Causes of aortic stenosis

Causes of aortic stenosis

Abstract: Causes of aortic stenosis include progressive degeneration and calcification of bicuspid aortic valve, degenerative calcific aortic stenosis, rheumatic aortic stenosis, familial hypercholesterolemia and ochronosis.

In a study of about six hundred and fifty patients who underwent aortic replacement at Mayo Clinic, the most frequent causes of pure aortic stenosis were calcification of congenital bicuspid aortic valve, degenerative calcification of aortic valve and post inflammatory calcification and fibrosis of aortic valve thought to be of rheumatic origin. These three causes together contributed about ninety five percent of the cases.¹ While calcified bicuspid aortic stenosis contributed thirty eight percent, senile calcific aortic stenosis was noted in one third of cases and possible rheumatic aortic stenosis occurred in about one fourth of cases. Bicuspid aortic stenosis was commoner in those younger than seventy years, contributing half the cases in this age group. In those above seventy years, about half the cases were due to degenerative calcification of a trileaflet aortic valve. They also noted a decrease in the frequency of post inflammatory (possibly rheumatic) variety over the years while degenerative calcific variety increased, becoming the commonest towards the end of the study period. This would reflect the trend of decreasing prevalence of rheumatic fever and the aging of the population.

Genetics of aortic stenosis

Calcification of the aortic valve has been recognized as the third leading cause of heart disease in adults. NOTCH1 mutations have been identified as a cause of developmental defects in the aortic valve leading to calcium deposition and progressive aortic stenosis.² NOTCH1 is a signalling and transcriptional regulator, mutations of which cause severe valve calcification and are transmitted in an autosomal dominant pattern.³
It has been shown that NOTCH1 represses the gene for bone morphogenetic protein 2 (BMP2).⁴ This in turn suppresses osteoblast like calcification pathways in aortic valve cells. This is by repression of activation runt-related transcription factor 2 (RUNX2) a transcription factor which is seen as upregulated in calcified human aortic valves.³

References

1. Passik CS, Ackermann DM, Pluth JR, Edwards WD. Temporal changes in the causes of aortic stenosis: a surgical pathologic study of 646 cases. Mayo Clin Proc. 1987 Feb;62(2):119-23.
2. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005 Sep 8;437(7056):270-4.
3. Garg V. Molecular genetics of aortic valve disease. Curr Opin Cardiol. 2006 May;21(3):180-4.
4. Nigam V, Srivastava D. Notch1 represses osteogenic pathways in aortic valve cells. J Mol Cell Cardiol. 2009 Dec;47(6):828-34.