Bicuspid aortic valve (BAV) associated with aortopathy is the most common congenital heart disease in the general population. Far from being a simple harmless valve malformation, it can be a complex and heterogeneous disease and a source of chronic and acute pathology (early valvular disease, aneurysm, dissection). In the previous years, intense research has been carried out to find out and understand its mechanisms, but the pathophysiology of the disease is still not fully understood and many questions remain open. Recent studies have discovered several genetic mutations involved in the development of valvular and aortic malformations, but still cannot explain more than 5–10% of cases. Other studies have also focused on molecular alterations and cellular processes (TGF-β pathway, microRNAs, degradation of the extracellular matrix, metalloproteinases, etc.), being a field in constant search and development, looking for a therapeutic target to prevent the development of the disease. Increased knowledge about this multifaceted disorder, derived from both basic and clinical research, may influence the diagnosis, follow-up, prognosis, and therapies of affected patients in the near future. This review focuses on the latest and outstanding developments on the molecular and genetic investigations of the bicuspid aortopathy.

Aortic valve stenosis is the most frequent valve disease in developed countries and its prevalence will increase with population aging. There is still no pharmaceutical treatment nor biomarker to determine the susceptibility to develop aortic stenosis. Therefore, we analyzed the association of polymorphisms in risk loci with calcific aortic stenosis. Patients with aortic valve disease were genotyped for PALMD rs6702619, LPA rs10455872, and IL6 rs1800795 polymorphisms and circulating levels of interleukin-6 (IL-6) were measured. Calcium content of leaflets obtained in valve replacement surgeries was determined by micro-computed tomography. In the genotyping of 578 individuals, we found significant association between PALMD and IL6 polymorphisms and aortic stenosis in patients with tricuspid aortic valve, independently of other potentially confounding variables such as age and dyslipidemia. There was no association of these polymorphisms with valve calcium content, but this value correlated with the mean aortic pressure gradient (r = 0.44; P < 0.001). The CC genotype of IL6 polymorphism was associated with higher levels of serum IL-6 compared to other genotypes (23.5 vs. 10.5 pg/ml, respectively; P = 0.029). Therefore, patients carrying the CC genotype of IL6 rs1800795 polymorphism present higher levels of circulating IL-6 and this could contribute to the severity of the aortic valve stenosis. Our results agree with the identification of IL6 as a locus risk for stenosis and also with the intervention of this cytokine in aortic valve calcification. A more exhaustive follow-up of those patients carrying risk genotypes is therefore recommended.

Antecedentes Los pacientes con válvula aórtica bicúspide (BAV), en comparación con las personas con válvula aórtica tricúspide normal, tienen un mayor riesgo de desarrollar dilatación de la aorta ascendente (DAA). La disfunción valvular significativa no explica una complicación aórtica desafortunada y, por lo tanto, los mecanismos moleculares involucrados se encuentran bajo investigación. Uno de los procesos involucrados es la inflamación y las citocinas como la interleucina-6 están asociados con las dimensiones aórticas y con la degeneración de la matriz extracelular aórtica en modelos animales. . Por este motivo, nos propusimos analizar un polimorfismo del gen de la interleucina-6 (IL6), que regula positivamente la transcripción y traducción del gen, en pacientes con VAB. Material y métodos Presentamos una serie de 119 pacientes con VAB genotipados para el polimorfismo rs1800795 en la región promotora del gen IL6 . Se realizaron modelos de regresión logística multivariable. Resultados y conclusiones Nuestros pacientes, todos con VAB, tenían una mediana de edad de 55 años, 76,5% hombres, 29,4% fumadores, 30% dislipidémicos, 35,3% hipertensos, 12,6% diabéticos y 44% con DAA de 39 a 49 mm. Homocigotos El genotipo para el alelo C del polimorfismo IL6 fue significativamente menos frecuente en pacientes con dilatación (OR = 0,32, IC del 95% = 0,11–0,96, P = 0,035). Tras ajustar por variables de confusión como sexo, edad, hipertensión arterial y valvulopatía, los pacientes portadores del genotipo CC seguían teniendo menor probabilidad de padecer DAA (OR = 0,25; IC95% = 0,07–0,76; P = 0,02). La identificación de individuos con predisposición genética para el desarrollo de DAA es fundamental en beneficio de un seguimiento médico más estrecho. Son necesarios más estudios para evaluar su uso en la aortopatía bicúspide. Investigación financiada por la Sociedad Española de Cardiología; ISCIII-PI1800694; Fundación-Asturcor;Programa Severo-Ochoa.

Background The Cellular Communication Network Factor-2 (CCN2/CTGF) has been traditionally described as a downstream mediator of other profibrotic factors including transforming growth factor (TGF)-ß and Angiotensin II. However, recent evidence from our group demonstrated the direct role of CCN2 in maintaining aortic wall homeostasis and, in addition, the development of acute and lethal aortic aneurysm induced by Angiotensin II in absence of CCN2 in mice. In order to translate these findings to humans, we evaluated the potential association between three polymorphisms in the CCN2 gene and the presence of thoracic aortic aneurysm (TAA). Material and methods 69 patients with TAA and 297 controls were genotyped for rs6918698, rs9402373 and rs12526196 polymorphisms related to CCN2 gene.Multivariable logistic regression models were performed. Results and conclusions While no associations were found between rs6918698 and rs9402373 with TAA development, patients carrying the C allele from rs12526196 polymorphism have a higher probability of suffering TAA compared to patients with TT genotype, independently of other risk factors such as sex, age, hypertension, type of valvulopathy and presence of bicuspid aortic valve (OR = 3.17; 95% CI = 1.30–7.88;P = 0.011). This study extrapolates to humans the relevance of CCN2 in aortic aneurysm observed in mice and postulate, for the first time, a protective role to CCN2 in aortic aneurysm pathology. Our results encourage future research to explore new variants, polymorphisms or mutations, in the CCN2 gene that could be predisposing to TAA development. Funding Research funded by ISCIII (PI20/000140, PI18/00694, PI19/00184, PI20/00639); RICORS2040-KIDNEY-DISEASE (RD21/0005/0002, RD21/0005/0017); Sara-Borrell-CD20/00042; Miguel-Servet-CP18/00106; Sociedad Española de Nefrología.

Cellular communication network factor 2 (CCN2/CTGF) has been traditionally described as a downstream mediator of other profibrotic factors including transforming growth factor (TGF)-β and angiotensin II. However, recent evidence from our group demonstrated the direct role of CCN2 in maintaining aortic wall homeostasis and acute and lethal aortic aneurysm development induced by angiotensin II in the absence of CCN2 in mice. In order to translate these findings to humans, we evaluated the potential association between three polymorphisms in the CCN2 gene and the presence of a thoracic aortic aneurysm (TAA). Patients with and without TAA retrospectively selected were genotyped for rs6918698, rs9402373 and rs12526196 polymorphisms related to the CCN2 gene. Multivariable logistic regression models were performed. In our population of 366 patients (69 with TAA), no associations were found between rs6918698 and rs9402373 and TAA. However, the presence of one C allele from rs12526196 was associated with TAA comparing with the TT genotype, independently of risk factors such as sex, age, hypertension, type of valvulopathy and the presence of a bicuspid aortic valve (OR = 3.17; 95% CI = 1.30–7.88; p = 0.011). In conclusion, we demonstrated an association between the C allele of rs12526196 in the CCN2 gene and the presence of TAA. This study extrapolates to humans the relevance of CCN2 in aortic aneurysm observed in mice and postulates, for the first time, a potential protective role to CCN2 in aortic aneurysm pathology. Our results encourage future research to explore new variants in the CCN2 gene that could be predisposed to TAA development.