Evaluation of thromboxane production and complement activation during myocardial ischemia in patients with angina pectoris

BACKGROUND. The complement system and arachidonic acid metabolites are involved in severe myocardial ischemia such as myocardial infarction. Furthermore, there is experimental evidence for C5a participation in thromboxane production. METHODS AND RESULTS. We examined whether C5a and thromboxane are produced during brief and reversible episodes of myocardial ischemia induced in patients with stable angina. Twenty-five patients underwent either atrial pacing or percutaneous transluminal coronary angioplasty associated with arterial and coronary sinus blood sampling. Rapid atrial stimulation of patients with effort angina caused significant ST segment depression (delta ST = -1.7 +/- 0.2 mm), decreased fractional lactate extraction (from +12.8 +/- 2.5% baseline to -13.7 +/- 4.6% at peak ischemia, n = 13, p less than 0.001), and increased coronary sinus plasma thromboxane B2 levels (from 345 +/- 85 pg/ml baseline to 1,684 +/- 64 pg/ml at peak ischemia, p less than 0.01). Changes of fractional lactate extraction correlated significantly with changes of coronary sinus plasma levels of thromboxane B2. There was no change of coronary sinus 6-keto-PGF1 alpha levels. Similar pacing of control subjects (n = 6) did not cause release of lactate or thromboxane. Seventeen other patients underwent exercise testing with noninvasive measurements of thromboxane and prostacyclin metabolites in urinary samples collected before and after the test. No detectable increase of urinary 11-dehydrothromboxane B2 was measured in patients with stable angina after exercise-induced myocardial ischemia. However, basal 11-dehydrothromboxane B2 levels were significantly higher in patients with angina (105 +/- 25 pg/mmol creatinine, n = 9) than in control patients (45 +/- 8 pg/mmol creatinine, n = 8, p less than 0.05 between groups). Coronary sinus plasma levels of the anaphylatoxin C5a always remained below 4 ng/ml in patients undergoing pacing. More severe myocardial ischemia after coronary angioplasty (percent lactate extraction decreased from +24.8 +/- 2.7% baseline to -41.6 +/- 22.4% at peak ischemia, p less than 0.05) was not associated with C3a or C5b-9 generation. In all patients, there was neither platelet sequestration nor platelet alpha-granule release (no changes of beta-thromboglobulin/platelet factor 4 levels) into the coronary sinus plasma. CONCLUSIONS. Patients with stable angina have chronically increased thromboxane synthesis as assessed by excretion of urinary metabolites. Thromboxane is acutely released into the coronary sinus during pacing-induced ischemia without significant intracoronary platelet aggregation. Complement does not appear to be activated in stable angina during brief and reversible episodes of myocardial ischemia and does not contribute to thromboxane production.     

Myocardial protection by intracoronary nicardipine administration during percutaneous transluminal coronary angioplasty

To determine if the calcium antagonist nicardipine protects the myocardium against ischemia, myocardial lactate, hypoxanthine and prostanoid function was studied in 12 patients during percutaneous transluminal coronary angioplasty (PTCA). Values were obtained before balloon inflation and during 4 minutes after deflation. Intracoronary injection of 0.2 mg of nicardipine distal to the stenosis was done randomly before the first or second inflation; the other inflation served as a control. One minute after deflation, coronary sinus flow levels were similar during the nicardipine and control procedure (161 +/- 61 vs 159 +/- 72 ml/min); lactate (-9 +/- 21% vs -17 +/- 21%, p less than 0.025) and hypoxanthine production (-107 +/- 85% vs -218 +/- 153%, p less than 0.05) were less severe after nicardipine pretreatment than after control. All patients reverted to lactate extraction 4 minutes after inflation plus nicardipine infusion, whereas lactate was still produced 4 minutes after control inflation. No significant changes in thromboxane B2 or prostacyclin levels were observed in the coronary sinus 1 minute after inflation, but higher arterial thromboxane B2 values were observed after control inflation than after inflation with nicardipine infusion (median values 169 vs 78 pg/ml, p less than 0.05). In conclusion, intracoronary infusion of nicardipine reduced signs of ischemia and alterations in prostanoid handling after coronary occlusion. The mechanisms of myocardial protection appeared unrelated to coronary sinus blood flow changes or to a systemic effect of nicardipine.     

Oxidative metabolism and myocardial blood flow changes after transthoracic DC countershocks in dogs.

Changes in oxidative metabolism and myocardial blood flow were investigated in adult greyhounds following transthoracic shocks from a DC cardiac defibrillator (400 Joules stored energy, damped sine wave, 0.5 min intervals). Myocardial lactate extraction became negative maximally at 1 min, following both two (mean -24% +/- SEM24) or five (-193% +/- 148) shocks and returned to baseline by 6-15 min. Transient reductions were also observed in myocardial extraction of pyruvate and free fatty acids but not glucose. Myocardial necrosis assessed at 4 h following the shocks was 0.05 g (+/- 0.03) after two shocks, 6.5 g (+/- 1.5) after five shocks and zero in controls. Mean peak noradrenaline levels in arterial (785 +/- 319 pg.ml-1) and coronary sinus (916 +/- 313 pg.ml-1) blood at 1 min after five shocks were higher than after 0 shocks (82 +/- 33 pg.ml-1 and 201 +/- 63 pg.ml-1 respectively), P < 0.05. Great cardiac venous blood flow was measured by a thermodilution technique, with continuous infusion of 0.9% saline, before, during and after five shocks. Mean blood flow fell from 47 +/- 13 ml.min-1 to a minimum of 36 +/- 7 ml.min-1 during shocks, and then rose to 83 +/- 17 ml.min-1 at 2 min after the fifth shock (P < 0.05). Following damaging countershocks, oxidative metabolism is depressed, in keeping with a primary disturbance of mitochondrial function. These metabolic changes are not secondary to ischaemia, since an increase in blood flow in the great cardiac vein (GCV) is observed. Vasodilatation of the coronary vascular bed must occur to account for this.     

Abnormal cardiocoronary thromboxane A2 production in patients with unstable angina

Thromboxane B2 (TXB2), the stable metabolite of thromboxane A2 (TXA2), was measured in the coronary sinus and in aortic blood before and after cold pressor test (CPT) in 21 patients suffering from ischemic heart disease (7 affected by stable effort angina and 14 by unstable angina) and in 12 patients not suffering from myocardial ischemia (control group) during coronary angiography. Aspirin (10 mg/kg intravenously) was administered before catheterization in order to prevent platelet and leukocyte TXA2 formation. Control subjects and patients with effort angina had TXB2 resting levels lower than unstable angina patients without a transcardiac gradient which, on the contrary, was found in unstable angina patients. Only in these patients CPT resulted in a significant TXB2 increase more marked in the coronary sinus (from 50.0 +/- 18.9 pg/ml to 73.0 +/- 35.1 pg/ml, p less than 0.001) than in the aorta (from 33.4 +/- 17.1 pg/ml to 42.6 +/- 24.0 pg/ml, p less than 0.05), so that the transcardiac TXB2 gradient significantly increased. In all but two unstable angina patients, TXB2 elevation was not associated with a fall of cardiac lactate extraction. The resting and CPT-induced TXB2 gradients were unrelated to the presence and severity of coronary angiographic lesions. These results indicate that unstable angina patients show an abnormal cardiocoronary capacity to synthesize TXA2, which seems not to be elicited by the occurrence of myocardial ischemia.     

Myocardial potassium uptake and catecholamine release during cardiac sympathetic nerve stimulation

To determine whether sympathetic nerve stimulation induces a significant potassium uptake in the myocardium, the changes in myocardial potassium balance, catecholamine release, lactate uptake, and oxygen consumption were recorded in eight anaesthetised open chest pigs during electrical stimulation of the right intermediate cardiac nerve at 10 Hz. Potassium concentrations were continuously measured by polyvinylchloride valinomycin minielectrodes in arterial and coronary sinus blood. Potassium concentration in coronary sinus blood fell to a nadir 0.42(0.21-0.61) mmol.litre-1 below control values (median and 95% confidence interval) and resulted in a peak potassium uptake of 65(38-102) mumol.min-1 100 g-1 after 2.5(2.0-3.0) min, which correlated (r = 0.94, p less than 0.001) with cardiac noradrenaline release. Accumulated myocardial potassium uptake amounted to 139(82-241) mumol.100 g-1 when a stable potassium concentration difference between arterial and coronary sinus blood was reached after 5.5(4.25-6.50) min. Cardiac contractility (LV dP/dt), myocardial oxygen consumption, and lactate uptake rose from control to peak potassium uptake (p less than 0.001) by 140%, 158%, and 92% respectively. Coronary sinus blood noradrenaline and adrenaline concentrations rose significantly (p less than 0.01) from 58(44-87) pg.ml-1 at control to 2208(1159-5627) pg.ml-1 at peak uptake and from 15(11-19) pg.ml-1 to 85(64-230) pg.ml-1 respectively. Arterial noradrenaline increased from 29(19-41) pg.ml-1 to 374(176-640) pg.ml-1 and arterial adrenaline rose from 15(11-23) pg.ml-1 to 31(24-52) pg.ml-1 (p less than 0.001). It is concluded that sympathetic nerve stimulation induces a substantial myocardial potassium uptake in a dose dependent relation to cardiac noradrenaline release and alters the contractile and metabolic state of the heart substantially with only minor changes in arterial catecholamine concentration.     

Thromboxane release in coronary artery disease: spontaneous versus pacing-induced angina

To determine thromboxane A2 release in coronary artery disease, we measured its stable metabolite thromboxane B2 by radioimmunoassay in 20 patients. In 15 patients with stable disease (last angina episode greater than 96 hours before study), coronary venous thromboxane B2 concentrations were lower than in aortic blood (mean 109 +/- 36 vs 194 +/- 40 pg/ml, p less than 0.001). In contrast, in five other patients with spontaneous angina, coronary venous thromboxane B2 concentrations were higher than aortic thromboxane B2 concentrations during the angina episode (mean 1716 +/- 316 vs 875 +/- 388 pg/ml, p less than 0.02). Plasma thromboxane B2 levels were in the normal range (mean 175 +/- 35 pg/ml) in patients with stable angina but significantly (p less than 0.02) higher in patients with spontaneous angina. With atrial pacing to the point of chest pain and/or ECG changes in patients with stable coronary artery disease, aortic thromboxane B2 concentrations increased in 10 of 13 patients (mean 283 +/- 70 pg/ml, p less than 0.02). Coronary venous thromboxane B2 concentrations increased in seven patients at peak pacing rates (mean 223 +/- 76 pg/ml) and in three other patients after termination of pacing. These data indicate that release of thromboxane A2 is much greater during spontaneous angina than with pacing stress in patients with coronary artery disease. Thromboxane A2 released during spontaneous or pacing-induced angina may modulate coronary and systemic vascular tone. Enhanced thromboxane A2 activity may either precede or follow myocardial ischemia and could be a factor in the initiation and propagation of the ischemic episode.     

Systemic and coronary hemodynamic effects of intravenous nicardipine at rest and in ischemia induced by rapid atrial stimulation

The systemic and coronary haemodynamic effects of intravenous nicardipine were investigated in 10 patients with a more than 70 p. 100 stenosis of the left coronary artery. Two brief atrial pacing tests (ST1 and ST2) were performed. ST2 was performed 30 minutes after an intravenous injection of nicardipine 2.5 mg over 5 minutes. Nicardipine produced a 25 p. 100 decrease in ventricular systolic pressure and a substantial increase in cardiac index (from 2.74 +/- 0.48 to 3.46 +/- 0.35 l/min/m2, p less than 0.001). Measurement of the coronary flow rate by the thermodilution method showed a 40 p. 100 increase in sinus blood flow while coronary resistance decreased not only in territories with normal supply but also in myocardial territories distal to the coronary stenosis (from 2.76 +/- 2.3 to 1.83 +/- 1.5 mmHg/ml, p less than 0.02). With the same paced heart rate the ventricular function parameters were significantly improved during ST2 (cardiac index ST2 3.56 +/- 0.65 vs ST1 2.8 +/- 0.48, p less than 0.001; dp/dt max ST2 2143 +/- 369 vs ST1 1874 +/- 301 mmHg/sec, p less than 0.05), reflecting a lower degree of myocardial ischaemia. This was confirmed by the lower amplitude of electrocardiographic depression and by a higher lactate extraction coefficient (LE ST1 6 +/- 7 p. 100 vs LE ST2 12 +/- 12 p. 100, p less than 0.05). Mean arterial blood pressure and coronary sinus blood flow rate values were identical during the two atrial pacing tests.(ABSTRACT TRUNCATED AT 250 WORDS)     

Significance of ST segment depression during paroxysmal supraventricular tachycardia

During paroxysmal supraventricular tachycardia, patients frequently experience chest pain and marked ST segment depression suggesting acute myocardial ischemia. The purpose of this study was to assess whether ST depression during supraventricular tachycardia is caused by myocardial ischemia as reflected by net myocardial lactate production. Twenty-five patients (14 men, 11 women) who had a history of paroxysmal supraventricular tachycardia and a mean age (+/- SD) of 38 +/- 14 years underwent electrophysiologic testing. Twenty-four of these patients had no evidence of coronary disease, whereas one patient had undergone previous coronary bypass surgery. Nineteen patients had orthodromic and six patients had atrioventricular node reentrant tachycardias. A 12 lead electrocardiogram and simultaneous femoral artery and coronary sinus blood samples for lactate determinations were obtained at baseline and at 5 and 10 min of supraventricular tachycardia. Mean baseline heart rate of 83 +/- 12 beats/min increased to 180 +/- 25 beats/min during supraventricular tachycardia. All patients had 1 to 8 mm of ST segment depression in 1 to 9 of the 12 leads. Chest pain occurred in 64% of patients during supraventricular tachycardia. Baseline myocardial lactate extraction was 28 +/- 13% with no significant change at 5 or 10 min of tachycardia. In contrast, in a comparison group of seven patients with known coronary artery disease, atrial pacing at 168 +/- 26 beats/min in five patients resulted in greater than or equal to 1 mm ST depression in 2 to 7 of the 12 leads and a change in lactate extraction from a baseline of 29 +/- 13% to -27 +/- 20% (p less than 0.05) indicating net myocardial lactate production.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased plasma level of endothelin-1-like immunoreactivity during coronary spasm in patients with coronary spastic angina

To examine the role of endothelin in coronary spasm, the plasma endothelin-1-like immunoreactivity in the coronary sinus and the aortic root was measured before and during spasm of the left coronary artery induced by injection of acetylcholine (20 to 100 micrograms) into the left coronary artery in 26 patients with coronary spastic angina. The plasma level of endothelin-1-like immunoreactivity was measured by the radioimmunoassay with a monoclonal antibody against endothelin-1. Plasma lactate levels in the coronary sinus and the aortic root were also measured to evaluate myocardial lactate metabolism during spasm. In 13 patients who had myocardial lactate production during spasm, the plasma level of endothelin-1-like immunoreactivity in the coronary sinus increased from 19.8 +/- 3.0 to 25.7 +/- 6.4 pg/ml (p less than 0.01), while that in the aortic root remained unchanged (from 20.2 +/- 5.9 to 21.3 +/- 5.8 pg/ml). No significant changes in the plasma levels of endothelin-1-like immunoreactivity in the coronary sinus (from 21.1 +/- 7.3 to 19.7 +/- 5.2 pg/ml) and the aortic root (from 21.1 +/- 5.7 to 19.7 +/- 5.6 pg/ml) were observed in 13 patients who did not show myocardial lactate production during spasm. On the other hand, 16 patients without ischemic heart disease showed no significant changes in the plasma levels of endothelin-1-like immunoreactivity in the coronary sinus (from 24.4 +/- 9.7 to 25.8 +/- 6.9 pg/ml) and the aortic root (from 23.0 +/- 7.1 to 23.4 +/- 5.8 pg/ml) by acetylcholine injection (100 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)     

Dipyridamole-induced myocardial ischaemia increases ANF release in man.

Atrial natriuretic factor (ANF) release is modulated by several haemodynamic factors, including ventricular and atrial wall stretch. Dipyridamole infusion, which is commonly used as a pharmacological stressor in patients with coronary artery disease, can acutely increase ventricular and atrial pressure via myocardial ischaemia. The aim of this study was to assess whether dipyridamole infusion (up to 0.84 mg kg-1 over 10') can affect ANF release in man. Nineteen patients (13 men, 6 women) with a history of chest pain were studied. Their drug regimen was interrupted and instead they were administered a dipyridamole infusion, combined with two-dimensional echocardiography and 12-lead ECG monitoring. Plasma ANF was measured by RIA while the patients rested, and after dipyridamole infusion. Eight patients had no evidence of myocardial ischaemia, as measured by electrocardiographic and/or echocardiographic criteria, during dipyridamole infusion: among them, ANF values were similar while they were at rest and at peak dipyridamole administration (23.9 +/- 9.5 vs 23.4 +/- 6.9 pg ml-1, P = ns). Eleven patients had dipyridamole-induced transient ischaemia (regional ventricular dyssynergy and/or ST segment depression): among them, ANF values rose significantly at peak dipyridamole administration (31.8 +/- 13.8 vs 65.5 +/- 36.4, P less than 0.01). We conclude that dipyridamole infusion does not increase ANF release in man in the absence of ischaemia. The induction of myocardial ischaemia acutely increases ANF release, probably through a rise in ventricular and atrial wall stress.     

Increased coronary sinus lactate concentration during pacing induced angina pectoris after clinical improvement by glyceryl trinitrate.

Ten patients with stable angina pectoris and obstructed coronary arteries (greater than 75% reduction in diameter) were studied before and during two periods of pacing, the second of which was preceded by sublingual administration of glyceryl trinitrate (mean dose 0.78 mg). Coronary sinus blood flow measurements and aortocoronary sinus blood sampling for metabolite determinations were carried out. Although the rate of pacing was increased by 10 beats/minute after glyceryl trinitrate administration, the onset of angina was delayed in eight patients during pacing. Drug administration decreased coronary sinus blood flow by 42% and myocardial oxygen uptake by 41% during pacing and induced a shift in mean lactate extraction towards a net release (from 3.1% to -12.6%). It increased the number of patients producing lactate from three to five. Glyceryl trinitrate administration decreased myocardial glucose uptake throughout the study, decreased lactate extraction during recovery, and increased the aortocoronary sinus citrate gradient at rest and during recovery, while the exchange of free fatty acids remained unchanged. A decrease in aortocoronary sinus lactate difference during pacing after glyceryl trinitrate administration correlated positively with the fall in coronary sinus blood flow. The metabolic data do not indicate an augmented myocardial lactate production after glyceryl trinitrate administration. A decrease in coronary sinus blood flow seems, therefore, to be of primary importance in explaining the elevated coronary sinus lactate concentration. Our finding that coronary sinus lactate concentration increased during pacing after glyceryl trinitrate administration despite clinical improvement questions the validity of its use as a quantitative index of ischaemia.     

The Sensitivity of the Symptom Angina Pectoris as a Marker of Transient Myocardial Ischaemia in Chronic Stable Angina Pectoris

ABSTRACT Therapeutic decisions in patients with angina pectoris are traditionally based on the history reported by the patient, since objective evidence of myocardial ischaemia during daily life is often not available. In this study, ambulatory ST segment monitoring was performed in 60 patients with a history of chronic stable angina pectoris, positive exercise test and/or positive coronary angiography, and a correlation was made between the episodes of chest pain and ST segment change. The patients were grouped according to the results of exercise testing and coronary arteriography, and one group was studied with and without antianginal medication. Overall, 195 episodes of angina were noted, only 94 of which (48%) were accompanied by ST segment depression. Pain and ST segment changes were best correlated in patients with a positive exercise test, positive angiography and who were not receiving antianginal medication. In 101 episodes of chest pain, ST segment change could not be identified; in 18 (18%) there was sinus tachycardia, in 12 (12%) ventricular premature beats, and in 71 (70%) sinus rhythm solely. Thus, anginal pain appears not to be the reliable indicator of transient myocardial ischaemia as was previously thought, a finding which supports the use of objective methods in identifying episodes of transient myocardial ischaemia in daily life.     

Lipid peroxidation during myocardial ischaemia induced by pacing

Oxygen derived free radical generation can be shown in experimental models of myocardial ischaemia and reperfusion and may cause cellular damage by peroxidizing polyunsaturated membrane phospholipids. An attempt was made to quantify human intracardiac lipid peroxidation during transient myocardial ischaemia by measuring the aortic and coronary sinus concentrations of malondialdehyde (a marker of lipid peroxidation) before, during, and after incremental pacing. Twenty six patients were paced until they had severe chest pain or 2 mm ST segment depression or they reached a paced rate of 180 beats/min. They were divided into two groups according to whether or not lactate was produced during pacing. Twelve patients (group 1), all with coronary artery disease, produced myocardial lactate during pacing. None of the other 14 patients (group 2), half of whom had coronary disease, produced lactate during pacing. Concentrations of malondialdehyde in the aorta and coronary sinus were significantly higher in group 1 than in group 2. Five minutes after the end of pacing coronary sinus malondialdehyde concentrations in group 1 had increased significantly from baseline values. There were no changes with time in the coronary sinus concentration of malondialdehyde in group 2 or in the aorta in either group. The negative malondialdehyde extraction ratio in group 1 suggests that intracardiac lipid peroxidation occurs during transient human myocardial ischaemia.     

Lipid peroxidation during myocardial ischaemia induced by pacing.

Oxygen derived free radical generation can be shown in experimental models of myocardial ischaemia and reperfusion and may cause cellular damage by peroxidizing polyunsaturated membrane phospholipids. An attempt was made to quantify human intracardiac lipid peroxidation during transient myocardial ischaemia by measuring the aortic and coronary sinus concentrations of malondialdehyde (a marker of lipid peroxidation) before, during, and after incremental pacing. Twenty six patients were paced until they had severe chest pain or 2 mm ST segment depression or they reached a paced rate of 180 beats/min. They were divided into two groups according to whether or not lactate was produced during pacing. Twelve patients (group 1), all with coronary artery disease, produced myocardial lactate during pacing. None of the other 14 patients (group 2), half of whom had coronary disease, produced lactate during pacing. Concentrations of malondialdehyde in the aorta and coronary sinus were significantly higher in group 1 than in group 2. Five minutes after the end of pacing coronary sinus malondialdehyde concentrations in group 1 had increased significantly from baseline values. There were no changes with time in the coronary sinus concentration of malondialdehyde in group 2 or in the aorta in either group. The negative malondialdehyde extraction ratio in group 1 suggests that intracardiac lipid peroxidation occurs during transient human myocardial ischaemia.     

Cardiac release of chemoattractants after ischaemia induced by coronary balloon angioplasty.

OBJECTIVE--To investigate the release of chemoattractants after myocardial ischaemia during balloon angioplasty. DESIGN--Sampling of femoral arterial and coronary sinus blood before and immediately after the first balloon inflation during angioplasty. In a study group of 16 patients the balloon was kept expanded for two minutes, whereas in a control group of eight patients the first balloon inflation was brief (< 10 s). MAIN OUTCOME MEASURES--Chemotaxis of neutrophils from healthy donors towards patient plasma (Boyden chamber), superoxide anion production by normal neutrophils after incubation with patient plasma (cytochrome C reduction). RESULTS--In the study group, coronary sinus plasma after balloon deflation was more chemoattractive to normal neutrophils (median relative increase 24% (quartiles: 4%, 45%), p = 0.008) and induced a higher superoxide anion production in normal neutrophils (44% (10%, 97%), p = 0.013) than arterial plasma. Concomitantly, the degree of activation of patient neutrophils was increased in coronary sinus blood compared with arterial blood, as shown by an increased proportion of neutrophils reducing nitro-blue tetrazolium (21% (9%, 38%), p = 0.006) and a decreased neutrophil filter-ability (-16%(-3%, -40%), p = 0.003) in coronary sinus blood. In the study group before balloon inflation and in the control group before and after balloon inflation differences between arterial and coronary sinus blood were not significant. Signs of ischaemia (lactate release, ST segment changes) were only detected in the study group. CONCLUSION--After transient myocardial ischaemia during balloon angioplasty there is a local release of chemoattractants, associated with neutrophil activation.     

Changes in myocardial metabolism during therapy in patients with chronic stable angina: a comparison of long-term dosing with propranolol and nicardipine

The long-term effects of antianginal therapy on coronary blood flow and myocardial metabolism were studied in 35 patients with chronic stable angina. Arterial and coronary sinus blood samples and coronary blood flow measurements were obtained before and after 1 month of oral administration of propranolol or of the calcium antagonist nicardipine. When the data obtained at a fixed heart rate (10% to 15% above the pretreatment sinus rhythm) were compared, no significant differences were evidenced between the propranolol and the nicardipine groups. Coronary blood flow and myocardial oxygen uptake were unchanged with both drugs. Myocardial lactate uptake increased in 11 patients of the propranolol group (from -2 +/- 42 to 66 +/- 47 mumol/min, p less than .001) and in 11 patients of the nicardipine group (from 0 +/- 36 to 31 +/- 29 mumol/min, p less than .001). In these 22 patients, the increase in lactate uptake was accompanied by reductions in uptake of free fatty acids and by a decrease in the coronary sinus concentration of thromboxane B2 from 131 +/- 87 to 61 +/- 32 pg/ml (p less than .01), whereas the transcardiac release of prostacyclin increased. None of these changes in free fatty acids or in prostanoid handling were observed in the nine patients (five in the propranolol and four in the nicardipine group) in whom lactate uptake was not augmented. During pacing-induced tachycardia, the metabolic effects of the two drugs appeared different. Myocardial lactate uptake decreased more in the patients receiving propranolol than in those receiving nicardipine and the combined productions of alanine and glutamine rose by 3.2 +/- 5.8 mumol/min in the propranolol group while it decreased by 3.1 +/- 8.2 mumol/min in the nicardipine group (p less than .025 propranolol vs nicardipine). In conclusion, long-term antianginal therapy with propranolol or nicardipine improved several markers of myocardial ischemia in approximately two-thirds of the patients. Although the changes observed at low heart rates were similar with the two drugs, the data also suggest that better metabolic protection is provided by the calcium antagonist during pacing-induced tachycardia.     

Myocardial metabolism during hypoxia: maintained lactate oxidation during increased glycolysis

In the intact animal, myocardial lactate utilization and oxidation during hypoxia are not well understood. Nine dogs were chronically instrumented with flow probes on the left anterior descending coronary artery and with a coronary sinus sampling catheter. [14C]lactate and [13C]glucose tracers, or [13C]lactate and [14C]glucose were administered to quantitate lactate and glucose oxidation, lactate conversion to glucose, and simultaneous lactate extraction and release. The animals were anesthetized and exposed to 90 minutes of severe hypoxia (PO2 = 25 +/- 4 torr). Hypoxia resulted in significant increases in heart rate, cardiac output and myocardial blood flow, but no significant change in myocardial oxygen consumption. The arterial/coronary sinus differences for glucose and lactate did not change from normoxia to hypoxia; however, the rate of glucose uptake increased significantly due to the increase in myocardial blood flow. Tracer-measured lactate extraction did not decrease with hypoxia, despite a 250% increase in lactate release. During hypoxia, 90% +/- 4% of the extracted 14C-lactate was accounted for by the appearance of 14CO2 in the coronary sinus, compared with 88% +/- 4% during normoxia. Thus, in addition to the expected increase in glucose uptake and lactate production, we observed an increase in lactate oxidation during hypoxia.     

Effects of pharmacologically-induced hypertension on myocardial ischemia and coronary hemodynamics in patients with fixed coronary obstruction

Twenty patients with fixed coronary artery obstruction were studied during rapid atrial pacing and methoxamine infusion. During pacing to heart rates of 142 +/- 4 (mean +/- SEM) beats per minute coronary sinus flow increased from 108 +/- 8 to 187 +/- 15 cc/min and myocardial oxygen consumption increased by + 80 +/- 11%. During methoxamine infusion that raised arterial systolic pressure to 196 +/- 5 mm Hg, similar increases in coronary sinus flow (to 179 +/- 13 cc/min) and myocardial oxygen consumption (+ 77 +/- 12%) occurred. Chest pain and ischemic ST segment changes developed in 17 and 14 patients respectively during atrial pacing, an incidence significantly greater (P less than 0.05) than during infusion of methoxamine (6 and 3 patients). Myocardial lactate extraction which averaged 26 +/- 4% during control was decreased to 10 +/- 8% during pacing and to 24 +/- 7% during methoxamine; the difference between decreases was not significant. The data show that at similar increases in myocardial oxygen consumption stress of increased heart rate results in more myocardial ischemia than stress of increased afterload.     

Effects of a selective thromboxane synthetase inhibitor, dazoxiben, and of acetylsalicylic acid on myocardial ischemia in patients with coronary artery disease

Thromboxane A2 (TxA2) may aggravate myocardial ischemia by inducing vasoconstriction and platelet aggregation in small coronary vessels, whereas prostacyclin (PGI2) counteracts these effects. Acetylsalicylic acid (ASA) inhibits the formation of TxA2 as well as PGI2, whereas dazoxiben, a thromboxane synthetase inhibitor, reduces TxA2 formation selectively. In 25 patients with coronary artery disease, 2 identical atrial pacing stress tests were performed: before and after the administration of dazoxiben (200 mg) in 15 patients and before and after ASA (250 mg) in 10. The ischemic response, quantified by coronary sinus and aortic lactate levels and by ST depression, was significantly reduced after administration of dazoxiben (p less than 0.02) but not after ASA. Heart rate at rest, myocardial extraction of free fatty acids and the arteriovenous oxygen difference was unaffected by medication. Both drugs reduced TxB2 levels to the same extent, whereas collagen-induced aggregation was more reduced after ASA than after dazoxiben. The effect of dazoxiben on ischemia was probably a result of inhibited TxA2 and preserved PGI2 production, which increased blood flow to ischemic regions.     

Comparison of coronary hemodynamic and cardiac metabolic alterations during coronary artery spasm associated with ST segment elevation or depression

Coronary vasospasms are usually indicated by ST elevation or depression in the electrocardiogram (ECG). To test the hypothesis that ST elevation represents more severe myocardial ischemia than does ST depression, we determined the coronary sinus blood flow (CSBF) and the transcardiac lactate extraction ratio (LER) in 19 selected patients who had focal vasospasms in the left anterior descending artery. In 10 patients, ergonovine (0.11 +/- 0.02 mg, mean +/- SEM) provoked severe (total or subtotal) coronary vasospasm with ST elevation. Under these conditions, CSBF significantly decreased (from 97 +/- 8 ml/min to 79 +/- 5 ml/min, p less than 0.01) with a marked reduction in LER (from 29 +/- 5% to -14 +/- 6%, p less than 0.01). In contrast, 10 vasospastic events with ST depression after ergonovine (0.15 +/- 0.04 mg, NS) were recognized as mild spastic narrowing or severe spasms with well developed collateral circulation. Alteration of CSBF was significant in only a few patients and the overall CSBF response was non-significant (from 106 +/- 12 ml/min to 103 +/- 13 ml/min). The reduction in LER in this group was less pronounced than those in patients with ST elevation (p less than 0.05). These results indicate that coronary vasospasm with ST elevation may be related to the more pronounced reduction in coronary blood flow accompanied by more severe myocardial ischemia. Such observations may support the contention that some ischemic events associated with ST elevation or depression can be interpreted as a continuous spectrum of vasospastic disorders.