tent nitroglycerin by applying patches for 12 hours followed by 12 nitrate-free hours, using a double-blind cross-over technique. The effect of the nitroglycerin treatment, which was evident during the first day, was largely lost during the sec- ond day and intermittent therapy, in the authors’ view, did not prevent the develop- ment of tolerance.

While statistical analysis of the mean changes in the frequency and duration of attacks might suggest this conclusion, a glance at the figures suggests that this is not justified. Thus, during day 1 on con- tinuous therapy treatment, the frequency of attacks appears to have been reduced in 8 of the 14 subjects (Figure 4). In 7 of these, a therapeutic gain on day 1 was lost during the second day on therapy. Inter- mittent therapy was also associated with a reduced frequency of episodes on day 1 in 8 of the 14 uatients. In onlv 4 of these, however, was’ the effect lost on day 2. In 4 patients it was slightly greater. Even greater benefit of the intermittent regime is suggested by review of the duration of attacks shown in Figure 4B.

Without the “aid” of statistics, the rea- sonable conclusion from these data would be that the intermittent regimen was asso- ciated with the development of less toler- ance in this study (4 of 8 vs 7 of 8). The mean values were influenced by the very great variability in the frequency and du- ration of spontaneous ischemia in these subjects. The inclusion of 6 patients in whom the patches apparently had no ef- fect or caused deterioration on day 1 con- tributed to this misleading conclusion since it is impossible to evaluate tolerance in the absence of any therapeutic effect.

Maurice McGregor, MD. FRCP Montreal, Canada

13 June 1989

1. Nabel EG, Barry J, Rocco MB, Mead K, Selwyn AP. Effects of dosing intervals on the development of tolerance to high dose transder- mal nitroglycerin. Am J Cardiol 1989;63:663- 669.

REPLY: We appreciate Dr. McGregor’s comments concerning tolerance to transdermal nitroglycerin therapy. The evidence in favor of intermittent dosing to prevent tolerance to nitroglycerin is based on data from exercise testing.‘m3 These studies have demonstrated that tolerance to nitroglycerin can be prevented, at least in part, by providing a nitrate-free inter- val. The objective endpoint for these stud- ies has been exercise tolerance. We chose the objective endpoint of ST-segment de- pression detected by FM ambulatory monitoring in order to study ischemia during daily life.4 Exercise testing and ambulatory monitoring are different methodologies, and one cannot expect a priori that they will produce the same in- formation. In addition, the data in support of intermittent dosing to prevent tolerance to transdermal nitroglycerin are mixed. While some studies have indicated that tolerance might be prevented by intermit-

tent dosing (exercise tolerance),5,6 other studies are not so straightforward.’

We also appreciated Dr. McGregor’s comments concerning individual re- sponses to intermittent dosing. If one looks carefully at Figure 4,4 it is true that several patients did benefit from the inter- mittent regimen. However, it is difficult to know the clinical utility of a post hoc, retrospective analysis. All patients were demonstrated nitrate responders before entering into the study. In addition, there were no clinical characteristics that sepa- rated those patients who benefited from intermittent dosing from those who did not. Therefore it is difficult to interpret the variable response to the intermittent regimen, other than to base our conclu- sion on the statistical means. We have rec- ommended that these initial findings be tested in a larger prospective study. This might lend additional useful information on the spectrum of individual responses.

This study evaluated the utility of an intermittent dosing regimen using high doses of transdermal nitroglycerin. Dif- ferent doses given on an intermittent basis as well as different dosing intervals might provide more efficacious treatment strate- gies.

Elizabeth G. Nabel. MD Andrew P. klwyn, MD Boston, Massachusetts

IO July 1989

1. Parker JO, Ferrell B, Lahey K, Moe G. Ef- fect of intervals between doses on the develop- ment of tolerance of isosorbide dinitrate. N Engl J Med 1987;316:1440-1444. 2. Luke R, Sharpe N, Coxon R. Transdermal nitroglycerin in angina pectoris: efficacy of in- termittent application. JACC /987;3;642-646. 3. Park JO:‘VanKoughnett KA, Fung H-L. Transdermal isosorbide dinitrate in angina pec- toris: effect of acute and sustained therapy. Am J Cardiol 1984;54:8-I 3. 4. Nabel EG, Barry J, Rocco MB, Mead K, Selwvn AP. Effects of dosine. intervals on the development of tolerance to h:gh dose transder- mal nitroglycerin. Am J Cardiol 1989;63:663- 669. 5. Schaer DH, Buff LA, Katz RJ. Sustained antianginal efficacy of transdermal nitroglycer- in patches using an overnight nitrate-free inter- val. Am J Cardiol 1988;61:46-50. 6. Cowan JC, Bourke JP, Reid DS, Julian DG. Prevention of tolerance to nitroglycerin patches by overnight removal. Am J Cardiol 1987: 60.271-275. 7. Reiniger G, Blasini R, Brugmann U, Ru- dolph W. Nitroglycerin patches in coronary ar- tery disease: can tolerance development be avoided through an interval therapy? Circula- tion 1985;72:111-431.

Acquired Bicuspid Aortic Valves

I read with interest the article on ac- quired bicuspid aortic valves by Cardella et al’ in the April issue. The investigators stated that, with the exception of 1 study in 19651,~ they were unable to find support for their concept that some bicuspid aortic valves may develop on the basis of an ac- quired disorder such as rheumatic disease rather than as a congenital malformation.

Other similar data are available, how- ever.3 5

In 198 1, we reported observations in 100 human hearts with bicuspid aortic valves, of which 50 were congeniraland 50 were acquired.’ A comparison between our 50 acquired valves and the 75 exam- ples of Cardella et al reveals similarities in mean ages (65 and 59 years, respectively) and male preponderance (82 and 73%, re- spectively). However, the relative fre- quency of fused commissures differs con- siderably. In our study, fusion of the right- left commissure predominated not only for congenital bicuspid valves but also for the acauired bicusoid state (72 and 66%. respectively). This& in contrast to the fre: quency of only 35% for right-left fusion in the study by Cardella et al.

This apparent discrepancy may be re- lated, in part, to the fact that in only 26 of our 50 hearts with acquired bicuspid aor- tic valves were the mitral valves clearly involved by rheumatic disease. Accord- ingly, some of our hearts may have repre- sented acquired stenosis of atypical con- genital bicusoid valves. in which fusion of The right-lefi commissure would be ex- pected to predominate. Other investiga- tions, cited in our study, have made simi- lar observations or have reported coexis- tent rheumatic involvement of congenital bicuspid aortic valves.

It is also of interest that acquired bicus- pid valves now represent the most com- monly observed form of rheumatic steno- sis among patients undergoing aortic valve replacement. In the setting of post- inflammatory (presumably rheumatic) disease, acquired fusion of only 1 commis- sure is found more frequently than fusion of 2,3 or no commissures. Combined data from 2 large surgical series at our institu- tion showed thatacquired bicuspid aortic valves accounted for 137 (49%) of 278 cases of postinflammatory aortic steno- sis.4,5 Furthermore, a rheumatic cause for these examples was supported by the fact that the mitral valve also was functionally abnormal in 129 (46%) of the 278 cases and was involved by apparent rheumatic disease in all 99 cases in which it was ex- cised and was available for inspection bv a pathologist.4,5

William D. Edwards, MD Rochester, Minnesota

I2 May 1989

1. Cardella JF, Kanjuh VI, Edwards JE. Asso- ciation of the acquired bicuspid aortic valve with rheumatic disease of atrioventricular valves. Am J Cardiol 1989;63:876-877. 2. Edwards JE. Pathology of left ventricular outflow tract obstruction. Circulation 1965; 31:586-599. 3. Lerer PK. Edwards WD. Coronary arterial anatomy in bicuspid aortic valve: necropsy study of 100 hearts. Br Heart J 1981;45:142- 147. 4. Subramanian R, Olson LJ, Edwards WD. Surgical pathology of pure aortic stenosis: a studv of 374 cases. Mayo Clin Proc 1984;59. 6831690. 5. Subramanian R. Olson LJ. Edwards WD. Surgical pathology of combined aortic stenosis and insuffuciency: a study of 2 I3 cases. Mayo Clin Pror 1985;60:247-254.

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