tachycardia, and 5) moderate to severe aortic stenosis (95, 96). Patients who are not excluded 
following this initial evaluation will be considered candidates for gene therapy if the operative 
risks are considered acceptable by the consultation services. It is likely that the patient will 
undergo a noninvasive evaluation for CAD preoperatively such as an exercise or dipyrimodale 
stress thallium test, and possibly a coronary angiogram. This will be left to the. discretion of 
the consultation services. 
We will also consider the lower risk, receptor-defective, patients if their CAD has 
advanced to the point where their prognosis is poor. The studies reviewed in Section II.B.3 on 
the natural history of homozygous FH do not specifically stratify the receptive defective 
population with respect to relative risk of mortality due to CAD. We will attempt to identify 
patients within this group who have increased risks of CAD by extrapolating from studies on 
normolipidemic populations. 
The most important predictor of mortality due to CAD in the normolipidemic population 
is the anatomy of the coronary arteries as determined by coronary angiography. A selected 
review of this literature is provided below. Lim et al. followed a group of 141 patients with 
disease of the left main coronary artery (97). Mortality at 1 year was 22% and at 5 years was 
52%. Prognosis was substantially worse in patients with decreased left ventricular function. 
Bruschke et al. determined the 5-year cardiac mortality in patients with symptomatic CAD who 
underwent cardiac catheterization (98). Mortality was highest in those with 3 vessel disease 
(54%) or left main coronary obstruction (57%). These data provide a maximal estimate of 
survival for FH homozygotes who have the same coronary anatomy and left ventricular function. 
One would expect, however, that the progression of CAD to be much more accelerated in FH 
homozygotes. Therefore, the prognosis may be much worse in the homozygous FH population 
than predicted by the studies in the normolipidemic population. This hypothesis is supported by 
the study of Kramer et al. where progression of CAD was quantified by serial coronary 
angiograms in several groups of patients symptomatic with CAD including FH heterozygotes, FH 
homozygotes, and patients with no dyslipidemias (99). CAD progression was greater in 
heterozygotes than in normolipidemic patients, and was 3-fold greater in homozygotes than in 
heterozygotes. We propose that FH homozygotes with 3 vessel or left main disease have 1 and 5 
year survival rates significantly worse than 20 and 50%, respectively. 
A second group of receptor defective patients that likely has a relatively poor prognosis 
are those who have undergone coronary revascularization (usually for triple vessel or left main 
disease). An estimate of survival in this group again must be extrapolated from a broader 
experience in the normolipemic population. Patients undergoing coronary revascularization 
have a slightly improved survival over those treated medically (100). The prognosis in FH 
homozygotes will likely be much worst because even modest hypercholesterolemia accelerates 
the rate of reocclusion of the bypass grafts (101). 
The strategy for evaluating receptor defective FH patients is summarized in Fig. 1. 
Receptors defective FH homozygotes that have symptomatic CAD will undergo a noninvasive 
cardiac evaluation to identify any contraindications which would exclude the patient from the 
protocol. The exclusion criteria have been listed above. Patients with no contraindications will 
undergo further testing to better assess prognosis. Any patient with a history of coronary 
revascularization will be considered to have advanced disease and therefore will be a candidate. 
A coronary angiogram will be performed in the remaining patients to identify those with severe 
disease that have a relatively poor prognosis. Severe disease will be defined as 1) significant 
stenosis of the left main coronary artery, or 2) stenosis and/or occlusions in all three of the 
major coronary arteries (right coronary artery, left anterior descending coronary artery, 
circumflex artery). Patients with mild to moderate CAD have a more favorable prognosis and 
would not be eligible for gene therapy because the risks of this invasive and innovative therapy 
would no justify the benefits in this relatively stable population. Patients with severe disease 
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