1. Natural history of Aortic stenosis
Dr Charles T Itty
Interventional Cardiology Fellow
John Hunter Hospital
Newcastle

2. Pre-catheter era

3. Calcareous (calcific) aortic valve stenosis was first described by Mockeberg in 1904.
Monckeberg, J. G. (1904). Virchows Archiv fur athologische Anatomie und Physiology undfur Klinische Medizin, 176, 472.

4. By 1920, many significant advances had been made in radiographic and fluoroscopic equipment and techniques.
Krohmer JS. 9 (6). Nov, 1989, Radiographics.

5. Dry, T. J. , and Willius F. A. : Am. Heart Journal, 17:138-157 (Feb

6. Dry, T. J., and Willius F. A.
Am. Heart Journal, 17: (Feb.), 1939.

7. Causes of death (n=106): Congestive heart failure, 32 patients (3o.5%)
Sudden death, 18 patients (17%)
Infective endocarditis, 5 patients (4.7%)
Acute coronary occlusion, 1 patient (0.9%)
Non cardiac cause, 50 patients (47%).
Dry, T. J., and Willius F. A.: Am. Heart Journal, 17: (Feb.), 1939.

8. ‘Majority of patients who died when the syndrome of congestive heart failure was present responded to therapy in a rather disappointing manner ...’
‘Symptoms are likely to remain in abeyance for many years, but with the onset of myocardial failure the outlook becomes serious’.
Dry, T. J., and Willius F. A.: Am. Heart Journal, 17: (Feb.), 1939.

9. Beginning of cardiac cath.

10. 1947 - Zimmerman discovered the technique of left heart cardiac catheterization.
He was later awarded the Nobel Prize for combined cardiac catheterization. 

11. occurred almost simultaneously.
The evaluation of the natural history of aortic stenosis has been difficult, because
the development of objective means for assessment of its severity by left heart catheterization, and
the initial attempts at operative treatment,
occurred almost simultaneously.

12. ‘The natural course of aortic stenosis was assembled
from clinical and postmortem studies largely from before 1955, and
from a few more recent analyses that are supported by hemodynamic information’.
Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

13. Patients included in this analysis:
Isolated valvular aortic stenosis of rheumatic aetiology.
Isolated calcific aortic stenosis with no history of rheumatic fever. (many were considered to have congenitally bicuspid valve).
The review focussed primarily on the prognostic significance of three major symptoms
angina pectoris,
syncope and
symptoms of left ventricular failure.
Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

14. ‘In determining prognosis from older studies, the problem arises of therapy for bacterial endocarditis and for congestive heart failure, which might now be considered inadequate’.
Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

15. This silent period is marked by
Symptoms usually begin during the sixth decade of life following a long latent period.
This silent period is marked by
Progressive stenosis, due to thickening and calcification
And/or by progressive myocardial dysfunction.
Once symptoms develop, the average course is short, culminating in death at an average age of 63 years.
Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

16. Data from postmortem studies
The average durations of various symptoms were:
Angina pectoris: 3 years,
Syncope: 3 years,
Dyspnea: 2 years and
Congestive heart failure: 1.5 to 2 years.
Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

17. Ross J, Braunwald E. Aortic stenosis
Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

18. Causes of death Congestive heart failure: 50-60%.
Infective endocarditis: 15-20%.
Sudden death: 15-20%.
Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

19. Sudden death Tended to occur in patients with symptoms.
65-80% of patients had history of angina pectoris, heart failure, or syncope.
12-20% of patients had evidence of old or recent myocardial infarction.
Only 3-5% of deaths appear to occur suddenly in patients without symptoms.
Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

20. Surgery for Aortic stenosis.
Surgical replacement of the aortic valve with a ball- valve prosthesis or aortic valve homograft:
Early mortality was approximately 10%.
Total mortality had averaged 23%.
In more than 80% of the survivors, the clinical result achieved has been described as good or excellent.
Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

21. Changing aetiology of AS

22. The Euro Heart Survey on Valvular Heart Disease
Iung B et al. Eur Heart J Jul;24(13):

23. What has changed?
Aortic stenosis in the 21st century is the result of 2 main pathological processes*
Congenital bicuspid aortic valves and
Atherosclerotic/calcific aortic valves.
The present patient population is older.
They have more associated coronary artery disease.
There has been improvements in the treatment of heart failure and infective endocarditis.
* Alpert JS. Am J Med Oct;123(10):875-6.

24. Bicuspid Aortic valves
They are present in 1% of all infants born (US data)#.
It is estimated that only 1 in 50 of children have clinically significant valve disease by adolescence*.
In the Olmsted County series (n=212), 27% of adults with BAV at baseline required cardiovascular surgery at 20 years of follow-up0.
They can develop clinically important aortic stenosis during late middle life, usually between the 5th and 6th decades of life#.
#Alpert JS. Am J Med Oct;123(10):875-6.
*Bonow RO et al. J Am Coll Cardiol 2006;48:e1–148.
0Samuel C et al. J. Am. Coll. Cardiol. 2010;55;

25. Degenerative calcific aortic stenosis
Degenerative calcific aortic stenosis usually manifests in individuals older than 75 years and occurs most frequently in males.
Often, these elderly patients have a number of associated co-morbid conditions which increases the surgical risk.
Townsend CM, et al. Sabiston Textbook of Surgery. 18th ed. Saunders; 2008:

26. Improvements in Surgery

27. US Data from a 1994 Nationwide Inpatient Sample
An estimated 46,397 aortic valve replacements (AVR) were performed.
In-hospital mortality occurred in
4.3% of first-time isolated AVR and
6.4% overall.
Astor BC et al. Ann Thorac Surg Dec;70(6):

28. STS Database STS U.S. cardiac surgery database, 1997
Patients in NYHA classes I or II had an operative mortality of <2%
NYHA III 3·7% and
NYHA IV 7·0%
European Heart Journal (2002) 23, 1417–1421

29. Can we generalize the results of the earlier studies to the current patient population ?

30. Retrospective study of
252 operated and
47 unoperated patients (who refused surgery)
with isolated aortic valve disease.
AVR was recommended to all patients based on clinical and hemodynamic data.
Circulation 1982; 66: 1105–10.

31. Circulation 1982; 66: 1105–10.

32. Schwarz F et al. The effect of aortic valve replacement on survival
Schwarz F et al. The effect of aortic valve replacement on survival. Circulation 1982; 66: 1105–10.

33. 362 patients with severe aortic stenosis who were screened and did not meet the inclusion/exclusion criteria for TAVI trial.
Group 1 (medical): 274 (75.7%), (64.6% had BAV).
Group 2 (surgical): 88 (24.3%).
Circulation. 2010;122[suppl 1]:S37–S42.

34. Circulation. 2010;122[suppl 1]:S37–S42.

35. Circulation. 2010;122[suppl 1]:S37–S42.

36. Medical/BAV group: Death
37.2% by 1 year
53.4% by 2 years.
Circulation. 2010;122[suppl 1]:S37–S42.

37. Medical arm of PARTNER trial

38. Severe aortic stenosis
Aortic-valve area <0.8 cm2
Mean aortic-valve gradient of 40 mm Hg or more or
Peak aortic-jet velocity of 4.0 m/s or more.
All patients had NYHA class II, III or IV symptoms.
Leon MB et al. (PARTNER Trial). NEJM. 363(17): , 2010 Oct 21.

39. Asymptomatic severe AS

41. Standard medical therapy (including BAV done in 83
Standard medical therapy (including BAV done in 83.8% patients) did not alter the natural history of severe aortic stenosis.
At the end of 1 year:
Rate of death from any cause was 50.7% and
Rate of death from cardiovascular causes was 44.6%.
Leon MB et al. (PARTNER Trial). NEJM. 363(17): , 2010 Oct 21.

42. Severe symptomatic aortic stenosis
‘One of the clearest decisions for a doctor is to recommend valve replacement for individuals with severe symptomatic aortic stenosis’.
‘Such patients have a dire outlook, with three-quarters dying within 3 years of symptom onset’.
‘Aortic valve replacement can be withheld in such patients only when compelling contraindications exist’.
Aortic stenosis. Blase A Carabello, Walter J Paulus. Lancet 2009; 373: 956–66

43. Asypmtomatic AS

44. Many patients with limited or no symptoms yet hemodynamically significant aortic stenosis are being identified with the routine use of echo and cardiac cath.
The dilemma is how best to treat these patients.

45. Contratto and Levine (1937)
180 patients with valvular AS followed up for 25 years.
They reported that sudden death:
occurred "rarely" in totally asymptomatic patients and
was often preceded by the development of symptoms.
Contratto AW eta al. Ann Intern Med 1937; 10:

46. Sudden death tended to occur in patients with symptoms.
Only 3 to 5% of the sudden deaths in acquired AS appear to occur in patients without symptoms.
It was proposed that patients with acquired valvular AS have surgery deferred until the onset of symptoms.
Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):V61-67

47. Turina J et al (1987).
Retrospective review of 73 patients with aortic stenosis.
17 asymptomatic or mildly symptomatic patients with severe AS or combined AS+AR.
None of the patients died or required valve surgery during the first 2 years.
At 5 years, 75% were event free (alive and not had surgery) and 94% survived.
Turina J et al. Eur Heart J 1987; 8:471-83

48. They concluded that asymptomatic or minimally symptomatic patients with severe AS are at low risk of death and that surgical treatment can be postponed until "marked symptoms" appear.
Turina J et al. Eur Heart J 1987; 8:471-83

49. Kelly TA et al. 51 asymptomatic patients with severe AS.
Followed up for a mean of 17 months.
21 (41%) patients became symptomatic.
Only two died of cardiac causes and both had become symptomatic for at least 3 months prior.
The conclusion was, that patients be followed up until symptoms develop.
Kelly TA et al. Am J Cardiol 1988; 61:123-30

50. Pellikka P et al. 113 asymptomatic patients with significant AS.
Mean follow-up was 20 months.
Three deaths:
2 sudden deaths
1 congestive heart failure.
In each case, the development of symptoms preceded death by at least 3 months.
Conclusion was that asymptomatic AS patients be followed up closely until symptoms develop.
Pellikka P etal. J Am Coll Cardiol 1990; 15:

51. Asymptomatic patients are at low risk for complications or mortality.
Risk of sudden death is <1% per year.
Surgical therapy should be considered as soon as the patient develops symptoms.
Steven J et al. Chest 1998;113;

52. Undertaking AVR in all asymptomatic patients would only benefit the <1% who would die suddenly before symptoms develop, while exposing all to the risks of surgery and prosthetic valve related complications.
Therefore, the thrust should be to define a high-risk group of asymptomatic patients in whom risk of no intervention is higher than that of AVR.
Aortic stenosis. Blase A Carabello, Walter J Paulus. Lancet 2009; 373: 956–66

53. Risk stratification might incorporate
Jet velocity,
Progression of valvular narrowing,
Response to exercise testing,
Co-morbidity,
Abnormally raised biomarkers,
Presence of ventricular dysfunction,
Degree of valvular calcification etc.
Aortic stenosis. Blase A Carabello, Walter J Paulus. Lancet 2009; 373: 956–66

54. 128 consecutive patients with asymptomatic, severe aortic stenosis.
Followed up for a mean of 22±18 months.
End point: Death (8 patients) or valve replacement necessitated by the development of symptoms (59 patients).
N Engl J Med 2000; 343:611-7.

55. N Engl J Med 2000; 343:611-7.

56. Five of the six deaths from cardiac disease were preceded by symptoms.
Event-free survival was
67±5% at one year,
56±5% at 2 years and
33±5% at 4 years.
Five of the six deaths from cardiac disease were preceded by symptoms.
One patient had sudden death while still asymptomatic.
N Engl J Med 2000; 343:611-7.

57. N Engl J Med 2000; 343:611-7.

58. The rate of progression of aortic-jet velocity was significantly higher in patients who had cardiac events. (0.45±0.38 vs. 0.14±0.18 m per second per year, P<0.001)

59. N Engl J Med 2000; 343:611-7.

60. In asymptomatic patients with aortic stenosis, it appears to be relatively safe to delay surgery until symptoms develop.
The presence of moderate or severe valvular calcification, together with a rapid increase in aortic- jet velocity, identifies patients with a very poor prognosis. These patients should be considered for early valve replacement.
N Engl J Med 2000; 343:611-7.

61. Peak systolic velocity ≥ 4 m/s.
622 patients with asymptomatic AS with mean follow up of 5.4±4.0 years.
Peak systolic velocity ≥ 4 m/s.
Circulation. 2005;111:

62. Predictors of symptom development
AV area
LVH.
Circulation. 2005;111:

63. Predictors of all- cause mortality.
Age
CRF
Inactivity
AV velocity
Circulation. 2005;111:

64. Most patients with asymptomatic, hemodynamically significant AS will develop symptoms within 5 years.
Sudden death without preceding symptoms occurred in 11 (4.1%) i.e. ≈1%/y.
Patients with peak velocity ≥4.5 m/s had a higher likelihood of developing symptoms (relative risk, 1.34) or having surgery or cardiac death (relative risk, 1.48).
Circulation. 2005;111:

65. Predefined end points:
107 patients with asymptomatic aortic stenosis followed up for 24 months.
Predefined end points:
Death or
AVR if symptoms or positive EST.
Circulation. 2009;120:69-75.

66. Circulation. 2009;120:69-75.

67. Score=[peak velocity (m/s)x2]+(natural logarithm of B-type natriuretic peptidex1.5)+1.5 (if female sex).
Event-free survival after 20 months was 80% for patients within the first score quartile compared with only 7% for the fourth quartile.
Circulation. 2009;120:69-75.

68. 116 consecutive asymptomatic patients with median follow up of 41 months.
Very severe isolated aortic stenosis defined by a peak aortic jet velocity (AV-Vel)≥5.0 m/s.
End points: Cardiac death or indication for aortic valve replacement according to the accepted guidelines.
Circulation. 2010;121:

69. cardiac deaths in 6 patients.
96 events
AVR in 90 patients and
cardiac deaths in 6 patients.
Sudden death without symptoms (n=1).
Congestive heart failure (n=4)
Myocardial infarction (n=1).
Circulation. 2010;121:

70. Circulation. 2010;121:

71. Circulation. 2010;121:

72. Patients with asymptomatic very severe aortic stenosis have a poor prognosis with a high event rate and a risk of rapid functional deterioration.
Early elective valve replacement surgery should therefore be considered in these patients.
Circulation. 2010;121:

73. Stenosis progression in aortic stenosis

74. Otto et al
The peak gradient changed by +12 mm Hg/yr (-10 to +34 mm Hg) and the
mean gradient changed by +8 mm Hg/yr (-7 to +23 mm Hg).
Mean reduction in aortic valve area of -0.1 cm2/yr (0.0 to -0.5 cm2).
J Am Coll Cardiol 1989; 13:545-50

75. Roger et al. Mean interval of 25 months,
Peak gradient increased to 44±16 mm Hg.
Average increase of 4.8 mm Hg/yr.
Am Heart J 1990; 2:331-38

76. Stenosis progression in AS.
Steven J et al. Chest 1998;113;

77. However, in any individual patient, this is highly variable.
Overall, on average, the aortic valve area decreases by approximately 0.1 cm2/yr and the peak instantaneous gradient increases by 10 mm Hg/yr.
However, in any individual patient, this is highly variable.
Steven J et al. Chest 1998;113;

78. Rapid Vs Slow progress.
There can be identified two distinct types of patients:
those whose conditions progress slowly and
others whose conditions progress rapidly.
There are no reliable clinical predictors to help us identify into which subgroup an individual patient will fall.
Steven J et al. Chest 1998;113;

79. Current guidelines

80. J. Am. Coll. Cardiol. 2008;52;e1-e142

81. J. Am. Coll. Cardiol. 2008;52;e1-e142

82. J. Am. Coll. Cardiol. 2008;52;e1-e142

83. J. Am. Coll. Cardiol. 2008;52;e1-e142

84. Conclusions
Currently available data suggest that careful weighing of risk and benefit does not justify the general recommendation of early elective surgery in asymptomatic patients with severe aortic stenosis.