Long-term clinical course of patients with normal coronary arteriography: Follow-up study of 121 patients with normal or nearly normal coronary arteriograms

American Founded

Heart Journal

in 1925

OCTOBER

1981 Volume I 02, Number 4

CLINICAL INVESTIGATIONS

Long-term clinical course of patients with normal coronary arteriography: Follow-up study of 121 patients with normal or nearly normal coronary arteriograms To determine the long-term couree of patlents with normal coronary arteriograms, follow-up data regarding frequency of morbid cardiac events and extent of persistent cllnlcal dieabtlity ware obtained in 121 patients (72 women, 49 men; mean age 49 years) wlth normal (90%) or nearly normal (10%) coronary arterlogramr. Mean length of follow-up was 4.3 years (range 1 to 11 years). Three (2.5%) patients died wddenly and unexpectedly. Four (3.4%) sunlvlng patients suffemd documented acute myocerdial infarction (AM) subsequent to initial arterlography. Three of eeven patients who underwent repeat coronary arteriography were found to have disease in exceee of that obeerved on Initial arterlograms. The overwhelming majority (W% or 80%) of surviving patients continued to eXperieWe chest discomfort similar to that for which they underwent coronary arteriography and 75 (84%) continued to use antianginal drugs. Thus the finding of normal or nearly normal coronary artarfogramr implies a highly favorable prognosis, although it does not establish immunity from a morbid cardiac event (AMI and/or sudden depth); the likely basis for these evenb is progression of fixed ob&KWa disease, rather than coronary artery spasm or underestimation of extent of coronary disease by arteriography. (AM HEART J 102:845, 1981.)

Jeffrey M. Isner, M.D., Herbert

Deeb N. Salem, M.D., John S. Banas, Jr., M.D., and

J. Levine, M.D. Boston, Mass.

The long-term course of patients with normal coronary arteriograms is of particular interest for several reasons. First among these is evidence that complications similar to those seen in patients with fixed coronary arterial obstructive disease (CAD) may also occur in patients without fixed obstruction, due to dynamic coronary narrowing or ccspasm.“1-3 Secondly, autopsy studies of patients studied by coronary arteriography shortly before death have indicated that coronary arteriography may at times underestimate the degree of fixed coronary arterial (CA) narrowing observed at autopsy.4-6 Finally, knowledge of the clinical course of patients with normal coronary arteriograms is central to the From the Cardiology Division, England Medical Center. Received Reprint Medical

for publication

March

Department

19, 1981; accepted

requests: Jetl’rey M. Isner, M.D., Center, 171 Harrison Ave., Boston,

0002-8703/81/100845

of

+ 09$00.90/O

Box MA

0 1981

Medicine, May

15, 1981.

70, Tufts-New 02111.

The

Tufts-New

England

C. V. Mosby

Co.

concept of “therapeutic catheterization”; that alteration in a patient’s symptoms and use of medications results from information of his coronary arteriograms being normal. 7 The present investigation was therefore undertaken to define the clinical course of those patients studied in our laboratory over the past 11 years in whom the results of coronary arteriography had been interpreted as showing no evidence of hemodynamically significant CA narrowing. METHODS Patients studied. The diagnostic index of the cardiac catheterization laboratory at Tufts-New England Medical Center was reviewed for all patients in whom coronary arteriograms performed between January, 1969, and September, 1979, were interpreted as normal or nearly normal, in the absence of valvular or other forms of noncoronary heart disease. Inclusion in the study group was determined according to description of coronary arteriograms made at the time of cardiac catheterization. 645

Oclaber.

646

Isner

et al.

Table I. Mortality

Am&an

in patient course postnormal coronary arteriography Cardiac catheterization Chest pain

Age at cath Pt. Sex 0 1

2 3

F F F

1981

Heart Journal

55 44 35

EvsR

TvsAt

E R E/R

Interval cath to death (mo)

Coronary Arteriograms Description

53 60 48

T At At

data

LM

of death

Cardiac arrest Sudden heart attack Postop cardiac arrest

LAD

Nl Nl Nl

<30%N Nl Nl

LC

RCA

LVEDP (mm Hg)

EF(%)

<:O%N Nl Nl

30%N Nl Nl

12 10 4

69 78 75

EF = ejection fraction; F = female; LAD = left Abbreviations: At = atypical; Cath = catheterization; E = exertion-related; LC = left circumflex; LM = left main; LVEDP = left ventricular end-diastolic pressure; mo = months; N = percent luminal Nl = normal; Pt = patient; R = rest-related; RCA = right coronary artery; T = typical; yrs = years,

anterior diameter

descending; narrowing;

Table II. AM1 in patient course postnormal coronary arteriography Cardiac catheterization

Pt.

sex

Age at cath 0

Interval cath to AMI (mo)

Total follow-up (mo)

Chest pain EvsR

TvsAt

Coramty AMI

data

arteriogram

LM

LAD

LC

RCA

LVEDP (mm Hgj

EF&)

AM1 subsequent to initial arteriography 1.

M

2. 3. 4.

M F F

AM1 5. 6.

prior M M

47 49 59 59 to initial 18 36

84 74 53 59

88 109 112 126

R R R R

At T At At

Ant/SE Ant/TM Ant/SE Ant/SE

Nl Nl Nl Nl

Nl 309bN Nl Nl

Nl 30%N Nl Nl

309bN 2O%N Nl Nl

5 10 9 7

61 12 70 63

T At

Inf/TM Ant/SE

Nl Nl

MB 20%N

Nl Nl

Nl Nl

2 5

65 79

arteriography 20 38

R

R

Abbreviations: AM1 = acute myocardial infarction; Ant = anterior; At = atypical; Cath tion; F = female; Inf = inferior; LAD = left anterior descending; LC = left circumflex; pressure; M = male; MB = myocardial bridge; mo = months; Nl = normal: Pt = patient; docardial; T = typical; TM =-transmural; & = years.

In 109 (90%) patients, the extramural coronary arteries contained no sites of appreciable narrowing. In seven (6%) patients, one major extramural CA was narrowed < 30% in luminal diameter. In one (1%) patient, two major extramural coronary arteries were narrowed < 30% in luminal diameter. In one (1%) patient three major extramural coronary arteries were narrowed < 30% in luminal ‘diameter. Finally, in three (2%) patients, one major extramural CA was narrowed < 50% in diameter. FoIIow-up pr0t000l. The coronary arteriograms of the following patients were reevaluated for the presence of fixed CA narrowing: all patients in whom coronary arteriograms had been initially interpreted as showing any appreciable degree of luminal narrowing (11); all patients in whom ECG and enzymatic data confirmed an remote acute myocardial infarction (AMI) (6); all patients in whom there was reason to suspect that death during the follow-up period was potentially cardiac in origin (3); and all patients in whom repeat coronary arteriography was performed. (7). Follow-up status on all 121 patients was achieved through a mailed questionnaire and/or outpatient interview. In specific cases, the patient’s physician was interviewed as well to confirm medications, frequency of hospitalization, alleged MI, or in those cases of sudden death to provide information regarding its circumstances.

= catheterization; E = exertion-related; EF = ejection fracLM = left main; LVEDP = left ventricular end-diastolic R = rest-related; RCA = right coronary artery; SE = suben-

Hospital records were reviewed in all cases (36) in which a patient and/or the patient’s physician reported that there had been admission for myocardial ischemia or AMI. RESULTS The majority of these 121 patients, 72 (60%) were women. This is in contradistinction to the overall sex distribution of patients undergoing coronary arteriography in our laboratory during this same period of 11 years, most of whom (62%) were men. The mean age of these patients was 49 years (range 18 to 77 years). Mean length of follow-up was 4.3 years (range 1 to 11 years). Mortality. Of the total group of 121 patients, three (2.5%) patients, 55,44, and 35 years old at catheterization, died 53, 60, and 48 months, respectively, following catheterization (Table I). All three patients were women. Patient No. 1 had complained of typical exertion-related angina; her husband described the death as “sudden” and “unexpected,” and the patient’s physician felt that she had probably had a “sudden heart attack.” Patient No. 2 had

Volume102 Number

Clinical

4

coronary arteriography

course postnormal

647

III. Repeat arteriography in patient course postnormal coronary arteriography

Table

Pt. Sex

Age at cath LM (yrs)

Initial arteriography

LAD

LC

RCA

Interval between arteriograms (mod

coronav

1 2 3 4 5

M F M M M

32 39 44 48 49

Nl Nl Nl * Nl

Nl Nl 30%N <3O%N Nl

Nl Nl Nl Nl Nl

Nl Nl Nl Nl Nl

72 20 21 4 18

6 7

M M

49 72

Nl Nl

3o%N <30%N

30%N Nl

2o%N Nl

187 79 30

*Initial later.

failed to adequately

Nl Nl Nl 75%N* Nl Nl Nl Nl

Nl NI 5O%N <30%N Nl Nl lOO%N <30%N

Nl Nl 50-75%N Nl Nl Nl <30%N Nl

RCA Nl Nl .W%N Nl Nl Nl Nl Nl

Neg ND ND ND ND Neg ND Neg

Pt = patient;

atypical chest pain unrelated to exertion; her husband also described the death as “sudden” and “unexpected,” and the family physician attributed her death to “cardiac arrest.” Patient No. 3 also had a history of atypical chest pain. According to the cardiologist who saw her in consultation, she died of “cardiac arrest” with no identifiable etiology, 36 hours following noncardiac (abdominal) surgery. Autopsy examination was not performed in any of these three patients. The coronary arteriograms of patient No. 1 had initially been interpreted as showing a single site of < 50% luminal narrowing in the right coronary artery (RCA). The left main (LM), left anterior descending (LAD), and left circumflex (LC) coronary arteries had all been interpreted as being “normal.” Retrospective evaluation of the coronary arteriograms from this patient disclosed that the proximal one third of the RCA was narrowed by approximately 30% in diameter. In addition, there were focal sites of < 30% diameter reduction in both the mid-LAD and in the LC at the origin of the left obtuse marginal CA. Retrospective evaluation of the coronary arteriograms from patients No. 2 and No. 3 confirmed the initial interpretation that these coronary arteriograms showed no sites of appreciable luminal narrowing. AMI. Of the 118 patients who survived over the 11-year period, 25 (21%) reported having been told by a physician that they had AMI. Discussions with their physicians and review of hospital records contlrmed that 6 of the 25 patients had ECG and enzymatic evidence of AM1 (Table II). In two of these patients, myocardial infarction (MI) was transmural by ECG, while in four it was subendo-

RCA

= right

ostial lesion at time of subsequent .

72 55 56 19 57

0 0 0 0 0

0 0 0 0 0

109 33

+$ 0

0 0

provocative of luminal

75%

left coronary

LC

tPatient underwent two repeat catheterizations, 18 and 36 months following initial arteriogram. $Transmural, anterior wall AMI 74 months following initial arteriogram. Abbreviations and symbols: + = positive; 0 = negative; AM1 = acute myocardial infarction; Cath = catheterization; Ergo = ergonovine testing; F = female; LAD = left anterior descending; LC = left circumflex; LM = left main; M = male; mos = months; N = narrowing

Nl = normal;

as

LAD

4 months

ND = not done; Neg = negative;

define what was interpreted

LM

Coronary Total event foL!ow-up Ergo (mos) AMI Death

arteriography

diameter;

atieriography

Repeat coronary arteriography

coronary

artery;

yrs = years.

cardial by ECG. Two of the patients had experienced documented remote MI prior to catheterization; in the remaining four (47, 49, 59, and 59 years old at catheterization) the MI occurred 84, 74, 53, and 59 months, respectively, following catheterization. In none of these patients was MI fatal; all were alive 23 to 67 months following their infarct. Complications of AMI were limited to two patients: patient No. 1 (Table II) required dopamine for mild transient hypotension; patient No. 3 developed ventricular tachycardia in association with quinidine. induced QT interval prolongation and, after successful cardioversion, suffered cerebrovascular accident. The results of coronary arteriography in these six patients are listed in Table II. In patient No. 5, an B-year-old male with a previously documented transmural inferior wall MI, a myocardial bridge had been identified at the midportion of the LAD; the origin and course of the extramural coronary arteries were otherwise normal. On retrospective evaluation of the coronary arteriograms in patient No. 1, a 47-year-old man with prior subendocardial anterior MI, 30% RCA narrowing was retrospectively identified. In patient No. 2, focal sites of 30%, 30%, and 20% diameter reduction were recognized in the LAD, LC, and RCA, respectively. Repeat catheterization in patient No. 2 post-MI (done elsewhere 6 years following initial study) disclosed total occlusion of the LAD, which filled retrograde from the posterior descending branch of the RCA. The LC and RCA were described as containing only minor lesions; the left ventriculogram appeared “slightly abnormal.” Repeat catheterization. Seven patients underwent

odobnr,lsa1

648

Isner et al.

AmeticanHeartJoumal

Typical CP R E

CHEST PAIN

CP postcath No CP postcath inished

Totals

Atypical CP E R

361~

6

19 14)

18 131

5

4

3

8

41

10

22

26

Numbers in ~aanhesn mier to number of patients in whom chest psm impmwd ( iB. bss chest pain I post-cath. Abbmviatimu: catb = r&mmriition; R = mst-mlamd.

Hg. i . Clinical course of chest pain subsequent ography in 118 surviving patients with normal normal coronary arteriograms.

to arterior nearly

repeat catheterization following an initial arteriogram that had been interpreted as normal or nearly normal (Table III). In one patient (No. 4) with atypical chest pain and normal resting ECG, a left ostial lesion was documented 4 months after initial arteriography had failed to adequately define a fixed lesion; this patient subsequently underwent successful coronary artery bypass graft surgery. A second patient (No. 6) underwent repeat arteriography 5 months following transmural anteroseptal MI at which time totally occluded LAD was seen to fill retrograde from the posterior descending- CA. Retrospective analysis of the initial coronary arteriograms obtained 74 months prior to AM1 disclosed that the LAD, LC, and RCA were each narrowed I 30% in luminal diameter. Progression of CAD was also documented in another patient (No. 3) compared to initial study performed 21 months earlier, although the extent of disease at time of the second study was still quite limited. In the remaining four patients, appearance of repeat arteriograms was identical to that obtained in the earlier study, including one patient (No. 5) who was studied on three different occasions by three different laboratories. Provocative testing with ergonovine maleate failed to elicit focal coronary arterial narrowing in all three patients (Nos. 1,5, and 7) in whom the drug was administered during repeat study. Cheat pain. Of the 118 surviving patients in the present study, only 24 (20%) experienced resolution of their chest discomfort following cardiac catheter-

CP = chest pm:

E = exertion-&ted,

Fig. 2. Clinical course of cheat pain analyzed as a function of typical vs atypical chest pain and exertion vs rest-related chest pain in 99 patients whose description of their chest discomfort allowed definite categorization. Atypical is defined as chest pain unresponsive to nitroglycerin and/or atypical for angina in terms of location, duration, and quality of pain.

ization (Fig. 1). The remaining 94 (80%) patients continued to complain of chest discomfort similar to that which brought them to arteriography. The majority (70 patients, 60%) maintained that their chest discomfort was unchanged, while 12 (10%) complained that it was worse; 12 -(lo%) patients stated that although persistent, their chest pain diminished in the period following coronary angiography. Thus for the overwhelming majority of patients, the nature, frequency, and intensity of their chest pain were unaffected by the information that their coronary arteriograms were normal. Resolution of chest pain was analyzed as a function both of typical vs atypical chest pain, and exertion vs rest-related chest pain among those patients in whom these aspects of their chest pain could be readily categorized (Fig. 2). Atypical was defined as chest pain unresponsive to nitroglycerin (NTG) and/or atypical for angina in terms of location, duration, and quality of pain. Resolution of rest-related chest pain was more common than chest pain related to exertion (p < 0.03): of 36 patients whose chest pain occurred exclusively at rest, 12 experienced complete resolution following catheterization, and three others noted improvement (less pain). In contrast, only 8 of 63 patients with exertion-related chest pain experienced no further chest pain following catheterization. Resolution of chest pain was not related to whether the chest pain was typical or atypical of angina. Finally, persistent chest pain following catheterization resulted in

voiume102

Clinical course postnormal coronary arteriography

Number 4

649

Table IV. Antianginal drug use in patient course postnorma1 coronary arteriography No. 6) 1. Number of 118 survivors using antianginal drugs a. Nitroglycerin alone b. Nitroglycerin and propranolol c. Nitroglycerin, propranolol, long-acting nitrate d. Propranolol alone e. Propranolol and long-acting nitrate f. Long-acting nitrate alone g. Nitroglycerin and long-acting nitrate h. Nitroglycerin and nifedipine* 2. Number of 118 survivors not using antianginal drugs *One patient, empirically treated with nifedipine for persistent in absence of documented fixed or dynamic coronary arterial experienced equivocal improvement.

75 (64) 18 (15) 16 (14)

---

Coronary as percent

arteriograms of all studies

14 (12) 12 (10) 9 (7) 3 (3)

2 (2) 1 (1)

43 (36) chest pain narrowing, II

I

1969

rehospitalization of 21 (18%) of the 118 surviving patients on at least one occasion following their initial study. Use of medfcatfons. Most patients continued to use antianginal drugs, despite being told that their coronary arteriograms were normal. Of 118 surviving patients, 75 (64%) reported continued use of antianginal agents following catheterization (Table IV). NTG, alone or in combination with another antianginal agent, was the most frequently used drug: 50 of the 75 patients continued to use NTG. Of the total 118 survivors, 75 (64%) reported that NTG use prior to their catheterization or during continued use following their catheterization, was effective in relieving their chest pain. Normal coronary arferfogram frequency during 11 years. The documented increase in the number of

coronary arteriograms performed in this country over the past 10 years8 suggests a significant decline in physician threshold for recommending and/or performing coronary arteriography. We explored the possibility, based on experience in our laboratory, that this might have resulted in a corresponding increase in the number of patients referred for catheterization in whom coronary arteriograms were found to be normal. While coronary arteriog-rams as percentage of all studies performed in our laboratory over the past 10 years increased from 57% in 1969 to 70% in 1979, the fraction of these studies which were normal remained essentially unchanged (Fig. 3). DISCUSSION Overall long-term clinical course of patients postnormal coronary arteriography. The present investigation

I

1971

I

I

1973

I

I

1975

I

I

1977

I

I

1979

Fig. 3. Normal coronary arteriograms as a percentage of all coronary arteriograms performed in our catheterization laboratory over an 11-year period (solid tine below). Coronary arteriograms as percentage of all left-heart catheterization studies performed over the same time period are displayed as the dashed line above.

of the clinical course of 121 patients with normal (90%) or nearly normal (10%) coronary arteriograms, followed for 1 to 11 years (average 4.3 years) disclosed the following: (1) three (2.5%) patients died suddenly and unexpectedly; (2) four (3.4%) surviving patients suffered documented AM1 subsequent to their initial catheterization; (3) three of seven patients who underwent repeat coronary arteriography were found to have disease in excess of that observed on initial arteriograms; (4) 94 (80%) surviving patients continued to complain of chest pain similar to that for which they underwent coronary arteriography; and (5) 75 (64%) continued to use an tianginal drugs. Previous reports of clinical course postnormal coronary arteriography. Review of previous follow-up

studies of patients with normal or nearly normal coronary arteriograms (Table VP-l8 demonstrates varying findings with respect to incidence of morbid cardiac events. For example, no deaths potentially caridac in origin occurred subsequent to the finding of normal coronary arteriograms in 7 of the 10 studies (Nos. 1, 4 to 8, and 10) listed in Table V. Similarly, 5 of the 10 studies listed in Table V (Nos. 1 to 3, 6, and 10) reported

no AM1 subsequent

to

initial arteriography. Substantive small degree of postnormal coronary arteriographlc morbid events requfres 10 years average follow-up. In contrast, Proudfit et al. (No. 9, Table

650

Isner

et al.

Anwkan

Table V. Previous

long-term

studies

of patients

with

normal

coronary

arteriography Follow-Up

Coronary arteriograma First No.

author

No.

Sex kF)

Year

Ok9

P&.

2. 3. 4. 5. 6. 7.

1971 1973 1973 1974 1974 1976 1978

Waxlelg Bemiller’o Kemp” Humphries” GensiniL3 Day” MarchandiseL5

8. 9.

1980 1980

Pastemak16 F’roudfit”

86 37 200 93 46 45 22k 26 159 357 101 63 57

1.

10.

1980

Ockene18

100 43 50 52 50 58 31 45 38 38 38 60

Mean

oclobef, lssl Head Jmmml

Spasm

Deatha

b-4

age

(Yrs)

Nl

44 43 47 50 43 49 49 46 48%b445 52% > 45

81 37 2000 93 46’ 45 22 159 357 -

48

57

Near-N1 5 308N 0 0 0

2MB 26 <50WN <3O%N <3O%Np 30-5O%Ng 0

ECG

Ergo

0 0 0 0 2’ -

0 0 0 0 0 0 0 0 0 0 0 0 O/6

0

Range 6-30 12-86 12-72 12-144 6-132 24 13-108 13-108 7-66 120 120 120 6-3

Avg 15 49 36 52 24 52 42 43 120 120 120 16

No.

(C)

1 6 5

(1)” (?)” (0) 0 0 0 0 0 (2) (2) (10) 0

28 28 18 0

AMI 0 0 4’ 5’ 3’ 0 2 1 2” 8h 4”

Abbreviations and symbols: AM1 = acute myocardial infarction; At = atypical; Avg = average; C = cardiac; ECG = electrocardiographic evidence of spasm; Ergo = arteriographic spasm with ergonovine; F = female; Hasp = hospitalization; MB = rnyocardial bridge; Meds = an&angina1 medication; P = progression of disease; Post-Cath or mo = months, N = percent luminal diameter narrowing; Nl = normal; No. = number; NTG = nitroglycerin; Post = post catheterization; Pre-Cath or Pre = pm-catheterization; pts = patients, Re-cath = recatheterization; Ref = reference; T = typical; yrs-yeas; = patient died suddenly and unexpectedly; b = 2 noncoronary, 4 unknown (autopsy in one showed normal coronaries); e = all prior to study; d = worse in 8%; * = patient reported AMI; ’ = pts with valvular disease, cardiomyopathy, or chest pain of uncertain origin; 6 = at least one major coronary branch; b = only transmural infarcts were considered; ’ = “progression” (to signihcant lesion) defined as “change to at least 80% diameter reduction and minimum of 20% increase in estimated obstruction; ’ = hospitalization rate post-cath was l/10 rate during the year pre-cath, * = worse in 12%; I = transient ST-segment elevation.

V) demonstrated a higher incidence of cardiac morbidity among 521 patients with normal coronary arteriograms followed at the Cleveland Clinic for 120 months subsequent to initial arteriography. Fourteen (2.7%) patients died (deaths potentially cardiac in origin), while 13 others and one who died (total 14, 2.9%) had documented transmural AMI. Our experience of morbid cardiac events (deaths 2.5%, subsequent AMI 3.4%) was similar to that of the Cleveland Clinic. The basis for the finding of any appreciable morbidity among our patients and those reported by Proudfit et al. is likely a combined function of sample size and time. For example, substantive degree of cardiac morbidity occurred in each of the four studies listed in Table V (Nos. 3 and 4, and 8 and 9), as well as our own (combined total number morbid events of 44), in which the sample size and time of follow-up consisted of a minimum of 2500 patient-months. In contrast, among the six studies in which follow-up consisted of less than 2500 patient-months (Nos. 1 and 2, 5 to 7, and 10, Table V), cardiac morbidity was clearly rare (three events). All seven of the morbid cardiac events that occurred subsequent to arteriography among our 121 patients occurred at follow-up interval of 48 months or more. Likewise, 23 of 28 morbid cardiac events reported by Proudfit et al. occurred past 48 months of follow-up.” Thus it would seem that

exposure of the small, though definite cardiac morbidity among patients with normal coronary arteriograms requires both a representative number of patients and a reasonably long follow-up period. Consideratfon of mechanisms of morbid events postnormal coronary artwlography. The basis for a morbid

cardiac event in patients with normal coronary arteriograms has never been elucidated. Various theories such as abnormal hemoglobin-oxygen dissociation, or extensive disease of the coronary microcirculation have never been substantiated.ls. *O A number of autopsy studk+ have demonstrated that arteriographic estimates of extramural CA luminal narrowing during life may be seriously discrepant from degrees of narrowing observed in the same vessels at autopsy. At least one autopsy study2’ and two clinical studie@* 23 have suggested that such discrepancies are ~most common in arteriographic evaluation of the LM coronary ostium and artery. Repeat coronary arteriography in one of our patients with atypical chest pain, in fact, disclosed a left ostial lesion that had been suspected, but not defined, at time of initial evaluation 4 months earlier. It is unlikely, however, that arteriographic underestimation of CA narrowing provides a fully adequate explanation for cardiac morbidity in patients with normal arteriograms, for two reasons. First, although such ostial and LM lesions have

Volume102

Clinical

Number 4

course postnormal

coronary

Chest Pain Re-cath

Hosp

PmCath

Post-Cath &)

No.

Results

Pre

Post

Tfi)

-WV

0 7 5 0 46 0 22 26 0 10 6 15 0

Same Same -

62 40 71 -

3 10 17 -

-

-

75 54 44 6 33 34 10 10 10 -

p2

Same p7 P4’ P3’ F9 -

Post-Cath

NTG

Less

None

9 46 56 92 67 _ -

46 20 36d 20 _ -

54 60 54 41 _ -

0 0 0 48 32 _ -

47

25

25

66 90 90 90 I

37 40 40 40 46*

37 40 40 40 12

26 30

45

44

principal mechanism of coronary arteriography.

Dynamic coronary arterial narrowing (“spasm”), now a well-documented element of the morbidity of coronary heart disease in general,26, 2’ has been previously suggested as an explanation for cardiac morbidity in patients with normal arteriograms.” Unfortunately, there are little data to support this latter concept. First, aside from two patients studied by Pastemak et al., l6 each of whom had transient ST segment elevation at rest, none of the patients studied by us or the authors in Table V had noninvasive evidence of coronary artery spasm. Second, although most patients in the present study, as well as most patients in the studies listed in Table V, were evaluated prior to more widespread use of ergonovine provocative testing, administration of this agent in six patients of Ockene et al.l* and in three patients of ours failed to elicit evidence of focal coronary spasm. Third, our own experience as well as that of othersZ*-30 regarding ergonovine provoca-

HekW

41

651

Medicines

Same

occasionally been described as an isolated finding,” the vast majority of such lesions occur in association with more extensive fixed CAD.‘” In fact, virtually all of reported arteriographic-necropsy discrepancies regarding degrees of CA luminal narrowing have been described in patients with multiple sites of fixed obstruction; there are little data to suggest that such discrepancies occur in patients without sites of hemodynamically significant CA luminal narrowing as depicted by coronary arteriography. Second, autopsy study of at least two patients with frankly normal (no appreciable or hemodynamically significant narrowing) coronary arteriograms disclosed no sites of fixed obstructive CAD.‘“. I1 Coronary spasm unlikely morbid events postnormal

Use of

arteriography

CV

Me& Qo) 24 75 25 30

No meds @) 25

25

tive testing would suggest a positive test is rare among patients whose angina, whether it be rest or exertion-related, is atypical in terms of location, duration, and quality of discomfort, or responsiveness to NTG; so that at least for the majority of patients studied in Table V, the atypical quality of their symptoms would suggest that coronary spasm was a less likely explanation for their chest pain. As previously noted, in five of the seven patients studied by us and in 23 of the 24 patients studied by Proudfit et alI7 in whom a morbid cardiac event was documented, the nature of the chest discomfort was atypical. Finally, in most patients studied at autopsy in whom ECG findings or ergonovine provocative testing have implicated coronary spasm as the cause for MI and/or cardiac death, subsequent autopsy examination of extramural coronary arteries has disclosed > 75% cross-sectional area narrowing by atherosclerotic plaque of one or more major extramural vessels.31 CAD progression as the principal cause of morbid events postnormal coronary arteriography. Progression

of disease was documented in one of our patients who had AM1 and in an unspecified number of the Cleveland Clinic patients who died or had documented MI. Certainly, the interval between arteriography and death or infarct (> 48 months both in our patients and in 23 of 28 of Proudfit’s patients) represents a suitable time frame during which progression of CAD would not be unexpected.32-34 Furthermore, the observation that AMI and death potentially cardiac in origin were significantly (p < 0.01) more frequent in patients with mild to moderate degrees (< 30% or.30’%0to 50%) of luminal narrowing than in patients with frankly normal

oclokr,

652

Isner et al.

arteriograms,” suggests that these hemodynamically insignificant lesions may well have progressed over a 4&month period to become hemodynamically significant. Four of our seven patients in whom a morbid cardiac event occurred had similar (< 30% or 30% to 50% luminal narrowing) arteriographic findings. Progression of established atherosclerotic coronary disease fails to provide an explanation for those patients with normal coronary arteriograms in whom MI was documented prior to arteriography (two in our series, and at least seven in previous studies”. l4 or in those patients without demonstrable CA narrowing at aut0psy.l. 35 Such events have previously been explained by either coronary artery spasm or coronary artery thrombosis with subsequent recanalization in AMI, or by coronary artery spasm or “primary” cardiac arrhythmias in sudden unexpected death. Morbid cardiac events (AM1 and sudden death potentially cardiac in origin) thus do occur in a very distinct minority of patients with normal or nearly normal coronary arteriograms. Review of the clinical course and arteriographic findings in our patients and those studied by others suggests that progression of disease, rather than coronary artery spasm or underestimation of coronary narrowing as depicted by arteriography, is the basis for most, though not all, of these events. Persistence of chest pain postnormal coronary arteri-

ography. The persistence of chest pain among the overwhelming majority (80%) of our patients is in keeping with the experience of others; of the seven studies listed in Table V that addressed this problem (Nos. 1 to 4, 6, 8, and lo), all seven observed that chest pain persisted in 52% to 100% of patients with normal coronary arteriograms. Unlike most previous studies, Ockene et al.‘* being the only exception, however, chest pain which persisted among our patients was particularly tenacious with only 13% of this group of 94 patients noting any improvement in frequency or intensity. Although continued use of antianginal agents by a significant albeit minority of patients has been a consistent finding of previous investigators (24 to 44% in six of the seven studies mentioned above), continued use of these drugs in our experience was similar to that of Bemiller et al.,“’ constituting a majority (64% and 60%, respectively) of patients in the follow-up group. Our data and that accumulated by others suggest, therefore, that there is limited validity to the notion of “therapeutic” cardiac catheterization. Persistent chest pain post-normal coronary arteriography non-cardiac related. However, the contrasting

findings majority

of persistent chest pain among the great of our patients on the one hand, and

Amwkan

1081

Heart Journal

limited cardiac morbidity on the other, clearly suggests that such chest pain in most of these patients is not related to the heart. The relationship between the symptom and the heart appears to be one of anatomic rather than physiologic proximity. As a corollary, it is fair to assume that continued use of antianginal agents in these patients is based largely on their placebo value. Continued use of these antianginal drugs, however, implies some form of physician compliance, as these drugs can obviously be obtained only by physician prescription. In the Ockene et al. follow-up of 57 patients with normal coronary arteriograms, for example, patients were reportedly instructed in explicit terms that their chest pain was a “discomfort and not an ailment that threatens life,“18 yet at least 25% continued to receive prescriptions for nitrates and/or proprano101. Continued prescription of these drugs thus implies a double message from physician to patient that may be the result of the physician opting for the placebo effect as a means of pacifying the patient. Conclusions. Our findings and those of the previous investigators listed in Table V have important implications regarding indications for repeat coronary arteriography in patients with previously documented normal coronary arteriograms. First, since chest pain persists in the majority of such patients, continued symptomatic disability alone is usually not an adequate indication. Second, since evidence suggests that underestimation of coronary heart disease by coronary arteriography occurs rarely in patients with frankly normal (no appreciable luminal irregularities) coronary arteriograms, review of initial study must suggest very specific technical inadequacie@ to fully justify repeat study. Third, since ergonovine provocative testing rarely implicates coronary artery spasm as the etiology of atypical chest pain, repeat arteriography for the specific purpose of including ergonovine provocation is probably not indicated in such patients. In patients with typical chest pain and previously frankly normal arteriograms, considering the low likelihood of exposing a fixed lesion on repeat study and the small though discrete risk of ergonovine provocation, 24-hour ambulatory monitoring for ECG evidence of spasm3? and/or an empirical trial of therapy with a calcium antagonist might be the preferred approach. Repeat coronary arteriography is probably best reserved for that subgroup of patients with luminal irregularities (< 50% luminal diameter narrowing) in whom signs or symptoms of coronary heart disease persist over a progressively longer period of time following initial arteriography.

Clinical course postnormal coronary arteriography The assistance of Mrs. Linda H. Oliphant this study is gratefully acknowledged.

in the completion

of

REFERENCES

1. El-Maraghi NRH, Sealey BJ: Recurrent myocardial infarction in a young man due to coronary arterial spasm demonstrated at autopsy. Circulation 61:199, 1980. 2. Madias JE: The syndrome of variant angina culminating in acute myocardial infarction, Circulation 59:297, 1979. 3. Johnson AD, Detwiler JH: Coronary spasm, variant angina, and recurrent myocardial infarctions. Circulation 55947, 1977. 4. Vlodaver Z, Frech R, Van Tassel RA, Edwards JE: Correlation of the antemortem coronary arteriogram and the postmortem specimen. Circulation 47:162, 1973. 5. Grondin CM, Dyrda I, Pasternac A, Campeau L, Bourassa MG, Lesperance J: Discrepancies between cineangiographic and postmortem findings in patients with coronary artery disease and recent myocardial revascularization. Circulation 49:703, 1974. 6. Amett EN, Isner JM, Redwood DR, Kent KM, Baker WP, Ackerstein H, Roberta WC: Coronary artery narrowing in coronary heart disease: Comparison of cineangiograpbic and necropsy findings. Ann Intern Med 91:350, 1979. 7. Sones FM, Shiiey EK: Cine coronary arteriography. Mod Concepts Cardiovasc Dis 31:735, 1962. 8. Hansing CE: The risk and cost of coronary arteriography. I. Cost of coronary angiography in Washington state. JAMA 242:731, 1979. 9. Waxler EB, Kimbiris D, Dreifus LS: The fate of women with normal coronary arteriograms and chest pain resembling angina pectoris. Am J Cardiol28:25, 1971. 10. Bemiller CR, Pepine CJ, Rogers AK: Long-term observations in patients with angina and normal coronary arteriograms. Circulation 47:36, 1973. 11. Kemp HG, Jr, Vokonas PS, Cohn PF, Gorlin R: The angina1 syndrome associated with normal coronary arteriograms. Report of a six-year experience. Am J Med 54:735, 1973. 12. Humphries JO, Kuller L, Ross RS, Friesinger GC, Page EE: Natural history of ischemic heart disease in relation to arteriographic findings. A twelve year study of 224 patients. Circulation 49:489, 1974. 13. Gensini GG, Esente P, Kelly A: Natural history of coronary disease in patients with and without coronary bypass graft surgery. Circulation 49 and 50:11-98, 1974. 14. Day I& Sowton E: Clinical features and follow-up of patients with angina and normal coronary arteries. Lancet 2334, 1976. 15. Marchandise B, Bourassa MG, Chaitman BR, Lesperance J: Angiographic evaluation of the natural history of normal coronary arteries and mild coronary atheroslcerosis. Am J Cardiol41:216, 1978. 16. Pasternak RC, Tbibault GE, Savoia M, DeSanctis RW, Hutter AM: Cheat pain with angiographically insignificant coronary arterial obstruction. Clinical presentation and long-term follow-up. Am J Med 68:813, 1989. 17. Proudfit WL, Bruschke AVG, Sones FM, Jr: Clinical course of patients with normal or slightly or moderately abnormal coronary arteriograms: IO-year follow-up of 521 patients. Circulation 62:712, 1980. 18. Ockene IS, Shay MJ, Alpert JS, Weiner BH, Dalen JE: Unexplained chest pain in patients with normal coronary arteriograms. A follow-up study of functional status. N Engl J Med 303:1249, 1989.

653

19. Vokonas PS, Cohn PF, Klein MD, Laver MB, Gorlin R: Hemoglobin affinity for oxygen in the angina1 syndrome with normal coronary arteriograms. Am J Cardiol 26:664, 1970. 20. James TN: Editorial. Angina without coronary disease (sic). Circulation 42189, 1970. 21. Isner JM, Kishel J, Kent KM, Ronan JA, Jr, Ross Am, Roberta WC: Accuracy of angiographic determination of left main coronary arterial narrowing: Angiographic-histologic correlative analysis in 28 natients. Circulation (In press1 22. Lipton MJ, Pfeifer JF, Murphy ML, Hultgren HN: bangers of left main coronary artery lesions: Angiograpbic technique and evaluation. Invest Radio1 12447, 1977. 23. Nath PH, Velasquez G, Castaneda-Zuniga WR, Zollikofer C, Formanek A, Amplatz K: An essential view in coronary arteriography. Circulation 60:101, 1979. 24. Pritchard CL, Mudd JG, Bamer HB: Coronary ostial stenosis. Circulation 5246, 1975. 25. Bulkley BH, Roberts WC: Atherosclerotic narrowing of the left main coronary artery. A necropsy analysis of 152 patients with fatal coronary heart disease and varying degrees of left main narrowing. Circulation 53823, 1976. 26. Oliva PB, Breckinridge JC: Arteriographic evidence of coronary arterial spasm in acute myocardial infarction. Circulation 56:366, 1977. 27. Maseri A, LAbbate A, Baroldi G, Chierchia S, Marzilli M, Ballestra AM, Severi S, Parodi 0, Biagini A, D&ante A, Peaola A: Coronary vasospasm as a possible cause of myocardial infarction: A conclusion derived from the study of “meinfarction am&a.” N Enel J Med 299:1271. 1978. 28. Schroeder JS, Bo&n JL, Quin‘i RA, Clark DA, Hayden WG, Higgins CB, Wexler L: Provocation of coronary spasm with ergonovine maleate. New teat with results in 57 patients undergoing coronary arteriography. Am J Cardiol 40:487, 1977. 29. Curry RC, Pepine CJ, Sabom MB, Feldman RL, Christie LG, Vamell JH, Conti CR: Hemodynamic and myocardial metabolic effects of ergonovine in patients with cheat pain. Circulation 58:648, 1978. 30. Heupler FA, Jr: Provocative testing for coronary arterial spasm: Risk, method and rationale. Am J Cardiol 46:335, 1986. 31. Isner JM, Curry RC, Roberts WC: Necropsy findings in patient with coronary spasm. (In preparation) 32. Seides SF, Borer JS, Kent KM, Rosing DR, McIntosh CL, Epstein SE: Long-term anatomic fate of coronary-artery bypass grafts and functional status of patients five years after operation. N Engl J Med 298:1213, 1978. 33. Kramer JR, Matauda Y, Mulligan JC, Aronow M, Proudfit WL: Progression of coronary atherosclerosis. Circulation 63:519, 1981. 34. Bruschke AVG, Wijers TS, Kolsters W, Landmann J: The anatomic evolution of coronary artery disease demonstrated by coronary arteriography in 256 non-operated patients. Circulation 63:527, 1981. 35. Eliot RS, Baroldi G, Leone A: Necropsy studies in myocardial infarction with minimal or no coronary luminal reduction due to atherosclerosis. Circulation 49:1127, 1974. 36. Pepine CJ, Feldman RL, Nichols WW, Conti CR: Coronary angiography: Potentially serious sources of error in interpretation. Cardiovasc Med 2747, 1977. 37. O’Rourke RA, Ross J, Jr: Ambulatory electrocardiographic monitoring to detect ischemic heart disease. Ann Intern Med 81:695, 1974.