Exercise-induced Myocardial Ischemia In Patients Research Articles

Impaired Endothelium-Dependent Vasodilation of Coronary Resistance Vessels Is Associated With Exercise-Induced Myocardial Ischemia

The release of endothelium-derived relaxing factors has been shown experimentally to be of pivotal importance for the maintenance of coronary blood flow during increased demand. In humans with coronary atherosclerosis, endothelial vasodilator dysfunction is not confined only to epicardial conductance vessels but may also extend into the coronary microcirculation. We therefore tested the hypothesis that endothelial vasodilator dysfunction of the coronary resistance vasculature is associated with myocardial ischemia during exercise in patients without hemodynamically significant epicardial artery stenoses. Coronary vasodilator function was assessed by subselective infusion of the endothelium-dependent dilator acetylcholine (0.036 to 3.6 micrograms/mL) and the endothelium-independent dilator papaverine (7 mg). Coronary blood flow responses were evaluated by intracoronary Doppler flow velocity recordings and quantitative angiography. Exercise-induced myocardial perfusion was determined by 201Tl single photon emission computed tomographic imaging. Thirteen patients had exercise-induced myocardial perfusion defects suggestive of myocardial ischemia, whereas 14 patients had normal thallium imaging during exercise. In patients with exercise-induced thallium perfusion defects, coronary blood flow responses to acetylcholine were significantly (P < .005) blunted compared with patients with normal thallium imaging during exercise. In contrast, coronary blood flow reserve to the endothelium-independent smooth muscle relaxant papaverine was similar in the two groups. Patients with exercise-induced thallium perfusion defects exhibited a significantly (P < .005) reduced (23.9 +/- 9.0% [mean +/- SD]) endothelium-mediated coronary vasodilator capacity compared with patients with normal thallium testing (56.2 +/- 27.8%). Epicardial artery vasoreactivity to acetylcholine did not differ between the two groups. Impaired endothelium-dependent vasodilation of the coronary microcirculation is associated with exercise-induced myocardial ischemia in patients without hemodynamically significant epicardial artery lesions. Endothelial vasodilator dysfunction extending into the coronary microcirculation may thus contribute to the ischemic manifestations of coronary artery disease during times of increased myocardial demand.

Effect of acadesine, a new metabolic agent, on exercise-induced myocardial ischemia in chronic stable angina

Acadesine, the first of a class of adenosine-regulating agents, has been shown to possess antiischemic properties in animal models. The aim of the study was to assess the effect of acadesine on exercise-induced myocardial ischemia in patients with chronic stable angina pectoris. Twelve patients with stable angina entered a five-way, randomized double-blind study comparing the effects of four doses of acadesine with placebo on time to 1 mm ST-segment depression and other parameters of exercise tolerance. At each study period patients underwent baseline exercise testing, followed by drug or placebo infusion after a 60 minute rest period. The exercise test was repeated after 30 minutes infusion, which continued throughout recovery. Time to angina, time to 1 mm ST depression, and total exercise time during the placebo infusion were 301.1 +/- 45.3, 314.8 +/- 50.9, and 399.4 +/- 47.6 seconds. The placebo-adjusted percentage change in time to 1-mm ST segment with acadesine 6, 12, 24, and 48 mg/kg was -0.1 +/- 6.2%, 11.1 +/- 13.8%, 12.9 +/- 8.6%, and -3.2 +/- 6.8%, respectively (p = NS vs. baseline). Time to angina, total exercise time, and recovery time of the ST segment were not consistently altered by acadesine. The lack of effect across all acadesine doses is consistent with animal data from ischemia-reperfusion injury studies, where a clear dose dependency was present with a loss of effect at higher doses. Alternatively, the extent of ischemia induced by treadmill exercise may have been insufficient for the antiischemic activity of acadesine to be evident.

Effect of a standardized meal on the threshold of exercise-induced myocardial ischemia in patients with stable angina

Objectives. This study was undertaken to determine the effect of a standardized meal on the ischemie threshold and exercise capacity in a series of 20 patients with stable angina, exerciseinduced ischemia and reversible exercise-induced perfusion defects.Background. It is generally accepted that exercise tolerance in patients with angina is reduced after a meal. However, studies that have addressed this phenomenon have yielded results that are contradictory and inconclusive.Methods. Two exercise tests using the Brace protocol with technetium-99m (99mTc)-sestamibi were performed on consecutive days in a randomized order. One test was performed in the fasting state and the other 30 min after a 1,000-calorle meal.Results. In the postprandial state, exercise time to ischemia was reduced by 20% from 248 ± 93 s to 197 ±87 s (p = 0.0007), time to angina by 15% from 340 ± 82 s to 287 ± 94 s (p = 0.002) and exercise tolerance by 9% from 376 ± 65 s to 344 ± 86 s (p = 0.002). Rate-pressure products at these exercise test end points were not significantly different in the fasting and postprandial tests, and the quantitative 99mTc-sestamibi ischemia score was unchanged.Conclusions. In patients with stable angina, a 1,000-calorie meal significantly reduced tine to ischemia, time to angina and exercise tolerance because of a more rapid increase in myocardial oxygen demand with exercise. The extent and severity of exerciseinduced ischemia were unchanged.

Beneficial effects of atrial natriuretic peptide on exercise-induced myocardial ischemia in patients with stable effort angina pectoris.

It has been shown that atrial natriuretic peptide (ANP), an endogenous vasodilator, dilates coronary arteries and decreases coronary vascular resistance. The purpose of this study was to determine whether an intravenous administration of ANP attenuated exercise-induced myocardial ischemia in 14 patients with stable effort angina pectoris. The first 12 patients (patients 1-12) who had exercise-induced ST segment depression underwent treadmill exercise testing and the last seven patients (patients 8-14) underwent the exercise 201Tl-single-photon emission computed tomography (SPECT) study while synthetic 28-amino acid alpha-human ANP (0.1 micrograms/kg per minute) or saline was intravenously infused in a double-blind, cross-over manner. The duration of exercise testing was the same during ANP and saline infusion, which was determined in preliminary exercise testings in each patient to cause a transient perfusion defect and/or ischemic ST segment depression. During saline infusion, all 12 patients developed exercise-induced ischemic ST segment depression, whereas no significant ST segment depression appeared during ANP infusion. Average ST segment depression during ANP infusion was significantly less (p < 0.01) than that during saline infusion (0.0 +/- 0.0 versus 0.2 +/- 0.1 mV, mean +/- SD). The averaged extent and severity scores assessed by 201Tl-SPECT were smaller (p < 0.05) during ANP infusion than during saline infusion (extent score: 0.22 +/- 0.20 versus 0.42 +/- 0.20; severity score: 18.77 +/- 23.45 versus 38.24 +/- 24.04, respectively). ANP decreased resting systolic blood pressure from 125 +/- 15 to 110 +/- 15 mm Hg (p < 0.01) but did not alter resting heart rate. At peak exercise, systolic blood pressure, heart rate, and the rate-pressure products did not differ during ANP and saline infusion. At peak exercise, plasma ANP increased from 98 +/- 45 to 4,383 +/- 2,782 pg/ml and cGMP increased from 3.6 +/- 1.7 to 34.5 +/- 16.1 pmol/ml during ANP infusion; values were significantly higher than those during saline infusion (from 96 +/- 42 to 133 +/- 66 pg/ml and from 3.4 +/- 1.8 to 4.6 +/- 1.8 pmol/ml, respectively). An intravenous administration of ANP attenuated exercise-induced myocardial ischemia in patients with stable effort angina pectoris. Although the mechanism by which ANP attenuated myocardial ischemia was not defined, increased myocardial perfusion to the ischemic region might be an important factor.

Enhanced release of atrial natriuretic factor during exercise-induced myocardial ischaemia in patients after acute myocardial infarction

To determine whether acute myocardial ischaemia induced by dynamic exercise can lead to changes in plasma levels of atrial natriuretic factor, we performed symptom-limited bicycle electrocardiographic tests in 20 males with recent acute myocardial infarction and in 8 control males. Ten patients developed exercise-induced myocardial ischaemia and 10 patients did not. There were no significant differences between the two groups with regard to age, site of myocardial infarction, urinary sodium, atrial sizes, radionuclide left ventricular ejection fraction, workload, baseline and peak-exercise heart rate, baseline and peak-exercise rate-pressure product, duration of exercise. Also baseline atrial natriuretic factor concentrations were similar in both groups (ischaemic patients: 34.51 ± 15.73 pg/ml; nonischaemic patients: 27.17 ± 8.74 pg/ml, NS), while peak-exercise atrial natriuretic factor concentrations were higher in patients with exercise-induced myocardial ischaemia (112.31 ± 35.5 pg/ml) than in the others (80.46 ± 23.43 pg/ml) ( P < 0.05). After 15 minutes of recovery, plasma atrial natriuretic factor levels were still raised only in the ischaemic patients (63.3 ± 15.44 pg/ml, P < 0.01), returning to baseline after 30 minutes in both groups. In control subjects, the behaviour of atrial natriuretic factor resembled that of the patients without exercise-induced ischaemia, with a significant increase at peak-exercise (from baseline levels of 23.1 ± 10.5 pg/ml to peak-exercise levels of 91.3 ± 14.5 pg/ml, P < 0.0005) and a rapid return to baseline levels after 15 minutes of recovery (28.5 ± 10.6 pg/ml, NS). Plasma atrial natriuretic factor levels were significantly higher in patients with exercise-induced myocardial ischaemia than in controls both at peak-exercise ( P < 0.05) and after 15 minutes of recovery ( P < 0.01). In conclusion, our data confirm that plasma atrial natriuretic factor levels increase during exercise in patients after acute myocardial infarction. Furthermore, atrial natriuretic factor levels increase to a larger extent in patients developing exercise-induced myocardial ischaemia, also showing a delayed return to baseline as compared either to nonischaemic patients or to control subjects. This particular behaviour could be due to the onset of left ventricular dysfunction depending on myocardial ischaemia or to the direct stimulatory effect of myosite hypoxia on the release of atrial natriuretic factor.

Effects of beta 2-adrenoceptor stimulation on exercise-induced myocardial ischemia

In large epicardial coronary arteries, β 2 adrenoceptors represent only 15% of the total population of β adrenoceptors. 1 Thus, their stimulation is unlikely to affect coronary blood flow significantly. 2 Conversely, in small coronary arteries, β 2 adrenoceptors represent 93% of the total population of β adrenoceptors. 1 Their stimulation causes vasodilation. 2 Experimental studies, however, have shown that β 2-adrenoceptor-mediated vasodilation of small coronary arteries is more pronounced in subepicardial than in subendocardial layers, thus provoking reduction of the endo/epicardial flow ratio. 3 As the subendocardium is more susceptible to myocardial ischemia than the subepicardium, 4 this redistribution of coronary blood flow toward the subepicardial layers, in the presence of critical coronary stenoses, might reduce the ischemic threshold during exercise. Furthermore, stimulation of β 2 adrenoceptors in the sinus node, recently demonstrated in humans, 5 might increase the heart rate, thus reducing exercise duration. We investigated the clinical importance of the detrimental consequences of β 2-adrenoceptor stimulation in a trial of the effects of salbutamol on exercise-induced myocardial ischemia in patients with stable angina pectoris. The confounding influence of β 1-adrenoceptor stimulation was prevented by pretreatment with atenolol. Furthermore, to establish whether nonselective β-adrenoceptor blockade is able to prevent these detrimental effects, salbutamol was given to another group of patients after pretreatment with propranolol.

Iodine-123 phenylpentadecanoic acid myocardial scintigraphy in patients with left ventricular hypertrophy: Alterations in left ventricular distribution and utilization

Regional alterations in myocardial substrate uptake and/or utilization have been demonstrated in rats with hypertension. To determine whether alterations in left ventricular fatty acid uptake and/or utilization are present in patients with left ventricular hypertrophy (LVH), we compared the results of rest and exercise iodine-123 phenylpentadecanoic acid (IPPA) myocardial scintigraphy in 10 patients with hypertension who had concentric LVH without evidence of coronary artery disease and in 15 normal subjects. Patients with LVH had more heterogeneous left ventricular activity of IPPA compared to normal subjects after exercise but not at rest (23 +/- 8% versus 13 +/- 5% difference in maximum segmental activity at 4 minutes after exercise; p = 0.005). Although IPPA clearance was similar in both patients with LVH and normal subjects, postexercise washout in segments showing decreased initial IPPA uptake was reduced compared to washout at rest in patients with LVH (11.7 +/- 7.5% versus 21.5 +/- 8.4% at 20 minutes after injection, n = 15; p = 0.005). Exercise thallium-201 (TI-201) scintigraphy was normal in all seven patients with LVH tested. Patients with LVH showed significantly greater heterogeneity in IPPA uptake compared to TI-201 uptake immediately after exercise (25 +/- 5% versus 16 +/- 6%; p = 0.013). We conclude that (1) compared to normal subjects, patients with LVH show heterogeneous myocardial IPPA activity after exercise but not at rest; (2) postexercise washout of IPPA was decreased in segments with reduced uptake after exercise in patients with LVH; and (3) the distribution of IPPA is more heterogeneous than that of TI-201 immediately after exercise in patients with concentric LVH. The postexercise heterogeneity in IPPA uptake and delayed washout in segments with reduced initial uptake is consistent with exercise-induced myocardial ischemia in patients with LVH.

Exercise-induced silent myocardial ischemia in patients with vasospastic angina

To clarify the incidence and clinical characteristics of exercise-induced myocardial ischemia in patients with vasospastic angina, we performed exercise thallium computed tomography in 25 patients who had no significant coronary artery stenosis greater than 70%. Coronary artery spasm was documented by coronary angiography in all patients. Eleven patients (44%) developed exercise-induced perfusion defects, but only four of them had anginal pain (36%). Diltiazem (90 mg, administered orally) prevented the development of exercise-induced perfusion defects in all patients. Multivessel coronary spasm was documented by coronary angiography in 11 patients, and nine of them (82%) showed exercise-induced perfusion defects (p less than 0.05). (1) Exercise-induced myocardial ischemia was demonstrated in 44% of patients who had vasospastic angina without fixed coronary stenosis, and 64% of them were asymptomatic. (2) Patients with multivessel spasm had a greater prevalence of exercise-induced myocardial ischemia than those with single-vessel spasm.

Haemodynamic implications of exercise-induced myocardial ischaemia in patients with recent inferior myocardial infarction.

Two hundred and forty patients with recent inferior myocardial infarction were studied by a symptom-limited ergometric test with haemodynamic monitoring (triple lumen tip-thermistor Swan-Ganz catheter) in order to investigate and quantify the haemodynamic effects of exercise-induced myocardial ischaemia in post-infarct patients and to assess whether the ST-segment changes give any indication of the degree of ventricular impairment. One hundred and thirteen patients showed no ST-segment changes during excercise; ST-segment elevation in leads with abnormal Q wave occurred in 14 patients, ST-segment depression was recorded in 88 subjects, and both ST-segment elevation and depression were found in 27 patients. In subjects with no ST-segment shift, as well as in those with exercise-induced ST-segment elevation, the resting and exertional haemodynamic patterns were normal or nearly normal. In subjects showing ST-segment depression or both ST-segment elevation and depression during exercise the mean pulmonary wedge pressure was abnormally elevated (at peak exercise 25 +/- 8 and 24 +/- 7 mm Hg, respectively). However, 31% of these showed a normal haemodynamic pattern either at rest or during exercise. The number of leads with ST-segment depression and the sum of ST-segment depressions in standard ECG does not reliably indicate the degree of ischaemia-dependent left ventricular impairment. In contrast, in patients grouped on the basis of time of ST depression appearance, the lower the ischaemic threshold the more severe was the left ventricular impairment. Finally, to assess the relative role of both scar and ischaemia in producing left ventricular dysfunction, the haemodynamic patterns of patients with and without exercise-induced ST-segment depression were compared in subsets with similar echocardiographic wall asynergy extent (inferior, infero-apical, infero-septo-apical). Among patients with small or medium-sized scar, the exertional left ventricular filling pressure was normal in patients with no ST-segment depression and abnormally elevated in those with ST-segment depression. In patients with large infarct, the exercise pulmonary wedge pressure was similarly elevated in both the ischaemic and non-ischaemic group, but in the latter cardiac output increase during exercise was limited. in patients with recent inferior myocardial infarction exercise-induced ST-segment depression is a marker of left ventricular impairment when the ischaemic threshold is low. The impairment consists of an abnormal elevation of left ventricular filling pressure in all subjects, associated with a reduced increase in cardiac output in patients with large infarct.

Exercise-Induced myocardial ischemia in patients with coronary artery disease: Lack of evidence for platelet activation or fibrin formation in peripheral venous blood

The hypothesis that exercise-induced myocardial ischemia is associated with abnormal platelet activation and fibrin formation or dissolution was tested in patients with coronary artery disease undergoing upright bicycle stress testing. In vivo platelet activation was assessed by radioimmunoassay of platelet factor 4, beta-thrombo-globulin and thromboxane B2. In vivo fibrin formation was assessed by radioimmunoassay of fibrinopeptide A, and fibrinolysis was assessed by radioimmunoassay of thrombin-increasable fibrinopeptide B which reflects plasmin cleavage of fibrin I. Peripheral venous concentrations of these substances were measured in 10 normal subjects and 13 patients with coronary artery disease at rest and during symptom-limited peak exercise. Platelet factor 4, beta-thromboglobulin and thromboxane B2 concentrations were correlated with rest and exercise catecholamine concentrations to determine if exercise-induced elevation of norepinephrine and epinephrine enhances platelet activation. Left ventricular end-diastolic and end-systolic volumes, ejection fraction and segmental wall motion were measured at rest and during peak exercise by first pass radionuclide angiography. All patients with coronary artery disease had documented exercise-induced myocardial ischemia manifested by angina pectoris, ischemic electrocardiographic changes, left ventricular segmental dyssynergy and a reduction in ejection fraction. Rest and peak exercise plasma concentrations were not significantly different for platelet factor 4, beta-thromboglobulin, thromboxane B2, fibrinopeptide A and thrombin-increasable fibrinopeptide B. Peripheral venous concentrations of norepinephrine and epinephrine increased significantly (p less than 0.001) in both groups of patients. The elevated catecholamine levels did not lead to detectable platelet activation. This study demonstrates that enhanced platelet activation, thromboxane release and fibrin formation or dissolution are not detectable in peripheral venous blood of patients with coronary disease during exercise-induced myocardial ischemia.