A. Overview [1]
[Figure] "Cardiac Cycle with Valvular Abnormalities"

1. Reduction in rheumatic heart disease has reduced incidence
2. Most common valve disorder in adults is now aortic stenosis
3. Basic Pathophysiology
   1. All valve disease places hemodynamic strain on left, right, or both ventricles
   2. Initially, the cardiovascular (CV) system compensates for the overload
   3. Chronic compensation includes cardiac muscle dysfunction (hypertrophy or dilatation)
   4. In general, pressure overloads (stenosis) lead to hypertrophy of ventricle(s)
   5. Volume overloads (regurgitation/insufficiency) lead to dilatation of ventricle(s)
   6. The muscle dysfunction inevitably leads to congestive heart failure and/or sudden death
4. Diagnosis
   1. Physical exam relatively unsensitive for mild to moderate disease
   2. Evaluation of cardiac murmurs is only 50% sensitive or specific at best [2]
   3. Greatly improved diagnostic imaging, particularly echocardiography, now available
   4. Further evaluation of murmurs uses coronary angiography to quantitate gradients
5. Major advances in treatment
   1. Medications are mildly effective for delaying some kind of invasive procedure
   2. Minimally invasive valve procedures are well tolerated by patients
   3. Heart valve replacement surgery available

1. Aortic sclerosis must be distinguished from stenosis
2. Sclerosis due to calcification of leaflets is very common in elderly persons
3. Calcification with aortic sclerosis associated with less morbidity/mortality than AS
4. AS is a clear and important risk factor for CV disease
5. AS is also a risk factor for perioperative complications in non-cardiac surgery [4]
6. Aortic sclerosis is a relatively mild CV risk factor (~1.5X) in in persons >65 years old [5]
7. Idiopathic hypertrophic subaortic stenosis (IHSS) may give similar murmur (no click)

B. Causes of AS

1. Calcification of Valve
   1. Similar to process in atherosclerosis
   2. Inflammation may be critical to process
   3. Associated with hypercholesterolemia
   4. Calcification leading to true AS is an important CV risk factor
2. Congenital hypertrophic cardiomyopathies
3. Rheumatic Heart Disease

C. Pathophysiologic Changes

1. Pressure overloaded LV leading to increased wall stress and LV hypertrophy
2. Result is initial hypertrophy of ventricular muscle and high LV end diastolic pressures
3. In early and mid course of disease, LV hypertrophy can maintain flow through AS
4. Relationship between Aortic Valve area and mean cross-valve pressure gradient [3]
   1. Valve area 3-4cm2 (normal), gradient 1.7-2.9 mmHg
   2. Valve area 2, gradient 6.6
   3. Valve area 0.9-1.0, gradient 26-32
   4. Valve area 0.7-0.8, gradient 43-51
   5. Valve area 0.6, gradient 73
   6. Valve area 0.5, gradient 105
5. Women tend to have greater wall thickness than men, worse diastolic dysfunction
6. Coagulation Defects [6,7]
   1. Acquired Type 2A von Willebrand syndrome associated with severe aortic stenosis
   2. Hayde's syndrome is aortic stenosis, gastrointestinal angiodysplasia, type 2A vWF
   3. Valve replacement with good patient-valve match reverse aortic stenosis vFW disease

D. Symptoms
[Figure] "Cardiac Cycle with Aortic Stenosis"

1. Asymptomatic
2. Angina - underperfusion of coronary artery due to poor cardiac output
3. Shortness of Breath - LV outflow obstruction with high capillary wedge pressures
4. Syncope - usually due to hypotension from poor cardiac output, associated with exertion
5. CHF - usually with LV hypertrophy, diastolic dysfunction, underperfusion

E. Physical Examination

1. Crescendo-Decrescendo Systolic Murmur
2. Best Heard at R upper sternal border in most patients; radiates to carotids
3. Carotids pulses are delayed and decreased (Pulsus parvis et tardes)
4. Inverse splitting of S2 with fixed delay (P2-Split Delay-A2)

F. Diagnosis

1. Physical Examination findings (as above)
2. Echocardiography
   1. With Doppler, can be used to determine peak gradient and valve area
   2. Also for evaluation of LV function
   3. Repeat echocardiography required to
3. Cardiac Catheterization - most accurate assessment of valve area and pressures
4. Severity of disease (and prognosis) is graded by valve area
   1. Severe AS has valve area <0.7cm2 (>50 mmHg gradient)
   2. Severe AS with symptoms is indication for surgical evaluation (see below)
   3. Severe AS without symptoms should undergo exercise testing
   4. Moderate AS has valve area <1.2cm2 (gradient 20mmHg)
5. Mild to moderate AS with symptoms should prompt search for other causes of symptoms
6. Exercise Testing Results
   1. Patients with severe AS should only exercise under physician supervision
   2. If normal exercise testing with severe AS, follow closely and limit exercise
   3. If AS becomes symptomatic on exercise testing, treat as symptomatic severe AS
7. Dobutamine echocardiography is useful for preoperative evaluation in patients with severe LV dysfunction and low transvalvular pressure gradients [8]
8. Noncardiac surgery in patients with asymptomatic severe AS is probably safe [3]

G. Treatment of AS

1. Treatment of Moderate and Severe AS [9]
   1. Often safe to delay treatment until symptoms develop
   2. However, presence of several factors make delaying therapy inadvisable:
   3. Valvular calcificiation with rapid increase in aortic-jet velocity are high risk however
   4. These patients should be considered for early surgical valve replacement
2. Medical therapy is usually suboptimal
   1. Most medical therapy does not alter mortality and may be harmful
   2. In severe AS, blood pressure is highly volume dependent; therefore, diuretics are avoided
   3. Afterload reduction was thought to be contraindicated due to hypotension risk
   4. However, nitroprusside for 24 hours improves cardiac index in severe AS with LV EF <35% and can be used as a bridge to oral afterload reduction (ACE inhibition preferred) [10]
   5. Use of vasodilators for afterload reduction in severe AS should be accompanied by careful monitoring, usually in an intensive care unit
   6. Parenteral vasodilators may be replaced by oral agents cautiously
   7. Oral agents include ACE inhibitors, angiotensin II blockers, or hydralazine/isosorbide dinitrate, again with caution and slow dose titration
   8. Slowing rate may improve symptoms by allowing LV emptying
   9. Aggressive lipid lowering (80mg qd atorvastatin, Lipitor®) does not affect calcific AS [18]
3. Valvuloplasty
   1. Majority of patients will restenose within 6 months
   2. High rate of complications perioperatively
   3. May be used as a bridge to surgery
   4. Valvuloplasty is effective for some congenital AS
4. Surgical Therapy
   1. Surgery is usually the only appropriate therapy for AS
   2. Early mortality in majority of patients is <4%
   3. May be effective in patients >80 years old, with excellent results overall
   4. Preoperative coronary angiography to evaluate for coronary artery disease (CAD)
   5. Intravenous nitroprusside may be used cautiously as a bridge to surgery [10]
   6. Patients with CAD should undergo valve replacement and coronary artery bypass (CABG)
   7. Patients with moderate AS (>20mmHg) undergoing heart surgery for other indications should probably undergo concomitant aortic valve replacement [3]
   8. Oral amiodarone 10mg/kg 6 days prior to through 6 days after surgery reduced risk of AFib ~50% and sustained VTach >50% regardless of ß-blocker use [21]
5. Percutaneous Heart Valve Implantation [20]
   1. Percuteous anterograde approach may be useful in nonsurgical candidates
   2. Novel construction with 3 pericardial leaflets;
   3. Tested with severe calcific aortic stenosis (NYHA functional class IV)
   4. Aortic valve area increased from 0.5cm2 to 1.70cm2
   5. Marked and sustained clinical and hemodynamic improvement

H. Prognosis

1. Sudden cardiac death occurs ~1%/year in patients with severe AS and LV hypertrophy
2. This risk regresses about 6 months after valve replacement
3. Angina and syncopal symptoms may become life threatening with severe disease
4. Average survival with untreated syncope <3 years, untreated angina <5 years
5. CHF cannot be treated effectively except with interventional therapy
6. Average survival with untreated aortic stenosis and CHF is <2 years

1. Relatively uncommon compared with mitral regurgitation and AS
2. Congenital
   1. Most common cause in Western countries
   2. Mixed diseases
   3. Isolated aortic bicuspid valve
3. Infection
   1. Endocarditis
   2. Rheumatic Heart Disease - most common cause in underdeveloped countries
4. Aortic Root Dilatation (± Aneurysm)
   1. Hypertension, atherosclerosis are most common in older persons
   2. Trauma is most common cause in younger persons
   3. Aortitis (inflammation) or abnormal collagen
5. Aortitis
   1. Vasculitis - Takayasu, Giant Cell (Temporal), Behcet's Syndrome, Cogan's Syndrome
   2. Infectious Aortitis - syphilis is most common
   3. HLA-B27 associated disease
6. Abnormal Collagen
   1. Marfan's Syndrome
   2. Ehlers-Danlos syndrome
   3. Osteogenesis imperfecta
7. Rupture, spontaneous or traumatic
8. Appetite Suppressants [12]
   1. Greatest increased risk with fenfluramine + phentermine
   2. Dexfenfluramine has increased risk as well, particularly with phentermine
   3. Lesions similar to carcinoid type changes
   4. Likely due to serotonin effects
   5. Overall relative risk of AI with fenfluramine or dexfenfluramine ~3X
   6. Progression of AI due to appetite suppressants does not occur or is minimal [13,14,15]
9. Subvalvular Disease: aneurysm of sinus of Valsalva, high ventricular septal defect
10. Prevalance of moderate to severe AI is ~0.5% [11]

B. Pathophysiologic Changes
[Figure] "Cardiac Cyle with Aortic Regurgitation"

1. Unique valve disease leading to left ventricular (LV) volume AND pressure overload
   1. Chronic volume increases accomplished by LV dilatation
   2. LV dilatation compensates for regurgitant volume during diastole
   3. This leads to reductions in LV ejection fraction (LV EF)
2. Peripheral volume underfill - tissues sense reduced perfusion
3. Attempt to increase cardiac output acutely leads to tachycardia
4. Drug therapy may reduce progression of LV dilatation

C. Evaluation of AI Murmer [16]

1. Decrescendo early diastolic murmur (blowing sound, high pitched)
2. Lub (S1) - Dub (S2) - diastolic insufficiency flow sound - Lub (S1) - Dub (S2) and so on
3. Best heard between 2nd and 3rd intercostal spaces on right sternal border
4. Also heard well in same area on left sternal border
5. Listen when patient stops breath at end expiration
6. Flint murmer is also heard in some patients
   1. Low pitched, late diastolic apical murmer
   2. Likely produced when regurgitant jet of blood collides with left ventricular endocardium
7. Systolic flow murmers may be present due to large volume of blood flowing out of LV
8. The typical diastolic murmer of AI is easily distinguished from mitral stenosis murmers
9. Diastolic murmers can also occur with renal failure and volume overload
10. Poor tolerance for bradycardia (which increases diastolic duration and regurgitant volume)

D. Physical and Other Findings [16,17]

1. Most eponyms found in textbooks are not matched in modern literature [17]
   1. Only the Hill Sign showed good correlation with objective findings in AI
   2. Austin-Flint Murmer, Corrigan pulse, Duroziez sign all showed very poor correlations
   3. Many of the findings only occur in severe disease (see classification below)
2. Brachial-Popliteal Pulse Gradient (Hill Sign): blood pressure in lower extremities is >20mmHg more than the blood pressure in the arms
3. "Water Hammer" (Corrigan) pulse: rapid rise with sudden collapse
4. Duroziez's Sign: to and fro murmur over femoral artery on light stethoscope compression
5. Quincke's Pulse: capillary pulsations (apply pressure to nail, get flushing then paling)
6. Widened pulse pressures: systolic >160; diastolic <40 mmHg OR difference >50mmHg
7. De Musset head bobbing sign: forward shaking of head with every heart beat
8. Other Findings
   1. Cardiomegaly
   2. High left ventricular diastolic pressures in acute AI
   3. Left ventricular dilitation (appears as increased voltage) ± strain on ECG
   4. Third heart sound (S3) may be present, particularly with heart failure
9. Echocardiography is the mainstay of monitoring progression

E. Classification of Severity (Table 1, Ref [11])

1. Reduce blood pressure (afterload reduction) to decrease regurgitant flow
   1. Nifedipine 20mg bid, but not digoxin, has been shown to delay time to valve replacement
   2. Enalapril appears to be superior to hydralazine in reducing LV dilatation at 12 months
   3. Nifedipine 20mg bid or enalapril 20mg qd did not prolong time to valve replacement versus placebo in patients with asymptomic severe AR with normal LV EF [19]
2. Avoid hear-rate slowing agents such as ß-blockers or verapamil (prolong diastole)
3. Treat congestive heart failure symptoms with diuretics, ACE-inhibitors
4. Surgical Management
   1. Valve Replacement when symptoms of heart failure (CHF) occur (NYHA Class III or IV)
   2. More severe symptoms associated with poorer outcomes with surgery
   3. Valve replacement may be indicated when LV end systolic diameter >50-55mm
   4. Surgery also recommended with LV EF <55% (even if NYHA Class II)
   5. Not appropriate for all patients because of procedure risks and prosthetic complications

References

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6. Sadler JE. 2003. NEJM. 349(4):323
7. Vincentelli A, Susen S, Le Tourneau T, et al. 2003. 349(4):343
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10. Khot UN, Novaro GM, Popovic ZB, et al. 2003. NEJM. 348(18):1756
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14. Gardin JM, Weissman NJ, Leung C, et al. 2001. JAMA. 286(16):2011
15. Mast ST, Jollis JG, Ryan T, et al. 2001. Ann Intern Med. 134(4):261
16. Choudhry NK and Etchells EE. 1999. JAMA. 281(23):2231
17. Babu AN, Kymes SM, Fryer SMC. 2003. Ann Intern Med. 138(9):736
18. Cowell SJ, Newby DE, Prescott RJ, et al. 2005. NEJM. 352(23):2389
19. Evangelista A, Tornos P, Sambola A, et al. 2005. NEJM. 353(13):1342
20. Cribier A, Eltchaninoff H, Tron C, et al. 2004. J Am Coll Cardiol. 43:698
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