A Novel-Design Poly-L-Lactic Acid Biodegradable Device for Closure of Atrial Septal Defect: Long-Term Results in Swine.

OBJECTIVES: The aim of this study is to evaluate the long-term effectiveness and safety of a self-expandable, double-disk biodegradable device made of poly-L-lactic acid (PLLA) for closure of atrial septal defects (ASDs) in swine. METHODS: ASDs were created by transseptal needle puncture followed by balloon dilatation in 20 piglets. The experimental group comprised 18 animals, while the remaining 2 animals were used as controls. Effectiveness and safety were evaluated by rectal temperature, leukocyte count, chest radiography, electrocardiogram, transthoracic echocardiography (TTE), intracardiac echocardiography (ICE), and histologic studies. Animals were followed up at 1, 3, 6, and 12 months. RESULTS: An ASD model was successfully created in 19 animals; 1 piglet died during the procedure. The ASD diameters that were created ranged from 5 to 6.4 mm. Devices were successfully implanted in 17 animals. No animal died during the follow-up studies. Rectal temperatures and electrocardiograms were normal at follow-up, while leukocyte counts transiently increased from 1 to 6 months. Radiography, TTE, ICE, and macroscopic studies demonstrated that PLLA occluders were positioned well, with no shifting, mural thrombus formation, or atrioventricular valve insufficiency. Histologic evaluations showed that PLLA devices were partially degraded in the follow-up study. CONCLUSIONS: ASD closure with the novel PLLA biodegradable device is safe and effective. Longer-term studies are needed to evaluate long-term biodegradability.

An endocardial pathway involving Tbx5, Gata4, and Nos3 required for atrial septum formation.

In humans, septal defects are among the most prevalent congenital heart diseases, but their cellular and molecular origins are not fully understood. We report that transcription factor Tbx5 is present in a subpopulation of endocardial cells and that its deletion therein results in fully penetrant, dose-dependent atrial septal defects in mice. Increased apoptosis of endocardial cells lacking Tbx5, as well as neighboring TBX5-positive myocardial cells of the atrial septum through activation of endocardial NOS (Nos3), is the underlying mechanism of disease. Compound Tbx5 and Nos3 haploinsufficiency in mice worsens the cardiac phenotype. The data identify a pathway for endocardial cell survival and unravel a cell-autonomous role for Tbx5 therein. The finding that Nos3, a gene regulated by many congenital heart disease risk factors including stress and diabetes, interacts genetically with Tbx5 provides a molecular framework to understand gene-environment interaction in the setting of human birth defects.

Atrial septal pouch - Morphological features and clinical considerations.

BACKGROUND: The atrial septal pouch (SP) is a new anatomical entity within the interatrial septum. The left-sided SP may be the source of thrombus and contribute to ischemic stroke. The aim of this study was to provide a detailed morphometric description of the SP. METHODS: Two hundred autopsied hearts (23% deriving from females) with a mean age of 46.7±19.1years were investigated. We assessed the morphology of the interatrial septum. We obtained measurements and casts of the SPs, and we conducted histological staining of the left-sided SPs. RESULTS: Patent foramen ovale was observed in 25% of hearts. We found a left SP in 41.5%, right in 5.5% and a double SP in 5.5% of hearts. We found the patent foramen ovale (PFO) more often in younger hearts, and the SP and smooth septum were more prevalently found in older hearts (p=.0023). The mean volume of the left-sided SP was 0.31±0.11ml, which represented 13.6±9.4% (range: 3.1-44.9%) of the left atrial appendage volume. The SP shape resembled a cone or a cylinder with some smaller diverticula originating from the main body. The SP free wall was composed of two layers of endocardium, transverse muscle fibers and connective tissue. CONCLUSIONS: A left-sided SP was present in 47% of individuals. The SP arises as a result of PFO channel closure. The anatomy of left-sided SP may promote blood stasis and thrombus formation. The universal formula for SP volume was calculated.

Ex vivo paracrine properties of cardiac tissue: Effects of chronic heart failure.

BACKGROUND: Cardiac regenerative responses are responsive to paracrine factors. We hypothesize that chronic heart failure (HF) in pediatric patients affects cardiac paracrine signaling relevant to resident c-kit(+)cluster of differentiation (CD)34- cardiac stem cells (CSCs). METHODS: Discarded atrial septum (huAS) and atrial appendages (huAA) from pediatric patients with HF (huAA-HF; n = 10) or without HF (n = 3) were explanted and suspension explant cultured in media. Conditioned media were screened for 120 human factors using unedited monoclonal antibody-based arrays. Significantly expressed (relative chemiluminescence >30 of 100) factors are reported (secretome). Emigrated cells were immunoselected for c-kit and enumerated as CSCs. RESULTS: After culture Day 7, CSCs emigrate from huAA but not huAS. The huAA secretome during CSC emigration included hepatocyte growth factor (HGF), epithelial cell-derived neutrophil attractant-78 (ENA-78)/chemokine (C-X-C motif) ligand (CXCL) 5, growth-regulated oncogene-α (GRO-α)/CXCL1, and macrophage migration inhibitory factor (MIF), candidate pro-migratory factors not present in the huAS secretome. Survival/proliferation of emigrated CSCs required coculture with cardiac tissue or tissue-conditioned media. Removal of huAA (Day 14) resulted in the loss of all emigrated CSCs (Day 28) and in decreased expression of 13 factors, including HGF, ENA-78/CXCL5, urokinase-type plasminogen activator receptor (uPAR)/CD87, and neutrophil-activating protein-2 (NAP-2)/CXCL7 candidate pro-survival factors. Secretomes of atrial appendages from HF patients have lower expression of 14 factors, including HGF, ENA-78/CXCL5, GRO-α/CXCL1, MIF, NAP-2/CXCL7, uPAR/CD87, and macrophage inflammatory protein-1α compared with AA from patients without HF. CONCLUSIONS: Suspension explant culturing models paracrine and innate CSC interactions in the heart. In pediatric patients, heart failure has an enduring effect on the ex vivo cardiac-derived secretome, with lower expression of candidate pro-migratory and pro-survival factors for CSCs.

sonic hedgehog is required in pulmonary endoderm for atrial septation.

The genesis of the septal structures of the mammalian heart is central to understanding the ontogeny of congenital heart disease and the evolution of cardiac organogenesis. We found that Hedgehog (Hh) signaling marked a subset of cardiac progenitors specific to the atrial septum and the pulmonary trunk in the mouse. Using genetic inducible fate mapping with Gli1(CreERT2), we marked Hh-receiving progenitors in anterior and posterior second heart field splanchnic mesoderm between E8 and E10. In the inflow tract, Hh-receiving progenitors migrated from the posterior second heart field through the dorsal mesocardium to form the atrial septum, including both the primary atrial septum and dorsal mesenchymal protrusion (DMP). In the outflow tract, Hh-receiving progenitors migrated from the anterior second heart field to populate the pulmonary trunk. Abrogation of Hh signaling during atrial septal progenitor specification resulted in atrial and atrioventricular septal defects and hypoplasia of the developing DMP. Hedgehog signaling appeared necessary and sufficient for atrial septal progenitor fate: Hh-receiving cells rendered unresponsive to the Hh ligand migrated into the atrium in normal numbers but populated the atrial free wall rather than the atrial septum. Conversely, constitutive activation of Hh signaling caused inappropriate enlargement of the atrial septum. The close proximity of posterior second heart field cardiac progenitors to pulmonary endoderm suggested a pulmonary source for the Hh ligand. We found that Shh is required in the pulmonary endoderm for atrial septation. Therefore, Hh signaling from distinct pulmonary and pharyngeal endoderm is required for inflow and outflow septation, respectively. These data suggest a model in which respiratory endoderm patterns the morphogenesis of cardiac structural components required for efficient cardiopulmonary circulation.

BMP4 is required in the anterior heart field and its derivatives for endocardial cushion remodeling, outflow tract septation, and semilunar valve development.

The endocardial cushions play a critical role in septation of the four-chambered mammalian heart and in the formation of the valve leaflets that control blood flow through the heart. Within the outflow tract (OFT), both cardiac neural crest and endocardial-derived mesenchymal cells contribute to the endocardial cushions. Bone morphogenetic protein 4 (BMP4) is required for endocardial cushion development and for normal septation of the OFT. In the present study, we show that anterior heart field (AHF)-derived myocardium is an essential source of BMP4 required for normal endocardial cushion expansion and remodeling. Loss of BMP4 from the AHF in mice results in an insufficient number of cells in the developing OFT endocardial cushions, defective cushion remodeling, ventricular septal defects, persistent truncus arteriosus, and abnormal semilunar valve formation.

Tratamiento de la hipertensión arterial pulmonar / Treatment of pulmonary arterial hypertension

El tratamiento de la hipertensión arterial pulmonar ha presentado importantes avances en los últimos 20 años. En la actualidad, existen 3 grupos de fármacos que han demostrado su utilidad en el tratamiento de esta enfermedad: los bloqueantes de los receptores de endotelina, los inhibidores de la fosfodiesterasa y la prostaciclina y sus análogos. Se recomienda iniciar el tratamiento de los pacientes con uno de estos fármacos, la elección del cual dependerá de la gravedad inicial del paciente y de las preferencias del médico que trata. Cuando el paciente no presenta una respuesta satisfactoria, se suelen añadir nuevos fármacos que actúan por vías distintas a la del fármaco inicial. En este momento el médico que trata al paciente debe plantearse la necesidad del trasplante pulmonar como alternativa. Ante esta enfermedad rara se recomienda agrupar la máxima experiencia en lo que se conoce como centros expertos. El tratamiento ha mejorado la supervivencia de estos pacientes, pero aún queda un largo camino por recorrer hasta la curación de esta terrible enfermedad (AU)

Treatment of pulmonary arterial hypertension has achieved significant progress over the past 20 years. Currently, 3 groups of drugs have proven useful for the treatment of this disease: endothelin receptor antagonist, phosphodiesterase inhibitors and prostacyclin and its analogues. It is recommended to initiate treatment with one of these drugs, the choice depending on the initial severity of patient disease and the preferences of the treating physician. When the patient does not have a satisfactory response, new drugs acting at a different pathway are most commonly added. At this time, considering referral for lung transplantation could be an alternative. Most experts recommend grouping maximum experience in what is known as expert centers. Treatment has led to better survival in these patients, but there is still a long way to cure this life-threatening disease (AU)