RAF-1 Mutation Associated with a Risk for Ventricular Arrhythmias in a Child with Noonan Syndrome and Cardiovascular Pathology.

Introduction: Noonan syndrome (NS) is a dominant autosomal disease, caused by mutations in genes involved in cell differentiation, growth and senescence, one of them being RAF1 mutation. Congenital heart disease may influence the prognosis of the disease. Case presentation: We report a case of an 18 month-old female patient who presented to our institute at the age of 2 months when she was diagnosed with obstructive hypertrophic cardiomyopathy, pulmonary infundibular and pulmonary valve stenosis, a small atrial septal defect and extrasystolic arrhythmia. She was born from healthy parents, a non-consanguineous marriage. Due to suggestive phenotype for NS molecular genetic testing for RASopathies was performed in a center abroad, establishing the presence of RAF-1 mutation. Following rapid progression of cardiac abnormalities, the surgical correction was performed at 14 months of age. In the early postoperative period, the patient developed episodes of sustained ventricular tachycardia with hemodynamic instability, for which associated treatment was instituted with successful conversion to sinus rhythm. At 3-month follow-up, the patient was hemodynamically stable in sinus rhythm. Conclusions: The presented case report certifies the importance of recognizing the genetic mutation in patients with NS, which allows predicting the severity of cardiac abnormalities and therefore establishing a proper therapeutic management of these patients.

A Rare Case of Undifferentiated Pleomorphic Cardiac Sarcoma with Inflammatory Pattern.

Cardiac undifferentiated pleomorphic sarcoma (UPS) associated with fever and inflammatory response is an extremely rare condition. Herein, we report a rare case of cardiac UPS with unusual clinical presentation and inflammatory response. A 67-year-old male complaining of progressive dyspnea and intermittent fever of unknown cause was referred to our hospital for surgical resection of a left atrial mass. Laboratory analysis showed leukocytosis (26 × 103/µL) and high C-reactive protein (CRP) levels (155.4 mg/L). Hemoculture tests and urine analysis were negative for infection. A contrast chest computed tomography revealed a mass measuring 5.5 × 4.5 cm, occupying the left atrium cavity. The patient underwent surgical excision of the mass, however, surgical margin of the resected tumor could not be evaluated, due to the multifragmented nature of the resection specimen. Postoperative CRP and leukocyte levels normalized, highlighting the relationship between the tumor and the inflammatory status. Early diagnosis is crucial for a proper management and favorable outcome, enabling patients to undergo chemotherapy and achieve complete surgical resection.

Preclinical Testing of Living Tissue-Engineered Heart Valves for Pediatric Patients, Challenges and Opportunities.

Introduction: Pediatric patients with cardiac congenital diseases require heart valve implants that can grow with their natural somatic increase in size. Current artificial valves perform poorly in children and cannot grow; thus, living-tissue-engineered valves capable of sustaining matrix homeostasis could overcome the current drawbacks of artificial prostheses and minimize the need for repeat surgeries. Materials and Methods: To prepare living-tissue-engineered valves, we produced completely acellular ovine pulmonary valves by perfusion. We then collected autologous adipose tissue, isolated stem cells, and differentiated them into fibroblasts and separately into endothelial cells. We seeded the fibroblasts in the cusp interstitium and onto the root adventitia and the endothelial cells inside the lumen, conditioned the living valves in dedicated pulmonary heart valve bioreactors, and pursued orthotopic implantation of autologous cell-seeded valves with 6 months follow-up. Unseeded valves served as controls. Results: Perfusion decellularization yielded acellular pulmonary valves that were stable, no degradable in vivo, cell friendly and biocompatible, had excellent hemodynamics, were not immunogenic or inflammatory, non thrombogenic, did not calcify in juvenile sheep, and served as substrates for cell repopulation. Autologous adipose-derived stem cells were easy to isolate and differentiate into fibroblasts and endothelial-like cells. Cell-seeded valves exhibited preserved viability after progressive bioreactor conditioning and functioned well in vivo for 6 months. At explantation, the implants and anastomoses were intact, and the valve root was well integrated into host tissues; valve leaflets were unchanged in size, non fibrotic, supple, and functional. Numerous cells positive for a-smooth muscle cell actin were found mostly in the sinus, base, and the fibrosa of the leaflets, and most surfaces were covered by endothelial cells, indicating a strong potential for repopulation of the scaffold. Conclusions: Tissue-engineered living valves can be generated in vitro using the approach described here. The technology is not trivial and can provide numerous challenges and opportunities, which are discussed in detail in this paper. Overall, we concluded that cell seeding did not negatively affect tissue-engineered heart valve (TEHV) performance as they exhibited as good hemodynamic performance as acellular valves in this model. Further understanding of cell fate after implantation and the timeline of repopulation of acellular scaffolds will help us evaluate the translational potential of this technology.

Challenges in Perioperative Animal Care for Orthotopic Implantation of Tissue-Engineered Pulmonary Valves in the Ovine Model.

BACKGROUND: Development of valvular substitutes meeting the performance criteria for surgical correction of congenital heart malformations is a major research challenge. The sheep is probably the most widely used animal model in heart valves regenerative medicine. Although the standard cardiopulmonary bypass (CPB) technique and various anesthetic and surgical protocols are reported to be feasible and safe, they are associated with significant morbidity and mortality rates. The premise of this paper is that the surgical technique itself, especially the perioperative animal care and management protocol, is essential for successful outcomes and survival. METHODS: Ten juvenile and adult female sheep aged 7.8-37.5 months and weighing 32.0-58.0 kg underwent orthotopic implantation of tissue-engineered pulmonary valve conduits on beating heart under normothermic CPB. The animals were followed-up for 6 months before scheduled euthanasia. RESULTS: Based on our observations, we established a guide for perioperative care, follow-up, and treatment containing information regarding the appropriate clinical, biological, and ultrasound examinations and recommendations for feasible and safe anesthetic, surgical, and euthanasia protocols. Specific recommendations were also included for perioperative care of juvenile versus adult sheep. CONCLUSION: The described surgical technique was feasible, with a low mortality rate and minimal surgical complications. The proposed anesthetic protocol was safe and effective, ensuring both adequate sedation and analgesia as well as rapid recovery from anesthesia without significant complications. The established guide for postoperative care, follow-up and treatment in sheep after open-heart surgery may help other research teams working in the field of heart valves tissue regeneration.

Different Manifestations in Familial Isolated Left Ventricular Non-compaction: Two Case Reports and Literature Review.

Left ventricular non-compaction (LVNC) is a form of cardiomyopathy characterized by prominent trabeculae and deep intertrabecular recesses which form a distinct "non-compacted" layer in the myocardium. It results from intrauterine arrest of the compaction process of the left ventricular myocardium. Clinical manifestations vary from asymptomatic to heart failure (HF), arrhythmias, or thromboembolic events. We present a case of mother and son diagnosed with isolated LVNC (ILVNC). A 4-years-old male patient, diagnosed at 3 months with ILVNC, and NYHA functional class IV HF, was admitted to the Emergency Institute for Cardiovascular Diseases and Transplantation of Targu Mures, Romania, for cardiologic reevaluation, and diagnosis confirmation. ILVNC was confirmed using echocardiography, revealing a non-compaction to compaction (NC/C) ratio of > 2.7. His evolution was stationary until the age of 8 years, when severe pneumonia caused hemodynamic decompensation, and he was listed for heart transplantation (HT). The patient underwent HT at the age of 11 years with favorable postoperative outcome. Meanwhile, a 22-years-old female patient, mother of the aforementioned patient, was also admitted to our institute due to severe fatigue, dyspnea, and recurrent palpitations with multiple implantable cardioverter defibrillator (ICD) shock delivery. Extensive medical history revealed that a presumptive ILVNC diagnosis was established when she was 11 years old. She was asymptomatic until 18 years old, when 3 months post-partum, she developed NYHA functional class III HF, and subsequently underwent ICD implantation. Her diagnosis was confirmed using multi-detector computed tomography angiography, which revealed a NC/C ratio of > 3.3. ICD adjustments were carried out with a favorable evolution under chronic drug therapy. The last evaluation, at 27 years old, revealed that she was in NYHA functional class II HF. In conclusion, ILVNC, even when familial, can present different clinical pictures and therefore requires different medical approaches.