Tetralogy Of Fallot

Pro-inflammatory Cytokines may Associate Periodontitis with Pregnancy Complications: A Short Review

Periodontitis is an oral inflammatory disease possessing detrimental impacts on supporting tissue of teeth (like gingiva, periodontal ligament, and alveolar bone) and involves a great number of individuals all over the world. One of the appropriate ways to prevent this disease is to find related risk factors. According to reports, pregnancy complications can be associated with this oral disease; however, the possible mechanisms linking these two conditions have not been exactly determined. Hence, in this review, we summarize documents related to pregnancy complications and periodontitis with a mechanistic insight.

Literature on the relevant topic was searched from scientific databases, including Scopus, Google Scholar, and PubMed, in English, between 1996 and 2022.

Based on reports, pregnancy complications (premature labor, low weight at birth, and preeclampsia) can be related to periodontitis. This linkage can be mediated by inflammatory reactions, one of the main pathogenic mechanisms in periodontitis. Pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, have the ability to induce labor and fetal toxicity and finally create preterm labor and low weight at birth. Besides, these cytokines can potentiate chronic inflammatory responses in the fetal-maternal interface, impair placentation, and create endothelial dysfunction.

It seems that pro-inflammatory reactions, like secretion of TNF-α, IL-1β, and IL-6, can be a bridge for associating periodontitis and pregnancy complications. However, more studies with larger sample sizes are needed to support these findings.

Real-time Strain-encoding Cardiovascular MRI for Assessment of Regional Heart Function in Tetralogy of Fallot Patients

Background: Tetralogy of Fallot (ToF) is the most common form of cyanotic congenital heart disease, where right ventricular (RV) function is an important determinant of subsequent intervention.

Objective: In this study, we evaluate the feasibility of fast strain-encoding (fastSENC; a one-heartbeat sequence) magnetic resonance imaging (MRI) for assessing regional cardiac function in ToF.

Methods: FastSENC was implemented to characterize regional circumferential (Ecc) and longitudinal (Ell) strains in the left ventricle (LV) and RV in postrepair ToF. Data analysis was conducted to compare strain measurements in the RV to those in the LV, as well as to those generated by the MRI Tissue-Tracking (MRI-TT) technique, and to assess the relationship between strain and ejection fraction (EF).

Results: Despite normal LVEF (55±8.5%), RVEF was borderline (46±6.4%), but significantly lower than LVEF. RV strains (RV-Ell=-20.2±2.9%, RVEcc=- 15.7±6.4%) were less than LV strains (LV-Ell=-21.7±3.7%, LV-Ecc=-18.3±4.7%), and Ell was the dominant strain component. Strain differences between fastSENC and MRI-TT were less significant in RV than in LV. There existed moderate and weak correlations for RV-Ecc and RV-Ell, respectively, against RVEF. Compared to LV strain, RV strain showed regional heterogeneity with a trend for reduced strain from the inferior to anterior regions. Inter-ventricular strain delay was larger for Ell (64±47ms) compared to Ecc (36±40ms), reflecting a trend for contraction dyssynchrony.

Conclusion: FastSENC allows for characterizing subclinical regional RV dysfunction in ToF. Due to its sensitivity for evaluating regional myocardial contractility patterns and real-time imaging capability without the need for breath-holding, fastSENC makes it more suitable for evaluating RV function in ToF.

Diagnostic Strategy for Suspected Unilateral Absence of the Pulmonary Artery

Background: Unilateral absence of the pulmonary artery (UAPA) is a very rare congenital anomaly.

Objective: To analyze the diagnostic strategy applied to seven patients with UAPA who were examined and subsequently treated at the National Lung Hospital, Hanoi, Vietnam.

Methods: All seven patients, including three pediatric cases (1, 2, and 14 years old) and four adult cases (21, 26, 44, and 53 years old), had a history of recurrent pneumonia, and the clinical symptoms on admission included cough, progressive dyspnea, chest pain, and fatigue. The patients were initially examined clinically, followed by hematological testing, blood biochemistry testing, and chest X-ray radiology. The results suggested UAPA, so echocardiography and contrast-enhanced chest computed tomography (CT) were performed as soon as practical.

Results: The echocardiographic and CT imaging findings confirmed the suspected diagnosis of UAPA in all seven patients, which was accompanied by congenital heart disease in three patients. Three of the seven patients had mild and medium pulmonary hypertension. All seven patients were treated with drugs, which led to improvement in symptoms.

Conclusion: Frontal chest X-ray provided the initial signs suggesting a diagnosis of UAPA. Subsequent echocardiography and contrast-enhanced chest CT were effective diagnostic tools for fast and accurate confirmation of UAPA.

Submaximal Field Walking Tests Applied in the Cardiopulmonary Assessment in Congenital Heart Diseases: A Systematic Review

Introduction: Submaximal field walking tests are easy to apply and low cost, but it is necessary to standardize their application, especially in the pediatric population. The feasibility and its use in patients with congenital heart disease have been studied. The goal of this study was to verify which are the submaximal field walking tests applied in the cardiopulmonary assessment of children and adolescents with CHD and to verify if they are being performed as recommended by the standardization protocols/guidelines.

Methods: Literature review through a search in six electronic databases, structured in PICO format, without date restrictions. Looking for studies that used submaximal field walking tests in children and adolescents with congenital heart disease aged 5 to 18 years. Methodological quality, effectiveness and safety and risk of bias were assessed.

Results: Five studies met the eligibility criteria with a sample of 160 individuals with congenital heart disease, and all used the six-minute walk test. Note that different methodologies and modifications are used. Only the clinical trial showed good methodological quality.Four studies had low risk of bias and one study had moderate risk.

Conclusion: Although the six-minute walk test is the only test used as a field test found in our research, there is no standardization in the application of the test, making it difficult to compare the results. In this sense, reducing the limitations and heterogeneity in the application of the test will enable more concrete outcomes and facilitate their reproduction in clinical practice.

Pulmonary Hypertension associated with Congenital Heart Disease

Pulmonary hypertension in patients with congenital heart disease is associated with significant mortality, morbidity and health services utilization. The predominant subtype of pulmonary hypertension in these patients is pulmonary arterial hypertension (PAH). PAH associated with congenital heart disease (PAH-CHD) comprises up to one-third of all PAH cases globally and is most commonly associated with anatomically simple shunt lesions. A myriad of clinical phenotypes of PAH-CHD are seen across the spectrum of shunt size, location and directionality. A conceptual framework to categorize these patients based on pathophysiology is described. Contemporary data regarding the management of the varied phenotypes are reviewed, and a novel algorithm to guide decision-making with shunt closure in patients with PAH-CHD is provided. Further data spanning the spectrum of basic, translational and clinical science are much needed to further inform the management of this highly complex and heterogeneous population.

The Right Ventricle in Pulmonary Arterial Hypertension: An Organ at the “Heart of the Problem”

Pulmonary Arterial Hypertension (PAH) is a progressive disease with no cure. A major determinant of outcome is the function of the right ventricle (RV). Unfortunately, progressive RV dysfunction and failure can occur despite PAH-specific therapies. While initial adaptive hypertrophic changes occur to maintain cardiac output and preserve contractile function and reserve, maladaptive changes occur in the RV muscle that contribute to RV systolic and diastolic dysfunction and failure. These include impaired angiogenesis / decreased capillary density with ischemia, fibrosis, cardiomyocyte apoptosis and impaired autophagy, inflammation, enhanced oxidative stress, altered metabolism, etc. Of note, there are no therapies currently approved that offset these changes and treatment of RV dysfunction is largely supportive only. Further patients often do not qualify for bilateral lung transplantation because of co-morbidities such as renal impairment. Thus, a dire unmet need exists regarding the management of RV dysfunction and failure in patients with PAH. In this State-of-the-Art review, we comprehensively outline the unique features of the RV compared to the left ventricle (LV) under normal circumstances and highlight the unique challenges faced by the RV when confronted with increased afterload as occurs in PAH. We provide detailed insights into the basis for the adaptive hypertrophic phase as well as detailed commentary into the pathophysiology of the maladapted dysfunctional state as well as the pathobiological aberrations occurring in the RV muscle that underlines the progressive dysfunction and failure that commonly ensues. We also review comprehensively the evaluation of RV function using all currently employed imaging, hemodynamic and other modalities and provide a balanced outline of strengths and limitations of such approaches with the treating clinician in mind. We outline the current approaches, albeit limited to chronic multi-modal management of RV dysfunction and failure. We further outline new possible approaches to treatment that include novel pharmacologic approaches, possible use of cellular/stem cell therapies and mechanical approaches. This review is directed to the treating clinician to provide comprehensive insights regarding the RV in patients with PAH.

Abnormalities of hsa-mir-16 and hsa-mir-124 Affect Mitochondrial Function and Fatty Acid Metabolism in Tetralogy of Fallot

Background: Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease in clinical practice. It is mainly due to cardiovascular hypoplasia during embryonic development. The study aimed to find the etiology of TOF.

Methods: Through the mRNA expression profile analysis of the GSE35776 dataset, differentially expressed genes (DEGs) were found, and the functional analysis and protein-protein interaction (PPI) network analysis were then performed on DEGs. Likewise, the hub genes and functional clusters of DEGs were analyzed using the PPI network. Differentially expressed miRNAs were analyzed from the GSE35490 dataset, followed by miRNet predicted transcription factors (TFs) and target genes. The key TF-miRNA-gene interaction mechanism was explored through the found significant difference between genes and target genes.

Results: A total of 191 differentially expressed genes and 57 differentially expressed miRNAs were identified. The main mechanisms involved in TOF were mitochondria-related and energy metabolism- related molecules and pathways in GO and KEGG analysis. This discovery was identical in TFs and target genes. The key miRNAs, hsa-mir-16 and hsa-mir-124, were discovered by the Venn diagram. A co-expression network with the mechanism of action centered on two miRNAs was made.

Conclusion: Hsa-mir-16 and hsa-mir-124 are the key miRNAs of TOF, which mainly regulate the expression of NT5DC1, ECHDC1, HSDL2, FCHO2, and ACAA2 involved in the conversion of ATP in the mitochondria and the metabolic rate of fatty acids (FA). Our research provides key molecules and pathways into the etiology of TOF, which can be used as therapeutic targets.

Chromosome 9 Inversion: Pathogenic or Benign? A Comprehensive Systematic Review of all Clinical Reports

Background: Inversion of chromosome 9 (inv[9]) is known as one of the most common structural balanced chromosomal variations. Chromosome 9 is highly susceptible to structural rearrangements, specifically to pericentric inversions. Various investigators have posited that inv(9) with different breakpoints could be the cause of several abnormal conditions in individuals, whereas others have considered it a benign variant. To our knowledge, a consensus regarding the effects of this inversion has yet to emerge.

Objective: This study aims to discuss the pathogenic/benign effects of inv(9) in all possible clinical conditions detected in the occurrence of this abnormality.

Methods: Studies on inv(9) were collected via PubMed, MalaCards, Google Scholar, and NORD, along with the search terms of inv(9), pericentric inv(9), and chromosome 9 variants. Additionally, the incidence of inv(9) and the karyotype and clinical findings of individuals reported with this variant were investigated.

Results: The collection of the studies reviewed shows that inv(9) is associated with various conditions such as congenital anomalies, growth retardation, infertility, recurrent pregnancy loss, and cancer. The clinical features associated with this variant in humans vary between growth stages. Further, there have been no shared clinical findings in a specific period.

Conclusion: Although there is no conclusive evidence for the pathogenicity of this rearrangement, prenatal genetic counseling on inv(9) and further clinical and molecular studies would be helpful in chromosome 9-related problems.

A Comparative Effectiveness Systematic Review and Meta-analysis of Drugs for the Prophylaxis of Junctional Ectopic Tachycardia

Background: Junctional Ectopic Tachycardia (JET) is an arrhythmia originating from the AV junction, which may occur following congenital heart surgery, especially when the intervention is near the atrioventricular junction.

Objective: The aim of this systematic review and meta-analysis is to compare the effectiveness of amiodarone, dexmedetomidine, and magnesium in preventing JET following congenital heart surgery.

Methods: This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement, where 11 electronic databases were searched from the date of inception to August 2020. The incidence of JET was calculated with the relative risk of 95% Confidence Interval (CI). Quality assessment of the included studies was assessed using the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement.

Results: Eleven studies met the predetermined inclusion criteria and were included in this meta-analysis. Amiodarone, dexmedetomidine, and magnesium significantly reduced the incidence of postoperative JET [Amiodarone: risk ratio 0.34; I2= 0%; Z=3.66 (P=0.0002); 95% CI 0.19-0.60. Dexmedetomidine: risk ratio 0.34; I2= 0%; Z=4.77 (P<0.00001); 95% CI 0.21-0.52. Magnesium: risk ratio 0.50; I2= 24%; Z=5.08 (P<0.00001); 95% CI 0.39-0.66].

Conclusion: All three drugs have shown promising results in reducing the incidence of JET. Our systematic review found that dexmedetomidine is better in reducing the length of ICU stays as well as mortality. In addition, dexmedetomidine also has the least pronounced side effects among the three. However, it should be noted that this conclusion was derived from studies with small sample sizes. Therefore, dexmedetomidine may be considered as the drug of choice for preventing JET.

Cardiovascular Diseases in Pregnancy - A Brief Overview

Even though, there have been many advances in maternal medical care and fertility treatments, the presence of cardiovascular disease has a significant impact on pregnancy. In pregnant women, several heart conditions, such as valvular heart disease, chronic hypertension, congenital heart defects and non-ischemic cardiomyopathies are linked to increased risk of fetal as well as maternal morbidity and mortality. To date, the management of the co-existing conditions of pregnancy and heart disease has been challenging. Therefore, in-depth information may be beneficial to tackle a difficult case scenario. Towards this end, this paper provides an overview of the recent updated knowledge of pregnancy-related cardiovascular diseases in women.

Frequency of Cardiac Arrhythmias in Children with Cardiological Consulting and Containing Electrocardiogram

Background: Heart diseases are the leading causes of mortality and Congenital Heart Disease (CHD) is the most common birth defect reported worldwide.

Objective: The aim of this study was to evaluate the incidence of arrhythmias and CHD and the association between the two, among infants and children reported to our center.

Methods: This cross-sectional study included infants and children who were referred to Shahid Madani Hospital, Khorramabad. Electrocardiogram (ECG) was performed in these children to determine the type of arrhythmia and records were used to obtain demographic data and the data regarding CHD.

Results: Of 200 children enrolled in the study, 10 children had arrhythmias, 12 had tachycardia, 5 had bradycardia, and 31 had congenital disease. Among children with arrhythmias, 1 had atrial fibrillation, 4 patients had paroxysmal supraventricular tachycardia, 1 person had right bundle branch block, 1 had ventricular tachycardia, 2 had premature ventricular contractions and 1 had junctional ectopic tachycardia. Of the 31 children with CHD, 9 patients were presented with small ventricular septal defect, 4 children had patent foramen ovale, 2 had pulmonary stenosis and 1 of the children had tetralogy of fallout, arterial and ventricular septal defects and transposition of greater arteries, respectively.

Conclusion: We reported a positive correlation between the arrhythmias and CHD. A larger number of studies collecting focusing on different age groups are therefore required to verify our findings.

Critical Congenital Heart Disease in Neonates: A Review Article

Critical congenital heart defects (CCHDs) are serious malformations that remain to be an important cause of neonatal mortality and morbidity. The clinical presentations of CCHD are shock, cyanosis, or respiratory distress, which may be similar to that of other neonatal conditions. Failure to diagnose these conditions early on after birth may result in acute cardiovascular collapse and death. Screening with routine pulse oximetry is efficient in distinguishing newborns with CCHD and other hypoxemic illnesses, which may otherwise be potentially life-threatening. If the cardiovascular system cannot be observed by echocardiography, then treatment with continuous prostaglandin-E1(PGE1) infusion should be started in any newborn whose condition deteriorates in the first few days of life. This review aims to provide a concise summary of the presentation and management of various CCHDs and to emphasize the role of timely diagnosis in the management.

Potential Roles of MyomiRs in Cardiac Development and Related Diseases

Muscle-specific miRNAs, which are known as MyomiRs, are crucial regulatory elements for cardiovascular development. MyomiRs are abundantly expressed in the myocardium and regulate certain aspects of physiological and pathological processes in myocardiocytes, including cardiovascular development, myocardial remodeling, and arise for cardiovascular diseases through different mechanisms, such as epigenetic pathways. Clinical and experimental studies have confirmed the myomiRs as promising diagnostic biomarkers for the early diagnosis of cardiac disorders. In this review, we have summarized recent findings in the field of epigenetic modulations of myomiRs and cardiac regeneration associated with cardiac diseases.

A Review of Selected Adult Congenital Heart Diseases Encountered in Daily Practice

The advancement in corrective surgical procedures and anaesthesia technology has resulted in the increased survival of patients with Congenital Heart Diseases (CHD). Most of the surviving CHD patients have successfully reached adulthood and those surviving adults now outnumber the infants born with the CHD. Unfortunately, the surviving adults with CHD do not get proper care due to either inconsistent follow-up or not getting care from a specialist in the field of CHD. It is imperative for general practicing clinicians to be aware of the congenital diseases as well as the current clinical recommendations. This manuscript reviews some of the common congenital diseases seen in adults such as cardiac shunts, left heart obstructive lesions, and aortopathies.

Clinical Applicability of Conditioning Techniques in Ischemia-Reperfusion Injury: A Review of the Literature

Ischemia refers to a reduced supply of oxygen and nutrient to the vital organ of the body. Reperfusion to the ischemic organ is the only way to salvage injury due to ischemia. Paradoxically, reperfusion itself induces the injury, which is more severe than the previous injury referred to as ischemia-reperfusion injury. Ischemia-reperfusion injury is the major cause of mortality in the case of ischemic diseases. The major hurdle for a clinician to treat ischemia is the reperfusion injury, which is encountered in different surgical as well as non-surgical situations. Several therapies, such as anti-platelets, anti-thrombolytic agents have been developed to contain ischemia-reperfusion injury, but with limited success. Over some time, some conditioning techniques such as preconditioning and postconditioning have been used by clinicians to overcome ischemia-reperfusion injury. The present review focuses on the clinical applications of different conditioning techniques in diverse pathological conditions of ischemia-reperfusion injury.

Epsilon Waves as an Extreme Form of Depolarization Delay: Focusing on the Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

Revision of the Task Force diagnostic criteria (TFC) for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), in 2010, has increased the sensitivity for the diagnosis of early and familial forms of the disease. Epsilon wave (EW) is a major diagnostic criterion in the context of ARVC/D, however, it remains unquantifiable and therefore, may leave room for substantial subjective interpretation, thus, explaining the existing high inter-observer variability in the assessment of EW. EW, when present, coexists with other disease characteristics, which are sufficient for ARVC/D diagnosis, making EW generally not required for ARVC/D diagnosis. Nevertheless, EW remains an important part of the electrocardiographic phenotype of ARVC/D that may be useful in planning diagnostic work-up, which needs to be recognized.

The Vectorcardiogram and the Main Dromotropic Disturbances

Until the mid-1980s, it was believed that the vectorcardiogram (VCG) presented a greater specificity, sensitivity and accuracy in comparison to the 12-lead electrocardiogram (ECG), in the cardiology diagnosis. Currently, the VCG still is superior to the ECG in specific situations, such as in the evaluation of myocardial infarctions when associated with intraventricular conduction disturbances, in the identification and location of accessory pathways in ventricular preexcitation, in the differential diagnosis of patterns varying from normal of electrical axis deviation, in the evaluation of particular aspects of Brugada syndrome, Brugada phenocopies, concealed form of arrhythmogenic right ventricular cardiomyopathy and zonal or fascicular blocks of the right bundle branch on right ventricular free wall.VCG allows us to analyze the presence of left septal fascicular block more accurately than ECG and in the diagnosis of the interatrial blocks and severity of some chambers enlargements. The three-dimensional spatial orientation of both the atrial and the ventricular activity provides a far more complete observation tool than the linear ECG. We believe that the ECG/VCG binomial simultaneously obtained by the technique called electro-vectorcardiography (ECG/VCG) brought a significant gain for the differential diagnosis of several pathologies. Finally, in the field of education and research, VCG provided a better and more rational tridimensional insight into the electrical phenomena that occurs spatially, and represented an important impact on the progress of electrocardiography.

Cardiovascular Complications in Patients with Klinefelter’s Syndrome

More than 70 years have passed since the first description of Klinefelter Syndrome (KS), the most frequent chromosome disorder causing male infertility and hypogonadism. KS is associated with increased cardiovascular (CV) mortality due to several comorbidities, including hypogonadism, as well as metabolic syndrome and type 2 diabetes, which are highly prevalent in these patients. Aside from metabolic disturbances, patients with KS suffer from both acquired and congenital CV abnormalities, cerebrovascular thromboembolic disease, subclinical atherosclerosis and endothelial dysfunction, which may all contribute to increased CV mortality. The mechanisms involved in this increased risk of CV morbidity and mortality are not entirely understood. More research is needed to better characterise the CV manifestations, elucidate the pathophysiological mechanisms and define the contribution of testosterone replacement to restoring CV health in KS patients. This review explores the complex association between KS, metabolic syndrome and CV risk in order to plan future studies and improve strategies to reduce mortality in this high-risk population.

Prediction of Tetralogy of Fallot using Fuzzy Clustering

Background: Congenital Heart Disease is one of the abnormalities in your heart's structure. To predict the tetralogy of fallot in a heart is a difficult task. Cluster is the collection of data objects, which are similar to one another within the same group and are different from the objects in the other clusters. To detect the edges, the clustering mechanism improve its accuracy by using segmentation, Colour space conversion of an image implemented in Fuzzy c-Means with Edge and Local Information.

Objective: To predict the tetralogy of fallot in a heart, the clustering mechanism is used. Fuzzy c-Means with Edge and Local Information gives an accuracy to detect the edges of a fallot to identify the congential heart disease in an efficient way.

Methods: One of the finest image clustering methods, called as Fuzzy c-Means with Edge and Local Information which will introduce the weights for a pixel value to increase the edge detection accuracy value. It will identify the pixel value within its local neighbor windows to improve the exactness. For evaluation , the Adjusted rand index metrics used to achieve the accurate measurement.

Results: The cluster metrics Adjusted rand index and jaccard index are used to evaluate the Fuzzy c- Means with Edge and Local Information. It gives an accurate results to identify the edges. By evaluating the clustering technique, the Adjusted Rand index, jaccard index gives the accurate values of 0.2, 0.6363, and 0.8333 compared to other clustering methods.

Conclusion: Tetralogy of fallot accurately identified and gives the better performance to detect the edges. And also it will be useful to identify more defects in various heart diseases in a accurate manner. Fuzzy c-Means with Edge and Local Information and Gray level Co-occurrence matrix are more promising than other Clustering Techniques.

Large Unrepaired Aortopulmonary Window Presenting in Adulthood

Background: Aortopulmonary window is an uncommon congenital heart disease, with untreated cases not surviving beyond childhood. However, very rarely it can present in adult patients with features of pulmonary hypertension. Clinically these patients cannot be differentiated from other more common conditions with left to right shunt. Transthoracic echocardiography if performed meticulously, can depict the defect in aortopulmonary septum.

Results: We report a case of large unrepaired aortopulmonary window in a 23 years old patient, diagnosed on transthoracic echocardiography.

Percutaneous Pulmonary Valve Implantation: Current Status and Future Perspectives

Patients with congenital heart disease (CHD) with right ventricle outflow tract (RVOT) dysfunction need sequential pulmonary valve replacements throughout their life in the majority of cases. Since their introduction in 2000, the number of percutaneous pulmonary valve implantations (PPVI) has grown and reached over 10,000 procedures worldwide. Overall, PPVI has been proven safe and effective, but some anatomical variations can limit procedural success. This review discusses the current status and future perspectives of the procedure.

Does Pharmacological Therapy Still Play a Role in Preventing Sudden Death in Surgically Treated Tetralogy of Fallot?

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, with a familial recurrence risk of 3%. Despite performing an optimal surgical repair, TOF patients may feature a poor medium and long-term survival rate: atrial re-entrant tachycardia will develop in more than 30% of patients and high-grade ventricular arrhythmias will be seen in about 10% of patients.

These life-threatening arrhythmias and consequent sudden death continue to represent serious complications following TOF repair. Radiofrequency ablation and implantable cardioverter defibrillator are today the most effective therapeutic tools in these subjects, while the administration of antiarrhythmic drugs (Ib agents, beta blockers, and amiodarone), widely prescribed in the past, is now limited to few conditions. However pharmacological therapy still plays a role in the management of those patients who are resistant to the above stated invasive electrophysiological treatments.

Editorial: Pharmacological Therapy to Prevent Sudden Cardiac Death: Indications and Limitations in the Era of Devices

Value of Abnormal Fetal Cardiac Axis in the Fetal Congenital Heart Disease

Background: Fetal echocardiography is an important method in prenatal diagnosis of Congenital Heart Disease (CHD). Fetal cardiac axis can be used as a reliable parameter in the diagnosis of CHD. The objective of this study was to discuss the abnormal fetal cardiac axis in the diagnostic value of fetal congenital heart disease.

Methods: In a 3-year period, 296 women with 20 and 40 weeks' singleton gestations referred for perinatal ultrasound consultation underwent evaluation of the fetal cardiac axis. For measurement of fetal cardiac axis, the chest axial image was obtained at the level of the four-chamber view. Of the 296 pregnancies, 260 healthy pregnancies were categorized as Group A while 36 pregnancies with severe heart disease were Group B. Cardiac anomaly was confirmed either by neonatal echocardiography or autopsy.

Results: Cardiac anomaly has been found in 36 women, 24 had abnormal axis (three with axis smaller than normal; 21 with axis larger than normal). The mean of cardiac axis for Group A (38.1±7.6°) was significantly smaller than that of Group B (52.6±19.8°) (P<0.001). The cardiac axis was independent from gestational age. With two standard deviations above and below the mean of Group A as normal cardiac axis (22.9°-53.5°), abnormal fetuses were defined as having axis < 23° or > 54°. There were 6 cases (2.3%) of cardiac axis larger than normal and no case (0%) smaller in group A, and 21 cases (58.3%) larger and 3 cases (8.3%) smaller in group B. The difference in two groups of patients with abnormal cardiac axis was statistically significant (P<0.01). The incidence of abnormal cardiac axis of group A was less than group B.

Conclusions: The measurement of fetal cardiac axis is simple and effective. Any larger or smaller fetal cardiac axis than normal is suggestive of a cardiac anomaly and requires further investigation. Four-chamber view is an important plane of fetal echocardiography.

Effects of Maternal Obesity on Maternal and Fetal Health

Obesity, as defined by body mass index (BMI) is one of the biggest challenges facing health care system including maternity services today, particularly in the industrialized nations. Maternal obesity is linked with a number of pregnancy complications including gestational diabetes, preeclampsia, venous thromboembolism, caesarean delivery, postpartum haemorrhage, macrosomia, shoulder dystocia and poor perinatal outcomes. Obesity has also been shown to be independently associated with higher odds of dying from specific pregnancy complications. These risks increases with increasing BMI and are highest in women with BMI ≥ 50. The mechanisms underlying these pathologies remain unclear. All obese women in reproductive age group should be counselled about weight gain, exercise programmes, nutrition and food choices, longer term health risks and increased risk of maternal and fetal complications, ideally before contemplating pregnancy. They should also be supported to lose weight and optimise their health before conception. Obese pregnant women should receive routine care supplemented by specialist services and facilities that are specific to their needs, to improve maternal and perinatal outcomes.

Targeting Notch as a Therapeutic Approach for Human Malignancies

Background: Notch is a multifaceted protein that plays a fundamental role in fetal development and tissue homeostasis by directing many cellular functions, including cell growth and differentiation, cell fate determination and regulation of stem cells maintenance. The Notch family consists of four receptors (Notch 1-4) and five ligands (Jagged1-2 and Delta-like 1-3-4) widely expressed in human tissues. Given the crucial contribution of Notch signaling in many physiological processes, it is not surprising that a variety of human malignancies is characterized by a dysregulation of one or more components of this pathway.

Methods: In this review, we are going to provide a broad overview on the role of Notch pathway in solid and hematological malignancies and a survey on possible Notch-directed therapeutic strategies.

Results: We present the most recent findings indicating that Notch signaling dysregulation in human cancers may be due to genetic and epigenetic alterations or to the interactions with other oncogenic pathways. Furthermore, Notch activity may have an oncogenic or a tumor suppressor effect. Finally, we describe the latest preclinical and clinical studies concerning the different pharmacological approaches targeting Notch.

Conclusion: The provided evidence confirms the importance of Notch pathway in human malignancies indicating that a strong rationale exists for the development of a Notch-tailored therapy.

Medical and Dental Implications of Down Syndrome: A Review Part 1: General and Craniofacial Characteristic

Down syndrome (DS) is a genetic disorder characterized by the presence of three chromosomes instead of two, specifically chromosome No. 21. The special needs status of DS individuals makes them more prone to several medical conditions such as congenital heart disease, gastrointestinal tract anomalies, immunodeficiency, visual impairment, skeletal defects, audiological dysfunction, seizures, acute leukaemia and thyroid disorders. A thorough knowledge of the unusual medical and orofacial abnormalities and their implications is crucial for a successful dental preventive and treatment planning. This paper provides an updated review of DS definition, etiology, epidemiology, medical problems and dentofacial abnormalities.

Future Targets in Endothelial Biology: Endothelial Cell to Mesenchymal Transition

Endothelial to mesenchymal transition (EndMT) is a poorly understood phenomenon that results in normal endothelial cells acquiring a mesenchymal phenotype. EndMT has been observed in a number of pathological conditions, from cancer to fibrosis to cardiovascular disease and the process itself may play an important mechanistic role in the development of these disease states.

Ovarian Stimulation, Intrauterine Insemination, Multiple Pregnancy and Major Congenital Malformations: A Systematic Review and Meta- Analysis- The ART_Rev Study

Introduction: Multiple pregnancies are a recognized adverse effect of assisted reproductive technologies; nevertheless, there is no consensus on the incremental risk associated with the ovarian stimulation (OS) used alone and intrauterine insemination (IUI). The relationship between OS and IUI and the risk of major congenital malformations (MCM) is unclear.

Objective: To summarise the literature and evaluate the risk of multiple pregnancy and MCM associated with OS used alone and IUI used with or without OS compared to natural conception (spontaneously conceived infants without any type of fertility treatments).

Methods: We carried out a systematic review to identify published papers between 1966 and 2014 in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials. We included observational studies and randomized clinical trials related to the risk of multiple pregnancies and MCM conceived following OS alone or IUI compared to natural conception (spontaneously conceived infants without any fertility treatments). The quality of the included studies was evaluated using The Cochrane Collaboration’s tool for assessing risk of bias for RCTs and the Newcastle–Ottawa Scale for observational studies.

Results: There were 63 studies included in this review. Our systematic review suggests that the use of any OS alone was associated with an increased risk of multiple pregnancy compared to natural conception (pooled RR 8.80, 95% CI 5.09- 15.20; p= 0.000; 9 studies). Similar increases in the risk of multiple pregnancies were observed following clomiphene citrate used without assisted reproductive technologies. Compared to natural conception, the use of IUI with or without OS was associated with an increased risk of multiple pregnancy (pooled RR 9.73, 95% CI 7.52 -12.60; p= 0.000; 6 studies). Compared to natural conception, the use of any OS alone was associated with an increased risk of any MCM (RR pooled 1.18, 95%CI 1.03-1.36; 11 studies), major musculoskeletal malformations (pooled RR 1.48, 95%CI 1.21-1.81; 7 studies), and malformations of the nervous system (pooled RR 1.73, 95%CI 1.15-2.61; 6 studies). Compared to natural conception, the use of IUI was associated with an increased risk of any MCM (pooled RR 1.23, 95%CI 1.10-1.37; 10 studies), major urogenital (pooled RR 1.52, 95%CI 1.04-2.22; 7 studies), and musculoskeletal malformations (pooled RR 1.54, 95%CI 1.20-1.98; 7 studies). The overall quality of the included studies was acceptable.

Conclusions: The increased risk of multiple pregnancy and certain types of MCM associated with the use of less invasive fertility treatments, such as OS and IUI, found in this review, highlights the importance of the practice framing. Heterogeneity in OS protocols, the combination with other fertility agents, the limited number of studies and the methodological quality differences reduce our ability to draw conclusions on specific treatment. More observational studies, assessing the risk of multiple pregnancy or MCM, as a primary outcome, using standardized methodologies, in larger and better clinically defined populations are needed.

Therapeutic Utilities of Pediatric Cardiac Catheterization

In an era when less invasive techniques are favored, therapeutic cardiac catheterization constantly evolves and widens its spectrum of usage in the pediatric population. The advent of sophisticated devices and well-designed equipment has made the management of many congenital cardiac lesions more efficient and safer, while providing more comfort to the patient. Nowadays, a large variety of heart diseases are managed with transcatheter techniques, such as patent foramen ovale, atrial and ventricular septal defects, valve stenosis, patent ductus arteriosus, aortic coarctation, pulmonary artery and vein stenosis and arteriovenous malformations. Moreover, hybrid procedures and catheter ablation have opened new paths in the treatment of complex cardiac lesions and arrhythmias, respectively. In this article, the main therapeutic utilities of cardiac catheterization in children are discussed.

Human Induced Pluripotent Stem Cells for Inherited Cardiovascular Diseases Modeling

Cardiovascular cells derived from patient specific induced Pluripotent Stem Cell (iPSC) harbor gene mutations associated with the pathogenesis of inherited cardiac diseases and congenital heart diseases (CHD). Numerous reports have demonstrated the utilization of human induced Pluripotent Stem Cell (hiPSC) to model cardiac diseases as a means of investigating their underlying mechanisms. So far, they have been shown to investigate the molecular mechanisms of many cardiac disorders, such as long-QT syndrome (LQT), catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), LEOPARD syndrome (LS), arrhythmogenic cardiomyopathy (ACM), Friedreich ataxia (FRDA), Barth syndrome (BTHS), hypoplastic left heart syndrome (HLHS), Marfan syndrome (MFS) and other CHD. This article summarizes the growing body of research related to modeling various cardiac diseases using hiPSCs. Moreover, by reviewing the methods used in previous studies, we propose multiple novel applications of hiPSCs to investigate comprehensive cardiovascular disorders and facilitate drug discovery.

Management of the Low Cardiac Output Syndrome Following Surgery for Congenital Heart Disease

The purpose of this review is to discuss the management of the low cardiac output syndrome (LCOS) following surgery for congenital heart disease. The LCOS is a well-recognized, frequent post-operative complication with an accepted collection of hemodynamic and physiologic aberrations. Approximately 25% of children experience a decrease in cardiac index of less than 2 L/min/m2 within 6-18 hours after cardiac surgery. Post-operative strategies that may be used to manage patients as risk for or in a state of low cardiac output include the use of hemodynamic monitoring, enabling a timely and accurate assessment of cardiovascular function and tissue oxygenation; optimization of ventricular loading conditions; the judicious use of inotropic agents; an appreciation of and the utilization of positive pressure ventilation for circulatory support; and, in some circumstances, mechanical circulatory support. All interventions and strategies should culminate in improving the relationship between oxygen supply and demand, ensuring adequate tissue oxygenation.

Diagnostic Cardiac Catheterization in the Pediatric Population

Although the utility of diagnostic cardiac catheterization in the clinical setting has diminished over the last years, due to the emergence of noninvasive imaging modalities, such as echocardiography, magnetic resonance imaging and computed tomography, catheterization for diagnostic reasons still constitutes a valuable tool in certain parts in the workup of pediatric heart disease. As a result, awareness of the main aspects of diagnostic catheterization is of great importance for the clinical cardiologist. In this article, the main variables measured and the main actions performed during diagnostic cardiac catheterization in children are discussed.

Therapeutic Potential of N-Acetylcysteine for Wound Healing, Acute Bronchiolitis, and Congenital Heart Defects

Background: Wound healing is a composite and vital process in which devitalized tissue layers and cellular structures repair themselves. Bronchiolitis is generally prompted by respiratory syncytial virus or human metapneumovirus; this condition is an acute inflammatory injury of bronchioles. Heart problems that develop before birth are known as congenital heart defects (CHDs), and pregestational diabetes is considered a major predisposing factor of CHDs. N-Acetylcysteine (NAC) is a transformed kind of amino acid cysteine which restores the intracellular levels of the natural antioxidant glutathione when taken internally, thereby assisting the cells’ ability to diminish the damaging effects of reactive oxygen species (ROS).

Objective: In the present communication, NAC’s therapeutic potential for wound healing, acute bronchiolitis, and congenital heart defects (CHDs) is critically analyzed by reviewing its effect on the various targets of these diseases. The multifunctional nature of NAC is outlined in a review of evidence from in vitro and in vivo studies.

Conclusion: In conclusion, NAC could be used as a therapeutic agent in the treatment of wound healing, acute bronchiolitis and congenital heart defects (CHDs). The focus of future research should be the following; (1) to examine NAC clinically to be considered in the treatment of wound healing; (2) to investigate whether NAC could be used alone or with insulin to prevent CHDs in infants with pregestational diabetes; (3) to evaluate the application of NAC as a potential agent for PAH treatment.

Cardiac Chamber Volumetric Assessment Using 3D Ultrasound - A Review

When designing clinical trials for testing novel cardiovascular therapies, it is highly relevant to understand what a given technology can provide in terms of information on the physiologic status of the heart and vessels. Ultrasound imaging has traditionally been the modality of choice to study the cardiovascular system as it has an excellent temporal resolution; it operates in real-time; it is very widespread and - not unimportant - it is cheap. Although this modality is mostly known clinically as a two-dimensional technology, it has recently matured into a true three-dimensional imaging technique. In this review paper, an overview is given of the available ultrasound technology for cardiac chamber quantification in terms of volume and function and evidence is given why these parameters are of value when testing the effect of new cardiovascular therapies.

Cellular and Molecular Mechanisms of Low Cardiac Output Syndrome after Pediatric Cardiac Surgery

Several cellular and molecular mechanisms have been implicated in the development of myocardial dysfunction and low cardiac output in pediatric patients undergoing heart surgery. Ischemia- reperfusion injury with alterations in calcium homeostasis as well as mitochondrial function has been strongly related to myocyte damage and heart failure in this population. In this article, we will review the main mechanisms of postoperative cardiac dysfunction at cellular and molecular levels and the subsequent protective strategies. In addition, we will describe cellular features of the neonatal or immature myocardium and will suggest possible protective management strategies. This article addresses the first of eight topics comprising the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

Pathophysiology of Post-Operative Low Cardiac Output Syndrome

Low cardiac output syndrome frequently complicates the post-operative care of infants and children following cardiac surgery. The onset of low cardiac output follows a predictable course in the hours following cardiopulmonary bypass, as myocardial performance declines in the face of an elevated demand for cardiac output. When demand outstrips supply, shock ensues, and early recognition and intervention can decrease mortality. Multifactorial in etiology, this article will discuss the pathophysiology of low cardiac output syndrome, including myocardial depression following bypass, altered cardiac loading conditions, and inflammation driving a hypermetabolic state. Contributions from altered neurohormonal, thyroid, and adrenal axes will also be discussed. Sources included the clinical experiences of four cardiac intensivists, supported throughout by primary sources and relevant reviews obtained through PubMed searches and from seminal textbooks in the field. This article addresses the second of eight topics comprising the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

A Review of Systemic Vasodilators in Low Cardiac Output Syndrome Following Pediatric Cardiac Surgery

Following surgery for congenital heart disease, patients develop a predictable and progressive decline in cardiac output known as low cardiac output syndrome. During low cardiac output states, a compensatory response to increase systemic perfusion occurs both innately and as part of the postoperative pharmacologic support strategies intended to increase or sustain adequate oxygen delivery. The result typically involves a rise in systemic vascular resistance and heart rate. These and other responses may actually limit the ability of the recently operated heart to provide sufficient cardiac output to meet the oxygen demands of the body. In order to improve systemic oxygen delivery, clinicians have increasingly employed systemic vasodilator therapy to reduce afterload and improve ventriculoarterial coupling. This review will summarize currently utilized pharmacologic agents that promote systemic vasodilation and improve cardiac output through afterload reduction. This article addresses the fourth of eight topics comprising the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

Pharmacological manipulation of peripheral vascular resistance in special clinical situations after pediatric cardiac surgery

Pediatric cardiac surgery patients commonly suffer from alterations in vascular tone in the early post-operative period. Pharmacologic manipulation of systemic vascular resistance (SVR) can be complex in a variety of special patient situations including extremes of age, presence of left sided valvar lesions and the use of mechanical circulatory support. Familiarity with how these special circumstances alter SVR and the response to pharmacologic intervention will allow for tailored therapy and hopefully, optimized outcomes. This article addresses the eighth topic of the special issue entitled “Pharmacologic strategies with afterload reduction in low cardiac output syndrome after pediatric cardiac surgery”.

New Insights into the Surgical Management of Tetralogy of Fallot: Physiological Fundamentals and Clinical Relevance

The surgical treatment of tetralogy of Fallot can be considered as a success story in the history of congenital heart diseases. Since the early outcome is no longer the main issue, the focus moved to the late sequelae of TOF repair, i.e. the pulmonary insufficiency and the secondary adaptation of the right ventricle. This review provides recent insights into the pathophysiological alterations of the right ventricle in relation to the reconstruction of the right ventricular outflow tract after repair of tetralogy of Fallot. Its clinical relevance is documented by addressing the policy changes regarding the optimal management at the time of surgical repair as well as properly defining criteria and timing for late pulmonary valve implantation.

Role of Genetic Factors in the Pathogenesis of Radial Deficiencies in Humans

Radial deficiencies (RDs), defined as under/abnormal development or absence of any of the structures of the forearm, radial carpal bones and thumb, occur with a live birth incidence ranging from 1 out of 30,000 to 1 out 6,000 newborns and represent about one third/one fourth of all the congenital upper limb anomalies. About half of radial disorders have a mendelian cause and pattern of inheritance, whereas the remaining half appears sporadic with no known gene involved. In sporadic forms certain anomalies, such as thumb or radial hypoplasia, may occur either alone or in association with systemic conditions, like vertebral abnormalities or renal defects. All the cases with a mendelian inheritance are syndromic forms, which include cardiac defects (in Holt-Oram syndrome), bone marrow failure (in Fanconi anemia), platelet deficiency (in thrombocytopenia-absent-radius syndrome), ocular motility impairment (in Okihiro syndrome). The genetics of radial deficiencies is complex, characterized by genetic heterogeneity and high inter- and intra-familial clinical variability: this review will analyze the etiopathogenesis and the genotype/phenotype correlations of the main radial deficiency disorders in humans.

Tetralogy of Fallot and Hypoplastic Left Heart Syndrome – Complex Clinical Phenotypes Meet Complex Genetic Networks

In many cases congenital heart disease (CHD) is represented by a complex phenotype and an array of several functional and morphological cardiac disorders. These malformations will be briefly summarized in the first part focusing on two severe CHD phenotypes, hypoplastic left heart syndrome (HLHS) and tetralogy of Fallot (TOF). In most cases of CHD the genetic origin remains largely unknown, though the complexity of the clinical picture strongly argues against a dysregulation which can be attributed to a single candidate gene but rather suggests a multifaceted polygenetic origin with elaborate interactions. Consistent with this idea, genome-wide approaches using whole exome sequencing, comparative sequence analysis of multiplex families to identify de novo mutations and global technologies to identify single nucleotide polymorphisms, copy number variants, dysregulation of the transcriptome and epigenetic variations have been conducted to obtain information about genetic alterations and potential predispositions possibly linked to the occurrence of a CHD phenotype. In the second part of this review we will summarize and discuss the available literature on identified genetic alterations linked to TOF and HLHS.

Predictors of Ominous Outcome in Infants who Undergo Cardiac Surgery and Cardiopulmonary By-Pass: S100B Protein

S100B protein has been recently proposed as a consolidated marker of brain damage and death in adult, children and newborn patients. The present study evaluates whether the longitudinal measurement of S100B at different perioperative time-points may be a useful tool to identify the occurrence of perioperative early death in congenital heart disease (CHD) newborns.

We conducted a case-control study in 88 CHD infants, without pre-existing neurological disorders or other co-morbidities, of whom 22 were complicated by perioperative death in the first week from surgery. Control group was composed by 66 uncomplicated CHD infants matched for age at surgical procedure. Blood samples were drawn at five predetermined timepoints before during and after surgery.

In all CHD children, S100B levels showed a pattern characterized by a significant increase in protein’s concentration from hospital admission up to 24-h after procedure reaching their maximum peak (P<0.01) during cardiopulmonary by-pass and at the end of the surgical procedure. Moreover, S100B concentrations in CHD death group were significantly higher (P<0.01) than controls at all monitoring time-points. The ROC curve analysis showed that S100B measured before surgical procedure was the best predictor of perioperative death, among a series of clinical and laboratory parameters, reaching at a cut-off of 0.1 µg/L a sensitivity of 100% and a specificity of 63.7%.

The present data suggest that in CHD infants biochemical monitoring in the perioperative period is becoming possible and S100B can be included among a series of parameters for adverse outcome prediction.

Chemistry, Physiology, and Pharmacology of β-Adrenergic Mechanisms in the Heart. Why are β-Blocker Antiarrhythmics Superior?

Stimulation of β-adrenergic receptors in the heart is the most effective endogenous way to increase the mechanical performance of cardiac tissues to meet the requirements of a fight-or-flight situation or stress. On the other hand, sustained activation of cardiac β-receptors initiates maladaptive remodeling of the myocardium leading to cardiomyopathies and heart failure. Since both acute and chronic stimulation of β-adrenoceptors are arrhythmogenic, the application of β-receptor blockers exerts effective antiarrhytmic actions at both short and long time scale. Compared to other classes of antiarrhythmic agents, β-blockers are the class of antiarrhythmics that was shown to decrease mortality in postinfarct patients. Chemical, physiological, and pharmacological properties of the β-adrenoceptor related signaling, the role of β-1, β-2, and β-3 receptor subtypes, consequences of acute and long term β-adrenergic stimulation and the underlying proarrhythmic mechanisms, including the changes in cardiac ion currents and Ca²⁺ handling, are reviewed in this paper together with the clinical relevance of cardioprotective β-blocking therapy.

Atrial Tachycardias Occurring Late After Open Heart Surgery

Atrial tachycardias are common after open heart surgery. Most commonly these are macro-reentrant including cavotricuspid isthmus dependent atrial flutter, incisional right atrial flutter and left atrial flutter. Focal atrial tachycardias occur less frequently. The specific type of atrial tachycardia highly depends on the type of surgical incision. Catheter ablation can be very effective, however requires a thorough understanding of anatomy and surgical technique.

Atrial Macroreentry in Congenital Heart Disease

Macroreentrant atrial tachycardia is a common complication following surgery for congenital heart disease (CHD), and is often highly symptomatic with potentially significant hamodynamic consequences. Medical management is often unsuccessful, requiring the use of invasive procedures. Cavotricuspid isthmus dependent flutter is the most common circuit but atypical circuits also exist, involving sites of surgical intervention or areas of scar related to abnormal hemodynamics. Ablation can be technically challenging, due to complex anatomy, and difficulty with catheter stability. A thorough assessment of the patients status and pre-catheter ablation planning is critical to successfully managing these patients.

Congenital Heart Disease: The Crossroads of Genetics, Epigenetics and Environment

Congenital heart diseases (CHDs) are recognized as the most common type of birth malformations. Although recent advances in pre- and neonatal diagnosis as well as in surgical procedures have reduced the morbidity and mortality for many CHD, the etiology for CHD remains undefined. In non-syndromic and isolated (without a familial history or a Mendelian inheritance) forms of CHDs, a multifactorial pathogenesis with interplay between inherited and non-inherited causes is recognized. In this paper, we discuss the current knowledge of the potential molecular mechanisms, mediating abnormal cardiac development in non-syndromic and isolated CHD, including mutations in cardiac transcription factors, the role of somatic mutations and epigenetic alterations as well as the influence of gene-environment interactions. In the near future, the advent of high-throughput genomic technologies with the integration of system biology will expand our understanding of isolated, non-syndromic CHDs for their prevention, early diagnosis and therapy.

The Role of Beta-Blocker in Heart Failure in Adults with Congenital Heart Disease

Thanks to the enormous progress in the field of cardiac surgery and paediatric cardiology since the mid of 20th century, more and more children with congenital heart defects reach the adulthood. This on the other hand encounter physician and patients various problems due to late complications after the heart surgery like congestive heart failure, arrhythmia and sudden death. One of the challenging area is the medical management of heart failure in these patients with complex anatomy and hemodynamics. The lack of evidence of the effectiveness of the anti congestive medications in this population in from of large randomized controlled trials, makes it difficult to establish universally accepted therapy guidelines.

In this article we will review the evidence of the beta-blockers in heart failure in patients with congenital heart disease. Also we will discuss the mechanisms of heart failure in this patient's cohort and will review the literature with respect to the use of neurohormonal antagonists in congenital heart disease. There is an urgent need to initiate well-designed clinical trials to prove if the positive results of neurohormonal blockade in acquired heart failure in adults can be translated in patients with congenital heart disease.

Editorial (Thematic Issue: The Long Way to a Successful Medical Therapy of Heart Failure with Beta-blockers in Children with Heart Disease)

Heart failure remains the main cause of death in children with heart disease. In USA and Europe hospital mortality of children with heart failure is about 7% of children, nearly twice as high as in adults. In this review a group of authors report about their experience with beta-blockers in childhood heart failure. Most of them start to treat children with severe heart failure at a time - 20 years ago - when beta blockers seem to be contraindicated in this situation. The physicians and their patients and/or parents all are aware of the risk of this decision. However, unproven medical therapies for heart failure are the most important therapeutical dilemma in pediatric cardiology. The authors carefully observed a highly selected group of patients with the highest risk to die and had the patience to wait for the longtime follow up. Today - based upon this experience –we know that beta blockers are safe and may save the lives of many children with heart disease all over the world. Together with young colleagues who enthusiastically support this idea the authors now intend to break down the “wall of ignorance” for this promising therapy in pediatric cardiology.

Editorial (Thematic Issue: Cardiovascular Drug Therapy in Paediatric Age: From Metabolomics to Clinical Practice)

In adult patients, cardiovascular drugs are widely administered in the treatment of numerous diseases. The indications and doses are strictly codified by international Guidelines, which are periodically updated by the American and European Societies of Cardiology. In paediatric patients, however, the situation is substantially different. The lack of large interventional studies on the use of these compounds has led to a greater uncertainty, with a less extensive administration and more limited indications. Furthermore, some important differences in therapeutic approach for the same diseases are present between the U.S. and Europe. The purpose of this Special Issue is to review the pharmacological treatment of certain heart diseases, such as heart failure, and arterial blood pressure, which can result in both adult and pediatric patients [1, 2]. Differences and similarities have been highlighted. Regarding the differences in medical treatment for the same disease in the U.S. and Europe, it has been emphasized that the regulation of drugs is largely determined not only by scientific considerations, but also by other concerns – legal, cultural - which vary in different parts of the world. Such discrepancies are found even in the informational documents provided by pharmaceutical companies (different in USA and Europe for the same drug) and drug agencies (different between FDA and equivalent agencies in Europe). In this issue of Current Medicinal Chemistry, a specific paper is dedicated to the pharmacological treatment of the patency of ductus arteriosus in neonates, which is still a controversial issue. In fact, notwithstanding ibuprofen appears to be lesser dangerous for newborns than indomethacin, with a similar efficacy in closing the ductus; in a number of countries the latter is still administered to all preterm subjects as a prophylactic tool [3]. An unusual case report is the interesting starting point to perform an extensive literature review about the new indications of beta blockers [4]. In this respect, beta blockers, most specifically propranolol, have serendipitously been shown to induce involution of infantile hemangiomas. Mechanisms of action, target doses, formulation, contraindications and cardiovascular monitoring for beta blockers have been analyzed as well. It has recently been demonstrated that preterm birth is negatively associated with an early onset of cardiovascular diseases. Cardiovascular mortality is higher among former preterm adults than those born at term. This condition is referred to as cardiovascular perinatal programming. Metabolomics, a new and promising technique which allows the systematic study of the complete set of metabolites in a biological sample, has been recently applied to the identification of a possible future cardiovascular system involvement in subjects born preterm. Based on these premises, the purpose of the last review was to analyse the relationship between impaired growth during intrauterine life and adult cardiovascular disease risk and death [5].

A PHACES Syndrome Unmasked by Propranolol Interruption in a Tetralogy of Fallot Patient: Case Report and Extensive Review on New Indications of Beta Blockers

Infantile hemangiomas (IHs) are the most common benign tumors of infancy and usually they don't require specific therapy. In 10-20% of cases IHs are able to generate complication and medical/surgical intervention is needed. For many decades standard treatment consisted in oral or intralesional corticosteroids until Leaute-Labreze and colleagues published the first report on the efficacy of propranolol for cutaneous infantile hemangiomas in 2008. IHs can be sometimes part of complex syndrome. Here we report the case of a patient with tetralogy of Fallot operated at 5 month of age who stopped propranolol treatment for hypoxic spells and unusually developed facial and subglottic IHs configuring the diagnosis of PHACES syndrome (posterior fossa brain malformations, hemangioma, arterial anomalies, cardiac defects and/or aortic coarctation, ocular anomalies and sternal defects). To our knowledge this is the first report in the international literature of a delayed appearance of an infantile hemangioma involving the skin and the airways (PHACES syndrome). The pathophysiological explanation relies on the mechanism of action of propranolol which seems to act initially with vasoconstriction, down-regulating proangiogenetic factors and inducing endothelial cell apoptosis. Many decades since their introduction β-blockers are useful in a growing group of diseases. The pleiotropic effect of β-adrenoceptors antagonists is not yet deeply understood, residing in neurohormonal regulation systems and angiogenesis and proving to be an effective treatment from cardiovascular to oncological illnesses.

Neurovascular Complications of Ovarian Hyperstimulation Syndrome (OHSS): From Pathophysiology to Recent Treatment Options

Ovarian hyperstimulation syndrome (OHSS) is a severe iatrogenic complication of ovulation induction, which has a very serious impact on the patient’s health, as it is often associated with a high morbidity and mortality risk. Indeed, patients classified as having severe OHSS presented with liquid imbalance signs (such as rapid weight gain, tense ascites, respiratory difficulty and progressive oliguria), which are related to the fluid shift from the intravascular space to third space compartments subsequent to an increased capillary permeability. In this way, cardiovascular system findings include decreased intravascular volume, decreased blood pressure, decreased central venous perfusion, and compensatory increased heart rate and cardiac output with arterial vasodilation might be found concomitantly. Notwithstanding that venous thromboembolic phenomena are a possible complication in advanced phases of OHSS, arterial ischemia involving the cerebral circulation is a rare but recently reported problem. The pathogenesis of thromboembolism in OHSS is not fully understood, even though hemoconcentration and blood hyperviscosity seem to play a role in developing thrombotic changes into both venous and arterial system. Interestingly, the presence of cardiac abnormalities in combination with inherited or acquired hypercoagulable state seems to increase the risk of cerebral infarct in these subjects, as recently shown by our group. This review is aimed at investigating the pathomechanism and the management of neurovascular complications related to OHSS, including new treatment options.

Variations and Abnormalities of Major Thoracic Vascular Structures

Purpose: To determine the variations and abnormalities of major thoracic vascular structures in patients exposed to thoracic examination via computerized tomography with 64 detectors.

Materials and Methods: In this retrospective study, 2,479 patients who underwent thoracic computed tomography between May 2006 and October 2007 in the Radiation Department at Dicle University’s School of Medicine were examined. Of these patients, 1,389 were male and 1,090 were female. No variations or abnormalities were detected in 1,588 of the patients.

Results: In 1,588 out of 2,479 patients (64.1%), no abnormalities or variations were detected. The most frequently detected variations occurred in the brachiocephalic trunk and the sole root point of the carotid artery from the aorta; these variations were detected in 838 (33.8%) patients.

In 74 of the 2,479 patients (3.0%) examined, it was found that the left vertebral artery directly initiated from the arch of the aorta. In addition, in 33 patients, the right brachiocephalic trunk and left major carotid artery initiated from the aorta as a single root.

Conclusion: Via multi-slice CT, it is possible to detect variations and abnormalities of major thoracic vascular structures; therefore, there is no need for extra diagnostic invasive digital subtraction angiography.

Fragmented ECG as a Risk Marker in Cardiovascular Diseases

Various noninvasive tests for risk stratification of sudden cardiac death (SCD) were studied, mostly in the context of structural heart disease such as coronary artery disease (CAD), cardiomyopathy and heart failure but have low positive predictive value for SCD. Fragmented QRS complexes (fQRS) on a 12-lead ECG is a marker of depolarization abnormality. fQRS include presence of various morphologies of the QRS wave with or without a Q wave and includes the presence of an additional R wave (R’) or notching in the nadir of the R’ (fragmentation) in two contiguous leads, corresponding to a major coronary artery territory. fQRS represents conduction delay from inhomogeneous activation of the ventricles due to myocardial scar. It has a high predictive value for myocardial scar and mortality in patients CAD. fQRS also predicts arrhythmic events and mortality in patients with implantable cardioverter defibrillator. It also signifies poor prognosis in patients with nonischemic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy and Brugada syndrome. However, fQRS is a nonspecific finding and its diagnostic prognostic should only be interpreted in the presence of pertinent clinical evidence and type of myocardial involvement (structural vs. structurally normal heart).

Medical Treatment of Aortic Aneurysms in Marfan Syndrome and other Heritable Conditions

Thoracic aortic aneurysms can be triggered by genetic disorders such as Marfan syndrome (MFS) and related aortic diseases as well as by inflammatory disorders such as giant cell arteritis or atherosclerosis. In all these conditions, cardiovascular risk factors, such as systemic arterial hypertension, may contribute to faster rate of aneurysm progression. Optimal medical management to prevent progressive aortic dilatation and aortic dissection is unknown. β-blockers have been the mainstay of medical treatment for many years despite limited evidence of beneficial effects. Recently, losartan, an angiotensin II type I receptor antagonist (ARB), has shown promising results in a mouse model of MFS and subsequently in humans with MFS and hence is increasingly used. Several ongoing trials comparing losartan to β -blockers and/or placebo will better define the role of ARBs in the near future. In addition, other medications, such as statins and tetracyclines have demonstrated potential benefit in experimental aortic aneurysm studies. Given the advances in our understanding of molecular mechanisms triggering aortic dilatation and dissection, individualized management tailored to the underlying genetic defect may be on the horizon of individualized medicine. We anticipate that ongoing research will address the question whether such genotype/pathogenesis-driven treatments can replace current phenotype/syndromedriven strategies and whether other forms of aortopathies should be treated similarly. In this work, we review currently used and promising medical treatment options for patients with heritable aortic aneurysmal disorders.

The Spatial QRS-T Angle: Implications in Clinical Practice

The ventricular gradient (VG) as a concept was conceived in the 1930s and its calculation yielded information that was not otherwise obtainable. The VG was not utilized by clinicians at large because it was not easy to understand and its computation time-consuming. The contemporary spatial QRS-T angle is based on the concept of the VG and defined as its mathematical and physiological integral. Its current major clinical use is to assess the cardiac primary repolarization abnormalities in 3-dimensional spatial vectorial plans which are normally untraced in the presence of secondary electrophysiological activity in a 2-dimensional routine electrocardiogram (ECG). Currently the calculation of the spatial QRS-T angle can be easily computed on the basis of a classical ECG and contributes to localization of arrhythmogenic areas in the heart by assessing overall and local heterogeneity of the myocardial ventricular action potention duration. Recent population-based studies suggest that the spatial QRS-T angle is a dominant ECG predictor of future cardiovascular events and death and it is superior to more conventional ECG parameters. Its assessment warrants consideration for intensified primary and secondary cardiovascular prevention efforts and should be included in everyday clinical practice. This review addresses the nature and diagnostic potential of the spatial QRS-T angle. The main focus is its role in ECG assessment of dispersion of repolarization, a key factor in arrythmogeneity.

Advanced Echocardiographic Imaging of the Congenitally Malformed Heart

There have been significant advancements in the ability of echocardiography to provide both morphological and functional information in children with congenitally malformed hearts. This progress has come through the development of improved technology such as matrix array probes and software which allows for the off line analysis of images to a high standard. This article focuses on these developments and discusses some newer concepts in advanced echocardiography such is multi-planar reformatting [MPR] and tissue motion annular displacement [TMAD].

Our aim is to discuss important aspects related to the quality and reproducibility of data, to review the most recent published data regarding advanced echocardiography in the malformed heart and to guide the reader to appropriate text for overcoming the technical challenges of using these methods. Many of the technical aspects of image acquisition and post processing have been discussed in recent reviews by the authors and we would urge readers to study these texts to gain a greater understanding [1]. The quality of the two dimensional image is paramount in both strain analysis and three dimensional echocardiography. An awareness of how to improve image quality is vital to acquiring accurate and usable data.

Three dimensional echocardiography (3DE) is an attempt to visualise the dynamic morphology of the heart. Although published media is the basis for theoretical knowledge of how to practically acquire images, electronic media [eg.www.3dechocardiography.com] is the only way of visualising the advantages of this technology in real time.

It is important to be aware of the limitations of this technology and that much of the data gleaned from using these methods is at a research stage and not yet in regular clinical practice.

Cardioprotection Techniques: Preconditioning, Postconditioning and Remote Con-ditioning (Basic Science)

Ischemic heart disease (IHD) is the leading cause of death and disability worldwide. The major pathological consequences of IHD arise from the detrimental effects of acute ischemia-reperfusion injury (IRI) on the myocardium. Therefore, in order to improve clinical outcomes in patients with IHD, novel therapeutic strategies are required to protect the myocardium from acute IRI and preserve cardiac function (cardioprotection). In this regard, endogenous cardioprotective strategies such as ischemic preconditioning (IPC), ischemic postconditioning (IPost) and remote ischemic conditioning (RIC) may provide novel approaches for protecting the heart in clinical settings in which the patient experiences acute myocardial IRI. In this review article, we provide an overview of these endogenous cardioprotective strategies with respect to the pre-clinical experimental literature, exploring their major characteristics and underlying signaling mechanisms. The application of these therapeutic strategies in the clinical setting for potential patient benefit is reviewed in another article in this special issue.

Safety of Anti-TNF Alpha Agents in the Pregnant Psoriatic Patient

Psoriasis is a chronic, often difficult to control condition which accounts for significant morbidity worldwide. The United States Food and Drug Administration (FDA) approved multiple TNF alpha blockers in the 21st century for the treatment of psoriasis. These agents provide an alternative treatment approach for those with moderate to severe psoriasis, who fail to respond adequately to traditional therapies. The increasing use of these agents in women of childbearing age raises questions concerning their safety in the pregnant psoriatic patient. A review of case reports and registry data was performed on the outcomes of pregnancies in psoriatic patients and in those with other inflammatory conditions who were exposed to these biologic agents. To date, it remains inadvisable to continue pregnant patients on these medications if alternative, well-established therapies are effective. However, for those women unable to tolerate alternative treatments or who are inadvertently exposed to TNF-alpha inhibitors during pregnancy, the published data do not indicate an increased risk of fetal malformation or a need to recommend pregnancy termination. Transplacental transfer of these drugs is greatest during the last two trimesters of pregnancy, which may result in persistent detectable drug levels in the newborn infant. If a fetus is exposed to TNF alpha blockers toward the end of pregnancy, then live vaccinations in these infants should be delayed until drug levels in infant serum are undetectable, or for at least 6-7 months if levels cannot be measured.

Normal Ventricular Functional Reference Parameters on Magnetic Resonance Imaging in Healthy Children

We aimed to research right and left ventricular functional reference values on magnetic resonance imaging in healthy children. Echocardiographically normal sixty healthy children were performed cardiac MRI between January 2009 and June 2010. Biventricular volumes, left myocardial mass, septal thickness, diameter of the ascending aorta and main pulmonary artery were calculated. It was investigated whether there was a difference or not between ventricular volumes and sexes, and the relationship age and body surface area with functional parameter results. The minimum, maximum, mean values of every parameters were determined in all children, boys, girls, and in the groups of age 8-12 and 13-18. There was a statistically significant difference in the left ventricular end-systolic diameter results between the sexes. There were statistical significant differences in parameter results except biventricular cardiac output and ejection fraction, right ventricular end-diastolic and end-systolic diameter between the age groups when the children were grouped as 8-12 and 13-18 years by ignoring their sexes. When it was compared the mean value of normal functional parameters after normalized to body surface area; the mean values of all parameters were higher in males, but there was a significant difference in only between right ventricular end-diastolic volumes. Biventricular cardiac output mean values were higher in the age group of 8-12 years.

Consequently, we determined the mean, minimum, and maximum values of normal ventricular volumes, left myocardial mass, septal thickness, diameter of the ascending aorta and main pulmonary artery in the 8-18 age group to be used as a reference in all diagnostic and follow-up stage.

Intrauterine Effects of Impaired Lipid Homeostasis in Pregnancy Diseases

Lipids are crucial structural and bioactive components that sustain embryo, fetal and placental development and growth. Intrauterine development can be disturbed by several diseases that impair maternal lipid homeostasis and lead to abnormal lipid concentrations in the fetal circulation. Deficiency in essential fatty acids can lead to congenital malformations and visual and cognitive problems in the newborn. Either deficient mother-to-fetus lipid transfer or abnormal maternal- fetal lipid metabolism can cause fetal growth restriction. On the other hand, excessive mother-to-fetus fatty acid transfer can induce fetal overgrowth and lipid overacummulation in different fetal organs and tissues. The placenta plays a fundamental role in the transfer of lipid moieties to the fetal compartment and is affected by maternal diseases associated with impaired lipid homeostasis. Postnatal consequences may be evident in the neonatal period or later in life. Indeed, both defects and excess of different lipid species can lead to the intrauterine programming of metabolic and cardiovascular diseases in the offspring. This review summarizes the lipid impairments induced by different pathologies, including placental insufficiency, malnutrition, obesity and diabetes, and their consequent developmental defects.

The Right Ventricle: Biologic Insights and Response to Disease: Updated

Despite ample evidence that right ventricular function is a critical determinant of the clinical response to a spectrum of cardiovascular diseases, there has been only a limited analysis of the unique and distinguishing physiologic properties of the RV under normal circumstances and in response to pathologic insults. This knowledge deficit is increasingly acknowledged. This review highlights some of these features and underscores the fact that rational therapy in RV failure needs to acknowledge its unique physiology and ought to be chamber specific. That is proven therapies for LV dysfunction do not necessarily apply to the RV. The updated version of this review now acknowledges recent advances in the understanding of metabolic, inflammatory and gender-specific influences on the right ventricle.

Clinical and Pharmacological Aspects of Immunoprophylaxis for Respiratory Syncytial Virus Infection in High-Risk Infants

Respiratory syncytial virus (RSV) is the leading cause of respiratory tract infection in infants and young children throughout the world. Although preterm birth has been considered for years the major risk factor for severe disease and hospitalization, recent findings indicate that prematurity is not a necessary condition, but one of the independent risk factors for severe RSV infection, together with chronic lung diseases, congenital heart disease and immunodeficiency. Furthermore, over 50% of infants hospitalized for RSV infections during the first year of life are healthy, full-term newborns, suggesting that other environmental and individual factors may be involved. Unfortunately, there is still no specific therapy against RSV infection and therefore prophylactic measures seem to be the only intervention to avoid disease complications. No safe and effective RSV vaccine is available for the prevention of serious RSV infection. Therefore, in addition to hygienic measures, the only approach is passive immunoprophylaxis with humanized monoclonal anti-RSV antibodies, such as palivizumab that have been developed for clinical use. Because of the high cost of these antibodies, a better definition of the individual risk profile for severe RSV infection and timing of administration is needed for optimal effectiveness and careful use of limited health care resources.

In this article, we have reviewed the clinical and pharmacological aspects of immunoprophylaxis with monoclonal antibodies for preventing RSV infection in high-risk infants.

The Patient with a Single Cardiac Ventricle

Patients born with a single cardiac ventricle are one of the most complex and challenging subgroups of congenital heart disease to manage, from their initial diagnosis to their long-term post-surgical sequelae. Advances in antenatal detection, operative techniques, and post-operative strategies have led to improved outcomes over the past two decades, yet morbidity and mortality remain high relative to other congenital heart lesions. Optimal management and outcome depend in part on a thorough understanding of the anatomy and physiology unique to these infants by all caregivers that may be involved including neonatologists, primary care pediatricians, emergency medicine physicians, and pediatric intensivists. This review will discuss in detail the course of these infants, from their birth through to their three stage surgical palliations and beyond. This review will also highlight many of the most recent medical and surgical innovations available to these infants.

Repair of Dilated Aortic Root and Sinotubular Junction Using a Stabilizer Ring

Aortic root aneurysm and dissection are potentially life-threatening conditions that involve a structural weakness of the aortic wall. Management of aortic root aneurysm (with or without aortic insufficiency) has recently been the subject of much scholarly discussion which resulted in some modifications. The current trend is a valve-sparing root repair or replacement as well as preserving or restoring the diameter of the aortic annulus and sinutubular junction. This manuscript reviews the etiology and diagnosis of aortic root aneurysm or dilated aortic annulus as well as a novel treatment approach. A newly patented apparatus that restores and repairs the aortic annulus and sinotubular junction is reviewed.

Genome-wide Analysis of Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are heterogeneous hematopoietic neoplasms characterized by ineffective hematopoiesis and a risk for progression to acute myeloid leukemia. A number of cytogenetic changes have been described that are characteristic to MDS and of clinical relevance; the specific gene targets of these alterations were largely unknown. On the other hand, over the past decade, technologies have been dramatically improved to enable high-throughput analysis of entire MDS genomes, leading to identification of frequent copy number neutral events and a number of novel gene targets implicated in the pathogenesis of MDS. In this review, we briefly overview the recent progress in the genetics of MDS, focusing on the newly identified gene targets in MDS.

Mechanical Ventilation Following Cardiac Surgery in Children

The application of positive pressure mechanical ventilation can result in complex changes in pulmonary and cardiovascular physiology. These cardiopulmonary interactions are particularly important in pediatric patients undergoing surgery for repair or palliation of congenital cardiac defects. In this article, we review the various effects of mechanical ventilation on right and left ventricular preload, afterload and contractility. We also address specific clinical scenarios, such as mechanical ventilation of the uncomplicated patient following cardiac surgery, ventilation of patients with delayed sternal closure, the Norwood procedure, bidirectional and total cavopulmonary anastomoses and patients with right ventricular diastolic dysfunction.

Roles of Connexins in Atherosclerosis and Ischemia-Reperfusion Injury

Connexins are members of a large family of transmembrane proteins that oligomerize to form connexons or hemichannels, and connexons of adjacent cells dock to make gap junction channels. These channels allow the exchange of ions and small metabolites between the cytosol and extracellular space, or between the cytosols of neighbouring cells. Connexins are important in cardiovascular physiology; they support conducted vascular responses and allow for coordinated contraction of the heart. Four main connexins are expressed in the cardiovascular system: Cx37, Cx40, Cx43 and Cx45. Their expression pattern is not uniform and depends on intrinsic and environmental factors. Significant changes in the expression pattern, the cellular localization and the opening of connexin channels have been described during the development of atherosclerosis and after ischemia and reperfusion. In this review, we provide an overview of the roles of different connexins in these pathologies.

Propranolol Safety Profile in Children

Data regarding the use of propranolol in pediatrics are limited despite its widespread use in adults. Since 1984, Propranolol has been used for the prevention of portal hypertensive hemorrhage in pediatric patients. Recently it has been also used for the managemnet of hemangiomas in addition to other indications. The purpose of this review is to evaluate safety and efficacy of propranolol use in the pediatric population, highlighting the most important reported side effects, warnings and precautions.

Current Pharmacologic Management of Pediatric Heart Failure in Congenital Heart Disease

Pharmacologic therapy represents the mainstay of treatment for heart failure in children. However, medical therapy for this population is not widely standardized. This is mainly due to the heterogeneity of potential etiologies, the specific challenge of patients with univentricular physiology and the lack of evidence-based prospective randomized clinical trials in pediatric patients. In fact, most current strategies are based largely on extrapolated data from adult studies. Although the classic drugs for heart failure i.e. diuretics, angiotensin-converting enzyme inhibitors, β-blockers and cardiac glycosides, still play a major role in the treatment of pediatric heart failure, newer alternative therapies such as levosimendan and nesiritide are increasingly utilized with promising early results. A systematic literature search of PubMed and MEDLINE databases using relevant terms was performed. All clinical trials and relevant manuscripts about the current pharmacologic treatment of heart failure in the pediatric population were reviewed. New drugs such as levosimendan and nesiritide and the treatment of single-ventricle patients were also included.

Clinical and Genetic Features of Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) Syndrome

WHIM syndrome is a dominantly inherited primary immunodeficiency disorder representing the first identified example of human disease caused by mutations in the gene encoding for the chemokine receptor CXCR4. Pathogenesis is mediated by CXCR4 hyperfunction, leading to increased responsiveness to its unique ligand CXCL12 (also known as SDF-1). The altered CXCR4/CXCL12 interaction likely impairs cellular homeostasis and trafficking, resulting in immunological dysfunctions. The acronym WHIM resumes the main features of the syndrome: Warts, Hypogammaglobulinemia, Infections and Myelokathexis, which is abnormal retention of mature neutrophils in the bone marrow. WHIM patients suffer from recurrent bacterial infections since childhood and manifest a specific susceptibility to HPV infections. Hematological findings include neutropenia, lymphopenia and hypogammaglobulinemia. Because of the rarity of the disease and the heterogeneity in clinical presentation, diagnosis is often delayed. In the majority of patients, the phenotype is incomplete at the onset and WHIM syndrome is not suspected. Early identification may improve clinical and therapeutic management. Symptomatic treatments include G-CSF, substitutive immunoglobulins and antibiotic prophylaxis. A new therapeutic strategy might include the potent inhibitor of CXCR4 function plerixafor (Mozobil), as an agent specifically targeting the molecular defect in order to attenuate the phenotypic manifestations of the syndrome.

Structural Chromosome Abnormalities Associated with Obesity: Report of Four New Subjects and Review of Literature

Obesity in humans is a complex polygenic trait with high inter-individual heritability estimated at 40 – 70%. Candidate gene, DNA linkage and genome-wide association studies (GWAS) have allowed for the identification of a large set of genes and genomic regions associated with obesity. Structural chromosome abnormalities usually result in congenital anomalies, growth retardation and developmental delay. Occasionally, they are associated with hyperphagia and obesity rather than growth delay. We report four new individuals with structural chromosome abnormalities involving 10q22.3-23.2, 16p11.2 and Xq27.1-q28 chromosomal regions with early childhood obesity and developmental delay. We also searched and summarized the literature for structural chromosome abnormalities reported in association with childhood obesity

Impact of Pulmonary Vascular Resistances in Heart Transplantation for Congenital Heart Disease

Congenital heart disease is one of the major diagnoses in pediatric heart transplantation recipients of all age groups. Assessment of pulmonary vascular resistance in these patients prior to transplantation is crucial to determine their candidacy, however, it is frequently inaccurate because of their abnormal anatomy and physiology. This problem places them at significant risk for pulmonary hypertension and right ventricular failure post transplantation. The pathophysiology of pulmonary vascular disease in children with congenital heart disease depends on their pulmonary blood flow patterns, systemic ventricle function, as well as semilunar valves and atrioventricular valves structure and function. In our review we analyze the pathophysiology of pulmonary vascular disease in children with congenital heart disease and end-stage heart failure, and outline the state of the art pre-transplantation medical and surgical management to achieve reverse remodeling of the pulmonary vasculature by using pulmonary vasodilators and mechanical circulatory support.

Heart Transplantation in Biventricular Congenital Heart Disease: Indications, Techniques, and Outcomes

Heart transplantation is an accepted therapeutic modality for end-stage congenital heart disease for both biventricular and univentricular anomalies. Many transplant centers have pushed the limits of transplantation to include patients with high pulmonary vascular resistance, high panel reactive antibodies, positive cross-matches, and ABOincompatibility. Excellent results have been possible, particularly with the development of improved diagnostic and therapeutic algorithms to prevent and treat rejection, infection, and post-transplant lymphoproliferative disease. Late graft failure and chronic rejection remain vexing problems. The vast majority of patients with biventricular congenital heart disease have undergone prior cardiac surgical procedures. Indications for transplantation in this subgroup are primarily progressive refractory heart failure following prior cardiac surgical reconstructive procedures. Contraindications to transplantation mimic those for other forms of end-stage heart disease. A determination of pulmonary vascular resistance is important in listing patients with biventricular congenital heart disease for heart transplantation. Modifications in the implant technique are necessary and vary depending on underlying recipient anatomy. Risk factors for perioperative outcomes in patients with biventricular congenital heart disease include the need for reoperation, the degree of anatomic reconstruction necessary during the implant procedure, and the degree of antibody sensitization, in addition to a number of other recipient and donor factors. Postoperative outcomes and survival are very good but remain inferior to those with cardiomyopathy in most series. In conclusion, patients with end-stage biventricular congenital heart disease represent a complex group of patients for heart transplantation, and require careful evaluation and management to ensure optimal outcomes.

Acute Respiratory Failure in Obstetric Patients

The pregnant woman is at risk of several pregnancy-specific conditions that may cause respiratory failure, as well as many conditions that are aggravated by the pregnant state. These conditions include pulmonary edema secondary to preeclampsia, amniotic fluid embolism, ARDS due to pregnancy complications and other causes, as well as aspiration of gastric contents, venous thromboembolism and pre-existing heart disease. Management of these patients requires understanding of the altered maternal physiology and avoidance of harm to the fetus. While radiological procedures and drug therapy may compromise fetal wellbeing, the greatest risk is deterioration in the maternal condition resulting in fetal hypoxia. Little data exist to guide prolonged mechanical ventilation in the pregnant woman, but usual principles can be applied to optimize oxygenation, while avoiding maternal alkalosis. If the fetus is at a viable gestation and is at risk due to intractable maternal hypoxia, there may be a benefit to the fetus in delivery. However, delivery purely in an attempt to improve maternal oxygenation or ventilation is often not successful.

Editorial from Guest Editors [Hot Topic: Children with Congenital Heart Disease (Guest Editors: Kris De Boeck and Tony Reybrouck)]

Pulmonary Complications After Congenital Heart Surgery

Pulmonary complications are the most common causes of morbidity and mortality in the postoperative period after congenital heart surgery. In this review we discuss the diverse pathological mechanisms that contribute to these pulmonary complications. Both mechanical and gas exchange abnormalities result in increased ventilatory requirements, ICU stay and mortality. Parenchymal lung disease can be caused by a variety of conditions including nosocomial pneumonia, atelectasis and use of cardiopulmonary bypass. Direct surgical trauma to the respiratory system can result in diaphragmatic paralysis, chylothorax, subglottic stenosis or vocal cord paralysis. Disturbances in the pulmonary vasculature can also trigger complications including pulmonary embolism, plastic bronchitis and even pulmonary hypertensive crises in certain at risk populations. Close monitoring with early detection and treatment of complications often prevents prolonged ventilation and hospitalization, e.g., cases of chylothorax where early intervention is beneficial. However, the therapies used to manage some of these complications in the pediatric population are nonspecific and varied e.g., therapies for postoperative atelectasis or treatment of plastic bronchitis. There is a paucity of studies that directly address therapy for many of these complications and more randomized controlled trials in the pediatric population are needed.

Respiratory Gas Exchange During Exercise in Children with Congenital Heart Disease: Methodology and Clinical Concepts

Cardiopulmonary exercise testing (CPET) in pediatric patients differs in many aspects from the tests as performed in adults. Childrens cardiopulmonary responses during exercise testing present different characteristics, particularly indices of respiratory gas exchange (e.g. oxygen uptake, ventilation and ventilatory efficiency), which are essential in interpreting hemodynamic data. Diseases that are associated with myocardial ischemia are very rare in children. Important indications for CPET in children are the evaluation of exercise capacity and the non-invasive identification of pathologic features. In this article we will review the methodology, and clinical concepts exercise testing and interpretation of respiratory gas-exchange during exercise in children with congenital heart disease.

Interaction of the Heart and Lungs During Exercise: Physiology and Pathophysiology in Children with Congenital Heart Disease

The modern era of surgical palliation, perioperative strategies, and myocardial preservation has dramatically altered the long-term outcome for children with congenital heart disease. Even children surgically corrected for more complex heart disease are now surviving to ages where physical activity and sports participation are not only considered but encouraged by pediatric cardiologists secondary to the benefits of regular physical activity on cardiovascular risk factors. In this review, basic cardiovascular and pulmonary responses to exercise performance are reviewed. In addition, the interaction of the cardiovascular and pulmonary systems during exercise in children with simple and complex congenital heart disease is reviewed.

Long-Term Outcome of Cardio Respiratory Exercise Performance After Surgery

Cardio respiratory exercise testing provides an objective measurement of aerobic exercise capacity in patients with congenital heart disease. Many patients with congenital heart disease have decreased exercise capacity despite a lack of symptoms. Patients with simple lesions tend to have better exercise capacity than those with complex lesions, but individual variation exists. The reasons for this impairment in exercise capacity cannot be explained by ventricular dysfunction alone. Chronotropic impairment, disturbances of pulmonary function and deconditioning also play a key role. In patients with congenital heart disease, cardio respiratory exercise testing has prognostic value and could be important in deciding the need for re-interventions.

Complications of the Chest Wall and the Respiratory System After Surgery and Functional Performance

In a population of patients after successful heart surgery for congenital heart defects (CHD) might emerge noncardiac morbidities. Malfunction of the respiratory system (RS) including chest wall deformities (CWD) may represent risk for a long-term functional performance and QoL of these subjects. This review aims for the long-term (abnormal pulmonary hemodynamics prior to surgery) or short-term (e.g. thoracotomy) harmful impacts on the developing RS. CHD with redundant lung recoil may induce dramatic worsening of the mechanical properties of the RS. Despite successful repair of CHD harmful and successive adaptive processes may affect future development of the RS. Surgical treatment of CHD requires thoracic wall incision (median sternotomy or lateral thoracotomy), which currently with other perioperative impacts may represent unfavourable formation of CWD. Surprisingly, heart surgery itself does not lead either to an improvement or marked change in the severity or frequency of preoperative lung abnormalities (mostly lung volume restriction, hyperinflation, stiff lung or airway obstruction). Causes of RS dysfunction and CWD in patients after surgical repair of CHD are multifactorial. Therefore, a management of these abnormalities especially in adult and aged CHD is difficult. The early primary repair of CHD and recent interventional approaches (e.g., superior ministernotomy or usage of Amplatz occluder) may provide advantages regarding developing organ systems and prevent secondary changes of the heart and the RS. Further research should focus on individual factors in the development of CWD and postoperative respiratory changes. Long-term and/or probably permanent follow up of subjects after CHD repair is a must.

Cardiac Autonomic Nervous System in Heart Failure: Imaging Technique and Clinical Implications

The autonomic nervous system interacts in the pathophysiology of heart failure. Dysfunction of the sympathetic nervous system has been identified as an important prognostic marker in patients with chronic heart failure. At present, cardiac sympathetic nerve imaging with 123-iodine metaiodobenzylguanidine [123-I MIBG] has been employed most frequently for the assessment of cardiac sympathetic innervation and activation pattern. The majority of studies have shown that cardiac sympathetic dysfunction as assessed with 123-I MIBG imaging is a powerful predictor for heart failure mortality and morbidity. Additionally, 123-I MIBG imaging can be used for prediction of potentially lethal ventricular tachyarrhythmias in heart failure patients. At present however, the lack of standardization of 123-I MIBG imaging procedures represents an evident issue. Standardized criteria on the use of 123-I MIBG imaging will further strengthen the clinical use of 123-I MIBG imaging in heart failure patients.

Smoking and Congenital Heart Disease: The Epidemiological and Biological Link

Cigarette smoking is a powerful human germ cell mutagen and teratogen. Congenital heart defects (CHD) are the most prevalent of all birth defects and leading cause of death in the first year of life. The purpose of this article is to review the epidemiology of the impact of cigarette smoking on CHD risk as well as to discuss the potential biological mechanisms of smoking – mediated abnormal cardiac development. Although epidemiological studies of association between parental smoking and CHD are limited, biological evidence supports the concept that cigarette smoking may substantially contribute to the aetiology of CHD through induction of either male and female germ-cell mutation or interference with epigenetic pathways. Further research is needed to better define the relationship between parental smoking and the risk of heart defects as well as to assess parental – fetal gene-smoking interactions.

Arterial Duct Stenting in Congenital Heart Disease with Duct-Dependent Pulmonary Circulation

Background: Despite current trends toward early primary repair, surgical systemic-to-pulmonary artery shunt is still an invaluable palliative option in some high-risk patients with congenital heart disease and duct-dependent pulmonary blood flow. However, maintaining arterial duct patency by stent implantation has been proposed as an effective alternative to surgical palliation in neonates who are unsuitable for primary repair or in whom there is anticipated spontaneous improvement of oxygen saturation as the pulmonary vascular resistance decreases. Recent advances in technology has made arterial duct stenting a safe and feasible tool for short-term palliation of newborns and young infants with this pathophysiologic arrangement. This option might be even more advisable in low-weight newborns, who are at higher risk for surgical palliation or repair and in whom repeat stent dilatations could be effective in tailoring the pulmonary flow to the patients growth. This paper highlights history, methodology and results of this innovative and minimally-invasive palliative option. Methods and Results: Following duct morphology evaluation, the stent is chosen to completely cover the entire ductal length and is dilated to about 75% of the proposed surgical shunt. The procedure can be performed from arterial or venous approach and is successfully completed in the vast majority of cases. Procedural failure mainly depends on ductal tortuosity, typically found in complex conotruncal anomalies such as tetralogy of Fallot or pulmonary atresia with ventricular septal defect. The morbidity rate ranges from 8 to 11% and mainly consists in stent embolization or thrombosis as well as vascular access injury. The mid-term fate of the stented duct is spontaneous, slow and progressive closure within a few months. However, the stented arterial duct promotes similar and more balanced pulmonary artery growth than surgical shunt over a mid-term follow-up. Conclusions: Arterial duct stenting is a technically feasible, safe and effective palliation in congenital heart disease with duct-dependent pulmonary circulation. The stented arterial duct is less durable than conventional surgical shunt but is highly effective in promoting global and balanced pulmonary artery growth.

Transcription Factor CHF1/Hey2 Regulates Specific Pathways in Serum Stimulated Primary Cardiac Myocytes: Implications for Cardiac Hypertrophy

We have previously found that overexpression of CHF1/Hey2 in the myocardium prevents the development of phenylephrine-induced hypertrophy. To identify transcriptional pathways regulated by CHF1/Hey2, we cultured primary neonatal mouse cardiac myocytes from wild type and transgenic mice overexpressing CHF1/Hey2 and treated them with serum, a potent hypertrophic stimulus. We verified that overexpression of CHF1/Hey2 suppressed cardiac myocyte hypertrophy induced by serum and then determined transcriptional profiles by microarray hybridization. We identified and verified important downstream target genes by single gene analysis and qRT-PCR and then identified important biological processes by Gene Set Analysis using Biological Process Gene Sets from the Gene Ontology Consortium. We found that CHF1/Hey2 suppresses pathways involved in water transport, adenylate cyclase activity, embryonic eye morphogenesis, gut development and fluid transport after serum stimulation. Genes involved in protein dephosphorylation, demonstrate increased expression in myocytes overexpressing CHF1/Hey2, independent of serum treatment. Genes overexpressed prior to serum treatment are involved in regulation of transcription factor activity, nuclear protein export and steroid hormone receptor signaling. Genes overexpressed after serum treatment are involved in autophagy, apoptosis and mitochondrial biogenesis.

Mending a Broken Heart: Bioengineered Patches and Scaffolds for Cardiac Repair

Cardiovascular disease is the leading cause of morbidity and mortality in the United States, accounting for more than one third of all deaths. In heart failure patients, progressive impairment in the ability of the heart to effectively pump blood to the body is caused by adverse remodeling, scar formation and loss of cardiomyocytes. In the past two decades, new bioengineering strategies to counteract the effects of heart failure on cardiac function have shown promise in experimental models. These include the innovative use of biological substrates and polymers to develop two- and threedimensional scaffolds and cardiomyocyte patches to replace or support damaged cardiac tissue. This patent review highlights developments in this arena in the past few years, focusing on the array of starting materials, both cellular and acellular, that are used in the creation of these patches and outlines the major challenges to the field that must be addressed to turn these approaches into viable therapies.

Genetics of Congenital Heart Disease

Cardiovascular malformations are the most common type of birth defect and result in significant mortality worldwide. The etiology for the majority of these anomalies remains unknown but genetic factors are being recognized as playing an increasingly important role. Advances in our molecular understanding of normal heart development have led to the identification of numerous genes necessary for cardiac morphogenesis. This work has aided the discovery of an increasing number of monogenic causes of human cardiovascular malformations. More recently, studies have identified single nucleotide polymorphisms and submicroscopic copy number abnormalities as having a role in the pathogenesis of congenital heart disease. This review discusses these discoveries and summarizes our increasing understanding of the genetic basis of congenital heart disease.

Anti-TNF Antibody Therapy for Inflammatory Bowel Disease During Pregnancy: A Clinical Review

The incidence of inflammatory bowel disease (IBD; Crohn ’ s disease, ulcerative colitis) is highest during the peak reproductive years, hence the increased concern with the safety of IBD drugs during pregnancy. Over the past 11 years, anti-TNF-α antibody therapy has emerged as a treatment approach for refractory IBD patients who have failed to achieve or maintain remission with corticosteroids and immunomodulator agents. The TNF-α inhibitors (anti-TNFs; infliximab, adalimumab, certolizumab pegol) have proven successful in inducing and maintaining remission of moderateto- severe IBD, but recommendations for the use of these compounds during pregnancy have lacked consensus. Balanced against the potential risk of these drugs on the fetus is the well-established fact that high disease activity has been found to poorly affect pregnancy outcomes in IBD, and the potential use of anti-TNF agents may control disease flare and severity during pregnancy. Concerns regarding the effect of anti-TNFs on the pregnancy and fetus have been assuaged by registry data which has demonstrated an overall positive safety record. Both the U.S. Food and Drug Administration and the European Crohns and Colitis Organization categorize anti-TNF agents as safe during pregnancy. New knowledge regarding the physiologic timing of placental transfer of therapeutic antibody subclasses and pegylated antibody fragments from the mother into the fetus has also helped to allay concerns. This review will examine the present state of knowledge regarding the use of anti-TNFs in pregnant women with IBD.

Troponin in Newborns and Pediatric Patients

Cardiac troponin represents a sensitive and specific marker of ischemic myocardial damage in adult and neonatal populations. Cardiac function in neonates could be influenced by the severity of respiratory distress and its ventilatory management. This short review summarizes the experimental and clinical evidence regarding the role of cardiac troponin in assessment of cardiac function, in following findings: neonatal intensive care, respiratory distress syndrome, asphyxia, congenital heart disease and post cardiac surgery.

Mechanistic Approach to Understanding Psychosis Risk in Velocardiofacial Syndrome

Velocardiofacial syndrome (VCFS), the most common chromosomal microdeletion syndrome in humans, is caused by a heterozygous deletion of chromosome 22q11.2. With an incidence of 1/2000-1/6000, it is associated with a vast array of abnormalities such as congenital heart disease, palatal dysfunction, immune deficiency, hypoparathyroidism and cognitive impairment. In addition to the numerous medical and developmental problems, retrospective studies in the last decade have reported a markedly high incidence (∼ 40%) of schizophrenia, bipolar disorder and depression in late adolescence and adulthood in individuals with the deletion. This risk of schizophrenia spectrum disorders in VCFS approaches that of a monozygotic twin of a patient with schizophrenia, or that of an individual with both parents with schizophrenia. These observations provide the strongest known link between psychosis and an identified genetic condition. In recent years, schizophrenia has been viewed as a neurodevelopmental disorder. This neurodevelopmental theory suggests that neurocognitive and neuroanatomical abnormalities often precede the development of overt psychosis. Genetic factors are thought to be contributory to these neurodevelopmental anomalies that are thought to ultimately culminate in schizophrenia spectrum disorders. However, gene identification has largely been unsuccessful, due to the complex nature of the inheritance of the genes and the probability that multiple genes of individual modest effect are involved. Identification of predisposing genetic markers would enable identification of a high-risk group that would enable the prospective study of the factors contributing to psychosis. The presence of a known genetic abnormality that causes neurodevelopmental deficits, confers a high-risk of psychosis and since the signs, symptoms and response to treatment of schizophrenia secondary to VCFS are thought to be no different to that in primary schizophrenic illness, it has been suggested that VCFS represents an ideal model for the study of the factors contributing to schizophrenia. This article delineates the current understanding of the psychological and psychiatric findings, brain morphometric abnormalities and genetic studies in VCFS and their relevance to schizophrenia spectrum disorders.

The Right Ventricle: Biologic Insights and Response to Disease

Cardiac Resynchronization Therapy in Children

Cardiac Resynchronization therapy has become an important management tool in adults with heart failure and dilated cardiomyopathy. The role of CRT in children with CHF is still unclear. Evidence is slowly emerging in the pediatric cardiology literature that CRT may have an important and useful role in certain select populations with CHF. These include patients with complete heart block who develop pacing-induced cardiomyopathy, certain forms of congenital heart disease associated with systemic ventricular failure (even if the systemic ventricle is a morphologic RV) and in patients with idiopathic dilated cardiomyopathy. Studies in children supporting the use of CRT include many case reports, a few studies of CRT in post-operative patients, and one multi-center registry reporting the use of CRT in children. These papers will be summarized.

Insights Into the Role of microRNAs in Cardiac Diseases: From Biological Signalling to Therapeutic Targets

microRNAs have recently opened new pathways to explain gene expression and disease biology in many scenarios, including cardiac diseases. microRNAs are endogenous small non-coding RNAs that mediate post-transcriptional repression or messenger RNA degradation. By annealing to inexactly complementary sequences in the 3 untranslated region of the target messenger RNA, protein level is down-regulated. Several microRNAs appear to act cooperatively through multiple target sites in one gene and, conversely, most microRNAs can target several genes. miR-133 and miR-1 are specifically expressed in cardiac and skeletal muscle and control myogenesis, cardiac development, cardiac performance and cardiomyocyte hypertrophy (mainly by tuning transcription factors and other growth-related targets). They also modulate the expression of certain cardiac ion channels and related proteins with proarrhythmic effect. Besides them, other microRNAs have been shown to exert influence on the myocardial growth, the electrical balance and the angiogenesis processes that take place in the heart. Bioinformatics is a useful tool to identify potential targets of a given microRNA, although there is still substantial concern about their reliability. Experimental manipulation of microRNAs has provided a tantalizing basis to speculate that future research on microRNAs may yield important progress in the prevention of sudden cardiac death and in the treatment of cardiac heart failure. However, the final effect of the blockage of microRNAs in vivo remains unclear, since each of them can target hundreds of genes with different intensity. The era of the microRNAs in cardiovascular diseases has just started.

Economic Evaluation in Paediatric Practice: Examples from Cardiac Critical Care

The National Institute for Clinical Excellence (NICE) uses economic evaluation as the means to assess new treatments: this is a process unfamiliar to many clinicians. High technology treatments used in paediatric intensive care are expensive and have been subject to economic evaluation. A systematic review of the literature was performed for economic evaluations of treatments used for critically ill children with cardio-pulmonary failure. Of 3604 potentially eligible studies identified, there were 16 cost minimisation studies addressing applicable treatments but only 9 cost effectiveness or cost utility evaluations were found and subjected to review. Three studies dealt with the UK trial of extracorporeal membrane oxygenation (ECMO) for neonates, two studies addressed ECMO and transplantation in paediatric cardiac patients, two studies evaluated ECMO in mixed paediatric respiratory failure populations and two studies assessed the cost effectiveness of inhaled nitric oxide in neonatal respiratory failure. There are inherent problems in performing economic studies in this paediatric field. However, economic evaluation with adherence to guidelines is recommended. Given recent NHS reforms, it is clear that economic evaluation will remain an important focus of debate and is likely to become more prevalent rather than less.

Strategy for a Genetic Assessment of Antipsychotic and Antidepressant- Related Proarrhythmia

Antidepressants and antipsychotics may affect several ion channels involved in the control of cardiac action potential and be proarrhythmic. In this field, accurate understanding of genetics, which per se is a non-controllable risk factor, may help clinicians to prevent life-threatening side effects. So far, a number of genes have been associated with arrhythmia: SCN5A, SCN4B, CACNL1AC, KCNH2, KCNQ1, KCNE1, ANK2, ALG10, KCNJ2, KCNE2, RYR2, KCND3, KCND2, ACE, NOS1AP, CASQ2 and Rad. These genes represent good candidates for the definition of a genetic pro-arrhythmic profile. A genetic analysis of these targets is provided and their possible pathophysiological role in arrhythmias is discussed. Special attention is devoted to the interactions between these genes and new generation antidepressants and antipsychotics. A list of relevant rare mutations within the selected genes is presented, together with a complete list of Tag SNPs covering the whole genetic sequence. The aim of this paper is to define a part of the genetic framework responsible for the proarrhythmic effects of antidepressants and antipsychotics. The selected variants, both mutations and polymorphisms, may help in defining a next-to-come genetic assessment to be performed before drug prescription in order to improve drug safety.

Notch Signaling in Cardiovascular Disease and Calcification

Recent increase in human lifespan has shifted the spectrum of aging-related disorders to an unprecedented upsurge in cardiovascular diseases, especially calcific aortic valve stenosis, which has an 80% risk of progression to heart failure and death. A current therapeutic option for calcified valves is surgical replacement, which provides only temporary relief. Recent progress in cardiovascular research has suggested that arterial and valve calcification are the result of an active process of osteogenic differentiation, induced by a pro-atherogenic inflammatory response. At molecular level, the calcification process is regulated by a network of signaling pathways, including Notch, Wnt and TGFbeta/BMP pathways, which control the master regulator of osteogenesis Cbfa1/Runx2. Genetic and in vitro studies have implicated Notch signaling in the regulation of macrophage activation and cardiovascular calcification. Individuals with inactivating Notch1 mutations have a high rate of cardiovascular disorders, including valve stenosis and calcification. This article reviews recent progress in the mechanism of cardiovascular calcification and discusses potential molecular mechanisms involved, focusing on Notch receptors. We propose a calcification model where extreme increases in vascular wall cell density due to inflammation-induced cell proliferation can trigger an osteogenic differentiation program mediated by Notch receptors.

Cardiac Role of the Transcription Factor NF-κB

The signaling pathways that control the life-death switch of a cell are of primary interest in modern biology. In this respect, NF-??B has emerged as a decisive transcription factor in the cells response to apoptotic challenge and its effects on apoptosis have far-reaching consequences for normal development and/or homeostasis in many cells and tissues, including the immune system, hair follicles, and epidermal appendages, liver, nervous system and recently in heart . In this review we analyze the pivotal role of the transcription factor NF-κB in the normal functioning of the cardiac cell and its implication in common cardiac pathologies, such as ischemia-reperfusion injury, ischemic precondition, hypertrophy, atherosclerosis and cardiac arrest. While NF-κB is usually cytoprotective, it can also be pro-apoptotic depending on the inducing stimulus and the cellular context. Significant progress has been made in elucidating NF-κBs mode of action and its interplay with other key factors. These studies identified some anti- and pro-apoptotic NF-κB regulated genes that mediate its activity. These important new insights fuel hope that novel approaches will be developed to control the effects of NF-κB in cardiac pathologies.

Neurocognitive Monitoring and Care During Pediatric Cardiopulmonary Bypass — Current and Future Directions

Neurologic injury in patients with congenital heart disease remains an important source of morbidity and mortality. Advances in surgical repair and perioperative management have resulted in longer life expectancies for these patients. Current practice and research must focus on identifying treatable risk factors for neurocognitive dysfunction, advancing methods for perioperative neuromonitoring, and refining treatment and care of the congenital heart patient with potential neurologic injury. Techniques for neuromonitoring and future directions will be discussed.

Characterization of Supraventricular Tachycardia in Infants: Clinical and Instrumental Diagnosis

Supraventricular tachycardia (SVT) is the most common symptomatic arrhythmias in children. Re-entry tachycardias are the most common form, on the contrary automatic tachycardias are relatively rare. There are four types or re-entry: along anomalous pathway with bi-directional (Wolff-Parkinson-White) or unidirectional conduction, intranodal re-entry, intra-atrial re-entry that is common after surgical procedure, and finally the uncommon sinus node re-entry. Automatic tachycardias may be atrial or junctional. The different types of tachycardia have a different incidence according to the age: in the first year of age re-entry along anomalous pathway is the dominant form, while intranodal reentry becomes common during adolescence. The age at the beginning of tachycardia is important for long term prognosis. When SVT starts in the first months of life it disappears in 80% of cases within the first year of life; on the contrary, if tachycardia starts later spontaneous remission is detected in only 15%-20% of patients. In infancy heart failure is the more common presenting symptom, thereafter palpitations become the principal cause of recognition of SVT. Syncope is reported in about 8% of cases and in another 15% usually neonates and infants, the SVT has an occasional detection. Electrocardiogram (ecg) usually allows the precise diagnosis of various types of SVT, and every effort should be made to record ecg during tachycardia. The parameters that should be evaluated are: heart rate, P wave axis, PR and RP interval, and finally presence or absence of AV block. Short lasting episodes should be difficult to be recorded; in these cases cardio-call and trans-telephonic transmission represent useful techniques to obtain SVT demonstration. Patients with SVT require a complete evaluation with others diagnostic techniques: echocardiogram, Holter monitoring, stress test, that should be chosen according the type of tachycardia. Electrophysiologic evaluation is now rarely performed for diagnostic purpose; trans-esophageal atrial stimulation being less invasive than intracardiac evaluation is more extensively employed when diagnosis of SVT is uncertain. Transesophageal stimulation is useful in the following situations: 1) evaluation of patients with symptoms suggestive of paroxistic tachycardia but without ecg documentation, 2) to assess the mechanism responsible for re-entry tachycardia: macro re-entry versus intranodal re-entry 3) to evaluate characteristics of anomalous pathway with bi-directional conduction, and 4)to terminate re-entrant SVT.

Secondary Stroke Prevention in Patients with Cryptogenic Stroke and Patent Foramen Ovale

The foramen ovale is an ellipsoidal-shaped tunnel in the interatrial septum of the foetal heart allowing a rightto- left shunt between the two atria. It generally closes soon after birth but remains permeable in about 30% of adults. The frequency of this patent foramen ovale (PFO) in stroke patients is higher than among the general population, particularly in individuals with stroke of unknown aetiology (cryptogenic stroke) and in younger patients. Three theories have been proposed to explain the role of PFO in cryptogenic stroke: the paradoxical embolism theory, the arrhythmogenic theory and the thrombogenic theory. None have as yet been irrefutably confirmed. However, several secondary stroke prevention strategies have been developed in these patients: antiplatelet agents, oral anticoagulants, percutaneous closure and surgical repair. Secondary stroke prevention in these patients is presently one of the most controversial issues among cerebrovascular disease experts. We present a state-of-the-art review of secondary stroke prevention evidence in patients with cryptogenic stroke and PFO.