs 49.0%,
p
= 0.02) and 26% fewer alpha-like cells (16.1% vs 21.8%
p
= 0.01). SUR1-mutant SC-beta cells were 61% more proliferative (1.23% vs 0.76%,
p
= 0.006), and this phenotype could be induced in SUR1-corrected cells with pharmacological K
ATP
-channel inactivation. The SUR1-mutant SC-islets secreted 3.2-fold more insulin in low glucose conditions (0.0174% vs 0.0054%/min,
p
= 0.0021) and did not respond to K
ATP
-channel-acting drugs in vitro. Mice carrying grafts of SUR1-mutant SC-islets presented with 38% lower fasting blood glucose (4.8 vs 7.7 mmol/l,
p
= 0.009) and their grafts failed to efficiently shut down insulin secretion during induced hypoglycaemia. Explanted SUR1-mutant grafts displayed an increase in SC-beta cell proportion and SC-beta cell nucleomegaly, which was independent of proliferation.
Conclusions/interpretation
We have created a model recapitulating the known pathophysiology of K
ATP
HI both in vitro and in vivo. We have also identified a novel role for K
ATP
-channel activity during human islet development. This model will enable further studies for the improved understanding and clinical management of K
ATP
HI without the need for primary patient tissue.
Graphical abstract
Nearly 70 inherited human glycosylation disorders span a breathtaking clinical spectrum, impacting nearly every organ system and launching a family-driven diagnostic odyssey. Advances in genetics, ...especially next generation sequencing, propelled discovery of many glycosylation disorders in single and multiple pathways. Interpretation of whole exome sequencing results, insights into pathological mechanisms, and possible therapies will hinge on biochemical analysis of patient-derived materials and animal models. Biochemical diagnostic markers and readouts offer a physiological context to confirm candidate genes. Recent discoveries suggest novel perspectives for textbook biochemistry and novel research opportunities. Basic science and patients are the immediate beneficiaries of this bidirectional collaboration.
Introduction
The use of flecainide and propafenone for medical cardioversion of atrial fibrillation (AF) and atrial flutter/intra‐atrial reentrant tachycardia (IART) is well‐described in adults ...without congenital heart disease (CHD). Data are sparse regarding their use for the same purpose in adults with CHD and in adolescent patients with anatomically normal hearts and we sought to describe the use of class IC drugs in this population and identify factors associated with decreased likelihood of success.
Methods
Single center retrospective cohort study of patients who received oral flecainide or propafenone for medical cardioversion of AF or IART from 2000 to 2022. The unit of analysis was each episode of AF/IART. We performed a time‐to‐sinus rhythm analysis using a Cox proportional hazards model clustering on the patient to identify factors associated with increased likelihood of success.
Results
We identified 45 episodes involving 41 patients. As only episodes of AF were successfully cardioverted with medical therapy, episodes of IART were excluded from our analyses. Use of flecainide was the only factor associated with increased likelihood of success. There was a statistically insignificant trend toward decreased likelihood of success in patients with CHD.
Conclusions
Flecainide was more effective than propafenone. We did not detect a difference in rate of conversion to sinus rhythm between patients with and without CHD and were likely underpowered to do so, however, there was a trend toward decreased likelihood of success in patients with CHD. That said, medical therapy was effective in >50% of patients with CHD with AF.
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