Markers of myocardial ischaemia

We read with interest the article by Giannitsis and Katus¹ onmarkers of myocardial ischaemia. Although their comments areauthoritative and scholarly, we feel that the authors failedto objectively summarize the evidence available for ischaemia-modifiedalbumin (IMA) as a marker of myocardial ischaemia. Researchfrom our unit     

Electrocardiographic correlates of myocardial ischaemia induced by atrial and ventricular pacing in dogs with coronary stenosis

We determined the electrocardiographic response to pacing-induced tachycardia in 45 dogs. Pacing was performed using left atrial, left atrial-right ventricular sequential or left atrial-left ventricular sequential modes at rates of 90 to 250 beats X min-1. Body surface isopotential maps in 15 dogs with normal coronary circulations defined the normal response to rate; surface potential extrema during the S-T segment increased in strength with increasing rate but spatial features remained constant. In the other 30 dogs, an ameroid constrictor was placed around the left circumflex coronary artery. Two weeks after implantation, atrial pacing to rates of 190 beats X min-1 or greater resulted in flat, S-T segment depression, with new and abnormal negative voltages registered over the inferior and left posterior torso. However, with either form of ventricular pacing, tachycardia with coronary obstruction did not alter the S-T segment response seen in control animals, in either intensity or spatial parameters. We interpret these findings to suggest that: in normal dogs, tachycardia produced a common electrocardiographic effect regardless of activation pattern; and tachycardia in the presence of coronary constriction results in subendocardial myocardial ischaemia that, with atrial pacing, reverses the normal transmural S-T segment potential gradient and causes body surface S-T segment depression, but with primary ventricular stimulation, the subendocardial ischaemia does not alter the transventricular repolarisation gradients sufficiently to generate body surface S-T segment shifts.     

Natriuretic peptides and myocardial ischaemia

In both experimental and clinical myocardial ischaemia, release of BNP occurs rapidly from ventricular myocardium, prompting speculation that the early activation of the natriuretic peptide receptor/cGMP signalling system may be an important autocrine/paracrine response to ischaemia. Among the growing list of pleiotropic actions of natriuretic peptides is the attenuation of tissue susceptibility to ischaemic injury. BNP and other natriuretic peptides limit the extent of tissue infarction during ischaemia and reperfusion. The mechanism of cytoprotection is related to cGMP accumulation and opening of ATP-sensitive K(+) channels. The effects of longer-term upregulation of natriuretic peptide expression in the heart following myocardial infarction could include the suppression of growth and proliferative responses in myocytes and fibroblasts. Thus, chronic elevation of natriuretic peptide expression in infarcted myocardium probably represents a negative regulatory system to counter the pro-hypertrophic and pro-fibrotic signalling activated by other mediators such as angiotensin II and catecholamines. The acute and chronic actions of natriuretic peptides in myocardial ischaemia suggest a profile of activity that may be therapeutically beneficial in the management of patients with acute coronary syndromes and for the optimisation of post-infarction remodelling.     

Relationship between ST-segment elevation and local tissue flow during myocardial ischaemia in dogs.

The relationship between electrocardiographic ST-segment changes and local tissue flow recorded from idential sites in the myocardium was determined by inserting platinum electrodes into the left ventricular wall of anaesthetized dogs. Local myocardial blood flow was measured during graded coronary constriction by recording tissue hydrogen desaturation rate. In the detection of ischaemic ST-segment elevation, intramural recordings proved to be more sensitive than corresponding epicardial recordings. Significant ST-segment elevation could only be detected by reducing local myocardial flow below 50% of control; by further reduction ST-segment elevation increased in proportion to the reduction in myocardial flow. Thus, significant myocardial ischaemia might exist without electrocardiographic alterations.     

Transmitral flow velocities and times during stress transthoracic echocardiography in patients with myocardial ischaemia

Twenty-nine men with chronic stable angina pectoris were investigatedusing stress electrocardiography (ECG) and stress transthoracicechocardiography by means of transoesophageal stimulation ofthe left atrium. At rest and after each stimulated frequency,ECG and 2-dimensional echocardiography combined with Dopplerwere performed simultaneously. Fourteen patients without ischaemiaat stress ECG and two patients who were subjected only to twodifferent frequencies of stimulation were excluded from ourstudy. Thirteen patients with ischaemic electrocardiographicresponse at stress, who were subjected to at least three stimulatedfrequencies, were evaluated. Their deceleration time of earlytransmitral filling was prolonged from 171±15.4 ms to178.1±14.4 ms (P = ns) after the first stimulated frequency,to 172.8±15.1 ms after the second stimulated frequency(P = ns) and was shortened to 143.6±7.9 ms (P<0.05)after the fastest stimulated frequency. The ratio of peak transmitralflow velocity in early diastole (E) to that during atrial contraction(A) decreased from 0.93±0.07 at rest to 0.85±0.07(P<0.05) after the first stimulated frequency, to 0.87±0.07(P=ns) after the second stimulated frequency and increased to1.13±0.08 (P<0.05) after the fastest stimulated frequency. In patients with angina pectoris and myocardial ischaemia, thechanges in the E/A ratio and deceleration time during stressare not linear and their direction depends on the moment oftheir evaluation. Their use for the quantitative evaluationof the diastolic function of the left ventricle is problematic.     

Transient myocardial ischaemia after acute myocardial infarction

The prevalence and characteristics of transient myocardial ischaemia were studied in 203 patients with recent acute myocardial infarction by both early (6.4 days) and late (38 days) ambulatory monitoring of the ST segment. Transient ST segment depression was much commoner during late (32% patients) than early (14%) monitoring. Most transient ischaemia (greater than 85% episodes) was silent and 80% of patients had only silent episodes. During late monitoring painful ST depression was accompanied by greater ST depression and tended to occur at a higher heart rate. Late transient ischaemia showed a diurnal distribution, occurred at a higher initial heart rate, and was more often accompanied by a further increase in heart rate than early ischaemia. Thus in the first 2 months after myocardial infarction transient ischaemia became increasingly common and more closely associated with increased myocardial oxygen demand. Because transient ischaemic episodes during early and late ambulatory monitoring have dissimilar characteristics they may also have different pathophysiologies and prognostic implications.     

Influence of haemodynamics and myocardial ischaemia on Doppler transmitral flow in patients undergoing dobutamine echocardiography

To examine whether pulsed Doppler left ventricular filling indicescan reliably detect myocardial ischaemia in patients with coronaryartery disease undergoing dobutamine stress echocardiographywe studied three groups matched for age and global indices ofleft ventricular function. Group 1 patients (n=10) had normalcoronary arteries whereas those in Groups 2 (n=12) and 3 (n=15)had significant coronary disease (70% diameter stenosis) atangiography. After stopping cardiouctive treatment, patientsunderwent incremental dobutamine stress (5, 10, 15 and 20 µg.kg^–1. min^–1) during pulsed Doppler interrogationof diastolic filling with simultaneous heart rate and bloodpressure measurements. Only Group 3 patients developed myocardialischaemia using electrocardiographic and cross sectional echocardiographiccriteria, subset 3A (n=4) comprised those with inducible mitralregurgitation on colour Doppler. Electrocardiographic R-R intervaldecreased (–311 ± 123 ms, P<0·001) andmean blood pressure altered (5±17 mmHg, P=ns) uniformlyacross groups. The respective changes in peak early velocity,peak atrial velocity and their ratio for Groups 1 (0·08± 0·09 m. s^–1, 0·26 ± 0·18m.s^–1 and – 0·32 ± 0·36), 2(0·07 ± 0·07 m.s^–1 0·18±0·15m.s^–1 and –0·13±0·21) and 3(0·09±0·12 m.s^–1, 0·20±0·13m.s^–1 and –0·17±0·21) weresimilar (all P=ns between groups). Corresponding data for subset3A (0·23 ± 0·04 m.s^–1 0·20± 0·10 m.s^–1and 0·00 ± 0·16)revealed a significantly greater increase in peak early velocityand normalized velocity ratio in these patients. Overall, changesin peak early (r= –0·47, P<0·01) andatrial velocity (r–0·65, P<0·001) andtheir ratio (r=0·35, P<0·05) correlated withreduction in R-R interval but not alterations in blood pressure.In conclusion, tachycardia during dobutamine stress masks theeffects of myocardial ischaemia on Doppler diastolic indicesalthough a minority of patients with inducible mitral regurgitationmanifest a relatively distinct filling profile.     

Phosphatidylcholine biosynthesis in myocardial ischaemia

In this study the effect of myocardial ischaemia was evaluated on two aspects of phospholipid metabolism: (i) the de novo synthesis of myocardial phospholipids, as indicated by the incorporation of (methyl-3H) choline and (ii) the incorporation of radiolabelled long chain fatty acids into tissue phospholipids. Two models of ischaemia were used namely normothermic ischaemic arrest and hypoxic, low-flow perfusion of the isolated rat heart. The results showed that within 10 min, hypoxic low-flow perfusion significantly inhibited the incorporation rate of (methyl-3H) choline into tissue phospholipids. Since the tissue choline content remained unaltered under these conditions, the results suggested that the de novo synthesis of phosphatidylcholine is very susceptible to ischaemic damage. Inhibition of (methyl-3H) choline incorporation into tissue phospholipids appeared to be due to both a reduction in choline uptake and specific inhibition of the CDP pathway. Perfusion with glucose (10 mM) as substrate completely abolished the ischaemia-induced reduction in (methyl-3H) choline incorporation, indicating that glycolytically produced ATP played an important role in phosphatidylcholine biosynthesis. In contrast to these results, myocardial ischaemia stimulated the incorporation of long-chain saturated and unsaturated fatty acids into tissue phospholipids. In summary, the results obtained showed that myocardial ischaemia profoundly affected phospholipid metabolism which, in turn, might contribute to membrane damage.     

Transient myocardial ischaemia after acute myocardial infarction.

The prevalence and characteristics of transient myocardial ischaemia were studied in 203 patients with recent acute myocardial infarction by both early (6.4 days) and late (38 days) ambulatory monitoring of the ST segment. Transient ST segment depression was much commoner during late (32% patients) than early (14%) monitoring. Most transient ischaemia (greater than 85% episodes) was silent and 80% of patients had only silent episodes. During late monitoring painful ST depression was accompanied by greater ST depression and tended to occur at a higher heart rate. Late transient ischaemia showed a diurnal distribution, occurred at a higher initial heart rate, and was more often accompanied by a further increase in heart rate than early ischaemia. Thus in the first 2 months after myocardial infarction transient ischaemia became increasingly common and more closely associated with increased myocardial oxygen demand. Because transient ischaemic episodes during early and late ambulatory monitoring have dissimilar characteristics they may also have different pathophysiologies and prognostic implications.     

Markers of myocardial ischaemia: reply

We thank Sinha and coworkers for their very interesting comments.We appreciate the overview on the evidence available for ischaemia-modifiedalbumin (IMA). In fact, our editorial¹ did not primarily focuson IMA but used IMA as an example to point to some     

Importance of vasomotor tone to myocardial function and regional metabolism during constant flow ischaemia in swine

STUDY OBJECTIVE--The aim was to test the hypothesis that the release of vascular tone with adenosine during constant flow ischaemia alters both transmural function and regional metabolism in a detrimental way. DESIGN--In one group of anaesthetised swine, the effects of graded reductions of flow on segmental left ventricular function, myocardial oxygen consumption (MVO2), and lactate production in the distribution of the left anterior descending coronary artery (LAD) were determined. In a second group, a model of constant flow ischaemia was induced to test how altering vascular tone with adenosine changed the relationship of flow, function, and metabolism. EXPERIMENTAL MATERIAL--The experiments were performed in 20 open chest, anaesthetised swine. Protocol A consisted of 11 animals and protocol B of nine animals. MEASUREMENTS AND MAIN RESULTS--In protocol A, during graded ischaemia, reductions in flow, % systolic wall thickening (WTh), normalised MVO2 and % lactate extraction (%LE) correlated well with reductions in coronary perfusion pressure when fitted with 3rd order polynominal curves (r = 0.78, 0.87, 0.85 and 0.81 respectively; p less than 0.00001). In protocol B, during constant flow ischaemia, at control, % WTh was 33 (SD 11)%, mean coronary artery pressure was 72(10) mm Hg, mean LAD transmural flow was 0.99(0.43) ml.min-1.g-1, and % LE was +14(9)%. With inflation of a hydraulic occluder on the LAD, perfusion pressure was lowered to 38(5) mm Hg and transmural flow dropped to 0.76(0.31) ml.min-1.g-1 (intact vasomotion). During an infusion of intracoronary adenosine with flow held constant (absent vasomotion), %WTh was further reduced from 27(9) to 13(10) (p less than 0.001), and %LE from -18(42) to -70(61) (p less than 0.05). MVO2 with and without vasomotion did not differ significantly at 3.14(0.75) and 3.18(0.86) ml.min-1.g-1 respectively. CONCLUSION--In swine coronary circulation, reductions in regional function, MVO2 and lactate production correlate well with reductions in flow and perfusion pressure during ischaemia with vasomotor tone intact. The effect of adenosine on vascular tone during constant flow ischaemia caused dramatic reductions in function and lactate extraction without altering MVO2. This emphasises the important role of vascular tone in protecting both transmural function and regional metabolism during moderate ischaemia.     

Regional blood flow correlates of ST segment depression in tachycardia-induced myocardial ischemia

Tachycardia produces subendocardial ischemia and ST segment abnormalities after coronary obstruction. To determine whether a quantitative relationship exists between these ST shifts and transmural blood flow, 19 dogs were studied. Coronary obstruction was produced by ameroid constriction of the left circumflex artery, and tachycardia was generated by atrial pacing at 90 to 210 beats/min. ST shifts were studied by body surface isopotential mapping with an 84-electrode torso grid, and blood flow was quantitated by serial radiolabeled microsphere injections. Isopotential maps at each paced rate, 40 msec into the ST segment, were classified as normal or ischemic based on spatial patterns of voltages. Pacing after 3 weeks of ameroid constriction reduced endocardial/epicardial flow ratios in 11 dogs from 1.16 +/- 0.22 at rest to 0.41 +/- 0.18 at 210 beats/min. Abnormal ST depression developed in these dogs at a rate of 184.0 +/- 16.5 beats/min. Endocardial/epicardial ratios with ST depression (0.45 +/- 0.15) were lower than at those without ST depression (1.05 +/- 0.19; p less than .01). Logistic regression analysis demonstrated that ST depression corresponded to an endocardial/epicardial ratio of 0.67 or less (p less than .01). With this model, 95.5% of data sets were correctly classified. Neither heart rate nor perfusion bed size were significant independent predictors of an ischemic electrocardiographic response. The magnitude of abnormal ST segment shift was significantly correlated (r = .87) with the transmural flow ratio. Thus development of electrocardiographic changes indicative of ischemia corresponds to a predictable degree of flow redistribution and the magnitude of the ST shift is correlated with the intensity of the flow abnormality.     

Unusual congenital coronary anomaly and myocardial ischaemia

Angiography was used to diagnose a rare congenital coronary anomaly with myocardial ischaemia in a woman with typical angina. All three coronary arteries arose from a solitary coronary ostium in the right aortic sinus; the left anterior descending coronary artery followed a septal course, the circumflex coronary artery ran behind the ascending aorta, and the right coronary artery followed a normal course. No significant coronary lumen narrowing was found. Transoesophageal echocardiography confirmed the anomalous origin and course of the aberrant coronary arteries. An exercise test reproduced angina, and ECG changes and myocardial perfusion study showed an anterior reversible defect. In contrast to previous reports, myocardial ischaemia was associated with the septal (intramuscular) course of the left anterior descending coronary artery; there was no other significant coronary artery disease.


Keywords: congenital heart defects; myocardial ischaemia; angiography; echocardiography