Why is the bicuspid aortic valve of my middle age patient with endocarditis so heavily calcified?

Congenital bicuspid aortic valve (BAV) is a significant risk factor for valvular calcification, occurring about 20 years earlier than people with normal tricuspid aortic valve as they age. In fact, despite its prevalence of only 1-2% in the population, BAV may account for 50% of aortic valve stenosis (1).

Two potential mechanisms could account for the propensity of patients with BAV to develop valve calcification. First, genetic mutations that  account for some of the cases of BAV disease, may also be associated with valvular calcification (1). NOTCH1 mutation is one such candidate causing early developmental defect in the aortic valve, while later causing de-repression of calcium deposition (2). A mutation of the gene for endothelial nitric oxide synthase (eNOS) involved in preventing calcification in animal and tissue experiments may be another factor (3,4).

Besides genetic explanations, alteration in the mechanical force environments of the BAV itself likely plays an important part in the premature degeneration and calcification of the valve (1). Stenotic and skewed forward flow along with increased jet velocity may increase shear forces on the valve. The resultant inflammatory response and apoptosis could lead to a diseased valve, not unlike what may be seen with tricuspid aortic valve under similar circumstances (5).


Perhaps more fascinating is the observation that fluid shear itself may influence bone morphogenetic protein expression, further contributing to valvular calcification (6).

Bonus Pearl: Did you know that the risk of infective endocarditis may be much higher (>20-fold) among patients with BAV compared to those with triscuspid aortic valve (7)?

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1. Yap CH, Saikrishanan N, Tamilselvan G, et al. The congenital bicuspid aortic valve can experience high-frequency unsteady shear stresses on its leaflet surface. Am J Physiol Heart Circ Physiol 2012; 303:H721-H731. doi:10.1152/ajpheart.00829.2011. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468455/
2. Nigam V, Srivastava D. Notch 1 represses osteogenic pathways in aortic valve cells. J Mol Cell Cardiol 2009;47:828-34. https://www.ncbi.nlm.nih.gov/pubmed/19695258
3. Rajamannan NM, Subramanian M, Stock SR, et al. Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve disease. Heart 2005;91:806-10. https://www.ncbi.nlm.nih.gov/pubmed/15894785
4. Kennedy JA, Hua X, Mishra K, et al. Inhibition of calcifying nodule formation in cultured porcine aortic valve cells by nitric oxide donors. Eur J Pharmacol 2009;602:28-35. https://www.ncbi.nlm.nih.gov/pubmed/19056377
5. Wallby L, Janerot-Sjöberg B, Steffensen T, Broqvist M. T lymphocyte infiltration in non-rheumatic aortic stenosis: a comparative descriptive study between tricuspid and bicuspid aortic valves. Heart 88: 348–351, 2002. https://www.ncbi.nlm.nih.gov/pubmed/12231589
6. Sorescu GP, Song H, Tressel SL, et al. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a nox1-based NADPH oxidase. Circ Res 2004;84:773-79. https://www.ncbi.nlm.nih.gov/pubmed/15388638
7. Kiyota Y, Corte AD, Vieira VM, et al. Risk and outcomes of aortic valve endocarditis among patients with bicuspid and tricuspid aortic valves. Open Heart J 2017;4:e000545. Doi:10.1136/opnhrt-2016-000545. https://openheart.bmj.com/content/openhrt/4/1/openhrt-2016-000545.full.pdf

Why is the bicuspid aortic valve of my middle age patient with endocarditis so heavily calcified?

My middle-aged patient with a history of mediastinal irradiation for Hodgkin’s lymphoma in his 20s now has moderate aortic regurgitation. Could his valvular disease be related to the radiation he received over 20 years ago?

Absolutely! Mediastinal irradiation is associated with several cardiac complications, including coronary artery disease, pericarditis, systolic or diastolic dysfunction and valvular disease. Valvular disease may occur in 2-37% of patients after mediastinal irradiation, is dose-dependent, and generally does not manifest until 10-20 years after the radiation exposure.1 Since mediastinal irradiation is common in young adults diagnosed with Hodgkin’s lymphoma, these complications may be seen in early middle-age or later.

Valvular retraction is usually the first radiation-induced valvular change, and most commonly leads to mitral and aortic valve regurgitation.2 This retraction tends to occur within 10 years of the radiation therapy, followed by fibrosis and calcification of the valves after 20 years.

Although the pathophysiology of radiation-induced valvular disease is not entirely understood, activation of fibrogenic growth factors (eg, tissue growth factor β1 and myofibroblasts) which promote the synthesis of collagen has been postulated.1 Additionally, irradiation of aortic interstitial cells has been shown to cause transformation to an osteogenic phenotype that produces bone morphogenic protein 2, osteopontin and alkaline phosphatase, all important factors in bone formation and possibly valvular calcification.3

Since radiation-induced heart disease is the most common cause of non-malignant morbidity and mortality in patients who have undergone mediastinal irradiation, some have recommended screening of asymptomatic patients for valvular disease every 5 years by echocardiography beginning 10 years after radiation therapy. 2  If an abnormality is found, the screening frequency should increase to every 2-3  years,  if the valvular abnormality is mild, or annually if the abnormality is moderate. For severe valvular abnormalities, the patients should be considered for valve replacement.

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    1. Gujral DM, Lloyd G, Bhattacharyya S. Radiation-induced valvular heart disease. Heart 2016;102:269–276. https://heart.bmj.com/content/heartjnl/102/4/269.full.pdf
    2. Cuomo JR, Sharma GK, Conger PD, Weintraub NL. Novel concepts in radiation-induced cardiovascular disease. World J Cardiol. 2016; 8 (9):504-519. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039353/
    3. Nadlonek NA, Weyant MJ, Yu JA, et al. Radiation induces osteogenesis in human aortic valve interstitial cells. J Thorac Cardiovasc Surg 2012;144:1466–70. doi:10.1016/j.jtcvs.2012.08.041 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665422/

Contributed by Rachel Wallwork, MD, Mass General Hospital, Boston, MA


My middle-aged patient with a history of mediastinal irradiation for Hodgkin’s lymphoma in his 20s now has moderate aortic regurgitation. Could his valvular disease be related to the radiation he received over 20 years ago?