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Calcium Signaling in Vertebrate Development and Its Role in Disease.

Int J Mol Sci. 2018 Oct 30;19(11):

Authors: Paudel S, Sindelar R, Saha M

Accumulating evidence over the past three decades suggests that altered calcium signaling during development may be a major driving force for adult pathophysiological events. Well over a hundred human genes encode proteins that are specifically dedicated to calcium homeostasis and calcium signaling, and the majority of these are expressed during embryonic development. Recent advances in molecular techniques have identified impaired calcium signaling during development due to either mutations or dysregulation of these proteins. This impaired signaling has been implicated in various human diseases ranging from cardiac malformations to epilepsy. Although the molecular basis of these and other diseases have been well studied in adult systems, the potential developmental origins of such diseases are less well characterized. In this review, we will discuss the recent evidence that examines different patterns of calcium activity during early development, as well as potential medical conditions associated with its dysregulation. Studies performed using various model organisms, including zebrafish, Xenopus, and mouse, have underscored the critical role of calcium activity in infertility, abortive pregnancy, developmental defects, and a range of diseases which manifest later in life. Understanding the underlying mechanisms by which calcium regulates these diverse developmental processes remains a challenge; however, this knowledge will potentially enable calcium signaling to be used as a therapeutic target in regenerative and personalized medicine.

PMID: 30380695 [PubMed - indexed for MEDLINE]

Diagnosis and treatment of pediatric pulmonary arterial hypertension.

Expert Rev Cardiovasc Ther. 2019 Jan 30;:

Authors: Farhat N, Lador F, Beghetti M

INTRODUCTION: Paediatric pulmonary arterial hypertension (PAH) remains a rare and severe disease with a poor prognosis. PAH may be idiopathic, heritable or associated to systemic conditions in particular associated with congenital heart disease. Areas covered: A thorough and extensive diagnostic approach is required for a correct diagnosis. Outcome has improved over the last decade with a better diagnostic approach and with the initiation of new targeted therapies. However, there is still significant progress to achieve as there is still no cure for this devastating disease. Expert opinion: Adapted clinical studies to define the best therapeutic approach are needed. Even if the treatment approach is still mainly derived from adult data and expert consensus, several studies and registries are currently underway and should deliver important information in the next future. This review aims to give an overview about the current diagnosis and treatment strategies of PAH.

PMID: 30698043 [PubMed - as supplied by publisher]

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

Cardiol Young. 2019 Jan 30;:1-5

Authors: Gleason LP, Deng LX, Khan AM, Drajpuch D, Fuller S, Ludmir J, Mascio CE, Partington SL, Tobin L, Kim YY, Kovacs AH

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.

PMID: 30698116 [PubMed - as supplied by publisher]

Obesity trends in children, adolescents, and young adults with congenital heart disease.

Congenit Heart Dis. 2019 Jan 30;:

Authors: Steele JM, Preminger TJ, Erenberg FG, Wang L, Dell K, Alsaied T, Zahka KG

OBJECTIVES: To determine the prevalence, age of onset, and risk factors for overweight and obesity in children with congenital heart disease (CHD).
STUDY DESIGN: Children with CHD who were seen at our institution from 1996 to 2017 were studied. Patients were full-time residents of the United States and were receiving all cardiac care at our institution. Patients were categorized by age and CHD diagnosis. The date of last normal weight for age and the date of first recorded weight in the range of overweight and obese were documented.
RESULTS: Nine hundred sixty-eight patients with CHD were included. The prevalence of overweight and obesity was 31.5% and 16.4%, respectively. For patients who became overweight or obese, the last recorded normal weight was between 6 and 10 years of age. Electrophysiologic disease and older age were risk factors for obesity.
CONCLUSIONS: Children with CHD have an increasing risk of becoming overweight and obese in early childhood. This study provides important information and identifies critical period to implement preventative measures and counsel families about the risk of obesity in CHD.

PMID: 30698365 [PubMed - as supplied by publisher]

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Impact of surgery on presence and dimensions of anatomical isthmuses in tetralogy of Fallot.

Heart. 2018 07;104(14):1200-1207

Authors: Kapel GFL, Laranjo S, Blom NA, Hazekamp MG, Schalij MJ, Bartelings MM, Jongbloed MRM, Zeppenfeld K

OBJECTIVE: In tetralogy of Fallot (TOF), the dominant ventricular tachycardia substrates are slow-conducting anatomical isthmuses. Surgical correction has evolved, which might have influenced isthmus presence and dimensions.
METHODS: One hundred and forty-two postmortem TOF specimens (84/58 corrected/uncorrected) were studied for isthmus presence. Isthmus 1 is located between the tricuspid annulus and right ventricular (RV) outflow tract (RVOT) patch/RV incision, isthmus 2 between RVOT patch/RV incision and pulmonary valve, isthmus 3 between pulmonary valve and ventricular septal defect (patch), isthmus 4 between ventricular septal defect (patch) and tricuspid annulus. Isthmus width and thickness were measured.
RESULTS: Of 84 corrected postmortem TOF specimens (death: 6.6 years (4.0-11.5)), 83 demonstrated isthmus 1 (99%, width=25±10 mm, thickness=5±2 mm), 35 isthmus 2 (42%, width=10±9 mm, thickness=3±2 mm), 83 isthmus 3 (99%, width=10±6 mm, thickness=5±2 mm), and 5 isthmus 4 (6%, width=4±2 mm, thickness=2±1 mm). Transatrial-transpulmonary correction (n=49) as compared with transventricular correction (n=35) prevented isthmus 2 (0% vs 100%, P<0.001). Transatrial-transpulmonary correction at age <1 year (n=7) as compared with ≥1 year (n=42) required a smaller transannular RVOT patch (28±15 vs 45±14 mm, P<0.001). Mode and timing of correction did not influence presence and dimensions of isthmus 3. In corrected and uncorrected TOF specimens (death 1.8 years (0.5-6.6)), the range of isthmus 3 dimensions was broad (width: min=2 mm, max=32 mm; thickness: min=1, max 13 mm) across all ages. Isthmus 3 width and thickness were strongly correlated (r=0.65, P<0.001).
CONCLUSIONS: In TOF, the current routine use of transatrial-transpulmonary correction prevents isthmus 2. Correction <1 year reduces transannular patch size, which may influence isthmus 1 width later in life. Mode and timing of correction did not change prevalence and dimensions of isthmus 3, in which dimensions varied widely in uncorrected and corrected TOF.

PMID: 29305559 [PubMed - indexed for MEDLINE]

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Contemporary management and outcomes in congenitally corrected transposition of the great arteries.

Heart. 2018 07;104(14):1148-1155

Authors: Kutty S, Danford DA, Diller GP, Tutarel O

Congenitally corrected transposition of the great arteries (ccTGA) can occur in isolation, or in combination with other structural cardiac anomalies, most commonly ventricular septal defect, pulmonary stenosis and tricuspid valve disease. Clinical recognition can be challenging, so echocardiography is often the means by which definitive diagnosis is made. The tricuspid valve and right ventricle are on the systemic arterial side of the ccTGA circulation, and are therefore subject to progressive functional deterioration. The natural history of ccTGA is also greatly influenced by the nature and severity of accompanying lesions, some of which require surgical repair. Some management strategies leave the right ventricle as the systemic arterial pump, but carry the risk of worsening heart failure. More complex 'double switch' repairs establish the left ventricle as the systemic pump, and include an atrial baffle to redirect venous return in combination with either arterial switch or Rastelli operation (if a suitable ventricular septal defect permits). Occasionally, the anatomic peculiarities of ccTGA do not allow straightforward biventricular repair, and Fontan palliation is a reasonable option. Regardless of the approach selected, late cardiovascular complications are relatively common, so ongoing outpatient surveillance should be established in an age-appropriate facility with expertise in congenital heart disease care.

PMID: 29326110 [PubMed - indexed for MEDLINE]

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Use of intravenous iron in cyanotic patients with congenital heart disease and/or pulmonary hypertension.

Int J Cardiol. 2018 Sep 15;267:79-83

Authors: Blanche C, Alonso-Gonzalez R, Uribarri A, Kempny A, Swan L, Price L, Wort SJ, Beghetti M, Dimopoulos K

BACKGROUND: Secondary erythrocytosis is common in patients with cyanosis secondary to congenital heart disease (CHD) and/or pulmonary hypertension (PH). This compensatory mechanism aims at increasing oxygen delivery to the tissues, but it requires adequate iron stores. Optimal methods of iron supplementation in this setting remain controversial, with fears of excessive erythropoiesis and hyperviscosity symptoms. We describe our experience using intravenous ferrous carboxymaltose.
METHODS AND RESULTS: 142 consecutive cyanotic patients were treated over 5.7 years (201 administrations). Mean age was 51.3 ± 17.6 years and 55 (38.7%) were male. Eisenmenger syndrome (ES) was present in 41 (28.8%), other pulmonary arterial hypertension (PAH) related to CHD (PAH-CHD) in 27 (19.0%), cyanotic CHD without PAH in 16 (11.3%) and PH without CHD in 58(40.8%). Baseline haemoglobin (Hb) concentration was 14.6 ± 3.0 g/dL and haematocrit 0.45 ± 0.09. A 500 mg dose of intravenous (IV) iron carboxymaltose was given in 163 (81.1%) of administrations and a 1000 mg dose in 37 (18.4%). A significant improvement in average Hb, haematocrit, ferritin and transferrin saturation was observed after a median follow-up of 100.0 [70.0-161.0] days (p ≤ 0.0001 for all). There were no cases of excessive erythropoiesis resulting in new hyperviscosity symptoms and/or requiring venesection. A minor transient rash was observed in 2 patients and one patient experienced an air embolus causing a transient ischemic attack.
CONCLUSIONS: Intravenous ferrous carboxymaltose appears to be safe in iron deficient patients with cyanosis due to CHD and/or PH, as long as care is taken to avoid air emboli. Further randomised studies are needed to confirm the safety and efficacy of intravenous iron in this setting.

PMID: 29807779 [PubMed - indexed for MEDLINE]

Related Articles

Surgical and percutaneous pulmonary valve replacement in England over the past two decades.

Heart. 2019 Jan 30;:

Authors: Larsen SH, Dimopoulos K, Gatzoulis MA, Uebing A, Shore DF, Alonso-Gonzalez R, Kempny A

OBJECTIVE: Pulmonary valve replacement (PVR) is often required in patients with congenital heart disease. We aimed to describe temporal trends in PVR in a nationwide English cohort between 1997 and 2014, survival and the need for re-PVR.
METHODS: Patients were identified in the Hospital Episode Statistics Database. Survival data were retrieved from the UK Office for National Statistics.
RESULTS: A total of 2733 patients underwent PVR (2845 procedures) over the study period. Median age at first procedure increased from 20.1 years in 1997-2005 to 24.7 years in 2006-2014. The annual number of PVRs increased from 23 in 1997 to 251 in 2014. Homografts were the most common choice in the early years, but the use of xenografts increased after 2005. During a median follow-up of 5.8 years, 176 patients died and 108 required redo PVR. Early (30 day) survival was 98% for all PVRs and was similar for all types of prostheses but longer-term mortality dropped to 92% at 10 years and 90% at 15 years. Age >16 years and percutaneous PVR were risk factors for death. The cumulative incidence for re-PVR at 10 years was 8% for all PVRs and 11% at 15 years. Risk factors for re-PVR were complex diagnosis, male gender and black ethnicity.
CONCLUSION: There was a significant increase in the number of PVRs performed in England over the last two decades and a significant change in the type of prosthesis employed. While early mortality was low across the board, longer-term mortality was not negligible in this young population.

PMID: 30700516 [PubMed - as supplied by publisher]

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Prognostic value of soluble ST2 in adults with congenital heart disease.

Heart. 2019 Jan 30;:

Authors: Geenen LW, Baggen VJM, van den Bosch AE, Eindhoven JA, Cuypers JAAE, Witsenburg M, Boersma E, Roos-Hesselink JW

OBJECTIVE: Soluble suppression of tumourigenicity-2 (sST2) is upregulated as response to myocardial stress and may be a potential biomarker for risk stratification in patients with adult congenital heart disease (ACHD). This study aimed to investigate the release of sST2 and its association with cardiovascular events in ACHD.
METHODS: In this prospective cohort study, 602 consecutive patients with ACHD visiting the outpatient clinic were included (2011-2013). The association between sST2 and a primary composite endpoint of all-cause mortality, heart failure, hospitalisation, arrhythmia, thromboembolic events or cardiac interventions was investigated using multivariable Cox regression.
RESULTS: sST2 was measured in 590 (98%) patients (median age 33 [25-41] years, 42% women). After a median follow-up of 5.8 [IQR 5.1-6.2) years, 225 (38.5%) reached the primary endpoint. sST2 was significantly associated with the primary endpoint when adjusted for age, sex, creatinine and N  terminal pro-B type brain natriuretic peptide (NT-proBNP) (HR per twofold higher sST2: 1.28, 95% CI 1.03 to 1.58, p=0.025). This association negated when adjusted for clinical variables and NT-proBNP (HR per twofold higher sST2: 1.19, 95% CI 0.96 to 1.48, p=0.106). Stratified analysis in complex ACHD did show a significant association between sST2 and the primary endpoint when adjusted for clinical variables and NT-proBNP (HR per twofold higher sST2: 1.31, 95% CI 1.01 to 1.69, p=0.043). Sex-specific analysis showed an association between sST2 and the primary endpoint in women (HR per twofold higher sST2 1.80, 95% CI 1.30 to 2.49, p<0.001) but not in men (HR per twofold higher sST2 1.19, 95% CI 0.90 to 1.56, p=0.223).
CONCLUSIONS: sST2 is a promising novel biomarker in patients with ACHD, specifically in complex ACHD and women. Future research is warranted to elucidate sex-specific and diagnosis-specific differences.

PMID: 30700520 [PubMed - as supplied by publisher]

Related Articles

Genetic analysis of CHARGE syndrome identifies overlapping molecular biology.

Genet Med. 2018 09;20(9):1022-1029

Authors: Moccia A, Srivastava A, Skidmore JM, Bernat JA, Wheeler M, Chong JX, Nickerson D, Bamshad M, Hefner MA, Martin DM, Bielas SL

PURPOSE: CHARGE syndrome is an autosomal-dominant, multiple congenital anomaly condition characterized by vision and hearing loss, congenital heart disease, and malformations of craniofacial and other structures. Pathogenic variants in CHD7, encoding adenosine triphosphate-dependent chromodomain helicase DNA binding protein 7, are present in the majority of affected individuals. However, no causal variant can be found in 5-30% (depending on the cohort) of individuals with a clinical diagnosis of CHARGE syndrome.
METHODS: We performed whole-exome sequencing (WES) on 28 families from which at least one individual presented with features highly suggestive of CHARGE syndrome.
RESULTS: Pathogenic variants in CHD7 were present in 15 of 28 individuals (53.6%), whereas 4 (14.3%) individuals had pathogenic variants in other genes (RERE, KMT2D, EP300, or PUF60). A variant of uncertain clinical significance in KDM6A was identified in one (3.5%) individual. The remaining eight (28.6%) individuals were not found to have pathogenic variants by WES.
CONCLUSION: These results demonstrate that the phenotypic features of CHARGE syndrome overlap with multiple other rare single-gene syndromes. Additionally, they implicate a shared molecular pathology that disrupts epigenetic regulation of multiple-organ development.

PMID: 29300383 [PubMed - indexed for MEDLINE]