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Successful cardiac transplantation outcomes in patients with adult congenital heart disease.

Heart. 2017 Mar 03;:

Authors: Menachem JN, Golbus JR, Molina M, Mazurek JA, Hornsby N, Atluri P, Fuller S, Birati EY, Kim YY, Goldberg LR, Wald JW

OBJECTIVES: The purpose of our study is (1) to characterise patients with congenital heart disease undergoing heart transplantation by adult cardiac surgeons in a large academic medical centre and (2) to describe successful outcomes associated with our multidisciplinary approach to the evaluation and treatment of adults with congenital heart disease (ACHD) undergoing orthotopic heart transplantation (OHT).
BACKGROUND: Heart failure is the leading cause of death in patients with ACHD leading to increasing referrals for OHT.
METHODS: The Penn Congenital Transplant Database comprises a cohort of patients with ACHD who underwent OHT between March 2010 and April 2016. We performed a retrospective cohort study of the 20 consecutive patients. Original cardiac diagnoses include single ventricle palliated with Fontan (n=8), dextro-transposition of the great arteries after atrial switch (n=4), tetralogy of Fallot (n=4), pulmonary atresia (n=1), Ebstein anomaly (n=1), unrepaired ventricular septal defect (n=1) and Noonan syndrome with coarctation of the aorta (n=1).
RESULTS: Eight patients required pretransplant inotropes and two required pretransplant mechanical support. Nine patients underwent heart-liver transplant and three underwent heart-lung transplant. Three patients required postoperative mechanical circulatory support. Patients were followed for an average of 38 months as of April 2016, with 100% survival at 30 days and 1 year and 94% overall survival (19/20 patients).
CONCLUSIONS: ACHD-OHT patients require highly specialised, complex and multidisciplinary healthcare. The success of our programme is attributed to using team-based, patient-centred care including our multidisciplinary staff and specialists across programmes and departments.

PMID: 28258242 [PubMed - as supplied by publisher]

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Outcomes of Direct Current Cardioversion in Adults With Congenital Heart Disease.

Am J Cardiol. 2017 Feb 09;:

Authors: Egbe AC, Asirvatham SJ, Connolly HM, Kapa S, Desimone CV, Vaidya VR, Deshmukh AJ, Khan AR, McLeod CJ, Melduni RM, Ammash NM

Few data exist on direct current cardioversion (DCCV) in adult patients with congenital heart disease (CHD). This is a retrospective case-control study of 279 adults with CHD and 279 adults without CHD (control group) who had elective DCCV for atrial arrhythmias at Mayo Clinic, 2001 to 2013. Control patients were matched by gender and arrhythmia type. The objective was to compare DCCV procedural failure (failure to terminate the presenting arrhythmia) and arrhythmia recurrence (AR). In the CHD group (mean age 55 ± 20 years; men 166 [59%]), the most common diagnosis was Fontan palliation (61; 22%). Transesophageal echocardiography was performed before DCCV in 216 patients (77%); 162 (58%) had atrial flutter, and 117 (42%) had atrial fibrillation. Procedural failure and AR between the case and the control groups were more common in the CHD group (14% vs 7%, p = 0.01) and (83% vs 66% at 60 months, p = 0.001) respectively. There were no deaths or thromboembolic complications. The multivariable risk factors for procedural failure were Fontan palliation and spontaneous echocardiographic contrast; the risk factors for AR were Fontan palliation and atrial fibrillation. When patients with Fontan palliation were excluded from the analysis, the outcome of DCCV (failure and recurrence rates) was similar for the CHD and non-CHD groups despite the age difference between the cohorts. In conclusion, the present study showed that DCCV outcomes were similar for CHD and non-CHD patients, with the exception of patients with Fontan palliation.

PMID: 28262200 [PubMed - as supplied by publisher]

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Bioinformatic Analysis of Genes and MicroRNAs Associated With Atrioventricular Septal Defect in Down Syndrome Patients.

Int Heart J. 2016 Jul 27;57(4):490-5

Authors: Wang L, Li Z, Song X, Liu L, Su G, Cui Y

Down syndrome (DS) is a common chromosome 21 abnormality disease, leading to various health problems, especially atrioventricular septal defect (AVSD). Genes and microRNAs (miRNAs) associated with AVSD in DS patients still need in-depth study.Gene expression data (GSE34457) of 22 DS patients without congenital heart disease and 7 DS patients with AVSD were downloaded from Gene Expression Omnibus. After screening differentially expressed genes (DEGs) based on limma package in R (criteria: P < 0.05 and |log2 fold change (FC)| > 0.5), pathway and functional enrichment analyses were performed using the online software DAVID (criterion: P < 0.05). The protein-protein interaction (PPI) networks of DEGs were constructed based on the online server STRING (criterion: combined score > 0.4). Next, miRNAs that targeted DEGs were predicted based on Webgestalt (criteria: P < 0.05 and target DEGs ≥ 2), and miRNA-DEG regulatory networks were visualized through Cytoscape.A total of 179 DEGs were identified. Next, 5 functions and 1 pathway were enriched by up-regulated DEGs, while 4 functions were enriched by down-regulated DEGs. Furthermore, miRNA-DEG regulatory networks were constructed. IL1B was the hub-gene of PPI networks, and AUTS2 and KIAA2022 were predicted to be targeted by miR-518a, miR518e, miR-518f, miR-528a, and miR-96.IL1B, IL12RB2, AUTS2, and KIAA2022 might participate in AVSD in DS patients, and AUTS2 and KIAA2022 might be targeted by miR-518a, miR-518e, miR-518f, miR-528a, and miR-96. The identified genes and miRNAs might provide a theoretical basis for understanding AVSD in DS patients.

PMID: 27396555 [PubMed - indexed for MEDLINE]

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Three-dimensional transesophageal echocardiography incremental value in a rare case of a bileaflet tricuspid valve.

Echocardiography. 2016 Sep;33(9):1438-40

Authors: Mahmoud HM, Walley H, Hosny H, Yacoub M

Detailed assessment of the tricuspid valve using two-dimensional echocardiography is always challenging, as only two of three leaflets can be seen at a time. Three-dimensional echocardiography can provide the enface view of the tricuspid valve that allows simultaneous visualization of all of the three leaflets. In a 42-year-old male patient scheduled for pulmonary endarterectomy, 3DTEE showed that the tricuspid valve is bileaflet, with one septal and another lateral leaflet. There were two commissures, one of them is anteriorly positioned and the other one is posterior. Our findings were confirmed intra-operatively by direct surgical visualization of the tricuspid valve.

PMID: 27493126 [PubMed - indexed for MEDLINE]

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MIPEP recessive variants cause a syndrome of left ventricular non-compaction, hypotonia, and infantile death.

Genome Med. 2016 11 01;8(1):106

Authors: Eldomery MK, Akdemir ZC, Vögtle FN, Charng WL, Mulica P, Rosenfeld JA, Gambin T, Gu S, Burrage LC, Al Shamsi A, Penney S, Jhangiani SN, Zimmerman HH, Muzny DM, Wang X, Tang J, Medikonda R, Ramachandran PV, Wong LJ, Boerwinkle E, Gibbs RA, Eng CM, Lalani SR, Hertecant J, Rodenburg RJ, Abdul-Rahman OA, Yang Y, Xia F, Wang MC, Lupski JR, Meisinger C, Sutton VR

BACKGROUND: Mitochondrial presequence proteases perform fundamental functions as they process about 70 % of all mitochondrial preproteins that are encoded in the nucleus and imported posttranslationally. The mitochondrial intermediate presequence protease MIP/Oct1, which carries out precursor processing, has not yet been established to have a role in human disease.
METHODS: Whole exome sequencing was performed on four unrelated probands with left ventricular non-compaction (LVNC), developmental delay (DD), seizures, and severe hypotonia. Proposed pathogenic variants were confirmed by Sanger sequencing or array comparative genomic hybridization. Functional analysis of the identified MIP variants was performed using the model organism Saccharomyces cerevisiae as the protein and its functions are highly conserved from yeast to human.
RESULTS: Biallelic single nucleotide variants (SNVs) or copy number variants (CNVs) in MIPEP, which encodes MIP, were present in all four probands, three of whom had infantile/childhood death. Two patients had compound heterozygous SNVs (p.L582R/p.L71Q and p.E602*/p.L306F) and one patient from a consanguineous family had a homozygous SNV (p.K343E). The fourth patient, identified through the GeneMatcher tool, a part of the Matchmaker Exchange Project, was found to have inherited a paternal SNV (p.H512D) and a maternal CNV (1.4-Mb deletion of 13q12.12) that includes MIPEP. All amino acids affected in the patients' missense variants are highly conserved from yeast to human and therefore S. cerevisiae was employed for functional analysis (for p.L71Q, p.L306F, and p.K343E). The mutations p.L339F (human p.L306F) and p.K376E (human p.K343E) resulted in a severe decrease of Oct1 protease activity and accumulation of non-processed Oct1 substrates and consequently impaired viability under respiratory growth conditions. The p.L83Q (human p.L71Q) failed to localize to the mitochondria.
CONCLUSIONS: Our findings reveal for the first time the role of the mitochondrial intermediate peptidase in human disease. Loss of MIP function results in a syndrome which consists of LVNC, DD, seizures, hypotonia, and cataracts. Our approach highlights the power of data exchange and the importance of an interrelationship between clinical and research efforts for disease gene discovery.

PMID: 27799064 [PubMed - indexed for MEDLINE]

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Genetic Drivers of Kidney Defects in the DiGeorge Syndrome.

N Engl J Med. 2017 02 23;376(8):742-754

Authors: Lopez-Rivera E, Liu YP, Verbitsky M, Anderson BR, Capone VP, Otto EA, Yan Z, Mitrotti A, Martino J, Steers NJ, Fasel DA, Vukojevic K, Deng R, Racedo SE, Liu Q, Werth M, Westland R, Vivante A, Makar GS, Bodria M, Sampson MG, Gillies CE, Vega-Warner V, Maiorana M, Petrey DS, Honig B, Lozanovski VJ, Salomon R, Heidet L, Carpentier W, Gaillard D, Carrea A, Gesualdo L, Cusi D, Izzi C, Scolari F, van Wijk JA, Arapovic A, Saraga-Babic M, Saraga M, Kunac N, Samii A, McDonald-McGinn DM, Crowley TB, Zackai EH, Drozdz D, Miklaszewska M, Tkaczyk M, Sikora P, Szczepanska M, Mizerska-Wasiak M, Krzemien G, Szmigielska A, Zaniew M, Darlow JM, Puri P, Barton D, Casolari E, Furth SL, Warady BA, Gucev Z, Hakonarson H, Flogelova H, Tasic V, Latos-Bielenska A, Materna-Kiryluk A, Allegri L, Wong CS, Drummond IA, D'Agati V, Imamoto A, Barasch JM, Hildebrandt F, Kiryluk K, Lifton RP, Morrow BE, Jeanpierre C, Papaioannou VE, Ghiggeri GM, Gharavi AG, Katsanis N, Sanna-Cherchi S

Background The DiGeorge syndrome, the most common of the microdeletion syndromes, affects multiple organs, including the heart, the nervous system, and the kidney. It is caused by deletions on chromosome 22q11.2; the genetic driver of the kidney defects is unknown. Methods We conducted a genomewide search for structural variants in two cohorts: 2080 patients with congenital kidney and urinary tract anomalies and 22,094 controls. We performed exome and targeted resequencing in samples obtained from 586 additional patients with congenital kidney anomalies. We also carried out functional studies using zebrafish and mice. Results We identified heterozygous deletions of 22q11.2 in 1.1% of the patients with congenital kidney anomalies and in 0.01% of population controls (odds ratio, 81.5; P=4.5×10(-14)). We localized the main drivers of renal disease in the DiGeorge syndrome to a 370-kb region containing nine genes. In zebrafish embryos, an induced loss of function in snap29, aifm3, and crkl resulted in renal defects; the loss of crkl alone was sufficient to induce defects. Five of 586 patients with congenital urinary anomalies had newly identified, heterozygous protein-altering variants, including a premature termination codon, in CRKL. The inactivation of Crkl in the mouse model induced developmental defects similar to those observed in patients with congenital urinary anomalies. Conclusions We identified a recurrent 370-kb deletion at the 22q11.2 locus as a driver of kidney defects in the DiGeorge syndrome and in sporadic congenital kidney and urinary tract anomalies. Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver. (Funded by the National Institutes of Health and others.).

PMID: 28121514 [PubMed - indexed for MEDLINE]

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Kommerell Diverticulum in Adults: Evaluation of Routine CT Examinations.

Tokai J Exp Clin Med. 2016 Jun 20;41(2):65-9

Authors: Ichikawa T, Koizumi J, Tanno K, Okochi T, Nomura T, Shimura S, Imai Y

UNLABELLED: Objection: To evaluate of Kommerell diverticulum (KD) in adults during routine CT examinations.
MATERIAL AND METHODS: Eighty-seven cases of left aortic arch with aberrant right subclavian artery (LAARS) and 28 cases of right aortic arch with aberrant left subclavian artery (RAALS) were found on routine CT examinations using 64-128 multidetector CT. We assessed the incidence of KD and measured the size of KD, and compared the results between both groups. We evaluated associated congenital and acquired cardiovascular diseases on both groups.
RESULTS: The incidence of KD in each group was as follows: RAALS 100 % and LAARS 48.3 % and incidence of KD in RAALS group was significant higher than in LAARS group. The mean KD size was as follows: RAALS 32.8 mm and LAARS 17.8 mm and, the size of KD in RAALS group was larger than that in LAARS group. Two cases were associated with congenital heart disease. Several cases were associated with acquired aortic diseases including aortic aneurysm, dissection, severe atherosclerosis and aortitis.
CONCLUSION: KD was common among adults with an ASA and some adults were associated with aortic diseases.

PMID: 27344995 [PubMed - indexed for MEDLINE]

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Congenital aneurysm of the left atrial wall.

J Card Surg. 2016 Dec;31(12):730-734

Authors: Cai Y, Wei X, Tang H, Dian K

A congenital aneurysm of the left atrial wall (ALAW) is a rare defect resulting from dysplasia and degeneration of myocardial cells in embryogenesis. We report a case of a 50-year-old female with ALAW, and review 16 previously reported cases and summarize the clinical features, imaging data, and the operations used to treat this rare disease.

PMID: 27804153 [PubMed - indexed for MEDLINE]

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Aortopathies in adult congenital heart disease and genetic aortopathy syndromes: management strategies and indications for surgery.

Heart. 2017 Mar 07;:

Authors: Kuijpers JM, Mulder BJ

PMID: 28270426 [PubMed - as supplied by publisher]

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Contemporary cardiac surgery for adults with congenital heart disease.

Heart. 2017 Mar 07;:

Authors: Beurtheret S, Tutarel O, Diller GP, West C, Ntalarizou E, Resseguier N, Papaioannou V, Jabbour R, Simpkin V, Bastin AJ, Babu-Narayan SV, Bonello B, Li W, Sethia B, Uemura H, Gatzoulis MA, Shore D

OBJECTIVE: Advances in early management of congenital heart disease (CHD) have led to an exponential growth in adults with CHD (ACHD). Many of these patients require cardiac surgery. This study sought to examine outcome and its predictors for ACHD cardiac surgery.
METHODS: This is an observational cohort study of prospectively collected data on 1090 consecutive adult patients with CHD, undergoing 1130 cardiac operations for CHD at the Royal Brompton Hospital between 2002 and 2011. Early mortality was the primary outcome measure. Midterm to longer-term survival, cumulative incidence of reoperation, other interventions and/or new-onset arrhythmia were secondary outcome measures. Predictors of early/total mortality were identified.
RESULTS: Age at surgery was 35±15 years, 53% male, 52.3% were in New York Heart Association (NYHA) class I, 37.2% in class II and 10.4% in class III/IV. Early mortality was 1.77% with independent predictors NYHA class ≥ III, tricuspid annular plane systolic excursion (TAPSE) <15 mm and female gender. Over a mean follow-up of 2.8±2.6 years, 46 patients died. Baseline predictors of total mortality were NYHA class ≥ III, TAPSE <15 mm and non-elective surgery. The number of sternotomies was not independently associated with neither early nor total mortality. At 10 years, probability of survival was 94%. NYHA class among survivors was significantly improved, compared with baseline.
CONCLUSIONS: Contemporary cardiac surgery for ACHD performed at a single, tertiary reference centre with a multidisciplinary approach is associated with low mortality and improved functional status. Also, our findings emphasise the point that surgery should not be delayed because of reluctance to reoperate only.

PMID: 28270427 [PubMed - as supplied by publisher]