Angina pectoris and coronary artery disease in severe aortic regurgitation

Angina Pectoris and Coronary Artery Disease in Severe Aortic Regurgitation PHILIPPE TIMMERMANS,

MD, JOS L. WILLEMS, MD, JAN PIESSENS, MD, and HILAIRE DE GEEST, MD

A consecutive series of 198 patients (148 men and 50 women, mean age 51 years, range 18 to 78) with pure, isolated, severe aortic regurgitation was retrospectively studied to determine the prevalence of angiographically significant coronary artery disease (CAD) and its relation to angina pectoris and coronary risk factors. Significant CAD (coronary diameter stenoses >50%) was found in 28 patients (14%). Typical angina was present in 18% and atypical chest pain in 18%. Angina alone had a sensitivity of 57% to detect significant CAD. The predictive accuracy of a positive history of angina

was 48 % and that of a negative test 93 % . By using multivariate logistic regression, a risk score could be calculated that increased the sensitivity to 74% at equal specificity. Almost 40% of the total population had a risk score of <-2.9 (only 1 patient in this group had CAD). It is concluded that coronary atieriography can safely be omitted in many patients with severe aortic regurgitation if they have no symptoms of myocardial ischemia or risk factors known to increase its incidence. (Am J Cardiol 1988;81:828-829)

P

basea A total of 198 patients (148 men and 50 women; mean age 51 years, range 18 to 76) were selected because they fulfilled the criteria for severe AR without any concomitant valvular disease. AR was graded from the aortic angiogram on a scale from 1 to 4. Trivial or grade-l AR was defined as a puff of dye entering the left ventricle during diastole. For grade 2, significantly more dye regurgitation was required, without complete filling of the left ventricle. Complete filling was needed for grade 3. Grade 4 consisted of complete opacification in the first diastole after injection, with contrast material remaining in the left ventricle for several beats. Only cases with AR of grade 3 (n = 83) and 4 [n = 115) were included in the present study. All patients with a peak-to-peak systolic gradient across the aortic valve of >lO mm Hg were excluded. Over the last decade, coronary arteriography is routinely performed in our institution during cardiac catheterization of patients with valvular heart disease and >3O years of age. In patients <30 years of age it is performed only when manifest chest discomfort compatible with angina pectoris is present. Cardiac catheterization: Right- and left-sided cardiac catheterization, left ventriculography, aortography and selective coronary angiography were performed in all 198 patients. Left ventriculography was performed in the right anterior oblique projection and aortography in the left anterior oblique projection. Se-

atients with severe aortic regurgitation (AR) often have a history of chest pain compatible with angina pectoris. It sometimes is even one of the first symptoms. However, there is significant controversy in the reported prevalence of angina pectoris and associated coronary artery disease (CAD).1-5As a result, disagreement exists with respect to the diagnostic workup of these patients. Some investigators recommend coronary arteriography only for patients with angina pectoris1-3whereas others advocate this examination for all cases irrespective of complaints4v5 Such conclusions were based on studies with relatively small sample sizes and assessed via univariate analysis only. The present study reviews clinical and cardiac catheterization findings in 198 cases seen in our institution.

Methods Patients: All cardiac catheterizations performed between January 1972 and August 1986 were retrospectively reviewed starting from a computerized data From the Departments of Cardiology and Medical Informatics, University Hospital Gasthuisberg, Leuven, Belgium. Manuscript received August 17, 1987; revised manuscript received and accepted November 23,1987. Address for reprints: Hilaire De Geest, MD, Department of Cardiology, University Hospital Gasthuisberg, 49 Herestraat, 3000 Leuven, Belgium. 626

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lective coronary arteriography was carried out in multiple projections using the Sones technique. Since April 1975 all coronary angiograms are standardly coded in our institution by means of a CAD-reporting system.’ Significant CAD was defined as >.50% diameter reduction of a major coronary artery or its side branches. Clinical findings: The medical records pertaining to all cases were reviewed to determine the presence and characteristics of angina pectoris, atypical chest pain, dyspnea, palpitations, fatigue, vertigo or syncope. The following variables were also recorded on data collection forms: smoking habits, family history of CAD, personal history of hypertension, diabetes or myocardial infarction, body weight, height, serum cholesterol, hematocrit and use of diuretics or digitalis. The Canadian classification was used to grade angina pectoris and the New York Heart Association (NYHA) to grade the functional status. For arterial hypertension a diastolic pressure of >90 mm Hg was required. Typical angina pectoris was defined as substernal discomfort or left precordial pain precipitated by exertion, emotional stress or exposure to cold, which was promptly relieved by rest or nitrates. Cases with nocturnal angina and typical angina at rest were also included. Patients with atypical chest pain, however, were not considered as having angina pectoris. Statistical analysis: Bivariate analysis was used in frequency distributions and cross-tabulations of all variables made first for the total group and then, separately, for both sexes and for patients with and without significant CAD. Differences were tested using the chi-square analysis [with Yates correction] and Fisher exact test for categorical variables and the Student t test for quantitative variables using the SAS statistical package.8 For multivariate analysis, stepwise logistic regression was used to derive a prediction model with parameters significantly related to CAD. A multivariate risk score was calculated to stratify patients into either CAD or non-CAD. Standard methods were applied to derive sensitivity, specificity and the predictive values of a positive and negative test result9

Results Bivariate analysis results: Thirty-five patients had typical angina pectoris (29 class I or II and 6 class III or IV] and 32 (16%) had atypical chest pain. Dyspnea on exertion was present in 111 patients (56%) and palpitations in 50 (25%). Dyspnea was grade III or IV in 32. Significant CAD (coronary diameter stenoses > 50701was present in 28 patients (14%; 17 men and 11 women). In the so-called non-CAD group, 19 patients had minor narrowing of 1 or more coronary arteries and 151 patients (76%] presented with complete normal arteries (n = 170). The patients with CAD were significantly older (mean age 58 versus 50 years: p <0.005). The youngest case with CAD was a W-yearold female with familial hypercholesterolemia and presenting with significant 2-vessel disease. In the CAD group, 14 patients had l-vessel disease, 5 had 2(18%)

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TABLE I Clinical Characteristics of Patients with Aortic Regurgitation With and Without Signif/cant Coronary Artery Disease Variable

CAD Absent (n = 170)

CAD Present (n = 28)

P Value

Mean age (yrs) Mean total cholesterol

50f 12 221 f 84

58f 11 247f83

0.005

22 (13%) 47(28%) 6(4%) 47(28%)

15 (54%)

0.001

1(4%) 14(52%)

0.02

61(37%)

16(59%)

0.03

0.042

CWdl) History of SH Family history of CAD Diabetes mellitus Total cholesterol >240 mg/dl Use of diuretics Cigarette smokers Ex-cigarette smokers CAD = coronary hypertension?

58(34%) 35 (21%)

artery disease;

11 (39%)

NS NS

9 (32%)

NS

IO (36%)

NS = not significant;

NS SH = systemic

TABLE II Performance of a Multiple Logistic Risk Score for Prediction of Significant Coronary Artery Disease in Patients With Severe Aortic Regurgitation CAD

<-2.92

Absent

761182 47% i 127 4% 76177 99%

Present Predictive value

Multiple Logistic Risk Score* >-I.35 <-2.00 124/162 77% 3127 11% 1241127 98%

19/162 12% 20127 74% 19/39 49%

>-0.65 91162 6% 16127 59% 18125 84%

l Risk score coefficient = -7.82 -I- 0.082 age (years) + 0.329 (sex: male = 1; female = 2) + 1.669 angina (yes = 1; no = 0) -I- 1.089 (sex X hypertension) + 1.607 (smoking X cholesterol >240 mg/dl).

vessel disease and 8 had 3-vessel disease. One patient had significant left main disease. A distribution of some clinical characteristics is given in Table I. The CAD group was not only older (p
a28

CORONARY

DISEASE

IN AORTIC REGURGITATION

TABLE III Prevalence of Angina Pectoris and Significant Coronary Artery Disease In Patients With Angiographically Severe Aortic Regurgitation Reference

No.

Basta et al, 1975’ Graboys and Cohn, 1977* Hakki et al, 19804 Pathak et al, 1986s Current study

20 29 31 78 198

l CAD defined as coronary 50% narrowing was used.

diameter

Angina Pectoris

CAD

4’ 11 29 28

10 18 8 36 35

(14%) (36%) (37%) (14%)

stenoses

Proven

275%;

(50%) (62%) (26%) (46%) (18%)

in all other studies

Due to missing values in some variables the analysis could only be performed for 189 cases, 27 with CAD and 162 without it. A risk score of <-2.9 was 99% predictive for the absence of significant disease; i.e. it was correct in 76 out of 77 cases (Table II]. When the threshold of the risk score was lowered to -2.4, the negative predictive value still remained very high (98%; 124 of 127 cases). However, at this level 3 patients with significant CAD also were labelled as having no CAD. A risk score >-Cl.65 was 59% (16 of 27) sensitive to predict the presence of CAD. This threshold resulted in 6% (9 of 1621of false positive cases. Lowering the threshold to -1.35 increased the sensitivity to 74~0, but at the cost of a decrease in specificity to 88%.

Discussion Patients with severe AR often have a history of chest pain compatible with angina pectoris. Angina may be due to a lower coronary perfusion pressure during diastole and to an increase in wall tension secondary to increased left ventricular volume 1oad.Q Obviously, significant coronary artery narrowing also is one of the main reasons for angina pectoris in these patients. There is wide variation in the reported prevalence of angina and significant CAD in AR.1-5J0J1An-. gina pectoris has been reported from 3%12 up to 78% .l* In studies reporting consecutive cardiac catheterization cases, similarly as in the present study, the prevalence of angina varied between 26 and 62% (Table III). The prevalence of significant, angiographically proved CAD has been reported to be within a range of 13 and 37%. Of the 11 patients [mean age 48years) with pure AR reported by Pichard and associates,13none had significant coronary narrowing by arteriography. Of the 17 patients (mean age 42 years] studied by Clark et a1,143 (18%) had significant CAD. In the present study the prevalence of angina and significant CAD was 18 and 1470, respectively. The wide variation in these prevalence figures depends on the group of patients studied and on the definitions that were applied. The highest prevalence figures were reported by Richardson et all1 with patients who had received valve replacement and myocardial revascularization. In most studies the number of patients was rather small. Some investigators have included atypical chest pain in the angina class.5 In the present study this symptom was present i-n 16%. Inclusion of such pa-

tients would almost have doubled the prevalence rate of angina pectoris. Some authors have used as criterion for significant CAD a luminal narrowing of 75%j whereas another used 60% .3However, in most studies 50% was used as threshold to define angiographically significant CAD. There is general agreement that such narrowing significantly disturbs the coronary circulation in these patients when myocardial oxygen demand is increased. In the present study, the largest on severe AR reported so far, 151 patients (76%) had angiographically complete normal coronary arteries. A minor degree of CAD was present in 47 patients (24%). However, significant coronary artery stenosis (>5O%) was found in only 28 (14%). This was very similar to the prevalence rate reported by Graboys and Cohn2 but 2.5 times less than the prevalence reported by Hakki et al4 and Pathak et a1.5In the latter studies, only patients >40 years were included. The mean age in these studies was 55 f 8 and 57 f 6 years, respectively, whereas in the present study it was 51 f 11. Age was significantly related to coronary artery narrowing, not only in our bivariate analysis but also in the multivariate analysis. The patients with significant CAD also had more frequently an elevated serum cholesterol, they smoked more and had more often a history of hypertension. When these variables were used in addition to angina, a multivariate risk score could be calculated that significantly increased the power to predict the presence or absence of CAD. In the 127 patients with a risk score <-2 no CAD was present in 124, resulting in a negative predictive value of 98%. The absence of angina had a negative predictive value of 93%. At 7470, the sensitivity of the multivariate risk score also proved to be significantly greater, as opposed to 57% with almost equal specificity (88 versus 89%] for angina pectoris alone. Clinical implications: There is general agreement that coronary arteriography should be performed in every patient with severe AR and angina pectoris evaluated with cardiac catheterization.‘However, there is disagreement as to whether coronary arteriography should be performed routinely in patients with no symptoms of angina pectoris. Some advocate this procedure for all patients over the age of 46, or even 36,4,5 whereas others are opposed to such measures.2,3J5J6 Our data are in more agreement with the latter. Based on the findings from the present study it may be concluded that coronary arteriography can safely be omitted before valve replacement in many patients (up to 40%] with severe AR who have no symptoms of ischemic heart disease and who lack risk factors known to increase its incidence. Acknowledgment: We are grateful for the secretarial assistance of V. Dillemans and I. Tassens, and for the computational help given by E. Lesaffre and I. Schoolmeesters of the Medical Informatics Division.

References 1. Basta LL, Raines D, Najjar S, Kioschos JM. Clinical, haemodynomic and coronary angiographic correlates of angina pectoris in patients with severe aortic valve disease. Br Heart J 1975;37:150-157.

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2. Graboys TB, Cohn PF. The prevalence of angina pectoris and abnormal coronary arteriograms in severe aortic valvular disease, Am Heart r 1977; 93:683-686. 3. Bonchek LI, Anderson RP, Riisch J, Should coronary arteriography be performed routinely before valve replacements. Am J Cardiol 1973;31:462466. 4. Hakki AH, Kimbiris D. Iskandrion AS, Segal BL, Mintz GS, Bemis C. Angina pectoris and coronary artery disease in patients with severe aortic valvular disease. Am Heart J 1989;199:441-449. 5. Pathak R. Padmanabhan VT, Tortolani AJ, Ong LY. Hall MH, Pizzarello RA. Angina pectoris and coronary artery disease in isolated, severe aortic regurgitation. Am J CardioJ 1986;57:649-651, 6. Willems JL, Piessens J, Boel A, Van de Werf F, DeWolf L, Lesaffre E. A cardiology data base with emphasis on chronic coronary artery disease [abstr). Proc Eur Cong CardioJ 1980;7:91. 7. Willems JL, Piessens J. Implementation and experiences with a computer based coronary artery reporting and information system. In: Ripley KL, ed. Computers in Cardiology. -. Long Beach, California: IEEE Computer Society, 1977;465-470.

8. SAS User’s Guide: Statistics. 5th ed. North Carolina: SAS Institute,

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1985:956. 9. Murphy EA. Biostotistics in Medicine. Baltimore: The Johns Hopkins University Press, 1982:252. 10. Segal J, Harvey WP, Hufnagel C. A clinical study of one hundred cases of severe aortic insufficiency. Am J Med 1956;21:200-210. 11. Richardson JV, Kouchoukos NT, Wright JO, Karp RB. Combined aortic valve replacement and myocordial revascularisation: results in 220 patients. CircuJation 1979;59:75-81. 12. Goldschlager N, Pfeifer J, Cohn K, Popper R, Seizer A. The natural history of aortic regurgitation. Am J Med 1973;54:577-588. 13. Pichard AD, Smith H, Holt J. Meller J, Gorlin R. Coronary vascular reserve in left ventricular hypertrophy secondary to chronic aortic regurgitation. Am J CardioJ 1983;51:315-320. 14. Clark DG. McAnulty JH, Rahimtoola SH. Valve replacement in aortic insufficiency with left ventricular dysfunction. Circulation 1980;61:411-421. 15. St John Suttdn MG, St John Sutton M, Oldershaw P. Valve replacement without preoperative cardiac catheterization. N EngJ J Med 1981;395:12331238. 16. Brandenburg RO. No more routine catheterization for valvular heart disease? [editorial). N EngJ J Med 1981;305:1277-1278.