Effect of intracoronary nifedipine on coronary bloodflow and myocardial metabolism during pacing-induced ischemia

The effects of intracoronary nifedipine on coronary bloodflow, its regional distribution, myocardial oxygen consumption and lactate metabolism during pacing-induced angina were evaluated in 15 subjects. These responses were directly compared to 10 subjects who received an alcohol-based control solvent. Myocardial bloodflow was measured by thermodilution, with changes in regional coronary flow assessed using a dual radiolabelled (technetium-99m and indium-111) intracoronary microsphere technique and single photon emission tomography. Neither intracoronary nifedipine (100 micrograms) or the control solvent produced changes in systemic arterial pressure (nifedipine -2 mmHg and control +2 mmHg, both not significant). Intracoronary nifedipine markedly increased left ventricular end diastolic pressure (pre-nifedipine 13.0 mmHg versus post nifedipine 20.1, P less than 0.05), while increasing total coronary sinus bloodflow (pre-nifedipine 134 mL/min versus post nifedipine 189, P less than 0.05): Regional coronary bloodflow increased in all myocardial segments, regardless of the severity of coronary stenosis (64 to 132% baseline, all P less than 0.05). In addition, intracoronary nifedipine increased myocardial oxygen consumption (pre-nifedipine 12.3 mL/min versus post nifedipine 15.7, P less than 0.05), with a trend towards improved lactate extraction (pre-nifedipine 0.24 mg/mL versus post nifedipine 0.12, not significant). Although decreased ventricular afterload (left ventricular systolic wall stress) may contribute to nifedipine's antianginal properties, a primary increase in regional coronary bloodflow also appears to be an important factor in the alleviation of myocardial ischemia.     

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.     

Effect of pressure-controlled intermittent coronary sinus occlusion on pacing-induced myocardial ischemia in domestic swine

This study tested the hypothesis that pressure-controlled intermittent coronary sinus occlusion (PICSO) would be useful in ameliorating myocardial ischemia under conditions characterized by preserved, but reduced (relative to demand), myocardial blood flow. Studies were conducted in closed-chest, sedated domestic swine prepared with an artificial stenosis that reduced luminal diameter of the animal's left anterior descending coronary artery by 80%. Measurements of hemodynamics, regional myocardial blood flow, and oxygen, lactate, and nucleoside metabolism were obtained in 10 animals (1) before placement of stenosis, (2) 30 min after insertion of stenosis, (3) after 30 and 60 min of PICSO, and (4) 30 min after discontinuation of PICSO. Two groups of control animals were studied to observe the natural history of metabolic markers of ischemia. Control group I consisted of four animals studied concurrently and subjected to the same protocol except for the fact that PICSO was not applied. Control group II consisted of eight additional animals studied as a group. A specially designed balloon-tipped catheter positioned in the proximal portion of the animal's great cardiac vein was used to provide PICSO. Heart rate was controlled by atrial pacing (rate, 145 beats/min) through the study. After placement of the stenosis, flow in endocardial and transmural layers distal to the stenosis declined significantly (p less than .01) vs control. Application of PICSO failed to increase arterial inflow distal to the stenosis in any myocardial layer. Myocardial aerobic metabolism was adversely affected by stenosis and changed from consumption of lactate, inosine, and hypoxanthine before stenosis to production at 30 min after stenosis. Although PICSO was associated with reduced production and a return toward consumption of lactate, inosine, and hypoxanthine, a similar pattern of changes in lactate, inosine, and hypoxanthine metabolism was observed in control animals over a comparable period of time. In addition, regional myocardial oxygen extraction and consumption were not changed vs poststenosis levels by PICSO. However, in comparison with controls, PICSO did accelerate the rate of resolution of myocardial ischemia as assessed by lactate metabolism. At 30 min of PICSO (or sham) the change vs poststenosis was +33.6 +/- 25.0 mumol/min/100 g in the PICSO but only +6.7 +/- 29.7 in the control group (p = .05). We conclude, therefore, that even though PICSO did not alter the final level of myocardial ischemia under conditions modeled in this study it did accelerate its rate of resolution, an effect that may be beneficial clinically.     

Effect of the calcium antagonist nisoldipine on coronary circulation and myocardial ischemia in temporary coronary occlusion

Sixteen patients undergoing PTCA of a significant lesion of the left anterior descending coronary artery received either 0.3 mg nisoldipine or placebo intravenously. Immediately before and during balloon inflation the following parameters were measured: aortic pressure, post-stenotic pressure, coronary occlusion pressure, diastolic pulmonary artery pressure, coronary sinus flow (thermodilution), and intracoronary ECG. After placebo there were no statistically significant changes. Nisoldipine led to a decrease in aortic pressure from 109 +/- 12 to 93 +/- 11 mm Hg (p less than 0.05) before, and from 103 +/- 14 to 92 +/- 8 mm Hg (NS) during balloon inflation. In contrast, coronary occlusion pressure remained unchanged. Heart rate increased from 80 +/- 13 to 96 +/- 16/min before (p less than 0.05), and from 87 +/- 18 to 97 +/- 17/min during balloon inflation (NS). Coronary sinus flow was increased from 95 +/- 16 to 116 +/- 13 ml/min before balloon inflation (p less than 0.01), and from 70 +/- 25 to 86 +/- 26 ml/min during balloon inflation (NS). ST-segment depression or elevation, severity of angina pectoris, and the diastolic pulmonary artery pressure remained unchanged. Thus, 0.3 mg nisoldipine led to a peripheral vasodilatation. While the aortic pressure decreased, coronary occlusion pressure remained unaffected. This could be explained by a marked dilatation of collateral vessels due to nisoldipine. However, myocardial ischemia remained unaffected as a result of the constant coronary occlusion pressure.     

Effects of nicorandil on coronary circulation and myocardial ischemia

The effect of the new antianginal drug, nicorandil, was studied in several models of myocardial ischemia in anesthetized dogs. In animals subjected to an acute or chronic coronary artery occlusion, nicorandil produced increases in collateral perfusion when changes in aortic pressure were minimized. In a model of irreversible ischemia, nicorandil produced a marked (50%) decrease in myocardial infarct size. In several models of reversible ischemiareperfusion injury, the “stunned myocardium,” nicorandil was shown to enhance the recovery of systolic segment shortening after a brief period (15 to 30 minutes) of coronary occlusion. Other vasodilators such as nitroglycerin or nifedipine were not as efficacious as nicorandil. In a model of multiple (n = 3) coronary occlusion (5 minutes) with intermittent (30 minutes) reperfusion, nicorandil improved the recovery of systolic segment shortening during reperfusion and prevented the loss of adenosine triphosphate and tissue edema that occurred in untreated hearts. The beneficial effects of nicorandil on functional and metabolic recovery after recurrent ischemia was shown to be partially the result of an energy-sparing effect of nicorandil to reduce free fatty acid use during the ischemic period. Cyclooxygenase blockade with indomethacin did not block the beneficial effects of nicorandil in the stunned myocardium. These results suggest that nicorandil does not promote an increase of prostacyclin. Finally, nicorandil was found to inhibit superoxide anion production by human neutrophils stimulated by formyl-methionyl-leucyl-phenylalanine plus cytochalasin B. These results suggest that part of the beneficial actions of nicorandil may occur during reperfusion and may be the result of a reduction in oxygen free radical production. Thus, nicorandil has been found to be a highly efficacious agent in reducing ischemia and reperfusion injury in a number of animal models by several mechanisms.     

Does exercise-induced myocardial ischaemia cause enhanced platelet activation and fibrin formation in patients with stable angina and severe coronary artery disease?

In this study, betathromboglobulin (BTG) and fibrinopeptideA (FPA) in peripheral venous blood were measured in 20 patientswith stable angina pectoris before and immediately after exercise-inducedmyocardial ischaemia; in 5 of the 20 patients stable anginawas associated with typical peripheral artery disease. A totalof 10 patients with angiographically documented peripheral arterydisease without angina and 10 normal volunteers were taken ascontrol groups. BTG and FPA in the 15 patients with stable anginabefore exercise were 41±14 ng ml^-1 and 2.3±09ng ml^-1 and were not statistically different from the valuesin normal controls; after exercise-induced myocardial ischaemiano significant increase occurred in these patients. Conversely,in the 5 patients with stable angina associated with peripheralartery disease BTG and FPA before exercise were 6l±10ng ml^-1 and 3.5±0.8 ng ml^-1 and increased to 114±14ng ml^-1 (P<0.001) and 4.l±0.5 ng ml^-1 (P<0.01):These results were similar to those found in the 10 patientswith isolated peripheral artery disease.We conclude that BTGand FPA in peripheral venous blood in patients with stable anginaare not elevated either at rest or after exercise-induced myocardialischaemia. Elevated values of BTG and FPA in patients with stableangina may reflect a major interaction between blood and atheroscleroticvessel wall, suggesting the presence of associated atheroscleroticlesions in peripheral artery disease.     

Lack of ouabain effect on pacing-induced myocardial ischemia in patients with coronary artery disease

Sixteen patients with significant two and three vessel coronary artery disease but without clinical congestive heart failure were studied during rapid atrial pacing before and after infusion of 0.015 mg/kg of ouabain. Seven patients with a decreased (less than 50 percent) election fraction and nine patients with a normal election fraction had a significant (P < 0.05) increase in resting arterial systolic pressure after the administration of ouabain. However, resting values for coronary sinus flow, coronary vascular resistance, myocardial oxygen consumption and myocardial lactate extraction did not change significantly in either group. During pacing, patients with a decreased ejection fraction demonstrated more ischemia than patients with a normal ejection fraction; however, the administration of ouabain did not significantly alter pacing-related changes in coronary sinus flow, myocardial oxygen consumption, myocardial lactate extraction, ischemic electrocardiographic changes or onset of chest pain in either group. The administration of ouabain has a negligible effect on coronary hemodynamics, myocardial metabolism or clinical signs of ischemia in patients with coronary artery disease with normal or abnormal left ventricular function.     

Fibrin formation and platelet activation in patients with myocardial infarction and normal coronary arteries

Coronary spasm is the mechanism most often postulated to explain the rare combination of myocardial infarction and angiographically normal coronary arteries, although the reported evidence for its role is circumstantial rather than conclusive. Whereas the importance of thrombosis in myocardial infarction is uncontested in the presence of significant coronary artery disease, there is little in vivo evidence for thrombosis in angiographically normal coronary arteries. Among 11 consecutive patients with acute myocardial infarction undergoing thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) 3.2 +/- 0.7 h after onset of chest pain, and angiography 10.2 +/- 4.5 days later, three young men had normal coronary arteries. Their cases are documented electrocardiographically, enzymatically and angiographically. Mean plasma levels of fibrinopeptide A (FPA) and beta-thromboglobulin (BTG) were clearly elevated before and during rtPA therapy: FPA 52 +/- 41 ng ml-1, BTG 257 +/- 46 ng ml-1. They did not differ significantly from corresponding mean plasma levels in the eight patients with severe coronary artery disease: FPA 67 +/- 66 ng ml-1, BTG181 +/- 75 ng ml-1. We conclude that fibrin formation and platelet activation are probably equally important in the early hours of myocardial infarction, whether or not significant coronary artery disease is present.     

Dynamic nature of thrombin generation,fibrin formation,and platelet activation in unstable angina and non-Q-wave myocardial infarction

Background Thrombin and platelets are directly involved in arterial thrombosis, typically occurring at sites of atherosclerotic plaque rupture among patients with acute coronary syndromes. Understanding the dynamic nature of pathologic thrombosis has important clinical implications.Methods Fibrinopeptide A (FPA), thrombin-antithrombin complexes (TAT), and prothrombin activation fragment 1.2 (F1.2), plasma markers of fibrin formation (thrombin activity) and thrombin generation, and platelet activation, determined by the recognition of a surface-expressed platelet -granule protein, P-selectin, using flow cytometry, were measured in 36 consecutive patients with unstable angina and non-Q-wave myocardial infarction participating in the Thrombolysis In Myocardial Ischemia (TIMI) III B trial.Results Thrombin generation (TAT 12.1 ± 17.8 ng/ml vs. 3.4 ± 1.0 ng/ml; F1.2 0.19 ± 0.14 nmol/1 vs. 0.12 ± 0.8 nmol/1), fibrin formation (FPA 15.8 ± 23.5 ng/ml vs. 7.5 ± 2.3 ng/ ml), and platelet activation) 10.6 ± 2.4% vs. 2.5 ± 2.0%) were increased significantly in patients compared with healthy, age-matched controls (p < 0.01). Fibrin formation, represented by plasma FPA levels, did not correlate with the percentage of activated platelets (r=– .10, p=0.69). Thrombin generation and platelet activation also did not correlate. A statistically insignificant trend between TAT and platelet activation was observed (r=.42, p=0.07); however, even with TAT levels in excess of 20 ng/ml (nearly sixfold greater than normal healthy controls) platelet activation was increased by only 1.7-fold.Conclusions Thrombin generation, fibrin formation, and platelet activation are increased modestly among patients with unstable angina and non-Q-wave myocardial infarction. Despite the involvement of platelets and coagulation proteins in arterial thrombotic processes, their relative contributions may vary, providing a pathophysiologic basis for the dynamic expression of disease and response to treatment observed commonly in clinical practice.     

Recordings of the local pacing-induced myocardial activation and repolarization

We have studied the endocardial ventricular evoked response which follows delivery of a unipolar stimulus down the sensing electrode. The system uses the same lead for both pacing and sensing and permits recordings of the evoked T wave representing a dominantly local repolarization which follows a pacing-induced depolarization at the same site. In 12 animal experiments and in the course of electrophysiological investigations in 19 patients, we evaluated changes in the morphology and duration of the paced evoked response following drug interventions which alter myocardial refractoriness and repolarization time. These changes paralleled results obtained by simultaneous, paced monophasic action potential recordings, and suggest that myocardial repolarization can be accurately assessed by this new technique, which could overcome some of the difficulties in comparing 'in vivo' experiments with the clinical effects of drugs in man.     

Effect of diltiazem on pacing-induced ischemia in conscious dogs with coronary stenosis: Improvement of postpacing deterioration of ischemic myocardial function

The effects of diltiazem on regional myocardial function were examined in conscious dogs subjected to rapid cardiac pacing during coronary arterial stenosis. Ultrasonic dimension gauges were implanted within the left ventricle for measurement of the control and ischemic segment lengths. During coronary stenosis, percent shortening in the ischemic segment decreased by 18 percent. Heart rate was then suddenly increased by rapid cardiac pacing and this resulted in a further reduction of ischemic segmental shortening. On cessation of pacing, there was early potentiation of rate of increase of left ventricular pressure (dP/dt) and of control segmental shortening with subsequent exponential decay in sequential beats. In the ischemic segment, percent shortening returned to the control level in the first postpacing beat, became severely depressed at 5 seconds after pacing and gradually returned to the control level over the subsequent 5 minutes.Twenty minutes after administration of diltiazem, cardiac pacing was repeated in the same manner and there was less marked potentiation of dP/dt of the first postpacing beat. There was no significant change in the postpacing dimension and function of the control segment; however, in the ischemic segment, although shortening of the first beat after termination of the pacing was similar, the post stimulation deterioration of shortening was significantly improved, percent shortening being augmented from 7.4 to 10.6 percent at 5 seconds (p <0.05). These findings indicate that diltiazem exerts protective effects on the ischemic myocardium by promoting a rapid recovery from ischemia.     

Beneficial effects of the coronary collateral circulation on tachycardia-induced myocardial ischemia during experimental coronary stenosis

This study was designed to determine whether coronary collaterals have preventive effects on tachycardia-induced myocardial ischemia under partial restriction of proximal coronary artery inflow. Studies were carried out in dogs with developed coronary collaterals and control dogs. ST-elevation in epicardial and intramyocardial electrograms was used for assessing the degree of regional myocardial ischemia. In control dogs with coronary constriction (80% reduction of i.d.) pacing-induced tachycardia produced significant ST-elevation, 1.48 +/- 0.17 mV in the inner layer and 0.79 +/- 0.29 mV in the middle layer at a cardiac rate of 150/min, 3.58 +/- 0.38 mV in the inner layer, 2.73 +/- 0.38 mV in the middle layer, and 1.93 +/- 0.36 mV in the outer layer at a rate of 180/min. In dogs with moderate collaterals ST-segment elevation was only 1.41 +/- 0.18 mV in the inner layer and 0.96 +/- 0.24 mV in the middle layer at a rate of 180/min. In dogs with abundant collaterals there was no significant ST-elevation during tachycardia. These findings indicate that blood supply to the affected myocardium via developed collaterals is sufficient to meet graded increases in metabolic requirements under the condition of limited coronary flow reserve in an experimental model simulating angina pectoris.     

Effects of nicardipine on exercise- and pacing-induced myocardial ischemia in angina pectoris

To define the effects of nicardipine, a new dihydropyridine calcium antagonist drug, on exercise- and pacing-induced myocardial ischemia, 15 men with coronary artery disease were studied during cardiac catheterization. Nicardipine was administered intravenously as a 2-mg bolus followed by an infusion titrated to maintain a 10- to 20-mm Hg decrease in systolic arterial pressure. At rest, nicardipine decreased systemic and coronary vascular resistances, left ventricular end-diastolic pressure and increased coronary blood flow, heart rate and myocardial oxygen consumption. During bicycle exercise-induced myocardial ischemia, nicardipine significantly prolonged exercise duration and time to 1 mm of ST-segment depression. These changes were associated with no alteration in the product of systolic pressure and heart rate, decreased left ventricular end-diastolic pressure, systemic and coronary vascular resistances and increased coronary blood flow, as well as myocardial oxygen consumption. During atrial pacing, the heart rate threshold for myocardial ischemia was not changed by nicardipine administration, despite improvement in the ratio of coronary blood flow to myocardial oxygen consumption and hemodynamic changes otherwise similar to those during exercise. Nicardipine favorably influenced myocardial metabolic state, as indexed by lactate extraction during pacing-induced ischemia. Nicardipine is a potent coronary and systemic vasodilating drug that improves exercise tolerance and myocardial metabolic response to pacing stress, the mechanism for which appears to be partially mediated through increased coronary blood flow.     

Temporal relation of changes in regional coronary flow and myocardial lactate and nucleoside metabolism during pacing-induced ischemia

The temporal relation between myocardial lactate and hypoxanthine metabolism and regional changes in krypton-81m perfusion during pacing-induced ischemia was studied in 17 patients with coronary artery disease (CAD). During incremental atrial pacing, lactate production and hypoxanthine release occurred early and simultaneously, accompanied by ST-segment changes, but before angina and only few minutes after a significant (17%) reduction in krypton-81m perfusion in areas with more than 90% luminal diameter reduction. During maximal pacing heart rates, krypton-81m distribution decreased to 68 ± 7% of control in areas with more than 90% diameter reduction and to 80 ± 4% in 70 to 90% reduction (both p < 0.05 vs control). Maximal lactate production occurred 15 seconds after pacing (extraction −15 ± 7% vs 16 ± 2% during control, p < 0.05) and peak hypoxanthine release 1 minute after pacing (Δ arteriovenous −2.64 ± 0.8 μM vs 0.08 ± 0.21 μM during control, p < 0.05). Krypton-81m perfusion decreased in 20 of the 21 CAD areas. Angina, ST-segment changes, hemodynamic alterations and lactate production occurred in 15, 14, 9 and 15 patients, respectively. In contrast, hypoxanthine release was found in all cases. After pacing, lactate production and all general indexes of ischemia persisted for only 2 to 3 minutes. In contrast, krypton-81m perfusion was still significantly reduced 5 minutes after pacing and was only accompanied by hypoxanthine release (Δ arteriovenous −1.41 ± 0.6 μM, p < 0.05 vs control). Therefore, although lactate production and hypoxanthine release occur early and simultaneously during pacing-induced ischemia, closely following coronary flow changes in high-stenotic areas, hypoxanthine appears to be more sensitive and consistent as indicator of ischemia. Persistant reductions in krypton-81m perfusion and hypoxanthine release strongly suggest prolonged ischemia after cessation of pacing.     

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)     

Prevention of creatine kinase-MB release in coronary artery disease and pacing-induced myocardial ischemia by isosorbide dinitrate spray

The effect of isosorbide dinitrate (ISDN) spray on release of the isoenzyme creatine kinase-MB (CK-MB) after myocardial ischemia induced by atrial pacing was evaluated in 8 patients with coronary artery disease. Atrial pacing to ischemia (ST-segment depression of greater than or equal to 1.5 mm for greater than or equal to 80 ms) resulted in elevation of CK-MB levels in plasma drawn from the coronary sinus, from 1.8 +/- 1.5 to 6.8 +/- 7.0 ng/ml (p less than 0.001) at 30 minutes after onset of ischemia. When atrial pacing was repeated at the same rate after 1 squirt of ISDN spray, 1.25 mg, the CK-MB levels were not altered despite significant ischemic ST-segment depression. It is concluded that ISDN prevents the process responsible for myocardial release of CK-MB, being either micronecroses or a reversible consequence of ischemia.