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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References
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 patient with aortic sclerosis has a loud systolic ejection murmur. What is the exact mechanism of this murmur?

We usually blame cardiac murmurs on the “turbulence” caused by blood flowing past an irregular valve surface but, believe it or not, how the murmur is created has been a matter of controversy. 1-4

For sure, murmurs are generated by disturbance of laminar blood flow (ie, turbulence) but over the years many have argued that turbulence per se fails to produce adequate acoustic force to be audible at the chest wall.2 Although challenged by some,1  the concept of “vortex shedding” borrowed from fluid dynamics is fascinating and has been proposed as a potential explanation.

Per this theory, just as a boulder causes a stream to separate and generate vortices, valves (particularly when abnormal) also create vortices. As the vortices are shed near the valve, they leave in their place relatively calm wakes which are then rapidly filled by flowing blood, creating the sound of a murmur.  

Two important variables in this theory are velocity and viscosity. When the velocity of blood flow increases substantially as in high cardiac output states (eg, fever, pregnancy), vortex shedding and the intensity of the murmur also increase. Similar phenomenon may be expected when the blood viscosity is lowered (eg, in anemia).

 

References

  1. Sabbah HN, Stein PD. Turbulent blood flow in humans: Its primary role in the production of ejection murmurs. Circ Res 1976;38: 513-24. https://www.ncbi.nlm.nih.gov/pubmed/1269101
  2. Alpert MA, Systolic murmurs. In Walker HK, Hall WD, Hurst JW. Clinical methods: The history, physical, and laboratory examinations. 3rd ed. Butterworths, Boston, 1990. https://www.ncbi.nlm.nih.gov/books/NBK345/
  3. Bruns D. A general theory of the causes of murmurs in the cardiovascular system. Am J Med 1959;27:360-74. http://www.amjmed.com/article/0002-9343(59)90002-6/fulltext
  4. Guntheroth WG. Innocent murmurs: A suspect diagnosis in non-pregnant adults. Am J Cardiol 2009;104:735-7. https://www.ncbi.nlm.nih.gov/pubmed/19699354
My patient with aortic sclerosis has a loud systolic ejection murmur. What is the exact mechanism of this murmur?

Can I assess the severity of aortic stenosis by physical exam alone?

Even in this age of high-tech medicine, physical exam is still a great starting point for assessing the severity of aortic stenosis (AS) even if you are not a skilled cardiologist like most.

Start out by listening over the right clavicle. If you don’t hear a systolic murmur, you can be pretty confident that your patient doesn’t have moderate to severe AS (>98% sensitivity, LR 0.10)1.

If you hear a systolic murmur look for combination of findings that may increase the likelihood of moderate to severe AS: slow carotid artery upstroke, reduced carotid artery volume, maximal murmur intensity at the second right intercostal space, and reduced intensity of the second heart sound.  The presence of 3 or 4 of these signs increases the likelihood of moderate to severe AS (LR 40), with less than 3 not helping much1.

When considered individually, many of the signs we often attribute to significant AS2 may not be as helpful in part because most of us are not skilled cardiologists and over the years the cause of AS has changed from primarily rheumatic heart disease-related to that advancing age and valve degeneration3.  

So it may not be surprising that murmur intensity (eg grade 3/6 or above) may have a poor sensitivity and is an unreliable predictor of the severity of AS when patients with left ventricular failure are also studied3.  Remember also that the absence of the 2nd sound may not distinguish between moderate and severe AS4

 

References

  1. Etchells E, Glenns V, Shadowitz S, et al. A bedside clinical prediction rule for detecting moderate or severe aortic stenosis. J Gen Intern Med 1998;13:699-704. https://link.springer.com/article/10.1046/j.1525-1497.1998.00207.x
  2. Etchells EE, Bell C. Robb KV. Does this patient have an abnormal systolic murmur? JAMA 1997;277:564-71. https://www.ncbi.nlm.nih.gov/pubmed/10376577
  3. Das P, Pocock C, Chambers J. The patient with a systolic murmur: severe aortic stenosis may be missed during cardiovascular examination. Q J Med 2000;93:685-8. https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/qjmed/93/10/10.1093_qjmed_93.10.685/1/930685.pdf?Expires=1500852139&Signature=TwyO6Z4fUfbPc1yiA~2xZC7jOjed0juH604DshdvRYy~VqeNQ57Sv1yE-LNsImthgQogkawMruBPdXn6PvVCVmdvXxE9QsMzQYhZ13JqXDTQhRiPBcsIBKDdROr~xbz0gp0nv-zEmjCp1M8-CXjrlVnjVtwJ6q2nIPTRW5h-CUOnDAmf8vCeJHRi2M9Dt3a4vGALDJQPaETvxKDfoADamBDtZHzzoCIH3OyXT3–jHRtv9AJI2uHlzN79Vzkh~oIrR-rI5mkHle3Yz0R3qIBY0l4P3PssMng~v-IXMNKS~Ghjav8YFTigHN23aEA5yUYllsC7hR25L6h9PA0SZP3QA__&Key-Pair-Id=APKAIUCZBIA4LVPAVW3Q
  4. Aronow WS, Kronzon I. Prevalence and severity of valvular aortic stenosis determined by Doppler echocardiography and its association with echocardiographic and electrocardiographic left  ventricular hypertrophy and physical signs of aortic stenosis in elderly patients. Am J Cardiol 1991;67:776-7. https://www.ncbi.nlm.nih.gov/pubmed/1826070
Can I assess the severity of aortic stenosis by physical exam alone?

Is my patient with aortic stenosis and no atrial fibrillation at higher risk of a cerebrovascular accident?

Several lines of evidence suggests that even in the absence of atrial fibrillation, patients with aortic stenosis (AS) may be at higher risk of a cerebrovascular accident (CVA).

A population-based study from Mayo Clinic examining the risk of cerebrovascular events (primarliy ischemic strokes or transient ischemic attacks) among patients with valvular heart disease reported severe aortic stenosis (study defined as mean pressure gradient >30 mm Hg) as a predictor of cerebrovascular event, independent from atrial fibrillation or age and at rates similar to those of mitral stenosis 1.  Similarly, the simvastatin and ezetimibe in AS study involving patients with mild-to-moderate AS not prescribed oral anticoagulation found that CHA2DS2-VASc was a major predictor of stroke, independent of atrial fibrillation or aortic valve replacement2. Thromboembolic CVA has also been reported in the setting of calcified bicuspid aortic valve with moderate-severe AS3.

Potential factors increasing the risk of CVA in AS include calcium embolization from the valve and increased microthrombus formation on the valve which may be present in 53% of stenotic aortic valves3,4.  In addition, severe AS may be a marker for other conditions that increase risk of CVA, such as atherosclerosis or prothrombotic tendencies1.

References

  1. Petty GW, Khandheria BK, Whisant JP. Predictors of cerebrovascular event and death among patients with valvular heart disease: A population-based study. Stroke 2000;31:2628-2635. http://stroke.ahajournals.org/content/strokeaha/31/11/2628.full.pdf
  2. Greve AM, Dalsgaard M, Bang CN, et al. Stroke in patients with aortic stenosis: The simvastatin and ezetimibe in aortic stenosis study. Stroke 2014;45:1939-1946. http://stroke.ahajournals.org/content/strokeaha/45/7/1939.full.pdf
  3. Mahajan N, Khetarpal V, Alfonso L. Stroke secondary to calcific bicuspid aortic valve: Case report and literature review. J Cardiol 2009;54:158-61. https://www.ncbi.nlm.nih.gov/pubmed/19632538
  4. Pleet AB, Massey EW, Vengrow ME. TIA, stroke, and the bicuspid aortic valve. Neurology 1981;31:1540-2. https://www.ncbi.nlm.nih.gov/pubmed/7198207 
Is my patient with aortic stenosis and no atrial fibrillation at higher risk of a cerebrovascular accident?