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Increased α-Actinin-2 Expression in the Atrial Myocardium of Patients with Atrial Fibrillation Related to Rheumatic Heart Disease.

Cardiology. 2016;135(3):151-159

Authors: Zhang L, Zhang N, Tang X, Liu F, Luo S, Xiao H

OBJECTIVES: Atrial fibrosis, a marker of atrial structural remodeling, plays a critical role in atrial fibrillation (AF). α- Actinin-2 is associated with structural remodeling related to stretching. The transforming growth factor-β1 (TGF-β1)/Smad pathway plays an important role in atrial fibrosis. We investigated the effects of the TGF-β1/Smad signaling pathway on α-actinin-2 in atrial fibrosis in patients with AF.
METHODS: Forty-one right atrial specimens obtained from patients with rheumatic heart disease (RHD) were divided into a chronic (c)AF group, i.e. RHD + cAF (n = 29), and a sinus rhythm group, i.e. RHD + sinus rhythm (n = 12). Patients with congenital heart disease (CHD) and sinus rhythm who underwent heart surgery served as controls (n = 10). Fibrosis was assessed by histological examination, and expression of α-actinin-2, TGF-β1 and Smad2/phosphorylated Smad2 (p-Smad2) was evaluated by immunohistochemistry, quantitative real-time PCR and Western blotting. In rat atrial fibroblasts treated with TGF-β1, the collagen content was measured using hydroxyproline detection, and α-actinin-2 and p-Smad2 were evaluated by semiquantitative reverse-transcription PCR and Western blotting.
RESULTS: The histology results revealed a significant increase in atrial fibrosis in AF patients. The collagen content, mRNA and protein expression levels of α-actinin-2 and the components of the TGF-β1/Smad signaling pathway were significantly gradually increased in the CHD + sinus rhythm, RHD + sinus rhythm and RHD + cAF groups (p < 0.05). The mRNA and protein levels of α-actinin-2 and TGF-β1 in RHD patients were positively correlated with the collagen volume fraction. A positive correlation between the expression of α-actinin-2 and TGF-β1 was also observed. In rat atrial fibroblasts treated with TGF-β1, the collagen content was greater than that in the control group (p < 0.05), and the expression levels of α- actinin-2 and p-Smad2 were also upregulated (p < 0.05).
CONCLUSIONS: α-Actinin-2 expression was increased in the atrial tissues of patients with AF secondary to RHD. α-Actinin-2 was upregulated via the TGF-β1/Smad pathway in atrial fibroblasts, which suggests that it may be involved in TGF-β1/Smad pathway-induced atrial fibrosis in patients with AF.

PMID: 27344599 [PubMed - indexed for MEDLINE]

Exercise self-efficacy in adults with congenital heart disease.

Int J Cardiol Heart Vasc. 2018 Mar;18:7-11

Authors: Bay A, Sandberg C, Thilén U, Wadell K, Johansson B

Background: Physical activity improves health, exercise tolerance and quality of life in adults with congenital heart disease (CHD), and exercise training is in most patients a high-benefit low risk intervention. However, factors that influence the confidence to perform exercise training, i.e. exercise self-efficacy (ESE), in CHD patients are virtually unknown. We aimed to identify factors related to low ESE in adults with CHD, and potential strategies for being physically active.
Methods: Seventy-nine adults with CHD; 38 with simple lesions (16 women) and 41 with complex lesions (17 women) with mean age 36.7 ± 14.6 years and 42 matched controls were recruited. All participants completed questionnaires on ESE and quality of life, carried an activity monitor (Actiheart) during four consecutive days and performed muscle endurance tests.
Results: ESE in patients was categorised into low, based on the lowest quartile within controls, (≤ 29 points, n = 34) and high (> 29 points, n = 45). Patients with low ESE were older (42.9 ± 15.1 vs. 32.0 ± 12.4 years, p = 0.001), had more complex lesions (65% vs. 42%, p = 0.05) more often had New York Heart Association functional class III (24% vs. 4%, p = 0.01) and performed fewer shoulder flexions (32.5 ± 15.5 vs. 47.7 ± 25.0, p = 0.001) compared with those with high ESE. In a logistic multivariate model age (OR; 1.06, 95% CI 1.02-1.10), and number of shoulder flexions (OR; 0.96, 95% CI 0.93-0.99) were associated with ESE.
Conclusion: In this study we show that many adults with CHD have low ESE. Age is an important predictor of low ESE and should, therefore, be considered in counselling patients with CHD. In addition, muscle endurance training may improve ESE, and thus enhance the potential for being physically active in this population.

PMID: 29349286 [PubMed]

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Exome sequencing reveals novel IRXI mutation in congenital heart disease.

Mol Med Rep. 2017 May;15(5):3193-3197

Authors: Guo C, Wang Q, Wang Y, Yang L, Luo H, Cao XF, An L, Qiu Y, Du M, Ma X, Li H, Lu C

Genetic variation in specific transcription factors during heart formation may lead to congenital heart disease (CHD) or even miscarriage. The aim of the present study was to identify CHD‑associated genes using next generation sequencing (NGS). The whole exome DNA sequence was obtained from a stillborn fetus diagnosed with tricuspid atresia and complete transposition of the great arteries using high‑throughput sequencing methods. Subsequently, genetic variants of CHD‑associated genes were selected and verified in 215 non‑syndromic CHD patients and 249 healthy control subjects using polymerase chain reaction combined with Sanger sequencing. Genetic variants of previously reported CHD‑inducing genes, such as cysteine rich with EGF like domains 1 and cbp/p300‑interacting transactivator with Glu/Asp rich carboxy‑terminal domain 2, were discovered through the NGS analysis. In addition, a novel non‑synonymous mutation of the iroquois homeobox 1 (IRX1) gene (p.Gln240Glu) was identified. A total of three non‑synonymous mutations (p.Gln240Glu, p.Ser298Asn and p.Ala381Glu) of the IRX1 gene were verified in 215 non‑syndromic CHD patients, but not in 249 healthy volunteers. The results demonstrated that NGS is a powerful tool to study the etiology of CHD. In addition, the results suggest that genetic variants of the IRX1 gene may contribute to the pathogenesis of CHD.

PMID: 28358424 [PubMed - indexed for MEDLINE]

[The significance of N-terminal pro-B natriuretic peptide in the management of adult patients with congenital heart disease - Results from the CSONGRAD Registry].

Orv Hetil. 2018 Jan;159(4):141-148

Authors: Ambrus N, Havasi K, Berek K, Kalapos A, Hartyánszky I, Bogáts G, Forster T, Nemes A

INTRODUCTION: The prognostic role of B-type natriuretic peptide (BNP) level was confirmed in chronic heart failure and congenital heart diseases irrespective of the aetiology.
AIM: The aim of this study was to compare NT‑proBNP measured in the clinical practice and important clinical and echocardiographic parameters in patients with adult congenital heart diseases under our care.
METHOD: Data of a total of 70 patients were analysed; 34 patients had corrected tetralogy of Fallot and 19 patients had corrected transposition of the great arteries. In 17 further cases, patients with other congenital vitiums have been involved in the study. In all cases, out-patient examination was performed with electrocardiography, echocardiography and NT-proBNP measurement. The New York Heart Association (NYHA) stages of the patients were determined and the patients filled in a questionnaire regarding their quality of life.
RESULTS: Elevated NT-proBNP level resulted in a worse quality of life (visual analogue scale, VAS) and an increased right ventricular end diastolic diameter; the incidence of arrhythmia increased as well. Negative correlation was found between the NT-proBNP level and the VAS value (r = -0.45, p = 0.0001) and the left ventricular ejection fraction (LV-EF) (r = -0.67, p = <0.0001). ROC analysis showed that NT‑proBNP≥668.1 pg/ml was the cut-off value that most accurately predicted NYHA class III-IV (sensitivity 93%, specificity 63%, area under the curve 80%, p = 0.001). Similarly, NT-proBNP≥184.7 pg/ml was found to be the cut-off value most accurately predicting LV-EF below 55% (sensitivity 66%, specificity 67%, area under the curve 77%, p = 0.02).
CONCLUSIONS: NT-proBNP has a role in the evaluation of adult patients with congenital heart diseases and in determining the prognosis of these patients, and in addition to other examinations used in the follow-up of these patients, NT-proBNP may help in determining the time of reoperation or potential heart transplantation. Orv Hetil. 2018; 159(4): 141-148.

PMID: 29353497 [PubMed - in process]

Blood-threshold CMR volume analysis of functional univentricular heart.

Radiol Med. 2018 Jan 22;:

Authors: Secchi F, Alì M, Petrini M, Pluchinotta FR, Cozzi A, Carminati M, Sardanelli F

PURPOSE: To validate a blood-threshold (BT) segmentation software for cardiac magnetic resonance (CMR) cine images in patients with functional univentricular heart (FUH).
MATERIALS AND METHODS: We evaluated retrospectively 44 FUH patients aged 25 ± 8 years (mean ± standard deviation). For each patient, the epicardial contour of the single ventricle was manually segmented on cine images by two readers and an automated BT algorithm was independently applied to calculate end-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), and cardiac mass (CM). Aortic flow analysis (AFA) was performed on through-plane images to obtain forward volumes and used as a benchmark. Reproducibility was tested in a subgroup of 24 randomly selected patients. Wilcoxon, Spearman, and Bland-Altman statistics were used.
RESULTS: No significant difference was found between SV (median 57.7 ml; interquartile range 47.9-75.6) and aortic forward flow (57.4 ml; 48.9-80.4) (p = 0.123), with a high correlation (r = 0.789, p < 0.001). Intra-reader reproducibility was 86% for SV segmentation, and 96% for AFA. Inter-reader reproducibility was 85 and 96%, respectively.
CONCLUSION: The BT segmentation provided an accurate and reproducible assessment of heart function in FUH patients.

PMID: 29357037 [PubMed - as supplied by publisher]

Bilateral branch pulmonary artery valve implantation in repaired tetralogy of fallot.

Catheter Cardiovasc Interv. 2018 Jan 22;:

Authors: Bansal N, Kobayashi D, Forbes TJ, Du W, Zerin JM, Joshi A, Turner DR

BACKGROUND: Transcatheter, bilateral branch pulmonary artery (PA) valve implantation is a novel treatment for patients with severe pulmonary insufficiency and oversized right ventricle (RV) outflow tract. There is scarce data on efficacy and safety of this approach.
METHODS: This was a retrospective study of 8 patients with repaired tetralogy of fallot (TOF) who underwent bilateral branch PA valve implantation. Demographics, echocardiography, cardiac catheterization, and axial imaging data were reviewed. Variables were compared by a paired sample t-test.
RESULTS: All patients were adult sized (weight 43-99 kg) with oversized RV outflow tract not suitable for conventional transcatheter pulmonary valve implantation. Staged bare metal PA stenting followed by valve implantation (interval 3-5 months) was technically successful in 7 patients with one stent embolization. In another patient, proximal stent migration prevented placement of bilateral pulmonary valve stents. There were a total of 14 valved branch PA stents placed (Melody valve n = 9, Sapien XT n = 2, Sapien 3 n = 3). In the 7 patients undergoing successful branch pulmonary valve placement, at median follow up of 10 months (range 3 months to 6 years), 13 (93%) valves had none/trivial insufficiency on echocardiography. Prevalve and postvalve implantation cardiac magnetic resonance imaging in five patients showed significant reduction of indexed RV end-diastolic volume (152 ± 27 to 105 ± 15 mL/m2 , P < .001).
CONCLUSIONS: Transcatheter, bilateral branch PA valve implantation was technically feasible with satisfactory efficacy and safety in patients with repaired TOF, severe pulmonary insufficiency, and oversized RV outflow tracts. Elimination of pulmonary insufficiency with this method resulted in reduced RV end-diastolic volume. This approach can be offered as an alternative to surgery, particularly in patients considered high risk for standard surgical placement and who are not candidates for the newer self-expanding valve prosthesis for placement in RV outflow tracts larger than 30 mm diameter.

PMID: 29357196 [PubMed - as supplied by publisher]

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Melody and rhythm in congenital heart disease.

Heart Rhythm. 2016 11;13(11):2142-2143

Authors: Khairy P

PMID: 27496587 [PubMed - indexed for MEDLINE]

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Clinical and pathologic implications of extending the spectrum of maternal autoantibodies reactive with ribonucleoproteins associated with cutaneous and now cardiac neonatal lupus from SSA/Ro and SSB/La to U1RNP.

Autoimmun Rev. 2017 Sep;16(9):980-983

Authors: Izmirly PM, Halushka MK, Rosenberg AZ, Whelton S, Rais-Bahrami K, Nath DS, Parton H, Clancy RM, Rasmussen S, Saxena A, Buyon JP

While the relationship between maternal connective tissue diseases and neonatal rashes was described in the 1960s and congenital heart block in the 1970s, the "culprit" antibody reactivity to the SSA/Ro-SSB/La ribonucleoprotein complex was not identified until the 1980s. However, studies have shown that approximately 10-15% of cases of congenital heart block are not exposed to anti-SSA/Ro-SSB/La. Whether those cases represent a different disease entity or whether another antibody is associated has yet to be determined. Moreover, the cutaneous manifestations of neonatal lupus have also been identified in infants exposed only to anti-U1RNP antibodies. In this review, we describe what we believe to be the first case of congenital heart block exposed to maternal anti-U1RNP antibodies absent anti-SSA/Ro-SSB/La. The clinical and pathologic characteristics of this fetus are compared to those typically seen associated with SSA/Ro and SSB/La. Current guidelines for fetal surveillance are reviewed and the potential impact conferred by this case is evaluated.

PMID: 28709760 [PubMed - indexed for MEDLINE]

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Gain-of-function mutations in GATA6 lead to atrial fibrillation.

Heart Rhythm. 2017 Feb;14(2):284-291

Authors: Tucker NR, Mahida S, Ye J, Abraham EJ, Mina JA, Parsons VA, McLellan MA, Shea MA, Hanley A, Benjamin EJ, Milan DJ, Lin H, Ellinor PT

BACKGROUND: The genetic basis of atrial fibrillation (AF) and congenital heart disease remains incompletely understood.
OBJECTIVE: We sought to determine the causative mutation in a family with AF, atrial septal defects, and ventricular septal defects.
METHODS: We evaluated a pedigree with 16 family members, 1 with an atrial septal defect, 1 with a ventricular septal defect, and 3 with AF; we performed whole exome sequencing in 3 affected family members. Given that early-onset AF was prominent in the family, we then screened individuals with early-onset AF, defined as an age of onset <66 years, for mutations in GATA6. Variants were functionally characterized using reporter assays in a mammalian cell line.
RESULTS: Exome sequencing in 3 affected individuals identified a conserved mutation, R585L, in the transcription factor gene GATA6. In the Massachusetts General Hospital Atrial Fibrillation (MGH AF) Study, the mean age of AF onset was 47.1 ± 10.9 years; 79% of the participants were men; and there was no evidence of structural heart disease. We identified 3 GATA6 variants (P91S, A177T, and A543G). Using wild-type and mutant GATA6 constructs driving atrial natriuretic peptide promoter reporter, we found that 3 of the 4 variants had a marked upregulation of luciferase activity (R585L: 4.1-fold, P < .0001; P91S: 2.5-fold, P = .0002; A177T; 1.7-fold, P = .03). In addition, when co-overexpressed with GATA4 and MEF2C, GATA6 variants exhibited upregulation of the alpha myosin heavy chain and atrial natriuretic peptide reporter activity.
CONCLUSION: Overall, we found gain-of-function mutations in GATA6 in both a family with early-onset AF and atrioventricular septal defects as well as in a family with sporadic, early-onset AF.

PMID: 27756709 [PubMed - indexed for MEDLINE]

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Mechanisms and predictors of recurrent tachycardia after catheter ablation for d-transposition of the great arteries after the Mustard or Senning operation.

Heart Rhythm. 2017 Mar;14(3):350-356

Authors: Gallotti RG, Madnawat H, Shannon KM, Aboulhosn JA, Nik-Ahd F, Moore JP

BACKGROUND: The Senning and Mustard operations for dextro-transposition of the great arteries are associated with an increased risk for supraventricular tachycardia. Catheter ablation has been shown to be acutely successful for achieving rhythm control in this population, but the mechanisms of recurrence are ill-defined.
OBJECTIVE: We hypothesized that the type and degree of recurrence would vary by the surgical technique used.
METHODS: All consecutive catheter ablation procedures for dextro-transposition of the great arteries after the Mustard or Senning operation between 2004 and 2016 at a single center were reviewed. Tachycardia mechanisms were determined by complete 3-dimensional mapping in addition to a standard electrophysiological technique for all cases.
RESULTS: Twenty-eight patients underwent 38 procedures during the study period. The most common mechanism at the index procedure was intra-atrial reentrant tachycardia using the cavotricuspid isthmus. Over a median follow-up period of 1.6 years, 9 patients experienced recurrent tachycardia (32%), all of whom underwent repeat catheter ablation. Tachycardia recurrence was more common after the Senning vs the Mustard operation (6 of 10 [60%] vs 3 of 18 [17%]; P = .034). In addition, substrates for recurrence were different from those encountered at the index procedure in 10 of 13 tachycardias (77%), with the single most common location being the posterior anastomosis after the Senning operation. Complete control was ultimately achieved in 27 patients (96%) when considering all procedures.
CONCLUSION: Recurrent tachycardia after catheter ablation appears to be more common after the Senning operation and to involve substrates unique to this repair. The posterior anastomosis is commonly implicated and should not be overlooked.

PMID: 27908766 [PubMed - indexed for MEDLINE]