Unstable preinfarction angina pectoris (PIA) occurs in perhaps 50% of patients who experience acute myocardial infarction (AMI).¹ Several mechanisms have been put forth to account for the improved prognosis of patients who have experienced several episodes of unstable angina before AMI. Some authors² have proposed that increases in pressure distal to a subtotal occlusion during episodes of unstable angina can play an important role in opening and developing thin-walled coronary collateral vessels. This mechanism appears to have an especially important role among diabetic patients.³ However, the protective role of PIA has been observed even in the absence of significant collateral circulation.

Another protective process—and probably the most important—is ischemic preconditioning of the myocardium during brief episodes of ischemia, before a sustained occlusion. This preconditioning stimulates adenosine receptors and decreases the cellular influx of calcium, thereby reducing myocardial energy demands and limiting the extent of myocardial injury.⁴ In addition, experimental and clinical studies have shown that myocardial ischemic preconditioning preserves the anatomic microvasculature, functional vascular reactivity, and myocyte function.^5–9 Some authors¹⁰ have emphasized that ischemic preconditioning increases the susceptibility to thrombolysis, which leads to earlier reperfusion and diminished myocardial damage. These functional effects likely form the basis for greater regional and global left ventricular functional recovery and for the better clinical outcomes in patients who have experienced PIA.

In our study, we evaluated the relationship between preinfarction angina (2 months before a 1st AMI) and the extent of postinfarction myocardial injury, myocardial perfusion, contractile function, and late recovery of global left ventricular contractile function.

We prospectively enrolled, with informed consent, 46 consecutive patients who had been admitted for a 1st, uncomplicated, single-vessel-disease AMI. The study was approved by our institutional review board. The AMI diagnosis arose from the presence of 2 or more of the following characteristics: typical ischemic chest pain persisting for 30 minutes or more, ischemic electrocardiographic changes in 2 or more contiguous leads, and the characteristic increase of serum cardio-specificenzymes (serum creatine kinase was measured every 6 hours during the course of 24 hours). Patients were excluded from the study if they had left main or multivessel disease, severe valvular heart disease, previous myocardial infarction, or idiopathic dilated cardiomyopathy. In addition, we excluded patients whose initial echocardiograms were of insufficient quality for further interpretation.

After enrollment in the study, all patients were asked whether they had experienced angina during the previous 2 months; and their recent medical documents were reviewed by attending physicians from the emergency department. Preinfarction angina was defined as intermittent chest pain or other chest discomfort that had occurred within 60 days before presentation to the emergency department for AMI. However, chest-pain episodes experienced only within 24 hours before AMI were not considered to be PIA. Patients were classified into 2 groups depending on whether they had experienced PIA or a complete absence of symptoms before the abrupt onset of myocardial infarction. Twenty-seven of 46 patients (58.7%) had experienced PIA before AMI. Their results were compared with the results of the control group: the 19 patients (41.3%) who had not experienced PIA.

Low-dose dobutamine echocardiography and technetium-99m-tetrofosmin scintigraphy were performed on all patients within 7 to 10 days of the acute coronary event.

Technetium-99m tetrofosmin is a lipophilic cationicagent (diphosphine group). Its myocardial uptake appears to occur by a passive diffusion process. When injected at rest, technetium-99m tetrofosmin appears to accumulate in viable myocardial tissue; infarcts are thereby delineated as areas that lack accumulation.^12–14 When injected at stress, technetium-99m tetrofosmin accumulates in myocardial tissue in relation to myocardial blood flow¹²; therefore, ischemic areas (for example, those supplied by stenotic vessels) are detectable as areas of less accumulation. Consequently, the accumulation of radioactivity in myocardial cells as a function of relative blood flow could provide an estimate of myocardial perfusion. Each segment was considered either to have adequate post-AMI perfusion (if tracer uptake was ≥75%) or to have severely reduced or absent perfusion (if tracer uptake was <50%).

At admission, there were no statistically significant differences between the 2 groups of patients in regard to clinical and laboratory characteristics, except for a higher mean creatine kinase-MB peak level in the group without PIA (P <0.039) (Table I).

TABLE I. Clinical and Laboratory Characteristics of Patients with and without Preinfarction Angina

Thirty-nine of the 46 patients (84.8%) included in the study had experienced an AMI with ST-segment elevation and underwent percutaneous transluminal coronary angioplasty with or without intravascular stenting, with satisfactory effect (Table II). The other 7 patients (15.2%) had experienced a non-Q-wave AMI. These patients underwent coronary angiography within 7 days of the acute phase of myocardial infarction and were found to have an infarct-related artery with no significant stenosis.

TABLE II. Angiographic Characteristics of Patients with and without Preinfarction Angina

Echocardiographic and scintigraphic data are presented in Table III. There was no difference between the 2 groups of patients in basal left ventricular ejection fraction (LVEF) during the acute phase (P=0.170) or in the global contractile function expressed through WMSI (P=0.521). Regional function shown as the number of segments with preserved regional contractile function was significantly higher in the group with PIA (P <0.0001). Analysis of scintigraphic results revealed better protection of myocardial perfusion in the group of patients with PIA. The group with PIA had a higher number of segments with intact perfusion (tracer activity >75%)—3.59 ± 2.98 segments versus 2.11 ± 2.35 in the group of patients without PIA—but this difference did not reach statistical significance (P=0.066). However, segments with severe perfusion defects (tracer activity <50%) were significantly more common in the group without PIA than in the group who had experienced PIA, 2.16 ± 2.01 vs 0.89 ± 1.09, P=0.008.

TABLE III. Echocardiographic and Scintigraphic Variables

After a follow-up period that ranged from 7 to 12 months, the recovery of LVEF expressed as a percentage was considerably greater among patients who had experienced PIA (P=0.032) (Table III).

Stepwise regression analysis revealed PIA (r²=0.317, P=0.032) as the only significant predictor for percentage increase in LVEF after the follow-up period (Table IV). Aside from PIA, the factors analyzed were prodromal angina pectoris, diabetes mellitus, hypertension, current smoking, segments with preserved contractility, segments with preserved perfusion, segments with damaged perfusion, and medical therapy.

TABLE IV. Predictors of Percent Recovery of Left Ventricular Ejection Fraction (Stepwise Regression Analysis)

A number of previous experimental and clinical studies have reported improved outcomes among patients who experienced angina preceding an AMI. Compared with patients who did not experience antecedent angina, PIA patients have a smaller infarct area,¹⁵ limited impairment of coronary arteriolar dilation, less arteriolar injury, and less endothelial dysfunction. Preservation of the vasodilatory response of arterioles and small arteries^5,6,16 produces an adenosine-induced increase in coronary flow during ischemic preconditioning—independent of baseline coronary flow velocity and distribution of the epicardial coronary artery.^9,17 Patients with PIA had better survival, less pump failure, fewer arrhythmias, and lower peak cardiac serum enzyme levels. Furthermore, these patients experienced enhanced recovery of cardiac contractile function and had reduced left ventricular remodeling.^18–24

The results of our study support the beneficial, protective role of PIA when it is experienced during the 8 weeks before AMI. Preinfarction angina was associated with decreased infarct size as measured by peak creatine kinase-MB fraction, which is in accordance with the findings of other authors.^15,23,24 Our echocardiographic results also confirmed the beneficial effect of PIA on regional contractility, through the significantly greater number of segments that showed preserved contractile reserve during inotropic stimulation (Table II), as has been reported elsewhere.⁹ Although we found less necrosis and improved maintenance of regional contractility in our patients with PIA, our 2 patient groups manifested similar global contractile function as expressed by acute LVEF (Table II). This difference between global and regional contractility might be explained, in part, by the fact that stunning—rather than necrosis—has a greater impact on global ventricular function immediately after an acute event. Furthermore, our patients with PIA more often had an anterior AMI, which was probably the basis for the stunning of a greater myocardial surface area.²⁵ Our tomoscintigraphic results show that microvascular function, and consequently myocardial perfusion, were less impaired in our group with PIA, because they had significantly fewer segments with severely defective perfusion. This cardioprotective manifestation of PIA on microvascular function and coronary flow has already been observed in some experimental and clinical studies.^9,17,26

Patients with PIA at the end of the follow-up period showed a significant improvement in global left ventricular function (Table II). Upon stepwise regression analysis, PIA was a predictor of the percentage of recovery of global left ventricular contractile function (r²=0.317, P=0.032). This is in accordance with reports of previous investigators.^3,9,22

Our study differs from most other studies—the exception being that of Solomon and colleagues²²—because we included patients who had experienced angina within the 2 months preceding AMI, which is a longer period than usually has been monitored. We observed in our PIA group less myocardial necrosis, more pronounced viability, and, at the same time, better preservation of myocardial perfusion. This may indicate a direct protective effect of PIA not only on cardiomyocytes but also on microvascular anatomy and function—or it might imply some other protective mechanism. This protective impact of preconditioning on the microvasculature may explain in a substantial way the postinfarction preservation of viable cardiomyocytes and their supportive role in the improvement of global contractile function.

In addition to the modest size of our series, our study was limited by relatively weak documentation of previous angina episodes (testimonials from patients, supplemented by available records). Furthermore, we were unable to obtain reliable information on doses and frequency of administration of medications that patients received before hospitalization. However, we undertook every effort to obtain accurate and complete data. Patients who experience PIA are probably more likely to take nitrates or β-antagonists, which in itself could contribute to the reduction of ischemic injury.