International Journal of Cardiac Imaging 9: 291-296, 1993. �9 1993 Kluwer Academic Publishers. Printed in the Netherlands.

Long-term effect of inducible silent ischaemia on left ventricular systolic function

Richard Lim, Lorraine Dyke & Duncan S. Dymond Department of Cardiology, St Bartholomew's Hospital, London, EC1A 7BE, UK

Accepted 13 July 1993

Key words: cardiac function, coronary artery disease

Abstract

Silent myocardial ischaemia is readily detected by exercise radionuclide ventriculography in patients with coronary artery disease. In those who remain asymptomatic and event-free, it is not known whether silent ischaemia which is inducible despite anti-ischaemic medication exerts an insidious detrimental effect on left ventricular function. To study this, 34 medically treated patients (mean age 57; 26 men) underwent prospec- tive measurement of left ventricular ejection fraction (LVEF) during rest and exercise radionuclide ventricu- lography without interruption of anti-ischaemic medication at baseline and 12 months later.

There was no significant mean (standard deviation, 95% confidence interval) deterioration from baseline to 12 months in LVEF at rest (50% v 49%, SD 5; 95% CI = - 3 to + 1), peak exercise (44% v 45%, SD 8; 95% CI = - 1 to + 4) and the change in LVEF from rest to exercise (- 6% v - 4%, SD 7; 95% CI = - 1 to + 5).

Thus, in coronary artery disease patients who remain asymptomatic and event-free on medical therapy, silent myocardial ischaemia which is readily inducible at baseline despite medication does not lead per se to deterioration of left ventricular systolic function at rest or exercise over 12 months.

Introduction

The persistence of silent myocardial ischaemia de- spite conventional background anti-ischaemic medication may increase the risk of cardiac mortal- ity [1] and ischaemic morbidity e.g. acute myocar- dial infarction or unstable angina [2]. However, in patients without such overt events, it is not known whether silent ischaemia, like hypertension, has an insidious deleterious effect on left ventricular func- tion, impairment of which is the most important fac- tor limiting prognosis in coronary artery disease. Although reversible silent ischaemia may cause acute reversible left ventricular dysfunction [3], the chronic effect of readily inducible silent ischaemia on left ventricular function has not been fully eval- uated. We have therefore performed a prospective

pilot study in minimally symptomatic patients with coronary artery disease and readily inducible silent ischaemia despite anti-ischaemic medication to de- termine whether those who remain asymptomatic and event-free suffer any silent deterioration of left ventricular systolic function over time.

Methods

Population

The group of 54 patients with documented silent is- chaemia during exercise radionuclide ventriculog- raphy included 22 patients previously studied [2]. None had left main stem disease, over heart failure, left bundle branch block or atrial fibrillation. Pa-

292

Table 1. Comparison between patients with and without SMI at 12 months.

SMI (n = 24) No SMI (n =10) P 95% CI

Age (years) 56 (37-68) 59 (46-69) 0.33 - 9 to + 3 Number of diseased vessels 2 (1-3) 2 (1-3) 0.60 - 0.8 to + 0.5 Baseline rest LVEF (%) 51 (26-67) 47 (34-66) 0.39 - 6 to + 14 Baseline exercise LVEF (%) 44 (23-59) 43 (26-65) 0.81 - 9 to + 11 Baseline ALVEF (%) - 7 (- 23 to 0) - 4 (- 12 to 0) 0.09 - 7 to + 1

Values expressed as mean (range). SMI, silent myocardial ischaemia; 95% CI, 95% confidence interval for mean difference; LVEE left ventricular ejection fraction.

t ients gave i n f o r m e d consent to pa r t i c ipa t ion in this

s tudy a p p r o v e d by the local r e sea rch b o a r d and ra-

d ia t ion p ro t ec t i on adviser .

A l l had signif icant co rona ry d isease visual ly de-

f ined as _> 50% lumina l s tenosis in _> 1 m a j o r epicar-

dial artery. C o r o n a r y a n g i o g r a p h y had b e e n per-

f o r m e d because of a h is tory of chest pa in o r a posi-

t ive exerc i se e l e c t r o c a r d i o g r a m ( E C G ) . A l l pa-

t ients were r e c o m m e n d e d med ica l t r e a t m e n t on the

basis of no or min ima l s y m p t o m s ( C a n a d i a n Car-

d iovascu la r Soc ie ty Class _ I) and non-cr i t ica l an-

g iograph ic d isease which was revascu la r i sab le in 41

bu t not su i tab le or idea l for r evascu la r i sa t ion in 13

(diffuse or d is ta l d isease) .

Exercise radionuclide ventriculography

(LVEF) , was m e a s u r e d in the upr igh t pos i t i on at

rest and at p e a k exercise. In these pa t ien t s wi th doc-

u m e n t e d c o r o n a r y a r t e ry disease, r ead i ly induc ib le

si lent i s chaemia was def ined as fa i lure to inc rease

g loba l L V E F f rom res t to exerc ise which was t e rmi -

n a t e d by leg fa t igue be fo re the onse t of Chest pain.

P r io r to s tudy t e rmina t ion , d isqual i fy ing events

had occu r red in 18 pa t i en t s (an t i - i schaemic med ica -

t ions or doses a l t e red in 4, uns tab le ang ina in 4, non-

fa ta l m y o c a r d i a l in farc t ion in 3, r evascu la r i sa t ion

because of worsen ing angina in 7). Two pa t ien t s

were lost to fol low-up. The r ema in ing pa t i en t s un-

d e r w e n t r e p e a t r ad ionuc l ide ven t r i cu log raphy to

the same exerc ise w o r k l o a d and d u r a t i o n at 12

mon ths whils t t ak ing the i r usual medica t ions . The

second tes t da t a were p roces sed and ana lysed inde-

p e n d e n t l y of the first.

A f t e r c o r o n a r y angiography, pa t ien t s were se lec ted

if t hey had s i lent i s chaemia dur ing base l ine first-

pass r ad ionuc l ide ven t r i cu log raphy p e r f o r m e d

wi thou t i n t e r rup t i on of an t i - i schaemic m e d i c a t i o n

using the Scint icor mul t ic rys ta l g a m m a c a m e r a sys-

t em (Scint icor Inc, Wiscons in , U S A ) , as p rev ious ly

desc r ibed [4]. Lef t ven t r i cu la r systol ic funct ion, ex-

p re s sed as g loba l left ven t r i cu la r e jec t ion f rac t ion

Subjects

The final s tudy g roup el igible for analysis com-

p r i sed 34 pa t ien t s who fo rm the basis for this repor t .

The m e a n age was 57 years ( range 37-69), 26 were

male, and all were phys ica l ly active. Signif icant nar-

rowing was p r e se n t in 1 c o r o n a r y a r t e ry in 13 pa-

Table 2. LVEF measurements at baseline and 12 months later (n = 34).

Baseline 12-month P value 95 % CI r

Rest LVEF (%) 50 (26-67; 12) 49 (28-76; 11) 0.31 - 3 to + 1 0.92* Exercise LVEF (%) 44 (23-65; 11) 45 (25-70; 11) 0.36 - 1 to + 4 0.78* ALVEF (%) - 6 (- 23 to 0; 6) - 4 (- 22 to + 16; 9) 0.11 - 1 to + 5 0.56* Workload (kg m/min) 729 (400-1200; 187) 729 (400-1200; 166) 1.00 - 24 to + 24 0.93*

Values expressed as mean (range; standard deviation). LVEE left ventricular ejection fraction; 95% CI, 95% confidence interval for mean difference; r, correlation coefficient; *P < 0.001.

Rest LVEF (%)

80

70

60

50

40

30

20

10

/

J

i I I 0

Baseline 12-month

Fig. 1. Individual values for left ventricular ejection fraction (LVEF) at rest. Group mean values denoted by -e-.

tients, 2 arteries in 12 and 3 arteries in 9. A [3-blocker was used in 16 patients, a calcium antagonist in 21 and a long-acting nitrate in 12. No bundle branch block or new pathological Q waves were evident on a 12-lead E C G at study termination.

Stat is t ical cons idera t ions

Based on group mean reproducibility data in our laboratory, the end-point was arbitrarily taken to be a mean absolute decline of > 8% in global LVEF at rest or exercise at 12 months. The study was expect- ed to detect this with > 80% power at P < 0.05 (two- sided) for a group size of >_ 30 and standard devia- tion (SD) < 8% for mean changes in LVEF indices [5]. Student 's paired t test was used to compare baseline and 12-month LVEF values. The strength of association between variables was tested by Pearson correlation (coefficient = r) analysis. Sta- tistical significance was assumed at P < 0.05.

293

R e s u l t s

At 12 months, 24 patients still had inducible silent ischaemia and 10 did not. There were no major dif- ferences between these patients (Table 1). There were no new regional ventricular abnormalities at rest suggesting interval myocardial infarction. No

patient had developed overt heart failure. How- ever, 5 patients showed an absolute decrease of > 8% in either rest LVEF (n = 2), exercise LVEF

(n = 4), or the change in LVEF from rest to exercise (ALVEF) (n = 2). Figures i to 3 depict the individu- al data for these LVEF indices.

For the entire group, there was a mean baseline fall of 6% (range 0 to 23) in LVEF from rest to exer- cise. There was no correlation between this is- chaemic burden at baseline and the change in rest LVEF (r = 0.19) or exercise LVEF(r ; 0.04) over 12 months. Overall, there was no significant difference between group mean results at baseline and 12 months later (Table 2).

Exercise LVEF

(%)

80

70

60

50

40

30

20

10

_ _ 1 l m 0

Baseline 1 2 - m o n t h

Fig. 2. Individual values for left ventricular ejection fraction (LVEF) at peak exercise. Group mean values denoted by -o-.

294

1 5 -

ALVEF (%)

10

-5

-10

-15

-20

I -25

Baseline I

12-month

Fig. 3. Individual values for change in left ventricular ejection fraction (ALVEF) from rest to peak exercise. Group mean val- ues denoted by - e -

D i s c u s s i o n

Left ventricular dysfunction

Myocardial ischaemia which is silent cannot be in- vestigated using an animal model. However, in dogs, repetitive ischaemia may exert a cumulative effect leading to myocardial necrosis [6]. Myocar- dial stunning may occur with exercise-induced is- chaemia [7]; it has been suggested that this, if suffi- ciently prolonged or repetitive, may lead to irre- versible subendocardial damage and deterioration of left ventricular function [8]. The destructive ef- fect of repeated brief episodes of severe ischaemia on myocardial collagen matrix has been postulated to promote the ventricular dilatation characteristic of ischaemic cardiomyopathy [9]. Even in the ab- sence of overt infarction, recurrent ischaemia may cause patchy myocardial fibrosis [10,11] and thence to progressive myocardial impairment and eventual pump failure. It is possible that such a decompen- rsated left ventricle compromised by repetitive si- ilent ischaemia eventually leads to the anatomic

substrate for sudden death in previously asympto- matic individuals.

Study limitations

However, the practicality of studying the chronic effect of repetitive silent ischaemia (as opposed to susceptibility to repetitive ischaemia) on left ven- tricular function is hampered by the fundamental lack of a validated technique for direct continuous measurement of the silent ischaemic load over suf- ficiently prolonged periods. It is also well docu- mented that the detection of ambulatory ischaemia is subject to temporal variability [12,13] and there is poor concordance between Holter ischaemia dur- ing daily life and radionuclide measures of ischae- mia [14-16]. However, the superior sensitivity of left ventricular dysfunction over ST depression or angi- na [3,15,17-19] combined with the observation that silent Holter ischaemia can occur during minimal physical activity [20, 21] supported the assumption that readily inducible silent ischaemia despite anti- ischaemic medication may reflect some measure of susceptibility to recurrent silent ischaemia during daily physical activity.

We therefore elected to use the same test, i.e. ex- ercise radionuctide ventriculography, to both de- fine such susceptibility to readily inducible silent is- chaemia as well as to measure the end-point of its effect on left ventricular systolic function. Though the severity of exercise-induced left ventricular dys- function is independent of the presence or absence of angina [22], it is likely that virtually asymptomat- ic coronary patients keep physically more active than those with limiting angina. Compared with our selected population in whom medical treatment was regarded as appropriate initial management, patients recommended early coronary surgery be- cause of critical anatomical disease and severe in- ducible ischaemia probably have a greater suscepti- bil!ty to repetitive silent ischaemia, However, prac- tical considerations preclude the extended study of these high-risk patients. In our practice, the few who infrequently refuse early revascularisation do not constitute a sufficiently sizable group to study.

Possible compensatory mechanisms

Lack of deterioration in ejection fraction with time may be due to various compensatory mechanisms. Ischaemia is a potent stimulus to the development of collateral vessels which may afford some protec- tion [23, 24]. Periods of less-than-severe ischaemia which do not exceed periods of restored coronary flow do not lead to cumulative deterioration of myocardial ultrastructure [6, 25, 26]. Myocardial hi- bernation [27] and preconditioning [28] may theo- retically limit necrosis and other potentially delete- rious effects of ischaemia. Finally, hypertrophy of non-ischaemic regions may compensate to some degree for the fibrosis that is concentrated in re- peatedly ischaemic regions, and help to preserve overall ejection fraction at rest [11].

Conclusion

If deterioration had been detected in this pilot in- vestigation, confirmation by a controlled study would be needed. Deterioration would imply pro- gressive decompensation and left ventricular dys- function impacting adversely on subsequent prog- nosis. If evident as early as 12 months, such an ag- gressive effect would further favour a strategy of early revascularisation over initial medical treat- ment in asymptomatic patients with inducible is- chaemia, on the basis that revascularisation might prevent further irreversible myocardial changes not just in ischaemic but also in non-ischaemic regions [291.

Instead, we have found that in coronary artery disease patients who remain asymptomatic and event-free on medical treatment, silent ischaemia which is readily inducible at baseline despite that medical treatment is not associated with silent dete- rioration of left ventricular systolic function at rest or exercise over 12 months. This suggests that left ventricular ejection fraction at rest and exercise is not a useful therapeutic end-point at 12 months when considering whether to treat silent ischaemia.

295

Acknowledgement

This study was supported by a Project Grant from the St Bartholomew's Hospital Joint Research Board. Presented in part at the 65 ~h Scientific Ses- sions of the American Heart Association, New Or- leans, November 1992.

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