Current practice of care for adolescent and adult patients after Fontan surgery in Poland

Background: The growing number of adults patients after the Fontan operation requires regular surveillance tests in the specialized centers. Aims: Evaluation of current practice of care for Fontan patients in Poland based on a multicenter survey. Methods: Eight centers were included in the study-5 adult congenital heart disease (ACHD) and 3 pediatric centers for adolescents. To aim for a comparison between the centers and facilitate the interpretation of the results, the Fontan Surveillance Score (FSS) was developed. The higher score is consistent with better care, with a maximum of 19 points. Results: The number of 398 Fontan patients (243 adults and 155 adolescents [age 14-18 years]) was included in the study. The median FSS was 13 points with variability between the centers (interquartile range 7-14 points). Centers providing continuous care from the pediatric period until 18 years of age achieved a higher FSS compared to ACHD centers (median: 14 points vs 12 points, p< 0.001). Most of the patients, both in the ACHD (82.3%) and in pediatric centers (89%), were seen annually and had a physical examination, electrocardiogram, and echocardiogram performed at each visit. However, unsatisfactory utilization of tests identifying the early stages of Fontan circulation failure (cardiopulmonary exercise tests, cardiac magnetic resonance, liver biochemistry and imaging, detection of protein-losing enteropathy) was observed. Conclusions: The results of the study showed that there is no unified surveillance approach for Fontan patients in Poland. The practice of care for adults differs from that of adolescents

Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia

International audienceAbstract Aims Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD. Methods and results We analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 × 10−4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on human prostaclycin receptor (hIP) signalling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro. Conclusions Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signalling in non-atherosclerotic stenosis and dissection

Rare Loss-of-function Mutations of PTGIR are enriched in Fibromuscular Dysplasia.

AimsFibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD.Methods and resultsWe analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 × 10−4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on human prostaclycin receptor (hIP) signalling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro.ConclusionsOur study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signalling in non-atherosclerotic stenosis and dissection.</div

Author Correction: Genetic investigation of fibromuscular dysplasia identifies risk loci and shared genetics with common cardiovascular diseases

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