Antianginal and cardiac metabolic effects of low-dose glucose infusion during pacing in patients with and without coronary artery disease

Anginal threshold and cardiac metabolism during infusion of glucose, 350 mg/min, were compared with control values before, during, and after pacing in nine patients with coronary artery disease (CAD) and nine patients without coronary artery disease (non-CAD). Pacing induced no ischemia in non-CAD patients; in CAD patients, intolerable angina developed in less than 5 minutes. However, glucose infusion in the latter group increased the time to onset of angina (110 +/- 24 seconds before infusion versus 140 +/- 24 seconds following infusion) and decreased the extent of ST segment depression (1.8 +/- 0.3 mm before infusion versus 0.9 +/- 0.2 mm following infusion, p less than 0.01) following pacing. In all subjects, arterial levels and cardiac uptake of glucose rose by 100% (p less than 0.001) and those of free fatty acids fell by 50% (p less than 0.01). Arterial lactate and uptake of lactate by nonischemic myocardium increased by 30% (p less than 0.05). During pacing in CAD patients, this elevated uptake was outweighed by similar increases of lactate release from ischemic areas, leaving mean negative global exchanges unaltered. In CAD patients solely, rebuilding of cardiac glycogen after pacing was suggested from augmented citrate efflux in the control period but not during glucose infusion, suggesting a glycogen-sparing effect. Arterial concentrations and net cardiac fluxes of oxygen, glutamate, and alanine remained unaltered. In conclusion, beneficial effects of glucose during ischemia are associated with increased aerobic and anaerobic glycolysis, saving of glycogen, and decreased lipolysis.     

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.     

Systemic neurohumoral activation and vasoconstriction during pacing-induced acute myocardial ischemia in patients with stable angina pectoris

To identify the effect of myocardial ischemia on systemic neurohormones and vascular resistance, 32 untreated, normotensive patients with coronary artery disease underwent incremental atrial pacing until angina. Arterial and coronary venous lactate and arterial values of catecholamines and angiotensin II were determined at control, at maximal pacing rates, and at 1, 2, 5 and 30 minutes after pacing. Based on pacing-induced ST-segment depression (greater than or equal to 0.1 mV) or myocardial lactate production, or both, patients were selected as ischemic (n = 25) or nonischemic (n = 7). Baseline clinical and hemodynamic data were comparable. During pacing, chest pain was similar (20 ischemic vs 7 nonischemic patients). Also, hemodynamic measurements were comparable, except for contractility, which did not improve, and left ventricular end-diastolic pressure, which significantly increased in ischemic patients. Moreover, during ischemia arterial pressures increased significantly (13%) and systemic resistance increased from 1,470 +/- 60 (control) to 1,632 +/- 76 dynes.s.cm-5 5 minutes after pacing (p less than 0.05) in ischemic but not in nonischemic patients. Pacing did not affect neurohormones in nonischemic patients. In contrast, norepinephrine in ischemic patients increased significantly from 1.7 +/- 0.2 (control) to 2.6 +/- 0.3 (maximal pacing) and to 3.0 +/- 0.4 nmol/liter (1 minute after pacing), whereas angiotensin II levels increased from 6.2 +/- 1.4 (control) to 9.3 +/- 2.1 pmol/liter (1 minute after pacing, p less than 0.05). Epinephrine only increased during maximal rates (0.9 +/- 0.1 vs 0.6 +/- 0.1 nmol/liter at control, p less than 0.05). Thus, myocardial ischemia activates circulating catecholamines and angiotensin II, accompanied by systemic vasoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

Metabolic and hemodynamic effects of nicardipine during pacing-induced angina pectoris

During repeat exercise testing in 10 patients with stable angina, individual optimal doses of nicardipine were determined. Hemodynamic values and cardiac metabolism were studied during 2 pacing periods carried out before and after this dose (mean 5.3 mg). Postpacing ST-segment depression diminished (1 mm) after nicardipine administration (p less than 0.05), whereas pacing time to onset of angina did not change. Nicardipine administration increased heart rate 16% (p less than 0.005) and reduced systolic (10%) and diastolic (8%) blood pressures (both p less than 0.005). Coronary blood flow increased 16% (p less than 0.05) and coronary vascular resistance decreased 24% (p less than 0.01). Myocardial oxygen consumption was unchanged despite an 11% decrease in rate-pressure product during pacing (p less than 0.02). In the control state before nicardipine administration, metabolic signs of ischemia included release of lactate across the heart in 7 patients, decreased mean free fatty acid and glutamate uptake and alanine release during pacing, together with increased glucose uptake and citrate release during recovery. After nicardipine lactate release decreased in 5 of the 7 patients, pacing no longer changed free fatty acid, glutamate and alanine uptake/release from the level at rest. During recovery glucose uptake was reduced and citrate release was unaffected. The hemodynamic data indicate that nicardipine is a systemic and coronary vasodilator, increasing oxygen supply to the ischemic myocardium. The metabolic results indicate a change in substrate utilization toward that of normal heart, suggesting improved aerobic energy supply.     

Chest pain and "normal" coronary arteries--role of small coronary arteries

To study the mechanism of chest pain in patients with insignificant epicardial coronary artery disease, 50 patients underwent great cardiac vein (GCV) flow, oxygen content and lactate determinations at rest and during pacing, and left ventricular end-diastolic pressure (LVEDP) measurements at rest and after pacing. Twenty-four patients having typical chest discomfort during pacing demonstrated significantly lower increase in flow from baseline (36 +/- 18% versus 86 +/- 24%, p less than 0.001) and decrease in coronary resistance (-17 +/- 12% versus -43 +/- 7%, p less than 0.001) compared with 26 patients without pacing-induced chest pain, despite no significant difference in myocardial oxygen consumption (MVO2) between the 2 groups. Lactate consumption at a heart rate (HR) of 150 beats/min was significantly less (28.3 +/- 21.5 versus 51.3 +/- 35.8 mM X ml/min, p less than 0.001) and the increase in LVEDP from rest to after pacing was significantly greater (5 +/- 2 versus 1 +/- 2 mm Hg, p less than 0.001) in the chest pain group. After administration of ergonovine, 0.15 mg intravenously, to 46 of these patients, 31 had typical pain either at rest (1 patient) or during pacing. This group had significantly lower increase in flow (38 +/- 20% versus 107 +/- 38%, p less than 0.001), and decrease in coronary resistance (-16 +/- 12% versus -45 +/- 11%, p less than 0.001) compared with the 15 patients not having chest pain, despite no significant difference in MVO2 between the 2 groups. Patients with chest pain also had lower lactate consumption at a HR of 150 beats/min (39.2 +/- 23.6 versus 65.3 +/- 46.3 mM X ml/min, p less than 0.01), greater arterial-GCV oxygen difference (12.5 +/- 1.3 versus 11.6 +/- 1.0 ml O2/100 ml, p less than 0.05), and a more marked increase in LVEDP from rest to after pacing (11 +/- 3 versus 5 +/- 2 mm Hg, p less than 0.001). Quantitative coronary arteriography demonstrated no significant luminal narrowing of the epicardial coronary arteries in response to ergonovine. These data are consistent with the hypothesis that some patients with chest pain and angiographically normal epicardial coronary arteries have dynamic abnormalities of the small coronary arteries or coronary microcirculation that cause abnormal vasodilator reserve or vasoconstriction, resulting in myocardial ischemia and angina pectoris.     

Effects of Ranolazine on Ischemic Threshold, Coronary Sinus Blood Flow, and Myocardial Metabolism in Coronary Artery Disease

Cytoprotection or metabolic modulation is a new principle in the treatment of angina pectoris. The effect of ranolazine (a cytoprotective drug) on ischemic threshold, coronary sinus blood flow, and myocardial metabolism was evaluated by means of two pacing sequences in nine male patients with coronary artery disease (CAD) and in eight male controls. Ranolazine was given as an intravenous bolus followed by continuous infusion; the mean total dose was 32.7 mg and 31.7 mg in patients and controls, respectively. Angina pectoris was relieved in two patients after ranolazine but pacing time to pain was unchanged in the remaining patients. Maximal ST depression was lower (p = 0.02), but pacing time to maximal and to 1-mm ST depression remained unchanged after the drug. Ranolazine had no overall influence on coronary sinus blood flow, cardiac oxygen consumption, blood pressure, and heart rate. Cardiac uptake of free fatty acids (FFA) was reduced (p = 0.01), and net uptakes of glucose (p = 0.07) and lactate (p = 0.06) tended to be lower after ranolazine in CAD patients and controls. Ranolazine had no direct influence on cardiac exchange of glutamate, alanine, and citrate or on the arterial concentration of any metabolite. In the present study ranolazine had minimal clinical effects. A decrease in myocardial FFA utilization, however, allows greater myocardial glucose oxidation, which may increase the energy production in relation to oxygen availability.     

Continuous monitoring of coronary sinus oxygen saturation during pacing loading in patients with syndrome X

To determine whether patients with syndrome X suffer from myocardial ischemia, coronary sinus oxygen saturation was continuously measured during pacing loading in 31 patients. Subjects were categorized by groups as syndrome X (11 patients), effort angina (14), and old myocardial infarction and valvular heart disease (6). Pacing loading induced evidence of ischemia in all syndrome X patients and in eight of the 11 patients with effort angina, while there was no such evidence in those with old myocardial infarction and valvular heart disease. Coronary sinus oxygen saturation in syndrome X decreased significantly from 44.2 +/- 5.8% to 33.5 +/- 4.4% (p less than 0.01), and it decreased from 47.0 +/- 4.9% to 31.2 +/- 4.0% (p less than 0.01) in effort angina with induced ischemic evidence, indicating that a significant reduction in coronary sinus oxygen saturation reflects the presence of myocardial ischemia. In the group with old myocardial infarction and valvular heart disease, coronary sinus oxygen saturation remained nearly unchanged during pacing. The pattern of depression of coronary sinus oxygen saturation during pacing was steeper in effort angina than in syndrome X. Therefore, we conclude that, although syndrome-X may not be a homogeneous group of patients, most of them may develop myocardial ischemia due to reduced vasodilator reserves of the small coronary artery.     

Myocardial catecholamine balance during angina: effects of calcium entry blockers, verapamil and nifedipine

To evaluate the effects of calcium entry blocking agents on cardiac sympathetic tone during angina pectoris, arterial and coronary sinus (CS) norepinephrine (NE) and epinephrine (E) concentrations and CS blood flow were determined at rest and during pacing-induced angina, both before and after verapamil in nine patients and after nifedipine in nine patients, all of whom had fixed obstructive coronary artery disease. Resting arterial NE and E concentrations and myocardial NE release and E uptake remained unchanged during angina before verapamil and nifedipine, suggesting unaltered systemic and cardiac sympathetic tone and myocardial E handling. Following verapamil and nifedipine, arterial NE and E concentrations remained unchanged. After verapamil, net myocardial NE release increased from 16,072 +/- 18,881 to 35,520 +/- 30,595 at preverapamil angina rate (p less than 0.01) and to 39,643 +/- 29,728 pg/min at postverapamil angina rate (p less than 0.01). NE release after nifedipine increased from -4207 +/- 8898 to 10,988 +/- 30,711 (p less than 0.05) at prenifedipine angina rate and to 19,942 +/- 26,644 pg/min (p less than 0.05) at postnifedipine angina rate. NE release was independent of changes in CS flow after verapamil or nifedipine. E uptake after verapamil and nifedipine remained unchanged. Although the precise mechanism is not known, myocardial alpha-adrenergic receptor blockage with verapamil and nifedipine remains a possible explanation for increased myocardial NE release.     

Coronary hemodynamics and myocardial metabolism in patients with syndrome X: response to pacing stress

Coronary hemodynamics, myocardial metabolism and left ventricular function at rest and after incremental atrial pacing were evaluated in 12 patients with stress-induced angina and ST segment depression, angiographically normal coronary arteries and no evidence of spasm, generally labeled as syndrome X, and in 10 normal subjects. At baseline study, great cardiac vein flow was comparable in patients and control subjects. During pacing, an equivalent rate-pressure product was reached in the two groups, but the slope of the relation between rate-pressure product and great cardiac vein flow was significantly less steep in patients than in normal subjects (0.0027 vs. 0.0054 ml/mm Hg.beat, p less than 0.001). Nevertheless, the left ventricular ejection fraction was comparable in both groups at rest (66 +/- 6% vs. 71 +/- 7%, p = NS) and during pacing (71 +/- 7% vs. 66 +/- 5%, p = NS). At baseline study, myocardial glucose extraction was more efficient in patients with syndrome X (p less than 0.05), but net myocardial exchange of pyruvate and alanine was, respectively, smaller and greater than in control subjects. Lactate was extracted to a similar extent in the two groups and in no instance was net lactate release observed during pacing or recovery. During pacing and recovery, patients with syndrome X showed net pyruvate release, unlike the control subjects in whom net pyruvate exchange was positive. In addition, patients with syndrome X continued to show net myocardial extraction of alanine during spacing and recovery, whereas normal subjects produced alanine throughout the study. Myocardial carbohydrate oxidation increased significantly during maximal pacing in normal subjects but not in patients, in whom it always remained below (p less than 0.01) the concurrent rate of myocardial uptake of carbohydrate equivalents (glucose, lactate, pyruvate, alanine). Myocardial energy expenditure was significantly lower in patients than in control subjects at maximal rate-pressure product levels (p less than 0.01). The metabolic pattern in patients with syndrome X therefore is not consistent with classic ischemia, although differences in the net exchange of circulating substrates (glucose, pyruvate, alanine) can be demonstrated. Thus, in patients with syndrome X, the symptoms, electrocardiographic signs and impairment in the increase in great cardiac vein flow during pacing coexist with preserved global and regional left ventricular function and myocardial energy efficiency.     

Catecholamine metabolism during pacing-induced angina pectoris and the effect of transcutaneous electrical nerve stimulation

The arterial levels of norepinephrine and epinephrine were estimated in 14 patients with severe coronary artery disease in order to assess the catecholamine metabolism during pacing-induced angina pectoris and to evaluate the effects of transcutaneous electrical nerve stimulation (TENS). Arterial levels of epinephrine and norepinephrine increased significantly during pacing to angina pectoris (p less than 0.05 and p less than 0.001, respectively), indicating that maximal atrial pacing induced an increase in sympathetic tone. At the corresponding pacing rate during TENS, myocardial lactate production was improved (p less than 0.01) and the ST segment depression was less pronounced (p less than 0.05). The maximal pacing rate during TENS was 141 +/- 24 compared to 123 +/- 19 (p less than 0.01) and the heart rate-blood pressure product was also significantly higher (p less than 0.01), suggesting an elevation of the anginal threshold by TENS. Systemic vascular resistance and systolic blood pressure were significantly reduced (both p less than 0.01). These beneficial results may be caused by a decrease in left ventricular afterload as reflected by a fall in systolic blood pressure and may be explained by reduced sympathetic activity. TENS may decrease the sympathetic activity either directly or indirectly as a consequence of pain inhibition. This hypothesis is supported by the fact that arterial levels of epinephrine and norepinephrine dropped during TENS in TENS responders.     

Myocardial energetics and efficiency in patients with idiopathic cardiomyopathy: response to dobutamine and amrinone

Nine consecutive patients having severe idiopathic dilated cardiomyopathy were studied for their response in ventricular function, coronary sinus blood flow and myocardial oxygen consumption, lactate extraction and efficiency following incremental doses of dobutamine, followed by the combination of dobutamine and the phosphodiesterase inhibitor amrinone. Results, presented as baseline and the response to the peak dose (15 micrograms/kg/min) of dobutamine and to the combination of dobutamine and amrinone (each at 15 micrograms/kg/min) (differences compared with baseline) were: wedge pressure decreased from 28 +/- 7 to 26 +/- 8 mm Hg (p = NS) and to 20 +/- 6 mm Hg (p less than 0.01); cardiac index rose from 1.47 +/- 0.44 L/min/m2 to 2.89 +/- 1.1 L/min/m2 (p less than 0.01) and to 3.64 +/- 1.05 L/min/m2 (p less than 0.001); myocardial oxygen consumption remained invariant (18 +/- 8, 17 +/- 5, and 19 +/- 5 ml/min) despite progressive increments in minute work from 2.96 +/- 1.1 to 6.98 +/- 3.9 kg - m/min (p less than 0.01) and to 9.38 +/- 4.3 kg - m/min (p less than 0.001); myocardial lactate extraction rose from 21 +/- 10% to 30 +/- 15% (p = NS) and to 35 +/- 10% with the addition of amrinone (p less than 0.01). No patient had net lactate efflux into the coronary sinus, and myocardial efficiency improved from 9.5 +/- 5% to 21.7 +/- 13.0% (p less than 0.01) and to 28.0 +/- 18.0% (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of left ventricular asynchrony on time constant and extrapolated pressure of left ventricular pressure decay in coronary artery disease

To elucidate the effects of ventricular asynchrony with or without myocardial ischemia on the time constant of left ventricular pressure decay and asymptote, that is, the level to which pressure would decrease if isovolumic pressure decrease continued infinitely, left ventriculography and pressure measurements were investigated in 14 normal subjects and 25 patients with coronary artery disease. Ventricular asynchrony was quantitated by the segmental area-time curve. This study consisted of two parts. 1) After a right atrial pacing stress test, the time constant and asymptote remained unchanged in eight normal subjects. In 18 patients with coronary artery disease and pacing-induced angina, asynchrony increased, the time constant was prolonged (64 +/- 13 to 94 +/- 17 ms, p less than 0.01) and the asymptote decreased (-22 +/- 10 to -46 +/- 20 mm Hg, p less than 0.01) after the pacing. 2) During right ventricular pacing at 80, 100 and 120 beats/min in the patients, asynchrony increased and the time constant was prolonged (55 +/- 7 versus 70 +/- 10, 47 +/- 11 versus 66 +/- 19, 36 +/- 7 versus 53 +/- 13 ms, respectively, p less than 0.01 versus right atrial pacing), whereas the asymptote was unchanged in six normal subjects compared with the value during right atrial pacing at each pacing rate. In seven patients with coronary artery disease, right ventricular pacing at 80, 100 and 120 beats/min also produced an increase in the time constant, while the asymptote was unchanged. Thus, prolongation of the time constant of left ventricular pressure decay may result from ventricular asynchrony even in the absence of myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of diltiazem on regional coronary hemodynamics during atrial pacing in patients with stable exertional angina: implications for mechanism of action

To investigate the mechanism of the antianginal action of diltiazem in stress-induced myocardial ischemia, we studied 12 patients with stable exertional angina and disease of the proximal left anterior descending artery by measuring great cardiac vein flow (GVCF) and calculating anterior regional coronary resistance (ARCR) during myocardial ischemia induced by atrial pacing before and after intravenous administration of diltiazem (0.25 mg/kg in a bolus dose followed by continuous infusion of 0.005 mg/kg/min). Diltiazem increased the pacing time to angina from 6.9 +/- 3.5 to 10.7 +/- 4 min (p less than .001). At peak pacing heart rate was increased after diltiazem (from 128 +/- 17 to 145 +/- 17 beats/min, p less than .005), while mean arterial pressure was decreased (from 131 +/- 19 to 113 +/- 17 mm Hg, p less than .025), leaving the double product unaltered. At peak pacing no changes were observed in GCVF (from 115 +/- 46 to 119 +/- 46 ml/min, p = NS), ARCR (from 1.3 +/- 0.4 to 1.1 +/- 0.4 mm Hg/ml/min), or myocardial oxygen consumption of the anterior region (from 14.5 +/- 4.2 to 13.4 +/- 4.7 ml/min). Reduction of myocardial oxygen demand plays a major role in the antianginal action of diltiazem in patients with stress-induced myocardial ischemia.     

Mechanisms of angina relief after nifedipine: a hemodynamic and myocardial metabolic study

To elucidate the mechanisms of action of nifedipine in angina pectoris, 14 patients were studied before and after sublingual administration of 10 mg nifedipine. Systemic and coronary hemodynamic and myocardial metabolic measurements were taken at rest and during pacing. At the pacing rate that induced pain in the control situation, no patient experienced angina after nifedipine administration. Lactate production during control turned into extraction after nifedipine administration (p less than .05), and the double product was reduced (p less than .001). Systemic and coronary vascular resistance were reduced by 26% (p less than .001) and 19% (p less than .005), respectively. Systolic blood pressure fell from 160 +/- 29 to 127 +/- 25 mm Hg (p less than .001) and diastolic from 100 +/- 14 to 79 +/- 11 mm Hg (p less than .001). Pulmonary artery diastolic blood pressure fell from 14 +/- 4 to 10 +/- 3 mm Hg (p less than .01). When the pacing rate was further increased after nifedipine administration until pain developed, the double product and the degree of lactate production were the same as during pain before nifedipine was administered. The pacing rate was 131 +/- 12 compared with 119 +/- 13 during control (p less than .001). Both the systolic and diastolic blood pressures were still significantly reduced compared with control pacing values, 131 +/- 26 mm Hg (p less than .01) and 84 +/- 13 mm Hg (p less than .01), respectively. Our data demonstrate that the antianginal efficiency can be partly explained by afterload reduction, which decreases myocardial oxygen consumption. The data also suggest additional mechanisms, possibly an increase in collateral flow, direct dilatation of stenotic parts of epicardial arteries, or a decrease in myocardial back pressure secondary to reduced left ventricular filling pressure.     

Impaired coronary vasodilator responsiveness as a cause of lactate production during pacing-induced ischemia in patients with angina pectoris and normal coronary arteries

Subgroups of patients with angina pectoris and normal coronary arteries are known to have pacing-induced lactate production and, therefore, myocardial ischemia. To examine the mechanism of this pacing-induced ischemia, the effect of incremental atrial pacing on coronary blood flow and metabolism was studied in 27 patients with angina and normal coronary arteries. Seventeen patients continued to exhibit normal lactate extraction even at heart rates up to 160 beats/min (Group 1), whereas in 10 patients (Group 2) lactate extraction changed to production at the highest pacing rate. Coronary blood flow increased in Group 1 patients by 18, 41 and 75%, respectively, as heart rate was increased by 20 beat/min increments from 100 to 160 beats/min. In contrast, coronary blood flow increased by only 8, 7 and 14%, at the three respective pacing rates in Group 2. Between the heart rates of 100 and 160 beats/min, coronary vascular resistance decreased 32% in Group 1 patients but was unchanged in Group 2 patients. There was no significant change in the ratio of myocardial O2 consumption/rate-pressure product in Group 1 patients, but this ratio decreased from 0.91 +/- 0.26 ml O2 X min-1 X (mm Hg X beats/min)-1 to 0.53 +/- 0.11 (p less than 0.05) in Group 2 patients as heart rate increased from baseline to 160 beats/min. Thus, patients with angina and normal coronary arteries who develop ischemia with pacing have a decreased coronary vasodilator response that interferes with their ability to increase myocardial oxygen supply to match the higher demand.     

Myocardial ischemia in patients with hypertrophic cardiomyopathy: contribution of inadequate vasodilator reserve and elevated left ventricular filling pressures

To study the mechanism and hemodynamic significance of myocardial ischemia in hypertrophic cardiomyopathy, 20 patients (nine with resting left ventricular outflow tract obstruction greater than or equal to 30 mm Hg) with a history of angina pectoris and angiographically normal coronary arteries underwent a pacing study with measurement of great cardiac vein flow, lactate and oxygen content, and left ventricular filling pressure. Compared with 28 control subjects without hypertrophic cardiomyopathy, their resting coronary blood flow was higher (91 +/- 27 vs 66 +/- 17 ml/min; p less than .001) and their coronary resistance was lower (1.13 +/- 0.38 vs 1.55 +/- 0.45 mm Hg/ml/min; p less than .001). Left ventricular end-diastolic pressure (16 +/- 6 vs 11 +/- 3 mm Hg; p less than .001) and pulmonary arterial wedge pressure (13 +/- 5 vs 7 +/- 3 mm Hg; p less than .001) were significantly higher in patients with hypertrophic cardiomyopathy. During pacing, coronary flow rose in both groups, although coronary and myocardial hemodynamics differed greatly. In contrast to the linear increase in flow in control subjects up to heart rate of 150 beats/min (66 +/- 17 to 125 +/- 28 ml/min), patients with hypertrophic cardiomyopathy demonstrated an initial rise in flow to 133 +/- 31 ml/min at an intermediate heart rate of 130 beats/min. At this point, 12 of 20 patients developed their typical chest pain. With continued pacing to a heart rate of 150 beats/min, mean coronary flow fell to 114 +/- 29 ml/min (p less than .002), with 18 of 20 patients experiencing their typical chest pain and metabolic evidence of myocardial ischemia. This fall in coronary flow was associated with a substantial rise in left ventricular end-diastolic pressure (30 +/- 9 mm Hg immediately after peak pacing). In the 14 patients whose coronary flow actually fell from intermediate to peak pacing, the rise in left ventricular end-diastolic pressure in the same interval was greater than that of the six patients whose flow remained unchanged or increased (11 +/- 8 vs 2 +/- 2 mm Hg; p less than .01). In addition, despite metabolic and hemodynamic evidence of myocardial ischemia, the arteriovenous O2 difference actually narrowed at peak pacing. Thus most patients with hypertrophic cardiomyopathy achieved maximum coronary vasodilation and flow at modest increases in heart rate. Elevation in left ventricular filling pressure, probably related to ischemia-induced changes in ventricular compliance, was associated with a decline in coronary flow.(ABSTRACT TRUNCATED AT 400 WORDS)     

Clinical significance of myoglobin and troponin-T in short-lasting severe myocardial ischemia

BACKGROUND: Myoglobin, cardiac troponin-T and creatine phosphokinase are biochemical indicators of acute coronary syndromes, however, the clinical significance in myocardial ischemia is not well established. Our aim was to elucidate their release kinetics in a well-defined short-lasting myocardial ischemia. METHODS: A coronary sinus lactate study with incremental atrial pacing was performed in 27 patients with significant coronary stenosis. Troponin-T, myoglobin and creatine phosphokinase samples were withdrawn from the coronary sinus and a peripheral vein before, 1, 5, 10, 30, 45 min and 1, 2, 3, 6, 12 h after pacing. RESULTS: Pacing stress induced a severe myocardial ischemia with a duration of 5.8+/-1.6 min, angina pectoris in 22/27, significant ST-segment depressions in 25/27 patients (0.34+/-0.11 mV) and a frank cardiac lactate production of 37.6+/-19.9%. Serum troponin-T levels as well as creatine phosphokinase were normal at baseline and remained unchanged. A transient rise of myoglobin after 1 h with a peak coronary sinus concentration after 2 h (101.5+/-39.0 microg/l) and peripheral venous concentration (90.5+/-32.5 microg/l) after 3 h (134.3% and 120.7%, respectively, of the upper normal limit, p<0.002) followed myocardial ischemia. In a control group of 20 patients without heart disease all variables remained unchanged. CONCLUSIONS: Severe short-lasting myocardial ischemia did not enhance troponin-T or creatine phoshokinase concentrations, whereas a transient slight cardiac release of myoglobin with a delay of 1 h and a coronary sinus peak concentration after 2 h was detected. This may be due to a rapid reperfusion effect on ischemic myocardium or minor damaged single myocardial cells.     

Estimation of myocardial oxygen extraction dynamics in effort angina by continuous measurement of coronary venous saturation

To estimate myocardial oxygen extraction dynamics in the situation of increased myocardial oxygen requirement, we made a continuous measurement of coronary venous oxygen saturation (CSO2-Sat) using the fiberoptic catheter system and a measurement of myocardial lactate extraction ratio (MLER) in 14 patients. Ten patients showed ischemic ST depression and/or anginal episodes during the pacing loading, while 4 patients did not. Although transient decreases in CSO2-Sat were observed in the non-ischemic 4 patients immediately after the initiation of pacing or with the increase in pacing rate. CSO2-Sat and MLER remained almost unchanged from the start of pacing to the time of maximal pacing. However, in the 10 patients who developed ischemia, CSO2-Sat fell from 39.5 +/- 1.8% before pacing to 32.9 +/- 2.8% at the time of maximal pacing (p less than 0.05), with an average decrease of 6.6 +/- 2.8%. Data of MLER obviously indicated the appearance of myocardial ischemia (32.1 +/- 4.7% to 9.2 +/- 10.3%, p less than 0.05). These findings suggest that myocardial oxygen extraction will increase transiently or continuously to meet the myocardial oxygen demand when increase in coronary blood flow is limited. Continuous measurement of coronary venous saturation may be useful for the early detection of myocardial ischemia.     

Myocardial release of inosine, hypoxanthine and lactate during pacing-induced angina in humans with coronary artery disease.

The applicability of the adenosine triphosphate (ATP) catabolites, inosine and hypoxanthine as markers of myocardial ischemia in humans with coronary artery disease has been investigated. Inosine and hypoxanthine were assayed enzymatically after separation by a new column chromatographic method. The myocardial lactate extraction at rest (17 +/- 13%) changed to production values (-23 +/- 28%) during pacing-induced angina (P less than 0.0005). Coronary venous inosine values increased from 535 +/- 185 nmol/l at rest to 1030 +/- 740 nmol/l during angina (P less than 0.005), the arterial values amounted to 770 +/- 325 nmol/l and 805 +/- 515 nmol/l respectively (P, NS). The calculated myocardial uptake of inosine at rest (27 +/- 16%) changed to production values (-25 +/- 29%) during angina (P less than 0.0005). Coronary venous hypoxanthine increased from 1000 +/- 760 nmol/l at rest to 1235 +/- 800 nmol/l during angina (P, NS), the arterial values amounted to 1300 +/- 1040 nmol/l and 1235 +/- 800 nmol/l respectively (P, NS). The myocardial extraction changed from 20 +/- 18% at rest to -5.4 +/- 29% during angina (P less than 0.0025). The significant positive correlation (r = 0.61, P less than 0.0025) between myocardial release and uptake of inosine and lactate during severe angina demonstrates that anaerobic glycolysis is accompanied by ATP breakdown. During a second pacing period at less increased pressure--rate product after nitroglycerin, lactate production (-1.7 +/- 22%) already occurred whereas extraction of inosine (19 +/- 19%) and hypoxanthine (24 +/- 15%) did not change. In conclusion, lactate functions as a sensitive marker of myocardial ischemia and inosine is useful in detecting ischemic myocardial energy deficiency by the indication of insufficient glycolytic ATP supply.     

The effects of trapidil on left ventricular function and platelet aggregation in patients with coronary artery disease subjected to pacing.

The effects of the intravenous administration of 100 mg of trapidil on systolic and diastolic left ventricular functions and coronary sinus blood flow, as well as on myocardial lactate metabolism and platelet aggregation, were investigated before and after pacing in 12 patients with coronary artery disease. Pacing without administration of trapidil provoked angina in 6 of these patients. During rest, trapidil decreased the mean blood pressure by an average of 5 mmHg (from 112 +/- 15 to 107 +/- 8 mmHg, p less than 0.05) and the left ventricular end-diastolic pressure by an average of 4 mmHg (from 10 +/- 3 to 6 +/- 2 mmHg, p less than 0.05). Trapidil also caused both the max dp/dt and the coronary sinus blood flow to increase slightly, although it had no significant effect on diastolic function, myocardial lactate metabolism, or platelet aggregation. During the pacing that followed trapidil administration, chest pain was not provoked in the same 6 patients who had previously experienced chest pain on pacing. The extent of ST-segment depression also improved from -1.6 +/- 0.3 to -0.9 +/- 0.7 mm (p less than 0.05) and there was a significant suppression of the production of myocardial lactate. When pacing was terminated, trapidil caused a decrease in left ventricular systolic pressure from 173 to 156 mmHg (p less than 0.05), and also caused a decrease of the left ventricular end-diastolic pressure, from 16 +/- 4 to 8 +/- 2 mmHg (p less than 0.05). Trapidil had no significant effect on platelet aggregation activity with either a 1 microM or a 2 microM dose of ADP (adenosine diphosphate). However, the beta-TG level was suppressed, decreasing from 119 +/- 14 to 99 +/- 19 ng/ml in the arterial blood (p less than 0.1) and from 114 +/- 9 to 103 +/- 17 ng/ml (p less than 0.1) in the coronary sinus blood. Reductions in the preload and afterload by trapidil were of far greater magnitude than either its coronary dilatory or positive chronotropic effects in patients with coronary artery disease. Thus trapidil, a new antianginal agent appears to inhibit the production of platelet derived growth factors and may, therefore, protect the arteries from atherosclerosis as it promotes beneficial systemic hemodynamics in patients with depressed ventricular function.