Progression of coronary artery disease in patients with chest pain and normal or intraluminal disease on arteriography

Progression of coronary artery disease in patients with chest pain and normal or intraluminal disease on arteriography

The incidence of progression of coronary artery disease (CAD) in symptomatic patients was determined from serial coronary arteriograms in 27 patients with normal coronary arteries on initial study, in 17 patients with intraluminal disease (narrowings 5 20%) (ILD), and in 125 patients with occlusive disease (CAD) on the first arteriogram. Interval between arteriograms ranged from 9 months to 13 years. The normal patients progressed less frequently (14.8%) than did either the ILD patients (58.8%) or CAD patients (80%) (p < 0.001). The incidence of progression was the same in those with ILD and CAD. These data suggest that patients with normal coronaries rarely progress to CAD and then only rarely in less than 4 years. However, ILD is a serious finding on arteriography and progresses to occlusive disease frequently in symptomatic patients. Repeat coronary arteriography is warranted at short intervals in

symptomatic patients with ILD. (AM HEART J 107:35, 1984.)

Jacob I. Waft, M.D., and Michael Bachik, M.D. Newark, N. J.

The timing of repeat coronary artariography in patients who continue to be symptomatic following their initial coronary arteriogram is a common clinical problem. This is especially troublesome among patients who are found to have normal arteries or only intraluminal disease on their first study. There have been a number of reports of serial arteriograms in patients with significant coronary artery disease (CAD) withl-lo or without surgery-14 between studies but few reports of patients with mild or no disease, and in the few such studies reported,e+15-‘8 it is unclear whether the patients were restudied because of persistent recurrent chest pain. At Saint Michael’s Medical Center, 44 patients with persistent or recurrent chest pain with normal or only intraluminal disease initially have had two or more coronary arteriograms. We have compared the incidence of coronary disease progression in these patients with that seen on serial arteriograms in 125 nonoperated patients who had significant coronary artery disease on their first study.

METHODS

Patients. Between July 1,1967, and November 1, 1981, approximately 6800 coronary arteriograms were per-

From the Department of Cardiology, Saint Michael’s Medical Center.

Received for publication Jan. 7, 1982; revision received July 7, 1982; accepted July 21, 1982.

Reprint requests: Jacob I. Haft, M.D., Department of Cardiology, Saint Michael’s Medical Center, 306 High St., Newark, NJ 07102.

formed at Saint Michael’s Medical Center. Arteriography was performed by the Sones technique via a brachial artery with selective coronary injection of radiopaque dye in multiple projections. From these arteriograms, those patients who had two or more arteriograms performed because of persistence or recurrence of chest discomfort suggestive or indicative of angina of sufficient severity to warrant coronary arteriography were selected for study.

Coronary arteriography. The arteriograms were reviewed and significant lesions were considered to be present if narrowing was greater than 50% of luminal diameter. Intraluminal disease (ILD) was considered present if no lesion was greater than 20%. The sequential arteriograms were compared by three observers and progression was considered to be present if: The repeat study showed a significant lesion where none had been present on the earlier study, or if a significant lesion had progressed by 215% or to total occlusion.

Statistics. Results were subjected to statistical analysis with the use of the chi-square test and Student’s t test for unpaired data.

RESULTS

Prevalence of CAD, ILD, and normal coronaries.

There were 300 patients with technically adequate coronary angiograms who were studied with at least two catheterizations at intervals from 9 months to 13 years. Two hundred fifty-six patients were found to have significant CAD on the initial arteriogram. One hundred thirty-one of these patients underwent operations between catheterizations and were not considered further in this study. Twenty-seven of

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36 Haft and Bachik January, 1984

American Heart Journal

Table I. Progression of coronary disease

Interval (yr)

Disease <I 1 2 3 4 5 6 7 8 9 10 11 12 13 Total

Normal patients No progression 1 4 3 4 0 1 2 2 2 1 0 2 0 1 23 Progression 0 0 0 0 1 0 1 0 1 1 0 0 0 0 4

Intraluminal disease No progression 0 1 1 1 1 1 2 0 0 0 0 0 0 0 7 Progression 0 2 2 0 0 2 0 0 1 1 0 0 1 1 10

Coronary disease No progression 1 15 16 3 2 5 2 1 3 2 0 0 0 0 50 Progression 6 15 14 13 10 8 8 1 0 0 0 0 0 0 75

Table II. Progression of coronary disease -

Normal Patients Age (mean t SD)

lntraluminal disease Coronary disease

Age Age

Total patients 27 46.1 -t 7.3 17 55.5 k 6.9 125 52.9 + 8.36 Progression 4 (14.8”;,) 52.8 k 4.6 10 (58.8”;. ) 54.3 + 6.45 75 (60%) 53.5 + 8.29 No progression 23 45.0 k 8.3 7 57.3 i 8.0 50 54.9 f 7.96

Men 12 46.6 + 8.0 14 55.4 f 7.35 98 51.8 -+ 8.45 Progression 3 (25”u) 8 (57.1 ?P) 59 (60.2 oc’ )

Women 15 45.9 i 9.0 3 56.0 + 6.24 21 54.9 s 7.96 Progression 1 (6.7”~) 2 (66.7”; ) 16 (59.3’-r)

the patients were found to have normal coronary arteriograms on their initial study and 17 were found to have only ILD. The mean ages of those patients with CAD and those with ILD were 52.9 and 55.5 years, respectively, and were not significantly different, whereas those with normal coronaries were 46.1 years, significantly different from both the CAD (p < 0.001) and ILD groups (p < 0.001). There were significantly more women in the group with normal coronary arteries compared with those with CAD (p < 0.001) or ILD (p < 0.025).

Incidence of progression of disease. Progression of CAD was present on the second study in 75 patients (60 % ) who had significant lesions at initial coronary arteriography (Tables I and II). Progression was seen in 58.8% of the patients with ILD on initial study, but only in 14.8% of those who had normal coronary arteriograms on initial study. There is no significant difference between the frequency of progression in those patients with ILD and those with CAD, but the normal group showed significantly less frequent progression than did either the CAD (p < 0.0005) or the ILD group (p < 0.005). Among those patients with CAD and ILD, there was no significant difference in the incidence of progression between men and women, and there was no signifi-

cant difference in age between the groups that did and did not progress (Table III). In the normal group, there was a trend to more men progressing and younger patients not progressing to significant lesions; but neither the sex nor age difference was statistically significantly different between those who progressed and those who did not. The majority of patients with CAD were restudied in the first 4 years, whereas the time interval between studies of those with normal coronary arteriograms or ILD on initial study were distributed evenly over a 13-year span (p < 0.025). Among those studied within 4 years of the initial arteriogram, there was a trend toward more progression among those with CAD compared to those with ILD although this was not statistically significant. No normal patients showed progression in less than 4 years. Beyond 4 years, the incidence of progression was the same in the CAD group compared to the ILD group but continued to be greater in both the ILD group and CAD group compared to the normal patients 0, < 0.05).

DISCUSSION

Although there have been a number of studies reporting serial coronary arteriograms,l-ls most of the studies have reported patients who have under- gone coronary artery bypass operation between the

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Table III. Statistical results

CAD progression of normal and diseased coronaries 37

Patients Results p Value

Incidence of progression Normal Normal CAD Normal men Normal men Normal women Normal women Normal in 4 yr ILD in 4 yr ILD in 4 yr Normal in ~5 yr Normal in 25 yr ILD in 25 yr Normal men ILD men CAD men

Male/female ratio Normal Normal ILD

Ages Normal Normal ILD Normal men ILD men CAD men Normal progression ILD progression CAD progression

vs CAD vs ILD vs ILD vs CAD men vs ILD men

vs CAD women vs ILD women vs CAD in 4 yr vs Normal in 4 yr vs CAD in 4 yr vs CAD in 25 yr vs ILD in 25 yr vs CAD in 25 yr vs Normal women vs ILD women vs CAD women

“S

vs

vs

vs vs vs vs vs vs vs vs vs

CAD ILD CAD

ILD CAD CAD Normal women ILD women CAD women Normal no progression ILD no progression CAD no progression

4127 vs 75/125 4127 vs lo/11

751125 vs 10117 3/12 vs 59/98 3/12 vs 8/19 l/l5 vs 16/27 l/15 vs 2/3 l/13 vs 37195

418 vs l/13 4/8 vs 37195 3/14 vs 17/30 3114 vs 619 619 vs 17/30 3112 vs l/l5 8114 vs 213

59198 vs 16127

12/15 vs 12/15 vs 14/3 vs

46.1 -t 7.3 46.1 -+ 7.3 55.5 r 6.9 46.6 2 8.0 55.4 + 7.4 51.8 zi 8.5 52.8 + 4.6 54.3 + 6.5 53.5 k 8.3

vs vs vs vs vs vs vs vs vs

98117 p < 0.001 14/3 p < 0.025 98114 NS

55.5 k 6.9 52.9 -+ 8.4 52.9 * 8.4 45.9 -+ 9.0 56.0 ? 6.2 54.9 -t 8.0 45.0 ? 8.3 57.3 r 8.0 54.9 + 8.0

p < 0.0005 p < 0.005 NS p < 0.05 NS p < 0.005 p < 0.025 p < 0.0005 p < 0.05 NS p < 0.05 p < 0.05 NS NS NS NS

p < 0.001 p < 0.001 NS NS NS NS NS NS NS

Abbreviations: ILD = intraluminal disease; CAD = coronary artery disease.

arteriograms.l-lo There have been only a few reports of serial arteriograms in patients who were not subjected to surgery’-l* and even fewer reports of patients with normal or only minimal disease on initial arteriographic studies who were subsequently restudied.sr 15-18

Previous studies. Among those with serial arteriograms who had bypass surgery, the incidence of progression of disease in the grafted vessels (over 4 months to 2 years) has been 16% to 56% proximal to the graft and 2% to 31% distal to the graft.‘-lo Of greater interest with regard to the natural history of CAD is the progression of the disease in the nongrafted vessels. Benchimol et a1.3 noted significant progression in 28.6% of 21 nongrafted coronary arteries in 19 patients over 3 months. Griffith et al. (1) found progression in 16% of nonbypassed arteries over 6.1 -+ 0.88 months in 71 patients. Ben-Zvi et a1.g noted progression in nongrafted arteries over a mean of 10.1 months in 6% of 65 surgically treated patients. Maurer et al2 found progression of disease in 23% of segments of nongrafted vessels in 121

patients over a mean of 11.7 months while Levine et a1.4 noted that 14% of the nongrafted arteries of 67 patients had significant progression with mean intervals of 12.6 months between studies (2.4). Frick et a1.5 found progression in the nongrafted vessels in 6 of 67 surgically treated patients (13.0 months mean interval). Itscoitz et al.” reported progression in 20% of nongrafted vessels in 20 patients over 22 months. Seides et a1.7 reported that in 22 surgical patients undergoing restudy after a mean of 66 months, 46% of the nongrafted vessels had significant progression of CAD. In another study with similarly long follow-up, 66 & 10 months, Palac et al.‘O recently reported that progression of coronary artery disease occurred in 22% of the nongrafted vessels of 32 patients.”

Studies of the natural progression of CAD with serial arteriograms in nonoperated patients who had significant CAD at the initial study have also been reported. Bemis et al.” noted that of 73 patients, 52% showed progression between 2 and 75 months (mean = 23.8 months). Kimbiris et alI2 found that

38 Haft and Bachik January. 1984

American Heart Journal

significant progression of coronary artery disease occurred in 68% of 35 patients with severe initial CAD over a mean period of 15 months. In an arteriographic study by Rosch et al.‘” progression of CAD was found in 66% of 58 patients over 7 to 74 months (m = 26 months). Gensini et al.* found 76.3% of 122 patients not undergoing coronary bypass surgery to progress in severity over a mean interval of 26 months.

In their series, Kimbiris et alI2 and Gensini et a1.8 also reported patients who were normal on initial coronary arteriography. None of the 12 normal patients reported by Kimbiris et al.” progressed over 15 to 73 months. Gensini et al.s found 4.3% of 46 normal patients to progress to significant lesions over a mean of 52 months. Marchandise et alI7 found that 22 normal patients remained normal when studied a mean of 42 months later. In a series of patients subjected to repeat angiography from the Cleveland Clinic, Proudfit et a1.,18 in 1980, found that 6 (46% 1 of 13 normal patients had developed CAD. One of the normal patients had CAD on restudy at 25 months, but the others with progression to CAD were all restudied angiographically at intervals greater than S1/2 years.

Progression of CAD and normal coronaries. Our findings in patients with significant CAD are similar to those previously reported, with 60% of our patients showing significant progression over 1 to 9 years. Our patients with normal coronary arteries on initial arteriogram progressed with greater frequency (14.8%) than was reported by Gensini,B Kimbi- ris,‘” or Marchandise17 and their group but although our follow-up was almost as long as that of Proudfit et a1.,18 we did not see as many patients progressing as they reported. The mean interval between studies was not reported in Proudfit’s series and may have been longer than the 5.2 -I- 3.5 years of our patients.

Progression of ILD. There have only been two series reported that have separated out a group of patients similar to our patients with intraluminal disease. The Cleveland Clinic group followed approximately 550 patients who had normal or mild CAD on initial coronary angiography. They divided their mild CAD patients into those with lesions 130% occlusion and those with >30% < 50% lesions. Unfortunately, even in their latest report,‘* with follow-up to >lO years, only 39 of their patients had come to repeat coronary arteriography. In their first report,“j with follow-up of 10 to 88 months, one of four patients with lesions <30% progressed and 6 of 10 patients with lesions >30 < 50% developed significant disease. Subsequently,‘B with intervals between angio-

grams up to 172 months, 66% of nine patients with mild lesions progressed and 65% of 17 patients with moderate disease progressed. Merchandise et al.” also identified a group with mild disease; 7 of 26 (22%) progressed over a mean of 42 months.

We have found that 58.5 % of our 17 patients with ILD progressed to significant disease over a 13-year period (mean = 5 +- 3.7 years). These findings are similar to those reported by Proudfit et a1.18 Four of the 10 of our patients who progressed did so in less than 3 years. This incidence and rapidity of progression is similar to that found among our patients with significant disease at initial arteriographic study. It is significantly higher than among the patients with initially normal arteriograms, none of whom progressed in less than 4 years. Our findings suggest that patients with intraluminal disease have a similar prognosis with respect to development of more severe lesions as those with occlusive coronary disease and should be treated similarly. These data suggest that during surgery for significant lesions in other vessels serious consideration be given to bypassing minimally diseased arteries.

Conclusions. Patients with persistent angina1 symptoms with normal coronary arteriograms infre- quently progress to significant CAD and then only rarely before 4 years. The incidence and rate of progression of CAD in patients with ILD are the same as among patients with significant CAD on initial coronary arteriography and are over 50% in those sufficiently symptomatic to warrant repeat coronary arteriography. Therefore, the finding of minor intraluminal disease is important, carries a far worse prognosis than normal coronaries, and repeat arteriography is warranted even within 2 years if symptoms progress or become unstable.

REFERENCES

1. Griffith LSC, Achuff SC, Conti R, Humphries JO, Brawleg RK, Gott VL, Ross RS: Changes in intrinsic coronary circulation and segmental ventricular motion after saphenous vein coronary bypass graft surgery. N Engl J Med 288:589, 1973.

2. Maurer BJ, Oberman A, Holt JH, Kouchoukos NT, Jones WB, Russell RO, Reeves TJ: Changes in grafted and nongrafted coronary arteries following saphenous vein bypass grafting. Circulation 50:293, 1974.

3. Benchimol A, Harris CL, Fleming H, Desser KB: Progression of obstructive coronary artery disease after implantation of aortocoronary saphenous vein bypass grafts. J Thorac Car- diovasc Surg 68:257, 1974.

4. Levine JA, Bechtel DJ, Gorlin R, Cohn PF, Herman MV, Cohn LH, Collins JJ: Coronary artery anatomy before and after direct revascularization surgery: Clinical and cinearteriographic studies in 67 selected patients. AM HEART J 89561, 1975.

5. Frick MH, Valle M, Harjola PT, Korhola 0: Changes in native coronary arteries after coronary bypass surgery. Am J Cardiol 36~744, 1975.

6. Itscoitz SB, Redwood DR, Stinson EB, Reis RL, Epstein SE:

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Saphenous vein bypass grafts: Long-term patency and effects on the native coronary circulation. Am J Cardiol 36:739, 1975.

7. 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 296:1213, 1978.

8. Gensini GG, Esente P, Kelly A: Natural history of coronary disease ip patients with and without coronary bypass graft surgery. Circulation (suppl II) 50:98, 1974.

9. Ben-Zvi J, Hildner FJ, Javier RP, Fester A, Samet P: Progression of coronary artery disease: Cinearteriographic and clinical observations in medically and surgically treated patients. Am J Cardiol 34:295, 1974.

10. Palac RJ, Hwang MH, Meadows WR, Crake RP, Pifarre R, Loeb HS, Gunner PM: Progression of coronary artery disease in medically and surgically treated patients 5 years after randomization. Circulation 64(suppl II):17, 1981.

11. Bemis CE, Gorlin R, Kemp HG, Herman MV: Progression of coronary artery disease. Circulation 47:455, 1973.

12. Kimbiris D, Lavine P, Van Den Broek H, Najmi M, Likoff W: Devolutionary patterns of coronary atherosclerosis in patients with angina pectoris. Am J Cardiol 33:7, 1974.

13. Rosch J, Antonovic R, Trenouth RS, Rahimtoola SH, Sim DN, Dotter CT: The natural history of coronary artery stenosis. Radiology 119:513, 1976.

14. Proudfit W, Bruschke C, Sones T: Natural history of obstructive coronary artery disease ten-year study of 601 non- surgical cases. Prog Cardiovasc Dis 21:53, 1978.

15. Bemiller CR, Pepine CJ, Rogers AK: Long-term observation in patients with angina and normal coronary arteriograms. Circulation 47:36, 1973.

16. Bruschke AVG, Proudfit WL, Sones FM: Clinical course of patients with normal and slightly or moderately abnormal coronary arteriogram. Circulation 47:936, 1973.

17. Marchandise B, Bourassa MG, Chaitman BR, Lesperance J: Angiographic evaluation of the natural history of normal coronary arteries and mild coronary atherosclerosis. Am J Cardiol 41:216, 1978.

18. Proudfit WL, Bruschke AVG, Sones FM: Clinical course of patients with normal or slightly or moderately abnormal coronary arteriograms: lo-year follow-up of 521 patients. Circulation 62:712, 1980.

Fibrinopeptide A and beta thromboglobulin in patients with angina pectoris and acute myocardial infarction

The purpose of this study was to investigate the degree of platelet activation and thrombin generation in 40 patients with stable angina pectoris and in 20 patients with acute myocardial infarction (AMI) by determining the plasma beta thromboglobulin (BTG) and fibrinopeptide A (FPA) concentrations. In patients with angina pectoris increased platelet activation correlated with extensive coronary pathology; the activation, however, was not influenced by a previous myocardial infarction, use of oral anticoagulants, beta-blocking agents, or hyperlipidemia. The plasma beta thromboglobulin concentration predicted more accurately the extent of the coronary artery disease than the functional angina pectoris classification. Thrombin generation was within the normal range. In patients with acute myocardial infarction increased platelet activation and enhanced thrombin generation were found, which were not related to the infarct localization, infarct size, or the presence of complications. Consequentfy, in these patients determination of plasma beta thromboglobulin and fibrinopeptide A concentrations is useless for the diagnosis of venous thromboembolism. (AM HEART J 107:39, 1984.)

Harry van Hulsteijn, M.D., Jaap Kolff, M.D., Ernest Bribt, M.D., Arnout van der Laarse, Ph.D., and Rogier Bertina, Ph.D. Leiden, The Netherlands

From the Thrombosis and Haemostasis Research Unit, the Department of Cardiology and the Laboratory of Cardiobiochemistry, University Hospital Leiden.

There is increasing evidence that platelets play an important role in atherosclerosis and arterial throm-

Supported by the Trombosestichting Nederland.

Received for publication Feb. 10, 1982; revision received July 2, 1982; accepted July 21, 1982.

Reprint requests: L. H. van Hulsteijn, M.D., Thrombosis and Haemostasis Research Unit, Building 30, IJniversity Hospital Leiden, Rijnsburgerweg 10, 2333 AA Leiden. The Netherlands.

basis.” 2 Therefore, one might expect that platelets are activated in patients with clinical manifestations of atherosclerosis, e.g., ischemic heart disease. Such activation has indeed been demonstrated by the finding of a shortened platelet survival time,3-4 by an

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Documents

Progression of coronary artery disease in patients with chest pain and normal or intraluminal disease on arteriography