PathFinder
Well-known member
I have not written for a long, but today I wanted to see how is it going here, and looking to the new forum-part BAV and CTD, I decided to put this thread.
OK, bicuspid aortic valve is a congenital defect of the aortic valve. Logicaly, we can not expect how a defect will be localized to a isolated area of tissue, which is the same as structure as the entite thoracic aorta. That's why, it is not so surprisingly, that the transverse aorta is affected by the congenital defect.
There are some speculations about, whther there is a disruption of the haemodynamics during embryonal period, leading to disseparation of the leaflets of the valve. This defective form, leads to constant vibrations causing disfunction of the endothelium of the aortic wall and respectively destruction of the wall structures. The outcomes are aneurysms and dilations. Some trials have proved the potencial of this theory.
However, there are to many signs of pathological status of the aortic ascendence, root and arch. Something more - there are many evidences of aneurysms of some arteries in the nech and head in patients with BAV. And finally - there is already a prooved defficiency of microfibril Fibrillin-1 in the aorta and the pulmonary artery of the BAV patients. In conclusion, these facts show us a realtion to a serious connective tissue disorder at histological and molecular level.
Here I nees to make some remarks of what I have read after my surgery:
- Fibrillin is a major component of the extracellular matrix in the great arteries. Its mutations causes the aneurysmal formation in the Marfan disease. Studies already showed the deficiency of Fibrillin in the BAVs. But many aothors suggest, that it is only defficient in the great arteries, not mutant. This defficiency may be caused by other factors, like alterations of the signaling pathways, encoding the gene FBN-1, encoding the major proteine.
- If there is a Fibrillin defficiency, why the BAV patients don't show another signs of systemic connective tissue disease in general? Because the defficiency is suspected to be systemic only for a area of the body - this area is shown to be the arteries of the outflow track (aorta and pulmonary artery) and the great and some more specificaly arteries in the neck and the head (but only in some subjects).
- The last suggests a system, responsible for that area of defective development by the bAVs. And this is the neural crest. The cardiac neural crest, which is an organ functioning in the embryons, delivers the cells migrating and forming the aortic valve commissures, root, make the separations of the aorta with the pulmonary artery, forms the endothelium of these arteries, the aortic arch with its branches and forms the muscular and sometimes occular arteries in the neck abd head.
Trials with removal of the neural crest from the embryo, shows 100% cardiac defects as patent ductus arteriosus (seen in some BAVs), aortic misdevelopment, arch misdevelopment and variety of head/neck maldevelopments.
This led the scientists to investigate the possible role of the neural crest in the BAV disease. This investigations are particular to the aortic coarctation (disease 50% - 70% accompanied by BAV) where are sometimes seen thyroid diseases and common arterial dissectins or aneurysms in the brain (very common 10-15% of cases). May be some more serious defect in the neural crest is responsible to the coarctation phenotype of the aortic pathology with thyroidal, parathyroidal and neck diseases (all of which are related to the neural crest).
This partly explanes why there is connective tissue disorder, but generally "localized" to the great arteries above the heart.
- eNOS, or endothelial nytric oxide synthase. Major factor in cardiac development. Trials with defficiency of eNOS in mice shows something revolutionary in searching the culprite gene. For first time, there are seen mice with bicuspid aortic valve. Some other gene defects may cause ventrucular or other septal defects, but the most important facts, is the appearance of a BAV in mice, lacking eNOS. You all, guys see what shall I say as a cosequence - all the mice with BAV develope aneurysms.
Of great interest it will be for us, if I add something interesting here. Variations of the eNOS genes cause occular migraines, seen in may be half of the BAV patients...
***
If you let me comment other discussions I have read, I will put some thoughts.
There is arising evidence of the heritable nature of many BAVs. More than 10%-35% of the cases show familial clustering.
HOWEVER, almost all the great investigators of the BAV reach the conclusion, that BAV may have many different causes, of many different genes, giving to the disease many different phenotypes.
Some autopsies of BAV patinents show no evidence of regurgitation or stenosis in people 90 years and beyound. There are seen asymptomatic cases of BAV in people over 100 years old!
So, there are heterogenous phenotypes. The BAV isn't even always the same - there are different types of fusion of the commissures (right and left; right and noncoronary; left and noncoronary; no raphes in the three cases; raphes in the three cases). This account of at least 5 phenotypes only in the BAV type. What may we say then about the aortic phenotypes. Many develope proximal aortic dilation; many have dilated root and normal aorta; many have "all-iclusive" program; many do not anything at all. Some develope stenosis, some regurgitation, some don't even have echocardiographic evidence of haemodynamic alteration!
Some BAV are related to Connective tissue diseases of autosomal dominant penetrance, as Marfan, Ehler Dahnlos, Turner syndromes. This is may be a consequence of the influence of these systemic disorders to a list of genes, potentialy encoding the process of forming the BAV (5-10%in the Marfan; 5-10% in EDS; 85-90% in Turner).
some other BAVs are replaced in totally healthy sportists, like Schwarzenegger or Kanu. The first is the greatest bodybuilder ever, the second became a soccer player of the world for the year over ten years ago - and that was after a BAV repair in USA... Does they look like persons with connective tissue disease? No. They just have one of the great variety of bAV phenotypes. Kanu is still a professional player in first league, despite his old age. Schwarzenegger has a familial occurence of BAV - his father and brother have it.
In talking about connective tissue diseases, a study in 2007 compared mitral valve prolapse persons with BAV persons for Body Mass Index. While the MVPs showed independently relation to very low BMI, the BAV persons didn't show any evidence of relation to some kind of heterogenous BMI.
Plus - Some cardiac defects are seen in BAVs, but the percentage is small and usually they are free of cardiac issues, except for those, caused by valve dysfunction.
Ok. that's from me now, thank you for reading my thread.
OK, bicuspid aortic valve is a congenital defect of the aortic valve. Logicaly, we can not expect how a defect will be localized to a isolated area of tissue, which is the same as structure as the entite thoracic aorta. That's why, it is not so surprisingly, that the transverse aorta is affected by the congenital defect.
There are some speculations about, whther there is a disruption of the haemodynamics during embryonal period, leading to disseparation of the leaflets of the valve. This defective form, leads to constant vibrations causing disfunction of the endothelium of the aortic wall and respectively destruction of the wall structures. The outcomes are aneurysms and dilations. Some trials have proved the potencial of this theory.
However, there are to many signs of pathological status of the aortic ascendence, root and arch. Something more - there are many evidences of aneurysms of some arteries in the nech and head in patients with BAV. And finally - there is already a prooved defficiency of microfibril Fibrillin-1 in the aorta and the pulmonary artery of the BAV patients. In conclusion, these facts show us a realtion to a serious connective tissue disorder at histological and molecular level.
Here I nees to make some remarks of what I have read after my surgery:
- Fibrillin is a major component of the extracellular matrix in the great arteries. Its mutations causes the aneurysmal formation in the Marfan disease. Studies already showed the deficiency of Fibrillin in the BAVs. But many aothors suggest, that it is only defficient in the great arteries, not mutant. This defficiency may be caused by other factors, like alterations of the signaling pathways, encoding the gene FBN-1, encoding the major proteine.
- If there is a Fibrillin defficiency, why the BAV patients don't show another signs of systemic connective tissue disease in general? Because the defficiency is suspected to be systemic only for a area of the body - this area is shown to be the arteries of the outflow track (aorta and pulmonary artery) and the great and some more specificaly arteries in the neck and the head (but only in some subjects).
- The last suggests a system, responsible for that area of defective development by the bAVs. And this is the neural crest. The cardiac neural crest, which is an organ functioning in the embryons, delivers the cells migrating and forming the aortic valve commissures, root, make the separations of the aorta with the pulmonary artery, forms the endothelium of these arteries, the aortic arch with its branches and forms the muscular and sometimes occular arteries in the neck abd head.
Trials with removal of the neural crest from the embryo, shows 100% cardiac defects as patent ductus arteriosus (seen in some BAVs), aortic misdevelopment, arch misdevelopment and variety of head/neck maldevelopments.
This led the scientists to investigate the possible role of the neural crest in the BAV disease. This investigations are particular to the aortic coarctation (disease 50% - 70% accompanied by BAV) where are sometimes seen thyroid diseases and common arterial dissectins or aneurysms in the brain (very common 10-15% of cases). May be some more serious defect in the neural crest is responsible to the coarctation phenotype of the aortic pathology with thyroidal, parathyroidal and neck diseases (all of which are related to the neural crest).
This partly explanes why there is connective tissue disorder, but generally "localized" to the great arteries above the heart.
- eNOS, or endothelial nytric oxide synthase. Major factor in cardiac development. Trials with defficiency of eNOS in mice shows something revolutionary in searching the culprite gene. For first time, there are seen mice with bicuspid aortic valve. Some other gene defects may cause ventrucular or other septal defects, but the most important facts, is the appearance of a BAV in mice, lacking eNOS. You all, guys see what shall I say as a cosequence - all the mice with BAV develope aneurysms.
Of great interest it will be for us, if I add something interesting here. Variations of the eNOS genes cause occular migraines, seen in may be half of the BAV patients...
***
If you let me comment other discussions I have read, I will put some thoughts.
There is arising evidence of the heritable nature of many BAVs. More than 10%-35% of the cases show familial clustering.
HOWEVER, almost all the great investigators of the BAV reach the conclusion, that BAV may have many different causes, of many different genes, giving to the disease many different phenotypes.
Some autopsies of BAV patinents show no evidence of regurgitation or stenosis in people 90 years and beyound. There are seen asymptomatic cases of BAV in people over 100 years old!
So, there are heterogenous phenotypes. The BAV isn't even always the same - there are different types of fusion of the commissures (right and left; right and noncoronary; left and noncoronary; no raphes in the three cases; raphes in the three cases). This account of at least 5 phenotypes only in the BAV type. What may we say then about the aortic phenotypes. Many develope proximal aortic dilation; many have dilated root and normal aorta; many have "all-iclusive" program; many do not anything at all. Some develope stenosis, some regurgitation, some don't even have echocardiographic evidence of haemodynamic alteration!
Some BAV are related to Connective tissue diseases of autosomal dominant penetrance, as Marfan, Ehler Dahnlos, Turner syndromes. This is may be a consequence of the influence of these systemic disorders to a list of genes, potentialy encoding the process of forming the BAV (5-10%in the Marfan; 5-10% in EDS; 85-90% in Turner).
some other BAVs are replaced in totally healthy sportists, like Schwarzenegger or Kanu. The first is the greatest bodybuilder ever, the second became a soccer player of the world for the year over ten years ago - and that was after a BAV repair in USA... Does they look like persons with connective tissue disease? No. They just have one of the great variety of bAV phenotypes. Kanu is still a professional player in first league, despite his old age. Schwarzenegger has a familial occurence of BAV - his father and brother have it.
In talking about connective tissue diseases, a study in 2007 compared mitral valve prolapse persons with BAV persons for Body Mass Index. While the MVPs showed independently relation to very low BMI, the BAV persons didn't show any evidence of relation to some kind of heterogenous BMI.
Plus - Some cardiac defects are seen in BAVs, but the percentage is small and usually they are free of cardiac issues, except for those, caused by valve dysfunction.
Ok. that's from me now, thank you for reading my thread.
Marguerite
