A. Study population
48 patients with aortic valve disease (aortic sclerosis and AS) identified by echocardiography with subsequent referral for invasive hemodynamic assessment of AS severity comprised the study population. All patients were referred for echocardiography by their treating physicians after a systolic murmur was detected. Patients underwent standard left and right heart catheterization for assessment of AS severity within one month of the echocardiogram. The institutional review board of Harbor-UCLA Research and Education Institute approved the study protocol. At the time of cardiac catheterization, information was obtained regarding the presence of traditional cardiovascular risk factors, including hypertension, family history of premature coronary artery disease, hyperlipidemia, smoking, and diabetes mellitus.
Patients were classified as having hypertension if they were receiving anti-hypertensive medications or had known but untreated hypertension (systolic blood pressure >140 mm Hg or diastolic blood pressure > 90 mm Hg). Family history of coronary artery disease was defined as premature coronary artery disease (occurring in men age less than 45 years and women age less than 55 years) in a first-degree relative. Hyperlipidemia was defined as use of cholesterol lowering medication or, in the absence of cholesterol lowering medication use, as having a total serum cholesterol >240 mg/dL. Smoking was defined as the use of >10 cigarettes/day. Patients receiving insulin or oral hypoglycemic agents were classified as having diabetes mellitus.
B. Cardiac catheterization
Standard retrograde left and right heart catheterization was performed to evaluate AS severity. The left ventricle was entered by the retrograde approach. Left ventricular and aortic pressures were measured simultaneously using a 6 French pigtail catheter within the left ventricle, and a second 6 French pigtail catheter positioned in the ascending aorta. Computer assisted measurements of the peak-to-peak, maximum and mean gradients were obtained. Cardiac output was measured by the Fick method. Aortic valve area was calculated using the Gorlin equation .
Aortic sclerosis was defined as the presence of aortic valve leaflet calcification or thickening (increased echogenicity) and no restriction to leaflet excursion by echocardiography and a maximum gradient by catheterization of less than 15 mm Hg. Mild AS was defined as a maximum gradient by catheterization of greater than 15 mm Hg and less than 36 mm Hg. Moderate AS was defined as a maximum gradient by catheterization of greater than 36 mm Hg and less than 64 mm Hg. Severe AS was defined as a maximum gradient by catheterization of greater than 64 mm Hg. For the statistical analysis, patients with mild AS and moderate AS were included as one group. Patients could be grouped in similar categories using the aortic valve area by the Gorlin equation (data not shown); however, the aortic valve area was not calculated for patients with a maximum gradient by catheterization of less than 15 mm Hg.
Doppler-echocardiography examinations were performed on a Hewlett-Packard 77020 AC echocardiographic scanner (Hewlett-Packard, Palo Alto, CA). The peak instantaneous transvalvular aortic jet velocity was determined by interrogating the aortic valve with continuous wave Doppler from multiple acoustic windows in order to obtain the highest jet velocity. Mean Doppler velocities were calculated by averaging the instantaneous Doppler gradients throughout the ejection period using an on-line quantification package. Three cardiac beats were averaged and the spectral display velocity curve was traced by hand. Anatomic measurements of the diameter of the left ventricular outflow tract were made from the two-dimensional parasternal long-axis view, parallel and adjacent to the aortic valve plane.
AS was defined as the presence of a peak instantaneous transaortic jet velocity of ≥ 2.0 m/sec and restriction to valve leaflet opening in the presence of normal left ventricular systolic function. Patients with AS were further classified as mild AS (transaortic jet velocity 2.0 to 3.0 m/sec), moderate AS (transaortic jet velocity 3.0 to 4.0 m/sec) and severe AS (transaortic jet velocity >4.0 m/sec) . Aortic sclerosis was defined as the presence of aortic valve leaflet calcium or leaflet thickening and a peak instantaneous transaortic jet velocity of < 2.0 m/sec.
The aortic valve leaflets were assessed for mobility and calcification according to the methods described by Bahler et. al. . The aortic valve leaflets were assessed in both the parasternal long- and short-axis views. Aortic leaflet calcification was graded according to the scale: 1 = none, 2 = ≥1 localized area of increased reflectivity but no areas of dense calcification, 3 = markedly increased reflectivity (calcification) in one leaflet but equal to or less than grade 2 changes in other leaflets, 4 = markedly increased reflectivity in 2 leaflets but equal to or less than grade 2 changes in the third leaflet, 5 = moderately increased reflectivity in all leaflets and 6 = severely increase reflectivity in all leaflets. Leaflet mobility was graded according to the scale: 1 = normal leaflet mobility, 2 = restriction of only 1 leaflet with normal mobility of the other leaflets or mild restriction of all leaflets, 3 = marked restriction of 2 leaflets or moderate restriction of all leaflets, and 4 = almost no mobility of any leaflet. The calcification and mobility scores were summed to yield the severity index.
C. Statistical analyses
Statistical analyses were performed using SAS v.6.12 (SAS Institute, Cary, NC) or GraphPad Prism, Version 3.02 (GraphPad Software, Inc., La Jolla, CA). Comparisons amongst the three groups (aortic sclerosis, mild to moderate AS and severe AS determined by cardiac catheterization) were done using one-way analysis of variance for continuous variables (age, maximum aortic valve gradient, transaortic jet velocity, severity index) and likelihood ratio chi-square for discrete variables (gender, hypertension, diabetes, hyperlipidemia, smoking, family history, aortic valve calcium, aortic valve mobility). These were overall tests to determine if any two groups differed from one another. Because cardiac catheterization gradients were not normally distributed, regression analysis with this variable was performed using square root-transformed values.