Pacing-induced Ischemia Research Articles

A New Metabolic Mechanism for Absence of Pain in Patients with Silent Myocardial Ischemia

We undertook this study to detect if there is a relationship between lactate production in the myocardium and the presence or absence of chest pain in patients with coronary artery disease (CAD). Forty six patients with significant CAD including left anterior descending artery underwent echocardiography study, coronary angiography and pacing-induced ischemia. Serum lactate levels were determined in four blood samples, from mid-LV cavity and from coronary sinus before and after pacing-induced ischemia. Twenty eight patients comprised angina group and 18 patients comprised silent myocardial ischemia (SMI) group during pacing-induced ischemia. Eighteen patients (64.3%) of angina group had lactate production during ischemia. Eighteen patients of SMI group (100%) had diminished lactate extraction, and none had lactate production. The novel finding of this study is that the major difference in metabolism during SMI and angina pectoris is in the state of lactate production, which is absent during SMI and present during angina. We assume that lactate is the stimulus of cardiac ischemic pain and when its level increases, it stimulates pain receptors leading to chest pain.

ST changes and temporal relation to the J point during heart rate increase and myocardial ischemia

There is no concensus concerning where in the ST segment to measure. We studied the relation between different J point intervals to ST results during tachycardia and ischemia. Symptomatic (anesthetized) patients with coronary artery disease were paced at ascending incremental levels until they became ischemic. ST vector magnitude and ST vector change from baseline (STC-VM) as well as the sum of ST changes from all 12 electrocardiogram (ECG) leads (ECG ST sum) were measured at J point 0 millisecond, J + 20, J + 60, and J + 80 milliseconds for 34 patients. ST segments increased in similar fashion during pacing and ischemia. There was no difference in ST results when measurement was performed at different time intervals for both STC-VM and ECG ST sum. We conclude that ST assessment by ST change from baseline is not affected by different J point intervals during increased heart rate and ischemia in this clinical model of pacing-induced ischemia and vectorcardiographic ST analysis.

Acute administration of 17β-estradiol reduces endothelin-1 release during pacing-induced ischemia

Objectives To assess whether acute administration of 17β-estradiol reduces pacing-induced cardiac release of endothelin-1 in female menopausal patients with coronary artery disease. Background Endothelin-1 is a potent vasoactive peptide which plays a pathogenetic role in myocardial ischemia and adverse clinical events in patients with coronary artery disease. Estrogens decrease plasma levels of endothelin-1 and improve stress-induced myocardial ischemia in menopausal women with coronary artery disease. Methods Twenty-two postmenopausal women with angiographically proven coronary artery entered a randomized, double blinded, placebo-controlled study. Patients were sampled into the coronary sinus and aorta for endothelin-1 at baseline and after incremental pacing. After baseline study, patients were randomized to receive either sublingual 17β-estradiol (1 mg) or placebo and underwent the sampling protocol 20 min thereafter. Results 17β-Estradiol but not placebo improved the time of onset of myocardial ischemia during pacing. The coronary sinus plasma levels of endothelin-1 were significantly reduced by estradiol administration but not by placebo, at each step of pacing protocol. The maximum reduction of endothelin-1 was noted at peak pacing (− 0.18 ng/l; − 0.09, − 0.3; 95% CI). No changes in endothelin-1 were noted in patients allocated to placebo ( −0.002 ng/l; − 0.06, − 0.01; 95% CI). Similarly, aorto-coronary sinus difference of endothelin-1 was significantly influenced by 17β-estradiol administration but not by placebo. Conclusion Acute administration of 17β-estradiol reduces pacing-induced cardiac release of endothelin-1 in postmenopausal women with coronary artery disease. This result may be related to the anti-ischemic or to a primary direct effect of the hormone upon myocyte release of the peptide, and may contribute to its anti-ischemic effect. Condensed abstract To assess effect of acute 17β-estradiol administration on pacing-induced cardiac release of endothelin-1, we studied 22 female menopausal patients with coronary artery diseases. In a randomized, double-blinded, placebo-controlled study, patients were randomized to receive either sublingual 17β-estradiol (1 mg) or placebo. Aortic and coronary sinus plasma endothelin-1 levels were evaluated at baseline, during incremental atrial pacing, and at peak pacing before and after the sublingual administration of either 17β-estradiol or placebo. The time to the onset of myocardial ischemia during pacing was significantly increased by 17β-estradiol vs. placebo. Moreover, coronary sinus endothelin-1 levels at peak pacing and aortic-coronary sinus changes were significantly improved by the administration of 17β-estradiol but not by placebo. Acute administration of 17β-estradiol reduces pacing-induced cardiac release of endothelin-1 in postmenopausal women with coronary artery disease.

Intracoronary Delivery of an Adenovirus Encoding Fibroblast Growth Factor-4 in Myocardial Ischemia: Effect of Serum Antibodies and Previous Exposure to Adenovirus

The presence of anti-adenoviral serotype 5 (Ad5) antibodies may limit the efficacy of Ad5-mediated gene transfer. We therefore tested the hypothesis that intracoronary delivery of an adenovirus encoding human fibroblast growth factor type 4 (Ad5.FGF4) would improve regional myocardial function in an animal model of ischemia when high antibody levels preexist or after a prior intracoronary dose of Ad5. High anti-Ad5 antibody levels were generated in pigs by subcutaneous immunization with an adenovirus encoding LacZ (Ad5.lacZ). Neutralizing antibody levels increased 648-fold (range, 82- to 2108-fold) above preimmunization levels, and persisted for the duration of the study. Myocardial function during pacing-induced ischemia was improved in the ischemic region (p<0.001) at both 2 and 4 weeks after Ad5.FGF4 administration despite the presence of preexisting antibodies to Ad5. In a second set of experiments, the efficacy of a second intracoronary administration of Ad5 was determined by exposing the animals first to an intracoronary dose of Ad5.lacZ, followed 7 weeks later by the therapeutic dose of Ad5.FGF4. After delivery of Ad5.lacZ, anti-Ad5 antibody levels increased 8-fold (range, 1- to 18-fold), but this prior exposure to Ad5 did not prevent the therapeutic effects after subsequent intracoronary dosing with Ad5.FGF4 (p<0.001). In the porcine Ameroid constrictor model of myocardial ischemia the presence of anti-Ad5 antibodies or prior intracoronary dosing with adenovirus does not prevent the ability of Ad5.FGF4, delivered by intracoronary injection, from normalizing regional myocardial function.

Coronary microcirculatory vasoconstriction is heterogeneously distributed in acutely ischemic myocardium

The classical model of coronary physiology implies the presence of maximal microcirculatory vasodilation during myocardial ischemia. However, Doppler monitoring of coronary blood flow (CBF) documented severe microcirculatory vasoconstriction during pacing-induced ischemia in patients with coronary artery disease. This study investigates the mechanisms that underlie this paradoxical behavior in nine patients with stable angina and single-vessel coronary disease who were candidates for stenting. While transstenotic pressures were continuously monitored, input CBF (in ml/min) to the poststenotic myocardium was measured by Doppler catheter and angiographic cross-sectional area. Simultaneously, specific myocardial blood flow (MBF, in ml.min(-1).g(-1)) was measured by 133Xe washout. Perfused tissue mass was calculated as CBF/MBF. Measurements were obtained at baseline, during pacing-induced ischemia, and after stenting. CBF and distal coronary pressure values were also measured during pacing with intracoronary adenosine administration. During pacing, CBF decreased to 64 +/- 24% of baseline and increased to 265 +/- 100% of ischemic flow after adenosine administration. In contrast, pacing increased MBF to 184 +/- 66% of baseline, measured as a function of the increased rate-pressure product (r = 0.69; P < 0.05). Thus, during pacing, perfused myocardial mass drastically decreased from 30 +/- 23 to 12 +/- 11 g (P < 0.01). Distal coronary pressure remained stable during pacing but decreased after adenosine administration. Stenting increased perfused myocardial mass to 39 +/- 23 g (P < 0.05 vs. baseline) as a function of the increase in distal coronary pressure (r = 0.71; P < 0.02). In conclusion, the vasoconstrictor response to pacing-induced ischemia is heterogeneously distributed and excludes a tissue fraction from perfusion. Within perfused tissue, the metabolic demand still controls the vasomotor tone.

Biphasic relaxation-frequency relations in patients with effort angina pectoris: a new marker of myocardial demand ischemia

Background Relaxation-frequency relations (RFR) during demand ischemia have not been fully examined in patients with effort angina pectoris (AP). We sought to clarify the effects of pacing and exercise on RFR in patients with AP. Methods We recorded left ventricular (LV) pressures during rapid atrial pacing and symptom-limited supine bicycle exercise. RFR were analyzed in 24 patients with AP and 10 controls. Results LV pressure half-time (T 1/2) in controls was gradually shortened with an increase in heart rate (HR) during pacing (−19% ± 6% at peak HR). The changes in T 1/2 during pacing were biphasic with initial shortening (−12% ± 5% at the critical HR) followed by prolongation (−3% ± 7% at peak HR) in all patients with AP. The critical HR, at which T 1/2 was minimum, preceded the HR at 0.1-mV ST-segment depression, and finally chest pain occurred. The critical HR was correlated negatively with the severity of ischemia as assessed by thallium-201 scintigraphy. T 1/2 was remarkably shortened during exercise in controls (−41% ± 10% at peak exercise). In patients with AP, 2 distinct patterns of RFR were observed during exercise. T 1/2 was shortened progressively (−37% ± 8% at peak exercise) in 15 patients, whereas RFR remained biphasic (−21% ± 10% at the critical HR and −11% ± 11% at peak exercise) in the other 9 patients. Coronary angiography and exercise scintigraphy suggested more severe ischemia in patients with biphasic RFR during exercise. Conclusions Impaired RFR might be the most sensitive parameter of pacing-induced ischemia. The critical HR was closely related with severity of ischemia. Adverse effects of ischemia on LV relaxation may be alleviated by exercise.

Paradoxical increase in microvascular resistance during tachycardia downstream from a severe stenosis in patients with coronary artery disease : reversal by angioplasty.

The pathophysiology of microvascular response to a severe coronary stenosis has not been conclusively identified. The aim of this study was to characterize the human vasomotor response to pacing-induced ischemia of both the stenotic arterial segment and the distal microcirculation. Sixteen patients with stable angina and single-vessel disease were studied. Blood flow velocity and transstenotic pressure gradient were monitored at baseline, after intracoronary adenosine (2 mg), and during ischemia induced by atrial pacing with and without adenosine. At the end of this protocol, the study was repeated after intracoronary phentolamine in 7 patients and after angioplasty in 9. Stenosis resistance was calculated as the ratio between mean pressure gradient and mean flow, and microvascular resistance as the ratio between mean distal pressure and mean flow; values were expressed as percent of baseline. Adenosine decreased (P<0.05) baseline microvascular resistance to 52+/-17%, but not stenosis resistance. Pacing increased both stenosis and microvascular resistances (244+/-96% and 164+/-60% of baseline, respectively, P<0.05). Addition of adenosine to pacing decreased both stenosis (143+/-96% of baseline, P<0.05 versus ischemia) and microvascular (51+/-17% of baseline, P<0.05 versus baseline and ischemia) resistances. Phentolamine did not affect coronary resistance at any step of the protocol. Angioplasty and stenting restored a progressive decline in microvascular resistance during pacing (51+/-19% of baseline, P<0.05 versus baseline). In patients with coronary artery disease, tachycardia-induced ischemia was associated with elevated resistance of both the stenotic segment and the microvasculature. Revascularization prevents this paradoxical behavior.

190 Doppler echocardiographic evaluation of left ventricular filling in patients with pacing-induced ischaemia

190 Doppler echocardiographic evaluation of left ventricular filling in patients with pacing-induced ischaemia

190 Doppler echocardiographic evaluation of left ventricular filling in patients with pacing-induced ischaemia

190 Doppler echocardiographic evaluation of left ventricular filling in patients with pacing-induced ischaemia

Acute anti–ischemic effects of perindoprilat in men with coronary artery disease and their relation with left ventricular function

Long-term angiotensin-converting enzyme (ACE) inhibition may reduce ischemic events in patients with coronary artery disease, but whether it protects against acute ischemia or the effects of preexisting left ventricular (LV) dysfunction on potential anti-ischemic properties is unknown. We performed a double-blind trial in 25 patients with exercise-induced ischemia. The effects of perindoprilat on pacing-induced myocardial ischemia were examined. Fourteen patients received perindoprilat and 11 patients received placebo. Based on LV function, 2 subgroups were formed in the perindoprilat group: 7 patients with LV dysfunction (LV ejection fraction <0.40), and 7 patients with normal LV function. After receiving the study medication, the pacing test was repeated. During the first pacing test both groups developed ischemia. After perindoprilat administration, the increase in systemic vascular resistance and LV end-diastolic pressure were significantly blunted (p <0.05). Further, the ischemia-induced increase in arterial and cardiac uptake of norepinephrine was inhibited by perindoprilat, and the increase in atrial natriuretic peptide was less pronounced; also, ST-segment depression was reduced by 32% compared with placebo (all p <0.05). In the group with LV dysfunction, perindoprilat reduced LV end-diastolic pressure significantly by 67% and myocardial lactate production was prevented, but this did not happen in the group with normal LV function. In addition, the increase in arterial norepinephrine was reduced by 74% and 33%, respectively (p <0.05). These results indicate that perindoprilat reduced acute, pacing-induced ischemia in normotensive patients. In patients with (asymptomatic) LV dysfunction these effects were more pronounced than in patients with normal LV function.

Atrial Natriuretic Peptide Attenuates Pacing-Induced Myocardial Ischemia During General Anesthesia in Patients with Coronary Artery Disease

Atrial natriuretic peptide (ANP) exerts a dilatory effect on coronary arteries in humans.We investigated the effects of ANP on pacing-induced myocardial ischemia during enflurane anesthesia in patients with coronary artery disease (CAD). In 20 patients with CAD, myocardial ischemia was induced by atrial pacing before and after an iv infusion of ANP (50 mg [center dot] kg-1 [center dot] min-1, n = 10) or placebo (n = 10). We studied the effects of ANP or placebo on pacing-induced changes in central hemodynamics, myocardial blood flow and regional myocardial indices of lactate uptake (RMLU), and oxygen consumption (RMVO2) and extraction (RMO (2) E). ST-segment depression was less pronounced during pacing with ANP compared with control pacing (-0.09 +/- 0.01 vs -0.24 +/- 0.02 mV; P < 0.001). RMLU decreased to -11.1 [micro sign]mol/min during control pacing compared with -0.7 [micro sign]mol/min during pacing with ANP (P < 0.01). ANP did not affect pacing-induced changes in RMVO (2), RMO2 E, or the rate pressure product. Placebo did not affect pacing-induced changes in ST-segment depression or RMLU. In conclusion, ANP attenuates ischemic ST-segment depression and lactate release during pacing-induced myocardial ischemia in patients with CAD. The antiischemic effect of ANP was not accompanied by any improvement in the regional myocardial oxygen supply/demand relationship. Implications: We evaluated the effects of IV atrial natriuretic peptide (50 ng [center dot] kg-1 [center dot] min-1) on pacing-induced myocardial ischemia during general anesthesia in patients with coronary artery disease. In contrast to placebo, atrial natriuretic peptide attenuated ST-segment depression and myocardial lactate production and improved left ventricular function during pacing-induced ischemia. (Anesth Analg 1999;88:279-85)

The anti-ischemic effects of CP-060 S during pacing-induced ischemia in anesthetized dogs

CP-060 S, (−)-( S)-2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-[3-[ N-methyl- N-[2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin-4-one hydrogen fumarate, is a novel cardioprotective drug which prevents Na +-, Ca 2+-overload and has Ca 2+ channel blocking activity. We compared the anti-ischemic effects of CP-060 S with those of diltiazem, a Ca 2+ channel blocker, and R56865, N-[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]- N-methyl-2-benzothiazolamine, a Na +-, Ca 2+-overload inhibitor, in a canine pacing-induced ischemia model. CP-060 S 100 μg kg −1 significantly suppressed the pacing-induced ischemic epicardial ST-segment elevation by maximally 75%, while diltiazem 100 μg kg −1 suppressed it by maximally 35%. R56865 100 μg kg −1 significantly suppressed the ST-segment elevation by maximally 30%. In addition, diltiazem 100 μg kg −1 caused synergistic suppression of ST-segment elevation by 70% when administered simultaneously with R56865 100 μg kg −1. These results suggest that a Na +-, Ca 2+-overload preventive action and a Ca 2+ channel blocking action independently contribute to the suppression of the ST-segment elevation. Therefore, CP-060 S may suppress pacing-induced ST-segment elevation by a dual action by preventing Na +-, Ca 2+-overload and the Ca 2+ channel blockade.

Effects of epanolol, a selective beta1-blocker with intrinsic sympathomimetic activity, in patients with ischemic left ventricular dysfunction.

Recently, different beta-blockers have been shown to be effective in the treatment of chronic heart failure (CHF), but the importance of their ancillary properties is not clear. Epanolol is a selective beta1-blocker with intrinsic sympathomimetic activity, which has been shown useful in angina pectoris, but its value in patients with left ventricular (LV) dysfunction and CHF is unknown. We examined the effects of epanolol in patients with LV dysfunction (n = 8; mean LV ejection fraction, 0.33 +/- 0.08) and compared them with patients with normal LV function (n = 8; mean LV ejection fraction, 0.52 +/- 0.04). Measurement of invasive hemodynamics and neurohormones was performed at rest and during myocardial ischemia, which was induced by atrial pacing. All measurements were performed before and after epanolol. Before epanolol, pacing-induced ischemia led to a similar increase in norepinephrine and coronary sinus blood flow in both groups. After epanolol, the increase in neurohormones was more pronounced in the group with LV dysfunction (norepinephrine, 1,130 +/- 164 pg/ml for patients with LV dysfunction vs. 637 +/- 41 pg/ml for normal subjects; p < 0.05). A similar effect was observed for angiotensin II. Further, in the LV-dysfunction group, coronary sinus blood flow increased less, and coronary vascular resistance decreased less (both values, p < 0.05). Despite the fact that the increase in double product was decreased to a similar extent in both groups, ischemia was reduced only in normal LV function (p < 0.05). In ischemic LV dysfunction, neurohumoral activation after epanolol may impair adequate coronary flow response, and this may limit its antiischemic properties. Because of the small size of the study, no definitive inference on the clinical benefit of epanolol in patients with ischemic LV function can be made from this study.

Differential effects on left atrial function of pacing-induced ischemia in patients with diseased proximal left anterior descending and proximal left circumflex coronary artery

Differential effects on left atrial function of pacing-induced ischemia in patients with diseased proximal left anterior descending and proximal left circumflex coronary artery

Differential Effects on Left Atrial Function of Pacing-induced Ischemia in Patients With Diseased Proximal Left Anterior Descending and Proximal Left Circumflex Coronary Artery

Differential Effects on Left Atrial Function of Pacing-induced Ischemia in Patients With Diseased Proximal Left Anterior Descending and Proximal Left Circumflex Coronary Artery

Pacing-induced Ischemia Results in Transcardiac Activation of Leukocyte to Produce Tumor Necrosis Factor-α in Patients With Angina Pectoris

Pacing-induced Ischemia Results in Transcardiac Activation of Leukocyte to Produce Tumor Necrosis Factor-α in Patients With Angina Pectoris

Pacing-induced ischemia results in transcardiac activation of leukocyte to produce tumor necrosis factor-α in patients with angina pectoris

Pacing-induced ischemia results in transcardiac activation of leukocyte to produce tumor necrosis factor-α in patients with angina pectoris

Short-term Anti-Ischemic Effect of 17β-Estradiol in Postmenopausal Women With Coronary Artery Disease

Short-term administration of 17beta-estradiol improves effort-induced myocardial ischemia in female patients with coronary artery disease. 17Beta-estradiol also has direct and indirect coronary vascular smooth muscle relaxing properties. The aim of the present study was to evaluate the effect of short-term administration of 17beta-estradiol on pacing-induced myocardial ischemia by means of continuous monitoring of coronary sinus pH in 16 postmenopausal female patients with coronary artery disease. Patients underwent incremental atrial pacing starting at a rate of 100 bpm and increments of 20 bpm every 2 minutes up to 160 bpm before and 20 minutes after either 17beta-estradiol (1 mg sublingual, 9 patients) or placebo (sublingual, 7 patients). The time to the onset of myocardial ischemia during pacing was significantly increased by 17beta-estradiol (mean+/-SD, 254+/-36 versus 298+/-23 seconds; P<.02) but not by placebo (262+/-45 versus 256+/-34 seconds; P=NS) The pH shift was significantly reduced by 17beta-estradiol but not by placebo at every step of the pacing protocol. The maximum pH shift at peak pacing was significantly reduced by the administration of 17beta-estradiol by 0.022 pH units (95% CI, 0.001, 0.043; P<.04) but not by sublingual placebo (-0.002 pH units; 95% CI, -0.0073, 0.0021; P=NS). The maximum pH shift at maximum comparable pacing was also reduced by 17beta-estradiol by 0.015 pH units (95% CI, 0.012, 0.017; P<.001) but not by placebo (-0.0022 pH units; 95% CI, -0.006, 0.0015; P=NS). 17Beta-estradiol reduces the degree of pacing-induced myocardial ischemia in postmenopausal patients with coronary artery disease. The reduction of pacing-induced coronary sinus pH shift is consistent with an anti-ischemic effect of the hormone and is not due to preconditioning, as evidenced by the absence of improvement after placebo.

Effect of acadesine on myocardial ischaemia in patients with coronary artery disease

Acadesine, an adenosine regulating agent, attenuates the adverse effects of ischaemia on ventricular function in animals. This study examined its influence on pacing-induced ischaemia in 47 patients undergoing coronary angiography. After 15 min of recovery from control pacing, an infusion of acadesine (5, 10, 20, 50 mg/kg i.v.) was commenced and after a further 15 min the protocol was repeated with the infusion continued. At higher doses, minor beneficial effects on ejection fraction and myocardial lactate metabolism were observed. Haemodynamics were unaffected. Systemic lactate rose in relation to acadesine, up to 60% ( P<0.001 versus placebo). The data may indicate that acadesine stimulates anaerobic glycolysis in man.

Coronary vasoconstriction during myocardial ischemia induced by rises in metabolic demand in patients with coronary artery disease.

In patients with coronary artery disease, a maximal vasodilation of the coronary microcirculation is generally assumed to occur during myocardial ischemia induced by rises in metabolic demand. However, vasoconstriction has been documented during severe prolonged ischemia in animals. The aim of this study was to investigate coronary vasomotor tone during pacing-induced ischemia in humans. The study included 11 patients with exercise-induced ischemia and single-vessel disease of the left anterior descending artery and 7 control subjects with normal coronary arteries. Blood flow velocity was monitored with a Doppler catheter in the left anterior descending artery. Coronary resistance index was calculated as the ratio between mean arterial pressure and flow velocity. Measurements were obtained at baseline, after intracoronary adenosine (2 mg), and during maximal atrial pacing in the absence and presence of adenosine. After adenosine administration at rest, coronary resistance decreased more in control subjects than in patients (25 +/- 7% of baseline versus 61 +/- 19%; P < .01). Coronary resistance decreased in all control subjects (P < .01) both at maximal pacing (60 +/- 17% of baseline) and after administration of adenosine during tachycardia (31 +/- 13% of baseline). By contrast, all 10 ischemic patients displayed increased coronary resistance at maximal heart rate (221 +/- 131% of baseline; P < .01 versus baseline, P < .01 versus control subjects). At this stage, adenosine decreased coronary resistance to 44 +/- 20% of values observed before injection. Additionally, it reduced ST-segment depression in 5 of 8 patients. In patients with coronary artery disease, transient myocardial ischemia induced by increased metabolic demand is not associated with maximal vasodilation. Rather, an inappropriate severe microvascular vasoconstriction is present that can be abolished by intracoronary adenosine.