Citations

Abstract Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) attributable to multifactorial molecular underpinnings. Multiple genetic loci have been implicated to increase the risk of disease, yet genotype-phenotype relationships remain poorly defined. Whole genome sequencing complemented by cardiac phenotype from five individuals in an HLHS-affected family enabled the identification of NOTCH1 as a prioritized candidate gene linked to CHD in three individuals with mutant allele burden significantly impairing Notch signaling in the HLHS-affected proband. To better understand a mechanistic basis through which NOTCH1 contributes to heart development, human induced pluripotent stem cells (hiPSCs) were created from the HLHS-affected parent-proband triad and differentiated into cardiovascular cell lineages for molecular characterization. HLHS-affected hiPSCs exhibited a deficiency in Notch signaling pathway components and a diminished capacity to generate hiPSC-cardiomyocytes. Optimization of conditions to procure HLHS-hiPSC-cardiomyocytes led to an approach that compensated for dysregulated nitric oxide (NO)-dependent Notch signaling in the earliest specification stages. Augmentation of HLHS-hiPSCs with small molecules stimulating NO signaling in the first 4 days of differentiation provided a cardiomyocyte yield equivalent to the parental hiPSCs. No discernable differences in calcium dynamics were observed between the bioengineered cardiomyocytes derived from the proband and the parents. We conclude that in vitro modeling with HLHS-hiPSCs bearing NOTCH1 mutations facilitated the discovery of a NO-dependent signaling component essential for cardiovascular cell lineage specification. Potentiation of NO signaling with small therapeutic molecules restored cardiogenesis in vitro and may identify a potential therapeutic target for patients affected by functionally compromised NOTCH1 variants.

Background: There is limited understanding of the role of cardiac computed tomography angiography (CCTA) for assessment of patients with spontaneous coronary artery dissection (SCAD). Methods: In this report we describe the diagnostic utility of CCTA in three young women presenting with signs and symptoms of myocardial ischemia who were eventually diagnosed with SCAD. Results: None of the women had traditional atherosclerotic risk factors. SCAD was not initially identified on CCTA in any of the three women, but was visualized during retrospective analysis in two patients after invasive coronary angiography. In two patients follow-up CCTA imaging was used successfully for subsequent management. Conclusions: In patients presenting with signs or symptoms of acute coronary syndrome, SCAD may be missed or not detectable on CCTA. A negative CCTA should not exclude a diagnosis of SCAD, and invasive coronary angiography should be considered for further evaluation.

A 66-year-old, Caucasian male presented with pain and swelling involving the left knee of one-week duration. Arthrocentesis was negative for evidence of septic arthritis. Magnetic resonance imaging (MRI) study of the left knee showed degenerative arthritis, partial tear of medial meniscus, and a complex fluid collection along the posteromedial aspect of the left knee suggestive of popliteal cyst. He underwent arthroscopy with partial medial meniscectomy. Intraoperative joint fluid was noted to be cloudy but cultures were negative. Arthroscopic procedure provided him with temporary relief but the pain and swelling in the posterior aspect of the left knee recurred in 6 weeks. Repeat MRI showed complex fluid collection in the posterolateral aspect of left knee. Ultrasound guided aspiration of the fluid collection revealed purulent material and cultures grewActinomyces meyeri. He was treated with 6 weeks of intravenous penicillin regimen followed by 18 months of oral penicillin.